Antibody-KRAS binder conjugates, pharmaceutical compositions, and therapeutic applications

Abstract

Provided herein are antibody-KRAS binder conjugates, for example, a compound of Formula (I), and pharmaceutical compositions thereof. Also provided herein are methods of their use for treating, preventing, or ameliorating one or more symptoms of a disorder, disease, or condition mediated by a KRAS.

Description

ANTIBODY-KRAS BINDER CONJUGATES, PHARMACEUTICAL COMPOSITIONS, AND THERAPEUTIC APPLICATIONSCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of the priority of U.S. Provisional ApplicationNos. 63 / 572,889, filed April 1, 2024; and 63 / 719,053, filed November 11, 2024; the disclosure of each of which is incorporated herein by reference in its entirety.FIELD

[0002] Provided herein are antibody-KRAS binder conjugates and pharmaceutical compositions thereof. Also provided herein are methods of their use for treating, preventing, or ameliorating one or more symptoms of a disorder, disease, or condition mediated by a KRAS.REFERENCE TO A SEQUENCE LISTING

[0003] The present specification is being filed with a Sequence Listing entitled 162A001W001 SEQLIST ST26.XML of 107,987 bytes in size and created March 31, 2025; the content of which is incorporated herein by reference in its entirety.BACKGROUND

[0004] The three RAS oncogenes, KRAS, HRAS, and NRAS, are from the most frequently mutated oncogene family in cancer. Milburn et al., Science 1990, 247, 939-45; Cox et al., Nat. Rev. Drug Discov. 2014, 13, 828-51; Papke and Der, Science 2017, 355, 1158-63; Moore et al., Nat. Rev. Drug Discov. 2020, 19, 533-52. Among the three, KRAS mutations are the most common, alone accounting for 85% of all RAS-related cancer and about a million death per year worldwide. Cox et al., Nat. Rev. Drug Discov. 2014, 13, 828-51; Simanshu et al., Cell 2017, 170, 17-33; McCarthy et al., ACS Omega 2019, 4, 2921-30; Moore et al., Nat. Rev. Drug Discov.2020, 19, 533-52. KRAS is mutated in approximately 40% of colorectal cancer (CRC), 90% of pancreatic ductal adenocarcinoma (PDAC), and 30% of non-small cell lung cancer (NSCLC). Prior etal., Cancer Res. 2020, 80, 2969-74; Johnson et al., Cancer Discov. 2022, 12, 913-23.Glycine 12 mutations are the most common, with KRAS(G12D) representing the most common substitution in CRC and PDAC. Moore et al., Nat. Rev. Drug Discov. 2020, 19, 533-52.

[0005] An antibody-drug conjugate (ADC) is a monoclonal antibody tethered to a cytotoxic drug (also known as a payload or warhead) via a chemical linker. 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, an ADC is a targeted biopharmaceutical drug that, via the specificity of its monoclonal antibody to a cancer cell surface antigen, delivers and releases its cytotoxic payload directly to targeted cancer cells, resulting in a greater potency and a broader therapeutic window as compared with the cytotoxic drug by itself. Polakis, Pharmacol. Rev. 2016, 68, 3-19; Chau et al., Lancet 2019, 394, 793-804. Mechanistically, an ADC exerts its biological functions by binding to a targeted cancer cell selectively, followed by the internalization of an ADC-antigen complex formed on the cell surface via clathrin-mediated endocytosis and the release of the cell-killing payload inside the targeted cancer cell. Chau etal., Lancet 2019, 394, 793-804. To date, no ADC delivering a small molecule KRAS binder has been derived. Lam et al. , Cells 2023, 12, 631.

[0006] Despite the advances in cancer treatment, cancer remains a major worldwide public health problem. It was estimated that there will be 2,001,140 new cancer cases diagnosed and 611,720 cancer deaths in the US alone in 2024. Siegel et al., CA Cancer J. Clin. 2024, 74, 12-49. Therefore, there is a need for an effective therapy for cancer treatment. Lam et al., Cells 2023, 12, 631.SUMMARY OF THE DISCLOSURE

[0007] Provided herein is 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, or hydrate thereof; wherein: each L is independently a linker; each X is independently (i) a bond or S; or (ii) heteroarylene or heterocyclylene;RAis an antibody or an antigen-binding fragment thereof; each RDis independently a KRAS binding moiety; and m is an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16; wherein the heteroarylene and heterocyclylene are each optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q; wherein each Q is independently selected from: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; and (c) -C(O)Ra, -C(O)ORa, -C(O)NRbRc, C(O)SRa, C(NRa)NRbRc, C(S)Ra, C(S)ORa, C(S)NRbRc, ORa, OC(O)Ra, OC(O)ORa, -OC(O)NRbRc, -OC(O)SRa, -OC(NRa)NRbRc, -OC(S)Ra, -OC(S)ORa, -OC(S)NRbRc, -OP(O)(ORa)ORd, -OS(O)Ra, -OS(O)2Ra, -OS(O)NRbRc, -OS(O)2NRbRc, -NRbRc, -NRaC(O)Rd, -NRaC(O)ORd, -NRaC(O)NRbRe, -NRaC(O)SRd, -NRaC(NRd)NRbRc, -NRaC(S)Rd, -NRaC(S)ORd, -NRaC(S)NRbRc, -NRaS(O)Rd, -NRaS(O)2Rd, -NRaS(O)NRbRc, -NRaS(O)2NRbRc, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRbRc, and -S(O)2NRbRc, wherein each Ra, Rb, Rc, and Rdis independently (i) hydrogen or deuterium; (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; or (iii) Rband Rctogether with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; wherein each Qais independently selected from: (a) deuterium, cyano, halo, nitro, imino, and oxo; (b) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, and heterocyclyl; and (c) -C(O)Re, -C(O)ORe, -C(O)NRfRg, -C(O)SRe, -C(NRe)NRfRg, -C(S)Re, -C(S)ORe, -C(S)NRfRg, -ORe, -OC(O)Re, -OC(O)ORe, -OC(O)NRfRg, -OC(O)SRe, -OC(NRe)NRfRg, -OC(S)Re, -OC(S)ORe, -OC(S)NRfRg, -OS(O)Re, -OS(O)2Re, -OS(O)NRfRg, -OS(O)2NRfRg, -NRfRg, -NReC(O)Rb, -NReC(O)ORf, -NReC(O)NRfRg, -NReC(O)SRf, -NReC(NRh)NRfRg, -NReC(S)Rh, -NReC(S)ORf, NReC(S)NRfRg, NReS(O)Rh, NReS(O)2Rh, NReS(O)NRfRg, NReS(O)2NRfRg, SRe, -S(O)Re, -S(O)2Re, -S(O)NRfRg, and -S(O)2NRfRg; wherein each Re, Rf, Rg, and Rhis independently (i) hydrogen or deuterium; (ii) C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; or (iii) Rfand Rgtogether with the N atom to which they are attached form heterocyclyl.

[0008] Also provided herein is a compound of Formula (II):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; wherein: each A is independently a bond, C1-6alkylene, C1-6heteroalkylene, or -O(CR6aR6b)n-; each E1is independently N, heterocyclyl, or C1-6heteroalkylene-heteroaryl; each L is independently a linker; each U is independently C(R2) or N; each X is independently (i) a bond or S; or (ii) heteroarylene or heterocyclylene; each R1, R2, R3, and R4is independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)Rla, -C(O)ORla, -C(O)NRlbRlc, -C(O)SRla, -C(NRla)NRlbRlc, -C(S)Rla, -C(S)ORla, -C(S)NRlbRlc, -ORla, -OC(O)Rla, -OC(O)ORla, OC(O)NRlbRlc, OC(O)SRla, OC(NRla)NRlbRlc, OC(S)Rla, OC(S)ORla, OC(S)NRlbRlc, -OS(O)Rla, -OS(O)2Rla, -OS(O)NRlbRlc, -OS(O)2NRlbRlc, -NRlbRlc, -NRlaC(O)Rld, -NRlaC(O)ORld, -NRlaC(O)NRlbRlc, -NRlaC(O)SRld, -NRlaC(NRld)NRlbRlc, -NRlaC(S)Rld, -NRlaC(S)ORld, -NRlaC(S)NRlbRle, -NRlaS(O)Rld, -NRlaS(O)2Rld, -NRlaS(O)NRlbRle, -NRlaS(O)2NRlbRlc, -SRla, -S(O)Rla, -S(O)2Rla, -S(O)NRlbRlc, or -S(O)2NRlbRlc; or R1and R2together with the carbon atoms to which they are attached form C3-10cycloalkyl or heterocyclyl; each R5is independently hydrogen, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; each Rla, Rlb, Rlc, and Rldis independently hydrogen, deuterium, C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; each R6aand R6bis independently (i) hydrogen, deuterium, cyano, halo, or nitro; or (ii) Ci- 6 alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; or R6aand R6btogether with the carbon atom to which they are attached form C3-10cycloalkylene or heterocyclylene; each R7ais independently (i) hydrogen, deuterium, cyano, halo, or nitro; or (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; or R1and R7aare linked together to form heterocyclyl;RAis 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; and n is an integer of 1, 2, 3, 4, or 5; wherein each alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkynyl, cycloalkyl, cycloalkylene, aryl, aralkyl, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q

[0009] Additionally provided herein is a compound of Formula (XVI):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; wherein: each A is independently a bond, C1-6alkylene, C1-6heteroalkylene, or -O(CR6aR6b)n-; each E2is independently C6-14arylene or heteroarylene; each L is independently a linker; each U is independently C(R2) or N; each X is independently (i) a bond or S; or (ii) heteroarylene or heterocyclylene; each R1, R2, and R4is independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)Rla, -C(O)ORla, -C(O)NRlbRle, -C(O)SRla, -C(NRla)NRlbRlc, -C(S)Rla, -C(S)ORla, -C(S)NRlbRlc, -ORla, -OC(O)Rla, -OC(O)ORla, -OC(O)NRlbRlc, -OC(O)SRla, -OC(NRla)NRlbRlc, -OC(S)Rla, -OC(S)ORla, -OC(S)NRlbRlc, -OS(O)Rla, -OS(O)2Rla, -OS(O)NRlbRlc, -OS(O)2NRlbRle, -NRlbRle, -NRlaC(O)Rld, -NRlaC(O)ORld, -NRlaC(O)NRlbRlc, -NRlaC(O)SRld, -NRlaC(NRld)NRlbRlc, -NRlaC(S)Rld, -NRlaC(S)ORld, -NRlaC(S)NRlbRlc, -NRlaS(O)Rld, -NRlaS(O)2Rld, -NRlaS(O)NRlbRlc, -NRlaS(O)2NRlbRle, -SRla, -S(O)Rla, -S(O)2Rla, -S(O)NRlbRlc, or -S(O)2NRlbRlc; or R1and R2together with the carbon atoms to which they are attached form C3-10cycloalkyl or heterocyclyl; each R5is independently hydrogen, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; each R7is independently (i) C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; or (ii) -NR7bR7c; or R1and R7are linked together to form heterocyclyl; each R6aand R6bis independently (i) hydrogen, deuterium, cyano, halo, or nitro; or (ii) Ci- 6 alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; or R6aand R6btogether with the carbon atom to which they are attached form C3-10cycloalkylene or heterocyclylene; each R7band R7eis independently (i) hydrogen; (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)Rla, -C(O)ORla, -C(O)NRlbRlc, -C(O)SRla, -C(NRla)NRlbRle, -C(S)Rla, -C(S)ORla, -C(S)NRlbRlc, -S(O)Rla, -S(O)2Rla, -S(O)NRlbRlc, or -S(O)2NRlbRlc; each Rla, Rlb, Rlc, and Rldis independently hydrogen, deuterium, C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl;RAis 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; and n is an integer of 1, 2, 3, 4, or 5; wherein each alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkynyl, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more, in one embodiment, one, two, three, or four,substituents Q.

[0010] Furthermore, provided herein is a compound of Formula (XXVI):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; wherein: each A is independently a bond, C1-6alkylene, C1-6heteroalkylene, or -O(CR6aR6b)n-; each E2is independently C3-10cycloalkylene, C6-14arylene, heteroarylene, or heterocyclylene; each L is independently a linker; each U is independently C(R2) or N; each X is independently (i) a bond or S; or (ii) heteroarylene or heterocyclylene; each R1, R2, R3, and R4is independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)Rla, -C(O)ORla, -C(O)NRlbRlc, -C(O)SRla, -C(NRla)NRlbRlc, -C(S)Rla, -C(S)ORla, -C(S)NRlbRlc, -ORla, -OC(O)Rla, -OC(O)ORla, -OC(O)NRlbRle, -OC(O)SRla, -OC(NRla)NRlbRlc, -OC(S)Rla, -OC(S)ORla, -OC(S)NRlbRlc, -OS(O)Rla, -OS(O)2Rla, -OS(O)NRlbRlc, -OS(O)2NRlbRlc, -NRlbRlc, -NRlaC(O)Rld, -NRlaC(O)ORld, -NRlaC(O)NRlbRlc, -NRlaC(O)SRld, -NRlaC(NRld)NRlbRlc, -NRlaC(S)Rld, -NRlaC(S)ORld, -NRlaC(S)NRlbRlc, -NRlaS(O)Rld, -NRlaS(O)2Rld, -NRlaS(O)NRlbRlc, -NRlaS(O)2NRlbRlc, -SRla-S(O)Rla, -S(O)2Rla, -S(O)NRlbRlc, or -S(O)2NRlbRlc; or R1and R2together with the carbon atoms to which they are attached form C3-10cycloalkyl or heterocyclyl; each R7is independently (i) C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; or (ii) -NR7bR7c; or R1and R7are linked together to form heterocyclyl; each R6aand R6bis independently (i) hydrogen, deuterium, cyano, halo, or nitro; or (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl,heteroaryl, or heterocyclyl; or R6aand R6btogether with the carbon atom to which they are attached form C3-10cycloalkylene or heterocyclylene; each R7band R7cis independently (i) hydrogen; (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)Rla, -C(O)ORla, -C(O)NRlbRlc, -C(O)SRla, -C(NRla)NRlbRle, -C(S)Rla, -C(S)ORla, -C(S)NRlbRlc, -S(O)Rla, -S(O)2Rla, -S(O)NRlbRlc, or -S(O)2NRlbRlc; each Rla, Rlb, Rlc, and Rldis independently hydrogen, deuterium, C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl;RAis 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; and n is an integer of 1, 2, 3, 4, or 5; wherein each alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkynyl, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q.

[0011] Provided herein is a compound of Formula (XXVIII):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; wherein: each A1is independently (i) C1-6alkylene or C1-6heteroalkylene; or (ii) C(O); each E3is independently C6-14arylene or heteroarylene; each L is independently a linker; each U is independently C(R2) or N; each U2is independently C1-6alkylene or C1-6heteroalkylene;each X is independently (i) a bond or S; or (ii) heteroarylene or heterocyclylene; each R2, R4, R4a, R8a, and R8bis independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)Rla, -C(O)ORla, -C(O)NRlbRlc, -C(O)SRla, -C(NRla)NRlbRlc, -C(S)Rla, -C(S)ORla, -C(S)NRlbRlc, -ORla, -OC(O)Rla, -OC(O)ORla, -OC(O)NRlbRlc, -OC(O)SRla, -OC(NRla)NRlbRlc, -OC(S)Rla, -OC(S)ORla, -OC(S)NRlbRlc, -OS(O)Rla, -OS(O)2Rla, -OS(O)NRlbRlc, -OS(O)2NRlbRlc, -NRlbRlc, -NRlaC(O)Rld, -NRlaC(O)ORld, -NRlaC(O)NRlbRlc, -NRlaC(O)SRld, -NRlaC(NRld)NRlbRlc, -NRlaC(S)Rld, -NRlaC(S)ORld, -NRlaC(S)NRlbRlc, -NRlaS(O)Rld, -NRlaS(O)2Rld, -NRlaS(O)NRlbRlc, NRlaS(O)2NRlbRlc, SRla, S(O)Rla, S(O)2Rla, S(O)NRlbRlc, or S(O)2NRlbRlc; each R7bis independently (i) hydrogen; (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)Rla, -C(O)ORla, -C(O)NRlbRlc, -C(O)SRla, -C(NRla)NRlbRlc, -C(S)Rla, -C(S)ORla, -C(S)NRlbRlc, -S(O)Rla, -S(O)2Rla, -S(O)NRlbRlc, or -S(O)2NRlbRlc; or R7band R8aare linked together to form heterocyclylene; or R7band R8bare linked together to form heterocyclylene; and each Rla, R1b, Rlc, and Rldis independently hydrogen, deuterium, C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl;RAis an antibody or an antigen-binding fragment thereof; and m is an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16; wherein each alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkynyl, cycloalkyl, aryl, arylene, aralkyl, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q.

[0012] Provided herein is a compound of Formula (XXXI):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; wherein: each A is independently a bond, C1-6alkylene, C1-6heteroalkylene, or -O(CR6aR6b)n-; each E4is independently C3-10cycloalkylene, C6-14arylene, heteroarylene, or heterocyclylene; each L is independently a linker; each U3is N and each V3is O; or each U3is O and each V3is N; each X is independently (i) a bond or S; or (ii) heteroarylene or heterocyclylene; each R5is independently hydrogen, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; each R11, R12, and R15is independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)Rla, -C(O)ORla, -C(O)NRlhRlc, -C(O)SRla, -C(NRla)NRlbRlc, -C(S)Rla, -C(S)ORla, -C(S)NRlbRlc, -ORla, -OC(O)Rla, -OC(O)ORla, -OC(O)NRlbRlc, -OC(O)SRla, -OC(NRla)NRlbRlc, -OC(S)Rla, -OC(S)ORla, -OC(S)NRlbRlc, -OS(O)Rla, -OS(O)2Rla, -OS(O)NRlbRlc, -0S(0)2NRlbRlc, -NRlbRlc, -NRlaC(O)Rld, -NRlaC(O)ORld, -NRlaC(O)NRlbRlc, -NRlaC(O)SRld, -NRlaC(NRld)NRlbRlc, -NRlaC(S)Rld, -NRlaC(S)ORld, -NRlaC(S)NRlbRlc, -NRlaS(O)Rld, -NRlaS(O)2Rld, -NRlaS(O)NRlbRlc, NRlaS(O)2NRlbRlc, SRla, S(O)Rla, S(O)2Rla, S(O)NRlbRlc, or S(O)2NRlbRlc; each R13and R14is independently (i) deuterium, cyano, halo, or nitro; (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)Rla, -C(O)ORla, -C(O)NRlbRlc, -C(O)SRla, -C(NRla)NRlbRlc, -C(S)Rla, -C(S)ORla, -C(S)NRlbRlc, -ORla, -OC(O)Rla, -OC(O)ORla, -OC(O)NRlbRlc,-OC(O)SRla, -OC(NRla)NRlbRlc, -OC(S)Rla, -OC(S)ORla, -OC(S)NRlbRlc, -OS(O)Rla, -OS(O)2Rla, -OS(O)NRlbRle, -OS(O)2NRlbRle, -NRlbRle, -NRlaC(O)Rld, -NRlaC(O)ORld, -NRlaC(O)NRlbRlc, -NRlaC(O)SRld, -NRlaC(NRld)NRlbRlc, -NRlaC(S)Rld, -NRlaC(S)ORld, -NRlaC(S)NRlbRlc, -NRlaS(O)Rld, -NRlaS(O)2Rld, -NRlaS(O)NRlbRlc, -NRlaS(O)2NRlbRlc, -SRla, -S(O)Rla, -S(O)2Rla, -S(O)NRlbRlc, or -S(O)2NRlbRlc; and each Rla, Rlb, Rlc, and Rldis independently hydrogen, deuterium, C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; each R6aand R6bis independently (i) hydrogen, deuterium, cyano, halo, or nitro; or (ii) Ci- 6 alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; or R6aand R6btogether with the carbon atom to which they are attached form C3-10cycloalkylene or heterocyclylene;RAis 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; n is an integer of 1, 2, 3, 4, or 5; and each p and q is independently an integer of 0, 1, 2, 3, 4, 5, or 6; wherein each alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkynyl, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q.

[0013] Provided herein is a compound of Formula (XXXVII):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 hydratethereof; wherein: each A is independently a bond, C1-6alkylene, C1-6heteroalkylene, or -O(CR6aR6b)n-; each L is independently a linker; each U3is N and each V3is O; or each U3is O and each V3is N; each X is independently (i) a bond or S; or (ii) heteroarylene or heterocyclylene; each R3is independently hydrogen, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; each R12, R15, and R16is independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)Rla, -C(O)ORla, -C(O)NRlbRlc, -C(O)SRla, -C(NRla)NRlbRlc, -C(S)Rla, -C(S)ORla, -C(S)NRlbRlc, -ORla, -OC(O)Rla, -OC(O)ORla, -OC(O)NRlbRlc, -OC(O)SRla, -OC(NRla)NRlbRlc, -OC(S)Rla, -OC(S)ORla, -OC(S)NRlbRlc, -OS(O)Rla, -OS(O)2Rla, -OS(O)NRlbRlc, -OS(O)2NRlbRlc, -NRlbRlc, -NRlaC(O)Rld, -NRlaC(O)ORld, -NRlaC(O)NRlbRlc, -NRlaC(O)SRld, -NRlaC(NRld)NRlbRlc, -NRlaC(S)Rld, -NRlaC(S)ORld, -NRlaC(S)NRlbRlc, -NRlaS(O)Rld, -NRlaS(O)2Rld, -NRlaS(O)NRlbRlc, -NR1 aS(O)2NR1bR1c, -SR1a, -S(O)Rla, -S(O)2R1a, -S(O)NRlbRlc, or -S(O)2NRlbR,c; each R13and R14is independently (i) deuterium, cyano, halo, or nitro; (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)Rla, -C(O)ORla, -C(O)NRlbRlc, -C(O)SRla, -C(NRla)NRlbRlc, -C(S)Rla, -C(S)ORla, -C(S)NRlbRlc, -ORla, -OC(O)Rla, -OC(O)ORla, -OC(O)NRlbRlc, -OC(O)SRla, -OC(NRla)NRlbRlc, -OC(S)Rla, -OC(S)ORla, -OC(S)NRlbRlc, -OS(O)Rla, -OS(O)2Rla, -OS(O)NRlbRlc, -OS(O)2NRlbRlc, -NRlbRlc, -NRlaC(O)Rld, -NRlaC(O)ORld, -NRlaC(O)NRlbRlc, -NRlaC(O)SRld, -NRlaC(NRld)NRlbRlc, -NRlaC(S)Rld, -NRlaC(S)ORld, -NRlaC(S)NRlbRlc, -NRlaS(O)Rld, -NRlaS(O)2Rld, -NRlaS(O)NRlbRlc, -NRlaS(O)2NRlbRlc, -SRla, -S(O)Rla, -S(O)2Rla, -S(O)NRlbRlc, or -S(O)2NRlbRlc; each Rla, Rlb, Rlc, and Rldis independently hydrogen, deuterium, C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; each R6aand R6bis independently (i) hydrogen, deuterium, cyano, halo, or nitro; or (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; or R6aand R6btogether with the carbon atom to which they areattached form C3-10cycloalkylene or heterocyclylene;RAis 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; n is an integer of 1, 2, 3, 4, or 5; and each p and q is independently an integer of 0, 1, 2, 3, 4, 5, or 6; wherein each alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkynyl, cycloalkyl, cycloalkylene, aryl, aralkyl, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q

[0014] Provided herein is a compound of Formula (XLIII):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; wherein: each E5is independently a bond oreach E6and Z is independently C3-10cycloalkylene, C6-14arylene, heteroarylene, or heterocyclylene; each E7is independently (i) C3-10cycloalkylene, C6-14arylene, heteroarylene, or heterocyclylene; or (ii) -NRlb-; each L is independently a linker; each X is independently (i) a bond or S; or (ii) heteroarylene or heterocyclylene; each R21is independently (i) hydrogen, deuterium, or cyano; or (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl;each R22and R27is independently (i) deuterium, cyano, halo, or nitro; (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)Rla, -C(O)ORla, -C(O)NRlbRlc, -C(O)SRla, -C(NRla)NRlbRlc, -C(S)Rla, -C(S)ORla, -C(S)NRlbRlc, -ORla, -OC(O)Rla, -OC(O)ORla, -OC(O)NRlbRlc, -OC(O)SRla, -OC(NRla)NRlbRlc, -OC(S)Rla, -OC(S)ORla, -OC(S)NRlbRlc, -OS(O)Rla, -OS(O)2Rla, -OS(O)NRlbRlc, -OS(O)2NRlbRlc, -NRlbRlc, -NRlaC(O)Rld, -NRlaC(O)ORld, -NRlaC(O)NRlbRlc, -NRlaC(O)SRld, -NRlaC(NRld)NRlbRlc, -NRlaC(S)Rld, -NRlaC(S)ORld, -NRlaC(S)NRlbRlc, -NRlaS(O)Rld, -NRlaS(O)2Rld, -NRlaS(O)NRlbRlc, -NRlaS(O)2NRlbRlc, -SRla, -S(O)Rla, -S(O)2Rla, -S(O)NRlbRlc, or -S(O)2NRlbRlc; each R23is independently (i) hydrogen; (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)Rla, -C(O)ORla, -C(O)NRlbRlc, -C(O)SRla, -C(NRla)NRlbRlc, -C(S)Rla, -C(S)ORla, -C(S)NRlbRlc, -S(O)Rla, -S(O)2Rla, -S(O)NRlbRlc, or -S(O)2NRlbRlc; each R24, R25, and R26is independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)R1 a, -C(O)OR1 a, -C(O)NR1bR1e, -C(O)SRla, -C(NRla)NRlbRlc, -C(S)Rla, -C(S)ORla, -C(S)NRlbRlc, -ORla, -OC(O)Rla, -OC(O)ORla, -OC(O)NRlbRlc, -OC(O)SRla, -OC(NRla)NRlbRlc, -OC(S)Rla, -OC(S)ORla, -OC(S)NRlbRlc, -OS(O)Rla, -OS(O)2Rla, -OS(O)NRlbRlc, -OS(O)2NRlbRle, -NRlbRlc, -NRlaC(O)Rld, -NRlaC(O)ORld, -NRlaC(O)NRlbRlc, -NRlaC(O)SRld, -NRlaC(NRld)NRlbRlc, -NRlaC(S)Rld, -NRlaC(S)ORld, -NRlaC(S)NRlbRle, -NRlaS(O)Rld, -NRlaS(O)2Rld, -NRlaS(O)NRlbRle, -NRlaS(O)2NRlbRlc, -SRla, -S(O)Rla, -S(O)2Rla, -S(O)NRlbRlc, or -S(O)2NRlbRlc; or R25and R26together with the carbon atoms to which they are attached form C3-10cycloalkylene or heterocyclylene; each Rla, Rlb, Rlc, and Rldis independently hydrogen, deuterium, C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl;RAis 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 s is independently an integer of 0, 1, 2, or 3; and each t is independently an integer of 0, 1, 2, 3, 4, 5, or 6;wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q.

[0015] Provided herein is a compound of Formula (XL VI):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; wherein: each E8and Z is independently C3-10cycloalkylene, C6-14arylene, heteroarylene, or heterocyclylene; each E9is independently a bond, C3-10cycloalkylene, C6-14arylene, heteroarylene, or heterocyclylene; each L is independently a linker; each X is independently (i) a bond or S; or (ii) heteroarylene or heterocyclylene; each R22and R27is independently (i) deuterium, cyano, halo, or nitro; (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)Rla, -C(O)ORla, -C(O)NRlbRlc, -C(O)SRla, -C(NRla)NRlbRlc, -C(S)Rla, -C(S)ORla, -C(S)NRlbRlc, -ORla, -OC(O)Rla, -OC(O)ORla, -OC(O)NRlbRlc, -OC(O)SRla, -OC(NRla)NRlbRlc, -OC(S)Rla, -OC(S)ORla, -OC(S)NRlbRlc, -OS(O)Rla, -OS(O)2Rl a, -OS(O)NR1bR1e, -OS(O)2NR,bR, e, -NR1bR1e, -NR1 aC(O)Rld, -NR1aC(O)ORld, -NRlaC(O)NRlbRlc, -NRlaC(O)SRld, -NRlaC(NRld)NRlbRlc, -NRlaC(S)Rld, -NRlaC(S)ORld, -NRlaC(S)NRlbRlc, -NRlaS(O)Rld, -NRlaS(O)2Rld, -NRlaS(O)NRlbRlc, -NRlaS(O)2NRlbRlc, -SRla, -S(O)Rla, -S(O)2Rla, -S(O)NRlbRlc, or -S(O)2NRlbRlc; each R23is independently (i) hydrogen; (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)Rla,-C(O)ORla, -C(O)NRlbRlc, -C(O)SRla, -C(NRla)NRlbRlc, -C(S)Rla, -C(S)ORla, -C(S)NRlbRlc, -S(O)Rla, -S(O)2Rla, -S(O)NRlbRlc, or -S(O)2NRlbRlc; each R25and R26is independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)Rla, -C(O)ORla, -C(O)NRlbRle, -C(O)SRla, -C(NRla)NRlbRlc, -C(S)Rla, -C(S)ORla, -C(S)NRlbRlc, -ORla, -OC(O)Rla, -OC(O)ORla, -OC(O)NRlbRlc, -OC(O)SRla, -OC(NRla)NRlbRlc, -OC(S)Rla, -OC(S)ORla, -OC(S)NRlbRlc, -OS(O)Rla, -OS(O)2Rla, -OS(O)NRlbRlc, -OS(O)2NRlbRle, -NRlbRlc, -NRlaC(O)Rld, -NRlaC(O)ORld, -NRlaC(O)NRlbRlc, -NRlaC(O)SRld, -NRlaC(NRld)NRlbRlc, -NRlaC(S)Rld, NRlaC(S)ORld, NRlaC(S)NRlbRlc, NRlaS(O)Rld, NRlaS(O)2Rld, NRlaS(O)NRlbRlc, -NRlaS(O)2NRlbRlc, -SRla, -S(O)Rla, -S(O)2Rla, -S(O)NRlbRlc, or -S(O)2NRlbRlc; or R25and R26together with the carbon atoms to which they are attached form C3-10cycloalkylene or heterocyclylene; each R28is independently hydrogen, C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; each Rla, R1b, Rlc, and Rldis independently hydrogen, deuterium, C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl;RAis 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 s is independently an integer of 0, 1, 2, or 3; and each t is independently an integer of 0, 1, 2, 3, 4, 5, or 6; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q.

[0016] Provided herein is a compound of Formula (XL VIII):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; wherein: each L is independently a linker; each X is independently (i) a bond or S; or (ii) heteroarylene or heterocyclylene; each Z is independently C3-10cycloalkylene, C6-14arylene, heteroarylene, or heterocyclylene; each R22and R27is independently (i) deuterium, cyano, halo, or nitro; (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)Rla, -C(O)ORla, -C(O)NRlbRlc, -C(O)SRla, -C(NRla)NRlbRlc, -C(S)Rla, -C(S)ORla, -C(S)NRlbRlc, -ORla, -OC(O)Rla, -OC(O)ORla, -OC(O)NRlbRlc, -OC(O)SRla, -OC(NRla)NRlbRlc, -OC(S)Rla, -OC(S)ORla, -OC(S)NRlbRlc, -OS(O)Rla, -OS(O)2Rla, -OS(O)NRlbRlc, -OS(O)2NRlbRlc, -NRlbRlc, -NRlaC(O)Rld, -NRlaC(O)ORld, -NRlaC(O)NRlbRlc, -NRlaC(O)SRld, -NRlaC(NRld)NRlbRlc, -NRlaC(S)Rld, -NRlaC(S)ORld, -NRlaC(S)NRlbRlc, -NRlaS(O)Rld, -NRlaS(O)2Rld, -NRlaS(O)NRlbRle, -NRlaS(O)2NRlbRlc, -SRla, -S(O)Rla, -S(O)2Rla, -S(O)NRlbRlc, or -S(O)2NRlbRlc; each R23is independently (i) hydrogen; (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)Rla, -C(O)ORla, -C(O)NRlbRlc, -C(O)SRla, -C(NRla)NRlbRlc, -C(S)Rla, -C(S)ORla, -C(S)NRlbRlc, -S(O)Rla, -S(O)2Rla, -S(O)NRlbRle, or -S(O)2NRlbRlc; each R24, R2 5and R26is independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)Rla, -C(O)ORla, -C(O)NRlbRlc, -C(O)SRla, -C(NRla)NRlbRlc, -C(S)Rla, -C(S)ORla, -C(S)NRlbRlc, -ORla, -OC(O)Rla, -OC(O)ORla, OC(O)NRlbRlc, OC(O)SRla, OC(NRla)NRlbRlc, OC(S)Rla, OC(S)ORla, OC(S)NRlbRlc,-OS(O)Rla, -OS(O)2Rla, -OS(O)NRlbRlc, -OS(O)2NRlbRlc, -NRlbRlc, -NRlaC(O)Rld, -NRlaC(O)ORld, -NRlaC(O)NRlbRlc, -NRlaC(O)SRld, -NRlaC(NRld)NRlbRlc, -NRlaC(S)Rld, -NRlaC(S)ORld, -NRlaC(S)NRlbRlc, -NRlaS(O)Rld, -NRlaS(O)2Rld, -NRlaS(O)NRlbRlc, -NRlaS(O)2NRlbRlc, -SRla, -S(O)Rla, -S(O)2Rla, -S(O)NRlbRlc, or -S(O)2NRlbRlc; or R25and R26together with the carbon atoms to which they are attached form C3-10cycloalkylene or heterocyclylene; each R28is independently hydrogen, C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14 aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; each Rla, Rlb, Rlc, and Rldis independently hydrogen, deuterium, C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl;RAis 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 s is independently an integer of 0, 1, 2, or 3; and each t is independently an integer of 0, 1, 2, 3, 4, 5, or 6; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q.

[0017] 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, or hydrate thereof; and a pharmaceutically acceptable excipient.

[0018] Provided herein is a method of treating, preventing, or ameliorating one or more symptoms of a disorder, disease, or condition mediated by a KRAS in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of 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, or hydrate thereof.

[0019] Provided herein is a method of treating, preventing, or ameliorating one or moresymptoms 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 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.

[0020] Provided herein is a method of inhibiting the growth of a cell, comprising contacting the cell with an effective amount of 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, or hydrate thereof.

[0021] Provided herein is a method of inhibiting a KRAS, comprising contacting the KRAS with an effective amount of 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, or hydrate thereof.DETAILED DESCRIPTION

[0022] To facilitate understanding of the disclosure set forth herein, a number of terms are defined below.

[0023] Generally, the nomenclature used herein and the laboratory procedures 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.

[0024] The term “subject” refers to an animal, including, but not limited to, a primate (e.g., human), cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms “subject” and “patient” are used interchangeably herein in reference, for example, to a mammalian subject, such as a human subject. In one embodiment, the subject is a human.

[0025] The terms “treat,” “treating,” and “treatment” are meant to include alleviating or abrogating a disorder, disease, or condition, or one or more of the symptoms associated with the disorder, disease, or condition; or alleviating or eradicating the cause(s) of the disorder, disease,or condition itself.

[0026] The terms “prevent,” “preventing,” and “prevention” are meant to include a method of delaying and / or precluding 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.

[0027] The terms “alleviate” and “alleviating” refer to easing or reducing one or more symptoms (e.g., pain) of a disorder, disease, or condition. The terms can also refer to reducing adverse effects associated with an 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.

[0028] The term “contacting” or “contact” is meant to refer to bringing together of a therapeutic agent and a biological molecule (e.g., a protein, enzyme, RNA, or DNA), cell, or tissue such that a physiological and / or chemical effect takes place as a result of such contact. Contacting can take place in vitro, ex vivo, or in vivo. In one embodiment, a therapeutic agent is contacted with a biological molecule in vitro to determine the effect of the therapeutic agent on the biological molecule. In another embodiment, a therapeutic agent is contacted with a cell in cell culture (in vitro) to determine the effect of the therapeutic agent on the cell. In yet another embodiment, the contacting of a therapeutic agent with a biological molecule, cell, or tissue includes the administration of a therapeutic agent to a subject having the biological molecule, cell, or tissue to be contacted.

[0029] The term “therapeutically effective amount” or “effective amount” is meant to include the amount of a compound that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the disorder, disease, or condition being treated. The term “therapeutically effective amount” or “effective amount” also refers to the amount of a compound that is sufficient to elicit a biological or medical response of a biological molecule (e.g., a protein, enzyme, RNA, or DNA), cell, tissue, system, animal, or human, which is being sought by a researcher, veterinarian, medical doctor, or clinician.

[0030] The term “pharmaceutically acceptable carrier,” “pharmaceutically acceptableexcipient,” “physiologically acceptable carrier,” or “physiologically acceptable excipient” refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid fdler, diluent, solvent, or encapsulating material. In one embodiment, each component is “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of a subject (e.g., a human or an animal) without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, and commensurate with a reasonable benefit / risk ratio. See, e.g., Remington: The Science and Practice of Pharmacy, 22nd ed.; Allen Ed.; Pharmaceutical Press: London, 2012; Handbook of Pharmaceutical Excipients, 8th ed.; Sheskey et al., Eds.; Pharmaceutical Press: London, 2017; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Synapse Information Resources: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; Drugs and the Pharmaceutical Sciences 199; Informa Healthcare: New York, NY, 2009.

[0031] The term “about” or “approximately” means 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.

[0032] The term “alkyl” refers to 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, C1-6alkyl 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, the alkyl is a linear saturated monovalent hydrocarbon radical that has 1 to 20 (C1-20), 1 to 15 (C1-15), 1 to 10 (C1-10), or 1 to 6 ( C1-6) carbon atoms, or branched saturated monovalent hydrocarbon radical of 3 to 20 (C3-20), 3 to 15 (C3-15), 3 to 10 (C3-10), or 3 to 6 (C3-6) carbon atoms. As used herein, linear C1-6and branched C3-6alkyl groups are also referred as “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. ., 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).

[0033] The terms “alkylene” and “alkanediyl” are used interchangeably herein in reference to a linear or branched saturated divalent hydrocarbon radical, wherein the alkanediyl is optionally substituted with one or more substituents Q as described herein. For example, C1-6alkanediyl 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, the alkanediyl is a linear saturated divalent hydrocarbon radical that has 1 to 30 (C1-30), 1 to 20 (C1-20), 1 to 15 (C1-15), 1 to 10 (C1-10), or 1 to 6 (C1-6) carbon atoms, or branched saturated divalent hydrocarbon radical of 3 to 30 (C3-30), 3 to 20 (C3-20), 3 to 15 (C3-15), 3 to 10 (C3-10), or 3 to 6 (C3-6) carbon atoms. As used herein, linear C1-6and branched C3-6alkanediyl groups are also referred as “lower alkanediyl.” Examples of alkanediyl groups include, but are not limited to, methane- diyl, ethanediyl (including all isomeric forms, e.g., ethane- 1,1 -diyl and ethane- 1 ,2-diyl), propane- diyl (including all isomeric forms, e.g., propane- 1,1 -diyl, propane- 1,2-diyl, and propane- 1,3 -diyl), butanediyl (including all isomeric forms, e.g., butane- 1,1 -diyl, butane- 1,2-diyl, butane- 1,3 -diyl, and butane- 1,4-diyl), pentanediyl (including all isomeric forms, e.g., pentane- 1,1 -diyl, pentane- 1,2-diyl, pentane-l,3-diyl, and pentane- 1,5 -diyl), and hexanediyl (including all isomeric forms, e.g., hexane- 1,1 -diyl, hexane- 1,2-diyl, hexane- 1,3-diyl, and hexane- 1,6-diyl). Examples of substituted alkanediyl groups include, but are not limited to, -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- -C(0)(CH2)10- -C(O)CH2C(O)-, -C(O)(CH2)2C(O)-, -C(O)(CH2)3C(O)-, -C(O)(CH2)4C(O)-, or -C(O)(CH2)5C(O)-.

[0034] The term “heteroalkyl” refers to a linear or branched saturated monovalent hydrocarbon radical that contains one or more heteroatoms on its main chain, each independently selected from O, S, and N. The heteroalkyl is optionally substituted with one or more substituents Q as described herein. For example, C1-6heteroalkyl 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, the heteroalkyl is a linear saturated monovalent hydrocarbon radical that has 1 to 20 (C1-20), 1 to 15 (C1-15), 1 to 10 (C1-10), or 1 to 6 (C1-6) carbon atoms, or branched saturated monovalent hydrocarbon radical of 3 to 20 (C3-20), 3 to15 (C3-15), 3 to 10 (C3-10), or 3 to 6 (C3-6) carbon atoms. As used herein, linear C1-6and branched C3-6heteroalkyl groups are also referred as “lower heteroalkyl.” Examples of heteroalkyl groups include, but are not limited to, -OCH3, -OCH2CH3, -CH2OCH3, -NHCH3, -ONHCH3, -NHOCH3, -SCH3, -CH2NHCH2CH3, and -NHCH2CH2CH3. Examples of substituted heteroalkyl groups include, but are not limited to, -CH2NHC(O)CH3 and -NHC(O)CH2CH3.

[0035] The terms “heteroalkylene” and “heteroalkanediyl” are used interchangeably herein in reference to a linear or branched saturated divalent hydrocarbon radical that contains one or more heteroatoms in its main chain, each independently selected from O, S, and N. The heteroalkylene is optionally substituted with one or more substituents Q as described herein. For example, C1-6heteroalkylene 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, the heteroalkylene is a linear saturated divalent hydrocarbon radical that has 1 to 20 (C1-20), 1 to 15 (C1-15), 1 to 10 (C1-10), or 1 to 6 (C1-6) carbon atoms, or branched saturated divalent hydrocarbon radical of 3 to 20 (C3-20), 3 to 15 (C3-15), 3 to 10 (C3-10), or 3 to 6 (C3-6) carbon atoms. As used herein, linear C1-6and branched C3-6heteroalkylene groups are also referred as “lower heteroalkylene.” Examples of heteroalkylene groups include, but are not limited to, -CH2O-, -(CH2)2O- -(CH2)3O-, -(CH2)4O- -(CH2)5O-, -(CH2)6O- -(CH2)7O-, -(CH2)8O- -(CH2)9O-, -(CH2)10O- -CH2OCH2- -CH2CH2O-, -(CH2CH2O)2- -(CH2CH2O)3- -(CH2CH2O)4-, -(CH2CH2O)5- -CH2NH-, -CH2NHCH2- -CH2CH2NH- -CH2S-, -CH2SCH2- and -CH2CH2S- Examples of substituted heteroalkylene groups include, but are not limited to, -C(O)CH2O-, -C(O)(CH2)2O- -C(O)(CH2)3O- -C(O)(CH2)4O- -C(O)(CH2)5O-, -C(O)(CH2)6O- -C(O)(CH2)7O- -C(O)(CH2)8O- -C(O)(CH2)9O- -C(0)(CH2)10O- -C(O)CH2OCH2CH2O-, -C(O)CH2O(CH2CH2O)2-, -C(O)CH2O(CH2CH2O)3-, -C(O)CH2O(CH2CH2O)4, -C(O)CH2O(CH2CH2O)5-, -CH2NHC(O)CH2-, or -CH2CH2C(O)NH-.

[0036] The term “alkenyl” refers to a linear or branched monovalent hydrocarbon radical, which contains one or more, in one embodiment, one, two, three, or four, 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” embraces radicals having a “cis” or “trans” configuration or a mixture thereof, or alternatively, a “Z” or “E” configuration or amixture thereof, as appreciated by those of ordinary skill in the art. For example, C2-6alkenyl 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, the alkenyl is a linear monovalent hydrocarbon radical of 2 to 20 (C2-20), 2 to 15 (C2-15), 2 to 10 (C2-10), or 2 to 6 (C2-6) carbon atoms, or a branched monovalent hydrocarbon radical of 3 to 20 (C3-20), 3 to 15 (C3-15), 3 to 10 (C3-10), or 3 to 6 (C3-6) carbon atoms. 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-l-yl).

[0037] The terms “alkenylene” and “alkenediyl” are used interchangeably herein in reference to a linear or branched divalent hydrocarbon radical, which contains one or more, in one embodiment, one, two, three, or four, 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” embraces radicals having a ''ci " or "trans" configuration or a mixture thereof, or alternatively, a “Z” orconfiguration or a mixture thereof, as appreciated by those of ordinary skill in the art. For example, C2-6alkenediyl 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, the alkenediyl is a linear divalent hydrocarbon radical of 2 to 30 (C2-30), 2 to 20 (C2-20), 2 to 15 (C2-15), 2 to 10 (C2-10), or 2 to 6 (C2-6) carbon atoms, or a branched divalent hydrocarbon radical of 3 to 30 (C3-30), 3 to 20 (C3-20), 3 to 15 (C3-15), 3 to 10 (C3-10), or 3 to 6 (C3-6) carbon atoms. Examples of alkenediyl groups include, but are not limited to, ethenediyl (including all isomeric forms, e.g., ethene- 1 , 1 -diyl and ethene- 1 ,2-diyl), propenediyl (including all isomeric forms, e.g., 1 -propene- 1,1 -diyl, l-propene-l,2-diyl, and l-propene-l,3-diyl), butenediyl (including all isomeric forms, e.g., 1 -butene- 1, 1 -diyl, 1- butene-l,2-diyl, and 1 -butene- 1,4-diyl), pentenediyl (including all isomeric forms, e.g., 1- pentene- 1,1 -diyl, 1 -pentene- 1,2-diyl, and 1 -pentene- 1,5 -diyl), and hexenediyl (including all isomeric forms, e.g., 1 -hexene- 1,1 -diyl, 1 -hexene- 1,2-diyl, l-hexene-l,3-diyl, 1 -hexene- 1,4-diyl, 1 -hexene- 1,5-diyl, and l-hexene-l,6-diyl).

[0038] The terms “heteroalkenyl ene” and “heteroalkenediyl” are used interchangeably herein in reference to a linear or branched divalent hydrocarbon radical, which contains one ormore, in one embodiment, one, two, three, or four, in another embodiment, one, carbon-carbon double bond(s), and which contains one or more heteroatoms each independently selected from O, S, and N in the hydrocarbon chain. The heteroalkenylene is optionally substituted with one or more substituents Q as described herein. The term “ heteroal kenylene” embraces radicals having a “cis” or “trans” configuration or a mixture thereof, or alternatively, a “Z” or “E” configuration or a mixture thereof, as appreciated by those of ordinary skill in the art. For example, C2-6heteroalkenylene 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, the heteroalkenylene is a linear divalent hydrocarbon radical of 2 to 20 (C2-20), 2 to 15 (C2-15), 2 to 10 (C2-10), or 2 to 6 (C2-6) carbon atoms, or a branched divalent hydrocarbon radical of 3 to 20 (C3-20), 3 to 15 (C3-15), 3 to 10 (C3-10), or 3 to 6 (C3-6) carbon atoms. Examples of heteroalkenylene groups include, but are not limited to, -CH=CHO-, -CH=CHOCH2- -CH=CHCH2O-, -CH=CHS-, -CH=CHSCH2-, -CH=CHCH2S-, or -CH=CHCH2NH-.

[0039] The term “alkynyl” refers to a linear or branched monovalent hydrocarbon radical, which contains one or more, in one embodiment, one, two, three, or four, in another embodiment, one, carbon-carbon triple bond(s). The alkynyl is optionally substituted with one or more substituents Q as described herein. For example, C2-6alkynyl 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 certain embodiments, the alkynyl is a linear monovalent hydrocarbon radical of 2 to 20 (C2-20), 2 to 15 (C2-15), 2 to 10 (C2-10), or 2 to 6 (C2-6) carbon atoms, or a branched monovalent hydrocarbon radical of 4 to 20 (C4-20), 4 to 15 (C4-15), 4 to 10 (C4-10), or 4 to 6 (C4-6) carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-OCH), propynyl (including all isomeric forms, e.g., 1-propynyl (-OCCH3) and propargyl (-CH2OCH)), butynyl (including all isomeric forms, e.g., 1-butyn-l- yl and 2-butyn-l-yl), pentynyl (including all isomeric forms, e.g., 1-pentyn-l-yl and l-methyl-2- butyn-l-yl), and hexynyl (including all isomeric forms, e.g., 1-hexyn-l-yl and 2-hexyn-l-yl).

[0040] The terms “alkynylene” and “alkynediyl” are used interchangeably herein in reference to a linear or branched divalent hydrocarbon radical, which contains one or more, in one embodiment, one, two, three, or four, in another embodiment, one, carbon-carbon triple bond(s). The alkynediyl is optionally substituted with one or more substituents Q as described herein. Forexample, C2-6alkynediyl 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, the alkynediyl is a linear divalent hydrocarbon radical of 2 to 30 (C2-30), 2 to 20 (C2-20), 2 to 15 (C2-15), 2 to 10 (C2-10), or 2 to 6 (C2-6) carbon atoms, or a branched divalent hydrocarbon radical of 4 to 30 (C4-30), 4 to 20 (C4-20), 4 to 15 (C4-15), 4 to 10 (C4-10), or 4 to 6 (C4- 6) carbon atoms. Examples of alkynediyl groups include, but are not limited to, ethynediyl, propynediyl (including all isomeric forms, e.g., 1 -propyne- 1,3 -diyl and l-propyne-3,3-diyl), butynediyl (including all isomeric forms, e.g., 1 -butyne- 1,3 -diyl, 1 -butyne- 1,4-diyl, and 2-butyne- 1,1 -diyl), pentynediyl (including all isomeric forms, e.g., 1 -pentyne- 1,3-diyl, 1 -pentyne- 1,4-diyl, and 2-pentyne-l,l-diyl), and hexynediyl (including all isomeric forms, e.g., 1 -hexyne- 1,3 -diyl, 1- hexyne- 1,4-diyl, and 2-hexyne- 1,1 -diyl).

[0041] The terms “heteroalkynylene” and “heteroalkynediyl” are used interchangeably herein in reference to a linear or branched divalent hydrocarbon radical, which contains one or more, in one embodiment, one, two, three, or four, in another embodiment, one, carbon-carbon triple bond(s), and which contains one or more heteroatoms in its main chain, each independently selected from O, S, and N. The heteroalkynylene is optionally substituted with one or more substituents Q as described herein. For example, C2-6heteroalkynylene 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, the hetero- alkynylene is a linear divalent hydrocarbon radical of 2 to 30 (C2-30), 2 to 20 (C2-20), 2 to 15 (C2-15), 2 to 10 (C2-10), or 2 to 6 (C2-6) carbon atoms, or a branched divalent hydrocarbon radical of 4 to 30 (C4-30), 4 to 20 (C4-20), 4 to 15 (C4-15), 4 to 10 (C4-10), or 4 to 6 (C4-6) carbon atoms.Examples of heteroalkynylene groups include, but are not limited to, C=CCH2O , -OCCH2S-, or -OCCH2NH-.

[0042] The term “cycloalkyl” refers to a cyclic monovalent hydrocarbon radical, which is 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 has from 3 to 20 (C3-20), from 3 to 15 (C3-15), from 3 to 10 (C3-10), or from 3 to 7 (C3-7) carbon atoms. In one embodiment, the cycloalkyl is monocyclic. In another embodiment, the cycloalkyl is bicyclic. In yet anotherembodiment, the cycloalkyl is tricyclic. In still another embodiment, the cycloalkyl is polycyclic. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclo- pentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptenyl, bicyclo[l.l. l]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]-octyl, decalinyl, and adamantyl.

[0043] The terms “cycloalkylene” and “cycloalkanediyl” are used interchangeably herein in reference to a cyclic divalent hydrocarbon radical, which may be optionally substituted with one or more substituents Q as described herein. In one embodiment, cycloalkanediyl groups may be saturated or unsaturated but non-aromatic, and / or bridged, and / or non-bridged, and / or fused bicyclic groups. In certain embodiments, the cycloalkanediyl has from 3 to 30 (C3-30), 3 to 20 (C3-20), from 3 to 15 (C3-15), from 3 to 10 (C3-10), or from 3 to 7 (C3-7) carbon atoms. Examples of cycloalkanediyl groups include, but are not limited to, cyclopropanediyl (including all isomeric forms, e.g., cyclopropane- 1,1 -diyl and cyclopropane- 1,2-diyl), cyclobutanediyl (including all isomeric forms, e.g., cyclobutane- 1,1 -diyl, cyclobutane- 1,2-diyl, and cyclobutane- 1,3 -diyl), cyclopentanediyl (including all isomeric forms, e.g., cyclopentane- 1,1 -diyl, cyclopentane- 1,2- diyl, and cyclopentane-l,3-diyl), cyclohexanediyl (including all isomeric forms, e.g., cyclohexane- 1,1 -diyl, cyclohexane- 1,2-diyl, cyclohexane-l,3-diyl, and cyclohex-l,4-diyl), cycloheptanediyl (including all isomeric forms, e.g., cycloheptane- 1,1 -diyl, cycloheptane- 1,2- diyl, cycloheptane- 1 ,3 -diyl, and cycloheptane-l ,4-diyl), decalinediyl (including all isomeric forms, e.g., decaline- 1,1 -diyl, decaline- 1,2-diyl, and decaline- 1,8-diyl), and adamantdiyl (including all isomeric forms, e.g., adamant- 1,2-diyl, adamant- 1,3 -diyl, and adamant- 1,8-diyl).

[0044] The term “aryl” refers to a monovalent monocyclic aromatic hydrocarbon radical and / or monovalent polycyclic aromatic hydrocarbon radical that contains at least one aromatic carbon ring. In certain embodiments, the aryl has from 6 to 20 (C6-20), from 6 to 15 (C6-15), or from 6 to 10 (C6-10) ring carbon atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, pyrenyl, biphenyl, and terphenyl. The aryl also refers to bicyclic or tricyclic carbon rings, where one of the rings is aromatic and the others of which may be saturated, partially unsaturated, or aromatic, for example, dihydronaphthyl, indenyl, indanyl, or tetrahydronaphthyl (tetralinyl). In one embodiment, the aryl is monocyclic. In another embodiment, the aryl is bicyclic. In yet another embodiment, thearyl is tricyclic. In still another embodiment, the aryl is polycyclic. In certain embodiments, the aryl is optionally substituted with one or more substituents Q as described herein.

[0045] The terms “arylene” and “arenediyl” are used interchangeably herein in reference to a divalent monocyclic aromatic hydrocarbon radical or divalent polycyclic aromatic hydrocarbon radical that contains at least one aromatic hydrocarbon ring. In certain embodiments, the arylene has from 6 to 20 (C6-20), from 6 to 15 (C6-15), or from 6 to 10 (C6-10) ring atoms. Examples of arylene groups include, but are not limited to, phenylene (including all isomeric forms, e.g., phen-l,2-diyl, phen- 1,3 -diyl, and phen-l,4-diyl), naphthylene (including all isomeric forms, e.g., naphth- 1,2-diyl, naphth- 1,3 -diyl, and naphth- 1,8-diyl), fluorenylene (including all isomeric forms, e.g., fluoren- 1,2-diyl, fluoren-l,3-diyl, and fluoren- 1,8-diyl), azulenylene (including all isomeric forms, e.g., azulen- 1,2-diyl, azulen- 1,3 -diyl, and azulen-1,8- diyl), anthrylene (including all isomeric forms, e.g., anthr- 1,2-diyl, anthr-l,3-diyl, and anthr-1,8- diyl), phenanthrylene (including all isomeric forms, e.g., phenanthr- 1,2-diyl, phenanthr- 1,3 -diyl, and phenanthr-l,8-diyl), pyrenylene (including all isomeric forms, e.g., pyren- 1,2-diyl, pyren-1,3- diyl, and pyren- 1,8-diyl), biphenylene (including all isomeric forms, e.g., biphen-2,3-diyl, biphen- 3,4’ -diyl, and biphen-4,4’-diyl), and terphenylene (including all isomeric forms, e.g., terphen-2,3- diyl, terphen-3,4’-diyl, and terphen-4,4’-diyl). Arylene also refers to bicyclic or tricyclic carbon rings, where one of the rings is aromatic and the others of which may be saturated, partially unsaturated, or aromatic, for example, dihydronaphthylene (including all isomeric forms, e.g., dihydronaphth- 1,2-diyl and dihydronaphth- 1,8-diyl), indenylene (including all isomeric forms, e.g., inden- 1,2-diyl, inden- 1,5-diyl, and inden- 1 ,7-diyl), indanylene (including all isomeric forms, e.g., indan- 1,2-diyl, indan- 1,5-diyl, and indan- 1 ,7-diyl), or tetrahydronaphthylene (tetralinylene) (including all isomeric forms, e.g., tetrahydronaphth- 1,2-diyl, tetrahydronaphth- 1,5 -diyl, and tetrahydronaphth-l,8-diyl). In certain embodiments, arylene is optionally substituted with one or more substituents Q as described herein.

[0046] The term “aralkyl” or “arylalkyl” refers to a monovalent alkyl group substituted with one or more aryl groups. In certain embodiments, the aralkyl has from 7 to 30 (C7-30), from 7 to 20 (C7-20), or from 7 to 16 (C7-16) carbon atoms. Examples of aralkyl groups include, but are not limited to, benzyl, phenyl ethyl (including all isomeric forms, e.g., 1 -phenylethyl and 2- phenylethyl), and phenylpropyl (including all isomeric forms, e.g., 1 -phenylpropyl, 2-phenyl-propyl, and 3-phenylpropyl). In certain embodiments, the aralkyl is optionally substituted with one or more substituents Q as described herein.

[0047] The term “aralkylene” or “arylalkylene” refers to a divalent alkyl group substituted with one or more aryl groups. In certain embodiments, the aralkylene has from 7 to 30 (C7-30), from 7 to 20 (C7-20), or from 7 to 16 (C7-16) 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-ethan- 1,1 -diyl and 2-phenyl-ethan- 1 ,2-diyl), and phenylpropylene (including all isomeric forms, e.g., 3-phenyl-propan- 1,1 -diyl, 3- phenyl-propan-l,2-diyl, and 3-phenyl-propan- 1,3 -diyl). In certain embodiments, the aralkylene is optionally substituted with one or more substituents Q as described herein.

[0048] The term “heteroaryl” refers to a monovalent monocyclic aromatic group or monovalent polycyclic aromatic group that contain at least one aromatic ring, wherein at least one aromatic ring contains one or more heteroatoms, each independently selected from O, S, and N, in the ring. The heteroaryl is bonded to the rest of a molecule through the aromatic ring. Each ring of a heteroaryl group can contain one or two O atoms, one or two S atoms, and / or one to four N atoms; provided that the total number of heteroatoms in each ring is four or less and each ring contains at least one carbon atom. In certain embodiments, the heteroaryl has from 5 to 20, from 5 to 15, or from 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, but are not limited to, benzofuranyl, benzimidazolyl, benzoisoxazolyl, 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), imidazopyridinyl (including all isomeric forms, e.g., imidazo[l,2-α ]pyridinyl, imidazo[4,5-b]pyridinyl, and imidazo[4,5-c]pyridinyl), imidazo- thiazolyl (including all isomeric forms, e.g., imidazo[2,l-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, e.g., 1,5-naphthyridinyl, 1,6-naphthyridinyl, 1,7-naphthyridinyl, and 1,8-naphthyridinyl), oxazolopyridinyl (including all isomeric forms, e.g., oxazolo[4,5-b]pyridinyl, oxazolo[4,5-c]pyridinyl, oxazolo[5,4-6]pyridinyl, and oxazolo[5,4-c]pyridinyl), phthalazinyl, pteridinyl, purinyl, pyrrolopyridyl (including all isomeric forms, e.g., pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-b]pyridinyl, and pyrrolo[3,2-c]pyridinyl), quinolinyl, quinoxalinyl, quinazolinyl, thiadiazol opyrimidyl (including all isomeric forms, e.g., [l,2,5]thiadiazolo[3,4-d]pyrimidinyl and [l,2,3]thiadiazolo- [4,5- ]pyrimidinyl), and thi enopyridyl (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, the 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, e.g., 1,5-phenanthrolinyl, 1,6-phenanthrolinyl, 1,7- phenanthrolinyl, 1,9-phenanthrolinyl, and 2,10-phenanthrolinyl), phenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and xanthenyl. In certain embodiments, the heteroaryl is optionally substituted with one or more substituents Q as described herein.

[0049] The terms “heteroarylene” and “heteroarenediyl” are used interchangeably herein in reference to a divalent monocyclic aromatic group or divalent polycyclic aromatic group that contains at least one aromatic ring, wherein at least one aromatic ring contains one or more heteroatoms in the ring, each of which is independently selected from O, S, and N. A heteroarylene group has at least one linkage to the rest of a molecule via its aromatic ring(s). Each ring of a heteroarylene group can contain one or two O atoms, one or two S atoms, and / or one to four N atoms, provided that the total number of heteroatoms in each ring is four or less and each ring contains at least one carbon atom. In certain embodiments, the heteroarylene has from 5 to 20, from 5 to 15, or from 5 to 10 ring atoms. Examples of monocyclic heteroarylene groups include, but are not limited to, furandiyl, imidazoldiyl, isothiazoldiyl, isoxazoldiyl, oxadiazoldiyl, oxazoldiyl, pyrazindiyl, pyrazoldiyl, pyridazindiyl, pyridindiyl, pyrimidindiyl, pyrroldiyl, thiadiazoldiyl, thiazoldiyl, thiendiyl, tetrazoldiyl, triazinediyl, and triazoldiyl. Examples of bicyclic heteroarylene groups include, but are not limited to, benzofurandiyl, benzimidazoldiyl, benzoisoxazoldiyl, benzopyrandiyl, benzothiadi azol diyl, benzothiazoldiyl, benzothiendiyl, benzotri azol diyl, benzoxazoldiyl, furopyridindiyl (including all isomeric forms, e.g., furo[2,3- b]pyridindiyl, furo[2,3-c]pyridindiyl, furo[3,2-b]pyridindiyl, furo[3,2-c]pyridindiyl, furo[3,4- b]pyridindiyl, and furo[3,4-c]pyridindiyl), imidazopyridindiyl (including all isomeric forms, e.g.,imidazo[l ,2-«]pyridindiyl, imidazo[4,5-b]pyridindiyl, and imidazo[4,5-c]pyridindiyl), imidazothiazoldiyl (including all isomeric forms, e.g., imidazo[2,l-b]thiazoldiyl and imidazo[4,5-d]thiazoldiyl), indazoldiyl, indolizindiyl, indoldiyl, isobenzofurandiyl, isobenzothiendiyl (i.e., benzo[c]thiendiyl), isoindoldiyl, isoquinolindiyl, naphthyri din diyl (including all isomeric forms, e.g., 1,5-naphthyridindiyl, 1,6-naphthyridindiyl, 1,7-naphthyridindiyl, and 1,8-naphthyridindiyl), oxazolopyridindiyl (including all isomeric forms, e.g., oxazolo[4,5-b]pyridindiyl, oxazolo[4,5- c]pyridindiyl, oxazolo[5,4-b]pyridindiyl, and oxazolo[5,4-c]pyridindiyl), phthalazindiyl, pteridindiyl, purindiyl, pyrrolopyridindiyl (including all isomeric forms, e.g., pyrrolo[2,3- b]pyridindiyl, pyrrolo[2,3-c]pyridindiyl, pyrrolo[3,2-b]pyridindiyl, and pyrrolo[3,2-c]pyridindiyl), quinolindiyl, quinoxalindiyl, quinazolindiyl, thiadiazolopyrimidindiyl (including all isomeric forms, e.g., [l,2,5]thiadiazolo[3,4-d]pyrimidindiyl and [l,2,3]thiadiazolo[4,5- ]pyrimidindiyl), and thienopyridindiyl (including all isomeric forms, e.g., thieno[2,3-b]pyridindiyl, thieno[2,3- c]pyridindiyl, thieno[3,2-b]pyridindiyl, and thieno[3,2-c]pyridindiyl). Examples of tricyclic heteroarylene groups include, but are not limited to, acridindiyl, benzindoldiyl, carbazoldiyl, dibenzofurandiyl, perimidindiyl, phenanthrolindiyl (including all isomeric forms, e.g., 1,5- phenanthrolindiyl, 1,6-phenanthrolindiyl, 1,7-phenanthrolindiyl, 1,9-phenanthrolindiyl, and 2,10- phenanthrolindiyl), phenanthridindiyl, phenarsazindiyl, phenazindiyl, phenothiazindiyl, phenoxazindiyl, and xanthendiyl. In certain embodiments, heteroarylene is optionally substituted with one or more substituents Q as described herein.

[0050] The term “heterocyclyl” or “heterocyclic” refers to a monovalent monocyclic non- aromatic ring system or monovalent polycyclic ring system that contains at least one non- aromatic ring, wherein one or more of the non-aromatic ring atoms are heteroatoms, each independently selected from O, S, and N; and the remaining ring atoms are carbon atoms. In certain embodiments, the heterocyclyl or heterocyclic group has from 3 to 20, from 3 to 15, from 3 to 10, from 3 to 8, from 4 to 7, or from 5 to 6 ring atoms. The heterocyclyl is bonded to the rest of a molecule through the non-aromatic ring. In certain embodiments, the 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 or 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 s and heterocyclic groups include, butare not limited to, azepinyl, benzodioxanyl, benzodioxolyl, benzofuran onyl, chromanyl, decahydroisoquinolinyl, dihydrobenzofuranyl, dihydrobenzisothiazolyl, dihydrobenzisoxazinyl (including all isomeric forms, e.g., l,4-dihydrobenzo[d][l,3]oxazinyl, 3,4-dihydrobenzo[c][l,2]- oxazinyl, and 3,4-dihydrobenzo[d][l,2]oxazinyl), dihydrobenzothienyl, dihydroisobenzofuranyl, dihydrobenzo[c]thienyl, dihydrofuryl, dihydroisoindolyl, dihydropyranyl, dihydropyrazolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, 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, tetrahydro- quinolinyl, and 1,3,5-trithianyl. In certain embodiments, the heterocyclyl is optionally substituted with one or more substituents Q as described herein.

[0051] The term “heterocyclylene” refers to a divalent monocyclic non-aromatic ring system or divalent polycyclic ring system that contains at least one non-aromatic ring, wherein one or more of the non-aromatic ring atoms are heteroatoms independently selected from O, S, and N; and the remaining ring atoms are carbon atoms. Heterocyclylene groups are bonded to the rest of a molecule through the non-aromatic ring. In certain embodiments, the heterocyclylene group has from 3 to 20, from 3 to 15, from 3 to 10, from 3 to 8, from 4 to 7, or from 5 to 6 ring atoms. In certain embodiments, the 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 quatemized, and some rings may be partially or 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 include, but are not limited to, azepindiyl, benzodi oxandiyl, benzodioxoldiyl, benzofuranondiyl, chromandiyl, decahydroisoquinolindiyl, dihydrobenzofurandiyl, dihydrobenzisothiazoldiyl, dihydrobenzisoxazindiyl (including all isomeric forms, e.g., l,4-dihydrobenzo[d][l,3]oxazindiyl, 3,4-dihydrobenzo[c][l,2]oxazindiyl, and 3,4-dihydrobenzo[d][l,2]oxazindiyl), dihydrobenzothiendiyl, dihydroisobenzofurandiyl, dihydrobenzo[c]thiendiyl, dihydrofurdiyl, dihydroisoindoldiyl, dihydropyrandiyl, dihydro- pyrazoldiyl, dihydropyrazindiyl, dihydropyridindiyl, dihydropyrimidindiyl, dihydropyrroldiyl,dioxolandiyl, 1 ,4-dithiandiyl, furanondiyl, imidazolidindiyl, imidazolindiyl, indolindiyl, isochromandiyl, isoindolindiyl, isothiazolidindiyl, isoxazolidindiyl, morpholindiyl, octahydro- indoldiyl, octahydroisoindoldiyl, oxazolidinondiyl, oxazolidindiyl, oxirandiyl, piperazindiyl, piperidindiyl, 4-piperidondiyl, pyrazolidindiyl, pyrazolindiyl, pyrrolidindiyl, pyrrolindiyl, quinuclidindiyl, tetrahydrofurdiyl, tetrahydroisoquinolindiyl, tetrahydropyrandiyl, tetrahydro- thiendiyl, thiamorpholindiyl, thiazolidindiyl, thiochromandiyl, tetrahydroquinolindiyl, and 1,3,5- trithiandiyl. In certain embodiments, the heterocyclylene is optionally substituted with one or more substituents Q as described herein.

[0052] The term “halogen,” “halide,” or “halo” refers to fluoro, chloro, bromo, and / or iodo.

[0053] The term “optionally substituted” is intended to mean that a group or substituent, such as an alkyl, heteroalkyl, alkylene, heteroalkylene, alkenyl, alkenylene, heteroal kenylene, alkynyl, alkynylene, heteroalkynylene, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, aralkylene, heteroaryl, heteroarylene, heterocyclyl, or heterocyclylene group, may be substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, each of which is independently selected from, e.g., (a) deuterium (-D), cyano (-CN), halo, imino (=NH), nitro (-NO2), and oxo (=0); (b) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; and (c) -C(O)Ra, -C(O)ORa, -C(0)NRbRc, -C(O)SRa, -C(NRa)NRbRc, -C(S)Ra, -C(S)ORa, -C(S)NRbRc, -ORa, -OC(O)Ra, -OC(O)ORa, -OC(O)NRbRc, -OC(O)SRa, -0C(NRa)NRbRc, -OC(S)Ra, -OC(S)ORa, -OC(S)NRbRc, -OP(O)(ORa)ORd, -OS(O)Ra, -OS(O)2Ra, -OS(O)NRbRc, -OS(O)2NRbRc, -NRbRc, -NRaC(O)Rd, -NRaC(0)0Rd, -NRaC(0)NRbRc, -NRaC(O)SRd, -NRaC(NRd)NRbRc, -NRaC(S)Rd, -NRaC(S)ORd, -NRaC(S)NRbRc, -NRaS(O)Rd, -NRaS(O)2Rd, -NRaS(O)NRbRe, -NRaS(O)2NRbRc, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRbRc, and -S(O)2NRbRc, wherein each Ra, Rb, Rc, and Rdis independently (i) hydrogen or deuterium; (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; or (iii) Rband Rctogether with the N atom to which they are attached form heterocyclyl optionally substituted with one or more, in oneembodiment, one, two, three, or four, substituents Qa. As used herein, all groups that can be substituted are “optionally substituted.”

[0054] In one embodiment, each Qais independently selected from: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, and heterocyclyl; and (c) -C(O)Re, -C(O)ORe, -C(O)NRfRg, -C(O)SRe, -C(NRe)NRfRg, -C(S)Re, -C(S)ORe, -C(S)NRfRg, -ORe, -OC(O)Re, -OC(O)ORe, -OC(O)NRfRg, -OC(O)SRe, -OC(NRe)NRfRs, -OC(S)Re, -OC(S)ORe, -OC(S)NRfRg, -OS(O)Re, -OS(O)2Re, -OS(O)NRfRg, -OS(O)2NRfRg, -NRfRg, -NReC(O)Rh,NReC(O)ORf, NReC(O)NRfRg, NReC(O)SRf, NReC(NRh)NRfRg, NReC(S)Rh, -NReC(S)ORf, -NReC(S)NRfRg, -NReS(O)Rh, -NReS(O)2Rh, -NReS(O)NRfRg, -NReS(O)2NRfRg, -SRe, -S(O)Re, -S(O)2Re, -S(O)NRfRg, and -S(O)2NRfRg; wherein each Re, Rf, Rg, and Rhis independently (i) hydrogen or deuterium; (ii) C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; or (iii) Rfand Rstogether with the N atom to which they are attached form heterocyclyl.

[0055] In certain embodiments, “optically active” and ’’enantiomerically active” refer to a collection of molecules, which has an enantiomeric excess of no less than about 80%, no less than about 90%, no less than about 91%, no less than about 92%, no less than about 93%, no less than about 94%, no less than about 95%, no less than about 96%, no less than about 97%, no less than about 98%, no less than about 99%, no less than about 99.5%, or no less than about 99.8%. In certain embodiments, an optically active compound comprises 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 question. In certain embodiments, an optically active compound comprises 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 question. In certain embodiments, an optically active compound comprises 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 in question.

[0056] In describing an optically active compound, the prefixes R and S are used to denote the absolute configuration of the compound about its chiral center(s). The (+) and (-) are used to denote the optical rotation of the compound, that is, the direction in which a plane of polarizedlight is rotated by the optically active compound. The (-) prefix indicates that the compound is levorotatory, that is, the compound rotates the plane of polarized light to the left or counterclockwise. The (+) prefix indicates that the compound is dextrorotatory, that is, the compound rotates the plane of polarized light to the right or clockwise. However, the sign of optical rotation, (+) and (-), is not related to the absolute configuration of the compound, R and S.

[0057] The term “isotopically enriched” refers to a compound that contains an unnatural proportion of an isotope at one or more of the atoms that constitute such a compound. In certain embodiments, an isotopically enriched compound contains unnatural proportions of one or more isotopes, including, but not limited to, hydrogen (1H), deuterium (2H), tritium (3H), carbon- 11 (11C), carbon-12 (12C), carbon-13 (13C), carbon-14 (14C), nitrogen-13 (13N), nitrogen-14 (14N), nitrogen-15 (15N), oxygen-14 (14O), oxygen-15 (15O), oxygen-16 (16O), oxygen-17 (17O), oxygen- 18 (18O), fluorine-17 (17F), fluorine-18 (18F), phosphorus-31 (31P), phosphorus-32 (32P), phosphorus-33 (33P), sulfur-32 (32S), sulfur-33 (33S), sulfur-34 (34S), sulfur-35 (35S), sulfur-36 (36S), chlorine-35 (35C1), chlorine-36 (36C1), chlorine-37 (37C1), bromine-79 (79Br), bromine-81 (81Br), iodine-123 (123I), iodine-125 (125I), iodine-127 (127I), iodine-129 (129I), and iodine-131 (131I). In certain embodiments, an isotopically enriched compound is in a stable form, that is, non-radioactive. In certain embodiments, an isotopically enriched compound contains unnatural proportions of one or more isotopes, including, but not limited to, hydrogen (1H), deuterium (2H), carbon- 12 (12C), carbon- 13 (13C), nitrogen- 14 (14N), nitrogen- 15 (15N), oxygen- 16 (16O), oxygen-17 (17O), oxygen-18 (18O), fluorine-17 (17F), phosphorus-31 (31P), sulfur-32 (32S), sulfur-33 (33S), sulfur-34 (34S), sulfur-36 (36S), chlorine-35 (35C1), chlorine-37 (37C1), bromine-79 (79Br), bromine- 81 (81Br), and iodine-127 (127I). In certain embodiments, an isotopically enriched compound is in an unstable form, that is, radioactive. In certain embodiments, an isotopically enriched compound contains unnatural proportions of one or more isotopes, including, but not limited to, tritium (3H), carbon-11 (11C), carbon-14 (14C), nitrogen-13 (13N), oxygen-14 (14O), oxygen-15 (15O), fluorine-18 (18F), phosphorus-32 (32P), phosphorus-33 (33P), sulfur-35 (35S), chlorine-36 (36C1), iodine-123 (123I), iodine-125 (123I), iodine-129 (129I), and iodine-131 (131I). It will be understood that, in a compound as provided herein, any hydrogen can be2H, as example, or any carbon can be13C, as example, or any nitrogen can be15N, as example, or any oxygen can be18O, as example, where feasible according to the judgment of one of ordinary skill in the art.

[0058] The term “isotopic enrichment” refers to the percentage of incorporation of a less prevalent isotope (e.g., D for deuterium or hydrogen-2) of an element at a given position in a molecule in the place of a more prevalent isotope (e.g.,1H for protium or hydrogen-1) of the element. As used herein, when an atom at a particular position in a molecule is designated as a particular less prevalent isotope, it is understood that the abundance of that isotope at that position is substantially greater than its natural abundance.

[0059] The term “isotopic enrichment factor” refers to the ratio between the isotopic abundance in an isotopically enriched compound and the natural abundance of a specific isotope.

[0060] The term “hydrogen” or the symbol “H” refers to the composition of naturally occurring hydrogen isotopes, which include protium (1H), deuterium (2H or D), and tritium (3H), in their natural abundances. Protium is the most common hydrogen isotope having a natural abundance of more than 99.98%. Deuterium is a less prevalent hydrogen isotope having a natural abundance of about 0.0156%.

[0061] The term “deuterium enrichment” refers to the percentage of incorporation of deuterium at a given position in a molecule in the place of hydrogen. For example, deuterium enrichment of 1% at a given position means that 1% of molecules in a given sample contain deuterium at the specified position. Because the naturally occurring distribution of deuterium is about 0.0156% on average, deuterium enrichment at any position in a compound synthesized using non-enriched starting materials is about 0.0156% on average. 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%).

[0062] The term “carbon” or the symbol “C” refers to the composition of naturally occurring carbon isotopes, which include carbon- 12 (12C) and carbon- 13 (13C) in their natural abundances. Carbon-12 is the most common carbon isotope having a natural abundance of more than 98.89%. Carbon-13 is a less prevalent carbon isotope having a natural abundance of about 1.11%.

[0063] The term “carbon- 13 enrichment” or “13C enrichment” refers to the percentage ofincorporation of carbon-13 at a given position in a molecule in the place of carbon. For example, carbon- 13 enrichment of 10% at a given position means that 10% of molecules in a given sample contain carbon-13 at the specified position. Because the naturally occurring distribution of carbon-13 is about 1.11% on average, carbon-13 enrichment at any position in a compound synthesized using non-enriched starting materials is about 1.11% on average. As used herein, when a particular position in an isotopically enriched compound is designated as having carbon- 13, it is understood that the abundance of carbon-13 at that position in the compound is substantially greater than its natural abundance (1.11%).

[0064] The terms “substantially pure” and “substantially homogeneous” mean, when referred to a substance, sufficiently homogeneous to appear free of readily detectable impurities as determined by a standard analytical method used by one of ordinary 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 such that further purification would not detectably alter the physical, chemical, biological, and / or pharmacological properties, such as enzymatic and biological activities, of the substance. In certain embodiments, “substantially pure” or “substantially homogeneous” refers to a collection of molecules, wherein 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 a single compound, including a single enantiomer, a racemic mixture, or a mixture 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 prevalent isotope, a molecule that contains other than the designated isotope at the specified position is an impurity with respect to the isotopically enriched compound. Thus, for a deuterated compound that has an atom at a particular position designated as deuterium, a compound that contains a protium at the same position is an impurity.

[0065] The term “solvate” refers to a complex or aggregate formed by one or more molecules of a solute, e.g., a compound provided herein, and one or more molecules of a solvent, which are present in stoichiometric or non-stoichiometric amount. Suitable solvents include, but are not limited to, water, methanol, ethanol, / / -propanol, isopropanol, and acetic acid. In certain embodiments, the solvent is pharmaceutically acceptable. In one embodiment, the complex oraggregate is in a crystalline form. In another embodiment, the complex or aggregate is in a noncrystalline form. Where the solvent is water, the solvate is a hydrate. Examples of hydrates include, but are not limited to, a hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, and pentahydrate.

[0066] For a divalent group described herein, no orientation is implied by the direction in which the divalent group is presented. For example, unless a particular orientation is specified, the formula -C(O)NH- represents both -C(O)NH- and - NHC(O)-.

[0067] 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, or hydrate 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 referenced therein; (ii) a pharmaceutically acceptable salt, solvate, or hydrate of the compound referenced therein; or (iii) a pharmaceutically acceptable salt, solvate, or hydrate 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 referenced therein.”Compounds

[0068] In one embodiment, provided herein is 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, or hydrate thereof; wherein: each L is independently a linker; each X is independently (i) a bond or S; or (ii) heteroarylene or heterocyclylene;RAis an antibody or an antigen-binding fragment thereof; each RDis independently a KRAS binding moiety; and m is an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16; wherein the heteroarylene and heterocyclylene are each optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q; wherein each Q isindependently selected from: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; and (c) -C(O)Ra, -C(O)ORa, -C(O)NRbRc, -C(O)SRa, -C(NRa)NRbRc, -C(S)Ra, -C(S)ORa, -C(S)NRbRc, -ORa, -OC(O)Ra, -OC(O)ORa, -OC(O)NRbRc, -OC(O)SRa, -OC(NRa)NRbRc, -OC(S)Ra, -OC(S)ORa, -OC(S)NRbRc, -OP(O)(ORa)ORd, -OS(O)Ra, -OS(O)2Ra, -OS(O)NRbRc, -OS(O)2NRbRc, -NRbRc, -NRaC(O)Rd, -NRaC(O)ORd, -NRaC(O)NRbRe, -NRaC(O)SRd, -NRaC(NRd)NRbRc, -NRaC(S)Rd, -NRaC(S)ORd, -NRaC(S)NRbRc, -NRaS(O)Rd, -NRaS(O)2Rd, -NRaS(O)NRbRc, NRaS(O)2NRbRc, SRa, S(O)Ra, S(O)2Ra, S(O)NRbRc, and S(O)2NRbRc, wherein each Ra, Rb, Rc, and Rdis independently (i) hydrogen or deuterium; (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; or (iii) Rband Rctogether with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; wherein each Qais independently selected from: (a) deuterium, cyano, halo, nitro, imino, and oxo; (b) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, and heterocyclyl; and (c) -C(O)Re, -C(O)ORe, -C(O)NRfRg, -C(O)SRe, -C(NRe)NRfRg, -C(S)Re, -C(S)ORe, -C(S)NRfRg, -ORe, -OC(O)Re, -OC(O)ORe, -OC(O)NRfRg, -OC(O)SRe, -OC(NRe)NRfRg, -OC(S)Re, -OC(S)ORe, -OC(S)NRfRg, -OS(O)Re, -OS(O)2Re, -OS(O)NRfRg, -OS(O)2NRfRg, -NRfRs, -NReC(O)Rh, -NReC(O)ORf, -NReC(O)NRfRg, -NReC(O)SRf, -NReC(NRh)NRfRg, -NReC(S)Rh, -NReC(S)ORf, -NReC(S)NRfRg, -NReS(O)Rh, -NReS(O)2Rh, -NReS(O)NRfRg, -NReS(O)2NRfRg, -SRe, -S(O)Re, -S(O)2Re, -S(O)NRfRg, and -S(O)2NRfRg; wherein each Re, Rf, Rg, and Rhis independently (i) hydrogen or deuterium; (ii) C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; or (iii) Rfand Rgtogether with the N atom to which they are attached form heterocyclyl.

[0069] In certain embodiments, each RDis independently a moiety of a KRAS switch-I pocket (SIP) binder. In certain embodiments, each RDis independently a moiety of a KRAS switch-II pocket (SUP) binder.

[0070] In certain embodiments, each RDis independently a moiety of a KRAS inhibitor. In certain embodiments, each RDis independently a moiety of a KRAS SIP inhibitor. In certain embodiments, each RDis independently a moiety of a KRAS SUP inhibitor.

[0071] In one embodiment, provided herein is a compound of Formula (II):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; wherein: each A is independently a bond, C1-6alkylene, C1-6heteroalkylene, or -O(CR6aR6b)n-; each E1is independently N, heterocyclyl, or C1-6heteroalkylene-heteroaryl; each U is independently C(R2) or N; each R1, R2, R3, and R4is independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)Rla, -C(O)ORla, -C(O)NRlbRlc, -C(O)SRla, -C(NRla)NRlbRle, -C(S)Rla, -C(S)ORla, -C(S)NRlbRlc, -ORla, -OC(O)Rla, -OC(O)ORla, -OC(O)NRlbRlc, -OC(O)SRla, -OC(NRla)NRlbRlc, -OC(S)Rla, -OC(S)ORla, -OC(S)NRlbRlc, OS(O)Rla, OS(O)2Rla, OS(O)NRlbRlc, OS(O)2NRlbRlc, NRlbRlc, NRlaC(O)Rld, -NRlaC(O)ORld, -NRlaC(O)NRlbRlc, -NRlaC(O)SRld, -NRlaC(NRld)NRlbRlc, -NRlaC(S)Rld, -NRlaC(S)ORld, -NRlaC(S)NRlbRlc, -NRlaS(O)Rld, -NRlaS(O)2Rld, -NRlaS(O)NRlbRlc, -NRlaS(O)2NRlbRle, -SRla, -S(O)Rla, -S(O)2Rla, -S(O)NRlbRlc, or -S(O)2NRlbRlc; or R1and R2together with the carbon atoms to which they are attached form C3-10cycloalkyl or heterocyclyl; each R5is independently hydrogen, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; each Rla, Rlb, Rlc, and Rldis independently hydrogen, deuterium, C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, orheterocyclyl; each R6aand R6bis independently (i) hydrogen, deuterium, cyano, halo, or nitro; or (ii) Ci- 6 alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; or R6aand R6btogether with the carbon atom to which they are attached form C3-10cycloalkylene or heterocyclyl ene; each R7ais independently (i) hydrogen, deuterium, cyano, halo, or nitro; or (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; or R1and R7aare linked together to form heterocyclyl; n is an integer of 1, 2, 3, 4, or 5; and each RA, L, X, and m is as defined herein; wherein each alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkynyl, cycloalkyl, cycloalkylene, aryl, aralkyl, heteroaryl, heterocyclyl, and heterocyclylene is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q.

[0072] In certain embodiments, each A is a bond. In certain embodiments, each A is independently C1-6heteroalkylene, optionally substituted with one or more substituents Q. In certain embodiments, each A is independently -O(CR6aR6b)n-, wherein each R6a, R6b, and n is as defined herein. In certain embodiments, each A is independently -OC(R6aR6b)-, wherein R6aand R6bare each as defined herein. In certain embodiments, each A is independently -OCH2-. In certain embodiments, each A is independently -OCH2(R6aR6b)CH2-, wherein R6aand R6bare each as defined herein. In certain embodiments, each A is independently -OCH2(R6aR6b)CH2- wherein R6aand R6btogether with the carbon atom to which they are attached form C3-10cycloalkylene, optionally substituted with one or more substituents Q. In certain embodiments, each A is independently -OCH2(R6aR6b)CH2-, wherein R6aand R6btogether with the carbon atom to which they are attached form monocyclic C3-10cycloalkylene, optionally substituted with one or more substituents Q. In certain embodiments, each A is independently -OCH2(R6aR6b)CH2- wherein R6aand R6btogether with the carbon atom to which they are attached form cyclopropane- diyl, optionally substituted with one or more substituents Q.

[0073] In certain embodiments, each E1is N.

[0074] In certain embodiments, each E1is independently heterocyclyl, optionallysubstituted with one or more substituents Q. In certain embodiments, each E1is independently monocyclic heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each E1is independently 3-, 4-, 5-, 6-, or 7-membered heterocyclyl, each optionally substituted with one or more substituents Q. In certain embodiments, each E1is independently 3- membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each E1is independently 4-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each E1is independently 5-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each E1is independently 6-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each E1is independently piperidinyl or piperazinyl, each optionally substituted with one or more substituents Q. In certain embodiments, each E1is independently piperazinyl, optionally substituted with one or more substituents Q. In certain embodiments, each E1is independently 7-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each E1is independently azepanyl, optionally substituted with one or more substituents Q.

[0075] In certain embodiments, each E1is independently bicyclic heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each E1is independently bridged, fused, or spiro heterocyclyl, each optionally substituted with one or more substituents Q. In certain embodiments, each E1is independently bridged heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each E1is independently 3,8- diazabicyclo[3.2. l]octyl, optionally substituted with one or more substituents Q. In certain embodiments, each E1is independently fused heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each E1is independently spiro heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each E1is independently 4,7-diazaspiro[2.5]octyl or 2,7-diazaspiro[3.5]nonyl, each optionally substituted with one or more substituents Q.

[0076] In certain embodiments, each E1is independently C1-6heteroalkylene-heteroaryl, each optionally substituted with one or more substituents Q. In certain embodiments, each E'-R7amoiety is independently wherein R7is as defined herein. In certainembodiments, each E'-R7amoiety is independentlywherein R7is as defined herein. In certain embodiments, each E'-R7amoiety is

[0077] In another embodiment, provided herein is a compound of Formula (III):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; wherein each R1, R3, R4, R5, R6a, R6b, R7a, RA, L, U, X, and m is as defined herein.

[0078] In certain embodiments, each R7ais independently hydrogen or C1-6alkyl, optionally substituted with one or more substituents Q. In certain embodiments, each R7ais hydrogen. In certain embodiments, each R7ais independently C1-6alkyl, optionally substituted with one or more substituents Q. In certain embodiments, each R7ais methyl.

[0079] In certain embodiments, R1and R7aare linked together to form monocyclic heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R1and R7aare linked together to form 5-, 6-, 7-, or 8-membered heterocyclyl, each optionally substituted with one or more substituents Q. In certain embodiments, R1and R7aare linked together to form 5-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R1and R7aare linked together to form 6-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R1and R7aare linked together to form 7-membered heterocyclyl, optionally substituted with one or moresubstituents Q. In certain embodiments, R1and R7aare linked together to form 8-membered heterocyclyl, optionally substituted with one or more substituents Q.

[0080] In certain embodiments, R1and R7aare linked together to form bicyclic heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R1and R7aare linked together to form bridged, fused, or spiro heterocyclyl, each optionally substituted with one or more substituents Q. In certain embodiments, R1and R7aare linked together to form bridged heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R1and R7aare linked together to form fused heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R1and R7aare linked together to form spiro heterocyclyl, optionally substituted with one or more substituents Q.

[0081] In yet another embodiment, provided herein is a compound of Formula (IV):or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein each V1is independently C1-6alkylene or C1-6heteroalkylene, each optionally substituted with one or more substituents Q; and each R3, R4, R3, R6a, R6b, RA, L, U, X, and m is as defined herein.

[0082] In certain embodiments, each V1is independently C1-6alkylene, optionally substituted with one or more substituents Q. In certain embodiments, each V1is independently methanediyl, ethanediyl, propanediyl, or butanediyl, each optionally substituted with one or more substituents Q. In certain embodiments, each V1is independently methane- 1,1 -diyl, ethane-1,2- diyl, propane- 1,2-diyl, propane-1, 3-diyl, or butane-2,3-diyl, each optionally substituted with one or more substituents Q.

[0083] In certain embodiments, each V1is independently C1-6heteroalkylene, optionallysubstituted with one or more substituents Q. In certain embodiments, each V1is independently -O-C1-6alkylene, optionally substituted with one or more substituents Q. In certain embodiments, each V1is independently -O-CH2- or -O-CH(CH3)-.

[0084] In yet another embodiment, provided herein is a compound of Formula (V):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; wherein each R8aand R8bis independently (i) hydrogen, deuterium, cyano, halo, or nitro;(ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; or (iii) -C(O)Rla, -C(O)ORla, -C(O)NRlbRle, -C(O)SRla, -C(NRla)NRlbRle, -C(S)Rla, -C(S)ORla, -C(S)NRlbRlc, -ORla, -OC(O)Rla, -OC(O)ORla, -OC(O)NRlbRlc, -OC(O)SRla, -OC(NRla)NRlbRlc, -OC(S)Rla, -OC(S)ORla, -OC(S)NRlbRlc, -OS(O)Rla, -OS(O)2Rla, -OS(O)NRlbRle, -OS(O)2NRlbRlc, -NRlbRlc, -NRlaC(O)Rld, -NRlaC(O)ORld, -NRlaC(O)NRlbRlc, -NRlaC(O)SRld, -NRlaC(NRld)NRlbRlc, -NRlaC(S)Rld, -NRlaC(S)ORld, NRlaC(S)NRlbRlc, NRlaS(O)Rld, NRlaS(O)2Rld, NRlaS(O)NRlbRlc, NRlaS(O)2NRlbRlc, -SRla, -S(O)Rla, -S(O)2Rla, -S(O)NRlbRlc, or -S(O)2NRlbRlc; and each R3, R4, R5, Rla, Rlb, Rlc, Rld, R6a, R6b, RA, L, U, X, and m is as defined herein.

[0085] In yet another embodiment, provided herein is a compound of Formula (VI):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; wherein each R8cand R8dis independently (i) hydrogen, deuterium, cyano, halo, or nitro;(ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; or (iii) -C(O)Rla, -C(O)ORla, -C(O)NRlbRlc, -C(O)SRla, -C(NRla)NRlbRle, -C(S)Rla, -C(S)ORla, -C(S)NRlbRlc, -ORla, -OC(O)Rla, -OC(O)ORla, -OC(O)NRlbRlc, -OC(O)SRla,OC(NRla)NRlbRlc, OC(S)Rla, OC(S)ORla, OC(S)NRlbRlc, OS(O)Rla, OS(O)2Rla, -OS(O)NRlbRlc, -OS(O)2NRlbRlc, -NRlbRlc, -NRlaC(O)Rld, -NRlaC(O)ORld, -NRlaC(O)NRlbRlc, -NRlaC(O)SRld, -NRlaC(NRld)NRlbRlc, -NRlaC(S)Rld, -NRlaC(S)ORld, -NRlaC(S)NRlbRlc, -NRlaS(O)Rld, -NRlaS(O)2Rld, -NRlaS(O)NRlbRlc, -NRlaS(O)2NRlbRlc, -SRla, -S(O)Rla, -S(O)2Rla, -S(O)NRlbRlc, or -S(O)2NRlbRlc; and each R3, R4, R5, Rla, Rlb, Rlc, Rld, R6a, R6b, R8a, R8b, RA, L, U, X, and m is as defined herein.

[0086] In yet another embodiment, provided herein is a compound of Formula (VII):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; wherein each R1, R3, R4, R5, R6a, R6b, RA, L, U, X, and m is as defined herein.

[0087] In certain embodiments, each R5is independently (i) hydrogen; or (ii) C3-10cycloalkyl or heterocyclyl, each optionally substituted with one or more substituents Q. Tn certain embodiments, each R5is hydrogen. In certain embodiments, each R5is independently C3-10cycloalkyl or heterocyclyl, each optionally substituted with one or more substituents Q. In certain embodiments, each R5is independently heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each R5is independently monocyclic heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each R5is independently 3-, 4-, 5-, 6-, or 7-membered heterocyclyl, each optionally substituted with one or more substituents Q. In certain embodiments, each R5is independently 3-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each R5is independently 4-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each R5is independently 5-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each R3is independently pyrrolidinyl, optionally substituted with one or more substituents Q. In certain embodiments, each R5is independently pyrrolidin-2-yl, optionally substituted with one or more substituents Q. In certain embodiments, each R5is independently l-methylpyrrolidin-2-yl or l-methyl-3- methoxypyrrolidin-2-yl. In certain embodiments, each R5is independently 6-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each R5is independently 7-membered heterocyclyl, optionally substituted with one or more substituents Q.

[0088] In certain embodiments, each R5is independently bicyclic heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each R5is independently bridged, fused, or spiro heterocyclyl, each optionally substituted with one or more substituents Q. In certain embodiments, each R5is independently bridged heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each R3is independently fused heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each R5is independently 5,5-, 5,6-, or 6,6-fused heterocyclyl, each optionally substituted with one or more substituents Q. In certain embodiments, each R3is independently 5,5-fused heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each R3is independently hexahydropyrrolizinyl, optionally substituted with one or more substituents Q. In certain embodiments, each R5is independently hexahydropyrrolizin-7a-yl, optionally substituted with one or more substituents Q. In certain embodiments, each R5is independently 5,6-fusedheterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each R5is independently 6,6-fused heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each R5is independently spiro heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each R5is independently tricyclic heterocyclyl, optionally substituted with one or more substituents Q.

[0089] In certain embodiments, each R5is independently hydrogen, l-methylpyrrolidin-2- yl, l-methyl-3-methoxypyrrolidin-2-yl, 2-fluorohexahydropyrrolizin-7a-yl, 3-(((l, 1,1, 3,3,3- hexafluoro-2-methylpropan-2-yl)oxy)methyl)hexahydropyrrolizin-7a-yl, 2-(difluoromethylene)- hexahydropyrrolizin-7a-yl, or 2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-l,2'-pyrrolizin]- 7a'(5'H )-yl.

[0090] In yet another embodiment, provided herein is a compound of Formula (VIII):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; wherein each R5a, R5b, and R5cis independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; or (iii) -C(O)Rla, -C(O)ORla, -C(O)NRlbRlc, -C(O)SRla, -C(NRla)NRlbRlc, -C(S)Rla, -C(S)ORla, -C(S)NRlbRlc, -ORla, -OC(O)Rla, -OC(O)ORla, -OC(O)NRlbRlc, -OC(O)SRla, -OC(NRla)NRlbRlc, -OC(S)Rla, -OC(S)ORla, -OC(S)NRlbRlc, -OS(O)Rla, -OS(O)2Rla, -OS(O)NRlbRlc, -OS(O)2NRlbRlc, -NRlbRlc, -NRlaC(O)Rld, -NRlaC(O)ORld, -NRlaC(O)NRlbRle, -NRlaC(O)SRld, -NRlaC(NRld)NRlbRlc, -NRlaC(S)Rld, -NRlaC(S)ORld, -NRlaC(S)NRlbRlc, -NRlaS(O)Rld, -NRlaS(O)2Rld, -NRlaS(O)NRlbRlc, -NRlaS(O)2NRlbRlc, SRla, S(O)Rla, S(O)2Rla, S(O)NRlbRlc, or -S(O)2NRlbRlc; or R5aand R5btogether with the carbon atom to which they are attached form C2-6alkenylene, C3-10cycloalkylene, orheterocyclylene, each optionally substituted with one or more substituents Q; and each R1, R3, R4, Rla, Rlb, Rlc, Rld, R6a, R6b, R7a, RA, L, U, X, and m is as defined herein.

[0091] In yet another embodiment, provided herein is a compound of Formula (IX):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; wherein each R1, R3, R4, R5a, R5b, R5c, R6a, R6b, R7a, RA, L, U, X, and m is as defined herein.

[0092] In yet another embodiment, provided herein is a compound of Formula (X):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; wherein each R3, R4, R5a, R5b, R5e, R6a, R6b, R8a, R8b, RA, L, U, X, and m is as defined herein.

[0093] In yet another embodiment, provided herein is a compound of Formula (XI):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; wherein each R3, R4, R5a, R5b, R5e, R6a, R6b, R8a, R8b, RA, L, U, X, and m is as defined herein.

[0094] In yet another embodiment, provided herein is a compound of Formula (XII):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; wherein each R3, R4, R5a, R5b, R5c, R6a, R6b, R8a, R8b, R8c, R8d, RA, L, U, X, and m is as defined herein.

[0095] In yet another embodiment, provided herein is a compound of Formula (XIII):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; wherein each R3, R4, R5a, R5b, R5c, R6a, R6b, R8a, R8b, R8c, R8d, RA, L, U, X, and m is as defined herein.

[0096] In yet another embodiment, provided herein is a compound of Formula (XIV):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; wherein each R1, R3, R4, R5a, R5b, R5e, R6a, R6b, RA, L, U, X, and m is as defined herein.

[0097] In still another embodiment, provided herein is a compound of Formula (XV):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; wherein each R1, R3, R4, R5a, R5b, R5c, R6a, R6b, RA, L, U, X, and m is as defined herein.

[0098] In certain embodiments, each R3is independently C6-14aryl or heteroaryl, each optionally substituted with one or more substituents Q. In certain embodiments, each R3is independently C6-14aryl, optionally substituted with one or more substituents Q. In certain embodiments, each R3is independently phenyl, optionally substituted with one or more substituents Q. In certain embodiments, each R3is independently phenyl, optionally substituted with one, two, three, or four substituents, each of which is independently (i) halo or cyano; (ii) Ci-6 alkyl, C1-6heteroalkyl, or C2-6alkynyl, each optionally substituted with one or more substituents Q; or (iii) -ORlaor -NRlbRle, wherein Rla, Rlb, and Rlcare each as defined herein. In certain embodiments, each R3is independently phenyl, optionally substituted with one, two, three, or four substituents, each of which is independently (i) halo; (ii) C1-6alkyl or C1-6heteroalkyl, each optionally substituted with one or more substituents Q; or (iii) -NRlbRlc, wherein Rlband Rlcare each as defined herein. In certain embodiments, each R3is independently phenyl, optionally substituted with one, two, three, or four substituents, each of which is independently fluoro, methyl, trifluoromethyl, or amino. In certain embodiments, each R3is 2-trifluoromethyl-3- methyl-4-fluoro-5-aminophenyl.

[0099] In certain embodiments, each R3is independently bicyclic C8-14aryl, optionally substituted with one or more substituents Q. In certain embodiments, each R3is independently naphthyl, optionally substituted with one or more substituents Q. In certain embodiments, each R3is independently naphthyl, optionally substituted with one, two, three, or four substituents, each of which is independently (i) halo or cyano; (ii) C1-6alkyl, C1-6heteroalkyl, or C2-6alkynyl, each optionally substituted with one or more substituents Q; or (iii) -ORlaor -NRlbRlc, wherein Rla, Rlb, and Rlcare each as defined herein. In certain embodiments, each R3is independently naphthyl, optionally substituted with one, two, or three substituents, each of which is independently (i) halo; (ii) C1-6alkyl or C2-6alkynyl, each optionally substituted with one or more substituents Q; or (iii) -ORla, wherein Rlais as defined herein. In certain embodiments, each R3is independently naphthyl, optionally substituted with one, two, or three substituents, each of which is independently fluoro, methyl, ethynyl, or hydroxyl. In certain embodiments, each R3is 3 -hy droxy-7-fluoro-8-ethynylnaphth- 1 -y 1.

[0100] In certain embodiments, each R3is independently heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, each R3is independently 5- or 6- membered heteroaryl, each optionally substituted with one or more substituents Q. In certain embodiments, each R3is independently 5-membered heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, each R3is independently 6-membered heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, each R3is independently pyridyl, optionally substituted with one or more substituents Q. In certain embodiments, each R3is independently pyridyl, optionally substituted with one, two, three, orfour substituents, each of which is independently (i) halo or cyano; (ii) C1-6alkyl, C1-6heteroalkyl, or C2-6alkynyl, each optionally substituted with one or more substituents Q; or (iii) -ORlaor -NRlbRlc, wherein Rla, Rlb, and Rlcare each as defined herein. In certain embodiments, each R3is independently pyridyl, optionally substituted with one, two, three, or four substituents, each of which is independently (i) halo; (ii) C1-6alkyl or C1-6heteroalkyl, each optionally substituted with one or more substituents Q; or (iii) -NRlbRlc, wherein Rlband Rlcare each as defined herein. In certain embodiments, each R3is independently pyridyl, optionally substituted with one, two, three, or four substituents, each of which is independently fluoro, methyl, trifluoromethyl, or amino. In certain embodiments, each R3is 3-trifluoromethyl-4-methyl-5-fluoro-6-aminopyrid-2- yi.

[0101] In certain embodiments, each R3is independently bicyclic heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, each R3is independently 5,5-, 5,6-, or 6,6-fused heteroaryl, each optionally substituted with one or more substituents Q. In certain embodiments, each R3is independently 5,5-fused heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, each R3is independently 5,6-fused heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, each R3is independently benzothienyl, optionally substituted with one or more substituents Q. In certain embodiments, each R3is independently benzothienyl, optionally substituted with one, two, three, or four substituents, each of which is independently (i) halo or cyano; (ii) C1-6alkyl, C1-6heteroalkyl, or C2-6alkynyl, each optionally substituted with one or more substituents Q; or (iii) -ORlaor -NRlbRlc, wherein Rla, Rlb, and Rlcare each as defined herein. In certain embodiments, each R3is independently benzothienyl, optionally substituted with one, two, three, or four substituents, each of which is independently (i) halo or cyano; or (ii) -NRlbRle, wherein Rlband Rlcare each as defined herein. In certain embodiments, each R3is independently benzothienyl, optionally substituted with one, two, three, or four substituents, each of which is independently fluoro, cyano, or amino. In certain embodiments, each R3is independently 2-amino-3-cyano- benzothien-4-yl or 2-amino-3-cyano-7-fluorobenzothien-4-yl. In certain embodiments, each R3is independently 6,6-fused heteroaryl, optionally substituted with one or more substituents Q.

[0102] In certain embodiments, each R3is independently C6-14aryl or heteroaryl, each optionally substituted with one, two, three, or four substituents, each of which is independently (i)halo or cyano; (ii) C1-6alkyl, C1-6heteroalkyl, or C2-6alkynyl, each optionally substituted with one or more substituents Q; or (iii) -ORlaor -NRlbRlc, wherein Rla, Rlb, and Rlcare each as defined herein. In certain embodiments, each R3is independently C6-14aryl or heteroaryl, each optionally substituted with one, two, three, or four substituents, each of which is independently fluoro, cyano, methyl, trifluoromethyl, ethynyl, hydroxyl, or amino.

[0103] In certain embodiments, each R3is independently phenyl, naphthyl, pyridyl, or benzothienyl, each optionally substituted with one, two, three, or four substituents, each of which is independently (i) halo or cyano; (ii) C1-6alkyl, C1-6heteroalkyl, or C2-6alkynyl, each optionally substituted with one or more substituents Q; or (iii) -ORlaor -NRlbRlc, wherein Rla, Rlb, and Rlcare each as defined herein. In certain embodiments, each R3is independently phenyl, naphth-l-yl, pyrid-2-yl, or benzothien-4-yl, each optionally substituted with one, two, three, or four substituents, each of which is independently (i) halo or cyano; (ii) C1-6alkyl, C1-6heteroalkyl, or C2-6alkynyl, each optionally substituted with one or more substituents Q; or (iii) -ORlaor -NRlbRlc, wherein Rla, Rlb, and Rlcare each as defined herein. In certain embodiments, each R3is independently phenyl, naphthyl, pyridyl, or benzothienyl, each optionally substituted with one, two, three, or four substituents, each of which is independently fluoro, cyano, methyl, trifluoro- methyl, ethynyl, hydroxyl, or amino. In certain embodiments, each R3is independently phenyl, naphth-l-yl, pyrid-2-yl, or benzothien-4-yl, each optionally substituted with one, two, three, or four substituents, each of which is independently fluoro, cyano, methyl, trifluoromethyl, ethynyl, hydroxyl, or amino. In certain embodiments, each R3is independently 2-trifluoromethyl-3- methyl-4-fluoro-5-aminophenyl, 3-hydroxy-7-fluoro-8-ethynylnaphth-l-yl, 3-trifluoromethyl-4- methyl-5-fluoro-6-aminopyrid-2-yl, 2-amino-3-cyano-benzothien-4-yl, or 2-amino-3-cyano-7- fluorobenzothien-4-yl.

[0104] In certain embodiments, each R7ais independently hydrogen, deuterium, or C1-6alkyl, optionally substituted with one or more substituents Q. In certain embodiments, each R7ais hydrogen. In certain embodiments, each R7ais independently C1-6alkyl, optionally substituted with one or more substituents Q. In certain embodiments, each R7ais independently methyl, optionally substituted with one or more substituents Q.

[0105] In certain embodiments, each R8ais independently hydrogen, deuterium, or C1-6alkyl, optionally substituted with one or more substituents Q. In certain embodiments, each R8ais hydrogen. In certain embodiments, each R8ais independently C1-6alkyl, optionally substituted with one or more substituents Q. In certain embodiments, each R8ais independently methyl or ethyl, each optionally substituted with one or more substituents Q. In certain embodiments, each R8ais methyl. In certain embodiments, each R8ais independently hydrogen, methyl, or l- hydroxy ethyl.

[0106] In certain embodiments, each R8bis independently hydrogen, deuterium, or C1-6alkyl, optionally substituted with one or more substituents Q. In certain embodiments, each R8bis hydrogen. In certain embodiments, each R8bis independently C1-6alkyl, optionally substituted with one or more substituents Q. In certain embodiments, each R8bis independently methyl or ethyl, each optionally substituted with one or more substituents Q. In certain embodiments, each R8bis methyl. In certain embodiments, each R8bis independently hydrogen, methyl, or 1- hydroxy ethyl.

[0107] In certain embodiments, each R8cis independently hydrogen, deuterium, or C1-6alkyl, optionally substituted with one or more substituents Q. In certain embodiments, each R8cis hydrogen. In certain embodiments, each R8cis independently C1-6alkyl, optionally substituted with one or more substituents Q. In certain embodiments, each R8cis independently methyl or ethyl, each optionally substituted with one or more substituents Q. In certain embodiments, each R8cis methyl. In certain embodiments, each R8cis independently hydrogen, methyl, or 1- hydroxy ethyl.

[0108] In certain embodiments, each R8dis independently hydrogen, deuterium, or C1-6alkyl, optionally substituted with one or more substituents Q. In certain embodiments, each R8dis hydrogen. In certain embodiments, each R8dis independently C1-6alkyl, optionally substituted with one or more substituents Q. In certain embodiments, each R8dis independently methyl or ethyl, each optionally substituted with one or more substituents Q. In certain embodiments, each R8dis methyl. In certain embodiments, each R8dis independently hydrogen, methyl, or 1- hydroxy ethyl.

[0109] In one embodiment, provided herein is a compound of Formula (XVI):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; wherein: each E2is independently C6-14arylene or heteroarylene, each optionally substituted with one or more substituents Q; each R1is as defined herein; each R7is independently (i) C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; or (ii) -NR7bR7c; or R1and R7are linked together to form heterocyclyl, optionally substituted with one or more substituents Q; each R7band R7eis independently (i) hydrogen; (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; or (iii) -C(O)Rla, -C(O)ORla, -C(O)NRlbRle, -C(O)SRla, -C(NRla)NRlbRlc, -C(S)Rla, -C(S)ORla, -C(S)NRlbRlc, -S(O)Rla, -S(O)2Rla, -S(O)NRlbRlc, or -S(O)2NRlbRlc; and each R4, R5, Rla, Rlb, Rlc, RA, A, L, U, X, and m is as defined herein.

[0110] In certain embodiments, each R7is independently (i) heterocyclyl, optionally substituted with one or more substituents Q; or (ii) -NR7bR7c, wherein R7band R7care each as defined herein. In certain embodiments, each R7is independently heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each R7is independently monocyclic heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each R7is independently 3-, 4-, 5-, 6-, 7-, or 8-membered heterocyclyl, each optionally substituted with one or more substituents Q. In certain embodiments, each R7is independently 3-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each R7is independently 4-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each R7is independently 5-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each R7is independently 6-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each R7is independently piperidinyl, morpholinyl, or piperazinyl, each optionally substituted with one or more substituents Q. In certain embodiments, each R7is independently piperidin-l-yl or piperazin- 1-yl, each optionally substituted with one or more substituents Q. In certain embodiments, each R7is independently 7- membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each R7is independently azepanyl, optionally substituted with one or more substituents Q. In certain embodiments, each R7is independently azepan-3-yl, optionally substituted with one or more substituents Q. In certain embodiments, each R7is independently 8- membered heterocyclyl, optionally substituted with one or more substituents Q.

[0111] In certain embodiments, each R7is independently bicyclic heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each R7is independently bridged, fused, or spiro heterocyclyl, each optionally substituted with one or more substituents Q. In certain embodiments, each R7is independently bridged heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each R7is independently 3,8-diaza- bicyclo[3.2. l]octanyl, optionally substituted with one or more substituents Q. In certain embodiments, each R7is independently 3,8-diazabicyclo-[3.2.1]octan-3-yl or 3,8-diazabicyclo- [3.2.1 ]octan-8-yl, each optionally substituted with one or more substituents Q. In certain embodiments, each R7is independently fused heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each R7is independently octahydropyrrolo[3,2-b]- pyridinyl, optionally substituted with one or more substituents Q. In certain embodiments, each R7is independently octahydropyrrolo[3,2-b]pyridin-l-yl, optionally substituted with one or more substituents Q. In certain embodiments, each R7is independently spiro heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each R7is independently l,6-diazaspiro[3.4]octanyl, 4,7-diazaspiro[2.5]octanyl, 2,7-diazaspiro[3.5]nonanyl, or 2,6-diaza- spiro[3.6]decanyl, each optionally substituted with one or more substituents Q. In certain embodiments, each R7is independently l,6-diazaspiro[3.4]octan-6-yl, 4,7-diazaspiro[2.5]octan-7- yl, 2,7-diazaspiro[3.5]nonan-7-yl, or 2,6-diazaspiro[3.6]decan-6-yl, each optionally substituted with one or more substituents Q.

[0112] In certain embodiments, each R7is independently -NR7bR7c, wherein R7band R7care each as defined herein. In certain embodiments, each R7is independently -NR7bR7c, wherein R7band R7care each independently C1-6alkyl or heterocyclyl, each optionally substituted with one or more substituents Q. In certain embodiments, each R7is independently (l-(2-aminopyridin-3- yl)ethyl)-(methyl)amino or (l-acryloyl-2-methylpyrrolidin-3-yl)(ethyl)amino. In certain embodiments, each R7is independently (R)-(l-(2-aminopyridin-3-yl)ethyl)(methyl)amino or ((2R,3R)-l-acryloyl-2-methyl-pyrrolidin-3-yl)(ethyl)amino.

[0113] In certain embodiments, each R7is independently pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, azepanyl, 3,8-diazabicyclo[3.2.1]octanyl, octahydropyrrolo[3,2-b]- pyridin-l-yl, l,6-diazaspiro[3.4]octanyl, 2,6-diazaspiro[3.6]decanyl, 4,7-diazaspiro[2.5]octyl, or2.7-diazaspiro[3.5]nonyl, each optionally substituted with one or more substituents Q. In certain embodiments, each R7is independently 4-acryloylpiperazin-l-yl, 4-acryloyl-2-methylpiperazin-l- yl, 3-methylaminoazepan-l-yl, 3-acryloylaminoazepan-l-yl, 3,8-diazabicyclo[3.2.1]octan-3-yl,3.8-diazabicyclo[3.2.1 ]octan-8-yl, 4-acryloyloctahydropyrrolo[3,2-b]pyridin- 1 -yl, 1 -acryloyl- 1 ,6- diazaspiro[3.4]octan-6-yl, 2-acryloyl-2,6-diazaspiro[3.6]decan-6-yl, ( 1 -(2-aminopyri din-3 -yl)- ethyl)(methyl)amino, or (l-acryloyl-2-methylpyrrolidin-3-yl)(ethyl)amino. In certain embodiments, each R7is independently 4-acryloylpiperazin-l-yl, (S)-4-acryloyl-2-methyl- piperazin-l-yl, 3-methylaminoazepan-l-yl, 3(R)-acryloylaminoazepan-l-yl, 3,8-diazabicyclo- [3.2.1 ]octan-3-yl, 3,8-diazabicyclo[3.2.1 ]octan-8-yl, 4-acryloyloctahydropyrrolo[3,2-b]pyridin-l - yl, l-acryloyl-l,6-diazaspiro[3.4]octan-6-yl, 2-acryloyl-2,6-diazaspiro[3.6]decan-6-yl, (R)-( 1 -(2- aminopyridin-3-yl)ethyl)(methyl)amino, or ((2R,3R)-l-acryloyl-2-methylpyrrolidin-3- yl)(ethyl)amino.

[0114] In certain embodiments, R1and R7are linked together to form heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R1and R7are linked together to form monocyclic heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R1and R7are linked together to form 5-, 6-, 7-, or 8- membered heterocyclyl, each optionally substituted with one or more substituents Q. In certain embodiments, R1and R7are linked together to form 5-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R1and R7are linked together to form 6-membered heterocyclyl, optionally substituted with one or more substituentsQ. In certain embodiments, R1and R7are linked together to form 7-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R1and R7are linked together to form 8-membered heterocyclyl, optionally substituted with one or more substituents Q.

[0115] In certain embodiments, R1and R7are linked together to form bicyclic heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R1and R7are linked together to form bridged, fused, or spiro heterocyclyl, each optionally substituted with one or more substituents Q. In certain embodiments, R1and R7are linked together to form bridged heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R1and R7are linked together to form fused heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R1and R7are linked together to form spiro heterocyclyl, optionally substituted with one or more substituents Q.

[0116] In another embodiment, provided herein is a compound of Formula (XVII):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; wherein each V2is independently C1-6alkylene or C1-6heteroalkylene, each optionally substituted with one or more substituents Q; and each R4, R5R7b, RA, A, E2, L, U, X, and m is each as defined herein.

[0117] In certain embodiments, each V2is independently C1-6alkylene, optionally substituted with one or more substituents Q. In certain embodiments, each V2is independently ethanediyl, propanediyl, or butanediyl, each optionally substituted with one or more substituents Q. In certain embodiments, each V2is independently ethane- 1,2-diyl, propane-1, 3-diyl, butane- 1,3-diyl, or butane- 1,4-diyl, each optionally substituted with one or more substituents Q.

[0118] In certain embodiments, each V2is independently C1-6heteroalkylene, optionallysubstituted with one or more substituents Q. In certain embodiments, each V2is independently -O-C1-6alkylene, optionally substituted with one or more substituents Q. In certain embodiments, each V2is independently -OCH2CH2- or -O-CH(CH3)-.

[0119] In yet another embodiment, provided herein is a compound of Formula (XVIII):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; wherein: each U2is independently C1-6alkylene or C1-6heteroalkylene, each optionally substituted with one or more substituents Q; each R7b, R8a, and R8bis as defined herein; or R7band R8aare linked together to form heterocyclylene, optionally substituted with one or more substituents Q; or R7band R8bare linked together to form heterocyclylene, optionally substituted with one or more substituents Q; and each R4, R5, RA, A, E2, L, U, X, and m is as defined herein.

[0120] In yet another embodiment, provided herein is a compound of Formula (XIX):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; wherein each R4, R5, R6a, R6b, R7b, R8a, R8b, RA, E2, L, U, U2, X, and m is as defined herein.

[0121] In yet another embodiment, provided herein is a compound of Formula (XX):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; wherein each R4, R5a, R5b, R5c, R6a, R6b, R7b, R8a, R8b, RA, E2, L, U, U2, X, and m is as defined herein.

[0122] In yet another embodiment, provided herein is a compound of Formula (XXI):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; wherein each R4, R5a, R5b, R5c, R6a, R6b, R7b, R8a, R8b, RA, E2, L, U, U2, X, and m is as defined herein.

[0123] In certain embodiments, each E2is independently C6-14arylene, optionally substituted with one or more substituents Q. In certain embodiments, each E2is independently phendiyl, optionally substituted with one or more substituents Q. In certain embodiments, each E2is independently phen-l,3-diyl, optionally substituted with one or more substituents Q. In certain embodiments, each E2is independently bicyclic C8-14arylene, optionally substituted with one or more substituents Q. In certain embodiments, each E2is independently naphthdiyl, optionally substituted with one or more substituents Q.

[0124] In certain embodiments, each E2is independently heteroarylene, optionallysubstituted with one or more substituents Q. In certain embodiments, each E2is independently monocyclic heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, each E2is independently 5- or 6-membered heteroarylene, each optionally substituted with one or more substituents Q. In certain embodiments, each E2is independently 5- membered heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, each E2is independently 6-membered heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, each E2is independently pyridindiyl, optionally substituted with one or more substituents Q. In certain embodiments, each E2is independently pyridin-2,6-diyl, optionally substituted with one or more substituents Q.

[0125] In certain embodiments, each E2is independently bicyclic heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, each E2is independently 5,5-, 5,6-, or 6,6-fused heteroarylene, each optionally substituted with one or more substituents Q. In certain embodiments, each E2is independently 5,5-fused heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, each E2is independently 5,6-fused heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, each E2is independently benzothiendiyl, optionally substituted with one or more substituents Q. In certain embodiments, each E2is independently benzothien-2,4-diyl, optionally substituted with one or more substituents Q. In certain embodiments, each E2is independently 6,6-fused heteroarylene, optionally substituted with one or more substituents Q.

[0126] In yet another embodiment, provided herein is a compound of Formula (XXII):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; wherein each R2a, R2b, R2c, and R2dis independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; or (iii) -C(O)Rla, -C(O)ORla, -C(O)NRlbRlc, -C(O)SRla, -C(NRla)NRlbRle, -C(S)Rla, -C(S)ORla, -C(S)NRlbRle, -ORla, -OC(O)Rla, -OC(O)ORla, -OC(O)NRlbRlc, -OC(O)SRla, -OC(NRla)NRlbRlc, -OC(S)Rla, -OC(S)ORla, -OC(S)NRlbRlc, -OS(O)Rla, -OS(O)2Rla, -OS(O)NRlbRlc, -OS(O)2NRlbRlc, -NRlbRlc, -NRlaC(O)Rld, -NRlaC(O)ORld, -NRlaC(O)NRlbRlc, -NRlaC(O)SRld, -NRlaC(NRld)NRlbRlc, -NRlaC(S)Rld, -NRlaC(S)ORld, -NRlaC(S)NRlbRlc, -NRlaS(O)Rld, -NRlaS(O)2Rld, -NRlaS(O)NRlbRlc, -NRlaS(O)2NRlbRlc, -SRla, -S(O)Rla, -S(O)2Rla, -S(O)NRlbRlc, or -S(O)2NRlbRlc; and each R4, Rla, Rlb, Rle, Rld, R5a, R5b, R5C, R6a, R6b, R7b, R8a, R8b, RA, L, U, U2, X, and m is as defined herein.

[0127] In yet another embodiment, provided herein is a compound of Formula (XXIII):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; wherein each R4, R2a, R2b, R2c, R2d, R5a, R5b, R5c, R6a, R6b, R7b, R8a, R8b, RA, L, U, U2, X, and m is as defined herein.

[0128] In certain embodiments, each R5ais independently hydrogen or deuterium. In certain embodiments, each R5ais hydrogen.

[0129] In certain embodiments, each R5bis independently hydrogen, deuterium, or halo. In certain embodiments, each R5bis hydrogen. In certain embodiments, each R5bis independently halo. In certain embodiments, each R5bis independently chloro or fluoro. In certain embodiments, each R5ais fluoro.

[0130] In certain embodiments, R5aand R3btogether with the carbon atom to which they are attached form C2-6alkenylene or C3-10cycloalkylene, each optionally substituted with one ormore substituents Q. In certain embodiments, R3aand R5btogether with the carbon atom to which they are attached form C2-6alkenylene, optionally substituted with one or more substituents Q. In certain embodiments, R5aand R5btogether with the carbon atom to which they are attached form C2-6alkenylene, optionally substituted with one or two halo. In certain embodiments, Raand R5btogether with the carbon atom to which they are attached form ethendiyl, optionally substituted with one or more substituents Q. In certain embodiments, R5aand R5btogether with the carbon atom to which they are attached form ethendiyl, optionally substituted with one or two halo. In certain embodiments, R5aand R5btogether with the carbon atom to which they are attached form ethendiyl, optionally substituted with one or two fluoro. In certain embodiments, R5aand R5btogether with the carbon atom to which they are attached form 2,2-difluoroethen-l,l-diyl.

[0131] In certain embodiments, R5aand R5btogether with the carbon atom to which they are attached form C3-10cycloalkylene, optionally substituted with one or more substituents Q. In certain embodiments, R5aand R5btogether with the carbon atom to which they are attached form monocyclic C3-10cycloalkylene, optionally substituted with one or more substituents Q. In certain embodiments, R5aand R5btogether with the carbon atom to which they are attached form monocyclic C3-10cycloalkylene, optionally substituted with one or two halo. In certain embodiments, R5aand R5btogether with the carbon atom to which they are attached form cyclopropanediyl, optionally substituted with one or more substituents Q. In certain embodiments, R3aand R5btogether with the carbon atom to which they are attached form cyclopropanediyl, optionally substituted with one or two halo. In certain embodiments, R5aand R5btogether with the carbon atom to which they are attached form cyclopropanediyl, optionally substituted with one or two fluoro. In certain embodiments, Raand R5btogether with the carbon atom to which they are attached form 2,2-difluorocycloprop-l,l-diyl. In certain embodiments, R5aand R5btogether with the carbon atom to which they are attached form bicyclic C3-10cycloalkylene, optionally substituted with one or more substituents Q.

[0132] In certain embodiments, each R5cis independently (i) hydrogen or deuterium; or (ii) C1-6alkylene or C1-6heteroalkylene, each optionally substituted with one or more substituents Q. In certain embodiments, each R5cis hydrogen. In certain embodiments, each R5cis independently C1-6alkylene, optionally substituted with one or more substituents Q. In certain embodiments, each R5cis independently methyl, optionally substituted with one or moresubstituents Q. In certain embodiments, each R5cis independently C1-6heteroalkylene, optionally substituted with one or more substituents Q. In certain embodiments, each R5cis independently hydrogen or (l,l-(di(trifluoromethyl)ethoxy)methyl.

[0133] In certain embodiments, each R7bis independently C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, or heterocyclyl, each optionally substituted with one or more substituents Q. In certain embodiments, each R7bis independently C1-6alkyl, optionally substituted with one or more substituents Q. In certain embodiments, each R7bis independently C1-6heteroalkyl, each optionally substituted with one or more substituents Q. In certain embodiments, each R7bis independently C2-6alkenyl, optionally substituted with one or more substituents Q.

[0134] In certain embodiments, each R7bis independently C1-6alkyl, C1-6heteroalkyl, or C2-6alkenyl, each substituted with one, two, or three substituents, each of which is independently halo or heteroaryl optionally substituted with one or more substituents Qa. In certain embodiments, each R7bis independently C1-6alkyl, C1-6heteroalkyl, or C2-6alkenyl, each substituted with one, two, or three substituents, each of which is independently halo or monocyclic heteroaryl optionally substituted with one or more substituents Qa. In certain embodiments, each R7bis independently C1-6alkyl, C1-6heteroalkyl, or C2-6alkenyl, each substituted with one, two, or three substituents, each of which is independently halo or 6- membered heteroaryl optionally substituted with one or more substituents Qa. In certain embodiments, each R7bis independently C1-6alkyl, C1-6heteroalkyl, or C2-6alkenyl, each substituted with one, two, or three substituents, each of which is independently fluoro or pyridyl optionally substituted with one or more substituents Qa. In certain embodiments, each R7bis independently 2,2-difluoroethyl, l-(2-aminopyrid-3-yl)ethyl, l-(2-aminopyrid-3-yl)-2,2- difluoroethyl, l-(2-aminopyrid-3-yl)-3-fluoroprop-2-enyl, l-(2-aminopyrid-3-yl)but-3-enyl, or 1- (4-aminopyrimid-5-yl)ethyl. In certain embodiments, each R7bis independently C1-6alkyl, C1-6heteroalkyl, or C2-6alkenyl, each substituted with one, two, or three substituents, each of which is independently halo or bicyclic heteroaryl optionally substituted with one or more substituents Qa.

[0135] In certain embodiments, each R7bis independently heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each R7bis independently monocyclic heterocyclyl, optionally substituted with one or more substituents Q. In certainembodiments, each R7bis independently 3-, 4-, 5-, 6-, or 7-membered heterocyclyl, each optionally substituted with one or more substituents Q. In certain embodiments, each R7bis independently 3-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each R7bis independently 4-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each R7bis independently 5-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each R7bis independently pyrrolidinyl, optionally substituted with one or more substituents Q. In certain embodiments, each R7bis independently pyrrolidin-3-yl, optionally substituted with one or more substituents Q. In certain embodiments, each R7bis l-acryloyl-2- methylpyrrolidin-3-yl. In certain embodiments, each R7bis independently 6-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each R7bis independently 7-membered heterocyclyl, optionally substituted with one or more substituents Q.

[0136] In certain embodiments, each R7bis independently bicyclic heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each R7bis independently bridged, fused, or spiro heterocyclyl, each optionally substituted with one or more substituents Q. In certain embodiments, each R7bis independently bridged heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each R7bis independently fused heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each R7bis independently spiro heterocyclyl, optionally substituted with one or more substituents Q

[0137] In certain embodiments, R7band R8aare linked together to form heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, R7band R8aare linked together to form monocyclic heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, R7band R8aare linked together to form 3-, 4-, 5-, 6-, or 7-membered heterocyclylene, each optionally substituted with one or more substituents Q. In certain embodiments, R7band R8aare linked together to form 3 -membered heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, R7band R8aare linked together to form 4-membered heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, R7band R8aare linked together to form 5-memberedheterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, R7band R8aare linked together to form 6-membered heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, R7band R8aare linked together to form piperidindiyl or piperazindiyl, each optionally substituted with one or more substituents Q. In certain embodiments, R7band R8aare linked together to form piperazin- 1,2-diyl, optionally substituted with one or more substituents Q. In certain embodiments, R7band R8aare linked together to form 7-membered heterocyclylene, optionally substituted with one or more substituents Q.

[0138] In certain embodiments, R7band R8aare linked together to form bicyclic heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, R7band R8aare linked together to form bridged, fused, or spiro heterocyclylene, each optionally substituted with one or more substituents Q. In certain embodiments, R7band R8aare linked together to form bridged heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, R7band R8aare linked together to form fused heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, R7band R8aare linked together to form spiro heterocyclylene, optionally substituted with one or more substituents Q.

[0139] In certain embodiments, R7band R8bare linked together to form heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, R7band R8bare linked together to form monocyclic heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, R7band R8bare linked together to form 3-, 4-, 5-, 6-, or 7-membered heterocyclylene, each optionally substituted with one or more substituents Q. In certain embodiments, R7band R8bare linked together to form 3 -membered heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, R7band R8bare linked together to form 4-membered heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, R7band R8bare linked together to form 5-membered heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, R7band R8bare linked together to form 6-membered heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, R7band R8bare linked together to form piperidindiyl or piperazindiyl, each optionally substituted with one or more substituents Q. In certain embodiments, R7band R8bare linked together to form piperazin- 1,2-diyl, optionallysubstituted with one or more substituents Q. In certain embodiments, R7band R8bare linked together to form 7-membered heterocyclylene, optionally substituted with one or more substituents Q.

[0140] In certain embodiments, R7band R8bare linked together to form bicyclic heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, R7band R8bare linked together to form bridged, fused, or spiro heterocyclylene, each optionally substituted with one or more substituents Q. In certain embodiments, R7band R8bare linked together to form bridged heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, R7band R8bare linked together to form fused heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, R7band R8bare linked together to form spiro heterocyclylene, optionally substituted with one or more substituents Q.

[0141] In yet another embodiment, provided herein is a compound of Formula (XXIV):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; wherein: each R7dis independently (i) hydrogen; (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14 aryl, C7-15aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; or (iii) -C(O)Rla, -C(O)ORla, -C(O)NRlbRlc, -C(O)SRla, -C(NRla)NRlbRlc, -C(S)Rla, -C(S)ORla, -C(S)NRlbRlc, -S(O)Rla, -S(O)2Rla, -S(O)NRlbRlc, or -S(O)2NRlbRlc; and each R4, R5, Rla, Rlb, Rlc, R2a, R2b, R2e, R2d, RA, A, L, U, U2, X, and m is as defined herein.

[0142] In still another embodiment, provided herein is a compound of Formula (XXV):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; wherein each R4, R5, R2a, R2b, R2c, R2d, R7d, RA, A, L, U, U2, X, and m is as defined herein.

[0143] In one embodiment, provided herein is a compound of Formula (XXVI):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; wherein: each E3is independently C3-10cycloalkylene, C6-14 arylene, heteroarylene, or heterocyclylene, each optionally substituted with one or more substituents Q; and each R1, R3, R4, R7, RA, A, L, U, X, and m is as defined herein.

[0144] In another embodiment, provided herein is a compound of Formula (XXVII):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 hydratethereof; wherein each R1, R3, R4, R7, R6a, R6b, RA, E3, L, U, X, and m is as defined herein.

[0145] In certain embodiments, each E3is independently heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, each E3is independently monocyclic heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, each E3is independently 3-, 4-, 5-, 6-, or 7-membered heterocyclylene, each optionally substituted with one or more substituents Q. In certain embodiments, each E3is independently 3-membered heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, each E3is independently 4-membered heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, each E3is independently 5- membered heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, each E3is independently pyrrolidindiyl, optionally substituted with one or more substituents Q. In certain embodiments, each E3is independently pyrrolidin-l,2-diyl, optionally substituted with one or more substituents Q. In certain embodiments, each E3is independently 6- membered heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, each E3is independently 7-membered heterocyclylene, optionally substituted with one or more substituents Q.

[0146] In certain embodiments, each E3is independently bicyclic heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, each E3is independently bridged, fused, or spiro heterocyclylene, each optionally substituted with one or more substituents Q. In certain embodiments, each E3is independently bridged heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, each E3is independently fused heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, each E3is independently hexahydropyrrolizindiyl, optionally substituted with one or more substituents Q. In certain embodiments, each E3is independently spiro heterocyclylene, optionally substituted with one or more substituents Q.

[0147] In one embodiment, provided herein is a compound of Formula (XXVIII):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; wherein: each A1is independently (i) C1-6alkylene or C1-6heteroalkylene, each optionally substituted with one or more substituents Q; or (ii) C(O); each R4ais independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; or (iii) -C(O)Rla, -C(O)ORla, -C(O)NRlbRlc, -C(O)SRla, -C(NRla)NRlbRlc, -C(S)Rla, -C(S)ORla, -C(S)NRlbRlc, -ORla, -OC(O)Rla, -OC(O)ORla, -OC(O)NRlbRle, -OC(O)SRla, -OC(NRla)NRlbRlc, -OC(S)Rla, -OC(S)ORla, -OC(S)NRlbRlc, -OS(O)Rla, -OS(O)2Rla, -OS(O)NRlbRlc, -OS(O)2NRlbRlc, -NRlbRlc, -NRlaC(O)Rld, -NRlaC(O)ORld, -NRlaC(O)NRlbRlc, -NRlaC(O)SRld, -NRlaC(NRld)NRlbRlc, -NRlaC(S)Rld, -NRlaC(S)ORld, -NRlaC(S)NRlbRlc, -NRlaS(O)Rld, -NRlaS(O)2Rld, -NRlaS(O)NRlbRlc, -NRlaS(O)2NRlbRlc, -SRla, -S(O)Rla, -S(O)2Rla, -S(O)NRlbRle, or -S(O)2NRlbRlc; and each R4, Rla, Rlb, Rlc, Rld, R7b, R8a, R8b, RA, E2, L, U, U2, X, and m is as defined herein.

[0148] In another embodiment, provided herein is a compound of Formula (XXIX):or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein each R4, R2a, R2b, R2c, R4a, R7d, RA, A1, L, U, U2, X, and m is as defined herein.

[0149] In yet another embodiment, provided herein is a compound of Formula (XXX):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; wherein each R4, R2a, R2b, R2c, R4a, R7d, RA, A1, L, U, U2, X, and m is as defined herein.

[0150] In certain embodiments, each A1is independently C1-6alkylene, optionally substituted with one or more substituents Q. In certain embodiments, each A1is independently methanediyl, optionally substituted with one or more substituents Q. In certain embodiments, each A1is C(O).

[0151] In certain embodiments, each R2ais independently hydrogen, deuterium, or cyano. In certain embodiments, each R2ais cyano.

[0152] In certain embodiments, each R2bis independently hydrogen or deuterium. In certain embodiments, each R2bis hydrogen.

[0153] In certain embodiments, each R2cis independently hydrogen or deuterium. In certain embodiments, each R2cis hydrogen.

[0154] In certain embodiments, each R2dis independently hydrogen, deuterium, or halo. In certain embodiments, each R2dis hydrogen. In certain embodiments, each R2dis independently halo. In certain embodiments, each R2dis fluoro.

[0155] In certain embodiments, each U2is independently C1-6alkylene, optionallysubstituted with one or more substituents Q. In certain embodiments, each U2is independently methanediyl, ethanediyl, propanediyl, or butanediyl, each optionally substituted with one or more substituents Q. In certain embodiments, each U2is independently methane- 1,1 -diyl, ethane-1,2- diyl, propane-1, 3-diyl, or butane-l,4-diyl, each optionally substituted with one or more substituents Q. In certain embodiments, each U2is independently methane- 1,1 -diyl or ethane-1,2- diyl, each optionally substituted with one or more substituents Q. In certain embodiments, each U2is independently ethane-l,2-diyl, optionally substituted with one or more substituents Q.

[0156] In certain embodiments, each R7dis hydrogen. In certain embodiments, each R7dis independently -C(O)Rla, wherein Rlais as defined herein. In certain embodiments, each R7dis independently -C(O)Rla, wherein Rlais C2-6alkenyl, C2-6alkynyl, or heteroaryl, each optionally substituted with one or more substituents Q. In certain embodiments, each R7dis independently -C(O)Rla, wherein Rlais C2-6alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, each R7dis acroyl, optionally substituted with one or more substituents Q. In certain embodiments, each R7dis independently -C(O)Rla, wherein Rlais C2-6alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, each R7dis propioloyl, optionally substituted with one or more substituents Q.

[0157] In certain embodiments, each U is independently C(R2), wherein R2is as defined herein. In certain embodiments, each U is N. In certain embodiments, each U is independently C(C1), C(CF3), or N.

[0158] In certain embodiments, each R1is independently hydrogen or deuterium. In certain embodiments, each R1is hydrogen.

[0159] In certain embodiments, each R2is independently (i) halo; or (ii) C1-6alkyl or C1-6heteroalkyl, each optionally substituted with one or more substituents Q. In certain embodiments, each R2is independently halo. In certain embodiments, each R2is independently fluoro or chloro. In certain embodiments, each R2is chloro. In certain embodiments, each R2is independently C1-6alkyl, optionally substituted with one or more substituents Q. In certain embodiments, each R2is independently C1-6heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, each R2is trifluoromethyl. In certain embodiments, each R2is independently halo or C1-6heteroalkyl. In certain embodiments, each R2is independently chloro or trifluoromethyl.

[0160] In certain embodiments, R1and R2together with the carbon atoms to which they are attached form heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R1and R2together with the carbon atoms to which they are attached form monocyclic heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R1and R2together with the carbon atoms to which they are attached form 5-, 6-, or 7-membered heterocyclyl, each optionally substituted with one or more substituents Q. In certain embodiments, R1and R2together with the carbon atoms to which they are attached form 5- membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R1and R2together with the carbon atoms to which they are attached form 6- membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, R1and R2together with the carbon atoms to which they are attached form 7- membered heterocyclyl, optionally substituted with one or more substituents Q.

[0161] In certain embodiments, each R4is independently halo. In certain embodiments, each R4is independently fluoro or chloro. In certain embodiments, each R4is fluoro.

[0162] In one embodiment, provided herein is a compound of Formula (XXXI):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; wherein: each E4is independently C3-10cycloalkylene, C6-14 arylene, heteroarylene, or heterocyclylene, each optionally substituted with one or more substituents Q; each U3is N and each V3is O; or each U3is O and each V3is N; each R11, R12, and R15is independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl,heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; or (iii) -C(O)Rla, -C(O)ORla, -C(O)NRlbRlc, -C(O)SRla, -C(NRla)NRlbRle, -C(S)Rla, -C(S)ORla, -C(S)NRlbRlc, -ORla, -OC(O)Rla, -OC(O)ORla, -OC(O)NRlbRlc, -OC(O)SRla, -OC(NRla)NRlbRlc, -OC(S)Rla, -OC(S)ORla, -OC(S)NRlbRlc, -OS(O)Rla, -OS(O)2Rla, -OS(O)NRlbRlc, -OS(O)2NRlbRlc, -NRlbRlc, -NRlaC(O)Rld, -NRlaC(O)ORld, -NRlaC(O)NRlbRlc, -NRlaC(O)SRld, -NRlaC(NRld)NRlbRlc, -NRlaC(S)Rld, -NRlaC(S)ORld, -NRlaC(S)NRlbRlc, -NRlaS(O)Rld, -NRlaS(O)2Rld, -NRlaS(O)NRlbRlc, -NRlaS(O)2NRlbRlc, -SRla, -S(O)Rla, -S(O)2Rla, -S(O)NRlbRlc, or -S(O)2NRlbRlc; each R13and R14is independently (i) deuterium, cyano, halo, or nitro; (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; or (iii) -C(O)Rla, -C(O)ORla, -C(O)NRlbRlc, -C(O)SRla, -C(NRla)NRlbRlc, -C(S)Rla, -C(S)ORla, -C(S)NRlbRlc, -ORla, -OC(O)Rla, -OC(O)ORla, -OC(O)NRlbRle, -OC(O)SRla, -OC(NRla)NRlbRlc, -OC(S)Rla, -OC(S)ORla, -OC(S)NRlbRlc, -OS(O)Rla, -OS(O)2Rla, -OS(O)NRlbRlc, -OS(O)2NRlbRlc, -NRlbRlc, -NRlaC(O)Rld, -NRlaC(O)ORld, -NRlaC(O)NRlbRlc, -NR1 aC(O)SRld, -NRlaC(NR1d)NR1bR1e, -NR1aC(S)Rld, -NRlaC(S)OR1d, -NRl aC(S)NRlbRlc, -NRlaS(O)Rld, -NRlaS(O)2Rld, -NRlaS(O)NRlbRlc, -NRlaS(O)2NRlbRlc, -SRla, -S(O)Rla, -S(O)2Rla, -S(O)NRlbRlc, or -S(O)2NRlbRlc; each p and q is independently an integer of 0, 1, 2, 3, 4, 5, or 6; and each R5, Rla, Rlb, Rlc, Rld, RA, A, L, X, and m is as defined herein.

[0163] In another embodiment, provided herein is a compound of Formula (XXXII):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 hydratethereof; wherein each R3, R11, R12, R13, R14, R15, R6a, R6b, RA, E4, L, U3, V3, X, m, p, and q is as defined herein.

[0164] In certain embodiments, each E4is independently heteroarylene or heterocyclylene, each optionally substituted with one or more substituents Q. In certain embodiments, each E4is independently heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, each E4is independently monocyclic heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, each E4is independently 5- or 6-membered heteroarylene, each optionally substituted with one or more substituents Q. In certain embodiments, each E4is independently 5-membered heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, each E4is independently pyrazoldiyl, optionally substituted with one or more substituents Q. In certain embodiments, each E4is independently pyrazol-l,3-diyl, optionally substituted with one or more substituents Q. In certain embodiments, each E4is independently 6-membered heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, each E4is independently bicyclic heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, each E4is independently 5,5-, 5,6-, or 6,6-fused heteroarylene, each optionally substituted with one or more substituents Q. In certain embodiments, each E4is independently 5,5-fused heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, each E4is independently 5,6-fused heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, each E4is independently 6,6-fused heteroarylene, optionally substituted with one or more substituents Q.

[0165] In certain embodiments, each E4is independently heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, each E4is independently monocyclic heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, each E4is independently 3-, 4-, 5-, 6-, or 7-membered heterocyclylene, each optionally substituted with one or more substituents Q. In certain embodiments, each E4is independently 3-membered heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, each E4is independently 4-membered heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, each E4is independently 5- membered heterocyclylene, optionally substituted with one or more substituents Q. In certainembodiments, each E4is independently 6-membered heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, each E4is independently piperidindiyl or piperazindiyl, each optionally substituted with one or more substituents Q. In certain embodiments, each E4is independently piperazin- 1 ,4-diyl, optionally substituted with one or more substituents Q. In certain embodiments, each E4is independently 7-membered heterocyclylene, optionally substituted with one or more substituents Q.

[0166] In certain embodiments, each E4is independently bicyclic heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, each E4is independently bridged, fused, or spiro heterocyclylene, each optionally substituted with one or more substituents Q. In certain embodiments, each E4is independently bridged heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, each E4is independently 3,8-diazabicyclo[3.2.1]octandiyl, optionally substituted with one or more substituents Q. In certain embodiments, each E4is independently 3,8-diazabicyclo[3.2. l]octan- 3,8-diyl, optionally substituted with one or more substituents Q. In certain embodiments, each E4is independently fused heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, each E4is independently spiro heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, each E4is independently 4,7-diazaspiro- [2.5]octandiyl or 2,7-diazaspiro[3.5]nonandiyl, each optionally substituted with one or more substituents Q. In certain embodiments, each E4is independently 4,7-diazaspiro[2.5]octan-4,7- diyl or 2,7-diazaspiro[3.5]non-2,7-diyl, each optionally substituted with one or more substituents Q

[0167] In certain embodiments, each U3is N and each V3is O. In certain embodiments, each U3is O and each V3is N.

[0168] In certain embodiments, each R6ais independently hydrogen or deuterium. In certain embodiments, each R6ais hydrogen.

[0169] In certain embodiments, each R6bis independently hydrogen or deuterium. In certain embodiments, each R6bis hydrogen.

[0170] In yet another embodiment, provided herein is a compound of Formula (XXXIII):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; wherein: each R17is independently (i) deuterium, cyano, halo, or nitro; (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; or (iii) -C(O)Rla, -C(O)ORla, -C(O)NRlbRlc, -C(O)SRla, -C(NRla)NRlbRlc, -C(S)Rla, -C(S)ORla, -C(S)NRlbRlc, -ORla, -OC(O)Rla, -OC(O)ORla, -OC(O)NRlbRlc, -OC(O)SRla, -OC(NRla)NRlbRlc, -OC(S)Rla, -OC(S)ORla, -OC(S)NRlbRlc, -OS(O)Rla, -OS(O)2Rla, -OS(O)NRlbRlc, -OS(O)2NRlbRlc, -NRlbRlc, -NRlaC(O)Rld, -NRlaC(O)ORld, -NRlaC(O)NRlbRlc, -NRlaC(O)SRld, -NRlaC(NRld)NRlbRle, -NRlaC(S)Rld, -NRlaC(S)ORld, -NRlaC(S)NRlbRlc, -NRlaS(O)Rld, -NRlaS(O)2Rld, -NRlaS(O)NRlbRlc, -NRlaS(O)2NRlbRlc, -SRla, -S(O)Rla, -S(O)2Rla, -S(O)NRlbRlc, or -S(O)2NRlbRlc; each r is independently an integer of 0, 1, 2, 3, 4, 5, or 6; and each R5, R11, R12, R13, R14, R15, Rla, Rlb, Rlc, Rld, R6a, R6b, RA, L, X, m, p, and q is as defined herein.

[0171] In yet another embodiment, provided herein is a compound of Formula (XXXIV):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; wherein each R5, R11, R12, R13, R14, R15, R17, R6a, R6b, RA, L, X, m, p, q, and r is as defined herein.

[0172] In yet another embodiment, provided herein is a compound of Formula (XXXV):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; wherein each R5, R11, R12, R13, R14, R15, R17, R6a, R6b, RA, L, X, m, p, q, and r is as defined herein.

[0173] In still another embodiment, provided herein is a compound of Formula (XXXVI):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; wherein each R3, R11, R12, R13, R14, R15, R17, R6a, R6b, RA, L, X, m, p, q, and r is as defined herein.

[0174] In certain embodiments, each R11is independently -NRlbRlc, wherein Rlband Rleare each as defined herein. In certain embodiments, each R11is amino.

[0175] In certain embodiments, each r is an integer of 0.

[0176] In one embodiment, provided herein is a compound of Formula (XXXVII):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; wherein each R16is independently (i) deuterium, cyano, halo, or nitro; (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; or (iii) -C(O)Rla, -C(O)ORla, -C(O)NRlbRlc, -C(O)SRla, -C(NRla)NRlbRlc, -C(S)Rla, -C(S)ORla, -C(S)NRlbRlc,-0Rla, -OC(O)Rla, -OC(O)ORla, -OC(O)NRlbRlc, -OC(O)SRla, -OC(NRla)NRlbRlc, -OC(S)Rla, -OC(S)ORla, -OC(S)NRlbRle, -OS(O)Rla, -OS(O)2Rla, -OS(O)NRlbRlc, -OS(O)2NRlbRlc, -NRlbRlc, -NRlaC(O)Rld, -NRlaC(O)ORld, -NRlaC(O)NRlbRlc, -NRlaC(O)SRld, -NRlaC(NRld)NRlbRlc, -NRlaC(S)Rld, -NRlaC(S)ORld, -NRlaC(S)NRlbRlc, -NRlaS(O)Rld, -NRlaS(O)2Rld, -NRlaS(O)NRlbRlc, -NRlaS(O)2NRlbRle, -SRla, -S(O)Rla, -S(O)2Rla, -S(O)NRlbRlc, or -S(O)2NRlbRlc; and each R5, R12, R13, R14, R15, Rla, Rlb, Rlc, Rld, RA, A, L, U3, V3, X, m, p, and q is as defined herein.

[0177] In another embodiment, provided herein is a compound of Formula (XXXVIII):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; wherein each R , R12, R13, R14, R15, R16, R6a, R6b, RA, L, U3, V3, X, m, p, and q is as defined herein.

[0178] In yet another embodiment, provided herein is a compound of Formula (XXXIX):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 hydratethereof; wherein each R3, R12, R13, R14, R13, R16, R6a, R6b, RA, L, X, m, p, and q is as defined herein.

[0179] In yet another embodiment, provided herein is a compound of Formula (XL):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; wherein each R5, R12, R13, R14, R15, R16, R6a, R6b, RA, L, X, m, p, and q is as defined herein.

[0180] In yet another embodiment, provided herein is a compound of Formula (XLI):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; wherein each R3, R12, R13, R14, R13, R16, R6a, R6b, RA, L, X, m, p, and q is as defined herein.

[0181] In still another embodiment, provided herein is a compound of Formula (XLII):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; wherein each R3, R12, R13, R14, R13, R16, R6a, R6b, RA, L, X, m, p, and q is as defined herein.

[0182] In certain embodiments, each R5is independently C3-10cycloalkyl or heterocyclyl, each optionally substituted with one or more substituents Q. In certain embodiments, each R3is independently heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each R5is independently monocyclic heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each R5is independently 3-, 4-, 5-, 6-, or 7- membered heterocyclyl, each optionally substituted with one or more substituents Q. In certain embodiments, each R5is independently 3-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each R5is independently 4-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each R5is independently 5-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each R5is independently pyrrolidinyl, optionally substituted with one or more substituents Q. In certain embodiments, each R3is independently pyrrolidin-2-yl, optionally substituted with one or more substituents Q. In certain embodiments, each R5is independently l-methylpyrrolidin-2-yl or l-methyl-3-methoxypyrrolidin-2-yl. In certain embodiments, each R5is independently 6-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each R3is independently 7-membered heterocyclyl, optionally substituted with one or more substituents Q.

[0183] In certain embodiments, each R5is independently bicyclic heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each R3is independentlybridged, fused, or spiro heterocyclyl, each optionally substituted with one or more substituents Q. In certain embodiments, each R5is independently bridged heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each R3is independently fused heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each R5is independently 5,5-, 5,6-, or 6,6-fused heterocyclyl, each optionally substituted with one or more substituents Q. In certain embodiments, each R3is independently 5,5-fused heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each R3is independently hexahydropyrrolizinyl, optionally substituted with one or more substituents Q. In certain embodiments, each R3is independently hexahydropyrrolizin-7a-yl, optionally substituted with one or more substituents Q. In certain embodiments, each R5is independently 5,6-fused heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each R5is independently 6,6-fused heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each R5is independently spiro heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each R5is independently tricyclic heterocyclyl, optionally substituted with one or more substituents Q.

[0184] In certain embodiments, each R5is independently l-methylpyrrolidin-2-yl, 1- methyl-3-methoxypyrrolidin-2-yl, 2-fluorohexahydropyrrolizin-7a-yl, 3-(((l,l,l,3,3,3-hexafluoro- 2-methylpropan-2-yl)oxy)-methyl)hexahydropyrrolizin-7a-yl, 2-(difluoromethylene)hexahydro- pyrrolizin-7a-yl, or 2,2-difluorodihydro-1'H,3'H-spiro[cyclopropane-l,2'-pyrrolizin]-7a'(5'H )-yl.

[0185] In certain embodiments, each R16is independently C6-14aryl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q. In certain embodiments, each R16is independently heteroaryl or heterocyclyl, each optionally substituted with one or more substituents Q. In certain embodiments, each R16is independently heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, each R16is independently monocyclic heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, each R16is independently 5- or 6-membered heteroaryl, each optionally substituted with one or more substituents Q. In certain embodiments, each R16is independently 5-membered heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, each R16is independently pyrazolyl, optionally substituted with one or more substituents Q. In certain embodiments, each R16is independently pyrazol-l-yl, optionallysubstituted with one or more substituents Q. In certain embodiments, each R16is independently 3-(aminocarbonyl)pyrazol-l-yl, 3-(isopropylaminocarbonyl)pyrazol-l-yl, or 3 -(tetrahydrofur-3 - ylaminocarbonyl)pyrazol-l-yl. In certain embodiments, each R16is independently 6-membered heteroaryl, optionally substituted with one or more substituents Q.

[0186] In certain embodiments, each R16is independently bicyclic heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, each R16is independently 5,5-, 5,6-, or 6,6-fused heteroaryl, each optionally substituted with one or more substituents Q. In certain embodiments, each R16is independently 5,5-fused heteroaryl, each optionally substituted with one or more substituents Q. In certain embodiments, each R16is independently 5,6-fused heteroaryl, each optionally substituted with one or more substituents Q. In certain embodiments, each R16is independently 6,6-fused heteroaryl, each optionally substituted with one or more substituents Q.

[0187] In certain embodiments, each R16is independently heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each R16is independently monocyclic heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each R16is independently 3-, 4-, 5-, 6-, or 7-membered heterocyclyl, each optionally substituted with one or more substituents Q. In certain embodiments, each R16is independently 3-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each R16is independently 4-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each R16is independently 5-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each R16is independently 6-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each R16is independently piperidinyl or piperazinyl, each optionally substituted with one or more substituents Q. In certain embodiments, each R16is independently 7-membered heterocyclyl, optionally substituted with one or more substituents Q.

[0188] In certain embodiments, each R16is independently bicyclic heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each R16is independently bridged, fused, or spiro heterocyclyl, each optionally substituted with one or more substituents Q.In certain embodiments, each R16is independently bridged heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each R16is independently 3,8-diaza- bicyclo[3.2.1]octyl, optionally substituted with one or more substituents Q. In certain embodiments, each R16is independently fused heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each R16is independently spiro heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each R16is independently 4,7-diazaspiro[2.5]octyl or 2,7-diazaspiro[3.5]nonyl, each optionally substituted with one or more substituents Q.

[0189] In certain embodiments, each R12is cyano.

[0190] In certain embodiments, each R15is independently hydrogen, deuterium, or halo.In certain embodiments, each R15is hydrogen. In certain embodiments, each R15is independently halo. In certain embodiments, each R15is fluoro. In certain embodiments, each R15is independently hydrogen or fluoro.

[0191] In certain embodiments, each R6ais independently hydrogen or deuterium. In certain embodiments, each R6ais hydrogen.

[0192] In certain embodiments, each R6bis independently hydrogen or deuterium. In certain embodiments, each R6bis hydrogen.

[0193] In certain embodiments, each p is an integer of 0.

[0194] In certain embodiments, each q is an integer of 0.

[0195] In one embodiment, provided herein is a compound of Formula (XLIII):or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein: each E5is independently a bond oreach E6and Z is independently C3-10cycloalkylene, C6-14arylene, heteroarylene, or heterocyclylene; each E7is independently (i) C3-10cycloalkylene, C6-14arylene, heteroarylene, or heterocyclylene; or (ii) -NRlb-; each R21is independently (i) hydrogen, deuterium, or cyano; or (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; each R22and R27is independently (i) deuterium, cyano, halo, or nitro; (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)Rla, -C(O)ORla, -C(O)NRlbRlc, -C(O)SRla, -C(NRla)NRlbRlc, -C(S)Rla, -C(S)ORla, -C(S)NRlbRlc, -ORla, -OC(O)Rla, -OC(O)ORla, -OC(O)NRlbRlc, -OC(O)SRla, -OC(NRla)NRlbRlc, -OC(S)Rla, -OC(S)ORla, -OC(S)NRlbRlc, -OS(O)Rla, -OS(O)2Rla, -OS(O)NRlbRlc, -OS(O)2NRlbRlc, -NRlbRlc, -NRlaC(O)Rld, -NRlaC(O)ORld, -NRlaC(O)NRlbRlc, -NRlaC(O)SRld, -NRlaC(NRld)NRlbRlc, -NRlaC(S)Rld, -NRlaC(S)ORld, -NRlaC(S)NRlbRlc, -NRlaS(O)Rld, -NRlaS(O)2Rld, -NRlaS(O)NRlbRle, -NRlaS(O)2NRlbRlc, -SRla, -S(O)Rla, -S(O)2Rla, -S(O)NRlbRlc, or -S(O)2NRlbRlc; each R23is independently (i) hydrogen; (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)Rla, -C(O)ORla, -C(O)NRlbRlc, -C(O)SRla, -C(NRla)NRlbRlc, -C(S)Rla, -C(S)ORla, -C(S)NRlbRlc, -S(O)Rla, -S(O)2Rla, -S(O)NRlbRle, or -S(O)2NRlbRlc; each R24, R25and R26is independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)Rla, -C(O)ORla, -C(O)NRlbRlc, -C(O)SRla, -C(NRla)NRlbRlc, -C(S)Rla, -C(S)ORla, -C(S)NRlbRlc, -ORla, -OC(O)Rla, -OC(O)ORla, OC(O)NRlbRlc, OC(O)SRla, OC(NRla)NRlbRlc, OC(S)Rla, OC(S)ORla, OC(S)NRlbRlc, -OS(O)Rla, -OS(O)2Rla, -OS(O)NRlbRlc, -OS(O)2NRlbRlc, -NRlbRlc, -NRlaC(O)Rld,-NRlaC(O)ORld, -NRlaC(O)NRlbRlc, -NRlaC(O)SRld, -NRlaC(NRld)NRlbRlc, -NRlaC(S)Rld, -NRlaC(S)ORld, -NRlaC(S)NRlbRlc, -NRlaS(O)Rld, -NRlaS(O)2Rld, -NRlaS(O)NRlbRlc, -NRlaS(O)2NRlbRlc, -SRla, -S(O)Rla, -S(O)2Rla, -S(O)NRlbRlc, or -S(O)2NRlbRlc; or R25and R26together with the carbon atoms to which they are attached form C3-10cycloalkylene or heterocyclylene; each s is independently an integer of 0, 1, 2, or 3; each t is independently an integer of 0, 1, 2, 3, 4, 5, or 6; and each Rla, Rlb, Rlc, Rld, RA, L, X, and m is as defined herein; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q.

[0196] In certain embodiments, each E5is a bond.

[0197] In another embodiment, provided herein is a compound of Formula (XLIV):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; wherein each R21, R22, R23, R24, R25, R26, R27, RA, E6, E7, L, X, Z, m, s, and t is as defined herein.

[0198] In yet another embodiment, provided herein is a compound of Formula (XLV):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; wherein each R21, R22, R23, R24, R25, R26, R27, RA, E5, E6, L, X, Z, m, s, and t is as defined herein.

[0199] In certain embodiments, each E6is independently C3-10cycloalkylene or heterocyclylene, each optionally substituted with one or more substituents Q. In certain embodiments, each E6is independently heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, each E6is independently monocyclic heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, each E6is independently 3-, 4-, 5-, 6-, or 7-membered heterocyclylene, each optionally substituted with one or more substituents Q. In certain embodiments, each E6is independently 3-membered heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, each E6is independently aziridindiyl, optionally substituted with one or more substituents Q. In certain embodiments, each E6is 3-cyclopropylaziridin-l,2-diyl. In certain embodiments, each E6is independently 4-membered heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, each E6is independently 5-membered heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, each E6is independently 6-membered heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, each E6is independently piperidindiyl, optionally substituted with one or more substituents Q. In certain embodiments, each E6is independently piperidin-l,4-diyl, optionally substituted with one or more substituents Q. In certain embodiments, each E6is independently 7-membered heterocyclylene, optionally substituted with one or more substituents Q

[0200] In certain embodiments, each E6is independently bicyclic heterocyclylene,optionally substituted with one or more substituents Q. In certain embodiments, each E6is independently bridged, fused, or spiro heterocyclylene, each optionally substituted with one or more substituents Q. In certain embodiments, each E6is independently bridged heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, each E6is independently fused heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, each E6is independently spiro heterocyclylene, optionally substituted with one or more substituents Q.

[0201] In certain embodiments, each E7is independently (i) C3-10cycloalkylene or heterocyclylene, each optionally substituted with one or more substituents Q; or (ii) -NRlb, wherein Rlbis as defined herein. In certain embodiments, each E7is independently C3-10cycloalkylene or heterocyclylene, each optionally substituted with one or more substituents Q. In certain embodiments, each E7is independently heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, each E7is independently monocyclic heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, each E7is independently 3-, 4-, 5-, 6-, or 7-membered heterocyclylene, each optionally substituted with one or more substituents Q. In certain embodiments, each E7is independently 3- membered heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, each E7is independently 4-membered heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, each E7is independently 5-membered heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, each E7is independently 6-membered heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, each E7is independently 7-membered heterocyclylene, optionally substituted with one or more substituents Q.

[0202] In certain embodiments, each E7is independently bicyclic heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, each E7is independently bridged, fused, or spiro heterocyclylene, each optionally substituted with one or more substituents Q. In certain embodiments, each E7is independently bridged heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, each E7is independently fused heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, each E7is independently spiro heterocyclylene, optionally substituted withone or more substituents Q. In certain embodiments, each E7is independently 2,7-diazaspiro-[4.4]nonandiyl, optionally substituted with one or more substituents Q. In certain embodiments, each E7is independently 2,7-diazaspiro[4.4]nonan-2,7-diyl, optionally substituted with one or more substituents Q. In certain embodiments, each E7is independently l-oxo-2,7-diazaspiro-[4.4]nonan-2,7-diyl.

[0203] In certain embodiments, each E7is independently -NRlb-, wherein Rlbis as defined herein. In certain embodiments, each E7is independently -NRlb-, wherein Rlbis C1-6alkyl, optionally substituted with one or more substituents Q. In certain embodiments, each E7is independently N(CH3) .

[0204] In certain embodiments, each R21is independently (i) hydrogen; or (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q. In certain embodiments, each R21is independently C1-6alkyl, C3-10cycloalkyl, or heterocyclyl, each optionally substituted with one or more substituents Q. In certain embodiments, each R21is independently C1-6alkyl, optionally substituted with one or more substituents Q. In certain embodiments, each R21is independently propyl, optionally substituted with one or more substituents Q. In certain embodiments, each R21is isopropyl, optionally substituted with one or more substituents Q. In certain embodiments, each R21is independently C3-10cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, each R21is independently monocyclic C3-10cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, each R21is independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, each optionally substituted with one or more substituents Q. In certain embodiments, each R21is independently cyclopentyl, optionally substituted with one or more substituents Q. In certain embodiments, each R21is independently bicyclic C3-10cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, each R21is independently bridged, fused, or spiro C3-10cycloalkyl, each optionally substituted with one or more substituents Q. In certain embodiments, each R21is independently bridged C3-10cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, each R21is independently fused C3-10cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, each R21is independently spiro C3-10cycloalkyl, optionally substituted withone or more substituents Q.

[0205] In certain embodiments, each R21is independently heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each R21is independently monocyclic heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each R21is independently 3-, 4-, 5-, 6-, or 7-membered heterocyclyl, each optionally substituted with one or more substituents Q. In certain embodiments, each R21is independently 3-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each R21is independently 4-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each R21is independently 5-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each R21is independently 6-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each R21is independently 7-membered heterocyclyl, optionally substituted with one or more substituents Q.

[0206] In certain embodiments, each R21is independently bicyclic heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each R21is independently bridged, fused, or spiro heterocyclyl, each optionally substituted with one or more substituents Q. In certain embodiments, each R21is independently bridged heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each R21is independently fused heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each R21is independently spiro heterocyclyl, optionally substituted with one or more substituents Q

[0207] In certain embodiments, each R24is independently C6-14aryl or heteroaryl, each optionally substituted with one or more substituents Q. In certain embodiments, each R24is independently C6-14aryl, optionally substituted with one or more substituents Q. In certain embodiments, each R24is independently phenyl, optionally substituted with one or more substituents Q. In certain embodiments, each R24is independently bicyclic Cs-i4 aryl, optionally substituted with one or more substituents Q.

[0208] In certain embodiments, each R24is independently heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, each R24is independentlymonocyclic heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, each R24is independently 5- or 6-membered heteroaryl, each optionally substituted with one or more substituents Q. In certain embodiments, each R24is independently 5-membered heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, each R24is independently 6-membered heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, each R24is independently pyridyl, optionally substituted with one or more substituents Q. In certain embodiments, each R24is independently pyrid-3-yl or pyrid-4-yl, each optionally substituted with one or more substituents Q. In certain embodiments, each R24is independently 2-(l-methoxyethyl)pyrid-3-yl or 2-(l-methoxyethyl)-5-(4-methylpiperaz-l-yl)- pyrid-3-yl. In certain embodiments, each R24is independently (S)-2-(l-methoxyethyl)pyrid-3-yl or (5)-2-( 1 -methoxy ethyl)-5-(4-methylpiperaz- 1 -yl)pyrid-3 -yl .

[0209] In certain embodiments, each R24is independently bicyclic heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, each R24is independently 5,5-, 5,6-, or 6,6-fused heteroaryl, each optionally substituted with one or more substituents Q. In certain embodiments, each R24is independently 5,5-fused heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, each R24is independently 5,6-fused heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, each R24is independently 6,6-fused heteroaryl, optionally substituted with one or more substituents Q.

[0210] In one embodiment, provided herein is a compound of Formula (XLVI):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; wherein: each E8is independently C3-10cycloalkylene, C6-14arylene, heteroarylene, or heterocyclylene, each optionally substituted with one or more substituents Q;each E9is independently (i) a bond; or (ii) C3-10cycloalkylene, C6-14arylene, heteroarylene, or heterocyclylene, each optionally substituted with one or more substituents Q; each R28is independently (i) hydrogen or deuterium; or (ii) C1-6alkyl, C1-6heteroalkyl, C2- 6 alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; and each R22, R23, R25, R26, R27, RA, L, X, Z, m, s, and t is as defined herein.

[0211] In another embodiment, provided herein is a compound of Formula (XL VII):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; wherein each R22, R23, R25, R26, R27, R28, RA, E8, E9, L, X, Z, m, s, and t is as defined herein.

[0212] In certain embodiments, each E8is independently C6-14arylene or heteroarylene, each optionally substituted with one or more substituents Q. In certain embodiments, each E8is independently C6-14arylene, optionally substituted with one or more substituents Q. In certain embodiments, each E8is independently phenyl, optionally substituted with one or more substituents Q. In certain embodiments, each E8is independently bicyclic C8-14arylene, optionally substituted with one or more substituents Q.

[0213] In certain embodiments, each E8is independently heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, each E8is independently monocyclic heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, each E8is independently 5- or 6-membered heteroarylene, each optionally substituted with one or more substituents Q. In certain embodiments, each E8is independently 5- membered heteroarylene, optionally substituted with one or more substituents Q. In certainembodiments, each E8is independently 6-membered heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, each E8is independently pyridindiyl, optionally substituted with one or more substituents Q. In certain embodiments, each E8is independently pyridin-l,3-diyl or pyridin-l,4-diyl, each optionally substituted with one or more substituents Q. In certain embodiments, each E8is independently pyri din- 1,3 -diyl, optionally substituted with one or more substituents Q. In certain embodiments, each E8is independently 2- ( 1 -m ethoxy ethyl)pyri din- 1 ,3 -diyl or 2-(l -methoxy ethyl)-5-(4-methylpiperaz- 1 -yl)pyridin- 1,3- diyl. In certain embodiments, each E8is independently (S)-2-(l-methoxyethyl)pyridin-l,3-diyl or (S)-2-(l-methoxyethyl)-5-(4-methylpiperaz-l-yl)pyridin-l,3-diyl.

[0214] In certain embodiments, each E8is independently bicyclic heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, each E8is independently 5,5-, 5,6-, or 6,6-fused heteroarylene, each optionally substituted with one or more substituents Q. In certain embodiments, each E8is independently 5,5-fused heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, each E8is independently 5,6-fused heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, each E8is independently 6,6-fused heteroarylene, optionally substituted with one or more substituents Q.

[0215] In certain embodiments, each E9is independently a bond, C3-10cycloalkylene, or heterocyclylene, each optionally substituted with one or more substituents Q. In certain embodiments, each E9is independently a bond. In certain embodiments, each E9is independently C3-10cycloalkylene, optionally substituted with one or more substituents Q. In certain embodiments, each E9is independently monocyclic C3-10cycloalkylene, optionally substituted with one or more substituents Q. In certain embodiments, each E9is independently bicyclic C4-10cycloalkylene, optionally substituted with one or more substituents Q.

[0216] In certain embodiments, each E9is independently heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, each E9is independently monocyclic heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, each E9is independently 3-, 4-, 5-, 6-, or 7-membered heterocyclylene, each optionally substituted with one or more substituents Q. In certain embodiments, each E9isindependently 3-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each E9is independently 4-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each E9is independently 5- membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each E9is independently 6-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each E9is independently piperazindiyl, optionally substituted with one or more substituents Q. In certain embodiments, each E9is independently piperazin- 1,4-diyl, optionally substituted with one or more substituents Q. In certain embodiments, each E9is independently 7-membered heterocyclyl, optionally substituted with one or more substituents Q.

[0217] In certain embodiments, each E9is independently bicyclic heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each E9is independently bridged, fused, or spiro heterocyclyl, each optionally substituted with one or more substituents Q. In certain embodiments, each E9is independently bridged heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each E9is independently fused heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each E9is independently spiro heterocyclyl, optionally substituted with one or more substituents Q

[0218] In one embodiment, provided herein is a compound of Formula (XL VIII):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; wherein each R22, R23, R24, R25, R26, R27, R28, RA, L, X, Z, m, s, and t is as defined herein.

[0219] In another embodiment, provided herein is a compound of Formula (XLIX):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; wherein each R22, R23, R24, R23, R26, R27, R28, RA, L, X, Z, m, s, and t is as defined herein.

[0220] In certain embodiments, each R28is independently C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q. In certain embodiments, each R28is independently C3-10cycloalkyl or heterocyclyl, each optionally substituted with one or more substituents Q. In certain embodiments, each R28is independently C3-10cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, each R28is independently monocyclic C3-10cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, each R28is independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, each optionally substituted with one or more substituents Q. In certain embodiments, each R28is independently cyclopropyl, optionally substituted with one or more substituents Q. In certain embodiments, each R28is 2-methylcyclopropyl. In certain embodiments, each R28is independently bicyclic C4-10cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, each R28is independently bridged, fused, or spiro C4-10cycloalkyl, each optionally substituted with one or more substituents Q. In certain embodiments, each R28is independently bridged C5-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, each R28is independently fused C4-10cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, each R28is independently spiro C5-10 cycloalkyl, optionally substituted with one or more substituents Q.

[0221] In certain embodiments, each R28is independently heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each R28is independentlymonocyclic heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each R28is independently 3-, 4-, 5-, 6-, or 7-membered heterocyclyl, each optionally substituted with one or more substituents Q. In certain embodiments, each R28is independently 3-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each R28is independently 4-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each R28is independently 5-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each R28is independently 6-membered heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each R28is independently 7-membered heterocyclyl, optionally substituted with one or more substituents Q.

[0222] In certain embodiments, each R28is independently bicyclic heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each R28is independently bridged, fused, or spiro heterocyclyl, each optionally substituted with one or more substituents Q. In certain embodiments, each R28is independently bridged heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each R28is independently fused heterocyclyl, optionally substituted with one or more substituents Q. In certain embodiments, each R28is independently spiro heterocyclyl, optionally substituted with one or more substituents Q

[0223] In certain embodiments, each Z is independently C6-14arylene, heteroarylene, or heterocyclylene, each optionally substituted with one or more substituents Q. In certain embodiments, each Z is independently C6-14arylene, optionally substituted with one or more substituents Q. In certain embodiments, each Z is independently phendiyl, optionally substituted with one or more substituents Q. In certain embodiments, each Z is independently phen-l,3-diyl, optionally substituted with one or more substituents Q. In certain embodiments, each Z is 3- hydroxyphen- 1,3 -diyl. In certain embodiments, each Z is independently bicyclic C8-14arylene, optionally substituted with one or more substituents Q.

[0224] In certain embodiments, each Z is independently heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, each Z is independently monocyclic heteroarylene, optionally substituted with one or more substituents Q. In certainembodiments, each Z is independently 5- or 6-membered heteroarylene, each optionally substituted with one or more substituents Q. In certain embodiments, each Z is independently 5- membered heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, each Z is independently thiazoldiyl, optionally substituted with one or more substituents Q. In certain embodiments, each Z is independently thiazol-2,4-diyl, optionally substituted with one or more substituents Q. In certain embodiments, each Z is independently 6- membered heteroarylene, optionally substituted with one or more substituents Q.

[0225] In certain embodiments, each Z is independently bicyclic heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, each Z is independently5.5-, 5,6-, or 6,6-fused heteroarylene, each optionally substituted with one or more substituents Q. In certain embodiments, each Z is independently 5,5-fused heteroarylene, each optionally substituted with one or more substituents Q. In certain embodiments, each Z is independently5.6-fused heteroarylene, each optionally substituted with one or more substituents Q. In certain embodiments, each Z is independently 6,6-fused heteroarylene, each optionally substituted with one or more substituents Q.

[0226] In certain embodiments, each Z is independently heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, each Z is independently monocyclic heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, each Z is independently 3-, 4-, 5-, 6-, or 7-membered heterocyclylene, each optionally substituted with one or more substituents Q. In certain embodiments, each Z is independently 3-membered heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, each Z is independently 4-membered heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, each Z is independently 5- membered heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, each Z is independently 6-membered heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, each Z is independently morpholindiyl, optionally substituted with one or more substituents Q. In certain embodiments, each Z is morpholin-2,4-diyl, optionally substituted with one or more substituents Q. In certain embodiments, each Z is independently 7-membered heterocyclylene, optionally substituted with one or more substituents Q.

[0227] In certain embodiments, each Z is independently bicyclic heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, each Z is independently bridged, fused, or spiro heterocyclylene, each optionally substituted with one or more substituents Q. In certain embodiments, each Z is independently bridged heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, each Z is independently fused heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, each Z is independently spiro heterocyclylene, optionally substituted with one or more substituents Q.

[0228] In certain embodiments, each R23is independently (i) hydrogen; or (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q. In certain embodiments, each R23is independently C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3- 10 cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q. In certain embodiments, each R23is independently C1-6alkyl or C1-6heteroalkyl, each optionally substituted with one or more substituents Q. In certain embodiments, each R23is independently C1-6alkyl, optionally substituted with one or more substituents Q. In certain embodiments, each R23is independently ethyl, optionally substituted with one or more substituents Q. In certain embodiments, each R23is independently C1-6heteroalkyl, optionally substituted with one or more substituents Q.

[0229] In certain embodiments, each R23is independently (i) hydrogen, deuterium, cyano, halo, or nitro; or (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q. In certain embodiments, each R25is independently (i) hydrogen or deuterium; or (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q. In certain embodiments, each R25is independently C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q. In certain embodiments, each R25is independently C1-6alkyl or C1-6heteroalkyl, each optionally substituted with one or more substituents Q. In certain embodiments, each R25is independently C1-6alkyl, optionally substituted with one ormore substituents Q. In certain embodiments, each R25is methyl. In certain embodiments, each R25is independently C1-6heteroalkyl, optionally substituted with one or more substituents Q.

[0230] In certain embodiments, each R26is independently (i) hydrogen, deuterium, cyano, halo, or nitro; or (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q. In certain embodiments, each R26is independently (i) hydrogen or deuterium; or (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q. In certain embodiments, each R26is independently C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q. In certain embodiments, each R26is independently C1-6alkyl or C1-6heteroalkyl, each optionally substituted with one or more substituents Q. In certain embodiments, each R26is independently C1-6alkyl, optionally substituted with one or more substituents Q. In certain embodiments, each R26is methyl. In certain embodiments, each R26is independently C1-6heteroalkyl, optionally substituted with one or more substituents Q.

[0231] In certain embodiments, R23and R26together with the carbon atoms to which they are attached form C3-10cycloalkylene or heterocyclyl ene, each optionally substituted with one or more substituents Q. In certain embodiments, R23and R26together with the carbon atoms to which they are attached form C3-10cycloalkylene, optionally substituted with one or more substituents Q. In certain embodiments, R25and R26together with the carbon atoms to which they are attached form monocyclic C3-10cycloalkylene, optionally substituted with one or more substituents Q. In certain embodiments, R25and R26together with the carbon atoms to which they are attached form bicyclic C4-10cycloalkylene, optionally substituted with one or more substituents Q. In certain embodiments, R25and R26together with the carbon atoms to which they are attached form bridged, fused, or spiro C4-10cycloalkylene, each optionally substituted with one or more substituents Q. In certain embodiments, R23and R26together with the carbon atoms to which they are attached form bridged C5-10 cycloalkylene, optionally substituted with one or more substituents Q. In certain embodiments, R23and R26together with the carbon atoms to which they are attached form fused C4-10cycloalkylene, optionally substituted with one or more substituents Q. In certain embodiments, R25and R26together with the carbon atoms to which theyare attached form spiro C5-10 cycloalkylene, optionally substituted with one or more substituents Q

[0232] In certain embodiments, R23and R26together with the carbon atoms to which they are attached form heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, R25and R26together with the carbon atoms to which they are attached form monocyclic heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, R25and R26together with the carbon atoms to which they are attached form 3-, 4-, 5-, 6-, or 7-membered heterocyclylene, each optionally substituted with one or more substituents Q. In certain embodiments, R25and R26together with the carbon atoms to which they are attached form 3-membered heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, R25and R26together with the carbon atoms to which they are attached form 4-membered heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, R23and R26together with the carbon atoms to which they are attached form 5-membered heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, R25and R26together with the carbon atoms to which they are attached form 6-membered heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, R25and R26together with the carbon atoms to which they are attached form 7-membered heterocyclylene, optionally substituted with one or more substituents Q

[0233] In certain embodiments, R25and R26together with the carbon atoms to which they are attached form bicyclic heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, R25and R26together with the carbon atoms to which they are attached form bridged, fused, or spiro heterocyclylene, each optionally substituted with one or more substituents Q. In certain embodiments, R25and R26together with the carbon atoms to which they are attached form bridged heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, R23and R26together with the carbon atoms to which they are attached form fused heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, R23and R26together with the carbon atoms to which they are attached form spiro heterocyclylene, optionally substituted with one or more substituents Q.

[0234] In certain embodiments, each s is an integer of 0.

[0235] In certain embodiments, each t is an integer of 0.

[0236] In certain embodiments, each RDis independently:or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.

[0237] In certain embodiments, each RDis:or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.

[0238] In certain embodiments, each RDis:or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.

[0239] In certain embodiments, each RDis independently:or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.

[0240] In certain embodiments, each RDis independently:or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.

[0241] In certain embodiments, each RDis independently:or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.

[0242] In certain embodiments, each RDis independently:or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.

[0243] In certain embodiments, each RDis independently:- Hl -or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.

[0244] In certain embodiments, each RDis independently:or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.

[0245] In certain embodiments, each RDis independently:or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.

[0246] In certain embodiments, each RDis independently:or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.

[0247] In certain embodiments, each RDis independently:or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.

[0248] In certain embodiments, each RDis independently:or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.

[0249] In certain embodiments, each RDis independently:or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.

[0250] In certain embodiments, each RDis independently:or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.

[0251] In certain embodiments, each RDis independently:or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.

[0252] In certain embodiments, each RDis independently:or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.

[0253] In certain embodiments, each RDis:or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.

[0254] In certain embodiments, each RDis:or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.

[0255] In certain embodiments, each RDis independently:or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.

[0256] In certain embodiments, each RDis independently a moiety of a KRAS binder disclosed in US 2024 / 0368191 Al, WO 2021 / 041671 Al, WO 2021 / 118877 Al, WO2022 / 173870 Al, WO 2022 / 184178 Al, WO 2022 / 212894 Al, WO 2022 / 216762 Al , WO 2022 / 235870 Al, WO 2022 / 247757 Al, WO 2022 / 268051 Al, WO 2023 / 004102 A2, WO 2023 / 099624 Al, WO 2023 / 103906 Al, WO 2023 / 150284 A2, WO 2023 / 172737 Al, WO 2023 / 183585 Al, WO 2023 / 205719 Al, WO 2023 / 215801 Al, WO 2023 / 225302 Al, WO 2024 / 083168 A2, WO 2024 / 138052 Al, WO 2024 / 158778 Al, WO 2024 / 173842 Al, WO 2024 / 254334 Al, and WO 2025 / 007000 Al; the disclosure of each of which is incorporated herein by reference in its entirety.

[0257] In one embodiment, each L is a non-cleavable linker. In another embodiment, each is a cleavable linker. In yet another embodiment, each L is a self-immolative linker.

[0258] In certain embodiments, each L is a cleavable linker that is sensitive to an acidic pH. In certain embodiments, each L is a cleavable linker comprising a reducible disulfide. In certain embodiments, each L is a linker cleavable by glutathione. In certain embodiments, each L is a linker cleavable by an enzyme. In certain embodiments, each L is a linker cleavable by a protease. In certain embodiments, each L is a linker cleavable by a lysosomal protease. In certain embodiments, each L is a linker cleavable by cathepsin B. In certain embodiments, each L is a linker cleavable by a glycosidase. In certain embodiments, each L is a linker cleavable by a 0- glycosidase. In certain embodiments, each L is a linker cleavable by a galactosidase. In certain embodiments, each L is a linker cleavable by a 0-galactosidase. In certain embodiments, each L is a linker cleavable by a glucuronidase. In certain embodiments, each L is a linker cleavable by a 0-glucuronidase. In certain embodiments, each L is a linker cleavable by a phosphatase.Exemplary linkers suitable for a compound provided herein include, but are not limited to, those disclosed in US 8,568,728 B2; US 11,103,593 B2; Beck et al., Nat. Rev. Drug Discov. 2017, 76, 317-37; Bargh et al., Chem. Soc. Rev. 2019, 48, 4361-74; the disclosure of each of which is incorporated herein by reference in its entirety.

[0259] In certain embodiments, each L is independently Ci-ioo alkylene, Ci-ioo heteroalkylene, C2-100 alkenylene, C2-100 heteroalkenylene, C2-100 alkynylene, C2-100 heteroalkynylene, C3-10cycloalkylene, C6-14 arylene, heteroarylene, or heterocyclylene, each optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C1-100alkylene, C1-100heteroalkylene, C2-100 alkenylene, C2-100 heteroalkenylene,C2-100 alkynylene, or C2-100 heteroal kynylene, each optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C1-100alkylene or C1-100heteroalkylene, which is optionally substituted with one or more substituents Q.

[0260] In certain embodiments, each L is independently C1-100alkylene, optionally substituted with one or substituents Q. In certain embodiments, each L is independently C1-75alkylene, optionally substituted with one or substituents Q. In certain embodiments, each L is independently C1-50alkylene, optionally substituted with one or substituents Q. In certain embodiments, each L is independently C1-40alkylene, optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C1-30alkylene, optionally substituted with one or more substituents Q. In certain embodiments, each L is independently Ci- 20 alkylene, optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C2-16alkylene, optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C2-12alkylene, optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C2-6alkylene, optionally substituted with one or more substituents Q. In certain embodiments, each L is independently Ci- 20 alkylene, optionally substituted with one or two oxo. In certain embodiments, each L is independently C2-16alkylene, optionally substituted with one or two oxo. In certain embodiments, each L is independently C2-12alkylene, optionally substituted with one or two oxo. In certain embodiments, each L is independently C2-6alkylene, optionally substituted with one or two oxo.

[0261] In certain embodiments, each L is independently C1-100heteroalkylene, optionally substituted with one or more substituents Q. In certain embodiments, each L is independently Ci- 75 heteroalkylene, optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C1-50heteroalkylene, optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C1-40heteroalkylene, optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C1-30heteroalkylene, optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C1-20heteroalkylene, optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C2-16heteroalkylene, optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C2-12heteroalkylene, optionally substituted with one or more substituentsQ. In certain embodiments, each L is independently C2-6heteroalkylene, optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C1-20heteroalkylene, optionally substituted with one, two, or three oxo. In certain embodiments, each L is independently C2-16heteroalkylene, optionally substituted with one, two, or three oxo. In certain embodiments, each L is independently C2-12heteroalkylene, optionally substituted with one, two, or three oxo. In certain embodiments, each L is independently C2-6heteroalkylene, optionally substituted with one, two, or three oxo.

[0262] In certain embodiments, each L is independently C2-100 heteroalkylene comprising an ethyleneoxy (-CH2CH2O-) group, optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C2-75heteroalkylene comprising an ethyleneoxy group, optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C2-50heteroalkylene comprising an ethyleneoxy group, optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C2-40heteroalkylene comprising an ethyleneoxy group, optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C2-30heteroalkylene comprising an ethyleneoxy group, optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C2-20heteroalkylene comprising an ethyleneoxy group, optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C2-14heteroalkylene comprising an ethyleneoxy group, optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C2-10heteroalkylene comprising an ethyleneoxy group, optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C2-6heteroalkylene comprising an ethyleneoxy group, optionally substituted with one or more substituents Q.

[0263] In certain embodiments, each L is independently C3-100heteroalkylene comprising a propyleneoxy (-CH2CH2CH2O-) group, optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C3-75heteroalkylene comprising a propyleneoxy group, optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C3-50heteroalkylene comprising a propyleneoxy group, optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C3-40heteroalkylene comprising a propyleneoxy group, optionally substituted with one or more substituents Q. Incertain embodiments, each L is independently C3-30heteroalkylene comprising a propyleneoxy group, optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C3-20heteroalkylene comprising a propyleneoxy group, optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C3-14heteroalkylene comprising a propyleneoxy group, optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C3-10heteroalkylene comprising a propyleneoxy group, optionally substituted with one or more substituents Q.

[0264] In certain embodiments, each L is independently C1-100alkylene, C1-100heteroalkylene, C2-100 alkenylene, C2-100 heteroalkenylene, C2-100 alkynylene, or C2-100 heteroalkynylene, wherein one or more methylene groups are each independently replaced by a divalent group; wherein each divalent group is independently C3-10cycloalkylene, C6-14arylene, heteroarylene, or heterocyclylene; 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, each L is independently C1-100alkylene or C1-100heteroalkylene, wherein one or more methylene groups are each independently replaced by a divalent group; wherein each divalent group is independently C3-10cycloalkylene, C6-14arylene, heteroarylene, or heterocyclylene; and wherein the alkylene, heteroalkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q.

[0265] In certain embodiments, each L is independently C1-100alkylene, wherein one or more methylene groups are each independently replaced by a divalent group; wherein each divalent group is independently C3-10cycloalkylene, C6-14arylene, heteroarylene, or heterocyclylene; and wherein the alkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C1-75alkylene, wherein one or more methylene groups are each independently replaced by a divalent group; wherein each divalent group is independently C3-10cycloalkylene, C6-14arylene, heteroarylene, or heterocyclylene; and wherein the alkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C1-50alkylene, wherein one or more methylene groups are each independently replaced by a divalent group;wherein each divalent group is independently C3-10cycloalkylene, C6-14arylene, heteroarylene, or heterocyclylene; and wherein the alkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C1-40alkylene, wherein one or more methylene groups are each independently replaced by a divalent group; wherein each divalent group is independently C3-10cycloalkylene, C6-14arylene, heteroarylene, or heterocyclylene; and wherein the alkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C1-30alkylene, wherein one or more methylene groups are each independently replaced by a divalent group; wherein each divalent group is independently C3-10cycloalkylene, C6-14arylene, heteroarylene, or heterocyclylene; and wherein the alkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C1-20alkylene, wherein one or more methylene groups are each independently replaced by a divalent group; wherein each divalent group is independently C3-10cycloalkylene, C6-14arylene, heteroarylene, or heterocyclylene; and wherein the alkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q.

[0266] In certain embodiments, each L is independently C1-100alkylene, wherein one, two, three, or four methylene groups are each independently replaced by a divalent group; wherein each divalent group is independently C3-10cycloalkylene, C6-14arylene, heteroarylene, or heterocyclylene; and wherein the alkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C1-75 alkylene, wherein one, two, three, or four methylene groups are each independently replaced by a divalent group; wherein each divalent group is independently C3-10cycloalkylene, C6-14arylene, heteroarylene, or heterocyclylene; and wherein the alkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q. In certain embodiments, each L is independently Ci- 50 alkylene, wherein one, two, three, or four methylene groups are each independently replaced by a divalent group; wherein each divalent group is independently C3-10cycloalkylene, C6-14arylene, heteroarylene, or heterocyclylene; and wherein the alkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituentsQ. In certain embodiments, each L is independently Ci-40 alkylene, wherein one, two, three, or four methylene groups are each independently replaced by a divalent group; wherein each divalent group is independently C3-10cycloalkylene, C6-14arylene, heteroarylene, or heterocyclylene; and wherein the alkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C1-30alkylene, wherein one, two, three, or four methylene groups are each independently replaced by a divalent group; wherein each divalent group is independently C3-10cycloalkylene, C6-14 arylene, heteroarylene, or heterocyclylene; and wherein the alkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q. In certain embodiments, each L is independently Ci- 20 alkylene, wherein one, two, three, or four methylene groups are each independently replaced by a divalent group; wherein each divalent group is independently C3-10cycloalkylene, C6-14arylene, heteroarylene, or heterocyclylene; and wherein the alkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C1-20alkylene, wherein one, two, three, or four methylene groups are each independently replaced by a divalent group; wherein each divalent group is independently cyclohexanediyl, phendiyl, triazoldiyl, or 2,5-dioxopyrrolidindiyl; and wherein the heteroalkylene is optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C1-20alkylene, wherein one, two, three, or four methylene groups are each independently replaced by a divalent group; wherein each divalent group is independently cyclohexane-l,4-diyl, phen-l,3-diyl, phen-l,4-diyl, l,2,3-triazol-l,4-diyl, or 2,5-dioxopyrrolidin-l,3-diyl; and wherein the heteroalkylene is optionally substituted with one or more substituents Q.

[0267] In certain embodiments, each L is independently C1-20alkylene, wherein one or two methylene groups are each independently replaced by a divalent group; wherein each divalent group is independently C3-10cycloalkylene, C6-14arylene, heteroarylene, or heterocyclylene; and wherein the alkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C1-20alkylene, wherein one or two methylene groups are each independently replaced by a divalent group; wherein each divalent group is independently cyclohexanediyl, phendiyl, triazoldiyl, or 2,5-dioxopyrrolidindiyl; and wherein the heteroalkylene is optionallysubstituted with one or more substituents Q. In certain embodiments, each L is independently Ci- 20 alkylene, wherein one or two methylene groups are each independently replaced by a divalent group; wherein each divalent group is independently cyclohexane- 1,4-diyl, phen-l,3-diyl, phen- 1 ,4-diyl, l,2,3-triazol-l,4-diyl, or 2,5-dioxopyrrolidin-l,3-diyl; and wherein the heteroalkylene is optionally substituted with one or more substituents Q.

[0268] In certain embodiments, each L is independently C1-20alkylene, wherein a methylene group is replaced by a divalent group; wherein the divalent group is C3-10cycloalkylene, C6-14arylene, heteroarylene, or heterocyclylene; and wherein the alkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C1-20alkylene, wherein a methylene group is replaced by a divalent group; wherein the divalent group is cyclohexanediyl, phendiyl, triazoldiyl, or 2,5-dioxopyrrolidindiyl; and wherein the heteroalkylene is optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C1-20alkylene, wherein a methylene group is replaced by a divalent group; wherein each divalent group is independently cyclohexane- 1,4-diyl, phen- 1,3 -diyl, phen- 1,4-diyl, 1,2,3- triazol- 1,4-diyl, or 2,5-dioxopyrrolidin-l,3-diyl; and wherein the heteroalkylene is optionally substituted with one or more substituents Q.

[0269] In certain embodiments, each L is independently C1-100heteroalkylene, wherein one or more methylene groups are each independently replaced by a divalent group; wherein each divalent group is independently C3-10cycloalkylene, C6-14arylene, heteroarylene, or heterocyclylene; and wherein the heteroalkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C1-75 heteroalkylene, wherein one or more methylene groups are each independently replaced by a divalent group; wherein each divalent group is independently C3-10cycloalkylene, C6-14arylene, heteroarylene, or heterocyclylene; and wherein the heteroalkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q. In certain embodiments, each L is independently Ci- 50 heteroalkylene, wherein one or more methylene groups are each independently replaced by a divalent group; wherein each divalent group is independently C3-10cycloalkylene, C6-14arylene, heteroarylene, or heterocyclylene; and wherein the heteroalkylene, cycloalkylene, arylene,heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C1-40heteroalkylene, wherein one or more methylene groups are each independently replaced by a divalent group; wherein each divalent group is independently C3-10cycloalkylene, C6-14arylene, heteroarylene, or heterocyclylene; and wherein the heteroalkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C1-30heteroalkylene, wherein one or more methylene groups are each independently replaced by a divalent group; wherein each divalent group is independently C3-10cycloalkylene, C6-14arylene, heteroarylene, or heterocyclylene; and wherein the heteroalkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C1-20heteroalkylene, wherein one or more methylene groups are each independently replaced by a divalent group; wherein each divalent group is independently C3-10cycloalkylene, C6-14arylene, heteroarylene, or heterocyclylene; and wherein the heteroalkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q

[0270] In certain embodiments, each L is independently C1-100heteroalkylene, wherein one, two, three, or four methylene groups are each independently replaced by a divalent group; wherein each divalent group is independently C3-10cycloalkylene, C6-14arylene, heteroarylene, or heterocyclylene; and wherein the heteroalkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C1-75 heteroalkylene, wherein one, two, three, or four methylene groups are each independently replaced by a divalent group; wherein each divalent group is independently C3-10cycloalkylene, C6-14arylene, heteroarylene, or heterocyclylene; and wherein the heteroalkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C1-50heteroalkylene, wherein one, two, three, or four methylene groups are each independently replaced by a divalent group; wherein each divalent group is independently C3-10cycloalkylene, C6-14arylene, heteroarylene, or heterocyclylene; and wherein the heteroalkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C1-40heteroalkylene, wherein one, two, three, or four methylene groups are each independently replaced by a divalent group; wherein each divalent group is independently C3-10cycloalkylene, C6-14arylene, heteroarylene, or heterocyclylene; and wherein the heteroalkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C1-30heteroalkylene, wherein one, two, three, or four methylene groups are each independently replaced by a divalent group; wherein each divalent group is independently C3-10cycloalkylene, C6-14arylene, heteroarylene, or heterocyclylene; and wherein the heteroalkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C1-20heteroalkylene, wherein one, two, three, or four methylene groups are each independently replaced by a divalent group; wherein each divalent group is independently C3-10cycloalkylene, C6-14arylene, heteroarylene, or heterocyclylene; and wherein the heteroalkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C1-20heteroalkylene, wherein one, two, three, or four methylene groups are each independently replaced by a divalent group; wherein each divalent group is independently cyclohexanediyl, phendiyl, triazoldiyl, or 2,5-dioxopyrrolidindiyl; and wherein the heteroalkylene is optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C1-20heteroalkylene, wherein one, two, three, or four methylene groups are each independently replaced by a divalent group; wherein each divalent group is independently cyclohexane-l,4-diyl, phen-l,3-diyl, phen-l,4-diyl, l,2,3-triazol-l,4-diyl, or 2,5-dioxopyrrolidin- 1 ,3 -diyl; and wherein the heteroalkylene is optionally substituted with one or more substituents Q.

[0271] In certain embodiments, each L is independently C1-20heteroalkylene, wherein one or two methylene groups are each independently replaced by a divalent group; wherein each divalent group is independently C3-10cycloalkylene, C6-14arylene, heteroarylene, or heterocyclylene; and wherein the heteroalkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C1-20heteroalkylene, wherein one or two methylene groups are each independently replaced by a divalent group; wherein each divalent group is independently cyclohexanediyl, phendiyl, triazoldiyl, or 2,5-dioxopyrrolidindiyl; and wherein the heteroalkylene is optionally substituted with one or more substituents Q. In certain embodiments,each L is independently C1-20heteroalkylene, wherein one or two methylene groups are each independently replaced by a divalent group; wherein each divalent group is independently cyclohexane- 1,4-diyl, phen-l,3-diyl, phen- 1,4-diyl, l,2,3-triazol-l,4-diyl, or 2,5-dioxopyrrolidin- 1 ,3 -diyl; and wherein the heteroalkylene is optionally substituted with one or more substituents Q.

[0272] In certain embodiments, each L is independently C1-20heteroalkylene, wherein a methylene group is replaced by a divalent group; wherein the divalent group is C3-10cycloalkylene, C6-14arylene, heteroarylene, or heterocyclylene; and wherein the heteroalkylene, cycloalkylene, arylene, heteroarylene, and heterocyclylene are each optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C1-20heteroalkylene, wherein a methylene group is replaced by a divalent group; wherein the divalent group is cyclohexanediyl, phendiyl, triazoldiyl, or 2,5-dioxopyrrolidindiyl; and wherein the heteroalkylene is optionally substituted with one or more substituents Q. In certain embodiments, each L is independently C1-20heteroalkylene, wherein a methylene group is replaced by a divalent group; wherein each divalent group is independently cyclohexane- 1,4-diyl, phen-l,3-diyl, phen- 1,4-diyl, l,2,3-triazol-l,4-diyl, or 2,5-dioxopyrrolidin-l,3-diyl; and wherein the heteroalkylene is optionally substituted with one or more substituents Q.

[0273] In certain embodiments, each L independently comprises a moiety of:wherein:A” is a bond or -OC(=O)-;T is a cleavable sugar unit and Y is O; or T is a cleavable polypeptide and Y is NR30; each R29is independently an electron-withdrawing group or Ci-4 alkyl;R30is hydrogen, C1-24alkyl, C2-6alkenyl, C3-8cycloalkyl, C6-10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, wherein the alkyl and alkenyl are each optionally interrupted by one or more groups, each independently selected from -O-, -S-, -C(O)-, -NR”- -C(O)NR”-, -NR”C(O)O-, -NR”C(O)NR”’-, and triazoldiyl;each R” and R’” is independently hydrogen or C1-6alkyl; and u is an integer of 0, 1, or 2.

[0274] In certain embodiments, each R29is independently cyano or nitro. In certain embodiments, each R29is nitro. In certain embodiments, T is a cleavable sugar unit. In certain embodiments, T is a cleavable sugar unit that is a glucuronide or a galactoside. In certain embodiments, T is a cleavable sugar unit having the structure of In certainembodiments, T is a cleavable polypeptide. In certain embodiments, T is a cleavable dipeptide.In certain embodiments, T is Val-Cit, Val-Ala, and Phe-Lys. In certain embodiments, T is. In certain embodiments, u is an integer of 0. In certain embodiments, u is an integer of 1.

[0275] In certain embodiments, each L independently comprises a moiety ofIn certain embodiments, each LIn certain embodiments, each L independently comprises a moiety of or

[0276] In certain embodiments, each L independently comprises a moiety having the structure of:wherein:K is a hydrophobicity masking entity, in one embodiment, a polysarcosine or polyethylene glycol (PEG);X1is a connector unit;R31is selected from the group consisting of hydrogen, C1-24 alkyl, C2-6alkenyl, C3-8cycloalkyl, C6-10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, wherein the alkyl and alkenyl are optionally interrupted by one or more heteroatom or chemical groups selected from -0- -S-, -C(O)-, -NR”-, -C(0)NR”-, -NR”C(0)0- -NR”C(0)NR”’-, and triazoldiyl;R32and R33is selected from the group consisting of hydrogen, C1-24 alkyl, and C2-6alkenyl, wherein the alkyl and alkenyl are optionally interrupted by one or more heteroatom or chemical groups selected from -O-, -S-, -C(O)-, and -NR”-; and each R29, R”, R’”, A”, T, Y, and u is as defined herein.

[0277] In certain embodiments, each L independently comprises a moiety having the structure of , wherein each R29, R31, R32, R33, A”, K, T, X1, Y, and u is as defined herein.

[0278] In certain embodiments, each L independently comprises a moiety having the structure of;wherein each R29, R31, R32, R33, A”, K, T, X1, Y, and u is asdefined herein.

[0279] In certain embodiments, K comprises a poly sarcosine. In certain embodiments, K is a polysarcosine. In certain embodiments, K is a polysarcosine comprising the structure of, wherein v is an integer ranging from about 2 and about 50 or from about 4 to about30. In certain embodiments, K is a polysarcosine having the structure ofwherein R3is -OH or -NH2; and each v is as defined herein. In certain embodiments, K is a polyethylene glycol moiety (PEG). In certain embodiments, K is a PEG comprising the structure of wherein w is an integer ranging from about 2 and about50.

[0280] In certain embodiments, X1is selected from the group consisting of one or moreamino acid(s), one or more ^-substituted amino acid, C1-12 alkylene, C2-C10 alkenylene, C3-8 cycloalkylene, C6-10arylene, 5- to 10 membered heteroarylene, or 5- to 10-membered heterocyclylene; wherein the alkylene and alkenylene are each optionally interrupted by one or more heteroatom or chemical groups selected from -O-, -S-, -C(O)-, -NR”-, -C(O)NR”-, -NR”C(O)O-, -NR”C(O)NR”’-, and triazoldiyl; and wherein the alkylene, alkenylene, cycloalkylene, arylene, heteroarylene, heterocyclylene are each optionally substituted with one or more substituents, each independently selected from the group consisting of halogen, oxo, hydroxyl, nitro, cyano, C1-6alkyl, C3-6cycloalkyl, C6-10aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heterocyclyl, C1-6alkoxy, C1-6haloalkyl, C1-6haloalkoxy, -(CO)R’, -O(CO)R’,(CO)OR’, (CO)NR”R”’, -NR”(CO)R’, and NR”R”; wherein each R’, R”, and R’” is independently hydrogen or C1-6alkyl. In certain embodiments, X1isembodiments, X1is

[0281] In certain embodiments, each L independently comprises a moiety ofis independently an integer ranging from about 2 and about 50 or from about 4 to about 30; in one embodiment, each v is an integer of 18. In certain embodiments, each L independently compriseswherein each v is as defined herein, in one embodiment, each v is an integer of 18.

[0282] In certain embodiments, each L independently comprises a moiety having the structure of wherein each R29, R30, A”, K, and u is as defined herein.

[0283] In certain embodiments, each L independently comprises a moiety of wherein v is as defined herein, in one embodiment, v is an integer of18. In certain embodiments, each L independently comprises a moiety of wherein v is as defined herein, in one embodiment, v is an integerof 18.

[0284] In certain embodiments, each L is independently a moiety having the structure ofwherein Z’ is an optional spacer; and each R29, R31, R32, R33, A”, K,T, X1, Y, and u is as defined herein.

[0285] In certain embodiments, each L is independently a moiety having the structure of, wherein each R29, R31, R32, R33, A”, K, T, X1, Y, Z’, and u is as defined herein. In certain embodiments, each L is independently a moiety having the structure of wherein each R29, R31, R32, R33, A”, K, T, X1, Y, Z’, and u is asdefined herein.

[0286] In certain embodiments, each L is independently a moiety having the structure ofwherein each R29, R30, A”, K, Z’, and u is as defined herein.

[0287] In certain embodiments, Z’ is selected from the group consisting of one or more amino acid(s), one or more A-substituted amino acid, C1-12 alkylene, C2-10alkenylene, C2-10alkynylene, C3-8cycloalkylene, C6-10arylene, 5- to 10-membered heteroarylene, 5- to 10- membered heterocyclylene, wherein the alkylene, alkenylene, and alkynylene are each optionallyinterrupted by one or more heteroatom or chemical groups selected from the group consisting of -O-, -S-, -C(0)-, -NR”-, -C(0)NR”-, -NR”C(0)0- -NR”C(0)NR”’-, and triazoldiyl; and wherein the alkylene, alkenylene, alkenylene, cycloalkylene, arylene, heteroarylene, hetero- cyclylene are each optionally substituted with one or more substituents, each independently selected from the group consisting of halogen, oxo, hydroxyl, nitro, cyano, C1-6alkyl, C3-6cycloalkyl, C6-10aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heterocyclyl, C1-6alkoxy, C1-6haloalkyl, C1-6haloalkoxy, -(CO)R’, -0(C0)R’, -(CO)OR’, -(C0)NR”R”’, -NR”(C0)R’, and -NR”R”; wherein each R’, R”, and R’” is independently hydrogen or C1-6alkyl.

[0289] In certain embodiments, each L is independently:

[0290] In certain embodiments, each L is independently:

[0291] In certain embodiments, each L is independently:wherein each A” is independently a bond or -OC(O)-.[wherein each A” is independently a bond or -OC(O)-; and each v is as defined herein, in oneembodiment, each v is an integer of about 18.wherein each A” is independently a bond or -OC(O)-; and each w is as defined herein, in one embodiment, each w is an integer of about 25.

[0294] In certain embodiments, each L is independently:wherein each A” is independently a bond or -OC(O)-; and each v is as defined herein, in one embodiment, each v is an integer of about 18.

[0295] In certain embodiments, each L is independently:wherein each A” is independently a bond or -OC(O)-; and each w is as defined herein, in one embodiment, each w is an integer of about 25.

[0296] In certain embodiments, each X is a bond. In certain embodiments, each X is S.

[0297] In certain embodiments, each X is independently heteroarylene or heterocyclylene, each optionally substituted with one or more substituents Q. In certain embodiments, each X is independently heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, each X is independently monocyclic heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, each X is independently 5- or 6-membered heteroarylene, each optionally substituted with one or more substituents Q. In certain embodiments, each X is independently 5-membered heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, each X is independently pyrimidindiyl, optionally substituted with one or more substituents Q. In certain embodiments, each X is independently pyrimidin-2,5-diyl, optionally substituted with one or more substituents Q. In certain embodiments, each X is independently 6-membered heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, each X is independently bicyclic heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, each X is independently 5,5-, 5,6-, or 6,6-fused heteroarylene, each optionally substituted with one or more substituents Q. In certain embodiments, each X is independently 5,5-fused heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments,each X is independently 5,6-fused heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, each X is independently 6,6-fused heteroarylene, optionally substituted with one or more substituents Q.

[0298] In certain embodiments, each X is independently heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, each X is independently monocyclic heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, each X is independently 3-, 4-, 5-, 6-, or 7-membered heterocyclylene, each optionally substituted with one or more substituents Q. In certain embodiments, each X is independently 3-membered heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, each X is independently 4-membered heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, each X is independently 5- membered heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, each X is independently pyrrolidindiyl, optionally substituted with one or more substituents Q. In certain embodiments, each X is independently pyrrolidin-l,3-diyl, optionally substituted with one or more substituents Q. In certain embodiments, each X is independently 2,5-dioxopyrrolidin-l,3-diyl. In certain embodiments, each X is independently 6-membered heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, each X is independently 7-membered heterocyclylene, optionally substituted with one or more substituents Q.

[0299] In certain embodiments, each X is independently bicyclic heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, each X is independently bridged, fused, or spiro heterocyclylene, each optionally substituted with one or more substituents Q. In certain embodiments, each X is independently bridged heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, each X is independently fused heterocyclylene, optionally substituted with one or more substituents Q. In certain embodiments, each X is independently spiro heterocyclylene, optionally substituted with one or more substituents Q.

[0300] In certain embodiments, each moiety L-X is independently a moiety having thestructure of wherein each R29, R31, R32, R33, A”, K, T, X, X1, Y,Z’, and u is as defined herein.

[0301] In certain embodiments, each moiety L-X is independently a moiety having the structure of, wherein each R29, R31, R32, R33, A”, K, T, X, X1, Y,Z’, and u is as defined herein. In certain embodiments, each moiety L-X is independently a moiety having the structure of, wherein each R29, R31, R32, R33, A”,K, T, X, X1, Y, Z’, and u is as defined herein.

[0302] In certain embodiments, each moiety L-X is independently a moiety having the structure of, wherein each R29, R30, A”, K, X, Z’, and u is as defined herein.

[0303] In certain embodiments, each moiety L-X is independently:

[0304] In certain embodiments, each moiety L-X is independently:

[0305] In certain embodiments, each moiety L-X is independently:-izSl --9SI -

[0306] In certain embodiments, each moiety L-X is independently:

[0307] In one embodiment, provided herein is a compound of Formula (L):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; wherein each RA, RD, A”, m, and v is as defined herein.

[0308] In another embodiment, provided herein is a compound of Formula (LI):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 hydratethereof; wherein each RA, RD, A”, m, and v is as defined herein.

[0309] In yet another embodiment, provided herein is a compound of Formula (LII):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; wherein each RA, RD, A”, m, and v is as defined herein.

[0310] In one embodiment, provided herein is a compound of Formula (LIII):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; wherein each RA, RD, A”, m, and v is as defined herein.

[0311] In another embodiment, provided herein is a compound of Formula (LIV):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; wherein each RA, RD, A”, m, and v is as defined herein.

[0312] In yet another embodiment, provided herein is a compound of Formula (LV):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; wherein each RA, RD, A”, m, and v is as defined herein.

[0313] In yet another embodiment, provided herein is a compound of Formula (LVI):or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein each RA, RD, A”, m, and v is as defined herein.

[0314] In one embodiment, provided herein is a compound of Formula (LVII):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; wherein each RA, RD, A”, m, and v is as defined herein.

[0315] In another embodiment, provided herein is a compound of Formula (LVIII):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; wherein each RA, RD, A”, m, and v is as defined herein.

[0316] In yet another embodiment, provided herein is a compound of Formula (LIX):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; wherein each RA, RD, A”, m, and v is as defined herein.

[0317] In still another embodiment, provided herein is a compound of Formula (LX):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; wherein each RA, RD, A”, m, and v is as defined herein.

[0318] In certain embodiments, in any one of Formulae (L) to (LX), the moiety A”-RDisIn certain embodiments, in any one of Formulae (L) to (LX),In certain embodiments, in any one of Formulae (L) to (LX), the moiety A”-RDis

[0319] In one embodiment, provided herein is a compound of Formula (LXI):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; wherein RAand m are each as defined herein.

[0320] In another embodiment, provided herein is a compound of Formula (LXII):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; wherein RAand m are each as defined herein.

[0321] In one embodiment, RAis a full length or intact monoclonal antibody. In another embodiment, RAis a monoclonal antibody or an antigen-binding fragment thereof. In yet another embodiment, RAis a single domain antibody or an antigen-binding fragment thereof. In yet another embodiment, RAis a VHH antibody. In still another embodiment, RAis a VNAR antibody.

[0322] In one embodiment, RAis a human, humanized, or chimeric antibody, or an antigen-binding fragment thereof. In another embodiment, RAis a human antibody or an antigen- binding fragment thereof. In yet another embodiment, RAis a humanized antibody or an antigen- binding fragment thereof. In still another embodiment, RAis a chimeric antibody or an antigen- binding fragment thereof.

[0323] In one embodiment, RAis an IgA, IgD, IgE, IgG, or IgM antibody, or an antigen- binding fragment thereof. In another embodiment, RAis an IgA antibody or an antigen-binding fragment thereof. In yet another embodiment, RAis an IgD antibody or an antigen-binding fragment thereof. In yet another embodiment, RAis an IgE antibody or an antigen-binding fragment thereof. In yet another embodiment, RAis an IgG antibody or an antigen-binding fragment thereof. In still another embodiment, RAis an IgM antibody or an antigen-binding fragment thereof.

[0324] In one embodiment, RAis an IgAl, IgA2, IgGl, IgG2, IgG3, or IgG4 antibody, or an antigen-binding fragment thereof. In another embodiment, RAis an IgAl or IgA2, or anantigen-binding fragment thereof. In yet another embodiment, RAis an IgAl or an antigen- binding fragment thereof. In yet another embodiment, RAis an IgA2 or an antigen-binding fragment thereof. In yet another embodiment, RAis an IgGl, IgG2, IgG3, or IgG4 antibody, or an antigen-binding fragment thereof. In yet another embodiment, RAis an IgGl antibody or an antigen-binding fragment thereof. In yet another embodiment, RAis an IgG2 antibody or an antigen-binding fragment thereof. In yet another embodiment, RAis an IgG3 antibody or an antigen-binding fragment thereof. In still another embodiment, RAis an IgG4 antibody or an antigen-binding fragment thereof.

[0325] In one embodiment, RAis 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. In another embodiment, RAis an scFv of an antibody provided herein. In yet another embodiment, RAis a Fab of an antibody provided herein. In yet another embodiment, RAis a Fab’ of an antibody provided herein. In yet another embodiment, RAis an F(ab)2 of an antibody provided herein. In yet another embodiment, RAis a F(ab’)2 of an antibody provided herein. In yet another embodiment, RAis a Fv of an antibody provided herein. In yet another embodiment, RAis a diabody of an antibody provided herein. In yet another embodiment, RAis a triabody of an antibody provided herein. In yet another embodiment, RAis a tetrabody of an antibody provided herein. In still another embodiment, RAis a minibody of an antibody provided herein.

[0326] In one embodiment, RAis a monospecific antibody or an antigen-binding fragment thereof. In another embodiment, RAis a bispecific antibody or an antigen-binding fragment thereof. In yet another embodiment, RAis a trispecific antibody or an antigen-binding fragment thereof. In still another embodiment, RAis a tetraspecific antibody or an antigen-binding fragment thereof.

[0327] In one embodiment, RAis an afucosylated antibody or an antigen-binding fragment thereof.

[0328] In one embodiment, RAis a recombinant antibody or an antigen-binding fragment thereof. In another embodiment, RAis a purified antibody or an antigen-binding fragment thereof. In yet another embodiment, RAis an isolated antibody or an antigen-binding fragment thereof.

[0329] In certain embodiments, RAis an antibody or an antigen-binding fragment thereof, wherein the antibody specifically binds to B7 homolog 3 (B7H3), cMET, cytotoxic T- lymphocyte-associated protein 4 (CTLA-4), epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), or vascular endothelial growth factor (VEGF).

[0330] In certain embodiments, RAis an anti-B7H3 antibody, anti-cMET antibody, anti- CTLA-4 antibody, anti -EGFR antibody, anti-HER2 antibody, anti -PD-1 antibody, anti-PD-Ll antibody, anti-VEGF antibody, or an antigen-binding fragment thereof. In certain embodiments, RAis an anti-B7H3 antibody or an antigen-binding fragment thereof. In certain embodiments, RAis an anti-cMET antibody or an antigen-binding fragment thereof. In certain embodiments, RAis an anti-CTLA-4 antibody or an antigen-binding fragment thereof. In certain embodiments, RAis an anti-EGFR antibody or an antigen-binding fragment thereof. In certain embodiments, RAis an anti-HER2 antibody or an antigen-binding fragment thereof. In certain embodiments, RAis an anti-PD-1 antibody or an antigen-binding fragment thereof. In certain embodiments, RAis an anti-PD-Ll antibody or an antigen-binding fragment thereof. In certain embodiments, RAis an anti-VEGF antibody or an antigen-binding fragment thereof.

[0331] In one embodiment, RAis an anti-B7H3 antibody or an antigen-binding fragment thereof, wherein the antibody comprises (i) a light chain complementarity determining region 1 (CDRL1) of SEQ ID NO: 1; (ii) a light chain complementarity determining region 2 (CDRL2) of SEQ ID NO: 2; (iii) a light chain complementarity determining region 3 (CDRL3) of SEQ ID NO: 3; (iv) a heavy chain complementarity determining region 1 (CDRH1) of SEQ ID NO: 4; (v) a heavy chain complementarity determining region 2 (CDRH2) of SEQ ID NO: 5; and (vi) a heavy chain complementarity determining region 3 (CDRH3) of SEQ ID NO: 6. In certain embodiments, the CDRs provided herein are defined according to the Kabat numbering system. In another embodiment, RAis an anti-B7H3 antibody or an antigen-binding fragment thereof, wherein the antibody comprises (i) a light chain variable region of SEQ ID NO: 7; and (ii) a heavy chain variable region of SEQ ID NO: 8. In yet another embodiment, RAis an anti-B7H3 antibody or an antigen-binding fragment thereof, wherein the antibody comprises (i) a light chain of SEQ ID NO: 9; and (ii) a heavy chain of SEQ ID NO: 10.

[0332] In one embodiment, RAis an anti-cMET antibody or an antigen-binding fragment thereof, wherein the antibody comprises (i) a CDRL1 of SEQ ID NO: 11; (ii) a CDRL2 of SEQ ID NO: 12; (iii) a CDRL3 of SEQ ID NO: 13; (iv) a CDRH1 of SEQ ID NO: 14; (v) a CDRH2 of SEQ ID NO: 15; and (vi) a CDRH3 of SEQ ID NO: 16. In certain embodiments, the CDRs provided herein are defined according to the Kabat numbering system. In another embodiment, RAis an anti-cMET antibody or an 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, RAis an anti-cMET antibody or an 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.

[0333] In one embodiment, RAis an anti-CTLA-4 antibody or an 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 Kabat numbering system. In another embodiment, RAis an anti-CTLA-4 antibody or an 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, RAis an anti-CTLA-4 antibody or an 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.

[0334] In one embodiment, RAis an anti-EGFR antibody or an 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 Kabat numbering system. In another embodiment, RAis an anti-EGFR antibody or an 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, RAis an anti-EGFR antibody or an 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.

[0335] In one embodiment, RAis an anti-HER2 antibody or an antigen-binding fragment thereof, wherein the antibody comprises (i) a CDRL1 of SEQ ID NO: 41; (ii) a CDRL2 of SEQ ID NO: 42; (iii) a CDRL3 of SEQ ID NO: 43; (iv) a CDRH1 of SEQ ID NO: 44; (v) a CDRH2 of SEQ ID NO: 45; and (vi) a CDRH3 of SEQ ID NO: 46. In certain embodiments, the CDRs provided herein are defined according to the Kabat numbering system. In another embodiment, RAis an anti-HER2 antibody or an antigen-binding fragment thereof, wherein the antibody comprises (i) a light chain variable region of SEQ ID NO: 47; and (ii) a heavy chain variable region of SEQ ID NO: 48. In yet another embodiment, RAis an anti-HER2 antibody or an antigen-binding fragment thereof, wherein the antibody comprises (i) a light chain of SEQ ID NO: 49; and (ii) a heavy chain of SEQ ID NO: 50.

[0336] In one embodiment, RAis an anti-PD-1 antibody or an antigen-binding fragment thereof, wherein the antibody comprises (i) a CDRL1 of SEQ ID NO: 51; (ii) a CDRL2 of SEQ ID NO: 52; (iii) a CDRL3 of SEQ ID NO: 53; (iv) a CDRH1 of SEQ ID NO: 54; (v) a CDRH2 of SEQ ID NO: 55; and (vi) a CDRH3 of SEQ ID NO: 56. In certain embodiments, the CDRs provided herein are defined according to the Kabat numbering system. In another embodiment, RAis an anti-PD-1 antibody or an antigen-binding fragment thereof, wherein the antibody comprises (i) a light chain variable region of SEQ ID NO: 57; and (ii) a heavy chain variable region of SEQ ID NO: 58. In yet another embodiment, RAis an anti-PD-1 antibody or an antigen- binding fragment thereof, wherein the antibody comprises (i) a light chain of SEQ ID NO: 59; and (ii) a heavy chain of SEQ ID NO: 60.

[0337] In one embodiment, RAis an anti-PD-Ll antibody or an antigen-binding fragment thereof, wherein the antibody comprises (i) a CDRL1 of SEQ ID NO: 61; (ii) a CDRL2 of SEQ ID NO: 62; (iii) a CDRL3 of SEQ ID NO: 63; (iv) a CDRH1 of SEQ ID NO: 64; (v) a CDRH2 of SEQ ID NO: 65; and (vi) a CDRH3 of SEQ ID NO: 66. In certain embodiments, the CDRs provided herein are defined according to the Kabat numbering system. In another embodiment, RAis an anti-PD-Ll antibody or an antigen-binding fragment thereof, wherein the antibody comprises (i) a light chain variable region of SEQ ID NO: 67; and (ii) a heavy chain variable region of SEQ ID NO: 68. In yet another embodiment, RAis an anti-PD-Ll antibody or an antigen-binding fragment thereof, wherein the antibody comprises (i) a light chain of SEQ ID NO: 69; and (ii) a heavy chain of SEQ ID NO: 70.

[0338] In one embodiment, RAis an anti-VEGF antibody or an antigen-binding fragment thereof, wherein the antibody comprises (i) a CDRL1 of SEQ ID NO: 71; (ii) a CDRL2 of SEQ ID NO: 72; (iii) a CDRL3 of SEQ ID NO: 73; (iv) a CDRH1 of SEQ ID NO: 74; (v) a CDRH2 of SEQ ID NO: 75; and (vi) a CDRH3 of SEQ ID NO: 76. In certain embodiments, the CDRs provided herein are defined according to the Kabat numbering system. In another embodiment, RAis an anti-VEGF antibody or an antigen-binding fragment thereof, wherein the antibody comprises (i) a light chain variable region of SEQ ID NO: 77; and (ii) a heavy chain variable region of SEQ ID NO: 78. In yet another embodiment, RAis an anti-VEGF antibody or an antigen-binding fragment thereof, wherein the antibody comprises (i) a light chain of SEQ ID NO: 79; and (ii) a heavy chain of SEQ ID NO: 80.

[0339] 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 certain embodiments, m is an integer of 13. In certain embodiments, m is an integer of 11. In certain embodiments, m is an integer of 14. In certain embodiments, m is an integer of 11. In certain embodiments, m is an integer of 15. In certain embodiments, m is an integer of 11. In certain embodiments, m is an integer of 16.

[0340] All combinations of the embodiments provided herein for the groups described in the formulae described herein, including Formulae (I) to (LXII) are within the scope of this disclosure.

[0341] In one embodiment, provided herein is ADC compound ADC-A1, ADC-A2,ADC-B1, ADC-B2, ADC-B11, ADC-B12, ADC-B13, ADC-C1, ADC-C2, or ADC-C3 In another embodiment, ADC-A1, ADC-A2, ADC-B11, ADC-B12, ADC-B13, ADC-C1, ADC-C2, and ADC-C3 are each an anti-EGFR antibody comprising (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 yet another embodiment, ADC-A1, ADC-A2, ADC-B11, ADC-B12, ADC-B13, ADC-C1, ADC-C2, and ADC-C3 are each an anti-EGFR antibody comprising a light chain variable region of SEQ ID NO: 37; and a heavy chain variable region of SEQ ID NO: 38. In yet another embodiment, ADC- Al, ADC-A2, ADC-B11, ADC-B12, ADC-B13, ADC-C1, ADC-C2, and ADC-C3 are each an anti-EGFR antibody comprising a light chain of SEQ ID NO: 39; and a heavy chain of SEQ ID NO: 40.

[0342] In certain embodiments, an ADC compound provided herein in a composition (e.g, a pharmaceutical composition) has a drug-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, an ADC compound provided herein in a composition (c.g, a pharmaceutical composition) has a DAR ranging from about 0.5 to about 12. In certain embodiments, an ADC compound provided herein in a composition (e.g., a pharmaceutical composition) has a DAR ranging from about 1 to about 10. In certain embodiments, an ADC compound provided herein in a composition (e.g., a pharmaceutical composition) has a DAR ranging from about 2 to about 8. In certain embodiments, an ADC compound provided herein in a composition (e.g., a pharmaceutical composition) has a DAR ranging from about 3 to about 5. In certain embodiments, an ADC compound provided herein in a composition (e.g., a pharmaceutical composition) has 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.

[0343] In one embodiment, provided herein is 4-((6’)-2-(( )-2-(6-(2,5-dioxo-2,5-dihydro- lH -pyrrol-l-yl)hexanamido)-3-methyl-butanamido)-5-ureidopentanamido)benzyl 3-(7-(8- ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH - pyrrolizin-7a(5H )-yl)methoxy)pyrido[4,3-d]-pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate Al; or A-(10-benzyl-l-(3-(7-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-l-yl)-8- fluoro-2-(((2R,7a5)-2-fluorotetrahydro-1H -pyrrolizin-7a(5H )-yl)methoxy)pyrido[4,3- d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-l,6,9,12,15-pentaoxo-3-oxa-5,8,l 1,14- tetraazahexadecan-16-yl)-6-(2,5-dioxo-2,5-dihydro-lH -pyrrol-l-yl)hexanamide A2; or adiastereomer, 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 another embodiment, provided herein is any one of compound A3 to All, Bl to B6, and Cl to C6, 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.

[0344] In certain embodiments, a compound provided herein is deuterium-enriched. In certain embodiments, a compound provided herein is carbon-13 enriched. In certain embodiments, a compound provided herein is carbon- 14 enriched. In certain embodiments, a compound provided herein contains one or more less prevalent isotopes for other elements, including, but not limited to,15N for nitrogen;17O or18O for oxygen, and34S,3?S, or36S for sulfur.

[0345] In certain embodiments, a compound provided herein is isolated or purified. In certain embodiments, a compound provided herein has a purity of at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 99.5% by weight.

[0346] The compounds provided herein are intended to encompass all possible stereoisomers, unless a particular stereochemistry is specified. Where a compound provided herein contains an alkenyl group, the compound may exist as one or mixture of geometric cisltrans (or Z / E) isomers. Where structural isomers are interconvertible, the compound may exist as a single tautomer or a mixture of tautomers. This can take the form of proton tautomerism in the compound that contains, for example, an imino, keto, or oxime group; or so- called valence tautomerism in the compound that contains an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism.

[0347] A compound provided herein can be enantiomerically pure, such as a single enantiomer or a single diastereomer, or be stereoisomeric mixtures, such as a mixture of enantiomers, e.g., a racemic mixture of two enantiomers; or a mixture of two or more diastereomers. As such, one of ordinary skill in the art will recognize that administration of a compound in its (R) form is equivalent, for the compound that undergoes epimerization in vivo, to administration of the compound in its (5) form. Conventional techniques for thepreparation / i solation of individual enantiomers include synthesis from a suitable optically pure precursor, asymmetric synthesis from achiral starting materials, or resolution of an enantiomeric mixture, for example, chiral chromatography, recrystallization, resolution, diastereomeric salt formation, or derivatization into diastereomeric adducts followed by separation.

[0348] When a compound provided herein contains an acidic or basic moiety, it can also be provided as a pharmaceutically acceptable salt. See, Berge et al., J. Pharm. Sci. 1977, 66, 1- 19; Handbook of Pharmaceutical Salts: Properties, Selection, and Use, 2nd ed.; Stahl and Wermuth Eds.; John Wiley & Sons, 2011. In certain embodiments, a pharmaceutically acceptable salt of a compound provided herein is a solvate. In certain embodiments, a pharmaceutically acceptable salt of a compound provided herein is a hydrate.

[0349] Suitable acids for use in the preparation of pharmaceutically acceptable salts of a compound provided herein include, but are not limited to, acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, boric acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(15)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamic acid, dodecylsulfuric acid, ethane-l,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, α- oxoglutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, lauric acid, maleic acid, (-)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-l,5-disulfonic acid, 1 -hydroxy -2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, perchloric acid, phosphoric acid, L- pyroglutamic acid, saccharic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid, and valeric acid.

[0350] Suitable bases for use in the preparation of pharmaceutically acceptable salts of a compound provided herein include, but are not limited to, inorganic bases, such as magnesium hydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, or sodium hydroxide; andorganic bases, such as primary, secondary, tertiary, and quaternary, aliphatic and aromatic amines, including, but not limited to, L-arginine, benethamine, benzathine, choline, deanol, diethanolamine, diethylamine, dimethylamine, dipropylamine, diisopropylamine, 2- (diethylamino)-ethanol, ethanolamine, ethylamine, ethylenediamine, isopropylamine, A-methyl- glucamine, hydrabamine, lH -imidazole, L-lysine, morpholine, 4-(2-hydroxyethyl)-morpholine, methylamine, piperidine, piperazine, propylamine, pyrrolidine, l-(2-hydroxyethyl)-pyrrolidine, pyridine, quinuclidine, quinoline, isoquinoline, triethanolamine, trimethylamine, triethylamine, N- methyl-D-glucamine, 2-amino-2-(hydroxymethyl)-l,3-propanediol, and tromethamine.Pharmaceutical Compositions

[0351] In one embodiment, provided herein is a pharmaceutical composition, comprising a compound provided herein, e.g., 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, or hydrate thereof; and a pharmaceutically acceptable excipient.

[0352] In one embodiment, the pharmaceutical composition provided herein is formulated in a dosage form for parenteral administration. In another embodiment, the pharmaceutical composition provided herein is formulated in a dosage form for intravenous administration. In yet another embodiment, the pharmaceutical composition provided herein is formulated in a dosage form for intramuscular administration. In still another embodiment, the pharmaceutical composition provided herein is formulated in a dosage form for subcutaneous administration.

[0353] The pharmaceutical composition provided herein can be provided in a unit-dosage form or multiple-dosage form. A unit-dosage form, as used herein, refers to physically discrete a unit suitable for administration to a subject, and packaged individually as is known in the art. Each unit-dose contains a predetermined quantity of an active ingredient(s) e.g., a compound provided herein) sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical excipient(s). Examples of a unit-dosage form include, but are not limited to, an ampoule and syringe. A unit-dosage form may be administered in fractions or multiples thereof. A multiple-dosage form is a plurality of identical unit-dosage forms packaged in a single container to be administered in a segregated unit-dosage form. Examples of a multiple-dosageform include, are not limited to, a vial or bottle of pints or gallons.

[0354] The pharmaceutical composition provided herein can be administered at once or multiple times at intervals of time. It is understood that the precise dosage and duration of treatment may vary with the age, weight, and condition of the subject being treated, and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test or diagnostic data. It is further understood that for any particular individual, specific dosage regimens should be adjusted over time according to the subject’s need and the professional judgment of the person administering or supervising the administration of the pharmaceutical composition.Methods of Use

[0355] In one embodiment, provided herein is a method of treating, preventing, or ameliorating one or more symptoms of a disorder, disease, or condition mediated by a KRAS in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a compound provided herein, e.g., 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, or hydrate thereof.

[0356] In certain embodiments, the disorder, disease, or condition mediated by a KRAS is a proliferative disease.

[0357] In another embodiment, 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 provided herein, e.g., 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, or hydrate thereof.

[0358] In certain embodiments, the proliferative disease is cancer. In certain embodiments, the cancer is a solid tumor.

[0359] In certain embodiments, the cancer is refractory and / or relapsed. In certainembodiments, the cancer is refractory. In certain embodiments, the cancer is relapsed. In certain embodiments, the cancer is metastatic. In certain embodiments, the cancer is unresectable. In certain embodiments, the cancer is metastatic.

[0360] In certain embodiments, the cancer is drug-resistant. In certain embodiment, the cancer is multidrug-resistant. In certain embodiments, the cancer is resistant to a chemotherapy. In certain embodiments, the cancer is resistant to an immunotherapy. In certain embodiments, the cancer is resistant to a standard therapy for the cancer.

[0361] In certain embodiments, the cancer bears a KRAS mutation. In certain embodiments, the cancer bears a KRAS mutation at the G12 or G13 position. In certain embodiments, the cancer bears a KRAS mutation of G12C, G12D, G12V, G12A, G12S, or G12R. In certain embodiments, the cancer bears a KRAS mutation of G12C. In certain embodiments, the cancer bears a KRAS mutation of G12D. In certain embodiments, the cancer bears a KRAS mutation of G12V. In certain embodiments, the cancer bears a KRAS mutation of G12A. In certain embodiments, the cancer bears a KRAS mutation of G12S. In certain embodiments, the cancer bears a KRAS mutation of G12R. In certain embodiments, the cancer bears a KRAS mutation at the G13 position. In certain embodiments, the cancer bears a KRAS mutation of G13D.

[0362] In certain embodiments, the cancer is a solid tumor with a KRAS mutation. In certain embodiments, the solid tumor bears a KRAS mutation at the G12 or G13 position. In certain embodiments, the solid tumor bears a KRAS mutation of G12C, G12D, G12V, G12A, G12S, or G12R. In certain embodiments, the solid tumor bears a KRAS mutation of G12C. In certain embodiments, the solid tumor bears a KRAS mutation of G12D. In certain embodiments, the solid tumor bears a KRAS mutation of G12V. In certain embodiments, the solid tumor bears a KRAS mutation of G12A. In certain embodiments, the solid tumor bears a KRAS mutation of G12S. In certain embodiments, the solid tumor bears a KRAS mutation of G12R. In certain embodiments, the solid tumor bears a KRAS mutation at the G13 position. In certain embodiments, the solid tumor bears a KRAS mutation of G13D.

[0363] In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a human.

[0364] In certain embodiments, the therapeutically effective amount of a compound provided herein is ranging from about 0.1 mg / kg every four weeks to about 20 mg / kg every week, from about 0.2 mg / kg every four weeks to about 10 mg / kg every week, from about 0.5 mg / kg every four weeks to about 5 mg / kg every week, or from about 1 mg / kg every four weeks to about 2 mg / kg every week.

[0365] In one embodiment, the therapeutically effective amount of a compound provided herein is ranging from about 0.1 mg / kg every four weeks to about 20 mg / kg every week. In another embodiment, the therapeutically effective amount of a compound provided herein is ranging from about 0.2 mg / kg every four weeks to about 10 mg / kg every week. In yet another embodiment, the therapeutically effective amount of a compound provided herein is ranging from about 0.5 mg / kg every four weeks to about 5 mg / kg every week. In yet another embodiment, the therapeutically effective amount of a compound provided herein is ranging from about 1 mg / kg every four weeks to about 2 mg / kg every week. In still another embodiment, the therapeutically effective amount of a compound provided herein is about 1, about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, or about 5 mg / kg every three weeks.

[0366] Depending on the disorder, disease, or condition to be treated and the subject’s condition, a compound provided herein may be administered by parenteral (e.g., intramuscular, intraperitoneal, intravenous, CIV, intracistemal injection or infusion, subcutaneous injection, or implant) routes of administration. A compound provided herein may be formulated in suitable dosage unit with a pharmaceutically acceptable excipient, carrier, adjuvant, or vehicle, appropriate for the route of administration.

[0367] In one embodiment, a compound provided herein is administered parenterally. In another embodiment, a compound provided herein is administered intravenously. In yet another embodiment, a compound provided herein is administered intramuscularly. In still another embodiment, a compound provided herein is administered subcutaneously.

[0368] A compound provided herein can be delivered as a single dose such as, e.g, a single bolus injection, or over time such as, e.g, continuous infusion over time or divided bolus doses over time. A compound provided herein can be administered repetitively if necessary, for example, until the subject experiences stable disease or regression, or until the patient experiencesdisease progression or unacceptable toxicity.

[0369] A compound provided herein can be administered once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, or once every six weeks. In one embodiment, a compound provided herein is administered once a week. In another embodiment, a compound provided herein is administered once every two weeks. In yet another embodiment, a compound provided herein is administered once every two weeks. In yet another embodiment, a compound provided herein is administered once every three weeks. In yet another embodiment, a compound provided herein is administered once every four weeks. In yet another embodiment, a compound provided herein is administered once every five weeks. In yet another embodiment, a compound provided herein is administered once every six weeks.

[0370] In certain embodiments, a compound provided herein is cyclically administered to a subject. Cycling therapy involves the administration of an active agent for a period of time, followed by a rest for a period of time, and repeating this sequential administration. Cycling therapy can reduce the development of resistance to one or more of the therapies, avoid or reduce the side effects of one of the therapies, and / or improves t...

Claims

What is claimed is:

1. 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, or hydrate thereof; wherein: each L is independently a linker; each X is independently (i) a bond or S; or (ii) heteroarylene or heterocyclylene;RAis an antibody or an antigen-binding fragment thereof; each RDis independently a KRAS binding moiety; and m is an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16; wherein the heteroarylene and heterocyclylene are each optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q; wherein each Q is independently selected from: (a) deuterium, cyano, halo, imino, nitro, and oxo; (b) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; and (c) -C(O)Ra, -C(O)ORa, -C(O)NRbRc, -C(O)SRa, -C(NRa)NRbRc, -C(S)Ra, -C(S)ORa, -C(S)NRbRc, -ORa, -OC(O)Ra, -OC(O)ORa, -OC(O)NRbRc, -OC(O)SRa, -OC(NRa)NRbRc, -OC(S)Ra, -OC(S)ORa, -OC(S)NRbRc, -OP(O)(ORa)ORd, -OS(O)Ra, -OS(O)2Ra, -OS(O)NRbRc, -OS(O)2NRbRc, -NRbRc, -NRaC(O)Rd, -NRaC(O)ORd, -NRaC(O)NRbRc, -NRaC(O)SRd, -NRaC(NRd)NRbRc, -NRaC(S)Rd, -NRaC(S)ORd, -NRaC(S)NRbRc, -NRaS(O)Rd, -NRaS(O)2Rd, -NRaS(O)NRbRc, -NRaS(O)2NRbRc, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRbRc, and -S(O)2NRbRc, wherein each Ra, Rb, Rc, and Rdis independently (i) hydrogen or deuterium; (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; or (iii) Rband Rctogether with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; wherein each Qais independently selected from: (a) deuterium, cyano, halo, nitro, imino,and oxo; (b) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7- 15 aralkyl, heteroaryl, and heterocyclyl; and (c) -C(O)Re, -C(O)ORe, -C(O)NRfRg, -C(O)SRe, -C(NRc)NRfRg, -C(S)Rc, -C(S)ORc, -C(S)NRfRg, -ORc, -OC(O)Rc, -OC(O)ORc, -OC(O)NRfRg, -OC(O)SRe, -OC(NRe)NRfRg, -OC(S)Re, -OC(S)ORe, -OC(S)NRfRg, -OS(O)Re, -OS(O)2Re, -OS(O)NRfRg, -OS(O)2NRfRg, -NRfRg, -NReC(O)Rb, -NReC(O)ORf, -NReC(O)NRfRg, -NReC(O)SRf, -NReC(NRb)NRfRg, -NReC(S)Rh, -NReC(S)ORf, -NReC(S)NRfRg, -NReS(O)Rh, -NReS(O)2Rh, -NReS(O)NRfRg, -NReS(O)2NRfRg, -SRe, -S(O)Re, -S(O)2Re, -S(O)NRfRg, and -S(O)2NRfRg; wherein each Re, Rf, Rg, and Rhis independently (i) hydrogen or deuterium; (ii) C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; or (iii) Rfand Rgtogether with the N atom to which they are attached form heterocyclyl.

2. The compound of claim 1, having the structure of Formula (II):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; wherein: each A is independently a bond, C1-6alkylene, C1-6heteroalkylene, or -O(CR6aR6b)n-; each E1is independently N, heterocyclyl, or C1-6heteroalky lene-heteroaryl; each U is independently C(R2) or N; each R1, R2, R3, and R4is independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)Rla, -C(O)ORla, -C(O)NRlbRlc, -C(O)SRla, -C(NRla)NRlbRlc, -C(S)Rla, -C(S)ORla, -C(S)NRlbRlc, -ORla, -OC(O)Rla, -OC(O)ORla, -OC(O)NRlbRlc, -OC(O)SRla, -OC(NRla)NRlbRlc, -OC(S)Rla, -OC(S)ORla, -OC(S)NRlbRlc, -OS(O)Rla, -OS(O)2Rla, -OS(O)NRlbRlc, -OS(O)2NRlbRlc, -NRlbRlc, -NRlaC(O)Rld, -NRlaC(O)ORld, -NRlaC(O)NRlbRlc, -NRlaC(O)SRld, -NRlaC(NRld)NRlbRlc, -NRlaC(S)Rld,-NRlaC(S)ORld, -NRlaC(S)NRlbRlc, -NRlaS(O)Rld, -NRlaS(O)2Rld, -NRlaS(O)NRlbRlc, -NRlaS(O)2NRlbRlc, -SRla, -S(O)Rla, -S(O)2Rla, -S(O)NRlbRlc, or -S(O)2NRlbRlc; or R1and R2together with the carbon atoms to which they are attached form C3-10cycloalkyl or heterocyclyl; each R5is independently C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; each Rla, Rlb, Rlc, and Rldis independently hydrogen, deuterium, C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; each R6aand R6bis independently (i) hydrogen, deuterium, cyano, halo, or nitro; or (ii) Ci- 6 alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; or R6aand R6btogether with the carbon atom to which they are attached form C3-10cycloalkylene or heterocyclylene; each R7ais independently (i) hydrogen, deuterium, cyano, halo, or nitro; or (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; or R1and R7aare linked together to form heterocyclyl; and n is an integer of 1, 2, 3, 4, or 5; wherein each alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkynyl, cycloalkyl, cycloalkylene, aryl, aralkyl, heteroaryl, heterocyclyl, and heterocyclylene is optionally substituted with one or more substituents Q.

3. The compound of claim 2, wherein each A is independently C1-6heteroalkylene, optionally substituted with one or more substituents Q.

4. The compound of claim 2 or 3, wherein each A is independently -O(CR6aR6b)n-5. The compound of any one of claims 2 to 4, wherein each E1is independently heterocyclyl, optionally substituted with one or more substituents Q.

6. The compound of any one of claims 2 to 5, wherein each E1is independently bicyclic heterocyclyl, optionally substituted with one or more substituents Q.

7. The compound of any one of claims 2 to 6, having the structure of Formula (III):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.

8. The compound of any one of claims 2 to 7, wherein R1and R7aare linked together to form heterocyclyl, optionally substituted with one or more substituents Q.

9. The compound of any one of claims 2 to 8, having the structure of Formula (IV):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; wherein each V1is independently C1-6alkylene or C1-6heteroalkylene, each optionally substituted with one or more substituents Q.

10. The compound of any one of claims 2 to 9, having the structure of Formula (V):or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein each R8aand R8bis independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; or (iii) -C(O)Rla, -C(O)ORla, -C(O)NRlbRlc, -C(O)SRla, -C(NRla)NRlbRlc, -C(S)Rla, -C(S)ORla, -C(S)NRlbRlc, -ORla, -OC(O)Rla, -OC(O)ORla, -OC(O)NRlbRlc, -OC(O)SRla, -OC(NRla)NRlbRlc, -OC(S)Rla, -OC(S)ORla, -OC(S)NRlbRlc, -OS(O)Rla, -OS(O)2Rla, -OS(O)NRlbRlc, -OS(O)2NRlbRlc, -NRlbRlc, -NRlaC(O)Rld, -NRlaC(O)ORld, -NRlaC(O)NRlbRlc, -NRlaC(O)SRld, -NRlaC(NRld)NRlbRlc, -NRlaC(S)Rld, -NRlaC(S)ORld,NRlaC(S)NRlbRlc, NRlaS(O)Rld, NRlaS(O)2Rld, NRlaS(O)NRlbRlc, NRlaS(O)2NRlbRlc, -SRla, -S(O)Rla, -S(O)2Rla, -S(O)NRlbRlc, or -S(O)2NRlbRlc.

11. The compound of any one of claims 2 to 9, having the structure of Formula (VI):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; wherein each R8a, R8b, R8c, and R8dis independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7- 15 aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; or (iii) -C(O)Rla, -C(O)ORla, -C(O)NRlbRlc, -C(O)SRla, -C(NRla)NRlbRlc, -C(S)Rla, -C(S)ORla, -C(S)NRlbRlc, -ORla, -OC(O)Rla, -OC(O)ORla, -OC(O)NRlbRlc, -OC(O)SRla, -OC(NRla)NRlbRlc, -OC(S)Rla, -OC(S)ORla, -OC(S)NRlbRlc, -OS(O)Rla, -OS(O)2Rla, -OS(O)NRlbRlc, -OS(O)2NRlbRlc, -NRlbRlc, -NRlaC(O)Rld, -NRlaC(O)ORld, -NRlaC(O)NRlbRlc, -NRlaC(O)SRld, -NRlaC(NRld)NRlbRlc, -NRlaC(S)Rld, -NRlaC(S)ORld, -NRlaC(S)NRlbRlc, -NRlaS(O)Rld, -NRlaS(O)2Rld, -NRlaS(O)NRlbRlc, -NRlaS(O)2NRlbRlc, -SRla, -S(O)Rla, -S(O)2Rla, -S(O)NRlbRlc, or -S(O)2NRlbRlc.

12. The compound of any one of claims 2 to 6, having the structure of Formula (VII):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.

13. The compound of any one of claims 2 to 12, wherein each R5is independently heterocyclyl, optionally substituted with one or more substituents Q.

14. The compound of any one of claims 2 to 13, wherein each R5is independently pyrrolidinyl or hexahydropyrrolizinyl, each optionally substituted with one or more substituents Q15. The compound of any one of claims 2 to 13, wherein each R5is independently 1- methylpyrrolidin-2-yl, l-methyl-3-methoxypyrrolidin-2-yl, 2-fluorohexahydropyrrolizin-7a-yl, 3- (((l,l,l,3,3,3-hexafluoro-2-methylpropan-2-yl)oxy)methyl)hexahydropyrrolizin-7a-yl, 2- (difluoromethylene)hexahydropyrrolizin-7a-yl, or 2,2-difluorodihydro-1'H,3'H-spiro[cyclo- propane- 1 ,2'-pyrrolizin]-7a'(5'H)-yl .

16. The compound of any one of claims 2 to 8, 13, and 14, having the structure of Formula (IX):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 hydratethereof; wherein each R5a, R5b, and R5cis independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; or (iii) -C(O)Rla, -C(O)ORla, -C(O)NRlbRlc, -C(O)SRla, -C(NRla)NRlbRlc, -C(S)Rla, -C(S)ORla, -C(S)NRlbRlc, -ORla, -OC(O)Rla, -OC(O)ORla, -OC(O)NRlbRlc, -OC(O)SRla, -OC(NRla)NRlbRlc, -OC(S)Rla, -OC(S)ORla, -OC(S)NRlbRlc, -OS(O)Rla, -OS(O)2Rla, -OS(O)NRlbRlc, -OS(O)2NRlbRlc, -NRlbRlc, -NRlaC(O)Rld, -NRlaC(O)ORld, -NRlaC(O)NRlbRlc, -NRlaC(O)SRld, -NRlaC(NRld)NRlbRlc, -NRlaC(S)Rld, -NRlaC(S)ORld, -NRlaC(S)NRlbRlc, -NRlaS(O)Rld, -NRlaS(O)2Rld, -NRlaS(O)NRlbRlc, -NRlaS(O)2NRlbRlc,SRla, S(O)Rla, S(O)2Rla, S(O)NRlbRlc, or -S(O)2NRlbRlc; or R5aand R5btogether with the carbon atom to which they are attached form C2-6alkenylene, C3-10cycloalkylene, or heterocyclylene, each optionally substituted with one or more substituents Q.

17. The compound of any one of claims 10, 13, 14, and 16, having the structure ofFormula (XI):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; wherein each R5a, R5b, and R5cis independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; or (iii) -C(O)Rla, -C(O)ORla, -C(O)NRlbRlc, -C(O)SRla, -C(NRla)NRlbRlc, -C(S)Rla, -C(S)ORla, -C(S)NRlbRlc, -ORla, -OC(O)Rla, -OC(O)ORla, -OC(O)NRlbRlc, -OC(O)SRla, -OC(NRla)NRlbRlc, -OC(S)Rla, -OC(S)ORla, -OC(S)NRlbRlc, -OS(O)Rla, -OS(O)2Rla, -OS(O)NRlbRlc, -OS(O)2NRlbRlc, -NRlbRlc, -NRlaC(O)Rld, -NRlaC(O)ORld, -NRlaC(O)NRlbRle, -NRlaC(O)SRld, -NRlaC(NRld)NRlbRlc, -NRlaC(S)Rld, -NRlaC(S)ORld,-NRlaC(S)NRlbRlc, -NRlaS(O)Rld, -NRlaS(O)2Rld, -NRlaS(O)NRlbRlc, -NRlaS(O)2NRlbRlc, -SRla, -S(O)Rla, -S(O)2Rla, -S(O)NRlbRlc, or -S(O)2NRlbRlc; or R5aand R5btogether with the carbon atom to which they are attached form C2-6alkenylene, C3-10cycloalkylene, or heterocyclylene, each optionally substituted with one or more substituents Q.

18. The compound of any one of claims 11, 13, 14, and 16, having the structure of Formula (XIII):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; wherein each R5a, R5b, and R5cis independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; or (iii) -C(O)Rla, -C(O)ORla, -C(O)NRlbRlc, -C(O)SRla, -C(NRla)NRlbRlc, -C(S)Rla, -C(S)ORla, -C(S)NRlbRlc, -ORla, -OC(O)Rla, -OC(O)ORla, -OC(O)NRlbRlc, -OC(O)SRla, -OC(NRla)NRlbRlc, -OC(S)Rla, -OC(S)ORla, -OC(S)NRlbRlc, -OS(O)Rla, -OS(O)2Rla, -OS(O)NRlbRlc, -OS(O)2NRlbRlc, -NRlbRlc, -NRlaC(O)Rld, -NRlaC(O)ORld, -NRlaC(O)NRlbRlc, -NRlaC(O)SRld, -NRlaC(NRld)NRlbRlc, -NRlaC(S)Rld, -NRlaC(S)ORld, -NRlaC(S)NRlbRlc, -NRlaS(O)Rld, -NRlaS(O)2Rld, -NRlaS(O)NRlbRlc, -NRlaS(O)2NRlbRlc,SRla, S(O)Rla, S(O)2Rla, S(O)NRlbRlc, or -S(O)2NRlbRlc; or R5aand R5btogether with the carbon atom to which they are attached form C2-6alkenylene, C3-10cycloalkylene, or heterocyclylene, each optionally substituted with one or more substituents Q.

19. The compound of any one of claims 12 to 14, having the structure of Formula(XV):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; wherein each R3a, R5b, and R5eis independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; or (iii) C(O)Rla, C(O)ORla, C(O)NRlbRlc, C(O)SRla, C(NRla)NRlbRle, C(S)Rla, -C(S)ORla, -C(S)NRlbRlc, -ORla, -OC(O)Rla, -OC(O)ORla, -OC(O)NRlbRlc, -OC(O)SRla, -OC(NRla)NRlbRlc, -OC(S)Rla, -OC(S)ORla, -OC(S)NRlbRlc, -OS(O)Rla, -OS(O)2Rla, -OS(O)NRlbRlc, -OS(O)2NRlbRlc, -NRlbRlc, -NRlaC(O)Rld, -NRlaC(O)ORld, -NRlaC(O)NRlbRlc, -NRlaC(O)SRld, -NRlaC(NRld)NRlbRlc, -NRlaC(S)Rld, -NRlaC(S)ORld, -NRlaC(S)NRlbRlc, -NRlaS(O)Rld, -NRlaS(O)2Rld, -NRlaS(O)NRlbRlc, -NRlaS(O)2NRlbRlc, -SR1a, -S(O)R1a, -S(O)2R1 a, -S(O)NR1bRle, or -S(O)2NRlbRlc; or R5aand R5btogether with the carbon atom to which they are attached form C2-6alkenylene, C3-10cycloalkylene, or heterocyclylene, each optionally substituted with one or more substituents Q.

20. The compound of any one of claims 2 to 19, wherein each R3is independently C6-14aryl or heteroaryl, each optionally substituted with one or more substituents Q.

21. The compound of any one of claims 2 to 20, wherein each R3is independently C6-14aryl or heteroaryl, each optionally substituted with one, two, three, or four substituents, each of which is independently (i) halo or cyano; (ii) C1-6alkyl, C1-6heteroalkyl, or C2-6alkynyl, each optionally substituted with one or more substituents Q; or (iii) -ORlaor -NRlbRlc.

22. The compound of any one of claims 2 to 21, wherein each R3is independently phenyl, naphthyl, pyridyl, or benzothienyl, each optionally substituted with one, two, three, or four substituents, each of which is independently fluoro, cyano, methyl, trifluoromethyl, ethynyl, hydroxyl, or amino.

23. The compound of any one of claims 2 to 22, wherein each R3is independently 2- trifluoromethyl-3-methyl-4-fluoro-5-aminophenyl, 3-hydroxy-7-fluoro-8-ethynylnaphth-l-yl, 3- trifluoromethyl-4-methyl-5-fluoro-6-aminopyrid-2-yl, 2-amino-3-cyanobenzothien-4-yl, or 2- amino-3-cyano-7-fluorobenzothien-4-yl.

24. The compound of any one of claims 2 to 7, 13 to 16, and 20 to 23, wherein each R7ais hydrogen.

25. The compound of any one of claims 10, 11, 13 to 15, 17, 18, and 20 to 24, wherein each R8aand R8bis independently hydrogen or C1-6alkyl, optionally substituted with one or more substituents Q.

26. The compound of any one of claims 10, 11, 13 to 15, 17, 18, and 20 to 25, wherein each R8aand R8bis independently hydrogen, methyl, or 1 -hydroxy ethyl.

27. The compound of any one of claims 11, 13 to 15, 18, and 20 to 26, wherein each R8cand R8dis independently hydrogen or C1-6alkyl, optionally substituted with one or more substituents Q.

28. The compound of any one of claims 1 1, 13 to 15, 18, and 20 to 27, wherein each R8cand R8dis independently hydrogen, methyl, or 1 -hydroxy ethyl.

29. The compound of claim 1, having the structure of Formula (XVI):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; wherein: each A is independently a bond, C1-6alkylene, C1-6heteroalkylene, or -O(CR6aR6b)n-; each E2is independently C6-14arylene or heteroarylene; each U is independently C(R2) or N; each R1, R2, and R4is independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)Rla, -C(O)ORla, -C(O)NRlbRlc, -C(O)SRla, -C(NRla)NRlbRlc, -C(S)Rla, -C(S)ORla, -C(S)NRlbRlc, -ORla, -OC(O)Rla, -OC(O)ORla, -OC(O)NRlbRlc, -OC(O)SRla, -OC(NRla)NRlbRlc, -OC(S)Rla, -OC(S)ORla, -OC(S)NRlbRlc, -OS(O)Rla, -OS(O)2Rla, -OS(O)NRlbRlc, -OS(O)2NRlbRle, -NRlbRlc, -NRlaC(O)Rld, -NRlaC(O)ORld, -NRlaC(O)NRlbRlc, -NRlaC(O)SRld, -NRlaC(NRld)NRlbRlc, -NRlaC(S)Rld, -NRlaC(S)ORld, -NRlaC(S)NRlbRlc, -NRlaS(O)Rld, -NRlaS(O)2Rld, -NRlaS(O)NRlbRlc, -NRlaS(O)2NRlbRlc, -SRla, -S(O)Rla, -S(O)2Rla, -S(O)NRlbRlc, or -S(O)2NRlbRlc; or R1and R2together with the carbon atoms to which they are attached form C3-10cycloalkyl or heterocyclyl; each R5is independently C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; each R7is independently (i) C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; or (ii) -NR7bR7c; or R1and R7are linked together to form heterocyclyl; each R6aand R6bis independently (i) hydrogen, deuterium, cyano, halo, or nitro; or (ii) Ci- 6 alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14 aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; or R6aand R6btogether with the carbon atom to which they are attached form C3-10cycloalkylene or heterocyclylene; each R7band R7cis independently (i) hydrogen; (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)Rla, -C(O)ORla, -C(O)NRlbRlc, -C(O)SRla, -C(NRla)NRlbRlc, -C(S)Rla, -C(S)ORla, -C(S)NRlbRlc, -S(O)Rla, -S(O)2Rla, -S(O)NRlbRlc, or -S(O)2NRlbRlc; each Rla, Rlb, Rlc, and Rldis independently hydrogen, deuterium, C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; and n is an integer of 1, 2, 3, 4, or 5; wherein each alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkynyl, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more substituents Q.

30. The compound of claim 29, wherein each R7is independently (i) heterocyclyl, optionally substituted with one or more substituents Q; or (ii) -NR7bR7c.31 . The compound of claim 29 or 30, wherein each R7is independently (i) monocyclic or bicyclic heterocyclyl, optionally substituted with one or more substituents Q; or (ii) -NR7bR7c.

32. The compound of claim 29 or 30, wherein each R7is independently pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, azepanyl, 3,8-diazabicyclo[3.2.1]octanyl, octahydro- pyrrolo[3,2-Z)]pyridin-l-yl, l,6-diazaspiro[3.4]octanyl, 2,6-diazaspiro[3.6]decanyl, 4,7-diaza- spiro[2.5]octyl, or 2,7-diazaspiro[3.5]nonyl, each optionally substituted with one or more substituents Q.

33. The compound of any one of claims 29 to 31, wherein each R7is independently 4- acryloylpiperazin-l-yl, 4-acryloyl-2-methylpiperazin-l-yl, 3-methylaminoazepan-l-yl, 3- acryloylamino-azepan-l-yl, 3,8-diazabicyclo[3.2.1]octan-3-yl, 3,8-diazabicyclo[3.2.1]octan-8-yl, 4-acryloyloctahydropyrrolo[3 ,2-b]pyridin- 1 -yl, 1 -acryloyl- 1 ,6-diazaspiro[3 ,4]octan-6-yl, 2- acryloyl-2,6-diazaspiro[3.6]decan-6-yl, (l-(2-aminopyridin-3-yl)ethyl)(methyl)amino, or (1- acryloyl-2-methyl-pyrrolidin-3-yl)(ethyl)amino.

34. The compound of claim 29, wherein R1and R7are linked together to form heterocyclyl, optionally substituted with one or more substituents Q.

35. The compound of claim 29 or 34, having the structure of Formula (XVII):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; wherein each V2is independently C1-6alkylene or C1-6heteroalkylene, each optionally substituted with one or more substituents Q.

36. The compound of any one of claims 29, 34, and 35, having the structure of Formula (XVIII):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; wherein: each U2is independently C1-6alkylene or C1-6heteroalkylene, each optionally substituted with one or more substituents Q; each R8aand R8bis independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; or (iii) -C(O)Rla, -C(O)ORla, -C(O)NRlbRlc, -C(O)SRla, -C(NRla)NRlbRlc, -C(S)Rla, -C(S)ORla, -C(S)NRlbRlc, -ORla, -OC(O)Rla, -OC(O)ORla, -OC(O)NRlbRlc, -OC(O)SRla, -OC(NRla)NRlbRlc, -OC(S)Rla, -OC(S)ORla, -OC(S)NRlbRlc, -OS(O)Rla, -OS(O)2Rla, -OS(O)NRlbRlc, -OS(O)2NRlbRlc, -NRlbRlc, -NRlaC(O)Rld, -NRlaC(O)ORld, -NRlaC(O)NRlbRlc, -NRlaC(O)SRld, -NRlaC(NRld)NRlbRlc, -NRlaC(S)Rld, -NRlaC(S)ORld, -NRlaC(S)NRlbRlc, -NRlaS(O)Rld, -NRlaS(O)2Rld, -NRlaS(O)NRlbRlc, -NRlaS(O)2NRlbRlc, -SRla, -S(O)Rla, -S(O)2Rla, -S(O)NRlbRlc, or -S(O)2NRlbRlc; or R7band R8aare linked together to form heterocyclyl ene, optionally substituted with one or more substituents Q; or R7band R8bare linked together to form heterocyclylene, optionally substituted with one or more substituents Q37. The compound of any one of claims 29 to 36, wherein each A is independently Ci- 6 heteroalkylene, optionally substituted with one or more substituents Q.

38. The compound of any one of claims 29 to 37, wherein each A is independently -O(CR6aR6b)n-.

39. The compound of any one of claims 36 to 38, having the structure of Formula (XIX):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.

40. The compound of any one of claims 29 to 39, wherein each R5is independently heterocyclyl, optionally substituted with one or more substituents Q.

41. The compound of any one of claims 29 to 40, wherein each R5is independently pyrrolidinyl or hexahydropyrrolizinyl, each optionally substituted with one or more substituents Q42. The compound of any one of claims 29 to 41, wherein each R5is independently 1- methylpyrrolidin-2-yl, l-methyl-3-methoxypyrrolidin-2-yl , 2-fluorohexahydropyrrolizin-7a-yl, 3- (((l,l,l,3,3,3-hexafluoro-2-methylpropan-2-yl)oxy)methyl)hexahydropyrrolizin-7a-yl, 2- (difluoromethylene)hexahydropyrrolizin-7a-yl, or 2, 2-difluorodihydro- 1'H ,3 'H -spiro[cyclo- propane- 1 ,2'-pyrrolizin]-7a'(5'H )-yl .

43. The compound of any one of claims 39 to 41, having the structure of Formula(XXI):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 hydratethereof; wherein each R5a, R5b, and R5cis independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; or (iii) -C(O)Rla, -C(O)ORla, -C(O)NRlbRlc, -C(O)SRla, -C(NRla)NRlbRlc, -C(S)Rla, -C(S)ORla, -C(S)NRlbRlc, -ORla, -OC(O)Rla, -OC(O)ORla, -OC(O)NRlbRlc, -OC(O)SRla, -OC(NRla)NRlbRlc, -OC(S)Rla, -OC(S)ORla, -OC(S)NRlbRlc, -OS(O)Rla, -OS(O)2Rla, -OS(O)NRlbRlc, -OS(O)2NRlbRlc, -NRlbRlc, -NRlaC(O)Rld, -NRlaC(O)ORld, -NRlaC(O)NRlbRlc, -NRlaC(O)SRld, -NRlaC(NRld)NRlbRlc, -NRlaC(S)Rld, -NRlaC(S)ORld, -NRlaC(S)NRlbRlc, -NRlaS(O)Rld, -NRlaS(O)2Rld, -NRlaS(O)NRlbRlc, -NRlaS(O)2NRlbRlc,SRla, S(O)Rla, S(O)2Rla, S(O)NRlbRlc, or -S(O)2NRlbRlc; or R5aand R5btogether with the carbon atom to which they are attached form C2-6alkenylene, C3-10cycloalkylene, or heterocyclylene, each optionally substituted with one or more substituents Q.

44. The compound of claim 1, having the structure of Formula (XXVIII):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; wherein: each A1is independently (i) C1-6alkylene or C1-6heteroalkylene; or (ii) C(O); each E2is independently C6-14arylene or heteroarylene; each U is independently C(R2) or N; each U2is independently C1-6alkylene or C1-6heteroalkylene; each R2, R4, R4a, R8a, and R8bis independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)Rla, -C(O)ORla, -C(O)NRlbRlc, -C(O)SRla, -C(NRla)NRlbRlc, -C(S)Rla, -C(S)ORla, -C(S)NRlbRlc, -ORla, -OC(O)Rla, -OC(O)ORla, -OC(O)NRlbRlc, -OC(O)SRla, -OC(NRla)NRlbRlc, -OC(S)Rla, -OC(S)ORla, -OC(S)NRlbRlc,-OS(O)Rla, -OS(O)2Rla, -OS(O)NRlbRlc, -OS(O)2NRlbRlc, -NRlbRlc, -NRlaC(O)Rld, -NRlaC(O)ORld, -NRlaC(O)NRlbRlc, -NRlaC(O)SRld, -NRlaC(NRld)NRlbRlc, -NRlaC(S)Rld, -NRlaC(S)ORld, -NRlaC(S)NRlbRlc, -NRlaS(O)Rld, -NRlaS(O)2Rld, -NRlaS(O)NRlbRlc, -NRlaS(O)2NRlbRlc, -SRla, -S(O)Rla, -S(O)2Rla, -S(O)NRlbRlc, or -S(O)2NRlbRlc; each R7bis independently (i) hydrogen; (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14 aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)Rla, -C(O)ORla, -C(O)NRlbRlc, -C(O)SRla, -C(NRla)NRlbRlc, -C(S)Rla, -C(S)ORla, -C(S)NRlbRlc, -S(O)Rla, -S(O)2Rla, -S(O)NRlbRlc, or -S(O)2NRlbRlc; or R7band R8aare linked together to form heterocyclylene; or R7band R8bare linked together to form heterocyclylene; and each Rla, Rlb, Rlc, and Rldis independently hydrogen, deuterium, C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; wherein each alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkynyl, cycloalkyl, aryl, arylene, aralkyl, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more substituents Q.

45. The compound of any one of claims 29 to 44, wherein each E2is independently C6- 14 arylene, optionally substituted with one or more substituents Q.

46. The compound of any one of claims 29 to 44, wherein each E2is independently heteroarylene, optionally substituted with one or more substituents Q.

47. The compound of any one of claims 29 to 44 and 46, wherein each E2is independently 6-membered or 5,6-fused heteroarylene, each optionally substituted with one or more substituents Q.

48. The compound of any one of claims 29 to 44, wherein each E2is independently phendiyl, naphthdiyl, pyridindiyl, or benzothiendiyl, each optionally substituted with one or more substituents Q.

49. The compound of any one of claims 35 to 48, wherein each R7bis independently C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, or heterocyclyl, each optionally substituted with one or more substituents Q.

50. The compound of any one of claims 35 to 49, wherein each R7bis independently 2,2-difluoroethyl, l-(2-aminopyrid-3-yl)ethyl, l-(2-aminopyrid-3-yl)-2,2-difluoroethyl, l-(2- aminopyrid-3-yl)-3-fluoroprop-2-enyl, l-(2-aminopyrid-3-yl)but-3-enyl, l-(4-aminopyrimid-5- yl)ethyl, or l-acryloyl-2-methylpyrrolidin-3-yl.

51. The compound of any one of claims 36 to 50, wherein each R8aand R8bis independently hydrogen or C1-6alkyl, optionally substituted with one or more substituents Q.

52. The compound of any one of claims 36 to 51, wherein each R8aand R8bis independently hydrogen, methyl, or 1 -hydroxy ethyl.

53. The compound of any one of claims 36 to 48, wherein R7band R8aare linked together to form heterocyclylene, optionally substituted with one or more substituents Q; or R7band R8bare linked together to form heterocyclylene, optionally substituted with one or more substituents Q.

54. The compound of claim 36 or 53, having the structure of Formula (XXV):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; wherein: each R2a, R2b, R2c, and R2dis independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14 aryl, C7-15aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; or (iii) -C(O)Rla, -C(O)ORla, -C(O)NRlbRlc, -C(O)SRla, -C(NRla)NRlbRlc, -C(S)Rla, -C(S)ORla, -C(S)NRlbRlc, -ORla, -OC(O)Rla, -OC(O)ORla, -OC(O)NRlbRlc, -OC(O)SRla, -OC(NRla)NRlbRlc, -OC(S)Rla, -OC(S)ORla, -OC(S)NRlbRlc, -OS(O)Rla, -OS(O)2Rla,-OS(O)NRlbRlc, -OS(O)2NRlbRlc, -NRlbRlc, -NRlaC(O)Rld, -NRlaC(O)ORld, -NRlaC(O)NRlbRlc, -NRlaC(O)SRld, -NRlaC(NRld)NRlbRlc, -NRlaC(S)Rld, -NRlaC(S)ORld, -NRlaC(S)NRlbRlc, -NRlaS(O)Rld, -NRlaS(O)2Rld, -NRlaS(O)NRlbRlc, -NRlaS(O)2NRlbRlc, -SRla, -S(O)Rla, -S(O)2Rla, -S(O)NRlbRlc, or -S(O)2NRlbRlc; and each R7dis independently (i) hydrogen; (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14 aryl, C7-15aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; or (iii) -C(O)Rla, -C(O)ORla, -C(O)NRlbRlc, -C(O)SRla, -C(NRla)NRlbRlc, -C(S)Rla, -C(S)ORla, -C(S)NRlbRlc, -S(O)Rla, -S(O)2Rla, -S(O)NRlbRlc, or -S(O)2NRlbRlc.

55. The compound of claim 54, wherein each A is independently (i) a bond; or (ii) C1-6heteroalkylene, optionally substituted with one or more substituents Q.

56. The compound of claim 54 or 55, wherein each A is independently (i) a bond; or (ii) -O(CR6aR6b)n-.

57. The compound of any one of claims 54 to 56, wherein each R5is independently heterocyclyl, optionally substituted with one or more substituents Q.

58. The compound of any one of claims 54 to 57, wherein each R5is independently pyrrolidinyl or hexahydropyrrolizinyl, each optionally substituted with one or more substituents Q59. The compound of any one of claims 54 to 58, wherein each R5is independently hydrogen, l-methylpyrrolidin-2-yl, l-methyl-3-methoxypyrrolidin-2-yl , 2-fluorohexahydro- pyrrolizin-7a-yl, 3 -((( 1 , 1 , 1 ,3 , 3 ,3 -hexafluoro-2-methylpropan-2-yl)oxy)methyl)hexahy dro- pyrrolizin-7a-yl, 2-(difluoromethylene)hexahydropyrrolizin-7a-yl, or 2,2-difluorodihydro- TH ,3'H-spiro[cyclo-propane-l,2'-pyrrolizin]-7a'(5'H)-yl.

60. The compound of claim 44 or 53, having the structure of Formula (XXX):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; wherein: each R2a, R2b, R2c, and R2dis independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14 aryl, C7-15aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; or (iii) -C(O)Rla, -C(O)ORla, -C(O)NRlbRlc, -C(O)SRla, -C(NRla)NRlbRlc, -C(S)Rla, -C(S)ORla, -C(S)NRlbRlc, -ORla, -OC(O)Rla, -OC(O)ORla, -OC(O)NRlbRlc, -OC(O)SRla, -OC(NRla)NRlbRlc, -OC(S)Rla, -OC(S)ORla, -OC(S)NRlbRlc, -OS(O)Rla, -OS(O)2Rla, -OS(O)NRlbRlc, -OS(O)2NRlbRlc, -NRlbRlc, -NRlaC(O)Rld, -NRlaC(O)ORld, -NRlaC(O)NRlbRlc, -NRlaC(O)SRld, -NRlaC(NRld)NRlbRlc, -NRlaC(S)Rld, -NRlaC(S)ORld, -NRlaC(S)NRlbRlc, -NRlaS(O)Rld, -NRlaS(O)2Rld, -NRlaS(O)NRlbRlc, -NRlaS(O)2NRlbRlc, -SRla, -S(O)Rla, -S(O)2Rla, -S(O)NRlbRlc, or -S(O)2NRlbRlc; and each R7dis independently (i) hydrogen; (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; or (iii) -C(O)Rla, -C(O)ORla, -C(O)NRlbRlc, -C(O)SRla, -C(NRla)NRlbRlc, -C(S)Rla, -C(S)ORla, -C(S)NRlbRlc, -S(O)Rla, -S(O)2Rla, -S(O)NRlbRlc, or -S(O)2NRlbRlc.

61. The compound of claim 60, wherein each R4ais hydrogen.

62. The compound of any one of claims 54 to 61, wherein each R2ais cyano.

63. The compound of any one of claims 54 to 62, wherein each R2band R2cis hydrogen.

64. The compound of any one of claims 54 to 63, wherein each R2dis halo.

65. The compound of any one of claims 54 to 64, wherein each R2dis fluoro.

66. The compound of any one of claims 54 to 65, wherein each R7dis independently-C(O)Rla.

67. The compound of any one of claims 54 to 66, wherein each R7dis independently acroyl or propioloyl, each optionally substituted with one or more substituents Q.

68. The compound of any one of claims 36 to 67, wherein each U2is independently C1-6alkylene, optionally substituted with one or more substituents Q.

69. The compound of any one of claims 36 to 68, wherein each U2is independently methane- 1,1 -diyl or ethane-l,2-diyl, each optionally substituted with one or more substituents Q.

70. The compound of any one of claims 2 to 69, wherein each U is independently C(R2).

71. The compound of any one of claims 2 to 69, wherein each U is N.

72. The compound of any one of claims 2 to 7, 12 to 16, 19 to 33, 37, 38, 40 to 42, 45 to 48, 70, and 71, wherein each R1is hydrogen.

73. The compound of claim 70 or 72, wherein each R2is independently (i) halo; or (ii) C1-6alkyl or C1-6heteroalkyl, each optionally substituted with one or more substituents Q.

74. The compound of any one of claims 70, 72, and 73, wherein each R2is independently chloro or trifluorom ethyl.

75. The compound of any one of claims 2 to 74, wherein each R4is independently halo.

76. The compound of any one of claims 2 to 75, wherein each R4is fluoro.

77. The compound of any one of claims 16 to 28, 43, 45 to 53, and 68 to 76, wherein each R5ais hydrogen.

78. The compound of any one of claims 16 to 28, 43, 45 to 53, and 68 to 77, wherein each R5bis independently hydrogen or halo.

79. The compound of any one of claims 16 to 28, 43, 45 to 53, and 68 to 78, wherein each R5bis hydrogen or fluoro.

80. The compound of any one of claims 16 to 28, 43, 45 to 53, and 68 to 76, wherein R5aand R5btogether with the carbon atom to which they are attached form C2-6alkenylene or C3-10cycloalkylene, each optionally substituted with one or more substituents Q.

81. The compound of any one of claims 16 to 28, 43, 45 to 53, 68 to 76, and 80, wherein R5aand R5btogether with the carbon atom to which they are attached form 2,2-difluoro- ethen- 1 , 1 -diyl or 2,2-difluorocycloprop- 1 , 1 -diyl .

82. The compound of any one of claims 16 to 28, 43, 45 to 53, and 68 to 81, wherein each R5cis independently (i) hydrogen; or (ii) C1-6alkylene or C1-6heteroalkylene, each optionally substituted with one or more substituents Q.

83. The compound of any one of claims 16 to 28, 43, 45 to 53, and 68 to 82, wherein each R5cis hydrogen or (l,l-(di(trifluoromethyl)ethoxy)methyl.

84. The compound of any one of claims 4 to 28, 38 to 43, 45 to 53, and 68 to 83, wherein each R6aand R6bis hydrogen.

85. The compound of claim 1, having the structure of Formula (XXVI):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; wherein: each A is independently a bond, C1-6alkylene, C1-6heteroalkylene, or -O(CR6aR6b)n-; each E3is independently C3-10cycloalkylene, C6-14arylene, heteroarylene, orheterocyclylene; each U is independently C(R2) or N; each R1, R2, R3, and R4is independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)Rla, -C(O)ORla, -C(O)NRlbRle, -C(O)SRla, -C(NRla)NRlbRlc, -C(S)Rla, -C(S)ORla, -C(S)NRlbRlc, -ORla, -OC(O)Rla, -OC(O)ORla, -OC(O)NRlbRlc, -OC(O)SRla, -OC(NRla)NRlbRlc, -OC(S)Rla, -OC(S)ORla, -OC(S)NRlbRlc, -OS(O)Rla, -OS(O)2Rla, -OS(O)NRlbRlc, -OS(O)2NRlbRlc, -NRlbRlc, -NRlaC(O)Rld, -NRlaC(O)ORld, -NRlaC(O)NRlbRlc, -NRlaC(O)SRld, -NRlaC(NRld)NRlbRlc, -NRlaC(S)Rld, NRlaC(S)ORld, NRlaC(S)NRlbRlc, NRlaS(O)Rld, NRlaS(O)2Rld, NRlaS(O)NRlbRlc, -NRlaS(O)2NRlbRlc, -SRla, -S(O)Rla, -S(O)2Rla, -S(O)NRlbRlc, or -S(O)2NRlbRlc; or R1and R2together with the carbon atoms to which they are attached form C3-10cycloalkyl or heterocyclyl; each R7is independently (i) C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; or (ii) -NR7bR7c; or R1and R7are linked together to form heterocyclyl; each R6aand R6bis independently (i) hydrogen, deuterium, cyano, halo, or nitro; or (ii) Ci- 6 alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; or R6aand R6btogether with the carbon atom to which they are attached form C3-10cycloalkylene or heterocyclyl ene; each R7band R7cis independently (i) hydrogen; (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)Rla, -C(O)ORla, -C(O)NRlbRlc, -C(O)SRla, -C(NRla)NRlbRlc, -C(S)Rla, -C(S)ORla, -C(S)NRlbRlc, -S(O)Rla, -S(O)2Rla, -S(O)NRlbRlc, or -S(O)2NRlbRlc; and each Rla, Rlb, Rlc, and Rldis independently hydrogen, deuterium, C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; n is an integer of 1, 2, 3, 4, or 5; wherein each alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkynyl, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more substituents Q.

86. The compound of claim 85, wherein each A is independently C1-6heteroalkylene,optionally substituted with one or more substituents Q.

87. The compound of claim 85 or 86, wherein each A is independently -O(CR6aR6b)n-88. The compound of any one of claims 85 to 87, having the structure of Formula (XXVII):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.

89. The compound of claim 1, having the structure of Formula (XXXI):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; wherein: each A is independently a bond, C1-6alkylene, C1-6heteroalkylene, or -O(CR6aR6b)n-; each E4is independently C3-10cycloalkylene, C6-14arylene, heteroarylene, or heterocyclylene, each optionally substituted with one or more substituents Q; each U3is N and each V3is O; or each U3is O and each V3is N; each R5is independently C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; each R11, R12, and R15is independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii)C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; or (iii) -C(O)Rla, -C(O)ORla, -C(O)NRlbRlc, -C(O)SRla, -C(NRla)NRlbRlc, -C(S)Rla, -C(S)ORla, -C(S)NRlbRlc, -ORla, -OC(O)Rla, -OC(O)ORla, -OC(O)NRlbRlc, -OC(O)SRla, -OC(NRla)NRlbRlc, -OC(S)Rla, -OC(S)ORla, -OC(S)NRlbRlc, -OS(O)Rla, -OS(O)2Rla, -OS(O)NRlbRlc, -OS(O)2NRlbRlc, -NRlbRlc, -NRlaC(O)Rld, -NRlaC(O)ORld, -NRlaC(O)NRlbRlc, -NRlaC(O)SRld, -NRlaC(NRld)NRlbRlc, -NRlaC(S)Rld, -NRlaC(S)ORld, -NRlaC(S)NRlbRlc, -NRlaS(O)Rld, -NRlaS(O)2Rld, -NRlaS(O)NRlbRlc, -NRlaS(O)2NRlbRlc, -SRla, -S(O)Rla, -S(O)2Rla, -S(O)NRlbRlc, or -S(O)2NRlbRlc; each R13and R14is independently (i) deuterium, cyano, halo, or nitro; (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; or (iii) -C(O)Rla, -C(O)ORla, -C(O)NRlbRlc, -C(O)SRla, -C(NRla)NRlbRlc, -C(S)Rla, -C(S)ORla, -C(S)NRlbRlc, -ORla, -OC(O)Rla, -OC(O)ORla, -OC(O)NRlbRlc, -OC(O)SRla, -OC(NRla)NRlbRlc, -OC(S)Rla, -OC(S)ORla, -OC(S)NRlbRlc, -OS(O)Rla, -OS(O)2Rla, -OS(O)NR1bRlc, -OS(O)2NR1bR1c, -NR1bRlc, -NR1aC(O)Rld, -NRlaC(O)ORl d, -NRlaC(O)NRlbRlc, -NRlaC(O)SRld, -NRlaC(NRld)NRlbRlc, -NRlaC(S)Rld, -NRlaC(S)ORld, -NRlaC(S)NRlbRlc, -NRlaS(O)Rld, -NRlaS(O)2Rld, -NRlaS(O)NRlbRlc, -NRlaS(O)2NRlbRlc, -SRla, -S(O)Rla, -S(O)2Rla, -S(O)NRlbRlc, or -S(O)2NRlbRlc; each Rla, Rlb, Rlc, and Rldis independently hydrogen, deuterium, C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; each R6aand R6bis independently (i) hydrogen, deuterium, cyano, halo, or nitro; or (ii) Ci- 6 alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; or R6aand R6btogether with the carbon atom to which they are attached form C3-10cycloalkylene or heterocyclylene; n is an integer of 1, 2, 3, 4, or 5; and each p and q is independently an integer of 0, 1, 2, 3, 4, 5, or 6; wherein each alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkynyl, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more substituents Q.

90. The compound of claim 89, wherein each A is independently C1-6heteroalkylene, optionally substituted with one or more substituents Q.

91. The compound of claim 89 or 90, wherein each A is independently-O(CR6aR6b)n-92. The compound of any one of claims 89 to 91, having the structure of Formula(XXXII):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.

93. The compound of any one of claims 89 to 92, wherein each E4is independently heteroarylene or heterocyclylene, each optionally substituted with one or more substituents Q.

94. The compound of any one of claims 89 to 93, wherein each E4is independently bicyclic heterocyclylene, optionally substituted with one or more substituents Q.

95. The compound of any one of claims 89 to 94, having the structure of Formula (XXXIV):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; wherein each R17is independently (i) deuterium, cyano, halo, or nitro; (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; or (iii) -C(O)Rla, -C(O)ORla, -C(O)NRlbRlc, -C(O)SRla, -C(NRla)NRlbRlc, -C(S)Rla, -C(S)ORla, -C(S)NRlbRlc, -ORla, -OC(O)Rla, -OC(O)ORla, -OC(O)NRlbRlc, -OC(O)SRla, -OC(NRla)NRlbRlc, -OC(S)Rla, -OC(S)ORla, -OC(S)NRlbRle, -OS(O)Rla, -OS(O)2Rla, -OS(O)NRlbRlc, -OS(O)2NRlbRlc, -NRlbRlc, -NRlaC(O)Rld, -NRlaC(O)ORld, -NRlaC(O)NRlbRlc, -NRlaC(O)SRld, -NRlaC(NRld)NRlbRle, -NRlaC(S)Rld, -NRlaC(S)ORld, -NRlaC(S)NRlbRlc, -NRlaS(O)Rld, -NRlaS(O)2Rld, -NRlaS(O)NRlbRlc, -NRlaS(O)2NRlbRlc, -SRla, -S(O)Rla, -S(O)2Rla, -S(O)NRlbRlc, or -S(O)2NRlbRlc; and each r is independently an integer of 0, 1, 2, 3, 4, 5, or 6.

96. The compound of any one of claims 89 to 94, having the structure of Formula (XXXVI):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; wherein each R17is independently (i) deuterium, cyano, halo, or nitro; (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q; or (iii) -C(O)Rla, -C(O)ORla, -C(O)NRlbRlc, -C(O)SRla, -C(NRla)NRlbRlc, -C(S)Rla, -C(S)ORla, -C(S)NRlbRlc, -ORla, -OC(O)Rla, -OC(O)ORla, -OC(O)NRlbRlc, -OC(O)SRla, -OC(NRla)NRlbRlc, -OC(S)Rla, -OC(S)ORla, -OC(S)NRlbRlc, -OS(O)Rla, -OS(O)2Rla, -OS(O)NRlbRlc, -OS(O)2NRlbRlc, -NRlbRlc, -NRlaC(O)Rld, -NRlaC(O)ORld, -NRlaC(O)NRlbRlc, -NRlaC(O)SRld, -NRlaC(NRld)NRlbRlc, -NRlaC(S)Rld, -NRlaC(S)ORld, -NRlaC(S)NRlbRlc, -NRlaS(O)Rld, -NRlaS(O)2Rld, -NRlaS(O)NRlbRlc, -NRlaS(O)2NRlbRlc, -SRla, -S(O)Rla, -S(O)2Rla, -S(O)NRlbRlc, or -S(0)2NRlbRlc; and each r is independently an integer of 0, 1, 2, 3, 4, 5, or 6.

97. The compound of claim 95 or 96, wherein each r is an integer of 0.

98. The compound of any one of claims 89 to 97, wherein each R11is independently -NRlbRlc.

99. The compound of any one of claims 89 to 98, wherein each R11is amino.

100. The compound of claim 1, having the structure of Formula (XXXVII):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; wherein: each A is independently a bond, C1-6alkylene, C1-6heteroalkylene, or -O(CR6aR6b)n-; each U3is N and each V3is O; or each U3is O and each V3is N; each R5is independently C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; each R12, R15, and R16is independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)Rla, -C(O)ORla, -C(O)NRlbRlc, -C(O)SRla, -C(NRla)NRlbRlc, -C(S)Rla, -C(S)ORla, -C(S)NRlbRlc, -ORla, -OC(O)Rla, -OC(O)ORla, -OC(O)NR1bR1c, -OC(O)SR’a, -OC(NR1a)NRlbR1 c, -OC(S)R1a, -OC(S)ORla, -OC(S)NRlbR1c, -OS(O)Rla, -OS(O)2Rla, -OS(O)NRlbRlc, -OS(O)2NRlbRlc, -NRlbRlc, -NRlaC(O)Rld, -NRlaC(O)ORld, -NRlaC(O)NRlbRlc, -NRlaC(O)SRld, -NRlaC(NRld)NRlbRlc, -NRlaC(S)Rld, -NRlaC(S)ORld, -NRlaC(S)NRlbRlc, -NRlaS(O)Rld, -NRlaS(O)2Rld, -NRlaS(O)NRlbRlc, -NRlaS(O)2NRlbRlc, -SRla, -S(O)Rla, -S(O)2Rla, -S(O)NRlbRlc, or -S(O)2NRlbRlc; each R13and R14is independently (i) deuterium, cyano, halo, or nitro; (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)Rla, -C(O)ORla, -C(O)NRlbRlc, -C(O)SRla, -C(NRla)NRlbRlc, -C(S)Rla, -C(S)ORla, -C(S)NRlbRlc, -ORla, -OC(O)Rla, -OC(O)ORla, -OC(O)NRlbRlc, -OC(O)SRla, -OC(NRla)NRlbRlc, -OC(S)Rla, -OC(S)ORla, -OC(S)NRlbRlc, -OS(O)Rla, -OS(O)2Rla, -OS(O)NRlbRlc, -OS(O)2NRlbRlc, -NRlbRlc, -NRlaC(O)Rld, -NRlaC(O)ORld, -NRlaC(O)NRlbRle, -NRlaC(O)SRld, -NRlaC(NRld)NRlbRlc, -NRlaC(S)Rld, -NRlaC(S)ORld, -NRlaC(S)NRlbRlc, -NRlaS(O)Rld, -NRlaS(O)2Rld, -NRlaS(O)NRlbRlc, -NRlaS(O)2NRlbRlc,-SRla, -S(O)Rla, -S(O)2Rla, -S(O)NRlbRlc, or -S(O)2NRlbRlc; each Rla, Rlb, Rlc, and Rldis independently hydrogen, deuterium, C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; each R6aand R6bis independently (i) hydrogen, deuterium, cyano, halo, or nitro; or (ii) Ci- 6 alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; or R6aand R6btogether with the carbon atom to which they are attached form C3-10cycloalkylene or heterocyclyl ene; n is an integer of 1, 2, 3, 4, or 5; and each p and q is independently an integer of 0, 1, 2, 3, 4, 5, or 6; wherein each alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkynyl, cycloalkyl, cycloalkylene, aryl, aralkyl, heteroaryl, heterocyclyl, and heterocyclylene is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q.

101. The compound of claim 100, wherein each A is independently C1-6heteroalkylene, optionally substituted with one or more substituents Q.

102. The compound of claim 100 or 101, wherein each A is independently-O(CR6aR6b)n-103. The compound of any one of claims 100 to 102, having the structure of Formula(XL):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.

104. The compound of any one of claims 100 to 102, having the structure of Formula(XLII):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.

105. The compound of any one of claims 100 to 104, wherein each R16is independently heteroaryl or heterocyclyl, each optionally substituted with one or more substituents Q.

106. The compound of any one of claims 100 to 105, wherein each R16is independently 3 -(aminocarbony l)pyrazol- 1 -yl , 3 -(i sopropylaminocarbony l)pyrazol- 1 -yl , 3 -(tetrahydrofur-3 - ylaminocarbonyl)pyrazol-l-yl, 4,7-diazaspiro[2.5]octyl, or 2,7-diazaspiro[3.5]nonyl.

107. The compound of any one of claims 100 to 106, wherein each R5is independently heterocyclyl, optionally substituted with one or more substituents Q.

108. The compound of any one of claims 100 to 107, wherein each R5is independently pyrrolidinyl or hexahydropyrrolizinyl, each optionally substituted with one or more substituents Q109. The compound of any one of claims 100 to 108, wherein each R5is independently l-methylpyrrolidin-2-yl, l-methyl-3-methoxypyrrolidin-2-yl, 2-fluorohexahydropyrrolizin-7a-yl, 3-(((l,l,l,3,3,3-hexafluoro-2-methylpropan-2-yl)oxy)methyl)hexahydropyrrolizin-7a-yl, 2- (difluoromethylene)hexahydropyrrolizin-7a-yl, or 2,2-difluorodihydro-TH ,3'H-spiro[cyclo- propane- 1 ,2'-pyrrolizin]-7a'(5'H)-yl .

110. The compound of any one of claims 100 to 109, wherein each R12is cyano.

111. The compound of any one of claims 100 to 110, wherein each R15is independently hydrogen or halo.

112. The compound of any one of claims 100 to 111, wherein each R13is independently hydrogen or fluoro.

113. The compound of any one of claims 102 to 112, wherein each R6aand R6bis hydrogen.

114. The compound of any one of claims 100 to 113, wherein each p and q is an integer of 0.

115. The compound of claim 1, having the structure of Formula (XLIII):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; wherein: each E5is independently a bond oreach E6and Z is independently C3-10cycloalkylene, C6-14arylene, heteroarylene, or heterocyclylene; each E7is independently (i) C3-10cycloalkylene, C6-14arylene, heteroarylene, or heterocyclylene; or (ii) -NRlb-; each R21is independently (i) hydrogen, deuterium, or cyano; or (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, orheterocyclyl; each R22and R27is independently (i) deuterium, cyano, halo, or nitro; (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)Rla, -C(O)ORla, -C(O)NRlbRlc, -C(O)SRla, -C(NRla)NRlbRlc, -C(S)Rla, -C(S)ORla, -C(S)NRlbRlc, -ORla, -OC(O)Rla, -OC(O)ORla, -OC(O)NRlbRle, -OC(O)SRla, -OC(NRla)NRlbRlc, -OC(S)Rla, -OC(S)ORla, -OC(S)NRlbRlc, -OS(O)Rla, -OS(O)2Rla, -OS(O)NRlbRlc, -OS(O)2NRlbRlc, -NRlbRlc, -NRlaC(O)Rld, -NRlaC(O)ORld, -NRlaC(O)NRlbRlc, -NRlaC(O)SRld, -NRlaC(NRld)NRlbRlc, -NRlaC(S)Rld, -NRlaC(S)ORld, -NRlaC(S)NRlbRlc, -NRlaS(O)Rld, -NRlaS(O)2Rld, -NRlaS(O)NRlbRlc, -NRlaS(O)2NRlbRlc, SRla, S(O)Rla, S(O)2Rla, S(O)NRlbRlc, or S(O)2NRlbRlc; each R23is independently (i) hydrogen; (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)Rla, -C(O)ORla, -C(O)NRlbRlc, -C(O)SRla, -C(NRla)NRlbRlc, -C(S)Rla, -C(S)ORla, -C(S)NRlbRlc, -S(O)Rla, -S(O)2Rla, -S(O)NRlbRlc, or -S(O)2NRlbRlc; each R24, R25, and R26is independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)Rla, -C(O)ORla, -C(O)NRlbRlc, -C(O)SRla, -C(NRla)NRlbRlc, -C(S)Rla, -C(S)ORla, -C(S)NRlbRlc, -ORla, -OC(O)Rla, -OC(O)ORla, -OC(O)NRlbRlc, -OC(O)SRla, -OC(NRla)NRlbRlc, -OC(S)Rla, -OC(S)ORla, -OC(S)NRlbRlc, -OS(O)Rla, -OS(O)2Rla, -OS(O)NRlbRlc, -OS(O)2NRlbRlc, -NRlbRlc, -NRlaC(O)Rld, -NRlaC(O)ORld, -NRlaC(O)NRlbRlc, -NRlaC(O)SRld, -NRlaC(NRld)NRlbRlc, -NRlaC(S)Rld, -NRlaC(S)ORld, -NRlaC(S)NRlbRlc, -NRlaS(O)Rld, -NRlaS(O)2Rld, -NRlaS(O)NRlbRlc, -NRlaS(O)2NRlbRlc, -SRla, -S(O)Rla, -S(O)2Rla, -S(O)NRlbRlc, or -S(O)2NRlbRlc; or R25and R26together with the carbon atoms to which they are attached form C3-10cycloalkylene or heterocyclylene; each Rla, Rlb, Rlc, and Rldis independently hydrogen, deuterium, C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; each s is independently an integer of 0, 1, 2, or 3; each t is independently an integer of 0, 1, 2, 3, 4, 5, or 6; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylene, aryl, arylene,aralkyl, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q.

116. The compound of claim 115, having the structure of Formula (XLV):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.

117. The compound of claim 115 or 116, wherein each E6is independently heterocyclylene, optionally substituted with one or more substituents Q.

118. The compound of any one of claims 115 to 117, wherein each E6is aziridindiyl or piperidindiyl, each optionally substituted with one or more substituents Q.

119. The compound of any one of claims 115 to 118, wherein each E6is 3-cyclopropyl- aziridin-l,2-diyl or piperidin-l,4-diyl.

120. The compound of any one of claims 115 to 119, wherein each E7is independently (i) heterocyclylene, optionally substituted with one or more substituents Q; or (ii) -NRlb-121. The compound of any one of claims 115 to 120, wherein each E7is 2,7-diaza- spiro[4.4]nonandiyl, optionally substituted with one or more substituents Q.

122. The compound of any one of claims 115 to 120, wherein each E7is l-oxo-2,7- diazaspiro[4.4]-nonan-2,7-diyl or -N(CH3)-.

123. The compound of any one of claims 115 to 122, wherein each R21is independently (i) hydrogen; or (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q.

124. The compound of any one of claims 115 to 123, wherein each R21is independently C1-6alkyl or C3-10cycloalkyl, each optionally substituted with one or more substituents Q.

125. The compound of any one of claims 115 to 124, wherein each R21is isopropyl or cyclopentyl, optionally substituted with one or more substituents Q.

126. The compound of any one of claims 115 to 125, wherein each R24is independently heteroaryl, optionally substituted with one or more substituents Q.

127. The compound of any one of claims 115 to 126, wherein each R24is independently pyridyl, optionally substituted with one or more substituents Q.

128. The compound of any one of claims 115 to 127, wherein each R24is independently 2-(l -methoxy ethyl)pyrid-3-yl or 2-(l -methoxy ethyl)-5-(4-methylpiperaz-l-yl)pyrid-3-yl.

129. The compound of claim 1, having the structure of Formula (XL VI):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; wherein: each E8and Z is independently C3-10cycloalkylene, C6-14arylene, heteroarylene, or heterocyclylene; each E9is independently a bond, C3-10cycloalkylene, C6-14arylene, heteroarylene, or heterocyclylene; each R22and R27is independently (i) deuterium, cyano, halo, or nitro; (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, orheterocyclyl; or (iii) -C(O)Rla, -C(O)ORla, -C(O)NRlbRlc, -C(O)SRla, -C(NRla)NRlbRlc, -C(S)Rla, -C(S)ORla, -C(S)NRlbRlc, -ORla, -OC(O)Rla, -OC(O)ORla, -OC(O)NRlbRlc, -OC(O)SRla, -OC(NRla)NRlbRlc, -OC(S)Rla, -OC(S)ORla, -OC(S)NRlbRlc, -OS(O)Rla, -OS(O)2Rla, -OS(O)NRlbRlc, -OS(O)2NRlbRlc, -NRlbRlc, -NRlaC(O)Rld, -NRlaC(O)ORld, -NRlaC(O)NRlbRlc, -NRlaC(O)SRld, -NRlaC(NRld)NRlbRlc, -NRlaC(S)Rld, -NRlaC(S)ORld, -NRlaC(S)NRlbRlc, -NRlaS(O)Rld, -NRlaS(O)2Rld, -NRlaS(O)NRlbRlc, -NRlaS(O)2NRlbRlc, -SRla, -S(O)Rla, -S(O)2Rla, -S(O)NRlbRlc, or -S(O)2NRlbRlc; each R23is independently hydrogen, C1-6alkyl, C1-6heteroalkyl, C2-6 alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; each R25, R26, and R28is independently hydrogen, deuterium, C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; each Rla, Rlb, Rlc, and Rldis independently hydrogen, deuterium, C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; each s is independently an integer of 0, 1, 2, or 3; and each t is independently an integer of 0, 1, 2, 3, 4, 5, or 6; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q.

130. The compound of claim 129, having the structure of Formula (XL VII):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.

131. The compound of claim 129 or 130, wherein each E8is independently monocyclicheteroarylene, optionally substituted with one or more substituents Q.

132. The compound of any one of claims 129 to 131, wherein each E8is independently pyridindiyl, optionally substituted with one or more substituents Q.

133. The compound of any one of claims 129 to 132, wherein each E9is independently a bond or heterocyclylene, optionally substituted with one or more substituents Q.

134. The compound of any one of claims 129 to 133, wherein each E9is independently piperazindiyl, optionally substituted with one or more substituents Q.

135. The compound of claim 1, having the structure of Formula (XLVIII):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; wherein each Z is independently C3-10cycloalkylene, C6-14arylene, heteroarylene, or heterocyclylene; each R22and R27is independently (i) deuterium, cyano, halo, or nitro; (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)Rla, -C(O)ORla, -C(O)NRlbRlc, -C(O)SRla, -C(NRla)NRlbRlc, -C(S)Rla, -C(S)ORla, -C(S)NRlbRlc, -ORla, -OC(O)Rla, -OC(O)ORla, -OC(O)NRlbRlc, -OC(O)SRla, -OC(NRla)NRlbRlc, -OC(S)Rla, -OC(S)ORla, -OC(S)NRlbRlc, -OS(O)Rla, -OS(O)2Rla, -OS(O)NRlbRlc, -OS(O)2NRlbRlc, -NRlbRlc, -NRlaC(O)Rld, -NRlaC(O)ORld, -NRlaC(O)NRlbRlc, -NRlaC(O)SRld, -NRlaC(NRld)NRlbRlc, -NRlaC(S)Rld, -NRlaC(S)ORld, NRlaC(S)NRlbRlc, NRlaS(O)Rld, NRlaS(O)2Rld, NRlaS(O)NRlbRlc, NRlaS(O)2NRlbRlc, -SRla, -S(O)Rla, -S(O)2Rla, -S(O)NRlbRlc, or -S(O)2NRlbRlc;each R23is independently (i) hydrogen; (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)Rla, -C(O)ORla, -C(O)NRlbRlc, -C(O)SRla, -C(NRla)NRlbRlc, -C(S)Rla, -C(S)ORla, -C(S)NRlbRlc, -S(O)Rla, -S(O)2Rla, -S(O)NRlbRlc, or -S(O)2NRlbRlc; each R24, R25, and R26is independently (i) hydrogen, deuterium, cyano, halo, or nitro; (ii) C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; or (iii) -C(O)Rla, -C(O)ORla, -C(O)NRlbRlc, -C(O)SRla, -C(NRla)NRlbRlc, -C(S)Rla, -C(S)ORla, -C(S)NRlbRlc, -ORla, -OC(O)Rla, -OC(O)ORla, -OC(O)NRlbRlc, -OC(O)SRla, -OC(NRla)NRlbRlc, -OC(S)Rla, -OC(S)ORla, -OC(S)NRlbRlc, OS(O)Rla, OS(O)2Rla, OS(O)NRlbRlc, OS(O)2NRlbRlc, NRlbRlc, NRlaC(O)Rld, -NRlaC(O)ORld, -NRlaC(O)NRlbRlc, -NRlaC(O)SRld, -NRlaC(NRld)NRlbRlc, -NRlaC(S)Rld, -NRlaC(S)ORld, -NRlaC(S)NRlbRlc, -NRlaS(O)Rld, -NRlaS(O)2Rld, -NRlaS(O)NRlbRlc, -NRlaS(O)2NRlbRlc, -SRla, -S(O)Rla, -S(O)2Rla, -S(O)NRlbRlc, or -S(O)2NRlbRlc; or R25and R26together with the carbon atoms to which they are attached form C3-10cycloalkylene or heterocyclylene; each R28is independently hydrogen, C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; each Rla, Rlb, Rlc, and Rldis independently hydrogen, deuterium, C1-6alkyl, C1-6heteroalkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C6-14aryl, C7-15aralkyl, heteroaryl, or heterocyclyl; each s is independently an integer of 0, 1, 2, or 3; and each t is independently an integer of 0, 1, 2, 3, 4, 5, or 6; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q.

136. The compound of claim 135, having the structure of Formula (XLIX):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.

137. The compound of any one of claims 129 to 136, wherein each Z is independently C6-14arylene or heteroarylene, each optionally substituted with one or more substituents Q.

138. The compound of any one of claims 129 to 137, wherein each Z is independently 3-hydroxyphen-l,3-diyl or thiazol-2,4-diyl.

139. The compound of any one of claims 129 to 138, wherein each R28is independently C3-10cycloalkyl or heterocyclyl, each optionally substituted with one or more substituents Q.

140. The compound of any one of claims 129 to 139, wherein each R28is independently cyclopropyl, optionally substituted with one or more substituents Q.

141. The compound of any one of claims 129 to 140, wherein each R23is independently C1-6alkyl, optionally substituted with one or more substituents Q.

142. The compound of any one of claims 129 to 141, wherein each R23is ethyl.

143. The compound of any one of claims 129 to 142, wherein each R25and R26is independently C1-6alkyl, optionally substituted with one or more substituents Q.

144. The compound of any one of claims 129 to 143, wherein each R25and R26is methyl.

145. The compound of any one of claims 129 to 144, wherein each s and t is an integerof 0.

146. The compound of claim 1, wherein each RDis independently:or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof.

147. The compound of any one of claims 1 to 146, wherein each L is independently Ci- 50 heteroalkylene, wherein one or more methylene groups are each independently and optionally replaced by a divalent group and each divalent group is independently C6-14arylene, heteroarylene, or heterocyclylene; and wherein each heteroalkylene, arylene, heteroarylene, and heterocyclylene is optionally substituted with one or more substituents Q.

148. The compound of any one of claims 1 to 147, wherein each L is independently Ci- 30 heteroalkylene; wherein one or more methylene groups are each independently and optionally replaced by a divalent group and each divalent group is independently each divalent group is independently cyclohexanediyl, phendiyl, triazoldiyl, or 2,5-dioxopyrrolidindiyl; and wherein the heteroalkylene is optionally substituted with one or more substituents Q.

149. The compound of any one of claims 1 to 148, wherein each L is independently Ci- 30 heteroalkylene; wherein one or more methylene groups are each independently and optionally replaced by a divalent group and each divalent group is independently each divalent group is independently cyclohexane-l,4-diyl, phen-l,3-diyl, phen-l,4-diyl, l,2,3-triazol-l,4-diyl, or 2,5- dioxopyrrolidin-l,3-diyl; and wherein the heteroalkylene is optionally substituted with one or more substituents Q.

150. The compound of any one of claims 1 to 146, wherein each L independently comprises a moiety of:wherein:A” is a bond or -OC(=O)-;T is a cleavable sugar unit and Y is O; or T is a cleavable polypeptide and Y is NR30; each R29is independently an electron-withdrawing group or Ci-4 alkyl;R30is hydrogen, C1-24 alkyl, C2-6alkenyl, C3-8 cycloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, wherein the alkyl and alkenyl are each optionally interrupted by one or more groups, each independently selected from -O-, -S-, -C(O)-, -NR”- -C(O)NR”-, -NR”C(O)O-, -NR”C(O)NR”’-, and triazoldiyl; each R” and R’” is independently hydrogen or C1-6alkyl; and u is an integer of 0, 1, or 2.

151. The compound of any one of claims 1 to 146, wherein each L independently comprises a moiety of:wherein:A” is a bond or -OC(=O)-;K is a hydrophobicity masking entity, in one embodiment, a polysarcosine or polyethylene glycol (PEG); each R29is independently an electron-withdrawing group or C1-4 alkyl;R30is hydrogen, C1-24 alkyl, C2-6alkenyl, C3-8 cycloalkyl, C6-10aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, wherein the alkyl and alkenyl are each optionally interrupted by one or more groups, each independently selected from -O-, -S-, -C(O)-, -NR”-, -C(O)NR”-, -NR”C(O)O- -NR”C(O)NR”’-, and triazoldiyl;each R” and R’” is independently hydrogen or C1-6alkyl; and u is an integer of 0, 1, or 2.

152. The compound of any one of claims 1 to 151, wherein each L is independently:%L1-wherein each A” is independently a bond or -OC(O)-; each v is independently an integer ranging from about 2 and about 50; and each v and w is independently an integer ranging from about 2 and about 50.

153. The compound of any one of claims 1 to 152, wherein each X is independently (i) a bond; or (ii) heteroarylene or heterocyclylene, each optionally substituted with one or more substituents Q.

154. The compound of any one of claims 1 to 153, wherein each X is independently 6-membered heteroarylene, optionally substituted with one or more substituents Q.

155. The compound of any one of claims 1 to 154, wherein each X is independently pyrimidin-2,5-diyl, optionally substituted with one or more substituents Q.

156. The compound of any one of claims 1 to 153, wherein each X is independently 5- membered heterocyclylene, optionally substituted with one or more substituents Q.

157. The compound of any one of claims 1 to 153 and 156, wherein each X is 2,5- dioxopyrrolidin- 1 ,3 -diyl .

158. The compound of any one of claims 1 to 157, wherein the moiety L-X is:- S8Z--Z.8Z-159. The compound of claim 1, having the structure of Formular (L)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; wherein each A” is a bond or -OC(=O)-; and each v is an integer ranging from about 2 to about 50.

160. The compound of claim 1, having the structure of Formular (LI)or a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; wherein each A” is a bond or -OC(=O)-; and each v is an integer ranging from about 2 to about 50.

161. The compound of claim 1, having the structure of Formular (LII)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; wherein each A” is a bond or -OC(=O)-; and each v is an integer ranging from about 2 to about 50.

162. The compound of claim 1, having the structure of Formular (LIII)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; wherein each A” is a bond or -OC(=O)-; and each v is an integer ranging from about 2 to about 50.

163. The compound of claim 1, having the structure of Formular (LIV)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; wherein each A” is a bond or -OC(=O)-; and each v is an integer ranging from about 2 to about 50.

164. The compound of claim 1, having the structure of Formular (LV)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; wherein each A” is a bond or -OC(=O)-; and each v is an integer ranging from about 2 to about 50.

165. The compound of claim 1, having the structure of Formular (LVI)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; wherein each A” is a bond or -OC(=O)-; and each v is an integer ranging from about 2 to about 50.

166. The compound of any one of claims 159 to 165, wherein the moiety A”-RDis167. The compound of any one of claims 159 to 165, wherein the moiety A”-RDis168. The compound of any one of claims 159 to 165, wherein the moiety A”-RDis169. The compound of any one of claims 1 to 168, wherein RAis a monoclonal antibody or an antigen-binding fragment thereof.

170. The compound of any one of claims 1 to 169, wherein RAis a human, humanized, or chimeric antibody, or an antigen-binding fragment thereof.

171. The compound of any one of claims 1 to 170, wherein RAis an IgGl, IgG2, IgG3, or lgG4 antibody, or an antigen-binding fragment thereof.

172. The compound of any one of claims 1 to 171, wherein RAis an anti-B7H3 antibody, anti-cMET antibody, anti-CTLA-4 antibody, anti-EGFR antibody, anti-HER2 antibody, anti-PD-1 antibody, anti-PD-Ll antibody, anti-VEGF antibody, or an antigen-binding fragment thereof.

173. The compound of any one of claims 1 to 172, wherein RAis an anti-B7H3 single domain antibody or an antigen-binding fragment thereof.

174. The compound of claim 173, wherein the anti-B7H3 single domain antibody comprises a CDRL1 of SEQ ID NO: 1; a CDRL2 of SEQ ID NO: 2; a CDRL3 of SEQ ID NO: 3; a CDRH1 of SEQ ID NO: 4; a CDRH2 of SEQ ID NO: 5; and a CDRH3 of SEQ ID NO: 6.

175. The compound of any one of claims 1 to 172, wherein RAis an anti-cMET antibody or an antigen-binding fragment thereof.

176. The compound of claim 175, wherein the anti-cMET antibody comprises a CDRL1 of SEQ ID NO: 11; a CDRL2 of SEQ ID NO: 12; a CDRL3) of SEQ ID NO: 13; a CDRH1 of SEQ ID NO: 14; a CDRH2 of SEQ ID NO: 15; and a CDRH3 of SEQ ID NO: 16.

177. The compound of any one of claims 1 to 172, wherein RAis an anti-CTLA-4 antibody or an antigen-binding fragment thereof.

178. The compound of claim 177, wherein the anti-CTLA-4 antibody comprises a CDRL1 of SEQ ID NO: 21; a CDRL2 of SEQ ID NO: 22; a CDRL3 of SEQ ID NO: 23; a CDRH1 of SEQ ID NO: 24; a CDRH2 of SEQ ID NO: 25; and a CDRH3 of SEQ ID NO: 26.

179. The compound of any one of claims 1 to 172, wherein RAis an anti-EGFR antibody or an antigen-binding fragment thereof.

180. The compound of claim 179, wherein the anti-EGFR antibody comprises a CDRL1 of SEQ ID NO: 31; a CDRL2 of SEQ ID NO: 32; a CDRL3 of SEQ ID NO: 33; a CDRH1 of SEQ ID NO: 34; a CDRH2 of SEQ ID NO: 35; and a CDRH3 of SEQ ID NO: 36.

181. The compound of any one of claims 1 to 172, wherein RAis an anti-HER2 single domain antibody or an antigen-binding fragment thereof.

182. The compound of claim 181, wherein the anti-HER2 antibody comprises a CDRL1 of SEQ ID NO: 41; a CDRL2 of SEQ ID NO: 42; a CDRL3 of SEQ ID NO: 43; a CDRH1 of SEQ ID NO: 44; a CDRH2 of SEQ ID NO: 45; and a CDRH3 of SEQ ID NO: 46.

183. The compound of any one of claims 1 to 172, wherein RAis an anti-PD-1 antibody or an antigen-binding fragment thereof.

184. The compound of claim 183, wherein the anti-PD-1 antibody comprises a CDRL1 of SEQ ID NO: 51; a CDRL2 of SEQ ID NO: 52; a CDRL3 of SEQ ID NO: 53; a CDRHl of SEQ ID NO: 54; a CDRH2 of SEQ ID NO: 55; and a CDRH3 of SEQ ID NO: 56.

185. The compound of any one of claims 1 to 172, wherein RAis an anti-PD-Ll antibody or an antigen-binding fragment thereof.

186. The compound of claim 185, wherein the anti-PD-Ll antibody comprises a CDRL1 of SEQ ID NO: 61; a CDRL2 of SEQ ID NO: 62; a CDRL3 of SEQ ID NO: 63; a CDRH1 of SEQ ID NO: 64; a CDRH2 of SEQ ID NO: 65; and a CDRH3 of SEQ ID NO: 66.

187. The compound of any one of claims 1 to 172, wherein RAis an anti-VEGF antibody or an antigen-binding fragment thereof.

188. The compound of claim 187, wherein the anti-VEGF antibody comprises a CDRL1 of SEQ ID NO: 71; a CDRL2 of SEQ ID NO: 72; a CDRL3 of SEQ ID NO: 73; a CDRH1 of SEQ ID NO: 74; a CDRH2 of SEQ ID NO: 75; and a CDRH3 of SEQ ID NO: 76.

189. The compound of any one of claims 1 to 188, wherein m is an integer of 4, 5, 6, 7, or 8.

190. A pharmaceutical composition comprising the compound of any one of claims 1 to 189, 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.

191. A method of treating, preventing, or ameliorating one or more symptoms of a disorder, disease, or condition mediated by a KRAS in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 189 or a pharmaceutical composition of claim 190.

192. 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 any one of claims 1 to 189 or a pharmaceutical composition of claim 190.

193. A method of inhibiting the growth of a cell, comprising contacting the cell with an effective amount of a compound of any one of claims 1 to 189 or a pharmaceutical composition of claim 190.

194. A method of inhibiting a KRAS, comprising contacting the KRAS with an effective amount of a compound of any one of claims 1 to 189 or a pharmaceutical composition of claim 190.

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