Antibody-drug conjugates, pharmaceutical compositions, and therapeutic applications

Abstract

Provided herein are antibody-drug conjugates, e.g., compounds of Formula (I), and pharmaceutical compositions thereof. Also provided herein are methods of their use to treat, prevent, or ameliorate one or more symptoms of a proliferative disorder. Additionally provided herein are functionalized compounds for conjugation to antibodies, e.g., compounds of Formula (IA). [Formula 1] TIFF2025526901000233.tif34170

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS)

[0002] This application claims priority to U.S. Provisional Application No. 63 / 371,400, filed August 15, 2022; and U.S. Provisional Application No. 63 / 483,739, filed February 7, 2023; the disclosures of each of which are incorporated herein by reference in their entireties.

[0003] (Field) Provided herein are antibody-drug conjugates and pharmaceutical compositions thereof. Also provided herein are methods of their use to treat, prevent, or ameliorate one or more symptoms of a proliferative disorder. Additionally provided herein are functionalized compounds for conjugation to antibodies.

[0004] (Reference to sequence listing)

[0005] This application is filed together with a Sequence Listing entitled 216A018WO01_ SEQLIST_ST26.XML, created on August 13, 2023, and having a size of 98,618 bytes; the contents of which are incorporated herein by reference in their entirety. [Background technology]

[0006] (background) Antibody-drug conjugates (ADCs) are monoclonal antibodies tethered to a cytotoxic drug (also known as a payload or warhead) via a chemical linker. (See Polakis, Pharmacol. Rev. 2016, 68, 3-19; Beck et al., Nat. Rev. Drug. Discov. 2017, 16, 315-37; Birrer et al., J. Natl. Cancer Inst. 2019, 111, 538-49; Chau et al., Lancet 2019, 394, 793-804.) Thus, ADCs are targeted biopharmaceuticals that rely on the specificity of the monoclonal antibody for cancer cell surface antigens to deliver and release its cytotoxic payload directly to targeted cancer cells, resulting in higher efficacy and a broader therapeutic window than the cytotoxic drug alone. Polakis, Pharmacol. Rev. 2016, 68, 3-19; Chau et al., Lancet 2019, 394, 793-804. Mechanistically, ADCs exert their biological function by selective binding to targeted cancer cells, followed by internalization of the cell surface-formed ADC-antigen complex via clathrin-mediated endocytosis and release of the cytocidal payload inside the targeted cancer cells. Chau et al., Lancet 2019, 394, 793-804.

[0007] Despite advances in cancer treatment, cancer remains a major global public health problem. In 2022, it is estimated that there will be 1,918,030 newly diagnosed cancer cases and 609,360 cancer-related deaths in the United States alone (Cancer Facts & Figures 2022). Cancer is the second leading cause of death worldwide. Therefore, there is a need for effective therapeutic agents to treat cancer. Summary of the Invention

[0008] (Disclosure Summary)

[0009] Provided herein are compounds of formula (I): [ka]

[0010] or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. (In the formula:

[0011] Each A is independently O, S, S(O), S(O2), or N(R 4 ) and;

[0012] each L is independently a linker;

[0013] Each R 1 , R 2 , and R 3 are independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) —C(O)R 1a , -C(O)OR 1a , -C(O)NR 1b R 1c , -C(O)SR 1a , -C(NR 1a )NR 1b R 1c , -C(S)R 1a , -C(S)OR 1a , -C(S)NR 1b R 1c , -OR 1a , -OC(O)R 1a , -OC(O)OR 1a , -OC(O)NR 1b R 1c , -OC(O)SR 1a, -OC(NR 1a )NR 1b R 1c , -OC(S)R 1a , -OC(S)OR 1a , -OC(S)NR 1b R 1c , -OS(O)R 1a , -OS(O)2R 1a , -OS(O)NR 1b R 1c , -OS(O)2NR 1b R 1c , -NR 1b R 1c , -NR 1a C(O)R 1d , -NR 1a C(O)OR 1d , -NR 1a C(O)NR 1b R 1c , -NR 1a C(O)SR 1d , -NR 1a C(NR 1d )NR 1b R 1c , -NR 1a C(S)R 1d , -NR 1a C(S)OR 1d , -NR 1a C(S)NR 1b R 1c , -NR 1a S(O)R 1d , -NR 1a S(O)2R 1d , -NR 1a S(O)NR 1b R 1c , -NR 1a S(O)NR 1b R 1c , -SR 1a , -S(O)R 1a , -S(O)2R 1a , -S(O)NR 1b R 1c , or -S(O)2NR 1b R 1c and;

[0014] Each R 4 are independently: (i) hydrogen; (ii) C1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) —C(O)R 1a , -C(O)OR 1a , -C(O)NR 1b R 1c , -C(O)SR 1a , -C(NR 1a )NR 1b R 1c , -C(S)R 1a , -C(S)OR 1a , -C(S)NR 1b R 1c , -S(O)R 1a , -S(O)2R 1a , -S(O)NR 1b R 1c , or -S(O)2NR 1b R 1c and;

[0015] Each R 1a , R 1b , R 1c , and R 1d are independently hydrogen, deuterium, and C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl;

[0016] R A is an antibody or an antigen-binding fragment thereof;

[0017] m is an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16; and

[0018] each p and q is independently an integer of 0, 1, or 2; provided that the sum of p and q is greater than 0;

[0019] wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more, and in one embodiment, one, two, three, or four, substituents Q, wherein each Q is independently: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) one or more, and in one embodiment, one, two, three, or four, substituents Q. a and each of these is further optionally substituted C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)R a , -C(O)OR a , -C(O)NR b R c , -C(O)SR a , -C(NR a )NR b R c , -C(S)R a , -C(S)OR a , -C(S)NR b R c , -OR a , -OC(O)R a , -OC(O)OR a , -OC(O)NR b R c , -OC(O)SR a , -OC(NR a )NR b R c , -OC(S)R a , -OC(S)OR a , -OC(S)NR b R c , -OP(O)(OR a ) OR d , -OS(O)R a, -OS(O)2R a , -OS(O)NR b R c , -OS(O)2NR b R c , -NR b R c , -NR a C(O)R d , -NR a C(O)OR d , -NR a C(O)NR b R c , -NR a C(O)SR d , -NR a C(NR d )NR b R c , -NR a C(S)R d , -NR a C(S)OR d , -NR a C(S)NR b R c , -NR a S(O)R d , -NR a S(O)2R d , -NR a S(O)NR b R c , -NR a S(O)NR b R c , -SR a , -S(O)R a , -S(O)2R a , -S(O)NR b R c , and -S(O)NR b R c (In the formula, each R a , R b , R c , and R d are independently (i) hydrogen or deuterium; (ii) each is one or more, in one embodiment one, two, three, or four, substituents Q a C optionally substituted with 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R b and R c together with the N atom to which they are attached, form one or more, in one embodiment one, two, three or four, substituents Q a forming an optionally substituted heterocyclyl;

[0020] Here, each Q a are independently: (a) deuterium, cyano, halo, nitro, imino, and oxo; (b) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)R e , -C(O)OR e , -C(O)NR f R g , -C(O)SR e , -C(NR e )NR f R g , -C(S)R e , -C(S)OR e , -C(S)NR f R g , -OR e , -OC(O)R e , -OC(O)OR e , -OC(O)NR f R g , -OC(O)SR e , -OC(NR e )NR f R g , -OC(S)R e , -OC(S)OR e , -OC(S)NR f R g , -OS(O)R e , -OS(O)2R e, -OS(O)NR f R g , -OS(O)2NR f R g , -NR f R g , -NR e C(O)R h , -NR e C(O)OR f , -NR e C(O)NR f R g , -NR e C(O)SR f , -NR e C(NR h )NR f R g , -NR e C(S)R h , -NR e C(S)OR f , -NR e C(S)NR f R g , -NR e S(O)R h , -NR e S(O)2R h , -NR e S(O)NR f R g , -NR e S(O)NR f R g , -SR e , -S(O)R e , -S(O)2R e , -S(O)NR f R g , and -S(O)NR f R g ;(In the formula, each R e , R f , R g , and R h are independently (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R fand R g are selected from: together with the N atom to which they are attached form a heterocyclyl).

[0021] Also provided herein is a pharmaceutical composition comprising a compound of Formula (I), or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and a pharmaceutically acceptable excipient.

[0022] Further provided herein is a method of treating, preventing, or ameliorating one or more symptoms of a proliferative disease in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a compound of formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0023] Further provided herein is a method of inhibiting proliferation of a cell, comprising contacting the cell with a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0024] Provided herein are compounds of formula (IA): [ka]

[0025] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof. (In the formula:

[0026] A is O, S, S(O), S(O2), or N(R 4 ) and;

[0027] X is C 1-40 Alkylene, C 1-40 Heteroalkylene, C 2-40 Alkenylene, C 2-40 Heteroalkenylene, C 2-40 Alkynylene, or C 2-40 heteroalkynylene, wherein one or more methylene groups are each independently and optionally replaced by a divalent radical, and each divalent radical is independently selected from the group consisting of: C 3-10 Cycloalkylene, C 6-14 arylene, heteroarylene, or heterocyclylene;

[0028] Y is a bond, C 1-6 Alkylene, C 1-6 Heteroalkylene, C 2-6 Alkenylene, C 2-6 Alkynylene, C 3-10 Cycloalkylene, C 6-14 Arylene, C 7-15 aralkylene, heteroarylene, or heterocyclylene;

[0029] Z is [ka] and;

[0030] Each R 1 , R 2 , R 3 , R 5a , and R 5bare independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) —C(O)R 1a , -C(O)OR 1a , -C(O)NR 1b R 1c , -C(O)SR 1a , -C(NR 1a )NR 1b R 1c , -C(S)R 1a , -C(S)OR 1a , -C(S)NR 1b R 1c , -OR 1a , -OC(O)R 1a , -OC(O)OR 1a , -OC(O)NR 1b R 1c , -OC(O)SR 1a , -OC(NR 1a )NR 1b R 1c , -OC(S)R 1a , -OC(S)OR 1a , -OC(S)NR 1b R 1c , -OS(O)R 1a , -OS(O)2R 1a , -OS(O)NR 1b R 1c , -OS(O)2NR 1b R 1c , -NR 1b R 1c , -NR 1a C(O)R 1d , -NR 1a C(O)OR 1d , -NR 1a C(O)NR 1b R 1c , -NR 1a C(O)SR 1d , -NR 1a C(NR1d )NR 1b R 1c , -NR 1a C(S)R 1d , -NR 1a C(S)OR 1d , -NR 1a C(S)NR 1b R 1c , -NR 1a S(O)R 1d , -NR 1a S(O)2R 1d , -NR 1a S(O)NR 1b R 1c , -NR 1a S(O)NR 1b R 1c , -SR 1a , -S(O)R 1a , -S(O)2R 1a , -S(O)NR 1b R 1c , or -S(O)2NR 1b R 1c and;

[0031] R 4 is (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) —C(O)R 1a , -C(O)OR 1a , -C(O)NR 1b R 1c , -C(O)SR 1a , -C(NR 1a )NR 1b R 1c , -C(S)R 1a , -C(S)OR 1a , -C(S)NR 1b R 1c , -S(O)R 1a , -S(O)2R 1a , -S(O)NR 1b R1c , or -S(O)2NR 1b R 1c and;

[0032] Each R 6 and R 7 are independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) —C(O)R 1a , -C(O)OR 1a , -C(O)NR 1b R 1c , -C(O)SR 1a , -C(NR 1a )NR 1b R 1c , -C(S)R 1a , -C(S)OR 1a , -C(S)NR 1b R 1c , -OR 1a , -OC(O)R 1a , -OC(O)OR 1a , -OC(O)NR 1b R 1c , -OC(O)SR 1a , -OC(NR 1a )NR 1b R 1c , -OC(S)R 1a , -OC(S)OR 1a , -OC(S)NR 1b R 1c , -OS(O)R 1a , -OS(O)2R 1a , -OS(O)NR 1b R 1c , -OS(O)2NR 1b R 1c , -NR 1b R 1c , -NR 1a C(O)R 1d , -NR 1a C(O)OR1d , -NR 1a C(O)NR 1b R 1c , -NR 1a C(O)SR 1d , -NR 1a C(NR 1d )NR 1b R 1c , -NR 1a C(S)R 1d , -NR 1a C(S)OR 1d , -NR 1a C(S)NR 1b R 1c , -NR 1a S(O)R 1d , -NR 1a S(O)2R 1d , -NR 1a S(O)NR 1b R 1c , -NR 1a S(O)NR 1b R 1c , -SR 1a , -S(O)R 1a , -S(O)2R 1a , -S(O)NR 1b R 1c , or -S(O)2NR 1b R 1c and;

[0033] Each R 8 are independently (i) hydrogen or deuterium; or (ii) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl;

[0034] Each R 1a , R 1b , R 1c , and R 1d are independently hydrogen, deuterium, and C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl;

[0035] p and q are each independently an integer of 0, 1, or 2; provided that the sum of p and q is greater than 0;

[0036] s is an integer of 0, 1, 2, or 3; and

[0037] t is an integer of 0, 1, 2, 3, or 4;

[0038] wherein each alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, alkynylene, heteroalkynylene, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, aralkylene, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more, and in one embodiment, one, two, three, or four, substituents Q, wherein each Q is independently: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) one or more, and in one embodiment, one, two, three, or four, substituents Q. a and each of these is further optionally substituted C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)R a , -C(O)OR a , -C(O)NR b R c , -C(O)SR a , -C(NR a )NR b R c , -C(S)R a、-C(S)OR a 、-C(S)NR b R c 、-OR a 、-OC(O)R a 、-OC(O)OR a 、-OC(O)NR b R c 、-OC(O)SR a 、-OC(NR a )NR b R c 、-OC(S)R a 、-OC(S)OR a 、-OC(S)NR b R c 、-OP(O)(OR a )OR d 、-OS(O)R a 、-OS(O)2R a 、-OS(O)NR b R c 、-OS(O)2NR b R c 、-NR b R c 、-NR a C(O)R d 、-NR a C(O)OR d 、-NR a C(O)NR b R c 、-NR a C(O)SR d 、-NR a C(NR d )NR b R c 、-NR a C(S)R d 、-NR a C(S)OR d 、-NR a C(S)NR b R c 、-NR a S(O)R d 、-NR a S(O)2R d 、-NR a S(O)NR b R c 、-NR a S(O)2NR b R c, -SR a , -S(O)R a , -S(O)2R a , -S(O)NR b R c , and -S(O)NR b R c where each R a , R b , R c , and R d are independently (i) hydrogen or deuterium; (ii) one or more, in one embodiment, one, two, three, or four, substituents Q a with arbitrary substitutions, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R b and R c together with the N atom to which they are attached, form one or more, in one embodiment one, two, three or four, substituents Q a forming an optionally substituted heterocyclyl;

[0039] Here, each Q a are independently: (a) deuterium, cyano, halo, nitro, imino, and oxo; (b) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)R e , -C(O)OR e , -C(O)NR f R g , -C(O)SR e , -C(NR e )NR f R g , -C(S)Re 、-C(S)OR e 、-C(S)NR f R g 、-OR e 、-OC(O)R e 、-OC(O)OR e 、-OC(O)NR f R g 、-OC(O)SR e 、-OC(NR e )NR f R g 、-OC(S)R e 、-OC(S)OR e 、-OC(S)NR f R g 、-OS(O)R e 、-OS(O)2R e 、-OS(O)NR f R g 、-OS(O)2NR f R g 、-NR f R g 、-NR e C(O)R h 、-NR e C(O)OR f 、-NR e C(O)NR f R g 、-NR e C(O)SR f 、-NR e C(NR h )NR f R g 、-NR e C(S)R h 、-NR e C(S)OR f 、-NR e C(S)NR f R g 、-NR e S(O)R h 、-NR e S(O)2R h 、-NR e S(O)NR f R g 、-NR e S(O)2NR f R g 、-SR e 、-S(O)Re , -S(O)2R e , -S(O)NR f R g , and -S(O)NR f R g ;(In the formula, each R e , R f , R g , and R h are independently (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R f and R g are selected from: together with the N atom to which they are attached form a heterocyclyl). [Brief explanation of the drawings]

[0040] BRIEF DESCRIPTION OF THE DRAWINGS [Figure 1] Figure 1 shows the anticancer activity of ADC compounds ADC-C2, ADC-C8, ADC-C29, ADC-C52, and trastuzumab deruxtecan (DS-8201) in a xenograft mouse model of human breast cancer (JIMT-1). DETAILED DESCRIPTION OF THE INVENTION

[0041] (Detailed explanation) To facilitate understanding of the disclosure set forth herein, several terms are defined below.

[0042] Generally, the nomenclature used herein and the laboratory methods in organic chemistry, medicinal chemistry, biochemistry, biology, immunology, and pharmacology described herein are those well known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0043] The term "subject" refers to an animal, including, but not limited to, a primate (e.g., a human), cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms "subject" and "patient" are used interchangeably herein in reference to a mammalian subject, such as, for example, a human subject. In one embodiment, the subject is a human.

[0044] The terms "treat," "treating," and "treatment" are intended to include alleviating or arresting a disorder, disease, or condition, or one or more symptoms associated with the disorder, disease, or condition; or alleviating or eradicating the cause of the disorder, disease, or condition itself.

[0045] The terms "prevent," "preventing," and "prevention" are intended to include methods of delaying and / or preventing the onset of a disorder, disease, or condition, and / or its attendant symptoms; barring a subject from acquiring a disorder, disease, or condition; or reducing a subject's risk of acquiring a disorder, disease, or condition.

[0046] The terms "alleviate" and "alleviating" mean to relieve or reduce one or more symptoms (e.g., pain) of a disorder, disease, or condition. The term can also mean to reduce adverse effects associated with the active ingredient. Sometimes, the beneficial effects that a subject derives from a prophylactic or therapeutic agent do not result in a cure of the disorder, disease, or condition.

[0047] The terms "contacting" or "contacting" refer to bringing together a therapeutic agent and a biomolecule (e.g., a protein, enzyme, RNA, or DNA), cell, or tissue such that a physiological and / or chemical effect occurs as a result of such contact. Contacting can occur in vitro, ex vivo, or in vivo. In one embodiment, a therapeutic agent is contacted with a biomolecule in vitro to determine the effect of the therapeutic agent on the biomolecule. In another embodiment, a therapeutic agent is contacted with cells in cell culture (in vitro) to determine the effect of the therapeutic agent on the cells. In yet another embodiment, contacting a therapeutic agent with a biomolecule, cell, or tissue comprises administering the therapeutic agent to a subject having the biomolecule, cell, or tissue to be contacted.

[0048] The terms "therapeutically effective amount" or "effective amount" are intended to include a quantity of a compound that, when administered, is sufficient to prevent the onset of, or to alleviate to some extent, one or more of the symptoms of, the disorder, disease, or condition being treated. The terms "therapeutically effective amount" or "effective amount" also refer to the amount of a compound sufficient to elicit the biological or medical response in a biomolecule (e.g., protein, enzyme, RNA, or DNA), cell, tissue, system, animal, or human that is desired by a researcher, veterinarian, medical doctor, or clinician.

[0049] The terms "pharmaceutically acceptable carrier," "pharmaceutically acceptable excipient," "physiologically acceptable carrier," or "physiologically acceptable excipient" mean a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulating material. In one embodiment, each component is "pharmaceutically acceptable" in the sense of being compatible with the other components of the pharmaceutical formulation, and suitable for use in contact with the tissues or organs of a subject (e.g., a human or animal) without undue toxicity, irritation, allergic response, immunogenicity, or other problem or complication, and commensurate with a reasonable benefit / risk ratio. See, for example, Remington: The Science and Practice of Pharmacy, 22nd Edition; Allen, ed.; Pharmaceutical Press: London, 2012; Handbook of Pharmaceutical Excipients, 8th Edition; Sheskey et al., eds.; Pharmaceutical Press: London, 2017; Handbook of Pharmaceutical Additives, 3rd Edition; Ash and Ash, eds.; Synapse Information Resources: 2007; Pharmaceutical Preformulation and Formulation, 2nd Edition; Gibson, ed.; Drugs and the Pharmaceutical Sciences 199; Informa Healthcare: New York, NY, 2009.

[0050] The term "about" or "approximately" refers to an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term "about" or "approximately" means within 1, 2, or 3 standard deviations. In certain embodiments, the term "about" or "approximately" means within 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

[0051] The term "alkyl" means a linear or branched saturated monovalent hydrocarbon radical, wherein the alkyl is optionally substituted with one or more substituents Q as described herein. For example, C 1-6 Alkyl refers to a linear saturated monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, alkyl refers to a group having 1 to 20 carbon atoms (C 1-20 ), 1~15 pieces (C 1-15 ), 1~10 pieces (C 1-10 ), or 1 to 6 (C 1-6 ) or a linear saturated monovalent hydrocarbon radical having 3 to 20 carbon atoms (C 3-20 ), 3~15 pieces (C 3-15 ), 3~10 pieces (C 3-10 ), or 3 to 6 (C 3-6 ) is a branched saturated monovalent hydrocarbon radical. As used herein, linear C 1-6 and branched C 3-6 An alkyl group is also referred to as a “lower alkyl.” Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl (including all isomeric forms, e.g., n-propyl and isopropyl), butyl (including all isomeric forms, e.g., n-butyl, isobutyl, sec-butyl, and t-butyl), pentyl (including all isomeric forms, e.g., n-pentyl, isopentyl, sec-pentyl, neopentyl, and tert-pentyl), and hexyl (including all isomeric forms, e.g., n-hexyl, isohexyl, and sec-hexyl).

[0052] The term "heteroalkyl" means a linear or branched saturated monovalent hydrocarbon radical having in its backbone one or more heteroatoms, each independently selected from O, S, and N. Heteroalkyl is optionally substituted with one or more substituents Q as described herein. For example, C 1-6 Heteroalkyl means a linear saturated monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon radical of 3 to 6 carbon atoms. In some embodiments, heteroalkyl is a group having 1 to 20 carbon atoms (C 1-20 ), 1~15 pieces (C 1-15 ), 1~10 pieces (C 1-10 ), or 1 to 6 (C 1-6 ) or a linear saturated monovalent hydrocarbon radical having 3 to 20 carbon atoms (C 3-20 ), 3~15 pieces (C 3-15 ), 3~10 pieces (C 3-10 ), or 3 to 6 (C 3-6 ) is a branched saturated monovalent hydrocarbon radical. As used herein, linear C 1-6 and branched C 3-6 Heteroalkyl groups are also referred to as "lower heteroalkyl." Examples of heteroalkyl groups include, but are not limited to, -OCH, -OCHCH, -CHOCH, -NHCH, -ONHCH, -NHOCH, -SCH, -CHNHCHCH, and -NHCHCHCH. Examples of substituted heteroalkyl groups include, but are not limited to, -CHNHC(O)CH and -NHC(O)CHCH.

[0053] The terms "alkylene" and "alkanediyl" are used interchangeably herein to refer to a linear or branched saturated divalent hydrocarbon radical, where the alkanediyl is optionally substituted with one or more substituents Q as described herein. For example, C 1-6Alkanediyl refers to a linear saturated divalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated divalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, alkanediyl refers to a hydrocarbon radical having 1 to 30 carbon atoms (C 1-30 ), 1~20 pieces (C 1-20 ), 1~15 pieces (C 1-15 ), 1~10 pieces (C 1-10 ), or 1 to 6 (C 1-6 ) or a linear saturated divalent hydrocarbon radical having 3 to 30 carbon atoms (C 3-30 ), 3~20 pieces (C 3-20 ), 3~15 pieces (C 3-15 ), 3~10 pieces (C 3-10 ), or 3 to 6 (C 3-6 ) is a branched saturated divalent hydrocarbon radical. As used herein, linear C 1-6 and branched C 3-6 Alkanediyl groups are also referred to as “lower alkanediyl.” Examples of alkanediyl groups include methanediyl, ethanediyl (including all isomeric forms, for example, ethane-1,1-diyl and ethane-1,2-diyl), propanediyl (including all isomeric forms, for example, propane-1,1-diyl, propane-1,2-diyl, and propane-1,3-diyl), butanediyl (including all isomeric forms, for example, butane-1,1-diyl, butane-1,2-diyl, butane-1,3-diyl, and butane-1,4-diyl), pentanediyl (including all isomeric forms, for example, pentane-1,1-diyl, pentane-1,2-diyl, pentane-1,3-diyl, and pentane-1,5-diyl), and hexanediyl (including all isomeric forms, for example, hexane-1,1-diyl, hexane-1,2-diyl, hexane-1,3-diyl, and hexane-1,6-diyl). Examples of substituted alkanediyl groups include -C(O)CH2-, -C(O)(CH2)2-, -C(O)(CH2)3-, -C(O)(CH2)4-, -C(O)(CH2)5-, -C(O)(CH2)6-, -C(O)(CH2)7-, -C(O)(CH2)8-, -C(O)(CH2)9-, and -C(O)(CH2) 10Examples include, but are not limited to, -, -C(O)CHC(O)-, -C(O)(CH)C(O)-, -C(O)(CH)C(O)-, -C(O)(CH)C(O)-, or -C(O)(CH)C(O)-.

[0054] The terms "heteroalkylene" and "heteroalkanediyl" are used interchangeably herein to refer to a linear or branched saturated divalent hydrocarbon radical having in its backbone one or more heteroatoms, each independently selected from O, S, and N. Heteroalkylene is optionally substituted with one or more substituents Q as described herein. For example, C 1-6 Heteroalkylene refers to a linear saturated divalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated divalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, heteroalkylene refers to a hydrocarbon radical having 1 to 20 carbon atoms (C 1-20 ), 1~15 pieces (C 1-15 ), 1~10 pieces (C 1-10 ), or 1 to 6 (C 1-6 ) or a linear saturated divalent hydrocarbon radical having 3 to 20 carbon atoms (C 3-20 ), 3~15 pieces (C 3-15 ), 3~10 pieces (C 3-10 ), or 3 to 6 (C 3-6 ) is a branched saturated divalent hydrocarbon radical. As used herein, linear C 1-6 and branched C 3-6 Heteroalkylene groups are also referred to as "lower heteroalkylene." Examples of heteroalkylene groups include -CHO-, -(CH)O-, -(CH)O-, -(CH)O-, -(CH)O-, -(CH)O-, -(CH)O-, -(CH)O-, -(CH)O-, -(CH)O-, -(CH) 10These include, but are not limited to, O-, -CH2OCH2-, -CH2CH2O-, -(CH2CH2O)2-, -(CH2CH2O)3-, -(CH2CH2O)4-, -(CH2CH2O)5-, -CH2NH-, -CH2NHCH2-, -CH2CH2NH-, -CH2S-, -CH2SCH2-, and -CH2CH2S-. Examples of substituted heteroalkylene groups include -C(O)CHO-, -C(O)(CH)O-, -C(O)(CH)O-, -C(O)(CH)O-, -C(O)(CH)O-, -C(O)(CH)O-, -C(O)(CH)O-, -C(O)(CH)O-, -C(O)(CH)O-, -C(O)(CH)O-, -C(O)(CH)O-, 10 Examples include, but are not limited to, O-, -C(O)CHOCHCHO-, -C(O)CHO(CHCHO)-, -C(O)CHO(CHCHO)-, -C(O)CHO(CHCHO)-, -C(O)CHO(CHCHO)-, -CHNHC(O)CH-, or -CHCHC(O)NH-.

[0055] The term "alkenyl" refers to a linear or branched monovalent hydrocarbon radical having one or more, in one embodiment one, two, three, or four, and in another embodiment one, carbon-carbon double bond(s). The alkenyl is optionally substituted with one or more substituents Q as described herein. The term "alkenyl" encompasses radicals having the "cis" or "trans" configuration or a mixture thereof, or the "Z" or "E" configuration or a mixture thereof, as recognized by one of ordinary skill in the art. For example, C 2-6 Alkenyl refers to a linear unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, alkenyl refers to a group having 2 to 20 carbon atoms (C 2-20 ), 2~15 pieces (C 2-15 ), 2~10 pieces (C 2-10 ), or 2 to 6 (C 2-6 ) or a linear monovalent hydrocarbon radical having 3 to 20 carbon atoms (C 3-20), 3~15 pieces (C 3-15 ), 3~10 pieces (C 3-10 ), or 3 to 6 (C 3-6 Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl (including all isomeric forms, e.g., propen-1-yl, propen-2-yl, and allyl), and butenyl (including all isomeric forms, e.g., buten-1-yl, buten-2-yl, buten-3-yl, and 2-buten-1-yl).

[0056] The terms "alkenylene" and "alkenediyl" are used interchangeably herein to refer to a straight-chain or branched divalent hydrocarbon radical having one or more, in one embodiment one, two, three, or four, and in another embodiment one, carbon-carbon double bond(s). The alkenediyl is optionally substituted with one or more substituents Q as described herein. The term "alkenediyl" encompasses radicals having "cis" or "trans" configurations or mixtures thereof, or "Z" or "E" configurations or mixtures thereof, as recognized by those skilled in the art. For example, C 2-6 Alkenediyl refers to a linear unsaturated divalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon radical of 3 to 6 carbon atoms. In some embodiments, alkenediyl refers to a hydrocarbon radical of 2 to 30 carbon atoms (C 2-30 ), 2~20 pieces (C 2-20 ), 2~15 pieces (C 2-15 ), 2~10 pieces (C 2-10 ), or 2 to 6 (C 2-6 ) or a linear divalent hydrocarbon radical having 3 to 30 carbon atoms (C 3-30 ), 3~20 pieces (C 3-20 ), 3~15 pieces (C 3-15 ), 3~10 pieces (C 3-10 ), or 3 to 6 (C 3-6Examples of alkenediyl groups include ethenediyl (including all isomeric forms, for example, ethene-1,1-diyl and ethene-1,2-diyl), propenediyl (including all isomeric forms, for example, 1-propene-1,1-diyl, 1-propene-1,2-diyl, and 1-propene-1,3-diyl), butenediyl (including all isomeric forms, for example, 1-butene-1,1-diyl, 1-butene-1,2-diyl, and 1-butene-1,4-diyl), pentendiyl, and the like. Examples of hexene dialkyl groups include, but are not limited to, hexenediyl (including all isomeric forms, for example, 1-pentene-1,1-diyl, 1-pentene-1,2-diyl, and 1-pentene-1,5-diyl), and hexenediyl (including all isomeric forms, for example, 1-hexene-1,1-diyl, 1-hexene-1,2-diyl, 1-hexene-1,3-diyl, 1-hexene-1,4-diyl, 1-hexene-1,5-diyl, and 1-hexene-1,6-diyl).

[0057] The terms "heteroalkenylene" and "heteroalkenediyl" are used interchangeably herein to refer to a straight-chain or branched divalent hydrocarbon radical having one or more, in one embodiment one, two, three, or four, and in another embodiment one, carbon-carbon double bond(s) and having one or more heteroatoms each independently selected from O, S, and N within the hydrocarbon chain. The heteroalkenylene is optionally substituted with one or more substituents Q as described herein. The term "heteroalkenylene" encompasses radicals having a "cis" or "trans" configuration or a mixture thereof, or a "Z" or "E" configuration or a mixture thereof, as recognized by those skilled in the art. For example, C 2-6 Heteroalkenylene refers to a linear unsaturated divalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, heteroalkenylene refers to a heteroalkenylene radical having 2 to 20 carbon atoms (C 2-20 ), 2~15 pieces (C 2-15 ), 2~10 pieces (C 2-10 ), or 2 to 6 (C2-6 ) or a linear divalent hydrocarbon radical having 3 to 20 carbon atoms (C 3-20 ), 3~15 pieces (C 3-15 ), 3~10 pieces (C 3-10 ), or 3 to 6 (C 3-6 Examples of heteroalkenylene groups include, but are not limited to, -CH=CHO-, -CH=CHOCH2-, -CH=CHCHO-, -CH=CHS-, -CH=CHSCH2-, -CH=CHCH2S-, or -CH=CHCH2NH-.

[0058] The term "alkynyl" refers to a linear or branched monovalent hydrocarbon radical having one or more, in one embodiment one, two, three, or four, and in another embodiment one, carbon-carbon triple bond(s). Alkynyl is optionally substituted with one or more substituents Q as described herein. For example, C 2-6 Alkynyl refers to a linear unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon radical of 4 to 6 carbon atoms. In some embodiments, alkynyl refers to a group having 2 to 20 carbon atoms (C 2-20 ), 2~15 pieces (C 2-15 ), 2~10 pieces (C 2-10 ), or 2 to 6 (C 2-6 ) or a linear monovalent hydrocarbon radical having 4 to 20 carbon atoms (C 4-20 ), 4~15 pieces (C 4-15 ), 4~10 pieces (C 4-10 ), or 4 to 6 (C 4-6) is a branched monovalent hydrocarbon radical. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propynyl (including all isomeric forms, e.g., 1-propynyl (-C≡CCH) and propargyl (-CHC≡CH)), butynyl (including all isomeric forms, e.g., 1-butyn-1-yl and 2-butyn-1-yl), pentynyl (including all isomeric forms, e.g., 1-pentyn-1-yl and 1-methyl-2-butyn-1-yl), and hexynyl (including all isomeric forms, e.g., 1-hexyn-1-yl and 2-hexyn-1-yl).

[0059] The terms "alkynylene" and "alkynediyl" are used interchangeably herein to refer to a linear or branched divalent hydrocarbon radical having one or more, in one embodiment one, two, three, or four, and in another embodiment one, carbon-carbon triple bond(s). The alkynediyl is optionally substituted with one or more substituents Q as described herein. For example, C 2-6 Alkynediyl refers to a linear unsaturated divalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon radical of 4 to 6 carbon atoms. In some embodiments, alkynediyl refers to a hydrocarbon radical of 2 to 30 carbon atoms (C 2-30 ), 2~20 pieces (C 2-20 ), 2~15 pieces (C 2-15 ), 2~10 pieces (C 2-10 ), or 2 to 6 (C 2-6 ) or a linear divalent hydrocarbon radical having 4 to 30 carbon atoms (C 4-30 ), 4~20 pieces (C 4-20 ), 4~15 pieces (C 4-15 ), 4~10 pieces (C 4-10 ), or 4 to 6 (C 4-6Examples of alkynediyl groups include, but are not limited to, ethynediyl, propynediyl (including all isomeric forms, for example, 1-propyne-1,3-diyl and 1-propyne-3,3-diyl), butynediyl (including all isomeric forms, for example, 1-butyne-1,3-diyl, 1-butyne-1,4-diyl, and 2-butyne-1,1-diyl), pentynediyl (including all isomeric forms, for example, 1-pentyne-1,3-diyl, 1-pentyne-1,4-diyl, and 2-pentyne-1,1-diyl), and hexynediyl (including all isomeric forms, for example, 1-hexyne-1,3-diyl, 1-hexyne-1,4-diyl, and 2-hexyne-1,1-diyl).

[0060] The terms "heteroalkynylene" and "heteroalkynediyl" are used interchangeably herein to refer to a straight-chain or branched divalent hydrocarbon radical having one or more, in one embodiment one, two, three, or four, and in another embodiment one, carbon-carbon triple bond(s) and having one or more heteroatoms each independently selected from O, S, and N within its backbone. Heteroalkynylene is optionally substituted with one or more substituents Q as described herein. For example, C 2-6 Heteroalkynylene refers to a linear unsaturated divalent hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon radical of 4 to 6 carbon atoms. In certain embodiments, heteroalkynylene refers to a heteroalkynylene having 2 to 30 carbon atoms (C 2-30 ), 2~20 pieces (C 2-20 ), 2~15 pieces (C 2-15 ), 2~10 pieces (C 2-10 ), or 2 to 6 (C 2-6 ) or a linear divalent hydrocarbon radical having 4 to 30 carbon atoms (C 4-30 ), 4~20 pieces (C 4-20 ), 4~15 pieces (C 4-15 ), 4~10 pieces (C 4-10 ), or 4 to 6 (C 4-6Examples of heteroalkynylene groups include, but are not limited to, -C≡CCH2O-, -C≡CCH2S-, or -C≡CCH2NH-.

[0061] The term "cycloalkyl" refers to a cyclic monovalent hydrocarbon radical optionally substituted with one or more substituents Q, as described herein. In one embodiment, the cycloalkyl is a saturated or unsaturated but non-aromatic, and / or bridged or non-bridged, and / or fused bicyclic group. In certain embodiments, the cycloalkyl is a cyclic group having 3 to 20 carbon atoms (C 3-20 ), 3~15 pieces (C 3-15 ), 3~10 pieces (C 3-10 ), or 3 to 7 (C 3-7 ) carbon atoms. In one embodiment, the cycloalkyl is monocyclic. In another embodiment, the cycloalkyl is bicyclic. In yet another embodiment, the cycloalkyl is tricyclic. In yet another embodiment, the cycloalkyl is polycyclic. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptenyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, decalinyl, and adamantyl.

[0062] The terms "cycloalkylene" and "cycloalkanediyl" are used interchangeably herein to refer to a cyclic divalent hydrocarbon radical that may be optionally substituted with one or more substituents Q, as described herein. In one embodiment, a cycloalkanediyl group can be a saturated or unsaturated but non-aromatic, and / or bridged, and / or non-bridged, and / or fused bicyclic group. In certain embodiments, a cycloalkanediyl is a cyclic group having 3 to 30 carbon atoms (C 3-30 ), 3~20 pieces (C 3-20 ), 3~15 pieces (C 3-15), 3~10 pieces (C 3-10 ), or 3 to 7 (C 3-7 Examples of cycloalkanediyl groups include cyclopropanediyl (including all isomeric forms, for example, cyclopropane-1,1-diyl and cyclopropane-1,2-diyl), cyclobutanediyl (including all isomeric forms, for example, cyclobutane-1,1-diyl, cyclobutane-1,2-diyl, and cyclobutane-1,3-diyl), cyclopentanediyl (including all isomeric forms, for example, cyclopentane-1,1-diyl, cyclopentane-1,2-diyl, and cyclopentane-1,3-diyl), cyclohexanediyl (including all isomeric forms, for example, cyclohexane-1,1-diyl, cyclohexane-1,2-diyl, cyclohexane-1,3-diyl, and cyclohexa-1,4-diyl), cycloheptanediyl (including all isomeric forms, for example, cycloheptane-1,1-diyl, cycloheptane-1,2-diyl, cycloheptane-1,3-diyl, and cycloheptane-1,4-diyl), decalindiyl (including all isomeric forms, for example, decalin-1,1-diyl, decalin-1,2-diyl, and decalin-1,8-diyl), and adamantodiyl (including all isomeric forms, for example, adamant-1,2-diyl, adamant-1,3-diyl, and adamant-1,8-diyl).

[0063] The term "aryl" refers to a monovalent monocyclic aromatic hydrocarbon radical and / or a monovalent polycyclic aromatic hydrocarbon radical having at least one aromatic carbocyclic ring. In certain embodiments, aryl refers to a monovalent aromatic hydrocarbon radical having 6 to 20 (C 6-20 ), 6~15 pieces (C 6-15 ), or 6 to 10 (C 6-10) ring carbon atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, pyrenyl, biphenyl, and terphenyl. Aryl can also refer to a bicyclic or tricyclic carbocyclic ring in which one ring is aromatic and the others can be saturated, partially unsaturated, or aromatic, such as dihydronaphthyl, indenyl, indanyl, or tetrahydronaphthyl (tetralinyl). In one embodiment, aryl is monocyclic. In another embodiment, aryl is bicyclic. In yet another embodiment, aryl is tricyclic. In yet another embodiment, aryl is polycyclic. In certain embodiments, aryl is optionally substituted with one or more substituents Q as described herein.

[0064] The terms "arylene" and "arenediyl" are used interchangeably herein to refer to a divalent monocyclic aromatic hydrocarbon radical or a divalent polycyclic aromatic hydrocarbon radical having at least one aromatic hydrocarbon ring. In certain embodiments, an arylene is a divalent aromatic hydrocarbon radical having 6 to 20 (C 6-20 ), 6~15 pieces (C 6-15 ), or 6 to 10 (C 6-10Examples of arylene groups include phenylene (including all isomeric forms, for example, phen-1,2-diyl, phen-1,3-diyl, and phen-1,4-diyl), naphthylene (including all isomeric forms, for example, naphth-1,2-diyl, naphth-1,3-diyl, and naphth-1,8-diyl), fluorenylene (including all isomeric forms, for example, fluorene-1,2-diyl, fluorene-1,3-diyl, and fluorene-1,8-diyl), azulenylene (including all isomeric forms, for example, azulene-1,2-diyl, azulene-1,3-diyl, and azulene-1,8-diyl), anthrylene (including all isomeric forms, for example, anthra-1,2-diyl, anthra-1,3-diyl), and the like. and anthra-1,8-diyl), phenanthrylene (including all isomeric forms, for example, phenanthra-1,2-diyl, phenanthra-1,3-diyl, and phenanthra-1,8-diyl), pyrenylene (including all isomeric forms, for example, pyrene-1,2-diyl, pyrene-1,3-diyl, and pyrene-1,8-diyl), biphenylene (including all isomeric forms, for example, biphen-2,3-diyl, biphen-3,4'-diyl, and biphen-4,4'-diyl), and terphenylene (including all isomeric forms, for example, terphen-2,3-diyl, terphen-3,4'-diyl, and terphen-4,4'-diyl).Arylene also refers to bicyclic or tricyclic carbocyclic rings in which one ring is aromatic and the others may be saturated, partially unsaturated, or aromatic, such as dihydronaphthylene (including all isomeric forms, e.g., dihydronaphth-1,2-diyl and dihydronaphth-1,8-diyl), indenylene (including all isomeric forms, e.g., indene-1,2-diyl, indene-1,5-diyl), and the like. In certain embodiments, arylene refers to arylene, including indene-1,7-diyl, indane-1,2-diyl, indane-1,5-diyl, and indane-1,7-diyl, indanylene (including all isomeric forms, for example, indan-1,2-diyl, indan-1,5-diyl, and indan-1,7-diyl), or tetrahydronaphthylene (tetralinylene) (including all isomeric forms, for example, tetrahydronaphth-1,2-diyl, tetrahydronaphth-1,5-diyl, and tetrahydronaphth-1,8-diyl). In certain embodiments, arylene is optionally substituted with one or more substituents Q as described herein.

[0065] The terms "aralkyl" or "arylalkyl" refer to a monovalent alkyl group substituted with one or more aryl groups. In certain embodiments, the aralkyl is an alkyl group having 7 to 30 carbon atoms (C 7-30 ), 7~20 pieces (C 7-20 ), or 7 to 16 (C 7-16 ) carbon atoms. Examples of aralkyl groups include, but are not limited to, benzyl, phenylethyl (including all isomeric forms, e.g., 1-phenylethyl and 2-phenylethyl), and phenylpropyl (including all isomeric forms, e.g., 1-phenylpropyl, 2-phenylpropyl, and 3-phenylpropyl). In certain embodiments, the aralkyl is optionally substituted with one or more substituents Q as described herein.

[0066] The terms "aralkylene" or "arylalkylene" refer to a divalent alkyl group substituted with one or more aryl groups. In certain embodiments, the aralkylene has 7 to 30 carbon atoms (C 7-30 ), 7~20 pieces (C 7-20 ), or 7 to 16 (C 7-16) carbon atoms. Examples of aralkylene groups include, but are not limited to, benzylene (including all isomeric forms, e.g., phenylmethdiyl), phenylethylene (including all isomeric forms, e.g., 2-phenyl-ethane-1,1-diyl and 2-phenyl-ethane-1,2-diyl), and phenylpropylene (including all isomeric forms, e.g., 3-phenyl-propane-1,1-diyl, 3-phenyl-propane-1,2-diyl, and 3-phenyl-propane-1,3-diyl). In certain embodiments, the aralkylene is optionally substituted with one or more substituents Q as described herein.

[0067] The term "heteroaryl" refers to a monovalent monocyclic aromatic or monovalent polycyclic aromatic group having at least one aromatic ring, wherein at least one aromatic ring has one or more heteroatoms, each independently selected from O, S, and N, within the ring. The heteroaryl is bonded to the remainder of the molecule via the aromatic ring. Each ring of the heteroaryl group can have 1 or 2 O atoms, 1 or 2 S atoms, and / or 1 to 4 N atoms; provided that the total number of heteroatoms in each ring is 4 or less, and each ring has at least one carbon atom. In certain embodiments, the heteroaryl has 5 to 20, 5 to 15, or 5 to 10 ring atoms. In one embodiment, the heteroaryl is monocyclic. Examples of monocyclic heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, and triazolyl. In another embodiment, the heteroaryl is bicyclic.Examples of bicyclic heteroaryl groups include benzofuranyl, benzimidazolyl, benzisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, furopyrindyl (including all isomeric forms, e.g., furo[2,3-b]pyridinyl, furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl, furo[3,2-c]pyridinyl, furo[3,4-b]pyridinyl, and furo[3,4-c]pyridinyl), imidazolyl, benzoisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, furopyrindyl (including all isomeric forms, e.g., furo[2,3-b]pyridinyl, furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl, furo[3,2-c]pyridinyl, furo[3,4-b]pyridinyl, and furo[3,4-c]pyridinyl), imidazolyl, benzoisoxazolyl, benzopyranyl, benzoisoxazol ... imidazopyridinyl (including all isomeric forms, for example, imidazo[1,2-a]pyridinyl, imidazo[4,5-b]pyridinyl, and imidazo[4,5-c]pyridinyl), imidazothiazolyl (including all isomeric forms, for example, imidazo[2,1-b]thiazolyl and imidazo[4,5-d]thiazolyl), indazolyl, indolizinyl, indolyl, isobenzofuranyl, isobenzothienyl (i.e., benzo[c]thienyl), isoindolyl, isoquinolinyl, naphthyridinyl (including all isomeric forms, for example, 1,5-naphthalene, phthalazinyl, pteridinyl, purinyl, pyrrolopyridyl (including all isomeric forms, for example, pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-b]pyridinyl, and pyrrolo[3,2-c]pyridinyl), quinolinyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidyl (including all isomeric forms, e.g., [1,2,5]thiadiazolo[3,4-d]pyrimidinyl and [1,2,3]thiadiazolo[4,5-d]pyrimidinyl), and thienopyridyl (including all isomeric forms, e.g., thieno[2,3-b]pyridinyl, thieno[2,3-c]pyridinyl, thieno[3,2-b]pyridinyl, and thieno[3,2-c]pyridinyl). In yet another embodiment, heteroaryl is tricyclic.Examples of tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, perimidinyl, phenanthrolinyl, phenanthridinyl (including all isomeric forms, for example, 1,5-phenanthrolinyl, 1,6-phenanthrolinyl, 1,7-phenanthrolinyl, 1,9-phenanthrolinyl, and 2,10-phenanthrolinyl), phenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and xanthenyl. In some embodiments, heteroaryl is optionally substituted with one or more substituents Q as described herein.

[0068] The terms "heteroarylene" and "heteroarenediyl" are used interchangeably herein to refer to a divalent monocyclic aromatic group or a divalent polycyclic aromatic group having at least one aromatic ring, wherein at least one aromatic ring has one or more heteroatoms, each independently selected from O, S, and N, within the ring. A heteroarylene group has at least one bond to the rest of the molecule through its aromatic ring(s). Each ring of a heteroarylene group can have 1 or 2 O atoms, 1 or 2 S atoms, and / or 1 to 4 N atoms, provided that the total number of heteroatoms in each ring is 4 or less and each ring has at least one carbon atom. In certain embodiments, a heteroarylene has 5 to 20, 5 to 15, or 5 to 10 ring atoms. Examples of monocyclic heteroarylene groups include, but are not limited to, furandiyl, imidazolediyl, isothiazolediyl, isoxazolediyl, oxadiazolediyl, oxazolediyl, pyrazinediyl, pyrazolediyl, pyridazinediyl, pyridinediyl, pyrimidinediyl, pyrrolediyl, thiadiazolediyl, thiazolidinyl, thienediyl, tetrazolidinyl, triazinediyl, and triazolediyl. Examples of bicyclic heteroarylene groups include benzofurandiyl, benzimidazolediyl, benzoisoxazolediyl, benzopyrandiyl, benzothiadiazolediyl, benzothienediyl, benzotriazolediyl, benzoxazolediyl, furopyridinediyl (all isomeric forms, e.g., furo[2,3-b]pyridinediyl, furo[2,3-c]pyridinediyl, furo[3,2-b]pyridinediyl). imidazo[1,2-a]pyridinediyl, imidazo[4,5-b]pyridinediyl, and imidazo[4,5-c]pyridinediyl), imidazothiazoldiyl (including all isomeric forms, for example, imidazo[2,1-b]thiazoldiyl and imidazo[4,5-d]thiazolediyl), indazolediyl, indolizinediyl, indolediyl, isobenzofurandiyl, isobenzothienediyl (i.e., benzo[c]thienediyl), isoindolediyl, isoquinolinediyl, naphthyridinediyl (including all isomeric forms, for example, 1,5-naphthyridinediyl, 1,6-naphthyridinediyl, 1,7-naphthyridinediyl, and 1,8-naphthyridinediyl), oxazolopyridinediyl (including all isomeric forms, for example, oxazolo[4,5-b]pyridinediyl, oxazolo[4,5-c]pyridinediyl, oxazolo[5,4-b]pyridinediyl, and oxazolo[5,4-c]pyridinediyl), phthalazinediyl, pteridinediyl, purinediyl, pyrrolopyridinediyl, dinediyl (including all isomeric forms, for example, pyrrolo[2,3-b]pyridinediyl, pyrrolo[2,3-c]pyridinediyl, pyrrolo[3,2-b]pyridinediyl, and pyrrolo[3,2-c]pyridinediyl), quinolinediyl, quinoxalinediyl, quinazolinediyl, thiadiazolopyrimidinediyl (including all isomeric forms, for example, [1,2,5]thiadiazolo[3,4 [1,2,3]thiadiazolo[4,5-d]pyrimidinediyl and [1,2,3]thiadiazolo[4,5-d]pyrimidinediyl), and thienopyridinediyl (including all isomeric forms, for example, thieno[2,3-b]pyridinediyl, thieno[2,3-c]pyridinediyl, thieno[3,2-b]pyridinediyl, and thieno[3,2-c]pyridinediyl). Examples of tricyclic heteroarylene groups include, but are not limited to, acridinediyl, benzoindolediyl, carbazolediyl, dibenzofurandiyl, perimidinediyl, phenanthrolinediyl (including all isomeric forms, e.g., 1,5-phenanthrolinediyl, 1,6-phenanthrolinediyl, 1,7-phenanthrolinediyl, 1,9-phenanthrolinediyl, and 2,10-phenanthrolinediyl), phenanthridinediyl, phenarsazinediyl, phenazinediyl, phenothiazinediyl, phenoxazinediyldiyl, and xanthenediyl. In certain embodiments, heteroarylene is optionally substituted with one or more substituents Q, as described herein.

[0069] The term "heterocyclyl" or "heterocyclic" refers to a monovalent monocyclic non-aromatic ring system or a monovalent polycyclic ring system having at least one non-aromatic ring, wherein one or more of the non-aromatic ring atoms is a heteroatom each independently selected from O, S, and N; and the remaining ring atoms are carbon atoms. In certain embodiments, a heterocyclyl or heterocyclic group has 3 to 20, 3 to 15, 3 to 10, 3 to 8, 4 to 7, or 5 to 6 ring atoms. A heterocyclyl is attached to the remainder of the molecule via a non-aromatic ring. In certain embodiments, a heterocyclyl is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may be fused or bridged, and in which nitrogen or sulfur atoms may be optionally oxidized, nitrogen atoms may be optionally quaternized, and some rings may be partially saturated, fully saturated, or aromatic. The heterocyclyl may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound.Examples of heterocyclyl and heterocyclic groups include azepinyl, benzodioxanyl, benzodioxolyl, benzofuranonyl, chromanyl, decahydroisoquinolinyl, dihydrobenzofuranyl, dihydrobenzisothiazolyl, dihydrobenzisoxazinyl (including all isomeric forms, e.g., 1,4-dihydrobenzo[d][1,3]oxazinyl, 3,4-dihydrobenzo[c][1,2]oxazinyl, and 3,4-dihydrobenzo[d][1,2]oxazinyl), dihydrobenzothienyl, dihydroisobenzofuranyl, dihydrobenzo[c]thienyl, dihydrofuryl, dihydroisoindolyl, dihydropyranyl, dihydropyrazolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, Examples of heterocyclyl include, but are not limited to, dihydropyrrolyl, dioxolanyl, 1,4-dithianyl, furanonyl, imidazolidinyl, imidazolinyl, indolinyl, isochromanyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinonyl, oxazolidinyl, oxiranyl, piperazinyl, piperidinyl, 4-piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydrothienyl, thiamorpholinyl, thiazolidinyl, thiochromanyl, tetrahydroquinolinyl, and 1,3,5-trithianyl. In certain embodiments, the heterocyclyl is optionally substituted with one or more substituents Q as described herein.

[0070] The term "heterocyclylene" refers to a divalent monocyclic non-aromatic ring system or a divalent polycyclic ring system having at least one non-aromatic ring, wherein one or more of the non-aromatic ring atoms is a heteroatom independently selected from O, S, and N; and the remaining ring atoms are carbon atoms. A heterocyclylene group is attached to the remainder of the molecule via a non-aromatic ring. In certain embodiments, a heterocyclylene group has 3 to 20, 3 to 15, 3 to 10, 3 to 8, 4 to 7, or 5 to 6 ring atoms. In certain embodiments, a heterocyclylene is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may be fused or bridged, and in which nitrogen or sulfur atoms may be optionally oxidized, nitrogen atoms may be optionally quaternized, and some rings may be partially saturated, fully saturated, or aromatic. The heterocyclylene may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound.Examples of such heterocyclylene groups are azepinediyl, benzodioxanediyl, benzodioxolediyl, benzofuranonediyl, chromandiyl, decahydroisoquinolinediyl, dihydrobenzofurandiyl, dihydrobenzisothiazolediyl, dihydrobenzisoxazinediyl (including all isomeric forms, e.g., 1,4-dihydrobenzo[d][1,3]oxazinediyl, 3,4-dihydrobenzo[c][1,2]oxazinediyl, and 3,4-dihydrobenzo[d][1,2]oxazinediyl), dihydrobenzothienediyl, dihydroisobenzofurandiyl, dihydrobenzo[c]thienediyl, dihydrofurdiyl, dihydroisoindolediyl, dihydropyrandiyl, dihydropyrazolediyl, dihydropyrazinediyl, dihydropyridinediyl, dihydropyrimidinediyl, dihydropyrrolediyl, dihydrobenzo[d][1,3]oxazine ...d][1,3]oxazinediyl, Examples include, but are not limited to, xolanediyl, 1,4-dithianediyl, furanonediyl, imidazolidinediyl, imidazolinediyl, indolinediyl, isochromanediyl, isoindolinediyl, isothiazolidinediyl, isoxazolidinediyl, morpholinediyl, octahydroindolediyl, octahydroisoindolediyl, oxazolidinonediyl, oxazolidinediyl, oxiranediyl, piperazinediyl, piperidinediyl, 4-piperidonediyl, pyrazolidinediyl, pyrazolindiyl, pyrrolidinediyl, pyrrolinediyl, quinuclidinediyl, tetrahydrofurdiyl, tetrahydroisoquinolinediyl, tetrahydropyrandiyl, tetrahydrothienediyl, thiamorpholinediyl, thiazolidinediyl, thiochromanediyl, tetrahydroquinolinediyl, and 1,3,5-trithianediyl. In certain embodiments, the heterocyclylene is optionally substituted with one or more substituents Q, as described herein.

[0071] The terms "halogen," "halide," or "halo" mean fluoro, chloro, bromo, and / or iodo.

[0072] The term "optionally substituted" refers to a group or substituent, such as an alkyl, heteroalkyl, alkylene, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, alkynylene, heteroalkynylene, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, aralkylene, heteroaryl, heteroarylene, heterocyclyl, or heterocyclylene group, that is optionally substituted with, for example, (a) deuterium (-D), cyano (-CN), halo, imino (=NH), nitro (-NO), and oxo (=O); (b) one or more, and in one embodiment, one, two, three, or four, substituents Q a and each of these is further optionally substituted C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)R a , -C(O)OR a , -C(O)NR b R c , -C(O)SR a , -C(NR a )NR b R c , -C(S)R a , -C(S)OR a , -C(S)NR b R c , -OR a , -OC(O)R a , -OC(O)OR a , -OC(O)NR b R c , -OC(O)SR a , -OC(NR a )NR b R c , -OC(S)R a , -OC(S)OR a , -OC(S)NR b R c , -OP(O)(OR a ) OR d , -OS(O)R a, -OS(O)2R a , -OS(O)NR b R c , -OS(O)2NR b R c , -NR b R c , -NR a C(O)R d , -NR a C(O)OR d , -NR a C(O)NR b R c , -NR a C(O)SR d , -NR a C(NR d )NR b R c , -NR a C(S)R d , -NR a C(S)OR d , -NR a C(S)NR b R c , -NR a S(O)R d , -NR a S(O)2R d , -NR a S(O)NR b R c , -NR a S(O)NR b R c , -SR a , -S(O)R a , -S(O)2R a , -S(O)NR b R c , and -S(O)NR b R c (In the formula, each R a , R b , R c , and R d are independently (i) hydrogen or deuterium; (ii) one or more, in one embodiment, one, two, three, or four, substituents Q a with arbitrary substitutions, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R b and R c together with the N atom to which they are attached, form one or more, in one embodiment one, two, three or four, substituents Q a Q is intended to mean that the group may be substituted with one or more, and in one embodiment, one, two, three, or four, substituents Q, each independently selected from:

[0073] In one embodiment, each Q a are independently: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)R e , -C(O)OR e , -C(O)NR f R g , -C(O)SR e , -C(NR e )NR f R g , -C(S)R e , -C(S)OR e , -C(S)NR f R g , -OR e , -OC(O)R e , -OC(O)OR e , -OC(O)NR f R g , -OC(O)SR e , -OC(NR e )NR f R g , -OC(S)Re , -OC(S)OR e , -OC(S)NR f R g , -OS(O)R e , -OS(O)2R e , -OS(O)NR f R g , -OS(O)2NR f R g , -NR f R g , -NR e C(O)R h , -NR e C(O)OR f , -NR e C(O)NR f R g , -NR e C(O)SR f , -NR e C(NR h )NR f R g , -NR e C(S)R h , -NR e C(S)OR f , -NR e C(S)NR f R g , -NR e S(O)R h , -NR e S(O)2R h , -NR e S(O)NR f R g , -NR e S(O)NR f R g , -SR e , -S(O)R e , -S(O)2R e , -S(O)NR f R g , and -S(O)NR f R g ;(In the formula, each R e , R f , R g , and R h are independently (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R f and R g together with the N atom to which they are attached form a heterocyclyl).

[0074] In certain embodiments, "optically active" and "enantiomerically active" refer to a population of molecules having an enantiomeric excess of about 80% or more, about 90% or more, about 91% or more, about 92% or more, about 93% or more, about 94% or more, about 95% or more, about 96% or more, about 97% or more, about 98% or more, about 99% or more, about 99.5% or more, or about 99.8% or more. In certain embodiments, an optically active compound contains about 95% or more of one enantiomer and about 5% or less of the other enantiomer, based on the total weight of the enantiomeric mixture. In certain embodiments, an optically active compound contains about 98% or more of one enantiomer and about 2% or less of the other enantiomer, based on the total weight of the enantiomeric mixture. In certain embodiments, an optically active compound contains about 99% or more of one enantiomer and about 1% or less of the other enantiomer, based on the total weight of the enantiomeric mixture.

[0075] In describing an optically active compound, the prefixes R and S are used to indicate the absolute configuration of the compound about its chiral center(s). The prefixes (+) and (-) are used to indicate the optical rotation of the compound, i.e., the direction in which a plane of polarized light is rotated by the optically active compound. The prefix (-) indicates that the compound is levorotatory, i.e., the compound rotates the plane of polarized light to the left or counterclockwise. The prefix (+) indicates that the compound is dextrorotatory, i.e., the compound rotates the plane of polarized light to the right or clockwise. However, the signs of optical rotation (+) and (-) are unrelated to the absolute configurations R and S of the compound.

[0076] The term "isotopically enriched" refers to a compound that contains unnatural proportions of isotopes at one or more of the atoms that constitute such compound. In certain embodiments, isotopically enriched compounds contain unnatural proportions of isotopes, including, but not limited to, hydrogen ( 1 H), deuterium ( 2 H), tritium ( 3 H), carbon-11( 11 C), carbon-12( 12 C), carbon-13( 13 C), carbon-14( 14 C), nitrogen-13( 13 N), nitrogen-14( 14 N), nitrogen-15( 15 N), oxygen-14( 14 O), oxygen-15( 15 O), oxygen-16( 16 O), oxygen-17( 17 O), oxygen-18( 18 O), fluorine-17( 17 F), fluorine-18( 18 F), Phosphorus-31( 31 P), phosphorus-32( 32 P), phosphorus-33( 33 P), sulfur-32( 32 S), sulfur-33( 33 S), sulfur-34( 34 S), sulfur-35( 35 S), sulfur-36( 36 S), chlorine-35( 35 Cl), chlorine-36( 36 Cl), chlorine-37( 37 Cl), Bromine-79( 79 Br), Bromine-81( 81 Br), iodine-123( 123 I), iodine-125( 125 I), iodine-127( 127 I), iodine-129( 129 I), and iodine-131( 131 In some embodiments, the isotopically enriched compound contains one or more isotopes, including, but not limited to, hydrogen (I). In some embodiments, the isotopically enriched compound is in a stable form, i.e., is non-radioactive. In some embodiments, the isotopically enriched compound contains unnatural proportions of hydrogen (I), including, but not limited to, hydrogen (I).1 H), deuterium ( 2 H), carbon-12( 12 C), carbon-13( 13 C), nitrogen-14( 14 N), nitrogen-15( 15 N), oxygen-16( 16 O), oxygen-17( 17 O), oxygen-18( 18 O), fluorine-17( 17 F), Phosphorus-31( 31 P), sulfur-32( 32 S), sulfur-33( 33 S), sulfur-34( 34 S), sulfur-36( 36 S), chlorine-35( 35 Cl), chlorine-37( 37 Cl), Bromine-79( 79 Br), Bromine-81( 81 Br), and iodine-127( 127 In some embodiments, the isotopically enriched compound contains one or more isotopes, including, but not limited to, tritium (I). In some embodiments, the isotopically enriched compound is in an unstable form, i.e., radioactive. In some embodiments, the isotopically enriched compound contains unnatural proportions of isotopes, including, but not limited to, tritium (I). 3 H), carbon-11( 11 C), carbon-14( 14 C), nitrogen-13( 13 N), oxygen-14( 14 O), oxygen-15( 15 O), Fluorine-18( 18 F), phosphorus-32( 32 P), phosphorus-33( 33 P), sulfur-35( 35 S), chlorine-36( 36 Cl), iodine-123( 123 I), iodine-125( 125 I), iodine-129( 129 I), and iodine-131( 131 In the compounds as provided herein, any hydrogen atom may be replaced by any isotope, for example, 1), where feasible according to the judgment of one skilled in the art. 2 H, or any carbon, e.g., 13C or any nitrogen, for example, 15 N or any oxygen, for example, 18 It will be understood that O may also be used.

[0077] The term "isotopically enriched" refers to the presence of a more common isotope of an element (e.g., protium or hydrogen-1) at a given position in a molecule. 1 "H" refers to the percentage of incorporation of a less common isotope of that element (e.g., D representing deuterium or hydrogen-2) at a position of hydrogen (H). As used herein, when an atom at a particular position in a molecule is designated to be a particular less common isotope, it is understood that the abundance of that isotope at that position is substantially greater than its natural abundance.

[0078] The term "isotopic enrichment factor" means the ratio between the isotopic abundance in an isotopically enriched compound and the natural abundance of a specified isotope.

[0079] The term "hydrogen" or the symbol "H" refers to the composition of naturally occurring hydrogen isotopes, including protium ( 1 H), deuterium ( 2 H or D), and tritium ( 3 H) at their natural abundance. Protium is the most common hydrogen isotope, with a natural abundance of greater than 99.98%. Deuterium is a less common hydrogen isotope, with a natural abundance of about 0.0156%.

[0080] The term "deuterium enrichment" refers to the percentage of deuterium incorporation at a given position in a molecule in place of hydrogen. For example, 1% deuterium enrichment at a given position means that 1% of the molecules in a given sample contain deuterium at the specified position. Because the distribution of naturally occurring deuterium is, on average, about 0.0156%, the deuterium enrichment at any position in a compound synthesized using non-enriched starting materials is, on average, about 0.0156%. As used herein, when a particular position in an isotopically enriched compound is designated as having deuterium, it is understood that the abundance of deuterium at that position in the compound is substantially greater than its natural abundance (0.0156%).

[0081] The term "carbon" or the symbol "C" refers to carbon-12 ( 12 C) and carbon-13 ( 13 Carbon-12 refers to the composition of naturally occurring carbon isotopes, including carbon-12, carbon-13, and carbon-14, carbon-15, carbon-16, carbon-17, carbon-18, carbon-19, carbon-20, carbon-21, carbon-22, carbon-23, carbon-24, carbon-25, carbon-26, carbon-27, carbon-28, carbon-29, carbon-30, carbon-31, carbon-32, carbon-33, carbon-34, carbon-35, carbon-36, carbon-37, carbon-38, carbon-39, carbon-40, carbon-41, carbon-42, carbon-43, carbon-44, carbon-45, carbon-46, carbon-47, carbon-48, carbon-49, carbon-50, carbon-51, carbon-52, carbon-53, carbon-54, carbon-55, carbon-56, carbon-57, carbon-58, carbon-

[0082] "Carbon-13 enriched" or " 13 The term "C enrichment" refers to the percentage of carbon-13 incorporation at a carbon at a given position within a molecule. For example, 10% carbon-13 enrichment at a given position means that 10% of the molecules in a given sample contain carbon-13 at that specified position. Because the distribution of naturally occurring carbon-13 averages about 1.11%, the carbon-13 at any position within an enriched compound synthesized using non-enriched starting materials will average about 1.11%. As used herein, when a particular position within an isotopically enriched compound is designated as having carbon-13, it is understood that the abundance of carbon-13 at that position within the compound is substantially greater than its natural abundance (1.11%).

[0083] The terms "substantially pure" and "substantially homogeneous," when referring to a substance, mean sufficiently homogeneous to appear free of readily detectable impurities as determined by standard analytical methods used by those of skill in the art, including, but not limited to, thin layer chromatography (TLC), gel electrophoresis, high performance liquid chromatography (HPLC), gas chromatography (GC), nuclear magnetic resonance (NMR), and mass spectrometry (MS); or sufficiently pure that further purification would not detectably alter the physical, chemical, biological, and / or pharmacological properties of the substance, such as enzymatic activity and biological activity. In certain embodiments, "substantially pure" or "substantially homogeneous" refers to a population of molecules in which at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 99.5% by weight of the molecules are single enantiomers, racemic mixtures, or single compounds, including mixtures of enantiomers, as determined by standard analytical methods. As used herein, when an atom at a particular position in an isotopically enriched molecule is designated as a particular, less common isotope, molecules containing other than the designated isotope at the designated position are impurities with respect to the isotopically enriched compound. Thus, for a deuterated compound having an atom at a particular position designated as deuterium, compounds containing protium at that same position are impurities.

[0084] The term "solvate" refers to a complex or aggregate formed by one or more molecules of a solute, for example, a compound provided herein, and one or more molecules of a solvent present in a stoichiometric or non-stoichiometric amount. Suitable solvents include, but are not limited to, water, methanol, ethanol, n-propanol, isopropanol, and acetic acid. In certain embodiments, the solvent is pharmaceutically acceptable. In one embodiment, the complex or aggregate is in a crystalline form. In another embodiment, the complex or aggregate is in a non-crystalline form. When the solvent is water, the solvate is a hydrate. Examples of hydrates include, but are not limited to, hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, and pentahydrate.

[0085] For divalent groups described herein, no orientation is implied in the direction in which the divalent group is shown. For example, unless a specific orientation is specified, the formula -C(O)NH- represents both -C(O)NH- and -NHC(O)-.

[0086] The phrase "a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof" has the same meaning as the phrase "(i) a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant of the compound referred to therein; (ii) a pharmaceutically acceptable salt, solvate, hydrate, or prodrug of the compound referred to therein; or (iii) a pharmaceutically acceptable salt, solvate, hydrate, or prodrug of a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant of the compound referred to therein."

[0087] The phrase "an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof" has the same meaning as the phrase "(i) an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant of the compound referred to therein; (ii) a pharmaceutically acceptable salt, solvate, or hydrate of the compound referred to therein; or (iii) a pharmaceutically acceptable salt, solvate, or hydrate of an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant of the compound referred to therein."

[0088] (compound)

[0089] In one embodiment, provided herein is a compound of formula (I): [ka]

[0090] or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. (In the formula:

[0091] Each A is independently O, S, S(O), S(O2), or N(R 4 ) and;

[0092] each L is independently a linker;

[0093] Each R 1 , R 2 , and R 3 are independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) C 1-6Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) —C(O)R 1a , -C(O)OR 1a , -C(O)NR 1b R 1c , -C(O)SR 1a , -C(NR 1a )NR 1b R 1c , -C(S)R 1a , -C(S)OR 1a , -C(S)NR 1b R 1c , -OR 1a , -OC(O)R 1a , -OC(O)OR 1a , -OC(O)NR 1b R 1c , -OC(O)SR 1a , -OC(NR 1a )NR 1b R 1c , -OC(S)R 1a , -OC(S)OR 1a , -OC(S)NR 1b R 1c , -OS(O)R 1a , -OS(O)2R 1a , -OS(O)NR 1b R 1c , -OS(O)2NR 1b R 1c , -NR 1b R 1c , -NR 1a C(O)R 1d , -NR 1a C(O)OR 1d , -NR 1a C(O)NR 1b R 1c , -NR 1a C(O)SR 1d , -NR 1a C(NR 1d )NR 1b R 1c , -NR1a C(S)R 1d , -NR 1a C(S)OR 1d , -NR 1a C(S)NR 1b R 1c , -NR 1a S(O)R 1d , -NR 1a S(O)2R 1d , -NR 1a S(O)NR 1b R 1c , -NR 1a S(O)NR 1b R 1c , -SR 1a , -S(O)R 1a , -S(O)2R 1a , -S(O)NR 1b R 1c , or -S(O)2NR 1b R 1c and;

[0094] Each R 4 are independently: (i) hydrogen; (ii) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) —C(O)R 1a , -C(O)OR 1a , -C(O)NR 1b R 1c , -C(O)SR 1a , -C(NR 1a )NR 1b R 1c , -C(S)R 1a , -C(S)OR 1a , -C(S)NR 1b R 1c , -S(O)R 1a , -S(O)2R 1a , -S(O)NR 1b R 1c , or -S(O)2NR 1b R 1cand;

[0095] Each R 1a , R 1b , R 1c , and R 1d are independently hydrogen, deuterium, and C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl;

[0096] R A is an antibody or an antigen-binding fragment thereof;

[0097] m is an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16; and

[0098] each p and q is independently an integer of 0, 1, or 2; provided that the sum of p and q is greater than 0;

[0099] wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more, and in one embodiment, one, two, three, or four, substituents Q, wherein each Q is independently: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) one or more, and in one embodiment, one, two, three, or four, substituents Q. a and each of these is further optionally substituted C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)R a , -C(O)OR a , -C(O)NRb R c 、-C(O)SR a 、-C(NR a )NR b R c 、-C(S)R a 、-C(S)OR a 、-C(S)NR b R c 、-OR a 、-OC(O)R a 、-OC(O)OR a 、-OC(O)NR b R c 、-OC(O)SR a 、-OC(NR a )NR b R c 、-OC(S)R a 、-OC(S)OR a 、-OC(S)NR b R c 、-OP(O)(OR a )OR d 、-OS(O)R a 、-OS(O)2R a 、-OS(O)NR b R c 、-OS(O)2NR b R c 、-NR b R c 、-NR a C(O)R d 、-NR a C(O)OR d 、-NR a C(O)NR b R c 、-NR a C(O)SR d 、-NR a C(NR d )NR b R c 、-NR a C(S)R d 、-NR a C(S)OR d 、-NR a C(S)NR b R c 、-NR a S(O)R d 、-NR aS(O)2R d , -NR a S(O)NR b R c , -NR a S(O)NR b R c , -SR a , -S(O)R a , -S(O)2R a , -S(O)NR b R c , and -S(O)NR b R c (In the formula, each R a , R b , R c , and R d are independently (i) hydrogen or deuterium; (ii) one or more, in one embodiment, one, two, three, or four, substituents Q a with arbitrary substitutions, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R b and R c together with the N atom to which they are attached, form one or more, in one embodiment one, two, three or four, substituents Q a forming an optionally substituted heterocyclyl;

[0100] Here, each Q a are independently: (a) deuterium, cyano, halo, nitro, imino, and oxo; (b) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)R e , -C(O)OR e、-C(O)NR f R g 、-C(O)SR e 、-C(NR e )NR f R g 、-C(S)R e 、-C(S)OR e 、-C(S)NR f R g 、-OR e 、-OC(O)R e 、-OC(O)OR e 、-OC(O)NR f R g 、-OC(O)SR e 、-OC(NR e )NR f R g 、-OC(S)R e 、-OC(S)OR e 、-OC(S)NR f R g 、-OS(O)R e 、-OS(O)2R e 、-OS(O)NR f R g 、-OS(O)2NR f R g 、-NR f R g 、-NR e C(O)R h 、-NR e C(O)OR f 、-NR e C(O)NR f R g 、-NR e C(O)SR f 、-NR e C(NR h )NR f R g 、-NR e C(S)R h 、-NR e C(S)OR f 、-NR e C(S)NR f R g 、-NR e S(O)R h 、-NR e S(O)2R h 、-NRe S(O)NR f R g , -NR e S(O)NR f R g , -SR e , -S(O)R e , -S(O)2R e , -S(O)NR f R g , and -S(O)NR f R;(In the formula, each R e , R f , R g , and R h are independently (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R f and R g are selected from: together with the N atom to which they are attached form a heterocyclyl).

[0101] In another embodiment, provided herein is a compound of formula (II): [ka]

[0102] or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. (In the formula:

[0103] Each X is independently 1-40 Alkylene, C 1-40 Heteroalkylene, C 2-40 Alkenylene, C 2-40 Heteroalkenylene, C 2-40 Alkynylene, or C 2-40heteroalkynylene, wherein one or more methylene groups are each independently and optionally replaced by a divalent radical, and each divalent radical is independently selected from the group consisting of: C 3-10 Cycloalkylene, C 6-14 arylene, heteroarylene, or heterocyclylene;

[0104] Each Y is independently a bond, C 1-6 Alkylene, C 1-6 Heteroalkylene, C 2-6 Alkenylene, C 2-6 Alkynylene, C 3-10 Cycloalkylene, C 6-14 Arylene, C 7-15 aralkylene, heteroarylene, or heterocyclylene; and

[0105] R 1 , R 2 , R 3 , R A , A, m, p, and q are each as defined herein;

[0106] wherein each alkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene is optionally substituted with one or more substituents Q).

[0107] In certain embodiments, in Formula (I) or Formula (II), each p is an integer of 0 and each q is an integer of 1. In certain embodiments, in Formula (I) or Formula (II), each p is an integer of 1 and each q is an integer of 0.

[0108] In certain embodiments, in Formula (I) or Formula (II), each p is an integer of 0, and each q is an integer of 2. In certain embodiments, in Formula (I) or Formula (II), each p and q is an integer of 1. In certain embodiments, in Formula (I) or Formula (II), each p is an integer of 2, and each q is an integer of 0.

[0109] In yet another embodiment, provided herein is a compound of formula (III): [ka]

[0110] (In the formula, R 1 , R 2 , R 3 , R A , A, L, and m are each as defined herein. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0111] In yet another embodiment, provided herein is a compound of formula (IV): [ka]

[0112] (In the formula, R 1 , R 2 , R 3 , R A , A, X, Y, and m are each as defined herein. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0113] In yet another embodiment, provided herein is a compound of formula (V): [ka]

[0114] (In the formula, R 1 , R 2 , R 3 , RA , A, L, and m are each as defined herein. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0115] In yet another embodiment, provided herein is a compound of formula (VI): [ka]

[0116] (In the formula, R 1 , R 2 , R 3 , R A , A, X, Y, and m are each as defined herein. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0117] In certain embodiments, in any one of Formulas (I) to (VI), each A is O. In certain embodiments, in any one of Formulas (I) to (VI), each A is S. In certain embodiments, in any one of Formulas (I) to (VI), each A is S(O). In certain embodiments, in any one of Formulas (I) to (VI), each A is S(O2). In certain embodiments, in any one of Formulas (I) to (VI), each A is independently N(R 4 )(wherein, R 4 is as defined herein). In certain embodiments, in any one of Formulas (I) through (VI), each A is independently N(R 4 )(wherein, R 4 is (i) hydrogen; (ii) C, each optionally substituted with one or more substituents Q; 1-6Alkyl or C 1-6 heteroalkyl; or (iii) —C(O)R 1a (In the formula, R 1a is as defined herein). In certain embodiments, in any one of Formulas (I) through (VI), each A is independently N(H), N(CH), or N(C(O)CH). In certain embodiments, in any one of Formulas (I) through (VI), each A is N(H).

[0118] In yet another embodiment, provided herein is a compound of formula (VII): [ka]

[0119] (In the formula, R 1 , R 2 , R 3 , R A , L, and m are each as defined herein. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0120] In yet another embodiment, provided herein is a compound of formula (VIII): [ka]

[0121] (In the formula, R 1 , R 2 , R 3 , R A , X, Y, and m are each as defined herein. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0122] In yet another embodiment, provided herein is a compound of formula (IX): [ka]

[0123] (In the formula, R 1 , R 2 , R 3 , R A , L, and m are each as defined herein. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0124] In yet another embodiment, provided herein is a compound of formula (X): [ka]

[0125] (In the formula, R 1 , R 2 , R 3 , R A , X, Y, and m are each as defined herein. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0126] In yet another embodiment, provided herein is a compound of formula (XI): [ka]

[0127] (In the formula, R 1 , R 2 , R 3 , R A , L, and m are each as defined herein. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0128] In yet another embodiment, provided herein is a compound of formula (XII): [ka]

[0129] (In the formula, R 1 , R 2 , R 3 , R A , X, Y, and m are each as defined herein. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0130] In yet another embodiment, provided herein is a compound of formula (XIII): [ka]

[0131] (In the formula, R 1 , R 2 , R 3 , R A , L, and m are each as defined herein. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0132] In yet another embodiment, provided herein is a compound of formula (XIV): [ka]

[0133] (In the formula, R 1 , R 2 , R 3 , R A , X, Y, and m are each as defined herein. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0134] In certain embodiments, in any one of Formulas (I) through (XIV), each R 1 is independently hydrogen, deuterium, or halo. In certain embodiments, in any one of Formulas (I) through (XIV), each R 1 is independently hydrogen, deuterium, or fluoro. In certain embodiments, in any one of Formulas (I) through (XIV), each R 1 is independently hydrogen or fluoro. In certain embodiments, in any one of Formulas (I) through (XIV), each R 1 is hydrogen. In certain embodiments, in any one of Formulas (I) through (XIV), each R 1 is fluoro.

[0135] In certain embodiments, in any one of Formulas (I) through (XIV), each R 2are independently (i) hydrogen or deuterium; (ii) heterocyclyl optionally substituted with one or more substituents Q; or (iii) -NR 1b R 1c or -NR 1a C(O)R 1d where R 1a , R 1b , R 1c , and R 1d and each are as defined herein. In certain embodiments, in any one of Formulas (I) through (XIV), each R 2 is independently hydrogen, amino, methylamino, acetamido, or hydroxyacetamido. In certain embodiments, in any one of Formulas (I) through (XIV), each R 2 is independently hydrogen or amino. In certain embodiments, in any one of Formulas (I) to (XIV), each R 2 is hydrogen. In certain embodiments, in any one of Formulas (I) through (XIV), each R 2 is an amino.

[0136] In certain embodiments, in any one of Formulas (I) through (XIV), each R 3 are independently C, each optionally substituted with one or more substituents Q; 1-6 Alkyl, C 1-6 Heteroalkyl, or C 2-6 In certain embodiments, in any one of Formulas (I) to (XIV), each R 3 is independently methyl, fluoromethyl, methoxymethyl, or ethenyl. In certain embodiments, in any one of Formulas (I) through (XIV), each R 3 is methyl.

[0137] In certain embodiments, in any one of Formulas (I) to (XIV),

[0138] Each R 1 are independently hydrogen, deuterium, or halo;

[0139] Each R 2 are independently (i) hydrogen or deuterium; (ii) heterocyclyl optionally substituted with one or more substituents Q; or (iii) -NR 1b R 1c or -NR 1a C(O)R 1d where R 1a , R 1b , R 1c , and R 1d are each as defined herein; and

[0140] Each R 3 are independently C, each optionally substituted with one or more substituents Q; 1-6 Alkyl, C 1-6 Heteroalkyl, or C 2-6 It is alkenyl.

[0141] In certain embodiments, in any one of Formulas (I) to (XIV),

[0142] Each R 1 are independently hydrogen, deuterium, or fluoro;

[0143] Each R 2 is independently hydrogen, amino, methylamino, acetamido, or hydroxyacetamido; and

[0144] Each R 3 is independently methyl, fluoromethyl, hydroxymethyl, or ethenyl.

[0145] In certain embodiments, in any one of Formulas (I) to (XIV),

[0146] Each R 1 are independently hydrogen or fluoro;

[0147] Each R 2 are independently hydrogen or amino; and

[0148] Each R 3are independently methyl.

[0149] In certain embodiments, in any one of Formulas (I) to (XIV),

[0150] Each R 1 are independently hydrogen or fluoro;

[0151] Each R 2 are independently hydrogen; and

[0152] Each R 3 are independently methyl.

[0153] In one embodiment, provided herein is a compound of formula (XV): [ka]

[0154] or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0155] (In the formula: Each R 6 are independently (i) deuterium, cyano, halo, or nitro; (ii) C, each optionally substituted with one or more substituents Q. 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) —C(O)R 1a , -C(O)OR 1a , -C(O)NR 1b R 1c , -C(O)SR 1a , -C(NR 1a )NR 1b R1c 、-C(S)R 1a 、-C(S)OR 1a 、-C(S)NR 1b R 1c 、-OR 1a 、-OC(O)R 1a 、-OC(O)OR 1a 、-OC(O)NR 1b R 1c 、-OC(O)SR 1a 、-OC(NR 1a )NR 1b R 1c 、-OC(S)R 1a 、-OC(S)OR 1a 、-OC(S)NR 1b R 1c 、-OS(O)R 1a 、-OS(O)2R 1a 、-OS(O)NR 1b R 1c 、-OS(O)2NR 1b R 1c 、-NR 1b R 1c 、-NR 1a C(O)R 1d 、-NR 1a C(O)OR 1d 、-NR 1a C(O)NR 1b R 1c 、-NR 1a C(O)SR 1d 、-NR 1a C(NR 1d )NR 1b R 1c 、-NR 1a C(S)R 1d 、-NR 1a C(S)OR 1d 、-NR 1a C(S)NR 1b R 1c 、-NR 1a S(O)R 1d 、-NR 1a S(O)2R 1d 、-NR 1a S(O)NR 1b R 1c 、-NR 1a S(O)2NR 1b R 1c 、-SR1a , -S(O)R 1a , -S(O)2R 1a , -S(O)NR 1b R 1c , or -S(O)2NR 1b R 1c and;

[0156] each s is independently an integer of 0, 1, 2, or 3; and

[0157] R 1 , R 2 , R 3 , R 1a , R 1b , R 1c , R 1d , R A , A, X, Y, m, p, and q are each as defined herein).

[0158] In certain embodiments, in Formula (XV), each R 6 is independently deuterium or halo. In certain embodiments, in Formula (XV), each R 6 is independently deuterium or fluoro. In certain embodiments, in Formula (XV), each R 6 is independently halo. In certain embodiments, in Formula (XV), each R 6 is fluoro.

[0159] In certain embodiments, in Formula (XV), each s is independently an integer of 0 or 1. In certain embodiments, in Formula (XV), each s is an integer of 0. In certain embodiments, in Formula (XV), each s is an integer of 1.

[0160] In another embodiment, provided herein is a compound of formula (XVI): [ka]

[0161] (In the formula, each R 6a , R 6b , and R 6care independently hydrogen or R 6 and R 1 , R 2 , R 3 , R 6 , R A , A, X, Y, m, p, and q are each as defined herein. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0162] In certain embodiments, in Formula (XV) or Formula (XVI), each p is an integer of 0 and each q is an integer of 1. In certain embodiments, in Formula (XV) or Formula (XVI), each p is an integer of 1 and each q is an integer of 0.

[0163] In certain embodiments, in Formula (XV) or Formula (XVI), each p is an integer of 0, and each q is an integer of 2. In certain embodiments, in Formula (XV) or Formula (XVI), each p and q is an integer of 1. In certain embodiments, in Formula (XV) or Formula (XVI), each p is an integer of 2, and each q is an integer of 0.

[0164] In yet another embodiment, provided herein is a compound of formula (XVII): [ka]

[0165] (In the formula, R 1 , R 2 , R 3 , R 6a , R 6b , R 6c , R A , A, X, Y, and m are each as defined herein. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0166] In yet another embodiment, provided herein is a compound of formula (XVIII): [ka]

[0167] (In the formula, R 1 , R 2 , R 3 , R 6a , R 6b , R 6c , R A , A, X, Y, and m are each as defined herein. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0168] In certain embodiments, in any one of Formulas (XV) to (XVIII), each A is O. In certain embodiments, in any one of Formulas (XV) to (XVIII), each A is S. In certain embodiments, in any one of Formulas (XV) to (XVIII), each A is S(O). In certain embodiments, in any one of Formulas (XV) to (XVIII), each A is S(O2). In certain embodiments, in any one of Formulas (XV) to (XVIII), each A is independently N(R 4 )(wherein, R 4 is as defined herein). In certain embodiments, in any one of Formulas (XV) to (XVIII), each A is independently N(R 4 )(wherein, R 4is (i) hydrogen; (ii) C, each optionally substituted with one or more substituents Q; 1-6 Alkyl or C 1-6 heteroalkyl; or (iii) —C(O)R 1a (In the formula, R 1a is as defined herein). In certain embodiments, in any one of Formulas (XV) through (XVIII), each A is independently N(H), N(CH), or N(C(O)CH). In certain embodiments, in any one of Formulas (XV) through (XVIII), each A is N(H).

[0169] In yet another embodiment, provided herein is a compound of formula (XIX): [ka]

[0170] (In the formula, R 1 , R 2 , R 3 , R 6a , R 6b , R 6c , R A , X, Y, and m are each as defined herein. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0171] In yet another embodiment, provided herein is a compound of formula (XX): [ka]

[0172] (In the formula, R 1 , R 2 , R 3 , R 6a , R 6b , R 6c , R A, X, Y, and m are each as defined herein. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0173] In yet another embodiment, provided herein is a compound of formula (XXI): [ka]

[0174] (In the formula, R 1 , R 2 , R 3 , R 6a , R 6b , R 6c , R A , X, Y, and m are each as defined herein. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0175] In yet another embodiment, provided herein is a compound of formula (XXII): [ka]

[0176] (In the formula, R 1 , R 2 , R 3 , R 6a , R 6b , R 6c , R A , X, Y, and m are each as defined herein. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0177] In certain embodiments, in any one of Formulas (XV) to (XXII), each R 1 is independently hydrogen, deuterium, or halo. In certain embodiments, in any one of Formulas (XV) to (XXII), each R 1 is independently hydrogen, deuterium, or fluoro. In certain embodiments, in any one of Formulas (XV) through (XXII), each R 1 is independently hydrogen or fluoro. In certain embodiments, in any one of Formulas (XV) to (XXII), each R 1 is hydrogen. In certain embodiments, in any one of Formulas (XV) to (XXII), each R 1 is fluoro.

[0178] In certain embodiments, in any one of Formulas (XV) to (XXII), each R 2 are independently (i) hydrogen or deuterium; (ii) heterocyclyl optionally substituted with one or more substituents Q; or (iii) -NR 1b R 1c or -NR 1a C(O)R 1d (In the formula, R 1a , R 1b , R 1c , and R 1d and each are as defined herein. In certain embodiments, in any one of Formulas (XV) through (XXII), each R 2 is independently hydrogen, amino, methylamino, acetamido, or hydroxyacetamido. In certain embodiments, in any one of Formulas (XV) through (XXII), each R 2 is independently hydrogen or amino. In certain embodiments, in any one of Formulas (XV) to (XXII), each R 2is hydrogen. In certain embodiments, in any one of Formulas (XV) to (XXII), each R 2 is an amino.

[0179] In certain embodiments, in any one of Formulas (XV) to (XXII), each R 3 are independently C, each optionally substituted with one or more substituents Q; 1-6 Alkyl, C 1-6 Heteroalkyl, or C 2-6 In certain embodiments, in any one of Formulas (XV) to (XXII), each R 3 is independently methyl, fluoromethyl, methoxymethyl, or ethenyl. In certain embodiments, in any one of Formulas (XV) through (XXII), each R 3 is methyl.

[0180] In certain embodiments, in any one of Formulas (XVI) to (XXII), each R 6a is independently hydrogen or deuterium. In certain embodiments, in any one of Formulas (XVI) to (XXII), each R 6a is hydrogen.

[0181] In certain embodiments, in any one of Formulas (XVI) to (XXII), each R 6b is independently hydrogen, deuterium, or halo. In certain embodiments, in any one of Formulas (XVI) to (XXII), each R 6b is independently hydrogen, deuterium, or fluoro. In certain embodiments, in any one of Formulas (XVI) to (XXII), each R 6b is independently hydrogen or fluoro. In certain embodiments, in any one of Formulas (XVI) to (XXII), each R 6b is hydrogen. In certain embodiments, in any one of Formulas (XVI) to (XXII), each R 6b is fluoro.

[0182] In certain embodiments, in any one of Formulas (XVI) to (XXII), each R 6c is independently hydrogen or deuterium. In certain embodiments, in any one of Formulas (XVI) to (XXII), each R 6c is hydrogen.

[0183] In one embodiment, in any one of Formulas (XVI) to (XXII),

[0184] Each R 1 are independently hydrogen, deuterium, or halo;

[0185] Each R 2 are independently (i) hydrogen or deuterium; (ii) heterocyclyl optionally substituted with one or more substituents Q; or (iii) -NR 1b R 1c or -NR 1a C(O)R 1d ;(In the formula, R 1a , R 1b , R 1c , and R 1d are each as defined herein);

[0186] Each R 3 are independently C, each optionally substituted with one or more substituents Q; 1-6 Alkyl, C 1-6 Heteroalkyl, or C 2-6 is alkenyl;

[0187] Each R 6a and R 6c are independently hydrogen or deuterium; and

[0188] Each R 6b is independently hydrogen or halo.

[0189] In one embodiment, in any one of Formulas (XVI) to (XXII),

[0190] Each R 1are independently hydrogen, deuterium, or fluoro;

[0191] Each R 2 are independently hydrogen, amino, methylamino, acetamido, or hydroxyacetamido;

[0192] Each R 3 is independently methyl, fluoromethyl, hydroxymethyl, or ethenyl;

[0193] Each R 6a and R 6c is hydrogen; and

[0194] Each R 6b is independently hydrogen or fluoro.

[0195] In one embodiment, in any one of Formulas (XVI) to (XXII),

[0196] Each R 1 are independently hydrogen or fluoro;

[0197] Each R 2 are independently hydrogen or amino;

[0198] Each R 3 is methyl;

[0199] Each R 6a and R 6c is hydrogen; and

[0200] Each R 6b is independently hydrogen or fluoro.

[0201] In one embodiment, in any one of Formulas (XVI) to (XXII),

[0202] Each R 1 are independently hydrogen or fluoro;

[0203] Each R 2 is hydrogen;

[0204] Each R 3 is methyl;

[0205] Each R 6a and R 6c is hydrogen; and

[0206] Each R 6b is independently hydrogen or fluoro.

[0207] In one embodiment, R A is a full-length or intact monoclonal antibody. A is a monoclonal antibody or antigen-binding fragment thereof. A is a single domain antibody or antigen-binding fragment thereof. A is V H In yet another embodiment, the R A is V NAR It is an antibody.

[0208] In one embodiment, R A is a human, humanized, or chimeric antibody, or an antigen-binding fragment thereof. A is a human antibody or antigen-binding fragment thereof. A is a humanized antibody or antigen-binding fragment thereof. A is a chimeric antibody or antigen-binding fragment thereof.

[0209] In one embodiment, R A is an IgA, IgD, IgE, IgG, or IgM antibody, or an antigen-binding fragment thereof. A is an IgA antibody or antigen-binding fragment thereof. A is an IgD antibody or antigen-binding fragment thereof. Ais an IgE antibody or antigen-binding fragment thereof. A is an IgG antibody or antigen-binding fragment thereof. A is an IgM antibody or antigen-binding fragment thereof.

[0210] In one embodiment, R A is an IgA1, IgA2, IgG1, IgG2, IgG3, or IgG4 antibody, or an antigen-binding fragment thereof. A is IgA1 or IgA2, or an antigen-binding fragment thereof. A is IgA1 or an antigen-binding fragment thereof. A is IgA2 or an antigen-binding fragment thereof. A is an IgG1, IgG2, IgG3, or IgG4 antibody, or an antigen-binding fragment thereof. A is an IgG1 antibody or an antigen-binding fragment thereof. A is an IgG2 antibody or an antigen-binding fragment thereof. A is an IgG3 antibody or antigen-binding fragment thereof. A is an IgG4 antibody or an antigen-binding fragment thereof.

[0211] In one embodiment, R A is a single chain variable fragment (scFv), Fab, Fab', F(ab)2, F(ab')2, Fv, diabody, triabody, tetrabody, or minibody of an antibody provided herein. A is an scFv of an antibody provided herein. A is the Fab of the antibody provided herein. A is the Fab' of the antibody provided herein. Ais the F(ab)2 of the antibody provided herein. In yet another embodiment, R A is the F(ab')2 of an antibody provided herein. In yet another embodiment, R A is the Fv of the antibody provided herein. A is a diabody of the antibodies provided herein. In yet another embodiment, R A is a triabody of the antibodies provided herein. In yet another embodiment, R A is a tetrabody of the antibodies provided herein. In yet another embodiment, R A is an antibody minibody provided herein.

[0212] In one embodiment, R A is a fucosylated antibody or antigen-binding fragment thereof.

[0213] In one embodiment, R A is a recombinant antibody or antigen-binding fragment thereof. A is a purified antibody or antigen-binding fragment thereof. A is an isolated antibody or antigen-binding fragment thereof.

[0214] In some embodiments, R Ais an antibody or antigen-binding fragment thereof, wherein the antibody binds to AXL, B7 homolog 3 (B7H3), B-cell maturation antigen (BCMA), cadherin 3, cadherin 6, CanAg, carbonic anhydrase VI (CA6), C4-4A, carcinoembryonic antigen-related cell adhesion molecule (CEACAM), CD19, CD20, CD22, CD25, CD30, CD33, CD37, CD44, CD56, CD70, CD74, CD79b, CD123, CD138, CD142, CD352, crypto-1 growth factor, delta-like 3 (DLL3), ectonucleotide pyrophosphatase / phosphor-diesterase family member 3 (ENPP3), endothelin receptor type B (ETBR), EPH receptor A2 (EPHA2), ephrin A4 , epidermal growth factor receptor (EGFR), FMS-like tyrosine kinase 3 (FLT3), fibroblast growth factor receptor 2 (FGFR2), fibroblast growth factor receptor 3 (FGFR3), folate receptor 1 (FOLR1 or FRα), guanylate cyclase 2C (GCC), hepatocyte growth factor receptor (HGFR), HER2, HER3, integrin αV, KIT, Lewis Y antigen, LIV-1, lymphocyte antigen 6E (LY6E), lysosome-associated membrane protein 1 (LAMP-1), mesothelin (MSLN), mucin 1 (MUC1), mucin-16 (MUC16), nectin-4, notch receptor 3 (notch3), osteoactivin, prostate-specific membrane antigen (PSMA), six-transmembrane epithelial antigen of the prostate 1 (STEAP1), SLAM family members It specifically binds to SLAMF7, SLITRK6, ST2, sodium-dependent phosphate transporter protein 2B (SLC34A2), T-cell immunoglobulin and mucin domain 1 (TIM-1), transferrin receptor protein 1, tumor-associated calcium signal transducer 2 (TROP2), or tyrosine-protein kinase-like 7 (PTK7).

[0215] In some embodiments, R A is an anti-B7H3 antibody, an anti-CD20 antibody, an anti-FOLR1 antibody, an anti-HER2 antibody, an anti-MSLN antibody, an anti-TROP2 antibody, or an antigen-binding fragment thereof. Ais an anti-B7H3 antibody or antigen-binding fragment thereof. In certain embodiments, R A is an anti-CD20 antibody or antigen-binding fragment thereof. In certain embodiments, R A is an anti-FOLR1 antibody or an antigen-binding fragment thereof. In certain embodiments, R A is an anti-HER2 antibody or antigen-binding fragment thereof. In certain embodiments, R A is an anti-MSLN antibody or antigen-binding fragment thereof. In one embodiment, R A is an anti-TROP2 antibody or an antigen-binding fragment thereof.

[0216] In one embodiment, R A is an anti-B7H3 single domain antibody or antigen-binding fragment thereof, wherein the antibody comprises (i) chain complementarity determining region 1 (CDR1) of SEQ ID NO: 1; (ii) chain complementarity determining region 2 (CDR2) of SEQ ID NO: 2; and (iii) chain complementarity determining region 3 (CDR3) of SEQ ID NO: 3. In certain embodiments, the CDRs provided herein are defined according to the IMGT or Kabat numbering system. In certain embodiments, the CDRs provided herein are defined according to the IMGT numbering system. In certain embodiments, the CDRs provided herein are defined according to the Kabat numbering system. In another embodiment, R A is an anti-B7H3 single domain antibody or antigen-binding fragment thereof, wherein the antibody comprises the variable region of SEQ ID NO:4. A is an anti-B7H3 single domain antibody or antigen-binding fragment thereof, wherein the antibody comprises the amino acid sequence of SEQ ID NO:5.

[0217] In one embodiment, R Ais an anti-B7H3 single domain antibody or antigen-binding fragment thereof, wherein the antibody comprises (i) CDR1 of SEQ ID NO:6; (ii) CDR2 of SEQ ID NO:7; and (iii) CDR3 of SEQ ID NO:8. In certain embodiments, the CDRs provided herein are defined according to the IMGT or Kabat numbering system. In certain embodiments, the CDRs provided herein are defined according to the IMGT numbering system. In certain embodiments, the CDRs provided herein are defined according to the Kabat numbering system. In another embodiment, R A is an anti-B7H3 single domain antibody or antigen-binding fragment thereof, wherein the antibody comprises the variable region of SEQ ID NO:9. A is an anti-B7H3 single domain antibody or antigen-binding fragment thereof, wherein the antibody comprises the amino acid sequence of SEQ ID NO:10.

[0218] In one embodiment, R A is an anti-CD20 antibody or antigen-binding fragment thereof, wherein the antibody comprises (i) light chain complementarity determining region 1 (CDRL1) of SEQ ID NO: 11; (ii) light chain complementarity determining region 2 (CDRL2) of SEQ ID NO: 12; (iii) light chain complementarity determining region 3 (CDRL3) of SEQ ID NO: 13; (iv) heavy chain complementarity determining region 1 (CDRH1) of SEQ ID NO: 14; (v) heavy chain complementarity determining region 2 (CDRH2) of SEQ ID NO: 15; and (vi) heavy chain complementarity determining region 3 (CDRH3) of SEQ ID NO: 16. In certain embodiments, the CDRs provided herein are defined according to the IMGT or Kabat numbering system. In certain embodiments, the CDRs provided herein are defined according to the IMGT numbering system. In certain embodiments, the CDRs provided herein are defined according to the Kabat numbering system. In another embodiment, R A is an anti-CD20 antibody or antigen-binding fragment thereof, wherein the antibody comprises (i) a light chain variable region of SEQ ID NO: 17; and (ii) a heavy chain variable region of SEQ ID NO: 18. In yet another embodiment, R Ais an anti-CD20 antibody or antigen-binding fragment thereof, wherein the antibody comprises (i) a light chain of SEQ ID NO:19; and (ii) a heavy chain of SEQ ID NO:20.

[0219] In one embodiment, R A is an anti-FOLR1 antibody or antigen-binding fragment thereof, wherein the antibody comprises (i) a CDRL1 of SEQ ID NO: 21; (ii) a CDRL2 of SEQ ID NO: 22; (iii) a CDRL3 of SEQ ID NO: 23; (iv) a CDRH1 of SEQ ID NO: 24; (v) a CDRH2 of SEQ ID NO: 25; and (vi) a CDRH3 of SEQ ID NO: 26. In certain embodiments, the CDRs provided herein are defined according to the IMGT or Kabat numbering system. In certain embodiments, the CDRs provided herein are defined according to the IMGT numbering system. In certain embodiments, the CDRs provided herein are defined according to the Kabat numbering system. In another embodiment, R A is an anti-FOLR1 antibody or antigen-binding fragment thereof, wherein the antibody comprises (i) a light chain variable region of SEQ ID NO: 27; and (ii) a heavy chain variable region of SEQ ID NO: 28. In yet another embodiment, R A is an anti-FOLR1 antibody or antigen-binding fragment thereof, wherein the antibody comprises (i) a light chain of SEQ ID NO:29; and (ii) a heavy chain of SEQ ID NO:30.

[0220] In one embodiment, R A is an anti-HER2 antibody or antigen-binding fragment thereof, wherein the antibody comprises (i) a CDRL1 of SEQ ID NO: 31; (ii) a CDRL2 of SEQ ID NO: 32; (iii) a CDRL3 of SEQ ID NO: 33; (iv) a CDRH1 of SEQ ID NO: 34; (v) a CDRH2 of SEQ ID NO: 35; and (vi) a CDRH3 of SEQ ID NO: 36. In certain embodiments, the CDRs provided herein are defined according to the IMGT or Kabat numbering system. In certain embodiments, the CDRs provided herein are defined according to the IMGT numbering system. In certain embodiments, the CDRs provided herein are defined according to the Kabat numbering system. In another embodiment, R Ais an anti-HER2 antibody or antigen-binding fragment thereof, wherein the antibody comprises (i) a light chain variable region of SEQ ID NO: 37; and (ii) a heavy chain variable region of SEQ ID NO: 38. In yet another embodiment, R A is an anti-HER2 antibody or antigen-binding fragment thereof, wherein the antibody comprises: (i) a light chain of SEQ ID NO:39; and (ii) a heavy chain of SEQ ID NO:40.

[0221] In one embodiment, R A is an anti-MSLN single domain antibody or antigen-binding fragment thereof, wherein the antibody comprises (i) CDR1 of SEQ ID NO: 41; (ii) CDR2 of SEQ ID NO: 42; and (iii) CDR3 of SEQ ID NO: 43. In certain embodiments, the CDRs provided herein are defined according to the IMGT or Kabat numbering system. In certain embodiments, the CDRs provided herein are defined according to the IMGT numbering system. In certain embodiments, the CDRs provided herein are defined according to the Kabat numbering system. In another embodiment, R A is an anti-MSLN single domain antibody or antigen-binding fragment thereof, wherein the antibody comprises the variable region of SEQ ID NO: 44. A is an anti-MSLN single domain antibody or antigen-binding fragment thereof, wherein the antibody comprises the amino acid sequence of SEQ ID NO:45.

[0222] In one embodiment, R A is an anti-MSLN single domain antibody or antigen-binding fragment thereof, wherein the antibody comprises (i) CDR1 of SEQ ID NO: 46; (ii) CDR2 of SEQ ID NO: 47; and (iii) CDR3 of GRY. In certain embodiments, the CDRs provided herein are defined according to the IMGT or Kabat numbering system. In certain embodiments, the CDRs provided herein are defined according to the IMGT numbering system. In certain embodiments, the CDRs provided herein are defined according to the Kabat numbering system. In another embodiment, R Ais an anti-MSLN single domain antibody or antigen-binding fragment thereof, wherein the antibody comprises the variable region of SEQ ID NO: 48. In yet another embodiment, R A is an anti-MSLN single domain antibody or antigen-binding fragment thereof, wherein the antibody comprises the amino acid sequence of SEQ ID NO:49.

[0223] Additional anti-MSLN single domain antibodies and antigen-binding fragments thereof include those disclosed in WO2019 / 246003A1, the disclosure of which is incorporated herein by reference in its entirety.

[0224] In one embodiment, R A is an anti-TROP2 antibody or antigen-binding fragment thereof, wherein the antibody comprises (i) a CDRL1 of SEQ ID NO: 50; (ii) a CDRL2 of SEQ ID NO: 51; (iii) a CDRL3 of SEQ ID NO: 52; (iv) a CDRH1 of SEQ ID NO: 53; (v) a CDRH2 of SEQ ID NO: 54; and (vi) a CDRH3 of SEQ ID NO: 55. In certain embodiments, the CDRs provided herein are defined according to the IMGT or Kabat numbering system. In certain embodiments, the CDRs provided herein are defined according to the IMGT numbering system. In certain embodiments, the CDRs provided herein are defined according to the Kabat numbering system. In another embodiment, R A is an anti-TROP2 antibody or antigen-binding fragment thereof, wherein the antibody comprises (i) a light chain variable region of SEQ ID NO: 56; and (ii) a heavy chain variable region of SEQ ID NO: 57. In yet another embodiment, R A is an anti-TROP2 antibody or antigen-binding fragment thereof, wherein the antibody comprises (i) a light chain of SEQ ID NO:58; and (ii) a heavy chain of SEQ ID NO:59.

[0225] In one embodiment, R Ais an anti-CD79b antibody or antigen-binding fragment thereof, wherein the antibody comprises (i) a CDRL1 of SEQ ID NO: 60; (ii) a CDRL2 of SEQ ID NO: 61; (iii) a CDRL3 of SEQ ID NO: 62; (iv) a CDRH1 of SEQ ID NO: 63; (v) a CDRH2 of SEQ ID NO: 64; and (vi) a CDRH3 of SEQ ID NO: 65. In certain embodiments, the CDRs provided herein are defined according to the IMGT or Kabat numbering system. In certain embodiments, the CDRs provided herein are defined according to the IMGT numbering system. In certain embodiments, the CDRs provided herein are defined according to the Kabat numbering system. In another embodiment, R A is an anti-TROP2 antibody or antigen-binding fragment thereof, wherein the antibody comprises (i) a light chain variable region of SEQ ID NO: 66; and (ii) a heavy chain variable region of SEQ ID NO: 67. In yet another embodiment, R A is an anti-TROP2 antibody or antigen-binding fragment thereof, wherein the antibody comprises (i) a light chain of SEQ ID NO:68; and (ii) a heavy chain of SEQ ID NO:69.

[0226] In one embodiment, R A is an anti-CD79b antibody or antigen-binding fragment thereof, wherein the antibody comprises (i) a CDRL1 of SEQ ID NO: 70; (ii) a CDRL2 of SEQ ID NO: 71; (iii) a CDRL3 of SEQ ID NO: 72; (iv) a CDRH1 of SEQ ID NO: 73; (v) a CDRH2 of SEQ ID NO: 74; and (vi) a CDRH3 of SEQ ID NO: 75. In certain embodiments, the CDRs provided herein are defined according to the IMGT or Kabat numbering system. In certain embodiments, the CDRs provided herein are defined according to the IMGT numbering system. In certain embodiments, the CDRs provided herein are defined according to the Kabat numbering system. In another embodiment, R A is an anti-TROP2 antibody or antigen-binding fragment thereof, wherein the antibody comprises (i) a light chain variable region of SEQ ID NO: 76; and (ii) a heavy chain variable region of SEQ ID NO: 77. In yet another embodiment, R Ais an anti-TROP2 antibody or antigen-binding fragment thereof, wherein the antibody comprises (i) a light chain of SEQ ID NO:78; and (ii) a heavy chain of SEQ ID NO:79.

[0227] In one embodiment, L is a cleavable linker. In another embodiment, L is a non-cleavable linker.

[0228] In certain embodiments, L is a cleavable linker that is sensitive to acidic pH. In certain embodiments, L is a cleavable linker comprising a reducible disulfide. In certain embodiments, L is a linker cleavable by glutathione. In certain embodiments, L is a linker cleavable by an enzyme. In certain embodiments, L is a linker cleavable by a protease. In certain embodiments, L is a linker cleavable by a lysosomal protease. In certain embodiments, L is a linker cleavable by cathepsin B. In certain embodiments, L is a linker cleavable by a glycosidase. In certain embodiments, L is a linker cleavable by a β-glycosidase. In certain embodiments, L is a linker cleavable by a galactosidase. In certain embodiments, L is a linker cleavable by a β-galactosidase. In certain embodiments, L is a linker cleavable by a glucuronidase. In certain embodiments, L is a linker cleavable by a β-glucuronidase. In some embodiments, L is a linker that can be cleaved by phosphatase.Exemplary linkers suitable for the compounds provided herein include but are not limited to those disclosed in Beck et al., Nat. Rev. Drug Discov. 2017, 16, 317-37; Bargh et al., Chem. Soc. Rev. 2019, 48, 4361-74, the disclosures of each of which are incorporated herein by reference in their entirety.

[0229] In certain embodiments, L is selected from the group consisting of C, each optionally substituted with one or more substituents Q. 1-50 Alkylene, C 1-50 Heteroalkylene, C 2-50 Alkenylene, C 2-50 Heteroalkenylene, C 2-50 Alkynylene, C 2-50 Heteroalkynylene, C 3-10 Cycloalkylene, C 6-14 In certain embodiments, L is arylene, heteroarylene, or heterocyclylene. 1-50 Alkylene, C 1-50 Heteroalkylene, C 2-50 Alkenylene, C 2-50 Heteroalkenylene, C 2-50 Alkynylene, or C 2-50 In certain embodiments, L is heteroalkynylene. 1-50 Alkylene or C 1-50 It is heteroalkylene.

[0230] In certain embodiments, L is C optionally substituted with one or more substituents Q. 1-50 In some embodiments, L is C optionally substituted with one or more substituents Q. 1-40 In some embodiments, L is C optionally substituted with one or more substituents Q. 1-30 In some embodiments, L is C optionally substituted with one or more substituents Q. 1-20 In some embodiments, L is C optionally substituted with one or more substituents Q. 2-16 In some embodiments, L is C optionally substituted with one or more substituents Q. 2-12 In some embodiments, L is C optionally substituted with one or more substituents Q. 2-6 In some embodiments, L is C optionally substituted with one or two oxo. 1-20In some embodiments, L is C optionally substituted with one or two oxo. 2-16 In some embodiments, L is C optionally substituted with one or two oxo. 2-12 In some embodiments, L is C optionally substituted with one or two oxo. 2-6 In certain embodiments, L is -(CH) optionally substituted with one or two oxo groups. u -; where u is an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16. In certain embodiments, L is -(CH) optionally substituted with one or two oxo. u -; where u is an integer of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12. In certain embodiments, L is -(CH) optionally substituted with one or two oxo. u -; (wherein r is an integer of 2, 3, 4, 5, or 6).

[0231] In certain embodiments, L is C optionally substituted with one or more substituents Q. 1-50 In some embodiments, L is a C optionally substituted with one or more substituents Q. 1-40 In some embodiments, L is a C optionally substituted with one or more substituents Q. 1-30 In some embodiments, L is a C optionally substituted with one or more substituents Q. 1-20 In some embodiments, L is a C optionally substituted with one or more substituents Q. 2-16 In certain embodiments, L is a C2- optionally substituted with one or more substituents Q. 12 In some embodiments, L is C heteroalkylene optionally substituted with one or more substituents Q. In some embodiments, L is C heteroalkylene optionally substituted with one, two, or three oxo. 1-20In some embodiments, L is C optionally substituted with 1, 2, or 3 oxo. 2-16 In some embodiments, L is C optionally substituted with 1, 2, or 3 oxo. 2-12 In some embodiments, L is C optionally substituted with 1, 2, or 3 oxo. 2-6 It is heteroalkylene.

[0232] In certain embodiments, L is a C 1 -C 2 -C ... 2-50 In some embodiments, L is a C 1 -containing ethyleneoxy group, optionally substituted with one or more substituents Q. 2-40 In some embodiments, L is a C 1 -containing ethyleneoxy group, optionally substituted with one or more substituents Q. 2-30 In some embodiments, L is a C 1 -containing ethyleneoxy group, optionally substituted with one or more substituents Q. 2-20 In some embodiments, L is a C 1 -containing ethyleneoxy group, optionally substituted with one or more substituents Q. 2-14 In some embodiments, L is a C 1 -containing ethyleneoxy group, optionally substituted with one or more substituents Q. 2-10 In some embodiments, L is a C 1 -containing ethyleneoxy group, optionally substituted with one or more substituents Q. 2-6 It is heteroalkylene.

[0233] In certain embodiments, L is a C 1 -C 2 -C ...1 -C 1 -C 1 -C 1 -C 1 -C 1 -C 1 -C 1 -C 1 - 3-50 In some embodiments, L is a C 1 -containing propyleneoxy group, optionally substituted with one or more substituents Q. 3-40 In some embodiments, L is a C 1 -containing propyleneoxy group, optionally substituted with one or more substituents Q. 3-30In some embodiments, L is a C 1 -containing propyleneoxy group, optionally substituted with one or more substituents Q. 3-20 In some embodiments, L is a C 1 -containing propyleneoxy group, optionally substituted with one or more substituents Q. 3-14 In some embodiments, L is a C 1 -containing propyleneoxy group, optionally substituted with one or more substituents Q. 3-10 It is heteroalkylene.

[0234] In certain embodiments, L is C 1-50 Alkylene, C 1-50 Heteroalkylene, C 2-50 Alkenylene, C 2-50 Heteroalkenylene, C 2-50 Alkynylene, or C 2-50 heteroalkynylene, wherein one or more methylene groups are each independently replaced by a divalent radical; and wherein each divalent radical is independently selected from the group consisting of C 3-10 Cycloalkylene, C 6-14 and wherein the alkylene, heteroalkylene, alkenylene, heteroalkenylene, alkynylene, heteroalkynylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q. In certain embodiments, L is C 1-50 Alkylene or C 1-50 heteroalkylene, wherein one or more methylene groups are each independently replaced by a divalent radical; and wherein each divalent radical is independently selected from the group consisting of C 3-10 Cycloalkylene, C 6-14 and wherein the alkylene, heteroalkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q.

[0235] In certain embodiments, L is C 1-50alkylene, wherein one or more methylene groups are each independently replaced by a divalent group; and wherein each divalent group is independently selected from the group consisting of C 3-10 Cycloalkylene, C 6-14 and wherein the alkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q. In certain embodiments, L is C 1-40 alkylene, wherein one or more methylene groups are each independently replaced by a divalent group; and wherein each divalent group is independently selected from the group consisting of C 3-10 Cycloalkylene, C 6-14 and wherein the alkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q. In certain embodiments, L is C 1-30 alkylene, wherein one or more methylene groups are each independently replaced by a divalent group; and wherein each divalent group is independently selected from the group consisting of C 3-10 Cycloalkylene, C 6-14 and wherein the alkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q. In certain embodiments, L is C 1-20 alkylene, wherein one or more methylene groups are each independently replaced by a divalent group; and wherein each divalent group is independently selected from the group consisting of C 3-10 Cycloalkylene, C 6-14 arylene, heteroarylene, or heterocyclylene; and wherein the alkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q.

[0236] In certain embodiments, L is C 1-50alkylene, wherein one, two, three, or four methylene groups are each independently replaced by a divalent radical; and wherein each divalent radical is independently selected from the group consisting of C 3-10 Cycloalkylene, C 6-14 and wherein the alkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q. In certain embodiments, L is C 1-40 alkylene, wherein one, two, three, or four methylene groups are each independently replaced by a divalent radical; and wherein each divalent radical is independently selected from the group consisting of C 3-10 Cycloalkylene, C 6-14 and wherein the alkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q. In certain embodiments, L is C 1-30 alkylene, wherein one, two, three, or four methylene groups are each independently replaced by a divalent radical; and wherein each divalent radical is independently selected from the group consisting of C 3-10 Cycloalkylene, C 6-14 and wherein the alkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q. In certain embodiments, L is C 1-20 alkylene, wherein one, two, three, or four methylene groups are each independently replaced by a divalent radical; and wherein each divalent radical is independently selected from the group consisting of C 3-10 Cycloalkylene, C 6-14 and wherein the alkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q. In certain embodiments, L is C 1-20In certain embodiments, L is alkylene, wherein one, two, three, or four methylene groups are each independently replaced by a divalent group; and wherein each divalent group is independently cyclohexanediyl, phendiyl, triazoldiyl, or 2,5-dioxopyrrolidinediyl. 1-20 alkylene, wherein one, two, three, or four methylene groups are each independently replaced by a divalent group; and wherein each divalent group is independently cyclohexane-1,4-diyl, phen-1,3-diyl, phen-1,4-diyl, 1,2,3-triazole-1,4-diyl, or 2,5-dioxopyrrolidine-1,3-diyl.

[0237] In certain embodiments, L is C 1-20 alkylene, wherein one or two methylene groups are each independently replaced by a divalent radical; and wherein each divalent radical is independently selected from C 3-10 Cycloalkylene, C 6-14 and wherein the alkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q. In certain embodiments, L is C 1-20 In some embodiments, L is alkylene, wherein one or two methylene groups are each independently replaced by a divalent group; and wherein each divalent group is independently cyclohexanediyl, phendiyl, triazoldiyl, or 2,5-dioxopyrrolidinediyl. 1-20 alkylene, wherein one or two methylene groups are each independently replaced by a divalent group; and wherein each divalent group is independently cyclohexane-1,4-diyl, phen-1,3-diyl, phen-1,4-diyl, 1,2,3-triazole-1,4-diyl, or 2,5-dioxopyrrolidine-1,3-diyl.

[0238] In certain embodiments, L is C 1-20alkylene, wherein a methylene group is replaced by a divalent radical; and wherein the divalent radical is C 3-10 Cycloalkylene, C 6-14 and wherein the alkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q. In certain embodiments, L is C 1-20 In certain embodiments, L is alkylene, wherein a methylene group is replaced by a divalent group; and wherein the divalent group is cyclohexanediyl, phendiyl, triazoldiyl, or 2,5-dioxopyrrolidinediyl. 1-20 alkylene, wherein a methylene group is replaced by a divalent group; and wherein each divalent group is independently cyclohexane-1,4-diyl, phen-1,3-diyl, phen-1,4-diyl, 1,2,3-triazole-1,4-diyl, or 2,5-dioxopyrrolidine-1,3-diyl.

[0239] In certain embodiments, L is C 1-50 heteroalkylene, wherein one or more methylene groups are each independently replaced by a divalent radical; and wherein each divalent radical is independently selected from the group consisting of C 3-10 Cycloalkylene, C 6-14 and wherein the heteroalkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q. In certain embodiments, L is C 1-40 heteroalkylene, wherein one or more methylene groups are each independently replaced by a divalent radical; and wherein each divalent radical is independently selected from the group consisting of C 3-10 Cycloalkylene, C 6-14and wherein the heteroalkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q. In certain embodiments, L is C 1-30 heteroalkylene, wherein one or more methylene groups are each independently replaced by a divalent radical; and wherein each divalent radical is independently selected from the group consisting of C 3-10 Cycloalkylene, C 6-14 and wherein the heteroalkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q. In certain embodiments, L is C 1-20 heteroalkylene, wherein one or more methylene groups are each independently replaced by a divalent radical; and wherein each divalent radical is independently selected from the group consisting of C 3-10 Cycloalkylene, C 6-14 arylene, heteroarylene, or heterocyclylene; and wherein the heteroalkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q.

[0240] In certain embodiments, L is C 1-50 heteroalkylene, wherein one, two, three, or four methylene groups are each independently replaced by a divalent radical; and wherein each divalent radical is independently selected from the group consisting of C 3-10 Cycloalkylene, C 6-14 and wherein the heteroalkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q. In certain embodiments, L is C 1-40 heteroalkylene, wherein one, two, three, or four methylene groups are each independently replaced by a divalent radical; and wherein each divalent radical is independently selected from the group consisting of C 3-10Cycloalkylene, C 6-14 and wherein the heteroalkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q. In certain embodiments, L is C 1-30 heteroalkylene, wherein one, two, three, or four methylene groups are each independently replaced by a divalent radical; and wherein each divalent radical is independently selected from the group consisting of C 3-10 Cycloalkylene, C 6-14 and wherein the heteroalkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q. In certain embodiments, L is C 1-20 heteroalkylene, wherein one, two, three, or four methylene groups are each independently replaced by a divalent radical; and wherein each divalent radical is independently selected from the group consisting of C 3-10 Cycloalkylene, C 6-14 and wherein the heteroalkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q. In certain embodiments, L is C 1-20 In certain embodiments, L is heteroalkylene, wherein one, two, three, or four methylene groups are each independently replaced by a divalent group; and wherein each divalent group is independently cyclohexanediyl, phendiyl, triazoldiyl, or 2,5-dioxopyrrolidinediyl. In certain embodiments, L is C 1-20 Heteroalkylene, wherein one, two, three, or four methylene groups are each independently replaced by a divalent group; and wherein each divalent group is independently cyclohexane-1,4-diyl, phen-1,3-diyl, phen-1,4-diyl, 1,2,3-triazole-1,4-diyl, or 2,5-dioxopyrrolidine-1,3-diyl.

[0241] In certain embodiments, L is C 1-20 heteroalkylene, wherein one or two methylene groups are each independently replaced by a divalent radical; and wherein each divalent radical is independently selected from C 3-10 Cycloalkylene, C 6-14 and wherein the heteroalkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q. In certain embodiments, L is C 1-20 In some embodiments, L is heteroalkylene, wherein one or two methylene groups are each independently replaced by a divalent group; and wherein each divalent group is independently cyclohexanediyl, phendiyl, triazoldiyl, or 2,5-dioxopyrrolidinediyl. 1-20 Heteroalkylene, wherein one or two methylene groups are each independently replaced by a divalent group; and wherein each divalent group is independently cyclohexane-1,4-diyl, phen-1,3-diyl, phen-1,4-diyl, 1,2,3-triazole-1,4-diyl, or 2,5-dioxopyrrolidine-1,3-diyl.

[0242] In certain embodiments, L is C 1-20 heteroalkylene, wherein a methylene group is replaced by a divalent radical; and wherein the divalent radical is C 3-10 Cycloalkylene, C 6-14 and wherein the heteroalkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q. In certain embodiments, L is C 1-20In certain embodiments, L is heteroalkylene, wherein a methylene group is replaced by a divalent group; and wherein the divalent group is cyclohexanediyl, phendiyl, triazoldiyl, or 2,5-dioxopyrrolidinediyl. 1-20 Heteroalkylene in which a methylene group is replaced by a divalent group; and in which each divalent group is independently cyclohexane-1,4-diyl, phen-1,3-diyl, phen-1,4-diyl, 1,2,3-triazole-1,4-diyl, or 2,5-dioxopyrrolidine-1,3-diyl.

[0243] In certain embodiments, L is C 1-40 Alkylene-C 3-10 Cycloalkylene, C 1-40 Heteroalkylene-C 3-10 Cycloalkylene, C 1-40 Alkylene-C 6-14 Arylene, C 1-40 Heteroalkylene-C 6-14 Arylene, C 1-40 Alkylene-heteroarylene, C 1-40 Heteroalkylene-heteroarylene, C 1-40 Alkylene-heterocyclylene, C 1-40 In certain embodiments, L is a heteroalkylene-heterocyclylene or heteroarylene-heterocyclylene, where each alkylene, heteroalkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene is optionally substituted with one or more substituents Q. In certain embodiments, L is C 1-40 Alkylene-C 3-10 In certain embodiments, L is C 1-40 Heteroalkylene-C 3-10 In certain embodiments, L is C 1-40 Alkylene-C 6-14In certain embodiments, L is C 1-40 Heteroalkylene-C 6-14 In certain embodiments, L is C 1-40 In certain embodiments, L is an alkylene-heteroarylene group, wherein the alkylene and heteroarylene are each optionally substituted with one or more substituents Q. In certain embodiments, L is C 1-40 In certain embodiments, L is a heteroalkylene-heteroarylene, wherein the heteroalkylene and heteroarylene are each optionally substituted with one or more substituents Q. In certain embodiments, L is C 1-40 In certain embodiments, L is an alkylene-heterocyclylene, wherein the alkylene and heterocyclylene are each optionally substituted with one or more substituents Q. In certain embodiments, L is C 1-40 In certain embodiments, L is a heteroalkylene-heterocyclylene, wherein the heteroalkylene and heterocyclylene are each optionally substituted with one or more substituents Q. In certain embodiments, L is C 1-40 heteroarylene-heterocyclylene, where the heteroarylene and heterocyclylene are each optionally substituted with one or more substituents Q.

[0244] In some embodiments, L is: [ka] is.

[0245] In some embodiments, L is: [ka] is.

[0246] In some embodiments, L is: [ka]

[0247] wherein, in one embodiment, each R 6b is independently hydrogen or halo; in another embodiment, each R 6b is independently hydrogen or fluoro; in yet another embodiment, each R 6b is hydrogen; and in yet another embodiment, each R 6b is fluoro) is.

[0248] In some embodiments, L is: [ka]

[0249] wherein, in one embodiment, each R 6b is independently hydrogen or halo; in another embodiment, each R 6b is independently hydrogen or fluoro; in yet another embodiment, each R 6b is hydrogen; and in yet another embodiment, each R 6b is fluoro) is.

[0250] In some embodiments, L is: [ka]

[0251] wherein, in one embodiment, each R 6b is independently hydrogen or halo; in another embodiment, each R 6b is independently hydrogen or fluoro; in yet another embodiment, each R 6b is hydrogen; and in yet another embodiment, each R 6b is fluoro; and in one embodiment, each u is independently an integer of 1, 2, 3, 4, 5, 6, 7, or 8; in another embodiment, each u is independently an integer of 4 or 8. is.

[0252] In some embodiments, L is: [ka]

[0253] wherein, in one embodiment, each R 6b is independently hydrogen or halo; in another embodiment, each R 6b is independently hydrogen or fluoro; in yet another embodiment, each R 6b is hydrogen; and in yet another embodiment, each R 6b is fluoro) is.

[0254] In some embodiments, L is: [ka]

[0255] wherein, in one embodiment, each R 6b is independently hydrogen or halo; in another embodiment, each R 6b is independently hydrogen or fluoro; in yet another embodiment, each R 6b is hydrogen; and in yet another embodiment, each R 6b is fluoro) is.

[0256] In some embodiments, L is: [ka]

[0257] wherein, in one embodiment, each R 6b is independently hydrogen or halo; in another embodiment, each R 6b is independently hydrogen or fluoro; in yet another embodiment, each R 6b is hydrogen; and in yet another embodiment, each R 6b is fluoro) is.

[0258] In some embodiments, L is: [ka]

[0259] wherein, in one embodiment, each R 6b is independently hydrogen or halo; in another embodiment, each R 6b is independently hydrogen or fluoro; in yet another embodiment, each R 6b is hydrogen; and in yet another embodiment, each R 6b is fluoro) is.

[0260] In some embodiments, L is: [ka]

[0261] wherein, in one embodiment, each R 6b is independently hydrogen or halo; in another embodiment, each R 6b is independently hydrogen or fluoro; in yet another embodiment, each R 6b is hydrogen; and in yet another embodiment, each R 6b is fluoro) is.

[0262] In some embodiments, L is: [ka]

[0263] wherein, in one embodiment, each R 6b is independently hydrogen or halo; in another embodiment, each R 6b is independently hydrogen or fluoro; in yet another embodiment, each R 6b is hydrogen; and in yet another embodiment, each R6b is fluoro; and in one embodiment, each u is independently an integer of 1, 2, 3, 4, 5, 6, 7, or 8; in another embodiment, each u is independently an integer of 4 or 8. is.

[0264] In one embodiment, each [ka] The parts are independent, [ka] is.

[0265] In one embodiment, each [ka] The parts are independent, [ka] is.

[0266] In one embodiment, provided herein is a compound of formula (IA): [ka]

[0267] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof. (In the formula:

[0268] A is O, S, S(O), S(O2), or N(R 4 ) and;

[0269] X is C 1-40 Alkylene, C 1-40 Heteroalkylene, C 2-40Alkenylene, C 2-40 Heteroalkenylene, C 2-40 Alkynylene, or C 2-40 heteroalkynylene, wherein one or more methylene groups are each independently and optionally replaced by a divalent radical, and each divalent radical is independently selected from the group consisting of: C 3-10 Cycloalkylene, C 6-14 arylene, heteroarylene, or heterocyclylene;

[0270] Y is a bond, C 1-6 Alkylene, C 1-6 Heteroalkylene, C 2-6 Alkenylene, C 2-6 Alkynylene, C 3-10 Cycloalkylene, C 6-14 Arylene, C 7-15 aralkylene, heteroarylene, or heterocyclylene;

[0271] Z is [ka] and each R 1 , R 2 , R 3 , R 5a , and R 5b are independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) —C(O)R 1a , -C(O)OR 1a , -C(O)NR 1b R 1c , -C(O)SR 1a , -C(NR 1a )NR 1b R 1c , -C(S)R 1a , -C(S)OR 1a、-C(S)NR 1b R 1c 、-OR 1a 、-OC(O)R 1a 、-OC(O)OR 1a 、-OC(O)NR 1b R 1c 、-OC(O)SR 1a 、-OC(NR 1a )NR 1b R 1c 、-OC(S)R 1a 、-OC(S)OR 1a 、-OC(S)NR 1b R 1c 、-OS(O)R 1a 、-OS(O)2R 1a 、-OS(O)NR 1b R 1c 、-OS(O)2NR 1b R 1c 、-NR 1b R 1c 、-NR 1a C(O)R 1d 、-NR 1a C(O)OR 1d 、-NR 1a C(O)NR 1b R 1c 、-NR 1a C(O)SR 1d 、-NR 1a C(NR 1d )NR 1b R 1c 、-NR 1a C(S)R 1d 、-NR 1a C(S)OR 1d 、-NR 1a C(S)NR 1b R 1c 、-NR 1a S(O)R 1d 、-NR 1a S(O)2R 1d 、-NR 1a S(O)NR 1b R 1c 、-NR 1a S(O)2NR 1b R 1c 、-SR 1a 、-S(O)R 1a 、-S(O)2R 1a, -S(O)NR 1b R 1c , or -S(O)2NR 1b R 1c and;

[0272] R 4 is (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) —C(O)R 1a , -C(O)OR 1a , -C(O)NR 1b R 1c , -C(O)SR 1a , -C(NR 1a )NR 1b R 1c , -C(S)R 1a , -C(S)OR 1a , -C(S)NR 1b R 1c , -S(O)R 1a , -S(O)2R 1a , -S(O)NR 1b R 1c , or -S(O)2NR 1b R 1c and;

[0273] Each R 6 and R 7 are independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) —C(O)R 1a , -C(O)OR 1a , -C(O)NR 1b R1c 、-C(O)SR 1a 、-C(NR 1a )NR 1b R 1c 、-C(S)R 1a 、-C(S)OR 1a 、-C(S)NR 1b R 1c 、-OR 1a 、-OC(O)R 1a 、-OC(O)OR 1a 、-OC(O)NR 1b R 1c 、-OC(O)SR 1a 、-OC(NR 1a )NR 1b R 1c 、-OC(S)R 1a 、-OC(S)OR 1a 、-OC(S)NR 1b R 1c 、-OS(O)R 1a 、-OS(O)2R 1a 、-OS(O)NR 1b R 1c 、-OS(O)2NR 1b R 1c 、-NR 1b R 1c 、-NR 1a C(O)R 1d 、-NR 1a C(O)OR 1d 、-NR 1a C(O)NR 1b R 1c 、-NR 1a C(O)SR 1d 、-NR 1a C(NR 1d )NR 1b R 1c 、-NR 1a C(S)R 1d 、-NR 1a C(S)OR 1d 、-NR 1a C(S)NR 1b R 1c 、-NR 1a S(O)R 1d 、-NR 1a S(O)2R 1d 、-NR 1a S(O)NR 1b R1c , -NR 1a S(O)NR 1b R 1c , -SR 1a , -S(O)R 1a , -S(O)2R 1a , -S(O)NR 1b R 1c , or -S(O)2NR 1b R 1c and;

[0274] Each R 8 are independently (i) hydrogen or deuterium; or (ii) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl;

[0275] Each R 1a , R 1b , R 1c , and R 1d are independently hydrogen, deuterium, and C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl;

[0276] p and q are each independently an integer of 0, 1, or 2; provided that the sum of p and q is greater than 0;

[0277] s is an integer of 0, 1, 2, or 3; and

[0278] t is an integer of 0, 1, 2, 3, or 4;

[0279] wherein each alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, alkynylene, heteroalkynylene, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, aralkylene, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more, and in one embodiment, one, two, three, or four, substituents Q, wherein each Q is independently: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) one or more, and in one embodiment, one, two, three, or four, substituents Q. a and each of these is further optionally substituted C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)R a , -C(O)OR a , -C(O)NR b R c , -C(O)SR a , -C(NR a )NR b R c , -C(S)R a , -C(S)OR a , -C(S)NR b R c , -OR a , -OC(O)R a , -OC(O)OR a , -OC(O)NR b R c , -OC(O)SR a , -OC(NR a )NR b R c , -OC(S)R a , -OC(S)OR a , -OC(S)NR b R c , -OP(O)(OR a ) OR d , -OS(O)R a, -OS(O)2R a , -OS(O)NR b R c , -OS(O)2NR b R c , -NR b R c , -NR a C(O)R d , -NR a C(O)OR d , -NR a C(O)NR b R c , -NR a C(O)SR d , -NR a C(NR d )NR b R c , -NR a C(S)R d , -NR a C(S)OR d , -NR a C(S)NR b R c , -NR a S(O)R d , -NR a S(O)2R d , -NR a S(O)NR b R c , -NR a S(O)NR b R c , -SR a , -S(O)R a , -S(O)2R a , -S(O)NR b R c , and -S(O)NR b R c (In the formula, each R a , R b , R c , and R d are independently (i) hydrogen or deuterium; (ii) one or more, in one embodiment, one, two, three, or four, substituents Q a with arbitrary substitutions, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R b and R c together with the N atom to which they are attached, form one or more, in one embodiment one, two, three or four, substituents Q a forming an optionally substituted heterocyclyl;

[0280] Here, each Q a are independently: (a) deuterium, cyano, halo, nitro, imino, and oxo; (b) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)R e , -C(O)OR e , -C(O)NR f R g , -C(O)SR e , -C(NR e )NR f R g , -C(S)R e , -C(S)OR e , -C(S)NR f R g , -OR e , -OC(O)R e , -OC(O)OR e , -OC(O)NR f R g , -OC(O)SR e , -OC(NR e )NR f R g , -OC(S)R e , -OC(S)OR e , -OC(S)NR f R g , -OS(O)R e , -OS(O)2R e, -OS(O)NR f R g , -OS(O)2NR f R g , -NR f R g , -NR e C(O)R h , -NR e C(O)OR f , -NR e C(O)NR f R g , -NR e C(O)SR f , -NR e C(NR h )NR f R g , -NR e C(S)R h , -NR e C(S)OR f , -NR e C(S)NR f R g , -NR e S(O)R h , -NR e S(O)2R h , -NR e S(O)NR f R g , -NR e S(O)NR f R g , -SR e , -S(O)R e , -S(O)2R e , -S(O)NR f R g , and -S(O)NR f R g ;(In the formula, each R e , R f , R g , and R h are independently (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R fand R g are selected from: together with the N atom to which they are attached form a heterocyclyl).

[0281] In some embodiments, Z is [ka] (In the formula, R 5a and R 5b are each as defined herein) is.

[0282] In another embodiment, provided herein is a compound of formula (IIA): [ka]

[0283] (In the formula, R 1 , R 2 , R 3 , A, X, Y, p, and q are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0284] In certain embodiments, in Formula (IA) or (IIA), p is an integer of 0 and q is an integer of 1. In certain embodiments, in Formula (IA) or (IIA), p is an integer of 1 and q is an integer of 0.

[0285] In certain embodiments, in Formula (IA) or (IIA), p is an integer of 0 and q is an integer of 2. In certain embodiments, in Formula (IA) or (IIA), p and q are each an integer of 1. In certain embodiments, in Formula (IA) or (IIA), p is an integer of 2 and q is an integer of 0.

[0286] In another embodiment, provided herein is a compound of formula (IIIA): [ka]

[0287] (In the formula, R 1 , R 2 , R 3 , A, X, and Y are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0288] In yet another embodiment, provided herein is a compound of formula (IVA): [ka]

[0289] (In the formula, R 1 , R 2 , R 3 , A, X, and Y are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0290] In certain embodiments, in any one of Formulas (IA) to (IVA), A is O. In certain embodiments, in any one of Formulas (IA) to (IVA), A is S. In certain embodiments, in any one of Formulas (IA) to (IVA), A is S(O). In certain embodiments, in any one of Formulas (IA) to (IVA), A is S(O2). In certain embodiments, in any one of Formulas (IA) to (IVA), A is N(R 4 )(wherein, R 4 is as defined herein). In certain embodiments, in any one of formulas (IA) to (IVA), A is N(R 4 )(wherein, R 4 is (i) hydrogen; (ii) C, each optionally substituted with one or more substituents Q; 1-6 Alkyl or C 1-6 heteroalkyl; or (iii) —C(O)R 1a (In the formula, R 1a is as defined herein). In certain embodiments, in any one of formulas (IA)-(IVA), A is N(H), N(CH), or N(C(O)CH). In certain embodiments, in any one of formulas (IA)-(IVA), A is N(H).

[0291] In yet another embodiment, provided herein is a compound of formula (VA): [ka]

[0292] (In the formula, R 1 , R 2 , R 3 , X, and Y are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0293] In yet another embodiment, provided herein is a compound of formula (VIA): [ka]

[0294] (In the formula, R 1 , R 2 , R 3 , X, and Y are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0295] In yet another embodiment, provided herein is a compound of formula (VIIA): [ka]

[0296] (In the formula, R 1 , R 2 , R 3 , X, and Y are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0297] In yet another embodiment, provided herein is a compound of formula (VIIIA): [ka]

[0298] (In the formula, R 1 , R 2, R 3 , X, and Y are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0299] In certain embodiments, in any one of Formulas (IA) to (VIIIA), R 1 is hydrogen, deuterium, or halo. In certain embodiments, in any one of Formulas (IA) to (VIIIA), R 1 is hydrogen, deuterium, or fluoro. In certain embodiments, in any one of Formulas (IA) through (VIIIA), R 1 is hydrogen or fluoro. In certain embodiments, in any one of Formulas (IA) to (VIIIA), R 1 is hydrogen. In certain embodiments, in any one of Formulas (IA) to (VIIIA), R 1 is fluoro.

[0300] In certain embodiments, in any one of Formulas (IA) to (VIIIA), R 2 is (i) hydrogen or deuterium; (ii) heterocyclyl optionally substituted with one or more substituents Q; or (iii) -NR 1b R 1c or -NR 1a C(O)R 1d ;(In the formula, R 1a , R 1b , R 1c , and R 1d and each are as defined herein. In certain embodiments, in any one of Formulas (IA) through (VIIIA), R 2 is hydrogen, amino, methylamino, acetamido, or hydroxyacetamido. In certain embodiments, in any one of Formulas (IA) through (VIIIA), R 2is hydrogen or amino. In certain embodiments, in any one of Formulas (IA) to (VIIIA), R 2 is hydrogen. In certain embodiments, in any one of Formulas (IA) to (VIIIA), R 2 is an amino.

[0301] In certain embodiments, in any one of Formulas (IA) to (VIIIA), R 3 is C, each optionally substituted with one or more substituents Q; 1-6 Alkyl, C 1-6 Heteroalkyl, or C 2-6 In certain embodiments, in any one of Formulas (IA) to (VIIIA), R 3 is methyl, fluoromethyl, methoxymethyl, or ethenyl. In certain embodiments, in any one of Formulas (IA) to (VIIIA), R 3 is methyl.

[0302] In certain embodiments, in any one of Formulas (IA) to (VIIIA),

[0303] R 1 is hydrogen, deuterium, or halo;

[0304] R 2 is (i) hydrogen or deuterium; (ii) heterocyclyl optionally substituted with one or more substituents Q; or (iii) -NR 1b R 1c or -NR 1a C(O)R 1d ;(In the formula, R 1a , R 1b , R 1c , and R 1d are each as defined herein; and

[0305] R 3 is C, each optionally substituted with one or more substituents Q; 1-6 Alkyl, C 1-6 Heteroalkyl, or C2-6 It is alkenyl.

[0306] In certain embodiments, in any one of Formulas (IA) to (VIIIA),

[0307] R 1 is hydrogen, deuterium, or fluoro;

[0308] R 2 is hydrogen, amino, methylamino, acetamido, or hydroxyacetamido; and

[0309] R 3 is methyl, fluoromethyl, hydroxymethyl, or ethenyl.

[0310] In certain embodiments, in any one of Formulas (IA) to (VIIIA),

[0311] R 1 is hydrogen or fluoro;

[0312] R 2 is hydrogen or amino; and

[0313] R 3 is methyl.

[0314] In certain embodiments, in any one of Formulas (IA) to (VIIIA),

[0315] R 1 is hydrogen or fluoro;

[0316] R 2 is hydrogen; and

[0317] R 3 is methyl.

[0318] In one embodiment, provided herein is a compound of formula (IXA): [ka]

[0319] (In the formula, R 1 , R 2 , R 3 , R 6 , R 8 , A, X, Y, p, q, and s are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0320] In certain embodiments, in Formula (IXA), each R 6 is independently deuterium or halo. In certain embodiments, in Formula (IXA), each R 6 is independently deuterium or fluoro. In certain embodiments, in Formula (IXA), each R 6 is independently halo. In certain embodiments, in Formula (IXA), each R 6 is fluoro.

[0321] In certain embodiments, in Formula (IXA), s is an integer of 0 or 1. In certain embodiments, in Formula (IXA), s is an integer of 0. In certain embodiments, in Formula (IXA), s is an integer of 1.

[0322] In another embodiment, provided herein is a compound of formula (XA): [ka]

[0323] (In the formula, R 6a , R 6b , and R 6c are each independently hydrogen or R 6 and R 1 , R 2 , R 3, R 6 , R 8 , A, X, Y, p, and q are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0324] In certain embodiments, in Formula (IXA) or Formula (XA), p is an integer of 0 and q is an integer of 1. In certain embodiments, in Formula (IXA) or Formula (XA), p is an integer of 1 and q is an integer of 0.

[0325] In certain embodiments, in Formula (IXA) or Formula (XA), p is an integer of 0 and q is an integer of 2. In certain embodiments, in Formula (IXA) or Formula (XA), p and q are each an integer of 1. In certain embodiments, in Formula (IXA) or Formula (XA), p is an integer of 2 and q is an integer of 0.

[0326] In yet another embodiment, provided herein is a compound of formula (XIA): [ka]

[0327] (In the formula, R 1 , R 2 , R 3 , R 8 , R 6a , R 6b , R 6c , A, X, and Y are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0328] In yet another embodiment, provided herein is a compound of formula (XIIA): [ka]

[0329] (In the formula, R 1 , R 2 , R 3 , R 8 , R 6a , R 6b , R 6c , A, X, and Y are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0330] In certain embodiments, in any one of Formulas (IXA) to (XIIA), A is O. In certain embodiments, in any one of Formulas (IXA) to (XIIA), A is S. In certain embodiments, in any one of Formulas (IXA) to (XIIA), A is S(O). In certain embodiments, in any one of Formulas (IXA) to (XIIA), A is S(O2). In certain embodiments, in any one of Formulas (IXA) to (XIIA), A is N(R 4 )(wherein, R 4 is as defined herein). In certain embodiments, in any one of Formulas (IXA) to (XIIA), A is N(R 4 )(wherein, R 4 is (i) hydrogen; (ii) C, each optionally substituted with one or more substituents Q; 1-6 Alkyl or C 1-6 heteroalkyl; or (iii) —C(O)R 1a (In the formula, R 1ais as defined herein). In certain embodiments, in any one of Formulas (IXA) to (XIIA), A is N(H), N(CH), or N(C(O)CH). In certain embodiments, in any one of Formulas (IXA) to (XIIA), A is N(H).

[0331] In yet another embodiment, provided herein is a compound of formula (XIIIA): [ka]

[0332] (In the formula, R 1 , R 2 , R 3 , R 8 , R 6a , R 6b , R 6c , X, and Y are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0333] In yet another embodiment, provided herein is a compound of formula (XIVA): [ka]

[0334] (In the formula, R 1 , R 2 , R 3 , R 8 , R 6a , R 6b , R 6c , X, and Y are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0335] In yet another embodiment, provided herein is a compound of formula (XVA): [ka]

[0336] (In the formula, R 1 , R 2 , R 3 , R 8 , R 6a , R 6b , R 6c , X, and Y are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0337] In yet another embodiment, provided herein is a compound of formula (XVIA): [ka]

[0338] (In the formula, R 1 , R 2 , R 3 , R 8 , R 6a , R 6b , R 6c , X, and Y are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0339] In certain embodiments, in any one of Formulas (IXA) to (XVIA), R 1 is hydrogen, deuterium, or halo. In certain embodiments, in any one of Formulas (IXA) to (XVIA), R 1 is hydrogen, deuterium, or fluoro. In certain embodiments, in any one of Formulas (IXA) to (XVIA), R 1 is hydrogen or fluoro. In certain embodiments, in any one of Formulas (IXA) to (XVIA), R 1 is hydrogen. In certain embodiments, in any one of Formulas (IXA) to (XVIA), R 1 is fluoro.

[0340] In certain embodiments, in any one of Formulas (IXA) to (XVIA), R 2 is (i) hydrogen or deuterium; (ii) heterocyclyl optionally substituted with one or more substituents Q; or (iii) -NR 1b R 1c or -NR 1a C(O)R 1d ;(In the formula, R 1a , R 1b , R 1c , and R 1d and each are as defined herein. In certain embodiments, in any one of Formulas (IXA) to (XVIA), R 2 is hydrogen, amino, methylamino, acetamido, or hydroxyacetamido. In certain embodiments, in any one of Formulas (IXA) to (XVIA), R 2 is hydrogen or amino. In certain embodiments, in any one of Formulas (IXA) to (XVIA), R 2is hydrogen. In certain embodiments, in any one of Formulas (IXA) to (XVIA), R 2 is an amino.

[0341] In certain embodiments, in any one of Formulas (IXA) to (XVIA), R 3 is C, each optionally substituted with one or more substituents Q; 1-6 Alkyl, C 1-6 Heteroalkyl, or C 2-6 In certain embodiments, in any one of Formulas (IXA) to (XVIA), R 3 is methyl, fluoromethyl, methoxymethyl, or ethenyl. In certain embodiments, in any one of Formulas (IXA) to (XVIA), R 3 is methyl.

[0342] In certain embodiments, in any one of Formulas (IXA) to (XVIA), R 8 is C, each optionally substituted with one or more substituents Q; 1-6 Alkyl, C 1-6 Heteroalkyl, or C 3-10 In certain embodiments, in any one of Formulas (IXA) to (XVIA), R 8 is C optionally substituted with one or more substituents Q 1-6 In certain embodiments, in any one of Formulas (IXA) to (XVIA), R 8 is methyl. In certain embodiments, in any one of Formulas (IXA) to (XVIA), R 8 is C optionally substituted with one or more substituents Q 1-6 In certain embodiments, in any one of Formulas (IXA) to (XVIA), R 8 is trifluoromethyl. In certain embodiments, in any one of Formulas (IXA) to (XVIA), R 8 is C optionally substituted with one or more substituents Q 3-10In certain embodiments, in any one of Formulas (IXA) to (XVIA), R 8 is a monocyclic C optionally substituted with one or more substituents Q 3-10 In certain embodiments, in any one of Formulas (IXA) to (XVIA), R 8 is cyclopropyl or 1-fluorocyclopropyl. In certain embodiments, in any one of Formulas (IXA) to (XVIA), R 8 is cyclopropyl.

[0343] In certain embodiments, in any one of Formulas (XA) to (XVIA), R 6a is hydrogen or deuterium. In certain embodiments, in any one of Formulas (XA) to (XVIA), R 6a is hydrogen.

[0344] In certain embodiments, in any one of Formulas (XA) to (XVIA), R 6b is hydrogen, deuterium, or halo. In certain embodiments, in any one of Formulas (XA) to (XVIA), R 6b is hydrogen, deuterium, or fluoro. In certain embodiments, in any one of Formulas (XA) to (XVIA), R 6b is hydrogen or fluoro. In certain embodiments, in any one of Formulas (XA) to (XVIA), R 6b is hydrogen. In certain embodiments, in any one of Formulas (XA) to (XVIA), R 6b is fluoro.

[0345] In certain embodiments, in any one of Formulas (XA) to (XVIA), R 6c is hydrogen or deuterium. In certain embodiments, in any one of Formulas (XA) to (XVIA), R 6c is hydrogen.

[0346] In one embodiment, in any one of Formulas (XA) to (XVIA),

[0347] R 1 is hydrogen, deuterium, or halo;

[0348] R 2 is (i) hydrogen or deuterium; (ii) heterocyclyl optionally substituted with one or more substituents Q; or (iii) -NR 1b R 1c or -NR 1a C(O)R 1d ;(In the formula, R 1a , R 1b , R 1c , and R 1d are each as defined herein; and

[0349] R 3 is C, each optionally substituted with one or more substituents Q; 1-6 Alkyl, C 1-6 Heteroalkyl, or C 2-6 is alkenyl;

[0350] R 8 is a C optionally substituted with one or more substituents Q 1-6 Alkyl, C 1-6 Heteroalkyl, or C 3-10 is cycloalkyl;

[0351] R 6a and R 6c are each independently hydrogen or deuterium; and

[0352] R 6b is hydrogen, deuterium, or halo.

[0353] In one embodiment, in any one of Formulas (XA) to (XVIA),

[0354] R 1 is hydrogen, deuterium, or fluoro;

[0355] R 2 is hydrogen, amino, methylamino, acetamido, or hydroxyacetamido; and

[0356] R 3 is methyl, fluoromethyl, hydroxymethyl, or ethenyl;

[0357] R 8 is methyl, fluoromethyl, cyclopropyl, or 1-fluorocyclopropyl;

[0358] R 6a and R 6c are each hydrogen; and

[0359] R 6b is hydrogen or fluoro.

[0360] In one embodiment, in any one of Formulas (XA) to (XVIA),

[0361] R 1 is hydrogen or fluoro;

[0362] R 2 is hydrogen or amino;

[0363] R 3 is methyl;

[0364] R 8 is methyl or cyclopropyl;

[0365] R 6a and R 6c are each hydrogen; and

[0366] R 6b is hydrogen or fluoro.

[0367] In one embodiment, in any one of Formulas (XA) to (XVIA),

[0368] R 1 is hydrogen or fluoro;

[0369] R 2 is hydrogen;

[0370] R 3 is methyl;

[0371] R 8 is methyl or cyclopropyl;

[0372] R 6a and R 6c are each hydrogen; and

[0373] R 6b is hydrogen or fluoro.

[0374] The group R in the formulae described herein, including formula (I) to formula (XXII) and formula (IA) to formula (XVIA) 1 , R 2 , R 3 , R 4 , R 6 , R 8 , R 5a , R 5b , R 6a , R 6b , R 6c , A, X, Y, Z, m, p, q, and s are further defined in the embodiments described herein. All combinations of the embodiments provided herein for such groups are within the scope of the present disclosure.

[0375] In certain embodiments, each R 1 is hydrogen. In certain embodiments, each R 1 is deuterium. In certain embodiments, each R 1 is cyano. In certain embodiments, each R 1 is independently halo. In certain embodiments, each R 1 is independently fluoro or chloro. In certain embodiments, each R 1 is fluoro. In certain embodiments, each R1 is nitro. In certain embodiments, each R 1 independently represents C optionally substituted with one or more substituents Q 1-6 In certain embodiments, each R 1 is independently methyl. In certain embodiments, each R 1 independently represents C optionally substituted with one or more substituents Q 1-6 In certain embodiments, each R 1 independently represents C optionally substituted with one or more substituents Q 2-6 alkenyl. In certain embodiments, each R 1 independently represents C optionally substituted with one or more substituents Q 2-6 In certain embodiments, each R 1 independently represents C optionally substituted with one or more substituents Q 3-10 In certain embodiments, each R 1 independently represents C optionally substituted with one or more substituents Q 6-14 In certain embodiments, each R 1 independently represents C optionally substituted with one or more substituents Q 7-15 In certain embodiments, each R 1 is independently heteroaryl optionally substituted with one or more substituents Q. In certain embodiments, each R 1 is independently heterocyclyl optionally substituted with one or more substituents Q. In certain embodiments, each R 1 is independently hydrogen or fluoro.

[0376] In certain embodiments, each R 1 are independently, -C(O)R 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 1 are independently -C(O)OR 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 1 are independently -C(O)NR1b R 1c (In the formula, R 1b and R 1c and each R is as defined herein. In certain embodiments, each R 1 are independently -C(O)SR 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 1 are independently -C(NR 1a )NR 1b R 1c (In the formula, R 1a , R 1b , and R 1c and each R is as defined herein. In certain embodiments, each R 1 are independently, -C(S)R 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 1 are independently, -C(S)OR 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 1 are independently, -C(S)NR 1b R 1c (In the formula, R 1b and R 1c and each R is as defined herein. In certain embodiments, each R 1 are independently, -OR 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 1 are independently, -OC(O)R 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 1 are independently, -OC(O)OR 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 1 are independently -OC(O)NR 1b R 1c(In the formula, R 1b and R 1c and each R is as defined herein. In certain embodiments, each R 1 are independently, -OC(O)SR 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 1 are independently, -OC(NR 1a )NR 1b R 1c (In the formula, R 1a , R 1b , and R 1c and each R is as defined herein. In certain embodiments, each R 1 are independently, -OC(S)R 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 1 are independently, -OC(S)OR 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 1 are independently, -OC(S)NR 1b R 1c (In the formula, R 1b and R 1c and each R is as defined herein. In certain embodiments, each R 1 are independently, -OS(O)R 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 1 are independently, -OS(O)2R 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 1 are independently, -OS(O)NR 1b R 1c (In the formula, R 1b and R 1c and each R is as defined herein. In certain embodiments, each R 1 are independently, -OS(O)2NR1b R 1c (In the formula, R 1b and R 1c and each R is as defined herein. In certain embodiments, each R 1 are independently, -NR 1b R 1c (In the formula, R 1b and R 1c and each R is as defined herein. In certain embodiments, each R 1 are independently, -NR 1a C(O)R 1d (In the formula, R 1a and R 1d and each R is as defined herein. In certain embodiments, each R 1 are independently, -NR 1a C(O)OR 1d (In the formula, R 1a and R 1d and each R is as defined herein. In certain embodiments, each R 1 are independently, -NR 1a C(O)NR 1b R 1c (In the formula, R 1a , R 1b , and R 1c and each R is as defined herein. In certain embodiments, each R 1 are independently, -NR 1a C(O)SR 1d (In the formula, R 1a and R 1d and each R is as defined herein. In certain embodiments, each R 1 are independently, -NR 1a C(NR 1d )NR 1b R 1c (In the formula, R 1a , R 1b , R 1c , and R 1d and each R is as defined herein. In certain embodiments, each R 1 are independently, -NR 1a C(S)R1d (In the formula, R 1a and R 1d and each R is as defined herein. In certain embodiments, each R 1 are independently, -NR 1a C(S)OR 1d (In the formula, R 1a and R 1d and each R is as defined herein. In certain embodiments, each R 1 are independently, -NR 1a C(S)NR 1b R 1c (In the formula, R 1a , R 1b , and R 1c and each R is as defined herein. In certain embodiments, each R 1 are independently, -NR 1a S(O)R 1d (In the formula, R 1a and R 1d and each R is as defined herein. In certain embodiments, each R 1 are independently, -NR 1a S(O)2R 1d (In the formula, R 1a and R 1d and each R is as defined herein. In certain embodiments, each R 1 are independently, -NR 1a S(O)NR 1b R 1c (In the formula, R 1a , R 1b , and R 1c and each R is as defined herein. In certain embodiments, each R 1 are independently, -NR 1a S(O)NR 1b R 1c (In the formula, R 1a , R 1b , and R 1c and each R is as defined herein. In certain embodiments, each R 1 are independently, -SR 1a (In the formula, R 1ais as defined herein. In certain embodiments, each R 1 are independently, -S(O)R 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 1 are independently -S(O)R 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 1 are independently -S(O)NR 1b R 1c (In the formula, R 1b and R 1c and each R is as defined herein. In certain embodiments, each R 1 are independently -S(O)2NR 1b R 1c (In the formula, R 1b and R 1c are each as defined herein).

[0377] In certain embodiments, each R 2 is hydrogen. In certain embodiments, each R 2 is deuterium. In certain embodiments, each R 2 is cyano. In certain embodiments, each R 2 is independently halo. In certain embodiments, each R 2 is independently fluoro or chloro. In certain embodiments, each R 2 is fluoro. In certain embodiments, each R 2 is nitro. In certain embodiments, each R 2 independently represents C optionally substituted with one or more substituents Q 1-6 In certain embodiments, each R 2 is methyl. In certain embodiments, each R 2 independently represents C optionally substituted with one or more substituents Q 1-6 In certain embodiments, each R 2 independently represents C optionally substituted with one or more substituents Q2-6 alkenyl. In certain embodiments, each R 2 independently represents C optionally substituted with one or more substituents Q 2-6 In certain embodiments, each R 2 independently represents C optionally substituted with one or more substituents Q 3-10 In certain embodiments, each R 2 independently represents C optionally substituted with one or more substituents Q 6-14 In certain embodiments, each R 2 independently represents C optionally substituted with one or more substituents Q 7-15 In certain embodiments, each R 2 is independently heteroaryl optionally substituted with one or more substituents Q. In certain embodiments, each R 2 is independently heterocyclyl optionally substituted with one or more substituents Q.

[0378] In certain embodiments, each R 2 are independently, -C(O)R 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 2 are independently -C(O)OR 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 2 are independently -C(O)NR 1b R 1c (In the formula, R 1b and R 1c and each R is as defined herein. In certain embodiments, each R 2 are independently -C(O)SR 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 2 are independently -C(NR 1a )NR 1b R 1c (In the formula, R 1a , R 1b , and R1c and each R is as defined herein. In certain embodiments, each R 2 are independently, -C(S)R 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 2 are independently, -C(S)OR 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 2 are independently, -C(S)NR 1b R 1c (In the formula, R 1b and R 1c and each R is as defined herein. In certain embodiments, each R 2 are independently, -OR 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 2 are independently, -OC(O)R 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 2 are independently, -OC(O)OR 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 2 are independently -OC(O)NR 1b R 1c (In the formula, R 1b and R 1c and each R is as defined herein. In certain embodiments, each R 2 are independently, -OC(O)SR 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 2 are independently, OC(NR 1a )NR 1b R 1c (In the formula, R 1a , R 1b , and R 1cand each R is as defined herein. In certain embodiments, each R 2 are independently, -OC(S)R 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 2 are independently, -OC(S)OR 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 2 are independently, -OC(S)NR 1b R 1c (In the formula, R 1b and R 1c and each R is as defined herein. In certain embodiments, each R 2 are independently, -OS(O)R 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 2 are independently, -OS(O)2R 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 2 are independently, -OS(O)NR 1b R 1c (In the formula, R 1b and R 1c and each R is as defined herein. In certain embodiments, each R 2 are independently, -OS(O)2NR 1b R 1c (In the formula, R 1b and R 1c and each R is as defined herein. In certain embodiments, each R 2 are independently, -NR 1b R 1c (In the formula, R 1b and R 1c and each R is as defined herein. In certain embodiments, each R 2 is independently amino (—NH) or methylamino (—NHCH). In certain embodiments, each R2 are independently, -NR 1a C(O)R 1d (In the formula, R 1a and R 1d and each R is as defined herein. In certain embodiments, each R 2 is independently acetamide or hydroxyacetamide. In certain embodiments, each R 2 are independently, -NR 1a C(O)OR 1d (In the formula, R 1a and R 1d and each R is as defined herein. In certain embodiments, each R 2 are independently, -NR 1a C(O)NR 1b R 1c (In the formula, R 1a , R 1b , and R 1c and each R is as defined herein. In certain embodiments, each R 2 are independently, -NR 1a C(O)SR 1d (In the formula, R 1a and R 1d and each R is as defined herein. In certain embodiments, each R 2 are independently, -NR 1a C(NR 1d )NR 1b R 1c (In the formula, R 1a , R 1b , R 1c , and R 1d and each R is as defined herein. In certain embodiments, each R 2 are independently, -NR 1a C(S)R 1d (In the formula, R 1a and R 1d and each R is as defined herein. In certain embodiments, each R 2 are independently, -NR 1a C(S)OR 1d (In the formula, R 1a and R 1dand each R is as defined herein. In certain embodiments, each R 2 are independently, -NR 1a C(S)NR 1b R 1c (In the formula, R 1a , R 1b , and R 1c and each R is as defined herein. In certain embodiments, each R 2 are independently, -NR 1a S(O)R 1d (In the formula, R 1a and R 1d and each R is as defined herein. In certain embodiments, each R 2 are independently, -NR 1a S(O)2R 1d (In the formula, R 1a and R 1d and each R is as defined herein. In certain embodiments, each R 2 are independently, -NR 1a S(O)NR 1b R 1c (In the formula, R 1a , R 1b , and R 1c and each R is as defined herein. In certain embodiments, each R 2 are independently, -NR 1a S(O)NR 1b R 1c (In the formula, R 1a , R 1b , and R 1c and each R is as defined herein. In certain embodiments, each R 2 are independently, -SR 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 2 are independently, -S(O)R 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 2 are independently -S(O)R 1a(In the formula, R 1a is as defined herein. In certain embodiments, each R 2 are independently -S(O)NR 1b R 1c (In the formula, R 1b and R 1c and each R is as defined herein. In certain embodiments, each R 2 are independently -S(O)2NR 1b R 1c (In the formula, R 1b and R 1c are each as defined herein).

[0379] In certain embodiments, each R 3 is hydrogen. In certain embodiments, each R 3 is deuterium. In certain embodiments, each R 3 is cyano. In certain embodiments, each R 3 is independently halo. In certain embodiments, each R 3 is independently fluoro or chloro. In certain embodiments, each R 3 is fluoro. In certain embodiments, each R 3 is nitro. In certain embodiments, each R 3 independently represents C optionally substituted with one or more substituents Q 1-6 In certain embodiments, each R 3 is independently methyl, fluoromethyl, or methoxymethyl. In certain embodiments, each R 3 is methyl. In certain embodiments, each R 3 independently represents C optionally substituted with one or more substituents Q 1-6 In certain embodiments, each R 3 independently represents C optionally substituted with one or more substituents Q 2-6 alkenyl. In certain embodiments, each R 3 is ethenyl. In certain embodiments, each R 3 independently represents C optionally substituted with one or more substituents Q 2-6In certain embodiments, each R 3 independently represents C optionally substituted with one or more substituents Q 3-10 In certain embodiments, each R 3 independently represents C optionally substituted with one or more substituents Q 6-14 In certain embodiments, each R 3 independently represents C optionally substituted with one or more substituents Q 7-15 In certain embodiments, each R 3 is independently heteroaryl optionally substituted with one or more substituents Q. In certain embodiments, each R 3 is independently heterocyclyl optionally substituted with one or more substituents Q.

[0380] In certain embodiments, each R 3 are independently, -C(O)R 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 3 are independently -C(O)OR 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 3 are independently -C(O)NR 1b R 1c (In the formula, R 1b and R 1c and each R is as defined herein. In certain embodiments, each R 3 are independently -C(O)SR 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 3 are independently -C(NR 1a )NR 1b R 1c (In the formula, R 1a , R 1b , and R 1c and each R is as defined herein. In certain embodiments, each R 3 are independently, -C(S)R 1a(In the formula, R 1a is as defined herein. In certain embodiments, each R 3 are independently, -C(S)OR 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 3 are independently, -C(S)NR 1b R 1c (In the formula, R 1b and R 1c and each R is as defined herein. In certain embodiments, each R 3 are independently, -OR 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 3 are independently, -OC(O)R 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 3 are independently, -OC(O)OR 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 3 are independently -OC(O)NR 1b R 1c (In the formula, R 1b and R 1c and each R is as defined herein. In certain embodiments, each R 3 are independently, -OC(O)SR 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 3 are independently, -OC(NR 1a )NR 1b R 1c (In the formula, R 1a , R 1b , and R 1c and each R is as defined herein. In certain embodiments, each R 3 are independently, -OC(S)R 1a (In the formula, R 1ais as defined herein. In certain embodiments, each R 3 are independently, -OC(S)OR 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 3 are independently, -OC(S)NR 1b R 1c (In the formula, R 1b and R 1c and each R is as defined herein. In certain embodiments, each R 3 are independently, -OS(O)R 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 3 are independently, -OS(O)3R 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 3 are independently, -OS(O)NR 1b R 1c (In the formula, R 1b and R 1c and each R is as defined herein. In certain embodiments, each R 3 are independently, -OS(O)2NR 1b R 1c (In the formula, R 1b and R 1c and each R is as defined herein. In certain embodiments, each R 3 are independently, -NR 1b R 1c (In the formula, R 1b and R 1c and each R is as defined herein. In certain embodiments, each R 3 are independently, -NR 1a C(O)R 1d (In the formula, R 1a and R 1d and each R is as defined herein. In certain embodiments, each R 3 are independently, -NR 1aC(O)OR 1d (In the formula, R 1a and R 1d and each R is as defined herein. In certain embodiments, each R 3 are independently, -NR 1a C(O)NR 1b R 1c (In the formula, R 1a , R 1b , and R 1c and each R is as defined herein. In certain embodiments, each R 3 are independently, -NR 1a C(O)SR 1d (In the formula, R 1a and R 1d and each R is as defined herein. In certain embodiments, each R 3 are independently, -NR 1a C(NR 1d )NR 1b R 1c (In the formula, R 1a , R 1b , R 1c , and R 1d and each R is as defined herein. In certain embodiments, each R 3 are independently, -NR 1a C(S)R 1d (In the formula, R 1a and R 1d and each R is as defined herein. In certain embodiments, each R 3 are independently, -NR 1a C(S)OR 1d (In the formula, R 1a and R 1d and each R is as defined herein. In certain embodiments, each R 3 are independently, -NR 1a C(S)NR 1b R 1c (In the formula, R 1a , R 1b , and R 1c and each R is as defined herein. In certain embodiments, each R 3are independently, -NR 1a S(O)R 1d (In the formula, R 1a and R 1d and each R is as defined herein. In certain embodiments, each R 3 are independently, -NR 1a S(O)2R 1d (In the formula, R 1a and R 1d and each R is as defined herein. In certain embodiments, each R 3 are independently, -NR 1a S(O)NR 1b R 1c (In the formula, R 1a , R 1b , and R 1c and each R is as defined herein. In certain embodiments, each R 3 are independently, -NR 1a S(O)NR 1b R 1c (In the formula, R 1a , R 1b , and R 1c and each R is as defined herein. In certain embodiments, each R 3 are independently, -SR 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 3 are independently, -S(O)R 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 3 are independently -S(O)R 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 3 are independently -S(O)NR 1b R 1c (In the formula, R 1b and R 1c and each R is as defined herein. In certain embodiments, each R 3 are independently -S(O)2NR1b R 1c (In the formula, R 1b and R 1c are each as defined herein).

[0381] In certain embodiments, each R 4 is hydrogen. In certain embodiments, each R 4 independently represents C optionally substituted with one or more substituents Q 1-6 In certain embodiments, each R 4 is methyl. In certain embodiments, each R 4 independently represents C optionally substituted with one or more substituents Q 1-6 In certain embodiments, each R 4 independently represents C optionally substituted with one or more substituents Q 2-6 alkenyl. In certain embodiments, each R 4 independently represents C optionally substituted with one or more substituents Q 2-6 In certain embodiments, each R 4 independently represents C optionally substituted with one or more substituents Q 3-10 In certain embodiments, each R 4 independently represents C optionally substituted with one or more substituents Q 6-14 In certain embodiments, each R 4 independently represents C optionally substituted with one or more substituents Q 7-15 In certain embodiments, each R 4 is independently heteroaryl optionally substituted with one or more substituents Q. In certain embodiments, each R 4 is independently heterocyclyl optionally substituted with one or more substituents Q.

[0382] In certain embodiments, each R 4 are independently, -C(O)R 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 4is acetyl. In certain embodiments, each R 4 are independently -C(O)OR 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 4 are independently -C(O)NR 1b R 1c (In the formula, R 1b and R 1c and each R is as defined herein. In certain embodiments, each R 4 are independently -C(O)SR 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 4 are independently -C(NR 1a )NR 1b R 1c (In the formula, R 1a , R 1b , and R 1c and each R is as defined herein. In certain embodiments, each R 4 are independently, -C(S)R 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 4 are independently, -C(S)OR 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 4 are independently, -C(S)NR 1b R 1c (In the formula, R 1b and R 1c and each R is as defined herein. In certain embodiments, each R 4 are independently, -S(O)R 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 4 are independently -S(O)R 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R4 are independently -S(O)NR 1b R 1c (In the formula, R 1b and R 1c and each R is as defined herein. In certain embodiments, each R 4 are independently -S(O)2NR 1b R 1c (In the formula, R 1b and R 1c are each as defined herein).

[0383] In certain embodiments, each R 6 is deuterium. In certain embodiments, each R 6 is cyano. In certain embodiments, each R 6 is independently halo. In certain embodiments, each R 6 is independently fluoro or chloro. In certain embodiments, each R 6 is fluoro. In certain embodiments, each R 6 is nitro. In certain embodiments, each R 6 independently represents C optionally substituted with one or more substituents Q 1-6 In certain embodiments, each R 6 is independently methyl or trifluoromethyl. In certain embodiments, each R 6 is methyl. In certain embodiments, each R 6 independently represents C optionally substituted with one or more substituents Q 1-6 In certain embodiments, each R 6 independently represents C optionally substituted with one or more substituents Q 2-6 alkenyl. In certain embodiments, each R 6 independently represents C optionally substituted with one or more substituents Q 2-6 In certain embodiments, each R 6 independently represents C optionally substituted with one or more substituents Q 3-10 In certain embodiments, each R 6 independently represents C optionally substituted with one or more substituents Q6-14 In certain embodiments, each R 6 independently represents C optionally substituted with one or more substituents Q 7-15 In certain embodiments, each R 6 is independently heteroaryl optionally substituted with one or more substituents Q. In certain embodiments, each R 6 is independently heterocyclyl optionally substituted with one or more substituents Q.

[0384] In certain embodiments, each R 6 are independently, -C(O)R 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 6 are independently -C(O)OR 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 6 are independently -C(O)NR 1b R 1c (In the formula, R 1b and R 1c and each R is as defined herein. In certain embodiments, each R 6 are independently -C(O)SR 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 6 are independently -C(NR 1a )NR 1b R 1c (In the formula, R 1a , R 1b , and R 1c and each R is as defined herein. In certain embodiments, each R 6 are independently, -C(S)R 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 6 are independently, -C(S)OR 1a (In the formula, R 1ais as defined herein. In certain embodiments, each R 6 are independently, -C(S)NR 1b R 1c (In the formula, R 1b and R 1c and each R is as defined herein. In certain embodiments, each R 6 are independently, -OR 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 6 are independently, -OC(O)R 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 6 are independently, -OC(O)OR 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 6 are independently -OC(O)NR 1b R 1c (In the formula, R 1b and R 1c and each R is as defined herein. In certain embodiments, each R 6 are independently, -OC(O)SR 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 6 are independently, -OC(NR 1a )NR 1b R 1c (In the formula, R 1a , R 1b , and R 1c and each R is as defined herein. In certain embodiments, each R 6 are independently, -OC(S)R 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 6 are independently, -OC(S)OR 1a (In the formula, R 1ais as defined herein. In certain embodiments, each R 6 are independently, -OC(S)NR 1b R 1c (In the formula, R 1b and R 1c and each R is as defined herein. In certain embodiments, each R 6 are independently, -OS(O)R 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 6 are independently, -OS(O)6R 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 6 are independently, -OS(O)NR 1b R 1c (In the formula, R 1b and R 1c and each R is as defined herein. In certain embodiments, each R 6 are independently, -OS(O)2NR 1b R 1c (In the formula, R 1b and R 1c and each R is as defined herein. In certain embodiments, each R 6 are independently, -NR 1b R 1c (In the formula, R 1b and R 1c and each R is as defined herein. In certain embodiments, each R 6 are independently, -NR 1a C(O)R 1d (In the formula, R 1a and R 1d and each R is as defined herein. In certain embodiments, each R 6 are independently, -NR 1a C(O)OR 1d (In the formula, R 1a and R 1d and each R is as defined herein. In certain embodiments, each R6 are independently, -NR 1a C(O)NR 1b R 1c (In the formula, R 1a , R 1b , and R 1c and each R is as defined herein. In certain embodiments, each R 6 are independently, -NR 1a C(O)SR 1d (In the formula, R 1a and R 1d and each R is as defined herein. In certain embodiments, each R 6 are independently, -NR 1a C(NR 1d )NR 1b R 1c (In the formula, R 1a , R 1b , R 1c , and R 1d and each R is as defined herein. In certain embodiments, each R 6 are independently, -NR 1a C(S)R 1d (In the formula, R 1a and R 1d and each R is as defined herein. In certain embodiments, each R 6 are independently, -NR 1a C(S)OR 1d (In the formula, R 1a and R 1d and each R is as defined herein. In certain embodiments, each R 6 are independently, -NR 1a C(S)NR 1b R 1c (In the formula, R 1a , R 1b , and R 1c and each R is as defined herein. In certain embodiments, each R 6 are independently, -NR 1a S(O)R 1d (In the formula, R 1a and R 1dand each R is as defined herein. In certain embodiments, each R 6 are independently, -NR 1a S(O)2R 1d (In the formula, R 1a and R 1d and each R is as defined herein. In certain embodiments, each R 6 are independently, -NR 1a S(O)NR 1b R 1c (In the formula, R 1a , R 1b , and R 1c and each R is as defined herein. In certain embodiments, each R 6 are independently, -NR 1a S(O)NR 1b R 1c (In the formula, R 1a , R 1b , and R 1c and each R is as defined herein. In certain embodiments, each R 6 are independently, -SR 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 6 are independently, -S(O)R 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 6 are independently -S(O)R 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 6 are independently -S(O)NR 1b R 1c (In the formula, R 1b and R 1c and each R is as defined herein. In certain embodiments, each R 6 are independently -S(O)2NR 1b R 1c (In the formula, R 1b and R 1care each as defined herein).

[0385] In some embodiments, R 8 is hydrogen. In certain embodiments, R 8 is deuterium. In certain embodiments, R 8 is C optionally substituted with one or more substituents Q 1-6 In some embodiments, R 8 is methyl or trifluoromethyl. In certain embodiments, R 8 is methyl. In certain embodiments, R 8 is C optionally substituted with one or more substituents Q 1-6 In some embodiments, R 8 is C optionally substituted with one or more substituents Q 2-6 In some embodiments, R 8 is C optionally substituted with one or more substituents Q 2-6 In certain embodiments, R 8 is C optionally substituted with one or more substituents Q 3-10 In certain embodiments, R 8 is a monocyclic C optionally substituted with one or more substituents Q 3-10 In certain embodiments, R 8 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, each optionally substituted with one or more substituents Q. In certain embodiments, R 8 is cyclopropyl or 1-fluorocyclopropyl. 8 is cyclopropyl. In certain embodiments, R 8 is a bicyclic C optionally substituted with one or more substituents Q 4-10 In certain embodiments, R 8 is a bridged, fused, or spiro C, each optionally substituted with one or more substituents Q; 4-10 In certain embodiments, each R8 independently represents C optionally substituted with one or more substituents Q 6-14 In certain embodiments, each R 8 independently represents C optionally substituted with one or more substituents Q 7-15 In certain embodiments, each R 8 is independently heteroaryl optionally substituted with one or more substituents Q. In certain embodiments, each R 8 is independently heterocyclyl optionally substituted with one or more substituents Q. In certain embodiments, each R 8 is independently a monocyclic heterocyclyl optionally substituted with one or more substituents Q. In certain embodiments, each R 8 is independently 3-, 4-, 5-, 6-, or 7-membered heterocyclyl, each optionally substituted with one or more substituents Q. In certain embodiments, each R 8 is independently a bicyclic heterocyclyl optionally substituted with one or more substituents Q. In certain embodiments, each R 8 are independently bridged, fused, or spiro heterocyclyl, each optionally substituted with one or more substituents Q.

[0386] In certain embodiments, each R 5a is hydrogen. In certain embodiments, each R 5a is deuterium. In certain embodiments, each R 5a is cyano. In certain embodiments, each R 5a is independently halo. In certain embodiments, each R 5a is independently fluoro or chloro. In certain embodiments, each R 5a is fluoro. In certain embodiments, each R 5a is nitro. In certain embodiments, each R 5a independently represents C optionally substituted with one or more substituents Q 1-6 In certain embodiments, each R 5a is independently methyl or trifluoromethyl. In certain embodiments, each R 5a is methyl. In certain embodiments, each R5a independently represents C optionally substituted with one or more substituents Q 1-6 In certain embodiments, each R 5a independently represents C optionally substituted with one or more substituents Q 2-6 alkenyl. In certain embodiments, each R 5a independently represents C optionally substituted with one or more substituents Q 2-6 In certain embodiments, each R 5a independently represents C optionally substituted with one or more substituents Q 3-10 In certain embodiments, each R 5a independently represents C optionally substituted with one or more substituents Q 6-14 In certain embodiments, each R 5a independently represents C optionally substituted with one or more substituents Q 7-15 In certain embodiments, each R 5a is independently heteroaryl optionally substituted with one or more substituents Q. In certain embodiments, each R 5a is independently heterocyclyl optionally substituted with one or more substituents Q.

[0387] In certain embodiments, each R 5a are independently, -C(O)R 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 5a are independently -C(O)OR 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 5a are independently -C(O)NR 1b R 1c (In the formula, R 1b and R 1c and each R is as defined herein. In certain embodiments, each R 5a are independently -C(O)SR 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R5a are independently -C(NR 1a )NR 1b R 1c (In the formula, R 1a , R 1b , and R 1c and each R is as defined herein. In certain embodiments, each R 5a are independently, -C(S)R 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 5a are independently, -C(S)OR 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 5a are independently, -C(S)NR 1b R 1c (In the formula, R 1b and R 1c and each R is as defined herein. In certain embodiments, each R 5a are independently, -OR 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 5a are independently, -OC(O)R 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 5a are independently, -OC(O)OR 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 5a are independently -OC(O)NR 1b R 1c (In the formula, R 1b and R 1c and each R is as defined herein. In certain embodiments, each R 5a are independently, -OC(O)SR 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 5a are independently, -OC(NR1a )NR 1b R 1c (In the formula, R 1a , R 1b , and R 1c and each R is as defined herein. In certain embodiments, each R 5a are independently, -OC(S)R 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 5a are independently, -OC(S)OR 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 5a are independently, -OC(S)NR 1b R 1c (In the formula, R 1b and R 1c and each R is as defined herein. In certain embodiments, each R 5a are independently, -OS(O)R 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 5a are independently, -OS(O) 5a R 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 5a are independently, -OS(O)NR 1b R 1c (In the formula, R 1b and R 1c and each R is as defined herein. In certain embodiments, each R 5a are independently, -OS(O)2NR 1b R 1c (In the formula, R 1b and R 1c and each R is as defined herein. In certain embodiments, each R 5a are independently, -NR 1b R 1c (In the formula, R 1b and R 1cand each R is as defined herein. In certain embodiments, each R 5a are independently, -NR 1a C(O)R 1d (In the formula, R 1a and R 1d and each R is as defined herein. In certain embodiments, each R 5a are independently, -NR 1a C(O)OR 1d (In the formula, R 1a and R 1d and each R is as defined herein. In certain embodiments, each R 5a are independently, -NR 1a C(O)NR 1b R 1c (In the formula, R 1a , R 1b , and R 1c and each R is as defined herein. In certain embodiments, each R 5a are independently, -NR 1a C(O)SR 1d (In the formula, R 1a and R 1d and each R is as defined herein. In certain embodiments, each R 5a are independently, -NR 1a C(NR 1d )NR 1b R 1c (In the formula, R 1a , R 1b , R 1c , and R 1d and each R is as defined herein. In certain embodiments, each R 5a are independently, -NR 1a C(S)R 1d (In the formula, R 1a and R 1d and each R is as defined herein. In certain embodiments, each R 5a are independently, -NR 1a C(S)OR 1d (In the formula, R 1a and R 1dand each R is as defined herein. In certain embodiments, each R 5a are independently, -NR 1a C(S)NR 1b R 1c (In the formula, R 1a , R 1b , and R 1c and each R is as defined herein. In certain embodiments, each R 5a are independently, -NR 1a S(O)R 1d (In the formula, R 1a and R 1d and each R is as defined herein. In certain embodiments, each R 5a are independently, -NR 1a S(O)2R 1d (In the formula, R 1a and R 1d and each R is as defined herein. In certain embodiments, each R 5a are independently, -NR 1a S(O)NR 1b R 1c (In the formula, R 1a , R 1b , and R 1c and each R is as defined herein. In certain embodiments, each R 5a are independently, -NR 1a S(O)NR 1b R 1c (In the formula, R 1a , R 1b , and R 1c and each R is as defined herein. In certain embodiments, each R 5a are independently, -SR 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 5a are independently, -S(O)R 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 5a are independently -S(O)R 1a(In the formula, R 1a is as defined herein. In certain embodiments, each R 5a are independently -S(O)NR 1b R 1c (In the formula, R 1b and R 1c and each R is as defined herein. In certain embodiments, each R 5a are independently -S(O)2NR 1b R 1c (In the formula, R 1b and R 1c are each as defined herein).

[0388] In certain embodiments, each R 5b is hydrogen. In certain embodiments, each R 5b is deuterium. In certain embodiments, each R 5b is cyano. In certain embodiments, each R 5b is independently halo. In certain embodiments, each R 5b is independently fluoro or chloro. In certain embodiments, each R 5b is fluoro. In certain embodiments, each R 5b is nitro. In certain embodiments, each R 5b independently represents C optionally substituted with one or more substituents Q 1-6 In certain embodiments, each R 5b is independently methyl or trifluoromethyl. In certain embodiments, each R 5b is methyl. In certain embodiments, each R 5b independently represents C optionally substituted with one or more substituents Q 1-6 In certain embodiments, each R 5b independently represents C optionally substituted with one or more substituents Q 2-6 alkenyl. In certain embodiments, each R 5b independently represents C optionally substituted with one or more substituents Q 2-6 In certain embodiments, each R 5bindependently represents C optionally substituted with one or more substituents Q 3-10 In certain embodiments, each R 5b independently represents C optionally substituted with one or more substituents Q 6-14 In certain embodiments, each R 5b independently represents C optionally substituted with one or more substituents Q 7-15 In certain embodiments, each R 5b is independently heteroaryl optionally substituted with one or more substituents Q. In certain embodiments, each R 5b is independently heterocyclyl optionally substituted with one or more substituents Q.

[0389] In certain embodiments, each R 5b are independently, -C(O)R 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 5b are independently -C(O)OR 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 5b are independently -C(O)NR 1b R 1c (In the formula, R 1b and R 1c and each R is as defined herein. In certain embodiments, each R 5b are independently -C(O)SR 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 5b are independently -C(NR 1a )NR 1b R 1c (In the formula, R 1a , R 1b , and R 1c and each R is as defined herein. In certain embodiments, each R 5b are independently, -C(S)R 1a (In the formula, R 1ais as defined herein. In certain embodiments, each R 5b are independently, -C(S)OR 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 5b are independently, -C(S)NR 1b R 1c (In the formula, R 1b and R 1c and each R is as defined herein. In certain embodiments, each R 5b are independently, -OR 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 5b are independently, -OC(O)R 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 5b are independently, -OC(O)OR 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 5b are independently -OC(O)NR 1b R 1c (In the formula, R 1b and R 1c and each R is as defined herein. In certain embodiments, each R 5b are independently, -OC(O)SR 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 5b are independently, -OC(NR 1a )NR 1b R 1c (In the formula, R 1a , R 1b , and R 1c and each R is as defined herein. In certain embodiments, each R 5b are independently, -OC(S)R 1a (In the formula, R 1ais as defined herein. In certain embodiments, each R 5b are independently, -OC(S)OR 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 5b are independently, -OC(S)NR 1b R 1c (In the formula, R 1b and R 1c and each R is as defined herein. In certain embodiments, each R 5b are independently, -OS(O)R 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 5b are independently, -OS(O) 5b R 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 5b are independently, -OS(O)NR 1b R 1c (In the formula, R 1b and R 1c and each R is as defined herein. In certain embodiments, each R 5b are independently, -OS(O)2NR 1b R 1c (In the formula, R 1b and R 1c and each R is as defined herein. In certain embodiments, each R 5b are independently, -NR 1b R 1c (In the formula, R 1b and R 1c and each R is as defined herein. In certain embodiments, each R 5b are independently, -NR 1a C(O)R 1d (In the formula, R 1a and R 1d and each R is as defined herein. In certain embodiments, each R 5b are independently, -NR1a C(O)OR 1d (In the formula, R 1a and R 1d and each R is as defined herein. In certain embodiments, each R 5b are independently, -NR 1a C(O)NR 1b R 1c (In the formula, R 1a , R 1b , and R 1c and each R is as defined herein. In certain embodiments, each R 5b are independently, -NR 1a C(O)SR 1d (In the formula, R 1a and R 1d and each R is as defined herein. In certain embodiments, each R 5b are independently, -NR 1a C(NR 1d )NR 1b R 1c (In the formula, R 1a , R 1b , R 1c , and R 1d and each R is as defined herein. In certain embodiments, each R 5b are independently, -NR 1a C(S)R 1d (In the formula, R 1a and R 1d and each R is as defined herein. In certain embodiments, each R 5b are independently, -NR 1a C(S)OR 1d (In the formula, R 1a and R 1d and each R is as defined herein. In certain embodiments, each R 5b are independently, -NR 1a C(S)NR 1b R 1c (In the formula, R 1a , R 1b , and R 1c and each R is as defined herein. In certain embodiments, each R5b are independently, -NR 1a S(O)R 1d (In the formula, R 1a and R 1d and each R is as defined herein. In certain embodiments, each R 5b are independently, -NR 1a S(O)2R 1d (In the formula, R 1a and R 1d and each R is as defined herein. In certain embodiments, each R 5b are independently, -NR 1a S(O)NR 1b R 1c (In the formula, R 1a , R 1b , and R 1c and each R is as defined herein. In certain embodiments, each R 5b are independently, -NR 1a S(O)NR 1b R 1c (In the formula, R 1a , R 1b , and R 1c and each R is as defined herein. In certain embodiments, each R 5b are independently, -SR 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 5b are independently, -S(O)R 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 5b are independently -S(O)R 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 5b are independently -S(O)NR 1b R 1c (In the formula, R 1b and R 1c and each R is as defined herein. In certain embodiments, each R 5bare independently -S(O)2NR 1b R 1c (In the formula, R 1b and R 1c are each as defined herein).

[0390] In certain embodiments, each R 6a is hydrogen. In certain embodiments, each R 6a is deuterium. In certain embodiments, each R 6a is cyano. In certain embodiments, each R 6a is independently halo. In certain embodiments, each R 6a is independently fluoro or chloro. In certain embodiments, each R 6a is fluoro. In certain embodiments, each R 6a is nitro. In certain embodiments, each R 6a independently represents C optionally substituted with one or more substituents Q 1-6 In certain embodiments, each R 6a is independently methyl or trifluoromethyl. In certain embodiments, each R 6a is methyl. In certain embodiments, each R 6a independently represents C optionally substituted with one or more substituents Q 1-6 In certain embodiments, each R 6a independently represents C optionally substituted with one or more substituents Q 2-6 alkenyl. In certain embodiments, each R 6a independently represents C optionally substituted with one or more substituents Q 2-6 In certain embodiments, each R 6a independently represents C optionally substituted with one or more substituents Q 3-10 In certain embodiments, each R 6a independently represents C optionally substituted with one or more substituents Q 6-14 In certain embodiments, each R 6a independently represents C optionally substituted with one or more substituents Q 7-15 In certain embodiments, each R6a is independently heteroaryl optionally substituted with one or more substituents Q. In certain embodiments, each R 6a is independently heterocyclyl optionally substituted with one or more substituents Q.

[0391] In certain embodiments, each R 6a are independently, -C(O)R 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 6a are independently -C(O)OR 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 6a are independently -C(O)NR 1b R 1c (In the formula, R 1b and R 1c and each R is as defined herein. In certain embodiments, each R 6a are independently -C(O)SR 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 6a are independently -C(NR 1a )NR 1b R 1c (In the formula, R 1a , R 1b , and R 1c and each R is as defined herein. In certain embodiments, each R 6a are independently, -C(S)R 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 6a are independently, -C(S)OR 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 6a are independently, -C(S)NR 1b R 1c (In the formula, R 1b and R 1cand each R is as defined herein. In certain embodiments, each R 6a are independently, -OR 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 6a are independently, -OC(O)R 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 6a are independently, -OC(O)OR 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 6a are independently -OC(O)NR 1b R 1c (In the formula, R 1b and R 1c and each R is as defined herein. In certain embodiments, each R 6a are independently, -OC(O)SR 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 6a are independently, -OC(NR 1a )NR 1b R 1c (In the formula, R 1a , R 1b , and R 1c and each R is as defined herein. In certain embodiments, each R 6a are independently, -OC(S)R 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 6a are independently, -OC(S)OR 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 6a are independently, -OC(S)NR 1b R 1c (In the formula, R 1b and R 1cand each R is as defined herein. In certain embodiments, each R 6a are independently, -OS(O)R 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 6a are independently, -OS(O) 6a R 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 6a are independently, -OS(O)NR 1b R 1c (In the formula, R 1b and R 1c and each R is as defined herein. In certain embodiments, each R 6a are independently, -OS(O)2NR 1b R 1c (In the formula, R 1b and R 1c and each R is as defined herein. In certain embodiments, each R 6a are independently, -NR 1b R 1c (In the formula, R 1b and R 1c and each R is as defined herein. In certain embodiments, each R 6a are independently, -NR 1a C(O)R 1d (In the formula, R 1a and R 1d and each R is as defined herein. In certain embodiments, each R 6a are independently, -NR 1a C(O)OR 1d (In the formula, R 1a and R 1d and each R is as defined herein. In certain embodiments, each R 6a are independently, -NR 1a C(O)NR 1b R 1c (In the formula, R 1a , R 1b , and R 1cand each R is as defined herein. In certain embodiments, each R 6a are independently, -NR 1a C(O)SR 1d (In the formula, R 1a and R 1d and each R is as defined herein. In certain embodiments, each R 6a are independently, -NR 1a C(NR 1d )NR 1b R 1c (In the formula, R 1a , R 1b , R 1c , and R 1d and each R is as defined herein. In certain embodiments, each R 6a are independently, -NR 1a C(S)R 1d (In the formula, R 1a and R 1d and each R is as defined herein. In certain embodiments, each R 6a are independently, -NR 1a C(S)OR 1d (In the formula, R 1a and R 1d and each R is as defined herein. In certain embodiments, each R 6a are independently, -NR 1a C(S)NR 1b R 1c (In the formula, R 1a , R 1b , and R 1c and each R is as defined herein. In certain embodiments, each R 6a are independently, -NR 1a S(O)R 1d (In the formula, R 1a and R 1d and each R is as defined herein. In certain embodiments, each R 6a are independently, -NR 1a S(O)2R 1d (In the formula, R 1a and R 1dand each R is as defined herein. In certain embodiments, each R 6a are independently, -NR 1a S(O)NR 1b R 1c (In the formula, R 1a , R 1b , and R 1c and each R is as defined herein. In certain embodiments, each R 6a are independently, -NR 1a S(O)NR 1b R 1c (In the formula, R 1a , R 1b , and R 1c and each R is as defined herein. In certain embodiments, each R 6a are independently, -SR 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 6a are independently, -S(O)R 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 6a are independently -S(O)R 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 6a are independently -S(O)NR 1b R 1c (In the formula, R 1b and R 1c and each R is as defined herein. In certain embodiments, each R 6a are independently -S(O)2NR 1b R 1c (In the formula, R 1b and R 1c are each as defined herein).

[0392] In certain embodiments, each R 6b is hydrogen. In certain embodiments, each R 6bis deuterium. In certain embodiments, each R 6b is cyano. In certain embodiments, each R 6b is independently halo. In certain embodiments, each R 6b is independently fluoro or chloro. In certain embodiments, each R 6b is fluoro. In certain embodiments, each R 6b is nitro. In certain embodiments, each R 6b independently represents C optionally substituted with one or more substituents Q 1-6 In certain embodiments, each R 6b is independently methyl or trifluoromethyl. In certain embodiments, each R 6b is methyl. In certain embodiments, each R 6b independently represents C optionally substituted with one or more substituents Q 1-6 In certain embodiments, each R 6b independently represents C optionally substituted with one or more substituents Q 2-6 alkenyl. In certain embodiments, each R 6b independently represents C optionally substituted with one or more substituents Q 2-6 In certain embodiments, each R 6b independently represents C optionally substituted with one or more substituents Q 3-10 In certain embodiments, each R 6b independently represents C optionally substituted with one or more substituents Q 6-14 In certain embodiments, each R 6b independently represents C optionally substituted with one or more substituents Q 7-15 In certain embodiments, each R 6b is independently heteroaryl optionally substituted with one or more substituents Q. In certain embodiments, each R 6b is independently heterocyclyl optionally substituted with one or more substituents Q.

[0393] In certain embodiments, each R 6b are independently, -C(O)R 1a (In the formula, R1a is as defined herein. In certain embodiments, each R 6b are independently -C(O)OR 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 6b are independently -C(O)NR 1b R 1c (In the formula, R 1b and R 1c and each R is as defined herein. In certain embodiments, each R 6b are independently -C(O)SR 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 6b are independently -C(NR 1a )NR 1b R 1c (In the formula, R 1a , R 1b , and R 1c and each R is as defined herein. In certain embodiments, each R 6b are independently, -C(S)R 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 6b are independently, -C(S)OR 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 6b are independently, -C(S)NR 1b R 1c (In the formula, R 1b and R 1c and each R is as defined herein. In certain embodiments, each R 6b are independently, -OR 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 6b are independently, -OC(O)R 1a (In the formula, R 1ais as defined herein. In certain embodiments, each R 6b are independently, -OC(O)OR 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 6b are independently -OC(O)NR 1b R 1c (In the formula, R 1b and R 1c and each R is as defined herein. In certain embodiments, each R 6b are independently, -OC(O)SR 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 6b are independently, -OC(NR 1a )NR 1b R 1c (In the formula, R 1a , R 1b , and R 1c and each R is as defined herein. In certain embodiments, each R 6b are independently, -OC(S)R 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 6b are independently, -OC(S)OR 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 6b are independently, -OC(S)NR 1b R 1c (In the formula, R 1b and R 1c and each R is as defined herein. In certain embodiments, each R 6b are independently, -OS(O)R 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 6b are independently, -OS(O) 6b R 1a (In the formula, R 1ais as defined herein. In certain embodiments, each R 6b are independently, -OS(O)NR 1b R 1c (In the formula, R 1b and R 1c and each R is as defined herein. In certain embodiments, each R 6b are independently, -OS(O)2NR 1b R 1c (In the formula, R 1b and R 1c and each R is as defined herein. In certain embodiments, each R 6b are independently, -NR 1b R 1c , (where R 1b and R 1c and each R is as defined herein. In certain embodiments, each R 6b are independently, -NR 1a C(O)R 1d (In the formula, R 1a and R 1d and each R is as defined herein. In certain embodiments, each R 6b are independently, -NR 1a C(O)OR 1d (In the formula, R 1a and R 1d and each R is as defined herein. In certain embodiments, each R 6b are independently, -NR 1a C(O)NR 1b R 1c (In the formula, R 1a , R 1b , and R 1c and each R is as defined herein. In certain embodiments, each R 6b are independently, -NR 1a C(O)SR 1d (In the formula, R 1a and R 1d and each R is as defined herein. In certain embodiments, each R 6b are independently, -NR 1aC(NR 1d )NR 1b R 1c (In the formula, R 1a , R 1b , R 1c , and R 1d and each R is as defined herein. In certain embodiments, each R 6b are independently, -NR 1a C(S)R 1d (In the formula, R 1a and R 1d and each R is as defined herein. In certain embodiments, each R 6b are independently, -NR 1a C(S)OR 1d (In the formula, R 1a and R 1d and each R is as defined herein. In certain embodiments, each R 6b are independently, -NR 1a C(S)NR 1b R 1c (In the formula, R 1a , R 1b , and R 1c and each R is as defined herein. In certain embodiments, each R 6b are independently, -NR 1a S(O)R 1d (In the formula, R 1a and R 1d and each R is as defined herein. In certain embodiments, each R 6b are independently, -NR 1a S(O)2R 1d (In the formula, R 1a and R 1d and each R is as defined herein. In certain embodiments, each R 6b are independently, -NR 1a S(O)NR 1b R 1c (In the formula, R 1a , R 1b , and R 1c and each R is as defined herein. In certain embodiments, each R 6bare independently, -NR 1a S(O)NR 1b R 1c (In the formula, R 1a , R 1b , and R 1c and each R is as defined herein. In certain embodiments, each R 6b are independently, -SR 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 6b are independently, -S(O)R 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 6b are independently -S(O)R 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 6b are independently -S(O)NR 1b R 1c (In the formula, R 1b and R 1c and each R is as defined herein. In certain embodiments, each R 6b are independently -S(O)2NR 1b R 1c (In the formula, R 1b and R 1c are each as defined herein).

[0394] In certain embodiments, each R 6c is hydrogen. In certain embodiments, each R 6c is deuterium. In certain embodiments, each R 6c is cyano. In certain embodiments, each R 6c is independently halo. In certain embodiments, each R 6c is independently fluoro or chloro. In certain embodiments, each R 6c is fluoro. In certain embodiments, each R 6c is nitro. In certain embodiments, each R 6cindependently represents C optionally substituted with one or more substituents Q 1-6 In certain embodiments, each R 6c is independently methyl or trifluoromethyl. In certain embodiments, each R 6c is methyl. In certain embodiments, each R 6c independently represents C optionally substituted with one or more substituents Q 1-6 In certain embodiments, each R 6c independently represents C optionally substituted with one or more substituents Q 2-6 alkenyl. In certain embodiments, each R 6c independently represents C optionally substituted with one or more substituents Q 2-6 In certain embodiments, each R 6c independently represents C optionally substituted with one or more substituents Q 3-10 In certain embodiments, each R 6c independently represents C optionally substituted with one or more substituents Q 6-14 In certain embodiments, each R 6c independently represents C optionally substituted with one or more substituents Q 7-15 In certain embodiments, each R 6c is independently heteroaryl optionally substituted with one or more substituents Q. In certain embodiments, each R 6c is independently heterocyclyl optionally substituted with one or more substituents Q.

[0395] In certain embodiments, each R 6c are independently, -C(O)R 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 6c are independently -C(O)OR 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 6c are independently -C(O)NR 1b R 1c (In the formula, R 1b and R1c and each R is as defined herein. In certain embodiments, each R 6c are independently -C(O)SR 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 6c are independently -C(NR 1a )NR 1b R 1c (In the formula, R 1a , R 1b , and R 1c and each R is as defined herein. In certain embodiments, each R 6c are independently, -C(S)R 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 6c are independently, -C(S)OR 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 6c are independently, -C(S)NR 1b R 1c (In the formula, R 1b and R 1c and each R is as defined herein. In certain embodiments, each R 6c are independently, -OR 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 6c are independently, -OC(O)R 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 6c are independently, -OC(O)OR 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 6c are independently -OC(O)NR 1b R 1c (In the formula, R 1b and R 1cand each R is as defined herein. In certain embodiments, each R 6c are independently, -OC(O)SR 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 6c are independently, -OC(NR 1a )NR 1b R 1c (In the formula, R 1a , R 1b , and R 1c and each R is as defined herein. In certain embodiments, each R 6c are independently, -OC(S)R 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 6c are independently, -OC(S)OR 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 6c are independently, -OC(S)NR 1b R 1c (In the formula, R 1b and R 1c and each R is as defined herein. In certain embodiments, each R 6c are independently, -OS(O)R 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 6c are independently. -OS(O) 6c R 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 6c are independently, -OS(O)NR 1b R 1c (In the formula, R 1b and R 1c and each R is as defined herein. In certain embodiments, each R 6c are independently, -OS(O)2NR 1b R 1c(In the formula, R 1b and R 1c and each R is as defined herein. In certain embodiments, each R 6c are independently, -NR 1b R 1c (In the formula, R 1b and R 1c and each R is as defined herein. In certain embodiments, each R 6c are independently, -NR 1a C(O)R 1d (In the formula, R 1a and R 1d and each R is as defined herein. In certain embodiments, each R 6c are independently, -NR 1a C(O)OR 1d (In the formula, R 1a and R 1d and each R is as defined herein. In certain embodiments, each R 6c are independently, -NR 1a C(O)NR 1b R 1c (In the formula, R 1a , R 1b , and R 1c and each R is as defined herein. In certain embodiments, each R 6c are independently, -NR 1a C(O)SR 1d (In the formula, R 1a and R 1d and each R is as defined herein. In certain embodiments, each R 6c are independently, -NR 1a C(NR 1d )NR 1b R 1c (In the formula, R 1a , R 1b , R 1c , and R 1d and each R is as defined herein. In certain embodiments, each R 6c are independently, -NR 1a C(S)R 1d (In the formula, R 1aand R 1d and each R is as defined herein. In certain embodiments, each R 6c are independently, -NR 1a C(S)OR 1d (In the formula, R 1a and R 1d and each R is as defined herein. In certain embodiments, each R 6c are independently, -NR 1a C(S)NR 1b R 1c (In the formula, R 1a , R 1b , and R 1c and each R is as defined herein. In certain embodiments, each R 6c are independently, -NR 1a S(O)R 1d (In the formula, R 1a and R 1d and each R is as defined herein. In certain embodiments, each R 6c are independently, -NR 1a S(O)2R 1d (In the formula, R 1a and R 1d and each R is as defined herein. In certain embodiments, each R 6c are independently, -NR 1a S(O)NR 1b R 1c (In the formula, R 1a , R 1b , and R 1c and each R is as defined herein. In certain embodiments, each R 6c are independently, -NR 1a S(O)NR 1b R 1c (In the formula, R 1a , R 1b , and R 1c and each R is as defined herein. In certain embodiments, each R 6c are independently, -SR 1a (In the formula, R 1ais as defined herein. In certain embodiments, each R 6c are independently, -S(O)R 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 6c are independently -S(O)R 1a (In the formula, R 1a is as defined herein. In certain embodiments, each R 6c are independently -S(O)NR 1b R 1c (In the formula, R 1b and R 1c and each R is as defined herein. In certain embodiments, each R 6c are independently -S(O)2NR 1b R 1c (In the formula, R 1b and R 1c are each as defined herein).

[0396] In some embodiments, each A is O. In some embodiments, each A is S. In some embodiments, each A is S(O). In some embodiments, each A is S(O). In some embodiments, each A is independently N(R 4 )(wherein, R 4 is as defined herein). In certain embodiments, each A is independently N(R 4 )(wherein, R 4 is (i) hydrogen; (ii) C, each optionally substituted with one or more substituents Q; 1-6 Alkyl or C 1-6 heteroalkyl; or (iii) —C(O)R 1a (In the formula, R 1a is as defined herein). In certain embodiments, each A is independently N(H), N(CH), or N(C(O)CH). In certain embodiments, each A is N(H).

[0397] In certain embodiments, each X independently represents a C optionally substituted with one or more substituents Q. 1-40 In some embodiments, each X is independently a C optionally substituted with one or more substituents Q. 1-30 In some embodiments, each X is independently a C optionally substituted with one or more substituents Q. 1-20 In some embodiments, each X is independently a C optionally substituted with one or more substituents Q. 1-40 In some embodiments, each X is independently a C optionally substituted with one or more substituents Q. 1-30 In some embodiments, each X is independently a C optionally substituted with one or more substituents Q. 1-20 In some embodiments, each X is independently a C optionally substituted with one or more substituents Q. 2-40 In some embodiments, each X is independently C optionally substituted with one or more substituents Q. 2-40 In some embodiments, each X is independently a C optionally substituted with one or more substituents Q. 2-40 In some embodiments, each X is independently a C optionally substituted with one or more substituents Q. 2-40 In some embodiments, each X is independently a C optionally substituted with one or more substituents Q. 3-10 In some embodiments, each X is independently a C optionally substituted with one or more substituents Q. 6-14 In certain embodiments, each X is independently heteroaryl optionally substituted with one or more substituents Q. In certain embodiments, each X is independently heteroaryl optionally substituted with one or more substituents Q.

[0398] In some embodiments, each X is independently C 1-40 alkylene, wherein one or more methylene groups are each independently and optionally replaced by a divalent radical, and each divalent radical is independently selected from the group consisting of: C 3-10 Cycloalkylene, C 6-14and wherein the alkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q. In certain embodiments, each X is independently selected from C 1-30 alkylene, wherein one or more methylene groups are each independently and optionally replaced by a divalent radical, and each divalent radical is independently selected from the group consisting of: C 3-10 Cycloalkylene, C 6-14 and wherein the alkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q. In certain embodiments, each X is independently selected from C 1-20 alkylene, wherein one or more methylene groups are each independently and optionally replaced by a divalent radical, and each divalent radical is independently selected from the group consisting of: C 3-10 Cycloalkylene, C 6-14 arylene, heteroarylene, or heterocyclylene; and wherein the alkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q.

[0399] In some embodiments, each X is independently C 1-40 heteroalkylene, wherein one or more methylene groups are each independently and optionally replaced by a divalent radical, and each divalent radical is independently selected from the group consisting of: C 3-10 Cycloalkylene, C 6-14 and wherein the heteroalkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q. In certain embodiments, each X is independently selected from C 1-30 heteroalkylene, wherein one or more methylene groups are each independently and optionally replaced by a divalent radical, and each divalent radical is independently selected from the group consisting of: C 3-10 Cycloalkylene, C6-14 and wherein the heteroalkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q. In certain embodiments, each X is independently selected from C 1-20 heteroalkylene, wherein one or more methylene groups are each independently and optionally replaced by a divalent radical, and each divalent radical is independently selected from the group consisting of: C 3-10 Cycloalkylene, C 6-14 arylene, heteroarylene, or heterocyclylene; and wherein the heteroalkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q.

[0400] In some embodiments, each X is independently C 2-40 alkenylene, wherein one or more methylene groups are each independently and optionally replaced by a divalent radical, and each divalent radical is independently selected from the group consisting of: C 3-10 Cycloalkylene, C 6-14 and wherein the alkenylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q. In certain embodiments, each X is independently C 2-40 heteroalkenylene, wherein one or more methylene groups are each independently and optionally replaced by a divalent radical, and each divalent radical is independently selected from the group consisting of: C 3-10 Cycloalkylene, C 6-14 and wherein the heteroalkenylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q. In certain embodiments, each X is independently selected from C 2-40 alkynylene, wherein one or more methylene groups are each independently and optionally replaced by a divalent radical, and each divalent radical is independently selected from the group consisting of: C3-10 Cycloalkylene, C 6-14 and wherein the alkynylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q. In certain embodiments, each X is independently C 2-40 heteroalkynylene, wherein one or more methylene groups are each independently and optionally replaced by a divalent radical, and each divalent radical is independently selected from the group consisting of: C 3-10 Cycloalkylene, C 6-14 arylene, heteroarylene, or heterocyclylene; and wherein the heteroalkynylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q.

[0401] In some embodiments, each X is independently: [ka] is.

[0402] In some embodiments, each X is independently: [ka] is.

[0403] In some embodiments, each X is independently: [ka]

[0404] wherein in one embodiment, each u is independently an integer of 1, 2, 3, 4, 5, 6, 7, or 8; in another embodiment, each u is independently an integer of 4 or 8. is.

[0405] In some embodiments, each X is independently: [ka]

[0406] wherein in one embodiment, each u is independently an integer of 1, 2, 3, 4, 5, 6, 7, or 8; in another embodiment, each u is independently an integer of 4 or 8. is.

[0407] In some embodiments, each X is independently: [ka] is.

[0408] In some embodiments, each X is independently: [ka] is.

[0409] In some embodiments, each X is independently: [ka] is.

[0410] In some embodiments, each X is independently: [ka]

[0411] wherein in one embodiment, each u is independently an integer of 1, 2, 3, 4, 5, 6, 7, or 8; in another embodiment, each u is independently an integer of 4 or 8. is.

[0412] In certain embodiments, each Y is a bond. In certain embodiments, each Y is independently a C optionally substituted with one or more substituents Q. 1-6 In some embodiments, each Y is independently —(CH) v- (wherein v is an integer of 1, 2, 3, 4, 5, or 6). In certain embodiments, each Y is independently ethanediyl, propanediyl, or butanediyl. In certain embodiments, each Y is independently ethane-1,1-diyl, propane-1,3-diyl, or 2-methylpropane-1,3-diyl. In certain embodiments, each Y is independently C optionally substituted with one or more substituents Q. 1-6 In some embodiments, each Y is -C(O)NH- or -OC(O)NH-. In some embodiments, each Y is independently -C(O)NH- or -OC(O)NH-, optionally substituted with one or more substituents Q. 2-6 In some embodiments, each Y is independently C optionally substituted with one or more substituents Q. 2-6 In some embodiments, each Y is independently alkynylene, optionally substituted with one or more substituents Q. 3-10 In some embodiments, each Y is independently a C optionally substituted with one or more substituents Q. 6-14 In some embodiments, each Y is independently selected from the group consisting of C, optionally substituted with one or more substituents Q, and arylene. 7-15 In certain embodiments, each Y is independently heteroarylene optionally substituted with one or more substituents Q. In certain embodiments, each Y is independently heterocyclylene optionally substituted with one or more substituents Q.

[0413] In some embodiments, Z is [ka] (In the formula, R 5a and R 5b are each as defined herein) In some embodiments, Z is [ka] In some embodiments, Z is [ka] (In the formula, each R 6 , R 8 and s is as defined herein. In certain embodiments, Z is [ka] (In the formula, R 8 and R 6b and R are each as defined herein. In certain embodiments, Z is [ka] (In the formula, R 8 is C, each optionally substituted with one or more substituents Q; 1-6 Alkyl, C 1-6 Heteroalkyl, or C 3-10 cycloalkyl; and R 6b is hydrogen or halo. In some embodiments, Z is [ka] (In the formula, R 8 is methyl, cyclopropyl, or 1-fluorocyclopropyl; and R 6b is hydrogen or fluoro. In some embodiments, Z is [ka] (In the formula, R 7 , R 8 , and t are each as defined herein. is.

[0414] In certain embodiments, m is an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12. In certain embodiments, m is an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In certain embodiments, m is an integer of 1, 2, 3, 4, 5, 6, 7, or 8. In certain embodiments, m is an integer of 1. In certain embodiments, m is an integer of 2. In certain embodiments, m is an integer of 3. In certain embodiments, m is an integer of 4. In certain embodiments, m is an integer of 5. In certain embodiments, m is an integer of 6. In certain embodiments, m is an integer of 7. In certain embodiments, m is an integer of 8. In certain embodiments, m is an integer of 9. In certain embodiments, m is an integer of 10. In certain embodiments, m is an integer of 11. In certain embodiments, m is an integer of 12. In certain embodiments, m is an integer of 11. In some embodiments, m is an integer of 13. In some embodiments, m is an integer of 11. In some embodiments, m is an integer of 14. In some embodiments, m is an integer of 11. In some embodiments, m is an integer of 15. In some embodiments, m is an integer of 11. In some embodiments, m is an integer of 16.

[0415] In certain embodiments, each p is an integer of 0. In certain embodiments, each p is an integer of 1. In certain embodiments, each p is an integer of 2.

[0416] In certain embodiments, each q is an integer of 0. In certain embodiments, each q is an integer of 1. In certain embodiments, each q is an integer of 2.

[0417] In some embodiments, each s is an integer of 0. In some embodiments, each s is an integer of 1. In some embodiments, each s is an integer of 2. In some embodiments, each s is an integer of 3.

[0418] In one embodiment, provided herein is: [ka]

[0419] (In the formula, each R 1 is as defined herein and in one embodiment is hydrogen or fluoro; R A is an antibody as defined herein, and in one embodiment is an anti-B7H3 antibody, an anti-CD20 antibody, an anti-FOLR1 antibody, an anti-HER2 antibody, an anti-MSLN antibody, or an anti-TROP2 antibody; each A is as defined herein and, in one embodiment, is O or S; and m is as defined herein and, in one embodiment, is an integer of 2, 3, 4, 5, 6, 7, or 8; and wherein each linker is independently covalently connected to a thiol group of a cysteine residue of the antibody. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0420] In another embodiment, provided herein is: [ka]

[0421] (In the formula, each R 1 is as defined herein and in one embodiment is hydrogen or fluoro; R A is an antibody as defined herein, and in one embodiment is an anti-B7H3 antibody, an anti-CD20 antibody, an anti-FOLR1 antibody, an anti-HER2 antibody, an anti-MSLN antibody, or an anti-TROP2 antibody; each A is as defined herein and, in one embodiment, is O or S; and m is as defined herein and, in one embodiment, is an integer of 2, 3, 4, 5, 6, 7, or 8; and wherein each linker is independently covalently connected to a thiol group of a cysteine residue of the antibody. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0422] In yet another embodiment, provided herein is: [ka]

[0423] (In the formula, each R 1 is as defined herein and in one embodiment is hydrogen or fluoro; R A is an antibody as defined herein, and in one embodiment is an anti-B7H3 antibody, an anti-CD20 antibody, an anti-FOLR1 antibody, an anti-HER2 antibody, an anti-MSLN antibody, or an anti-TROP2 antibody; each A is as defined herein and, in one embodiment, is O or S; and m is as defined herein and, in one embodiment, is an integer of 2, 3, 4, 5, 6, 7, or 8; and wherein each linker is independently covalently connected to a thiol group of a cysteine residue of the antibody. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0424] In yet another embodiment, provided herein is: [ka]

[0425] (In the formula, each R 1 is as defined herein and in one embodiment is hydrogen or fluoro; R Ais an antibody as defined herein, and in one embodiment is an anti-B7H3 antibody, an anti-CD20 antibody, an anti-FOLR1 antibody, an anti-HER2 antibody, an anti-MSLN antibody, or an anti-TROP2 antibody; each A is as defined herein and, in one embodiment, is O or S; and m is as defined herein and, in one embodiment, is an integer of 2, 3, 4, 5, 6, 7, or 8; and wherein each linker is independently covalently connected to a thiol group of a cysteine residue of the antibody. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0426] In yet another embodiment, provided herein is: [ka]

[0427] (In the formula, each R 1 is as defined herein and in one embodiment is hydrogen or fluoro; R A is an antibody as defined herein, and in one embodiment is an anti-B7H3 antibody, an anti-CD20 antibody, an anti-FOLR1 antibody, an anti-HER2 antibody, an anti-MSLN antibody, or an anti-TROP2 antibody; each A is as defined herein and, in one embodiment, is O or S; and m is as defined herein and, in one embodiment, is an integer of 2, 3, 4, 5, 6, 7, or 8; and wherein each linker is independently covalently connected to a thiol group of a cysteine residue of the antibody. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0428] In yet another embodiment, provided herein is: [ka]

[0429] (In the formula, each R 1 is as defined herein and in one embodiment is hydrogen or fluoro; R A is an antibody as defined herein, and in one embodiment is an anti-B7H3 antibody, an anti-CD20 antibody, an anti-FOLR1 antibody, an anti-HER2 antibody, an anti-MSLN antibody, or an anti-TROP2 antibody; each A is as defined herein and, in one embodiment, is O or S; and m is as defined herein and, in one embodiment, is an integer of 2, 3, 4, 5, 6, 7, or 8; and wherein each linker is independently covalently connected to a thiol group of a cysteine residue of the antibody. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0430] In one embodiment, provided herein is: [ka]

[0431] (In the formula, each R 1 is as defined herein and, in one embodiment, is hydrogen or fluoro; 6b is as defined herein and in one embodiment is hydrogen or fluoro; R Ais an antibody as defined herein, and in one embodiment is an anti-B7H3 antibody, an anti-CD20 antibody, an anti-FOLR1 antibody, an anti-HER2 antibody, an anti-MSLN antibody, or an anti-TROP2 antibody; each A is as defined herein and, in one embodiment, is O or S; and m is as defined herein and, in one embodiment, is an integer of 2, 3, 4, 5, 6, 7, or 8; and wherein each linker is independently covalently connected to a thiol group of a cysteine residue of the antibody. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0432] In another embodiment, provided herein is: [ka]

[0433] (In the formula, each R 1 is as defined herein and, in one embodiment, is hydrogen or fluoro; 6b is as defined herein and in one embodiment is hydrogen or fluoro; R A is an antibody as defined herein, and in one embodiment is an anti-B7H3 antibody, an anti-CD20 antibody, an anti-FOLR1 antibody, an anti-HER2 antibody, an anti-MSLN antibody, or an anti-TROP2 antibody; each A is as defined herein and, in one embodiment, is O or S; and m is as defined herein and, in one embodiment, is an integer of 2, 3, 4, 5, 6, 7, or 8; and wherein each linker is independently covalently connected to a thiol group of a cysteine residue of the antibody. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0434] In yet another embodiment, provided herein is: [ka]

[0435] (In the formula, each R 1 is as defined herein and, in one embodiment, is hydrogen or fluoro; 6b is as defined herein and in one embodiment is hydrogen or fluoro; R A is an antibody as defined herein, and in one embodiment is an anti-B7H3 antibody, an anti-CD20 antibody, an anti-FOLR1 antibody, an anti-HER2 antibody, an anti-MSLN antibody, or an anti-TROP2 antibody; each A is as defined herein and, in one embodiment, is O or S; and m is as defined herein and, in one embodiment, is an integer of 2, 3, 4, 5, 6, 7, or 8; and wherein each linker is independently covalently connected to a thiol group of a cysteine residue of the antibody. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0436] In yet another embodiment, provided herein is: [ka]

[0437] (In the formula, each R 1 is as defined herein and, in one embodiment, is hydrogen or fluoro; 6b is as defined herein and in one embodiment is hydrogen or fluoro; R Ais an antibody as defined herein, and in one embodiment is an anti-B7H3 antibody, an anti-CD20 antibody, an anti-FOLR1 antibody, an anti-HER2 antibody, an anti-MSLN antibody, or an anti-TROP2 antibody; each A is as defined herein and, in one embodiment, is O or S; and m is as defined herein and, in one embodiment, is an integer of 2, 3, 4, 5, 6, 7, or 8; and wherein each linker is independently covalently connected to a thiol group of a cysteine residue of the antibody. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0438] In yet another embodiment, provided herein is: [ka]

[0439] (In the formula, each R 1 is as defined herein and, in one embodiment, is hydrogen or fluoro; 6b is as defined herein and in one embodiment is hydrogen or fluoro; R A is an antibody as defined herein, and in one embodiment is an anti-B7H3 antibody, an anti-CD20 antibody, an anti-FOLR1 antibody, an anti-HER2 antibody, an anti-MSLN antibody, or an anti-TROP2 antibody; each A is as defined herein and, in one embodiment, is O or S; and m is as defined herein and, in one embodiment, is an integer of 2, 3, 4, 5, 6, 7, or 8; and wherein each linker is independently covalently connected to a thiol group of a cysteine residue of the antibody. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0440] In yet another embodiment, provided herein is: [ka]

[0441] (In the formula, each R 1 is as defined herein and, in one embodiment, is hydrogen or fluoro; 6b is as defined herein and in one embodiment is hydrogen or fluoro; R A is an antibody as defined herein, and in one embodiment is an anti-B7H3 antibody, an anti-CD20 antibody, an anti-FOLR1 antibody, an anti-HER2 antibody, an anti-MSLN antibody, or an anti-TROP2 antibody; each A is as defined herein and, in one embodiment, is O or S; and m is as defined herein and, in one embodiment, is an integer of 2, 3, 4, 5, 6, 7, or 8; and wherein each linker is independently covalently connected to a thiol group of a cysteine residue of the antibody. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0442] In one embodiment, provided herein is: [ka]

[0443] (In the formula, each R 1 is as defined herein and, in one embodiment, is hydrogen or fluoro; 6b is as defined herein and in one embodiment is hydrogen or fluoro; R Ais an antibody as defined herein, and in one embodiment is an anti-B7H3 antibody, an anti-CD20 antibody, an anti-FOLR1 antibody, an anti-HER2 antibody, an anti-MSLN antibody, or an anti-TROP2 antibody; each A is as defined herein and, in one embodiment, is O or S; and m is as defined herein and, in one embodiment, is an integer of 2, 3, 4, 5, 6, 7, or 8; and wherein each linker is independently covalently connected to a thiol group of a cysteine residue of the antibody. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0444] In another embodiment, provided herein is: [ka]

[0445] (In the formula, each R 1 is as defined herein and, in one embodiment, is hydrogen or fluoro; 6b is as defined herein and in one embodiment is hydrogen or fluoro; R A is an antibody as defined herein, and in one embodiment is an anti-B7H3 antibody, an anti-CD20 antibody, an anti-FOLR1 antibody, an anti-HER2 antibody, an anti-MSLN antibody, or an anti-TROP2 antibody; each A is as defined herein and, in one embodiment, is O or S; and m is as defined herein and, in one embodiment, is an integer of 2, 3, 4, 5, 6, 7, or 8; and wherein each linker is independently covalently connected to a thiol group of a cysteine residue of the antibody. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0446] In yet another embodiment, provided herein is: [ka]

[0447] (In the formula, each R 1 is as defined herein and, in one embodiment, is hydrogen or fluoro; 6b is as defined herein and in one embodiment is hydrogen or fluoro; R A is an antibody as defined herein, and in one embodiment is an anti-B7H3 antibody, an anti-CD20 antibody, an anti-FOLR1 antibody, an anti-HER2 antibody, an anti-MSLN antibody, or an anti-TROP2 antibody; each A is as defined herein and, in one embodiment, is O or S; and m is as defined herein and, in one embodiment, is an integer of 2, 3, 4, 5, 6, 7, or 8; and wherein each linker is independently covalently connected to a thiol group of a cysteine residue of the antibody. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0448] In yet another embodiment, provided herein is: [ka]

[0449] (In the formula, each R 1 is as defined herein and, in one embodiment, is hydrogen or fluoro; 6b is as defined herein and in one embodiment is hydrogen or fluoro; R Ais an antibody as defined herein, and in one embodiment is an anti-B7H3 antibody, an anti-CD20 antibody, an anti-FOLR1 antibody, an anti-HER2 antibody, an anti-MSLN antibody, or an anti-TROP2 antibody; each A is as defined herein and, in one embodiment, is O or S; and m is as defined herein and, in one embodiment, is an integer of 2, 3, 4, 5, 6, 7, or 8; and wherein each linker is independently covalently connected to a thiol group of a cysteine residue of the antibody. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0450] In yet another embodiment, provided herein is: [ka]

[0451] (In the formula, each R 1 is as defined herein and, in one embodiment, is hydrogen or fluoro; 6b is as defined herein and in one embodiment is hydrogen or fluoro; R A is an antibody as defined herein, and in one embodiment is an anti-B7H3 antibody, an anti-CD20 antibody, an anti-FOLR1 antibody, an anti-HER2 antibody, an anti-MSLN antibody, or an anti-TROP2 antibody; each A is as defined herein and, in one embodiment, is O or S; and m is as defined herein and, in one embodiment, is an integer of 2, 3, 4, 5, 6, 7, or 8; and wherein each linker is independently covalently connected to a thiol group of a cysteine residue of the antibody. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0452] In yet another embodiment, provided herein is: [ka]

[0453] (In the formula, each R 1 is as defined herein and, in one embodiment, is hydrogen or fluoro; 6b is as defined herein and in one embodiment is hydrogen or fluoro; R A is an antibody as defined herein, and in one embodiment is an anti-B7H3 antibody, an anti-CD20 antibody, an anti-FOLR1 antibody, an anti-HER2 antibody, an anti-MSLN antibody, or an anti-TROP2 antibody; each A is as defined herein and, in one embodiment, is O or S; and m is as defined herein and, in one embodiment, is an integer of 2, 3, 4, 5, 6, 7, or 8; and wherein each linker is independently covalently connected to a thiol group of a cysteine residue of the antibody. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0454] In one embodiment, provided herein is: [ka]

[0455] (In the formula, each R 1 is as defined herein and, in one embodiment, is hydrogen or fluoro; 6b is as defined herein and in one embodiment is hydrogen or fluoro; R Ais an antibody as defined herein, and in one embodiment is an anti-B7H3 antibody, an anti-CD20 antibody, an anti-FOLR1 antibody, an anti-HER2 antibody, an anti-MSLN antibody, or an anti-TROP2 antibody; each A is as defined herein and, in one embodiment, is O or S; and m is as defined herein and, in one embodiment, is an integer of 2, 3, 4, 5, 6, 7, or 8; and wherein each linker is independently covalently connected to a thiol group of a cysteine residue of the antibody. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0456] In another embodiment, provided herein is: [ka]

[0457] (In the formula, each R 1 is as defined herein and, in one embodiment, is hydrogen or fluoro; 6b is as defined herein and in one embodiment is hydrogen or fluoro; R A is an antibody as defined herein, and in one embodiment is an anti-B7H3 antibody, an anti-CD20 antibody, an anti-FOLR1 antibody, an anti-HER2 antibody, an anti-MSLN antibody, or an anti-TROP2 antibody; each A is as defined herein and, in one embodiment, is O or S; and m is as defined herein and, in one embodiment, is an integer of 2, 3, 4, 5, 6, 7, or 8; and wherein each linker is independently covalently connected to a thiol group of a cysteine residue of the antibody. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0458] In yet another embodiment, provided herein is: [ka]

[0459] (In the formula, each R 1 is as defined herein and, in one embodiment, is hydrogen or fluoro; 6b is as defined herein and in one embodiment is hydrogen or fluoro; R A is an antibody as defined herein, and in one embodiment is an anti-B7H3 antibody, an anti-CD20 antibody, an anti-FOLR1 antibody, an anti-HER2 antibody, an anti-MSLN antibody, or an anti-TROP2 antibody; each A is as defined herein and, in one embodiment, is O or S; and m is as defined herein and, in one embodiment, is an integer of 2, 3, 4, 5, 6, 7, or 8; and wherein each linker is independently covalently connected to a thiol group of a cysteine residue of the antibody. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0460] In yet another embodiment, provided herein is: [ka]

[0461] (In the formula, each R 1 is as defined herein and, in one embodiment, is hydrogen or fluoro; 6b is as defined herein and in one embodiment is hydrogen or fluoro; R Ais an antibody as defined herein, and in one embodiment is an anti-B7H3 antibody, an anti-CD20 antibody, an anti-FOLR1 antibody, an anti-HER2 antibody, an anti-MSLN antibody, or an anti-TROP2 antibody; each A is as defined herein and, in one embodiment, is O or S; and m is as defined herein and, in one embodiment, is an integer of 2, 3, 4, 5, 6, 7, or 8; and wherein each linker is independently covalently connected to a thiol group of a cysteine residue of the antibody. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0462] In yet another embodiment, provided herein is: [ka]

[0463] (In the formula, each R 1 is as defined herein and, in one embodiment, is hydrogen or fluoro; 6b is as defined herein and in one embodiment is hydrogen or fluoro; R A is an antibody as defined herein, and in one embodiment is an anti-B7H3 antibody, an anti-CD20 antibody, an anti-FOLR1 antibody, an anti-HER2 antibody, an anti-MSLN antibody, or an anti-TROP2 antibody; each A is as defined herein and, in one embodiment, is O or S; and m is as defined herein and, in one embodiment, is an integer of 2, 3, 4, 5, 6, 7, or 8; and wherein each linker is independently covalently connected to a thiol group of a cysteine residue of the antibody. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0464] In yet another embodiment, provided herein is: [ka]

[0465] (In the formula, each R 1 is as defined herein and, in one embodiment, is hydrogen or fluoro; 6b is as defined herein and in one embodiment is hydrogen or fluoro; R A is an antibody as defined herein, and in one embodiment is an anti-B7H3 antibody, an anti-CD20 antibody, an anti-FOLR1 antibody, an anti-HER2 antibody, an anti-MSLN antibody, or an anti-TROP2 antibody; each A is as defined herein and, in one embodiment, is O or S; and m is as defined herein and, in one embodiment, is an integer of 2, 3, 4, 5, 6, 7, or 8; and wherein each linker is independently covalently connected to a thiol group of a cysteine residue of the antibody. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0466] In one embodiment, provided herein is: [ka]

[0467] (In the formula, each R 1 is as defined herein and, in one embodiment, is hydrogen or fluoro; 6b is as defined herein and in one embodiment is hydrogen or fluoro; R Ais an antibody as defined herein, and in one embodiment is an anti-B7H3 antibody, an anti-CD20 antibody, an anti-FOLR1 antibody, an anti-HER2 antibody, an anti-MSLN antibody, or an anti-TROP2 antibody; each A is as defined herein and in one embodiment is O or S; m is as defined herein and in one embodiment is an integer of 2, 3, 4, 5, 6, 7, or 8; and each u is an integer of 1, 2, 3, 4, 5, 6, 7, or 8, and in one embodiment is an integer of 4 or 8; and wherein each linker is independently covalently connected to a thiol group of a cysteine residue of the antibody. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0468] In another embodiment, provided herein is: [ka]

[0469] (In the formula, each R 1 is as defined herein and, in one embodiment, is hydrogen or fluoro; 6b is as defined herein and in one embodiment is hydrogen or fluoro; R A is an antibody as defined herein, and in one embodiment is an anti-B7H3 antibody, an anti-CD20 antibody, an anti-FOLR1 antibody, an anti-HER2 antibody, an anti-MSLN antibody, or an anti-TROP2 antibody; each A is as defined herein and in one embodiment is O or S; m is as defined herein and in one embodiment is an integer of 2, 3, 4, 5, 6, 7, or 8; and each u is as defined herein and in one embodiment is an integer of 4 or 8; and wherein each linker is independently covalently connected to a thiol group of a cysteine residue of the antibody. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0470] In yet another embodiment, provided herein is: [ka]

[0471] (In the formula, each R 1 is as defined herein and, in one embodiment, is hydrogen or fluoro; 6b is as defined herein and in one embodiment is hydrogen or fluoro; R A is an antibody as defined herein, and in one embodiment is an anti-B7H3 antibody, an anti-CD20 antibody, an anti-FOLR1 antibody, an anti-HER2 antibody, an anti-MSLN antibody, or an anti-TROP2 antibody; each A is as defined herein and in one embodiment is O or S; m is as defined herein and in one embodiment is an integer of 2, 3, 4, 5, 6, 7, or 8; and each u is as defined herein and in one embodiment is an integer of 4 or 8; and wherein each linker is independently covalently connected to a thiol group of a cysteine residue of the antibody. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0472] In yet another embodiment, provided herein is: [ka]

[0473] (In the formula, each R 1is as defined herein and, in one embodiment, is hydrogen or fluoro; 6b is as defined herein and in one embodiment is hydrogen or fluoro; R A is an antibody as defined herein, and in one embodiment is an anti-B7H3 antibody, an anti-CD20 antibody, an anti-FOLR1 antibody, an anti-HER2 antibody, an anti-MSLN antibody, or an anti-TROP2 antibody; each A is as defined herein and in one embodiment is O or S; m is as defined herein and in one embodiment is an integer of 2, 3, 4, 5, 6, 7, or 8; and each u is as defined herein and in one embodiment is an integer of 4 or 8; and wherein each linker is independently covalently connected to a thiol group of a cysteine residue of the antibody. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0474] In yet another embodiment, provided herein is: [ka]

[0475] (In the formula, each R 1 is as defined herein and, in one embodiment, is hydrogen or fluoro; 6b is as defined herein and in one embodiment is hydrogen or fluoro; R Ais an antibody as defined herein, and in one embodiment is an anti-B7H3 antibody, an anti-CD20 antibody, an anti-FOLR1 antibody, an anti-HER2 antibody, an anti-MSLN antibody, or an anti-TROP2 antibody; each A is as defined herein and in one embodiment is O or S; m is as defined herein and in one embodiment is an integer of 2, 3, 4, 5, 6, 7, or 8; and each u is as defined herein and in one embodiment is an integer of 4 or 8; and wherein each linker is independently covalently connected to a thiol group of a cysteine residue of the antibody. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0476] In yet another embodiment, provided herein is: [ka]

[0477] (In the formula, each R 1 is as defined herein and, in one embodiment, is hydrogen or fluoro; 6b is as defined herein and in one embodiment is hydrogen or fluoro; R A is an antibody as defined herein, and in one embodiment is an anti-B7H3 antibody, an anti-CD20 antibody, an anti-FOLR1 antibody, an anti-HER2 antibody, an anti-MSLN antibody, or an anti-TROP2 antibody; each A is as defined herein and in one embodiment is O or S; m is as defined herein and in one embodiment is an integer of 2, 3, 4, 5, 6, 7, or 8; and each u is as defined herein and in one embodiment is an integer of 4 or 8; and wherein each linker is independently covalently connected to a thiol group of a cysteine residue of the antibody. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0478] In one embodiment, provided herein is: [ka]

[0479] (In the formula, each R 1 is as defined herein and, in one embodiment, is hydrogen or fluoro; 6b is as defined herein and in one embodiment is hydrogen or fluoro; R A is an antibody as defined herein, and in one embodiment is an anti-B7H3 antibody, an anti-CD20 antibody, an anti-FOLR1 antibody, an anti-HER2 antibody, an anti-MSLN antibody, or an anti-TROP2 antibody; each A is as defined herein and, in one embodiment, is O or S; m is as defined herein and, in one embodiment, is an integer of 2, 3, 4, 5, 6, 7, or 8; and each u is as defined herein and, in one embodiment, is an integer of 4 or 8; and wherein each linker is independently covalently connected to a thiol group of a cysteine residue of the antibody. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0480] In another embodiment, provided herein is: [ka]

[0481] (In the formula, each R 1is as defined herein and, in one embodiment, is hydrogen or fluoro; 6b is as defined herein and in one embodiment is hydrogen or fluoro; R A is an antibody as defined herein, and in one embodiment is an anti-B7H3 antibody, an anti-CD20 antibody, an anti-FOLR1 antibody, an anti-HER2 antibody, an anti-MSLN antibody, or an anti-TROP2 antibody; each A is as defined herein and in one embodiment is O or S; m is as defined herein and in one embodiment is an integer of 2, 3, 4, 5, 6, 7, or 8; and each u is as defined herein and in one embodiment is an integer of 4 or 8; and wherein each linker is independently covalently connected to a thiol group of a cysteine residue of the antibody. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0482] In yet another embodiment, provided herein is: [ka]

[0483] (In the formula, each R 1 is as defined herein and, in one embodiment, is hydrogen or fluoro; 6b is as defined herein and in one embodiment is hydrogen or fluoro; R Ais an antibody as defined herein, and in one embodiment is an anti-B7H3 antibody, an anti-CD20 antibody, an anti-FOLR1 antibody, an anti-HER2 antibody, an anti-MSLN antibody, or an anti-TROP2 antibody; each A is as defined herein and in one embodiment is O or S; m is as defined herein and in one embodiment is an integer of 2, 3, 4, 5, 6, 7, or 8; and each u is as defined herein and in one embodiment is an integer of 4 or 8; and wherein each linker is independently covalently connected to a thiol group of a cysteine residue of the antibody. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0484] In yet another embodiment, provided herein is: [ka]

[0485] (In the formula, each R 1 is as defined herein and, in one embodiment, is hydrogen or fluoro; 6b is as defined herein and in one embodiment is hydrogen or fluoro; R A is an antibody as defined herein, and in one embodiment is an anti-B7H3 antibody, an anti-CD20 antibody, an anti-FOLR1 antibody, an anti-HER2 antibody, an anti-MSLN antibody, or an anti-TROP2 antibody; each A is as defined herein and in one embodiment is O or S; m is as defined herein and in one embodiment is an integer of 2, 3, 4, 5, 6, 7, or 8; and each u is as defined herein and in one embodiment is an integer of 4 or 8; and wherein each linker is independently covalently connected to a thiol group of a cysteine residue of the antibody. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0486] In yet another embodiment, provided herein is: [ka]

[0487] (In the formula, each R 1 is as defined herein and, in one embodiment, is hydrogen or fluoro; 6b is as defined herein and in one embodiment is hydrogen or fluoro; R A is an antibody as defined herein, and in one embodiment is an anti-B7H3 antibody, an anti-CD20 antibody, an anti-FOLR1 antibody, an anti-HER2 antibody, an anti-MSLN antibody, or an anti-TROP2 antibody; each A is as defined herein and in one embodiment is O or S; m is as defined herein and in one embodiment is an integer of 2, 3, 4, 5, 6, 7, or 8; and each u is as defined herein and in one embodiment is an integer of 4 or 8; and wherein each linker is independently covalently connected to a thiol group of a cysteine residue of the antibody. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0488] In yet another embodiment, provided herein is: [ka]

[0489] (In the formula, each R 1is as defined herein and, in one embodiment, is hydrogen or fluoro; 6b is as defined herein and in one embodiment is hydrogen or fluoro; R A is an antibody as defined herein, and in one embodiment is an anti-B7H3 antibody, an anti-CD20 antibody, an anti-FOLR1 antibody, an anti-HER2 antibody, an anti-MSLN antibody, or an anti-TROP2 antibody; each A is as defined herein and in one embodiment is O or S; m is as defined herein and in one embodiment is an integer of 2, 3, 4, 5, 6, 7, or 8; and each u is as defined herein and in one embodiment is an integer of 4 or 8; and wherein each linker is independently covalently connected to a thiol group of a cysteine residue of the antibody. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0490] In one embodiment, provided herein is: [ka]

[0491] (In the formula, each R 1 is as defined herein and, in one embodiment, is hydrogen or fluoro; 6b is as defined herein and in one embodiment is hydrogen or fluoro; R Ais an antibody as defined herein, and in one embodiment is an anti-B7H3 antibody, an anti-CD20 antibody, an anti-FOLR1 antibody, an anti-HER2 antibody, an anti-MSLN antibody, or an anti-TROP2 antibody; each A is as defined herein and, in one embodiment, is O or S; and m is as defined herein and, in one embodiment, is an integer of 2, 3, 4, 5, 6, 7, or 8; and wherein each linker is independently covalently connected to a thiol group of a cysteine residue of the antibody. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0492] In another embodiment, provided herein is: [ka]

[0493] (In the formula, each R 1 is as defined herein and, in one embodiment, is hydrogen or fluoro; 6b is as defined herein and in one embodiment is hydrogen or fluoro; R A is an antibody as defined herein, and in one embodiment is an anti-B7H3 antibody, an anti-CD20 antibody, an anti-FOLR1 antibody, an anti-HER2 antibody, an anti-MSLN antibody, or an anti-TROP2 antibody; each A is as defined herein and, in one embodiment, is O or S; and m is as defined herein and, in one embodiment, is an integer of 2, 3, 4, 5, 6, 7, or 8; and wherein each linker is independently covalently connected to a thiol group of a cysteine residue of the antibody. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0494] In yet another embodiment, provided herein is: [ka]

[0495] (In the formula, each R 1 is as defined herein and, in one embodiment, is hydrogen or fluoro; 6b is as defined herein and in one embodiment is hydrogen or fluoro; R A is an antibody as defined herein, and in one embodiment is an anti-B7H3 antibody, an anti-CD20 antibody, an anti-FOLR1 antibody, an anti-HER2 antibody, an anti-MSLN antibody, or an anti-TROP2 antibody; each A is as defined herein and, in one embodiment, is O or S; and m is as defined herein and, in one embodiment, is an integer of 2, 3, 4, 5, 6, 7, or 8; and wherein each linker is independently covalently connected to a thiol group of a cysteine residue of the antibody. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0496] In yet another embodiment, provided herein is: [ka]

[0497] (In the formula, each R 1 is as defined herein and, in one embodiment, is hydrogen or fluoro; 6b is as defined herein and in one embodiment is hydrogen or fluoro; R Ais an antibody as defined herein, and in one embodiment is an anti-B7H3 antibody, an anti-CD20 antibody, an anti-FOLR1 antibody, an anti-HER2 antibody, an anti-MSLN antibody, or an anti-TROP2 antibody; each A is as defined herein and, in one embodiment, is O or S; and m is as defined herein and, in one embodiment, is an integer of 2, 3, 4, 5, 6, 7, or 8; and wherein each linker is independently covalently connected to a thiol group of a cysteine residue of the antibody. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0498] In yet another embodiment, provided herein is: [ka]

[0499] (In the formula, each R 1 is as defined herein and, in one embodiment, is hydrogen or fluoro; 6b is as defined herein and in one embodiment is hydrogen or fluoro; R A is an antibody as defined herein, and in one embodiment is an anti-B7H3 antibody, an anti-CD20 antibody, an anti-FOLR1 antibody, an anti-HER2 antibody, an anti-MSLN antibody, or an anti-TROP2 antibody; each A is as defined herein and, in one embodiment, is O or S; and m is as defined herein and, in one embodiment, is an integer of 2, 3, 4, 5, 6, 7, or 8; and wherein each linker is independently covalently connected to a thiol group of a cysteine residue of the antibody. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0500] In yet another embodiment, provided herein is: [ka]

[0501] (In the formula, each R 1 is as defined herein and, in one embodiment, is hydrogen or fluoro; 6b is as defined herein and in one embodiment is hydrogen or fluoro; R A is an antibody as defined herein, and in one embodiment is an anti-B7H3 antibody, an anti-CD20 antibody, an anti-FOLR1 antibody, an anti-HER2 antibody, an anti-MSLN antibody, or an anti-TROP2 antibody; each A is as defined herein and, in one embodiment, is O or S; and m is as defined herein and, in one embodiment, is an integer of 2, 3, 4, 5, 6, 7, or 8; and wherein each linker is independently covalently connected to a thiol group of a cysteine residue of the antibody. or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0502] In certain embodiments, the ADC compounds provided in compositions (e.g., pharmaceutical compositions) herein have a drug-to-antibody ratio (DAR) ranging from about 0.5 to about 12, from about 1 to about 10, from about 2 to about 8, or from about 3 to about 5. In certain embodiments, the ADC compounds provided in compositions (e.g., pharmaceutical compositions) herein have a DAR ranging from about 0.5 to about 12. In certain embodiments, the ADC compounds provided in compositions (e.g., pharmaceutical compositions) herein have a DAR ranging from about 1 to about 10. In certain embodiments, the ADC compounds provided in compositions (e.g., pharmaceutical compositions) herein have a DAR ranging from about 2 to about 8. In certain embodiments, the ADC compounds provided in compositions (e.g., pharmaceutical compositions) herein have a DAR ranging from about 3 to about 5. In certain embodiments, the ADC compounds provided in compositions (e.g., pharmaceutical compositions) herein have a DAR of about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, about 7, about 7.5, or about 8.

[0503] In one embodiment, provided herein is:

[0504] 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N-((S)-1-(((S)-1-(((S)-9-ethyl-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]-quinolin-4-yl)amino)-1-oxopropan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)-hexanamide A1;

[0505] 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N-((S)-1-(((S)-1-(((S)-9-ethyl-5-fluoro-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]-indolizino[1,2-b]quinolin-4-yl)amino)-1-oxopropan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)-hexanamide A2;

[0506] 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N-(2-((2-(((S)-1-((2-(((S)-9-ethyl-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]-indolizino[1,2-b]quinolin-4-yl)amino)-2-oxoethyl)amino)-1-oxo-3-phenylpropan-2-yl)amino)-2-oxoethyl)-amino)-2-oxoethyl)hexanamide A3;

[0507] 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N-(2-((2-(((S)-1-((2-(((S)-9-ethyl-5-fluoro-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]-indolizino[1,2-b]quinolin-4-yl)amino)-2-oxoethyl)amino)-1-oxo-3-phenylpropan-2-yl)amino)-2-oxoethyl)amino)-2-oxoethyl)hexanamide A4;

[0508] 4-((S)-2-((S)-2-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanamido)-3-methyl-butanamido)-5-ureidopentanamido)benzyl ((S)-9-ethyl-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl)carbamate A5;

[0509] 4-((S)-2-((S)-2-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanamido)-3-methyl-butanamido)-5-ureidopentanamido)benzyl ((S)-9-ethyl-5-fluoro-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl)-carbamate A6;

[0510] 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N-((S)-1-(((S)-1-(((S)-9-ethyl-9-hydroxy-10,13-dioxo-9,10,13,15-tetrahydro-1H,3H,12H-pyrano[3,4,5-de]pyrano[3',4':6,7]-indolizino[1,2-b]quinolin-4-yl)amino)-1-oxopropan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)-hexanamide A7; or

[0511] 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N-((S)-1-(((S)-1-(((S)-9-ethyl-5-fluoro-9-hydroxy-10,13-dioxo-9,10,13,15-tetrahydro-1H,3H,12H-pyrano[3,4,5-de]pyrano[3',4':6,7]-indolizino[1,2-b]quinolin-4-yl)amino)-1-oxopropan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)-hexanamide A8;

[0512] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0513] In another embodiment, provided herein is:

[0514] 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N-((S)-1-(((S)-1-(((S)-9-ethyl-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[3',4':6,7]indolizino[1,2-b]-thiopyrano[4,3,2-de]quinolin-4-yl)amino)-1-oxopropan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)-hexanamide B1;

[0515] 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N-((S)-1-(((S)-1-(((S)-9-ethyl-5-fluoro-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[3',4':6,7]indolizino[1,2-b]thio-pyrano[4,3,2-de]quinolin-4-yl)amino)-1-oxopropan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)-hexanamide B2;

[0516] 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N-(2-((2-(((S)-1-((2-(((S)-9-ethyl-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[3',4':6,7]indolizino[1,2-b]thio-pyrano[4,3,2-de]quinolin-4-yl)amino)-2-oxoethyl)amino)-1-oxo-3-phenylpropan-2-yl)amino)-2-oxoethyl)amino)-2-oxoethyl)hexanamide B3;

[0517] 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N-(2-((2-(((S)-1-((2-(((S)-9-ethyl-5-fluoro-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[3',4':6,7]indolizino[1,2-b]-thiopyrano[4,3,2-de]quinolin-4-yl)amino)-2-oxoethyl)amino)-1-oxo-3-phenylpropan-2-yl)-amino)-2-oxoethyl)amino)-2-oxoethyl)hexanamide B4;

[0518] 4-((S)-2-((S)-2-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanamido)-3-methyl-butanamido)-5-ureidopentanamido)benzyl ((S)-9-ethyl-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[3',4':6,7]indolizino[1,2-b]thiopyrano[4,3,2-de]quinolin-4-yl)carbamate B5;

[0519] 4-((S)-2-((S)-2-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanamido)-3-methyl-butanamido)-5-ureidopentanamido)benzyl ((S)-9-ethyl-5-fluoro-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[3',4':6,7]indolizino[1,2-b]thiopyrano[4,3,2-de]quinolin-4-yl)carbamate B6;

[0520] 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N-((S)-1-(((S)-1-(((S)-9-ethyl-9-hydroxy-10,13-dioxo-9,10,13,15-tetrahydro-1H,3H,12H-pyrano[3',4':6,7]indolizino[1,2-b]-thiopyrano[3,4,5-de]quinolin-4-yl)amino)-1-oxopropan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)-hexanamide B7; or

[0521] 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N-((S)-1-(((S)-1-(((S)-9-ethyl-5-fluoro-9-hydroxy-10,13-dioxo-9,10,13,15-tetrahydro-1H,3H,12H-pyrano[3',4':6,7]indolizino[1,2-b]-thiopyrano[3,4,5-de]quinolin-4-yl)amino)-1-oxopropan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)hexanamide B8;

[0522] or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0523] In yet another embodiment, provided herein is:

[0524] N-((S)-1-(((S)-1-(((S)-9-ethyl-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl)amino)-1-oxopropan-2-yl)-amino)-3-methyl-1-oxobutan-2-yl)-2-(methylsulfonyl)benzo[d]thiazole-6-carboxamide C1;

[0525] N-(2-((2-(((S)-1-((2-(((S)-9-ethyl-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl)amino)-2-oxoethyl)amino)-1-oxo-3-phenylpropan-2-yl)amino)-2-oxoethyl)amino)-2-oxoethyl)-2-(methylsulfonyl)benzo[d]-thiazole-6-carboxamide C2;

[0526] 4-((S)-2-((S)-3-methyl-2-(2-(methylsulfonyl)benzo[d]thiazole-6-carboxamido)-butanamido)-5-ureidopentanamido)benzyl ((S)-9-ethyl-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl)carbamate C3;

[0527] 2-(cyclopropylsulfonyl)-N-((S)-1-(((S)-1-(((S)-9-ethyl-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl)-amino)-1-oxopropan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)benzo[d]thiazole-6-carboxamide C4;

[0528] 2-(Cyclopropylsulfonyl)-N-(2-((2-(((S)-1-((2-(((S)-9-ethyl-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]-quinolin-4-yl)amino)-2-oxoethyl)amino)-1-oxo-3-phenylpropan-2-yl)amino)-2-oxoethyl)amino)-2-oxo-ethyl)benzo[d]thiazole-6-carboxamide C5;

[0529] 4-((S)-2-((S)-2-(2-(cyclopropylsulfonyl)benzo[d]thiazole-6-carboxamido)-3-methyl-butanamido)-5-ureidopentanamido)benzyl ((S)-9-ethyl-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl)carbamate C6;

[0530] N-((S)-1-(((S)-1-(((S)-9-ethyl-5-fluoro-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl)amino)-1-oxopropan-2-yl)-amino)-3-methyl-1-oxobutan-2-yl)-2-(methylsulfonyl)benzo[d]thiazole-6-carboxamide C7;

[0531] N-(2-((2-(((S)-1-((2-(((S)-9-ethyl-5-fluoro-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl)amino)-2-oxoethyl)amino)-1-oxo-3-phenylpropan-2-yl)amino)-2-oxoethyl)amino)-2-oxoethyl)-2-(methyl-sulfonyl)benzo[d]thiazole-6-carboxamide C8;

[0532] 4-((S)-2-((S)-3-methyl-2-(2-(methylsulfonyl)benzo[d]thiazole-6-carboxamido)-butanamido)-5-ureidopentanamido)benzyl ((S)-9-ethyl-5-fluoro-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl)carbamate C9;

[0533] 2-(cyclopropylsulfonyl)-N-((S)-1-(((S)-1-(((S)-9-ethyl-5-fluoro-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl)-amino)-1-oxopropan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)benzo[d]thiazole-6-carboxamide C10;

[0534] 2-(Cyclopropylsulfonyl)-N-(2-((2-(((S)-1-((2-(((S)-9-ethyl-5-fluoro-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]-quinolin-4-yl)amino)-2-oxoethyl)amino)-1-oxo-3-phenylpropan-2-yl)amino)-2-oxoethyl)amino)-2-oxoethyl)benzo[d]thiazole-6-carboxamide C11;

[0535] 4-((S)-2-((S)-2-(2-(cyclopropylsulfonyl)benzo[d]thiazole-6-carboxamido)-3-methyl-butanamido)-5-ureidopentanamido)benzyl ((S)-9-ethyl-5-fluoro-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl)carbamate C12;

[0536] N-((S)-1-(((S)-1-(((S)-9-ethyl-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl)amino)-1-oxopropan-2-yl)-amino)-3-methyl-1-oxobutan-2-yl)-5-fluoro-2-(methylsulfonyl)benzo[d]-thiazole-6-carboxamide C13;

[0537] N-(2-((2-(((S)-1-((2-(((S)-9-ethyl-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl)amino)-2-oxoethyl)amino)-1-oxo-3-phenylpropan-2-yl)amino)-2-oxoethyl)amino)-2-oxoethyl)-5-fluoro-2-(methylsulfonyl)-benzo[d]thiazole-6-carboxamide C14;

[0538] 4-((S)-2-((S)-3-methyl-2-(5-fluoro-2-(methylsulfonyl)benzo[d]thiazole-6-carboxamido)-butanamido)-5-ureidopentanamido)benzyl ((S)-9-ethyl-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl)carbamate C15;

[0539] 2-(Cyclopropylsulfonyl)-N-((S)-1-(((S)-1-(((S)-9-ethyl-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]-quinolin-4-yl)amino)-1-oxopropan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)-5-fluorobenzo[d]thiazole-6-carboxamide C16;

[0540] 2-(Cyclopropylsulfonyl)-N-(2-((2-(((S)-1-((2-(((S)-9-ethyl-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]-quinolin-4-yl)amino)-2-oxoethyl)amino)-1-oxo-3-phenylpropan-2-yl)amino)-2-oxoethyl)amino)-2-oxoethyl)-5-fluorobenzo[d]thiazole-6-carboxamide C17;

[0541] 4-((S)-2-((S)-2-(2-(cyclopropylsulfonyl)-5-fluorobenzo[d]thiazole-6-carboxamido)-3-methylbutanamido)-5-ureidopentanamido)benzyl ((S)-9-ethyl-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]-indolizino[1,2-b]-quinolin-4-yl)carbamate C18;

[0542] N-((S)-1-(((S)-1-(((S)-9-ethyl-5-fluoro-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl)amino)-1-oxopropan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)-5-fluoro-2-(methylsulfonyl)benzo[d]-thiazole-6-carboxamide C19;

[0543] N-(2-((2-(((S)-1-((2-(((S)-9-ethyl-5-fluoro-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl)amino)-2-oxo-ethyl)amino)-1-oxo-3-phenylpropan-2-yl)amino)-2-oxoethyl)amino)-2-oxoethyl)-5-fluoro-2-(methylsulfonyl)benzo[d]thiazole-6-carboxamide C20;

[0544] 4-((S)-2-((S)-3-methyl-2-(5-fluoro-2-(methylsulfonyl)benzo[d]thiazole-6-carboxamido)-butanamido)-5-ureidopentanamido)benzyl ((S)-9-ethyl-5-fluoro-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl)carbamate C21;

[0545] 2-(Cyclopropylsulfonyl)-N-((S)-1-(((S)-1-(((S)-9-ethyl-5-fluoro-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]-quinolin-4-yl)amino)-1-oxopropan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)-5-fluorobenzo[d]-thiazole-6-carboxamide C22;

[0546] 2-(Cyclopropylsulfonyl)-N-(2-((2-(((S)-1-((2-(((S)-9-ethyl-5-fluoro-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]-quinolin-4-yl)amino)-2-oxoethyl)amino)-1-oxo-3-phenylpropan-2-yl)amino)-2-oxoethyl)amino)-2-oxoethyl)-5-fluorobenzo[d]thiazole-6-carboxamide C23;

[0547] 4-((S)-2-((S)-2-(2-(cyclopropylsulfonyl)-5-fluorobenzo[d]thiazole-6-carboxamido)-3-methylbutanamido)-5-ureidopentanamido)benzyl ((S)-9-ethyl-5-fluoro-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]-indolizino[1,2-b]quinolin-4-yl)carbamate C24;

[0548] (S)-N-((S)-1-(((S)-9-ethyl-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl)amino)-1-oxopropan-2-yl)-3-methyl-2-(2-((2-(methylsulfonyl)benzo[d]thiazol-6-yl)oxy)acetamido)butanamide C25;

[0549] (S)-N-(2-(((S)-9-ethyl-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano-[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl)amino)-2-oxoethyl)-2-(2-(2-(2-((2-(methylsulfonyl)benzo[d]thiazol-6-yl)oxy)acetamido)acetamido)acetamido)-3-phenyl-propanamide C26;

[0550] 4-((S)-2-((S)-3-methyl-2-(2-((2-(methylsulfonyl)benzo[d]thiazol-6-yl)oxy)-acetamido)-butanamido)-5-ureidopentanamido)benzyl ((S)-9-ethyl-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl)carbamate C27;

[0551] (S)-N-((S)-1-(((S)-9-ethyl-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl)amino)-1-oxopropan-2-yl)-3-methyl-2-(3-((2-(methylsulfonyl)benzo[d]thiazol-6-yl)oxy)propanamide)butanamide C28;

[0552] (S)-N-(2-(((S)-9-ethyl-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano-[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl)amino)-2-oxoethyl)-2-(2-(2-(3-((2-(methylsulfonyl)benzo[d]thiazol-6-yl)oxy)propanamide)acetamide)acetamido)-3-phenyl-propanamide C29;

[0553] 4-((S)-2-((S)-3-methyl-2-(3-((2-(methylsulfonyl)benzo[d]thiazol-6-yl)oxy)-propanamido)butanamido)-5-ureidopentanamido)benzyl ((S)-9-ethyl-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl)carbamate C30;

[0554] N-((17S,20S)-21-(((S)-9-ethyl-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl)amino)-17-isopropyl-20-methyl-15,18,21-trioxo-3,6,9,12-tetraoxa-16,19-diazahenicosyl)-5-fluoro-2-(methylsulfonyl)-benzo[d]thiazole-6-carboxamide C31;

[0555] N-((17S,20S)-21-(((S)-9-ethyl-5-fluoro-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl)amino)-17-isopropyl-20-methyl-15,18,21-trioxo-3,6,9,12-tetraoxa-16,19-diazahenicosyl)-5-fluoro-2-(methylsulfonyl)benzo[d]thiazole-6-carboxamide C32;

[0556] 2-(Cyclopropylsulfonyl)-N-((17S,20S)-21-(((S)-9-ethyl-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl)amino)-17-isopropyl-20-methyl-15,18,21-trioxo-3,6,9,12-tetraoxa-16,19-diazahenicosyl)-5-fluorobenzo[d]thiazole-6-carboxamide C33;

[0557] 2-(cyclopropylsulfonyl)-N-((17S,20S)-21-(((S)-9-ethyl-5-fluoro-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl)amino)-17-isopropyl-20-methyl-15,18,21-trioxo-3,6,9,12-tetraoxa-16,19-diazahenicosyl)-5-fluorobenzo[d]thiazole-6-carboxamide C34;

[0558] N-((29S,32S)-33-(((S)-9-ethyl-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl)amino)-29-isopropyl-32-methyl-27,30,33-trioxo-3,6,9,12,15,18,21,24-octaoxa-28,31-diazatritriacontyl)-5-fluoro-2-(methylsulfonyl)benzo[d]thiazole-6-carboxamide C35;

[0559] N-((29S,32S)-33-(((S)-9-ethyl-5-fluoro-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl)amino)-29-isopropyl-32-methyl-27,30,33-trioxo-3,6,9,12,15,18,21,24-octaoxa-28,31-diazatritriacontyl)-5-fluoro-2-(methylsulfonyl)benzo[d]thiazole-6-carboxamide C36;

[0560] 2-(cyclopropylsulfonyl)-N-((29S,32S)-33-(((S)-9-ethyl-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl)amino)-29-isopropyl-32-methyl-27,30,33-trioxo-3,6,9,12,15,18,21,24-octaoxa-28,31-diaza-tritriacontyl)-5-fluorobenzo[d]thiazole-6-carboxamide C37;

[0561] 2-(cyclopropylsulfonyl)-N-((29S,32S)-33-(((S)-9-ethyl-5-fluoro-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]-quinolin-4-yl)amino)-29-isopropyl-32-methyl-27,30,33-trioxo-3,6,9,12,15,18,21,24-octaoxa-28,31-diazatritriacontyl)-5-fluoro...

Claims

1. Formula (XV): 【Chemical 1】 (In the formula: Each A is independently O, S, S(O), S(O 2 ), or N(R 4 ) and; Each X is independently 1-40 Alkylene, C 1-40 Heteroalkylene, C 2-40 Alkenylene, C 2-40 Heteroalkenylene, C 2-40 Alkynylene, or C 2-40 heteroalkynylene, wherein one or more methylene groups are each independently and optionally replaced by a divalent radical, and each divalent radical is independently selected from the group consisting of: C 3-10 Cycloalkylene, C 6-14 arylene, heteroarylene, or heterocyclylene; Each Y is independently a bond, C 1-6 Alkylene, C 1-6 Heteroalkylene, C 2-6 Alkenylene, C 2-6 Alkynylene, C 3-10 Cycloalkylene, C 6-14 Arylene, C 7-15 aralkylene, heteroarylene, or heterocyclylene; Each R 1 , R 2 , and R 3 are independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) —C(O)R 1a , -C(O)OR 1a , -C(O)NR 1b R 1c , -C(O)SR 1a , -C(NR 1a )NR 1b R 1c , -C(S)R 1a , -C(S)OR 1a , -C(S)NR 1b R 1c , -OR 1a , -OC(O)R 1a , -OC(O)OR 1a , -OC(O)NR 1b R 1c , -OC(O)SR 1a , -OC(NR 1a )NR 1b R 1c , -OC(S)R 1a , -OC(S)OR 1a , -OC(S)NR 1b R 1c , -OS(O)R 1a , -OS(O) 2 R 1a , -OS(O)NR 1b R 1c , -OS(O) 2 NR 1b R 1c , -NR 1b R 1c , -NR 1a C(O)R 1d , -NR 1a C(O)OR 1d , -NR 1a C(O)NR 1b R 1c , -NR 1a C(O)SR 1d , -NR 1a C(NR 1d )NR 1b R 1c , -NR 1a C(S)R 1d , -NR 1a C(S)OR 1d , -NR 1a C(S)NR 1b R 1c , -NR 1a S(O)R 1d , -NR 1a S(O) 2 R 1d , -NR 1a S(O)NR 1b R 1c , -NR 1a S(O) 2 NR 1b R 1c , -SR 1a , -S(O)R 1a , -S(O) 2 R 1a , -S(O)NR 1b R 1c , or -S(O) 2 NR 1b R 1c and; Each R 4 are independently: (i) hydrogen; (ii) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) —C(O)R 1a , -C(O)OR 1a , -C(O)NR 1b R 1c , -C(O)SR 1a , -C(NR 1a )NR 1b R 1c , -C(S)R 1a , -C(S)OR 1a , -C(S)NR 1b R 1c , -S(O)R 1a , -S(O) 2 R 1a , -S(O)NR 1b R 1c , or -S(O) 2 NR 1b R 1c and; Each R 6 are independently (i) deuterium, cyano, halo, or nitro; (ii) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) —C(O)R 1a , -C(O)OR 1a , -C(O)NR 1b R 1c , -C(O)SR 1a , -C(NR 1a )NR 1b R 1c , -C(S)R 1a , -C(S)OR 1a , -C(S)NR 1b R 1c , -OR 1a , -OC(O)R 1a , -OC(O)OR 1a , -OC(O)NR 1b R 1c , -OC(O)SR 1a , -OC(NR 1a )NR 1b R 1c , -OC(S)R 1a , -OC(S)OR 1a , -OC(S)NR 1b R 1c , -OS(O)R 1a , -OS(O) 2 R 1a , -OS(O)NR 1b R 1c , -OS(O) 2 NR 1b R 1c , -NR 1b R 1c , -NR 1a C(O)R 1d , -NR 1a C(O)OR 1d , -NR 1a C(O)NR 1b R 1c , -NR 1a C(O)SR 1d , -NR 1a C(NR 1d )NR 1b R 1c , -NR 1a C(S)R 1d , -NR 1a C(S)OR 1d , -NR 1a C(S)NR 1b R 1c , -NR 1a S(O)R 1d , -NR 1a S(O) 2 R 1d , -NR 1a S(O)NR 1b R 1c , -NR 1a S(O) 2 NR 1b R 1c , -SR 1a , -S(O)R 1a , -S(O) 2 R 1a , -S(O)NR 1b R 1c , or -S(O) 2 NR 1b R 1c and; Each R 1a , R 1b , R 1c , and R 1d are independently hydrogen, deuterium, and C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; R A is an antibody or an antigen-binding fragment thereof; m is an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16; each p and q is independently an integer of 0, 1, or 2; provided that the sum of p and q is greater than 0; and each s is independently an integer of 0, 1, 2, or 3; wherein each alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, alkynylene, heteroalkynylene, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, aralkylene, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more, and in one embodiment, one, two, three, or four, substituents Q, wherein each Q is independently: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) one or more, and in one embodiment, one, two, three, or four, substituents Q. a and each of these is further optionally substituted C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)R a , -C(O)OR a , -C(O)NR b R c , -C(O)SR a , -C(NR a )NR b R c , -C(S)R a , -C(S)OR a , -C(S)NR b R c , -OR a , -OC(O)R a , -OC(O)OR a , -OC(O)NR b R c , -OC(O)SR a , -OC(NR a )NR b R c , -OC(S)R a , -OC(S)OR a , -OC(S)NR b R c , -OP(O)(OR a ) OR d , -OS(O)R a , -OS(O) 2 R a , -OS(O)NR b R c , -OS(O) 2 NR b R c , -NR b R c , -NR a C(O)R d , -NR a C(O)OR d , -NR a C(O)NR b R c , -NR a C(O)SR d , -NR a C(NR d )NR b R c , -NR a C(S)R d , -NR a C(S)OR d , -NR a C(S)NR b R c , -NR a S(O)R d , -NR a S(O) 2 R d , -NR a S(O)NR b R c , -NR a S(O) 2 NR b R c , -SR a , -S(O)R a , -S(O) 2 R a , -S(O)NR b R c , and -S(O) 2 NR b R c (In the formula, each R a , R b , R c , and R d are independently (i) hydrogen or deuterium; (ii) one or more, in one embodiment, one, two, three, or four, substituents Q a with arbitrary substitutions, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R b and R c together with the N atom to which they are attached, form one or more, in one embodiment one, two, three or four, substituents Q a forming an optionally substituted heterocyclyl; Here, each Q a are independently: (a) deuterium, cyano, halo, nitro, imino, and oxo; (b) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)R e , -C(O)OR e , -C(O)NR f R g , -C(O)SR e , -C(NR e )NR f R g , -C(S)R e , -C(S)OR e , -C(S)NR f R g , -OR e , -OC(O)R e , -OC(O)OR e , -OC(O)NR f R g , -OC(O)SR e , -OC(NR e )NR f R g , -OC(S)R e , -OC(S)OR e , -OC(S)NR f R g , -OS(O)R e , -OS(O) 2 R e , -OS(O)NR f R g , -OS(O) 2 NR f R g , -NR f R g , -NR e C(O)R h , -NR e C(O)OR f , -NR e C(O)NR f R g , -NR e C(O)SR f , -NR e C(NR h )NR f R g , -NR e C(S)R h , -NR e C(S)OR f , -NR e C(S)NR f R g , -NR e S(O)R h , -NR e S(O) 2 R h , -NR e S(O)NR f R g , -NR e S(O) 2 NR f R g , -SR e , -S(O)R e , -S(O) 2 R e , -S(O)NR f R g , and -S(O) 2 NR f R g ;(In the formula, each R e , R f , R g , and R h are independently (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R f and R g are selected from: or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

2. Formula (XVI): 【Chemistry 2】 (In the formula, each R 6a , R 6b , and R 6c are independently hydrogen or R 6 is) or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

3. 3. The compound of claim 1 or 2, wherein each p is an integer equal to 0.

4. 3. The compound of claim 1 or 2, wherein each p is an integer equal to 1.

5. 3. The compound of claim 1 or 2, wherein each p is an integer of 2.

6. 6. The compound of any one of claims 1 to 5, wherein each q is an integer equal to 0.

7. 6. The compound of any one of claims 1 to 5, wherein each q is an integer of 1.

8. 6. The compound of any one of claims 1 to 5, wherein each q is an integer of 2.

9. Formula (XVII): 【Chemistry 3】 10. The compound of claim 2, having the structure:

10. Formula (XVIII): 【Chemistry 4】 10. The compound of claim 2, having the structure:

11. R 6a The compound of any one of claims 2 to 10, wherein is hydrogen.

12. R 6c The compound of any one of claims 2 to 11, wherein is hydrogen.

13. Each X is independently, C 1-40 heteroalkylene, wherein one or more methylene groups are each independently and optionally replaced by a divalent radical, and each divalent radical is independently selected from the group consisting of: C 6-14 13. The compound of any one of claims 1-12, wherein each heteroalkylene, arylene, heteroarylene, and heterocyclylene is optionally substituted with one or more substituents Q.

14. For each X independently: 【Chemistry 5】 【change】 wherein each u is independently an integer of 1, 2, 3, 4, 5, 6, 7, or 8.

14. The compound of any one of claims 1 to 13, wherein

15. 15. The compound of any one of claims 1 to 14, wherein each Y is a bond.

16. Each R 2 are independently (i) hydrogen or deuterium; (ii) heterocyclyl optionally substituted with one or more substituents Q; or (iii) -NR 1b R 1c or -NR 1a C(O)R 1d 16. The compound of any one of claims 1 to 15, wherein

17. Each R 2 17. The compound of any one of claims 1 to 16, wherein is independently hydrogen, amino, methylamino, acetamido, or hydroxyacetamido.

18. Each R 2 The compound of any one of claims 1 to 17, wherein is hydrogen.

19. Each R 3 are independently selected from the group consisting of C, ... 1-6 Alkyl, C 1-6 Heteroalkyl, or C 2-6 19. The compound of any one of claims 1 to 18, which is alkenyl.

20. Each R 3 is independently methyl, fluoromethyl, methoxymethyl, or ethenyl.

21. Each R 3 The compound of any one of claims 1 to 20, wherein is methyl.

22. [Chemical 6] 3. The compound of claim 2, wherein:

23. 【Chemical 7】 3. The compound of claim 2, wherein:

24. [Chemical 8] 3. The compound of claim 2, wherein:

25. 【Chemical 9】 wherein each u is independently an integer of 1, 2, 3, 4, 5, 6, 7, or 8.

3. The compound of claim 2, wherein:

26. [Catalog 10] wherein each u is independently an integer of 1, 2, 3, 4, 5, 6, 7, or 8.

3. The compound of claim 2, wherein:

27. 【Catalog 11】 3. The compound of claim 2, wherein:

28. Each R 1 28. The compound of any one of claims 1-27, wherein is independently hydrogen or halo.

29. Each R 1 The compound of any one of claims 1 to 28, wherein is hydrogen.

30. Each R 1 29. The compound of any one of claims 1-28, wherein is independently halo.

31. Each R 1 The compound of any one of claims 1 to 28 and 30, wherein is fluoro.

32. 32. The compound of any one of claims 1-31, wherein each A is O.

33. 32. The compound of any one of claims 1-31, wherein each A is S.

34. Each R 6b 34. The compound of any one of claims 1 to 33, wherein is hydrogen.

35. Each R 6b 34. The compound of any one of claims 1-33, wherein is independently halo.

36. Each R 6b The compound of any one of claims 1 to 33 and 35, wherein is fluoro.

37. R A 37. The compound of any one of claims 1 to 36, wherein is a monoclonal antibody or an antigen-binding fragment thereof.

38. R A 38. The compound of any one of claims 1 to 37, wherein is a human, humanized, or chimeric antibody, or an antigen-binding fragment thereof.

39. R A 39. The compound of any one of claims 1-38, wherein is an IgG1, IgG2, IgG3, or IgG4 antibody, or an antigen-binding fragment thereof.

40. R A The compound of any one of claims 1 to 39, wherein is an anti-B7H3 antibody, an anti-CD20 antibody, an anti-FOLR1 antibody, an anti-HER2 antibody, an anti-MSLN antibody, an anti-TROP2 antibody, or an antigen-binding fragment thereof.

41. R A 41. The compound of any one of claims 1 to 40, wherein said compound is an anti-B7H3 single domain antibody or an antigen-binding fragment thereof.

42. The compound of claim 41, wherein the anti-B7H3 single domain antibody comprises: (i) CDR1 of SEQ ID NO: 1, CDR2 of SEQ ID NO: 2, and CDR3 of SEQ ID NO: 3; or (ii) CDR1 of SEQ ID NO: 6, CDR2 of SEQ ID NO: 7, and CDR3 of SEQ ID NO:

8.

43. R A 41. The compound of any one of claims 1 to 40, wherein is an anti-CD20 antibody or an antigen-binding fragment thereof.

44. The compound of claim 43, wherein the anti-CD20 antibody comprises CDRL1 of SEQ ID NO: 11; CDRL2 of SEQ ID NO: 12; CDRL3 of SEQ ID NO: 13; CDRH1 of SEQ ID NO: 14; CDRH2 of SEQ ID NO: 15; and CDRH3 of SEQ ID NO:

16.

45. R A The compound of any one of claims 1 to 40, wherein said compound is an anti-FOLR1 antibody or an antigen-binding fragment thereof.

46. The compound of claim 45, wherein the anti-FOLR1 antibody comprises CDRL1 of SEQ ID NO: 21; CDRL2 of SEQ ID NO: 22; CDRL3 of SEQ ID NO: 23; CDRH1 of SEQ ID NO: 24; CDRH2 of SEQ ID NO: 25; and CDRH3 of SEQ ID NO:

26.

47. R A The compound of any one of claims 1 to 40, wherein is an anti-HER2 antibody or an antigen-binding fragment thereof.

48. The compound of claim 47, wherein the anti-HER2 antibody comprises CDRL1 of SEQ ID NO: 31; CDRL2 of SEQ ID NO: 32; CDRL3 of SEQ ID NO: 33; CDRH1 of SEQ ID NO: 34; CDRH2 of SEQ ID NO: 35; and CDRH3 of SEQ ID NO:

36.

49. 49. The compound of claim 47 or 48, wherein the anti-HER2 antibody comprises a light chain variable region of SEQ ID NO:37 and a heavy chain variable region of SEQ ID NO:

38.

50. 50. The compound of any one of claims 47 to 49, wherein the anti-HER2 antibody comprises a light chain of SEQ ID NO: 39 and a heavy chain of SEQ ID NO:

40.

51. R A The compound of any one of claims 1 to 40, wherein said compound is an anti-MSLN single domain antibody or an antigen-binding fragment thereof.

52. The compound of claim 51, wherein the anti-MSLN single domain antibody comprises: (i) CDR1 of SEQ ID NO: 41, CDR2 of SEQ ID NO: 42, and CDR3 of SEQ ID NO: 43; or (ii) CDR1 of SEQ ID NO: 46, CDR2 of SEQ ID NO: 47, and CDR3 of GRY.

53. R A The compound of any one of claims 1 to 40, wherein said compound is an anti-TROP2 antibody or an antigen-binding fragment thereof.

54. The compound of claim 53, wherein the anti-TROP2 antibody comprises CDRL1 of SEQ ID NO: 50; CDRL2 of SEQ ID NO: 51; CDRL3 of SEQ ID NO: 52; CDRH1 of SEQ ID NO: 53; CDRH2 of SEQ ID NO: 54; and CDRH3 of SEQ ID NO:

55.

55. R A 41. The compound of any one of claims 1 to 40, wherein said compound is an anti-CD79b antibody or an antigen-binding fragment thereof.

56. The compound of claim 55, wherein the anti-CD79b antibody comprises CDRL1 of SEQ ID NO: 60; CDRL2 of SEQ ID NO: 61; CDRL3 of SEQ ID NO: 62; CDRH1 of SEQ ID NO: 63; CDRH2 of SEQ ID NO: 64; and CDRH3 of SEQ ID NO:

65.

57. The compound of claim 55, wherein the anti-CD79b antibody comprises CDRL1 of SEQ ID NO: 70; CDRL2 of SEQ ID NO: 71; CDRL3 of SEQ ID NO: 72; CDRH1 of SEQ ID NO: 73; CDRH2 of SEQ ID NO: 74; and CDRH3 of SEQ ID NO:

75.

58. 58. The compound of any one of claims 1 to 57, wherein m is an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12.

59. 59. The compound of any one of claims 1 to 58, wherein m is an integer of 4, 5, 6, 7, or 8.

60. 60. The compound of any one of claims 1 to 59, wherein m is an integer equal to 8.

61. 61. The compound of any one of claims 14-21, 25, 26, and 28-60, wherein each u is independently an integer of 4 or 8.

62. 62. The compound of any one of claims 14-21, 25, 26, and 28-61, wherein each u is independently an integer of 4.

63. The compound of claim 1, which is an ADC of trastuzumab selected from ADC-C1 to ADC-C53, wherein trastuzumab is an anti-HER2 antibody comprising CDRL1 of SEQ ID NO: 31, CDRL2 of SEQ ID NO: 32, CDRL3 of SEQ ID NO: 33, CDRH1 of SEQ ID NO: 34, CDRH2 of SEQ ID NO: 35, and CDRH3 of SEQ ID NO:

36.

64. 64. A pharmaceutical composition comprising a compound of any one of claims 1 to 63, or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; and a pharmaceutically acceptable excipient.

65. 65. The pharmaceutical composition of claim 64, in a unitary dosage form.

66. 66. The pharmaceutical composition of claim 64 or 65, in parenteral or intravenous dosage form.

67. 67. The pharmaceutical composition of claim 66, formulated in an intravenous dosage form.

68. 68. A method of treating, preventing, or ameliorating one or more symptoms of a proliferative disease in a subject, comprising administering to said subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-63 or a pharmaceutical composition of any one of claims 64-67.

69. 69. The method of claim 68, wherein the proliferative disease is cancer.

70. 70. The method of claim 68 or 69, wherein the cancer is recurrent or refractory.

71. 71. The method of any one of claims 68 to 70, wherein the cancer is metastatic.

72. 72. The method of any one of claims 68 to 71, wherein the cancer is drug resistant.

73. The method of any one of claims 68 to 72, wherein the subject is a human.

74. 68. A method of inhibiting proliferation of a cell, comprising contacting said cell with an effective amount of a compound of any one of claims 1-63 or a pharmaceutical composition of any one of claims 64-67.

75. 75. The method of claim 74, wherein the cell is a cancerous cell.

76. Formula (IA): 【Chemistry 12】 (In the formula: A is O, S, S(O), S(O 2 ), or N(R 4 ) and; X is C 1-40 Alkylene, C 1-40 Heteroalkylene, C 2-40 Alkenylene, C 2-40 Heteroalkenylene, C 2-40 Alkynylene, or C 2-40 heteroalkynylene, wherein one or more methylene groups are each independently and optionally replaced by a divalent radical, and each divalent radical is independently selected from the group consisting of: C 3-10 Cycloalkylene, C 6-14 arylene, heteroarylene, or heterocyclylene; Y is a bond, C 1-6 Alkylene, C 1-6 Heteroalkylene, C 2-6 Alkenylene, C 2-6 Alkynylene, C 3-10 Cycloalkylene, C 6-14 Arylene, C 7-15 aralkylene, heteroarylene, or heterocyclylene; Z is 【Chemistry 13】 and; Each R 1 , R 2 , and R 3 are independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) —C(O)R 1a , -C(O)OR 1a , -C(O)NR 1b R 1c , -C(O)SR 1a , -C(NR 1a )NR 1b R 1c , -C(S)R 1a , -C(S)OR 1a , -C(S)NR 1b R 1c , -OR 1a , -OC(O)R 1a , -OC(O)OR 1a , -OC(O)NR 1b R 1c , -OC(O)SR 1a , -OC(NR 1a )NR 1b R 1c , -OC(S)R 1a , -OC(S)OR 1a , -OC(S)NR 1b R 1c , -OS(O)R 1a , -OS(O) 2 R 1a , -OS(O)NR 1b R 1c , -OS(O) 2 NR 1b R 1c , -NR 1b R 1c , -NR 1a C(O)R 1d , -NR 1a C(O)OR 1d , -NR 1a C(O)NR 1b R 1c , -NR 1a C(O)SR 1d , -NR 1a C(NR 1d )NR 1b R 1c , -NR 1a C(S)R 1d , -NR 1a C(S)OR 1d , -NR 1a C(S)NR 1b R 1c , -NR 1a S(O)R 1d , -NR 1a S(O) 2 R 1d , -NR 1a S(O)NR 1b R 1c , -NR 1a S(O) 2 NR 1b R 1c , -SR 1a , -S(O)R 1a , -S(O) 2 R 1a , -S(O)NR 1b R 1c , or -S(O) 2 NR 1b R 1c and; R 4 is (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) —C(O)R 1a , -C(O)OR 1a , -C(O)NR 1b R 1c , -C(O)SR 1a , -C(NR 1a )NR 1b R 1c , -C(S)R 1a , -C(S)OR 1a , -C(S)NR 1b R 1c , -S(O)R 1a , -S(O) 2 R 1a , -S(O)NR 1b R 1c , or -S(O) 2 NR 1b R 1c and; Each R 6 and R 7 are independently (i) deuterium, cyano, halo, or nitro; (ii) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) —C(O)R 1a , -C(O)OR 1a , -C(O)NR 1b R 1c , -C(O)SR 1a , -C(NR 1a )NR 1b R 1c , -C(S)R 1a , -C(S)OR 1a , -C(S)NR 1b R 1c , -OR 1a , -OC(O)R 1a , -OC(O)OR 1a , -OC(O)NR 1b R 1c , -OC(O)SR 1a , -OC(NR 1a )NR 1b R 1c , -OC(S)R 1a , -OC(S)OR 1a , -OC(S)NR 1b R 1c , -OS(O)R 1a , -OS(O) 2 R 1a , -OS(O)NR 1b R 1c , -OS(O) 2 NR 1b R 1c , -NR 1b R 1c , -NR 1a C(O)R 1d , -NR 1a C(O)OR 1d , -NR 1a C(O)NR 1b R 1c , -NR 1a C(O)SR 1d , -NR 1a C(NR 1d )NR 1b R 1c , -NR 1a C(S)R 1d , -NR 1a C(S)OR 1d , -NR 1a C(S)NR 1b R 1c , -NR 1a S(O)R 1d , -NR 1a S(O) 2 R 1d , -NR 1a S(O)NR 1b R 1c , -NR 1a S(O) 2 NR 1b R 1c , -SR 1a , -S(O)R 1a , -S(O) 2 R 1a , -S(O)NR 1b R 1c , or -S(O) 2 NR 1b R 1c and; Each R 8 are independently (i) hydrogen or deuterium; or (ii) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; Each R 1a , R 1b , R 1c , and R 1d are independently hydrogen, deuterium, and C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; p and q are each independently an integer of 0, 1, or 2; provided that the sum of p and q is greater than 0; s is an integer of 0, 1, 2, or 3; and t is an integer of 0, 1, 2, 3, or 4; wherein each alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, alkynylene, heteroalkynylene, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, aralkylene, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more, and in one embodiment, one, two, three, or four, substituents Q, wherein each Q is independently: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) one or more, and in one embodiment, one, two, three, or four, substituents Q. a each of which is further optionally substituted, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)R a , -C(O)OR a , -C(O)NR b R c , -C(O)SR a , -C(NR a )NR b R c , -C(S)R a , -C(S)OR a , -C(S)NR b R c , -OR a , -OC(O)R a , -OC(O)OR a , -OC(O)NR b R c , -OC(O)SR a , -OC(NR a )NR b R c , -OC(S)R a , -OC(S)OR a , -OC(S)NR b R c , -OP(O)(OR a ) OR d , -OS(O)R a , -OS(O) 2 R a , -OS(O)NR b R c , -OS(O) 2 NR b R c , -NR b R c , -NR a C(O)R d , -NR a C(O)OR d , -NR a C(O)NR b R c , -NR a C(O)SR d , -NR a C(NR d )NR b R c , -NR a C(S)R d , -NR a C(S)OR d , -NR a C(S)NR b R c , -NR a S(O)R d , -NR a S(O) 2 R d , -NR a S(O)NR b R c , -NR a S(O) 2 NR b R c , -SR a , -S(O)R a , -S(O) 2 R a , -S(O)NR b R c , and -S(O) 2 NR b R c (In the formula, each R a , R b , R c , and R d are independently (i) hydrogen or deuterium; (ii) one or more, in one embodiment, one, two, three, or four, substituents Q a with arbitrary substitutions, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R b and R c together with the N atom to which they are attached, form one or more, in one embodiment one, two, three or four, substituents Q a forming an optionally substituted heterocyclyl; Here, each Q a are independently: (a) deuterium, cyano, halo, nitro, imino, and oxo; (b) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)R e , -C(O)OR e , -C(O)NR f R g , -C(O)SR e , -C(NR e )NR f R g , -C(S)R e , -C(S)OR e , -C(S)NR f R g , -OR e , -OC(O)R e , -OC(O)OR e , -OC(O)NR f R g , -OC(O)SR e , -OC(NR e )NR f R g , -OC(S)R e , -OC(S)OR e , -OC(S)NR f R g , -OS(O)R e , -OS(O) 2 R e , -OS(O)NR f R g , -OS(O) 2 NR f R g , -NR f R g , -NR e C(O)R h , -NR e C(O)OR f , -NR e C(O)NR f R g , -NR e C(O)SR f , -NR e C(NR h )NR f R g , -NR e C(S)R h , -NR e C(S)OR f , -NR e C(S)NR f R g , -NR e S(O)R h , -NR e S(O) 2 R h , -NR e S(O)NR f R g , -NR e S(O) 2 NR f R g , -SR e , -S(O)R e , -S(O) 2 R e , -S(O)NR f R g , and -S(O) 2 NR f R g ;(In the formula, each R e , R f , R g , and R h are independently (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R f and R g are selected from: or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

77. Formula (IXA): 【Chemistry 14】 77. The compound of claim 76, having the structure: or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

78. Formula (XA): 【Chemistry 15】 (In the formula, each R 6a , R 6b , and R 6c are independently hydrogen or R 6 is) 78. The compound of claim 76 or 77, having the structure: or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

79. 79. The compound of any one of claims 76-78, wherein each p is an integer equal to 0.

80. 79. The compound of any one of claims 76-78, wherein each p is an integer of 1.

81. 79. The compound of any one of claims 76-78, wherein each p is an integer of 2.

82. 82. The compound of any one of claims 76-81, wherein each q is an integer equal to 0.

83. 82. The compound of any one of claims 83-81, wherein each q is an integer of 1.

84. 82. The compound of any one of claims 83-81, wherein each q is an integer of 2.

85. Formula (XIA): 【Chemistry 16】 79. The compound of claim 78, having the structure: or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

86. Formula (XIIA): 【Chemistry 17】 79. The compound of claim 78, having the structure: or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

87. R 6a 87. The compound of any one of claims 78-86, wherein is hydrogen.

88. R 6b 88. The compound of any one of claims 78-87, wherein is hydrogen.

89. R 6b 88. The compound of any one of claims 78-87, wherein is halo.

90. R 6b 90. The compound of any one of claims 78-87 and 89, wherein is fluoro.

91. R 6c The compound of any one of claims 78-90, wherein is hydrogen.

92. 92. The compound of any one of claims 76-91, wherein A is O.

93. 92. The compound of any one of claims 76-91, wherein A is S.

94. R 1 is hydrogen or halo.

95. R 1 The compound of any one of claims 76-94, wherein is hydrogen.

96. R 1 The compound of any one of claims 76-94, wherein is halo.

97. R 1 97. The compound of any one of claims 76-94 and 96, wherein is fluoro.

98. R 2 is (i) hydrogen or deuterium; (ii) heterocyclyl optionally substituted with one or more substituents Q; or (iii) —NR 1b R 1c or -NR 1a C(O)R 1d 98. The compound of any one of claims 76 to 97, wherein

99. R 2 99. The compound of any one of claims 76-98, wherein is hydrogen, amino, methylamino, acetamido, or hydroxyacetamido.

100. R 2 100. The compound of any one of claims 76-99, wherein is hydrogen.

101. R 3 C, each optionally substituted with one or more substituents Q; 1-6 Alkyl, C 1-6 Heteroalkyl, or C 2-6 The compound of any one of claims 76-100, which is alkenyl.

102. R 3 is methyl, fluoromethyl, methoxymethyl, or ethenyl.

103. R 3 The compound of any one of claims 76-102, wherein is methyl.

104. X is C 1-40 heteroalkylene, wherein one or more methylene groups are each independently and optionally replaced by a divalent radical, and each divalent radical is independently selected from the group consisting of: C 6-14 arylene, heteroarylene, or heterocyclylene; and wherein each heteroalkylene, arylene, heteroarylene, and heterocyclylene is optionally substituted with one or more substituents Q.

105. X is: 【Chemistry 18】 【change】 wherein each u is independently an integer of 1, 2, 3, 4, 5, 6, 7, or 8. The compound of any one of claims 76 to 104, wherein

106. 106. The compound of any one of claims 76-105, wherein Y is a bond.

107. 107. The compound of claim 105 or 106, wherein each u is independently an integer of 4 or 8.

108. N-((S)-1-(((S)-1-(((S)-9-ethyl-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl)amino)-1-oxopropan-2-yl)-amino)-3-methyl-1-oxobutan-2-yl)-2-(methylsulfonyl)benzo[d]thiazole-6-carboxamide C1; N-(2-((2-(((S)-1-((2-(((S)-9-ethyl-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl)amino)-2-oxoethyl)amino)-1-oxo-3-phenylpropan-2-yl)amino)-2-oxoethyl)amino)-2-oxoethyl)-2-(methylsulfonyl)benzo[d]-thiazole-6-carboxamide C2; 4-((S)-2-((S)-3-methyl-2-(2-(methylsulfonyl)benzo[d]thiazole-6-carboxamido)-butanamido)-5-ureidopentanamido)benzyl ((S)-9-ethyl-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl)carbamate C3; 2-(cyclopropylsulfonyl)-N-((S)-1-(((S)-1-(((S)-9-ethyl-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl)-amino)-1-oxopropan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)benzo[d]thiazole-6-carboxamide C4; 2-(Cyclopropylsulfonyl)-N-(2-((2-(((S)-1-((2-(((S)-9-ethyl-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]-quinolin-4-yl)amino)-2-oxoethyl)amino)-1-oxo-3-phenylpropan-2-yl)amino)-2-oxoethyl)amino)-2-oxo-ethyl)benzo[d]thiazole-6-carboxamide C5; 4-((S)-2-((S)-2-(2-(cyclopropylsulfonyl)benzo[d]thiazole-6-carboxamido)-3-methyl-butanamido)-5-ureidopentanamido)benzyl ((S)-9-ethyl-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl)carbamate C6; N-((S)-1-(((S)-1-(((S)-9-ethyl-5-fluoro-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl)amino)-1-oxopropan-2-yl)-amino)-3-methyl-1-oxobutan-2-yl)-2-(methylsulfonyl)benzo[d]thiazole-6-carboxamide C7; N-(2-((2-(((S)-1-((2-(((S)-9-ethyl-5-fluoro-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl)amino)-2-oxoethyl)amino)-1-oxo-3-phenylpropan-2-yl)amino)-2-oxoethyl)amino)-2-oxoethyl)-2-(methyl-sulfonyl)benzo[d]thiazole-6-carboxamide C8; 4-((S)-2-((S)-3-methyl-2-(2-(methylsulfonyl)benzo[d]thiazole-6-carboxamido)-butanamido)-5-ureidopentanamido)benzyl ((S)-9-ethyl-5-fluoro-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl)carbamate C9; 2-(cyclopropylsulfonyl)-N-((S)-1-(((S)-1-(((S)-9-ethyl-5-fluoro-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl)-amino)-1-oxopropan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)benzo[d]thiazole-6-carboxamide C10; 2-(Cyclopropylsulfonyl)-N-(2-((2-(((S)-1-((2-(((S)-9-ethyl-5-fluoro-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]-quinolin-4-yl)amino)-2-oxoethyl)amino)-1-oxo-3-phenylpropan-2-yl)amino)-2-oxoethyl)amino)-2-oxoethyl)benzo[d]thiazole-6-carboxamide C11; 4-((S)-2-((S)-2-(2-(cyclopropylsulfonyl)benzo[d]thiazole-6-carboxamido)-3-methyl-butanamido)-5-ureidopentanamido)benzyl ((S)-9-ethyl-5-fluoro-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl)carbamate C12; N-((S)-1-(((S)-1-(((S)-9-ethyl-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl)amino)-1-oxopropan-2-yl)-amino)-3-methyl-1-oxobutan-2-yl)-5-fluoro-2-(methylsulfonyl)benzo[d]-thiazole-6-carboxamide C13; N-(2-((2-(((S)-1-((2-(((S)-9-ethyl-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl)amino)-2-oxoethyl)amino)-1-oxo-3-phenylpropan-2-yl)amino)-2-oxoethyl)amino)-2-oxoethyl)-5-fluoro-2-(methylsulfonyl)-benzo[d]thiazole-6-carboxamide C14; 4-((S)-2-((S)-3-methyl-2-(5-fluoro-2-(methylsulfonyl)benzo[d]thiazole-6-carboxamido)-butanamido)-5-ureidopentanamido)benzyl ((S)-9-ethyl-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl)carbamate C15; 2-(Cyclopropylsulfonyl)-N-((S)-1-(((S)-1-(((S)-9-ethyl-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]-quinolin-4-yl)amino)-1-oxopropan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)-5-fluorobenzo[d]thiazole-6-carboxamide C16; 2-(Cyclopropylsulfonyl)-N-(2-((2-(((S)-1-((2-(((S)-9-ethyl-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]-quinolin-4-yl)amino)-2-oxoethyl)amino)-1-oxo-3-phenylpropan-2-yl)amino)-2-oxoethyl)amino)-2-oxoethyl)-5-fluorobenzo[d]thiazole-6-carboxamide C17; 4-((S)-2-((S)-2-(2-(cyclopropylsulfonyl)-5-fluorobenzo[d]thiazole-6-carboxamido)-3-methylbutanamido)-5-ureidopentanamido)benzyl ((S)-9-ethyl-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]-indolizino[1,2-b]-quinolin-4-yl)carbamate C18; N-((S)-1-(((S)-1-(((S)-9-ethyl-5-fluoro-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl)amino)-1-oxopropan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)-5-fluoro-2-(methylsulfonyl)benzo[d]-thiazole-6-carboxamide C19; N-(2-((2-(((S)-1-((2-(((S)-9-ethyl-5-fluoro-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl)amino)-2-oxo-ethyl)amino)-1-oxo-3-phenylpropan-2-yl)amino)-2-oxoethyl)amino)-2-oxoethyl)-5-fluoro-2-(methylsulfonyl)benzo[d]thiazole-6-carboxamide C20; 4-((S)-2-((S)-3-methyl-2-(5-fluoro-2-(methylsulfonyl)benzo[d]thiazole-6-carboxamido)-butanamido)-5-ureidopentanamido)benzyl ((S)-9-ethyl-5-fluoro-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl)carbamate C21; 2-(Cyclopropylsulfonyl)-N-((S)-1-(((S)-1-(((S)-9-ethyl-5-fluoro-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]-quinolin-4-yl)amino)-1-oxopropan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)-5-fluorobenzo[d]-thiazole-6-carboxamide C22; 2-(Cyclopropylsulfonyl)-N-(2-((2-(((S)-1-((2-(((S)-9-ethyl-5-fluoro-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]-quinolin-4-yl)amino)-2-oxoethyl)amino)-1-oxo-3-phenylpropan-2-yl)amino)-2-oxoethyl)amino)-2-oxoethyl)-5-fluorobenzo[d]thiazole-6-carboxamide C23; 4-((S)-2-((S)-2-(2-(cyclopropylsulfonyl)-5-fluorobenzo[d]thiazole-6-carboxamido)-3-methylbutanamido)-5-ureidopentanamido)benzyl ((S)-9-ethyl-5-fluoro-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]-indolizino[1,2-b]quinolin-4-yl)carbamate C24; (S)-N-((S)-1-(((S)-9-ethyl-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl)amino)-1-oxopropan-2-yl)-3-methyl-2-(2-((2-(methylsulfonyl)benzo[d]thiazol-6-yl)oxy)acetamido)butanamide C25; (S)-N-(2-(((S)-9-ethyl-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano-[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl)amino)-2-oxoethyl)-2-(2-(2-(2-((2-(methylsulfonyl)benzo[d]thiazol-6-yl)oxy)acetamido)acetamido)acetamido)-3-phenyl-propanamide C26; 4-((S)-2-((S)-3-methyl-2-(2-((2-(methylsulfonyl)benzo[d]thiazol-6-yl)oxy)-acetamido)-butanamido)-5-ureidopentanamido)benzyl ((S)-9-ethyl-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl)carbamate C27; (S)-N-((S)-1-(((S)-9-ethyl-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl)amino)-1-oxopropan-2-yl)-3-methyl-2-(3-((2-(methylsulfonyl)benzo[d]thiazol-6-yl)oxy)propanamide)butanamide C28; (S)-N-(2-(((S)-9-ethyl-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano-[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl)amino)-2-oxoethyl)-2-(2-(2-(3-((2-(methylsulfonyl)benzo[d]thiazol-6-yl)oxy)propanamide)acetamide)acetamido)-3-phenyl-propanamide C29; 4-((S)-2-((S)-3-methyl-2-(3-((2-(methylsulfonyl)benzo[d]thiazol-6-yl)oxy)-propanamido)butanamido)-5-ureidopentanamido)benzyl ((S)-9-ethyl-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl)carbamate C30; N-((17S,20S)-21-(((S)-9-ethyl-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl)amino)-17-isopropyl-20-methyl-15,18,21-trioxo-3,6,9,12-tetraoxa-16,19-diazahenicosyl)-5-fluoro-2-(methylsulfonyl)-benzo[d]thiazole-6-carboxamide C31; N-((17S,20S)-21-(((S)-9-ethyl-5-fluoro-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl)amino)-17-isopropyl-20-methyl-15,18,21-trioxo-3,6,9,12-tetraoxa-16,19-diazahenicosyl)-5-fluoro-2-(methylsulfonyl)benzo[d]thiazole-6-carboxamide C32; 2-(Cyclopropylsulfonyl)-N-((17S,20S)-21-(((S)-9-ethyl-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl)amino)-17-isopropyl-20-methyl-15,18,21-trioxo-3,6,9,12-tetraoxa-16,19-diazahenicosyl)-5-fluorobenzo[d]thiazole-6-carboxamide C33; 2-(cyclopropylsulfonyl)-N-((17S,20S)-21-(((S)-9-ethyl-5-fluoro-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl)amino)-17-isopropyl-20-methyl-15,18,21-trioxo-3,6,9,12-tetraoxa-16,19-diazahenicosyl)-5-fluorobenzo[d]thiazole-6-carboxamide C34; N-((29S,32S)-33-(((S)-9-ethyl-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl)amino)-29-isopropyl-32-methyl-27,30,33-trioxo-3,6,9,12,15,18,21,24-octaoxa-28,31-diazatritriacontyl)-5-fluoro-2-(methylsulfonyl)benzo[d]thiazole-6-carboxamide C35; N-((29S,32S)-33-(((S)-9-ethyl-5-fluoro-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl)amino)-29-isopropyl-32-methyl-27,30,33-trioxo-3,6,9,12,15,18,21,24-octaoxa-28,31-diazatritriacontyl)-5-fluoro-2-(methylsulfonyl)benzo[d]thiazole-6-carboxamide C36; 2-(cyclopropylsulfonyl)-N-((29S,32S)-33-(((S)-9-ethyl-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl)amino)-29-isopropyl-32-methyl-27,30,33-trioxo-3,6,9,12,15,18,21,24-octaoxa-28,31-diaza-tritriacontyl)-5-fluorobenzo[d]thiazole-6-carboxamide C37; 2-(cyclopropylsulfonyl)-N-((29S,32S)-33-(((S)-9-ethyl-5-fluoro-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]-quinolin-4-yl)amino)-29-isopropyl-32-methyl-27,30,33-trioxo-3,6,9,12,15,18,21,24-octaoxa-28,31-diazatritriacontyl)-5-fluorobenzo[d]thiazole-6-carboxamide C38; N-((S)-1-(((S)-1-(((S)-9-ethyl-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl)amino)-1-oxopropan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)-1-(3-((2-(methylsulfonyl)benzo[d]thiazol-6-yl)oxy)-propanamide)-3,6,9,12-tetraoxapentadecan-15-amide C39; N-((S)-1-(((S)-1-(((S)-9-ethyl-5-fluoro-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl)amino)-1-oxo-propan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)-1-(3-((2-(methylsulfonyl)benzo[d]thiazol-6-yl)oxy)propanamide)-3,6,9,12-tetraoxapentadecan-15-amide C40; N-((S)-1-(((S)-1-(((S)-9-ethyl-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl)amino)-1-oxopropan-2-yl)-amino)-3-methyl-1-oxobutan-2-yl)-1-(3-((2-(methylsulfonyl)benzo[d]thiazol-6-yl)oxy)-propanamide)-3,6,9,12,15,18,21,24-octaoxaheptacosane-27-amide C41; N-((S)-1-(((S)-1-(((S)-9-ethyl-5-fluoro-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl)amino)-1-oxo-propan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)-1-(3-((2-(methylsulfonyl)benzo[d]thiazol-6-yl)-oxy)propanamide)-3,6,9,12,15,18,21,24-octaoxaheptacosane-27-amide C42; N-(6-(((S)-1-(((S)-1-(((S)-9-ethyl-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl)amino)-1-oxopropan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)amino)-6-oxohexyl)-2-(methylsulfonyl)-benzo[d]thiazole-6-carboxamide C43; N-((S)-5-benzyl-1-(((S)-9-ethyl-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexa-hydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl)amino)-1,4,7,10,13-pentaoxo-3,6,9,12-tetraazaoctadecan-18-yl)-2-(methylsulfonyl)benzo[d]thiazole-6-carboxamide C44; 4-((S)-2-((S)-3-methyl-2-(6-(2-(methylsulfonyl)benzo[d]thiazole-6-carboxamido)-hexanamido)butanamido)-5-ureidopentanamido)benzyl ((S)-9-ethyl-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]-quinolin-4-yl)carbamate C45; 2-(cyclopropylsulfonyl)-N-(6-(((S)-1-(((S)-1-(((S)-9-ethyl-5-fluoro-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]-quinolin-4-yl)amino)-1-oxopropan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)amino)-6-oxohexyl)-benzo[d]thiazole-6-carboxamide C46; N-((S)-5-benzyl-1-(((S)-9-ethyl-5-fluoro-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl)amino)-1,4,7,10,13-pentaoxo-3,6,9,12-tetraazaoctadecan-18-yl)-2-(cyclopropylsulfonyl)benzo[d]-thiazole-6-carboxamide C47; 4-((S)-2-((S)-2-(6-(2-(cyclopropylsulfonyl)benzo[d]thiazole-6-carboxamido)-hexanamido)-3-methylbutanamido)-5-ureidopentanamido)benzyl ((S)-9-ethyl-5-fluoro-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]-indolizino[1,2-b]quinolin-4-yl)carbamate C48; 2-(cyclopropylsulfonyl)-N-(6-(((S)-1-(((S)-1-(((S)-9-ethyl-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]-quinolin-4-yl)amino)-1-oxopropan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)amino)-6-oxohexyl)-5-fluoro-benzo[d]thiazole-6-carboxamide C49; N-((S)-5-benzyl-1-(((S)-9-ethyl-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexa-hydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl)amino)-1,4,7,10,13-pentaoxo-3,6,9,12-tetraazaoctadecan-18-yl)-2-(cyclopropylsulfonyl)-5-fluorobenzo[d]thiazole-6-carboxamide C50; 4-((S)-2-((S)-2-(6-(2-(cyclopropylsulfonyl)-5-fluorobenzo[d]thiazole-6-carboxamido)-hexanamido)-3-methylbutanamido)-5-ureidopentanamido)benzyl ((S)-9-ethyl-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]-indolizino[1,2-b]-quinolin-4-yl)carbamate C51; (S)-N-(2-(((S)-9-ethyl-5-fluoro-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano-[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl)amino)-2-oxoethyl)-2-(2-(2-(3-((2-(methylsulfonyl)benzo[d]thiazol-6-yl)oxy)propanamide)acetamide)acetamido)-3-phenyl-propanamide C52; or N-((S)-5-benzyl-1-(((S)-9-ethyl-9-hydroxy-10,13-dioxo-1,2,9,10,13,15-hexahydro-12H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl)amino)-1,4,7,10,13-pentaoxo-16,19,22,25-tetraoxa-3,6,9,12-tetraazaheptacosan-27-yl)-2-(methylsulfonyl)benzo[d]thiazole-6-carboxamide C53; 77. The compound of claim 76, wherein:

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