Heterocyclic conjugates and uses thereof

Abstract

The present disclosure provides compounds and pharmaceutically acceptable salts thereof, and methods of using the same. The compounds and methods have a range of utilities as therapeutics, diagnostics, and research tools. In particular, the subject compositions and methods are useful for reducing signaling output of oncogenic protein.

Description

[0001] HETEROCYCLIC CONJUGATES AND USES THEREOF

[0002] BACKGROUND

[0003] CROSS-REFERENCE

[0004]

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 550,553, filed February 6, 2024; and U.S. Provisional Application No. 63 / 700,538, filed September 27, 2024, each incorporated herein by reference in its entirety.

[0005] SEQUENCE LISTING

[0006]

[0002] The instant application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on February 4, 2025, is named 56690_786_602_SL.xml and is 18,724 bytes in size.

[0007] BACKGROUND

[0008]

[0003] Cancer (e.g., tumor, neoplasm, metastases) is the second leading cause of death worldwide estimated to be responsible for about 10 million deaths each year. Many types of cancers are marked with mutations in one or more proteins involved in various signaling pathways leading to unregulated growth of cancerous cells. In some cases, about 25 to 30 percent (%) of tumors are known to harbor Rat sarcoma (Ras) mutations. In particular, mutations in the Kirsten Ras oncogene (K-Ras) are one of the most frequent Ras mutations detected in human cancers, including lung adenocarcinomas (LUADs) and pancreatic ductal adenocarcinoma (PDAC).

[0009]

[0004] Ras proteins have long been considered “undruggable,” due to, in part, high affinity to their substrate guanosine-5'-triphosphate (GTP) and / or their smooth surfaces without any obvious targeting region. The specific G12C Ras gene mutation has been identified as a druggable target to which a number of G12C specific inhibitors have been developed. However, such therapeutics are still of limited application, as the G12C mutation in Ras exhibits a much lower prevalence rate as compared to other known Ras mutations, such as G12D and G12V. Drug resistance and lack of durability impose further limitations to such therapeutics.

[0010] SUMMARY

[0011]

[0005] In view of the foregoing, there remains a considerable need for a new design of therapeutics and diagnostics that can specifically target Ras, including wildtype Ras, mutants and / or associated proteins of Ras to reduce Ras signaling output, as well as other signaling pathways in conjunction with the Ras signaling. Of particular interest are KRas inhibitors, including pan KRas inhibitors capable of inhibiting two or more KRas mutants and / or wildtype KRas within this given Ras isoform (e.g., inhibitors targeting mutant KRas proteins such as KRas G12D, G12C, G12S, G13D, and / or G12V, for the treatment of Ras-associated diseases (e.g., cancer). Such compositions and methods can be particularly useful for treating a variety of diseases including, but not limited to, cancers and neoplasia conditions. The present disclosure addresses these needs, and provides additional advantages applicable for diagnosis, prognosis, and / or treatment for a wide diversity of diseases.

[0012]

[0006] In certain aspects, the present disclosure provides a conjugate comprising an antigen binding unit exhibiting binding specificity for at least a first antigen that is not KRAS, wherein the antigen binding unit is covalently attached to a small-molecule KRAS inhibitor, optionally through a chemical linker, and wherein the antigen binding unit and the KRAS inhibitor in the conjugate synergistically inhibits signaling output of the first antigen or KRAS. In some embodiments, the conjugate provided herein comprises an antigen binding unit exhibiting binding specificity for at least a first antigen that is not KRAS, wherein the antigen binding unit is covalently attached to the small-molecule KRAS inhibitor through a chemical linker. In certain aspects, the present disclosure provides a conjugate comprising an antigen binding unit exhibiting binding specificity for at least a first antigen that is not KRAS, wherein the antigen binding unit is covalently attached to a small-molecule KRAS inhibitor, optionally through a chemical linker, and wherein the antigen binding unit and the KRAS inhibitor in the conjugate synergistically inhibits signaling output of the first antigen and KRAS. In some embodiments, the KRAS inhibitor is characterized by a PAMPA permeability (Pe) less than 1 x 10-6cm / s. In some embodiments, the conjugate is characterized by an enhanced therapeutic efficacy as ascertained by the formula: TIconjugate / TlKRASi> 1 , wherein Tlconjugate= TD50c / ED50c, wherein TD50cis the dose of conjugate required to produce a toxic effect in 50% of test subjects and ED50cis the dose of conjugate required to produce a therapeutic effect in 50% of test subjects; and wherein TIKRASI = TD50k / ED50k, wherein TD50kis the dose of KRAS inhibitor required to produce a toxic effect in 50% of test subjects and ED50kis the dose of KRAS inhibitor required to produce a therapeutic effect in 50% of the test subjects. In some embodiments, the conjugate is characterized by reduced plasma concentration of the KRAS inhibitor as ascertained by the formula: [KRASi]p-c / [KRASi]p-k< 1, wherein [KRASi]p-cis plasma concentration of the KRAS inhibitor at a first time-point following administration of the conjugate; and wherein [KRASi]p-kis plasma concentration of the KRAS inhibitor following administration of the KRAS inhibitor alone at an equivalent dose at the same time-point. In some embodiments, the conjugate is characterized by an increased concentration of the KRAS inhibitor in tumor tissue relative to plasma as ascertained by the formula: ([KRASi]t-c / [KRASi]p-c) / ([KRASi]t-k / [KRASi]p-k) > 1, wherein [KRASi]t-cis concentration of the KRAS inhibitor in tumor tissue at a first time -point following administration of the conjugate; wherein [KRASi]p-cis plasma concentration of the KRAS inhibitor at the same time-point following the administration of the conjugate; wherein [KRASi]t-kis concentration of the KRAS inhibitor in tumor tissue following administration of the KRAS inhibitor alone at an equivalent dose at the same time-point; and wherein [KRASi]p-kis plasma concentration of the KRAS inhibitor at the same time -point following the administration of the KRAS inhibitor alone at the equivalent dose.

[0013]

[0007] In certain aspects, the present disclosure provides a conjugate of Formula (A): wherein:

[0014] AgB is an antigen binding unit;

[0015] L is a chemical linker;

[0016] D is independently selected at each occurrence from a small-molecule KRAS inhibitor, a cytotoxic smallmolecule and a small-molecule agent that selectively modulates a non-KRAS target, wherein at least one D is a KRAS inhibitor; p is selected from 1 to 20; and q is selected from 1 to 20.

[0017]

[0008] In some embodiments, for a conjugate described herein, the antigen binding unit is an antibody or an antigen-binding fragment thereof. In some embodiments, the antigen binding unit is selected from a monoclonal antibody, a Fab, a Fab’, an F(ab’), an Fv, a disulfide linked Fc, an scFv, a single domain antibody, a diabody, a bispecific antibody, and a multi-specific antibody. In some embodiments, the antigen binding unit is a monoclonal antibody. In some embodiments, the antigen binding unit specifically binds a target, such target may include but is not limited to, AG7, B7-H3, BCMA, CA15-3, CD19, CD20, CD22, CD30, CD33, CD38, CD52, CD70, CD71, CD79B, CEA, CLDN18.2, EGFR, FOLR1, GCC, GPC1, HER2, HER3, ICAM1, LeX, LeY, MET, MSLN, MUCl, NECTIN4, SLC44A4, TF, or Trop-2. In some embodiments, the antigen binding unit is selected from cetuximab, bevacizumab, paitumumab, ofatumumab, inotuzumab, gemtuzumab, alemtuzumab, and trastuzumab. In some embodiments, the antigen binding unit is an anti-EGFR antibody, such as cetuximab. In some embodiments, the antigen binding unit is an anti-Trop2 antibody, such as sacituzumab.

[0018]

[0009] In some embodiments, for a conjugate described herein, the linker comprises one or more components independently selected from alkyl, alkene, alkyne, aryl, cycloalkyl, heterocycle, glycoside, silyl ether, hydroxy, ether, ketone, ester, carbonate, amide, urea, carbamate, sulfide, disulfide, sulfate, sulfonamide, phosphate, hydrazone, and succinimide. In some embodiments, the linker comprises one or more components independently selected from alkyl, polyethylene glycol, a hydrazone, maleimide, succinimide, asparagine, aspartic acid, cysteine, glutamic acid, lysine, glutamine, arginine, serine, ornithine, threonine, valine, alanine, glycine, leucine, isoleucine, methionine, tryptophan, proline, histidine, citrulline, phenylalanine, carboxylate, and p-aminobenzyloxycarbonyl. In some embodiments, the linker comprises one or more components selected from Val-Cit, Glu-Val-Cit, Val-Ala, Val- Val, Val-Gly, Gly-Gly, Gly-Cit, Glu-Gly-Cit, Ala-Ala-Asn, Ala-Gly-Ala, Ala-Pro, Ala-Ser, and Phe-Lys. In some embodiments, p is selected from 2 to 8. In some embodiments, q is selected from 1 to 4. In some embodiments, D is a small-molecule KRAS inhibitor.

[0019]

[0010] In some embodiments, for a conjugate described herein, the KRAS inhibitor is a compound of Formula (I): or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0020] X is selected from N and C(R6);

[0021] Z is selected from O, N, C(R5)2, C(O), S, S(O), and S(O)2;

[0022] R2, R5, R6, and R8are each independently selected at each occurrence from hydrogen, halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered hetero alky nyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalky l)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), -OR12, -SR12, - N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), -N(R12)C(O)N(R12)(R13), -N(R12)C(O)OR12, -N(R12)S(O)2R12, - C(O)R12, -S(O)R12, -OC(O)R12, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R12)C(O)R12, -S(O)2R12, - S(O)(NR12)R12, -S(O)2N(R12)(R13), -S(O)(NR12)N(R12)(R13), and -OCH2C(O)OR12, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered hetero alkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle) are optionally substituted with one or more R20; optionally wherein two R5are taken together with the atom to which they are attached to form C3-8carbocycle or 3- to 8-membered heterocycle, each of which is optionally substituted with one or more R20; and further optionally wherein two R5are taken together to form =O, =NR12, or =C(R14)2;

[0023] R3is independently selected at each occurrence from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), -OR12, -SR12, -N(R12)(R13), -C(O)OR12, - OC(O)N(R12)(R13), -N(R12)C(O)N(R12)(R13), -N(R12)C(O)OR12, -N(R12)S(O)2R12, -C(O)R12, -S(O)R12, -OC(O)R12, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R12)C(O)R12, -S(O)2R12, -S(O)(NR12)R12, -S(O)2N(R12)(R13), - S(O)(NR12)N(R12)(R13), and -OCH2C(O)OR12, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalky l)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle) are optionally substituted with one or more R20; optionally wherein two R3are taken together with the atom or atoms to which they are attached to form C3-8carbocycle or 3- to 8- membered heterocycle, each of which is optionally substituted with one or more R20; optionally wherein two R3are taken together to form =O, =NR12, or =C(R14)2; and further optionally wherein one R3and R4are taken together with the atoms to which they are attached to form 3- to 10-membered heterocycle optionally substituted with one or more R20;

[0024] R4is selected from hydrogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalky l)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -C(O)OR12, -C(O)R12, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -S(O)2R12, - S(O)(NR12)R12, -S(O)2N(R12)(R13), and -S(=O)(=NR12)N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), and - (2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle) are optionally substituted with one or more R20;

[0025] R7is selected from C6-12aryl and 5- to 12-membered heteroaryl, each of which is optionally substituted with one or more R20; m is 0, 1, 2, or 3; n is 1 or 2;

[0026] R12is independently selected at each occurrence from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle) are optionally substituted with one, two, or three R20;

[0027] R13is independently selected at each occurrence from hydrogen, C1-6alkyl, and C1-6haloalky I: or R12and R13attached to the same nitrogen atom form 3- to 10-membered heterocycle optionally substituted with one, two, or three R20;

[0028] R14is independently selected at each occurrence from hydrogen, halogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle), or two R14are taken together with the carbon atom to which they are attached to form C3-12carbocycle or 3- to 12-membered heterocycle, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6alkyl-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), C3-12carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one, two, or three R20;

[0029] R20is independently selected at each occurrence from halogen, oxo, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), -OR22, -SR22, -N(R22)(R23), =NR22, =C(R21)2, -C(O)OR22, -OC(O)N(R22)(R23), -N(R22)C(O)N(R22)(R23), -N(R22)C(O)OR22, -N(R22)S(O)2R22, -C(O)R22, -S(O)R22, -OC(O)R22, -C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), -N(R22)C(O)R22, -OS(O)2R22, -S(O)2R22, - S(O)(NR22)R22, -S(O)2N(R22)(R23)-, -S(O)(NR22)N(R22)(R23), and -OCH2C(O)OR22; wherein two R20attached to the same or adjacent atoms optionally join to form C3-12carbocycle or 3- to 12-membered heterocycle; wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered hetero alky nyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalky l)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), C3-12carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, -OR22, -SR22, -N(R22)(R23), =NR22, =C(R21)2, -C(O)OR22, -OC(O)N(R22)(R23), -N(R22)C(O)N(R22)(R23), -N(R22)C(O)OR22, -N(R22)S(O)2R22, -C(O)R22, -S(O)R22, -OC(O)R22, -C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), -N(R22)C(O)R22, -OS(O)2R22, -S(O)2R22, - S(O)(NR22)R22, -S(O)2N(R22)(R23), and -S(O)(NR22)N(R22)(R23);

[0030] R21is independently selected at each occurrence from hydrogen, halogen, C1-6alkyl, C1-6haloalkyl, -C0-6alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle), or two R21are taken together with the carbon atom to which they are attached to form C3-12carbocycle or 3- to 12-membered heterocycle, each of which is optionally substituted with one, two, or three substituents independently selected from halogen, C1-3alkyl, C1-3haloalkyl, and -OH;

[0031] R22is independently selected at each occurrence from hydrogen, C1-6alkyl, C1-6haloalkyl, -C0-6alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle); and

[0032] R23is independently selected at each occurrence from hydrogen and C1-6alkyl; or R22and R23attached to the same nitrogen atom form 3- to 10 membered heterocycle; wherein one hydrogen of the compound of Formula (I) is replaced with a bond to the antigen binding unit or the chemical linker.

[0033]

[0011] In some embodiments, the compound of Formula (I) is a compound of Formula (I-a): or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0034] A is 6-membered heteroaryl comprising one, two, or three ring nitrogen atoms;

[0035] R9and R10are independently selected from hydrogen, halogen, oxo, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), -OR22, -SR22, -N(R22)(R23), =NR22, =C(R21)2, -C(O)OR22, -OC(O)N(R22)(R23), -N(R22)C(O)N(R22)(R23), -N(R22)C(O)OR22, -N(R22)S(O)2R22, -C(O)R22, -S(O)R22, -OC(O)R22, -C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), -N(R22)C(O)R22, -OS(O)2R22, -S(O)2R22, - S(O)(NR22)R22, -S(O)2N(R22)(R23)-, -S(O)(NR22)N(R22)(R23), and -OCH2C(O)OR22; wherein R9and R10optionally join to form C3-12carbocycle or 3- to 12-membered heterocycle; wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), C3-12carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, -OR22, -SR22, -N(R22)(R23), =NR22, =C(R21)2, -C(O)OR22, - OC(O)N(R22)(R23), -N(R22)C(O)N(R22)(R23), -N(R22)C(O)OR22, -N(R22)S(O)2R22, -C(O)R22, -S(O)R22, -OC(O)R22, - C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), -N(R22)C(O)R22, -OS(O)2R22, -S(O)2R22, -S(O)(NR22)R22, - S(O)2N(R22)(R23), and -S(O)(NR22)N(R22)(R23); and

[0036] R11is selected from hydrogen, C1-6alkyl, C1-6haloalkyl, -C0-6alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle).

[0037]

[0012] In some embodiments, for a compound of Formula (I-a), A is selected from pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl, such as A is pyridinyl. In some embodiments, R11is hydrogen. In some embodiments, R10is selected from hydrogen and halogen; or R9and R10, together with the atoms to which they are attached, form C4-8carbocycle or 4- to 8-membered heterocycle, each of which is optionally substituted. In some embodiments, R10is hydrogen. In some embodiments, In some embodiments, R9is optionally substituted

[0038] C1-3alkyl, such as R9is CH3.

[0039]

[0013] In some embodiments, for a compound of Formula (I), R4is selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle), each of which is optionally substituted with one or more R20. In some embodiments, R4is selected from C1-6alkyl and -C0-6alkyl-(3- to 12- membered heterocycle), each of which is optionally substituted with one or more substituents independently selected from halogen, -CH3, -NH2, -NHCH3, and -N(CH3)2-

[0040]

[0014] In some embodiments, for a compound of Formula (I) or (I-a), X is C(R6). In some embodiments, X is N. In some embodiments, Z is O.

[0041]

[0015] In some embodiments, for a compound of Formula (I) or (I-a), R7is selected from naphthyl, isoquinolinyl, indazolyl, benzothiazolyl, benzothiophenyl, phenyl, and pyridinyl, each of which is optionally substituted with one, two, three, or four R20. In some embodiments, R7is benzothiophenyl optionally substituted with one, two, three, or four R20. In some embodiments, R7is substituted with one, two, three, or four substituents independently selected from halogen, -CN, C1-3alkyl, C1-3haloalkyl, C2-3alkenyl, C2-3alkynyl, -OR22, -N(R22)(R23), and C3-6cycloalkyl. In some embodiments, R7is substituted with one, two, three, or four substituents independently selected from halogen, -CN, -CH3, -CH2CH3, -CH=CH2, -CF3, -C=CH, -OH, -NH2, and -cyclopropyl. In some embodiments, R7is selected

[0042]

[0016] In some embodiments, for a compound of Formula (I-a):

[0043] X is C(R6);

[0044] A is selected from pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl;

[0045] R2, R6, and R8are each independently selected at each occurrence from hydrogen, halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C3-8carbocycle, 3- to 8-membered heterocycle, -OR12, -N(R12)(R13), -C(O)OR12, - N(R12)C(O)N(R12)(R13), -C(O)R12, -OC(O)R12, -C(O)N(R12)(R13), and -N(R12)C(O)R12, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C3-8carbocycle, and 3- to 8-membered heterocycle are optionally substituted with one, two, or three R20;

[0046] R3is independently selected at each occurrence from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, - C3-8carbocycle, 3- to 8-membered heterocycle, -OR12, -N(R12)(R13), -C(O)OR12, -N(R12)C(O)N(R12)(R13), -C(O)R12, -OC(O)R12, -C(O)N(R12)(R13), and -N(R12)C(O)R12, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C3-8carbocycle, and 3- to 8-membered heterocycle are optionally substituted with one, two, or three R20; wherein two R3are optionally taken together with the atom or atoms to which they are attached to form C3-8carbocycle or 3- to 8- membered heterocycle, each of which is optionally substituted with one, two, or three R20; and further wherein two R3are optionally taken together to form =O, =NR12, or =C(R14)2;

[0047] R7is benzo [b]thiophen-4-yl optionally substituted with one, two, three, or four R20;

[0048] R9is C1-3alkyl optionally substituted with one, two, or three R20;

[0049] R10is selected from hydrogen, halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8carbocycle, 3- to 8- membered heterocycle, -OR22, -N(R22)(R23), -C(O)OR22, -N(R22)C(O)N(R22)(R23), -C(O)R22, -OC(O)R22, - C(O)N(R22)(R23), and -N(R22)C(O)R22, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C3-8carbocycle, and 3- to 8- membered heterocycle are optionally substituted with one, two, or three substituents independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, -OR22, -SR22, -N(R22)(R23), =NR22, =C(R21)2, -C(O)OR22, -OC(O)N(R22)(R23), -N(R22)C(O)N(R22)(R23), -N(R22)C(O)OR22, -N(R22)S(O)2R22, -C(O)R22,

[0050] -S(O)R22, -OC(O)R22, -C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), -N(R22)C(O)R22, -OS(O)2R22, -S(O)2R22, -

[0051] S(O)(NR22)R22, -S(O)2N(R22)(R23), and -S(O)(NR22)N(R22)(R23);

[0052] R11is hydrogen; m is 0 or 1 ; and n is 1 or 2.

[0053]

[0017] In some embodiments, the compound of Formula (I) or (I-a) is a compound of Formula (I-b): or a pharmaceutically acceptable salt or solvate thereof.

[0054]

[0018] In some embodiments, the compound of Formula (I) or (I-a) is a compound of Formula (I-c): or a pharmaceutically acceptable salt or solvate thereof.

[0055]

[0019] In some embodiments, for a compound of Formula (I), (I-a), (I-b), or (I-c), R2is selected from hydrogen,

[0056] C1-3alkyl, -OR12, and 3- to 10-membered heterocycle, wherein C1-3alkyl and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R20. In some embodiments, R2is -OR12. In some embodiments, R2is -

[0057] O(C1-3alkyl)(4- to 10-membered heterocycle) optionally substituted with one, two, or three substituents independently selected from halogen, C1-3alkyl, C1-3haloalkyl, and =C(R21)2, wherein R21is independently selected at each occurrence from hydrogen, halogen, and C1-3alkyl. In some embodiments, R2is selected from

[0058]

[0020] In some embodiments, for a compound of Formula (I), (I-a), (I-b), or (I-c), R3is independently selected at each occurrence from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8carbocycle, and 3- to 8-membered heterocycle, each of which is optionally substituted with one, two, or three R20. In some embodiments, R3is independently selected at each occurrence from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8carbocycle, and 3- to 8-membered heterocycle, each of which is optionally substituted with one, two, or three substituents independently selected from halogen, -CN, - OH, and -OCH3. In some embodiments, m is 0 or 1, such as m is 0. In some embodiments, R6and R8are independently selected from hydrogen, halogen, and C1-3haloalkyl. In some embodiments, R6is selected from chlorine and -CF3. In some embodiments, R8is fluorine. In some embodiments, n is 1.

[0059]

[0021] In certain aspects, the present disclosure provides a pharmaceutical composition comprising the conjugate described herein, or a salt thereof, and a pharmaceutically acceptable excipient.

[0060]

[0022] In certain aspects, the present disclosure provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a conjugate described herein, or a salt thereof. In certain aspects, the present disclosure provides a method of treating cancer in a subject comprising a Ras mutant protein, the method comprising: inhibiting the Ras mutant protein of said subject by administering to said subject a conjugate described herein, or a salt thereof. The cancer of a method described herein may be a solid tumor or a hematological cancer. In some embodiments, the cancer comprises a wildtype K-Ras or a mutant K-Ras including but not limited to K-Ras G12C, G12D, G12S, or G12V mutant protein.

[0061]

[0023] In certain aspects, the present disclosure provides a method of modulating signaling output of a Ras protein, comprising contacting a Ras protein with an effective amount of a conjugate described herein, or a salt thereof, thereby modulating the signaling output of the Ras protein. In certain aspects, the present disclosure provides a method of inhibiting cell growth, comprising administering an effective amount of a conjugate described herein, or a salt thereof, to a cell expressing a Ras protein, thereby inhibiting growth of said cells. A method described herein may further comprise administering an additional agent.

[0062]

[0024] In certain aspects, the present disclosure provides a method of delivering a small-molecule KRAS inhibitor that exhibits low permeability as characterized by a PAMPA assay, comprising contacting a tumor cell with a conjugate described herein, or a salt thereof, wherein the KRAS inhibitor exhibits a PAMPA permeability (Pe) value less than 1 x 10-6cm / s. In certain aspects, the present disclosure provides a method of enhancing therapeutic efficacy of a small-molecule KRAS inhibitor, comprising providing a conjugate described herein to a subject, wherein enhanced therapeutic efficacy is ascertained by the formula: TIconjugate / TlKRASi> 1 , wherein TIconjugate= TD50c / ED50c, wherein TD50cis the dose of conjugate required to produce a toxic effect in 50% of test subjects and ED50cis the dose of conjugate required to produce a therapeutic effect in 50% of test subjects; and wherein TIKRASI = TD50k / ED50k, wherein TD50kis the dose of KRAS inhibitor required to produce a toxic effect in 50% of test subjects and ED50kis the dose of KRAS inhibitor required to produce a therapeutic effect in 50% of the test subjects. In certain aspects, the present disclosure provides a method of reducing plasma concentration of a small-molecule KRAS inhibitor, comprising providing a conjugate described herein to a subject, wherein reduced plasma concentration is ascertained by the formula: [KRASi]p-c / [KRASi]p-k< 1 , wherein [KRASi]p-cis plasma concentration of the KRAS inhibitor at a first time -point following administration of the conjugate; and wherein [KRASi]p-kis plasma concentration of the KRAS inhibitor following administration of the KRAS inhibitor alone at an equivalent dose at the same time-point. In certain aspects, the present disclosure provides a method of increasing concentration of a small-molecule KRAS inhibitor in tumor tissue, comprising providing a conjugate described herein to a subject, wherein increased tumor tissue concentration is ascertained by the formula: ([KRASi]t-c / [KRASi]p-c) / ([KRASi]t. k / [KRASi]p-k) > 1, wherein [KRASi]t-cis concentration of the KRAS inhibitor in tumor tissue at a first time-point following administration of the conjugate; wherein [KRASi]p-cis plasma concentration of the KRAS inhibitor at the same time-point following the administration of the conjugate; wherein [KRASi]t-kis concentration of the KRAS inhibitor in tumor tissue following administration of the KRAS inhibitor alone at an equivalent dose at the same time -point; and wherein [KRASi]p-kis plasma concentration of the KRAS inhibitor at the same time -point following the administration of the KRAS inhibitor alone at the equivalent dose.

[0063]

[0025] In certain aspects, the present disclosure provides a method of delivering a small-molecule KRAS inhibitor to the central nervous system of a subject, comprising administering a conjugate described herein to the subject, wherein the KRAS inhibitor is released from the conjugate after entering the CNS of the subject. In certain aspects, the present disclosure provides a method of generating a slow-release form of a small-molecule KRAS inhibitor, the method comprising conjugating an antigen binding unit to a small-molecule KRAS inhibitor through a chemical linker, wherein the small-molecule inhibitor is released from the conjugate upon introducing the conjugate into a subject or a cell. In practicing any of the subject methods, efficacy of the conjugate may be greater than efficacy of a combination of the antigen binding unit and the KRAS inhibitor when each is administered at a comparable concentration. In some embodiments, toxicity of the conjugate is less than toxicity of a combination of the antigen binding unit and the KRAS inhibitor when each is administered at a comparable concentration.

[0064] INCORPORATION BY REFERENCE

[0065]

[0026] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

[0066] BRIEF DESCRIPTION OF THE DRAWINGS

[0067]

[0027] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:

[0068]

[0028] FIG. 1 depicts a sequence alignment of various wild type Ras proteins including K-Ras, H-Ras, N-Ras, RalA, and RalB, from top to bottom.

[0069]

[0029] FIG. 2 shows fluorescence of A-431 cells treated with cetuximab, isotype IgGl, cetuximab-MMAE ADC, Cet-KRAS A, Cet-KRAS B, isotype IgGl KRAS A conjugate, or isotype IgGl KRAS B conjugate, each of which is covalently attached to pH-sensitive pHAB dye. DETAILED DESCRIPTION

[0070]

[0030] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this disclosure belongs. In the event that there are a plurality of definitions for terms herein, those in this section prevail. All patents, patent applications, publications and published nucleotide and amino acid sequences (e.g., sequences available in GenBank or other databases) referred to herein are incorporated by reference. Chemical structures are named herein according to IUPAC conventions as implemented in ChemDraw® software (Perkin Elmer, Inc., Cambridge, MA). The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. As used in the specification and claims, the singular forms “a”, “an” and “the” include plural references unless the context clearly dictates otherwise. Furthermore, use of the term “including” as well as other forms, such as “include”, “includes”, and “included”, is not limiting. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0071]

[0031] The term “Cx-y” or “Cx-Cy” when used in conjunction with a chemical moiety, such as alkyl, alkenyl, or alkynyl, is meant to include groups that contain from x to y carbons in the chain. For example, the term “Cx-yalkyl” refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched- chain alkyl groups, that contain from x to y carbons in the chain.

[0072]

[0032] “Alkyl” refers to substituted or unsubstituted saturated hydrocarbon groups, including linear and branched alkyl groups. An alkyl group may contain from one to twelve carbon atoms (e.g., C1-12alkyl), such as one to eight carbon atoms (C1-8alkyl) or one to six carbon atoms (C1-6alkyl). Exemplary alkyl groups include methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, septyl, octyl, nonyl, and decyl. An alkyl group is attached to the rest of the molecule by a single bond. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted by one or more substituents such as those substituents described herein.

[0073]

[0033] “Haloalkyl” refers to an alkyl group that is substituted by one or more halogens. Exemplary haloalkyl groups include trifluoromethyl, difluoromethyl, tri chloromethyl, 2,2,2-trifluoroethyl, 1 ,2-difluoroethyl, 3-bromo-2- fluoropropyl, and 1 ,2-dibromoethyl.

[0074]

[0034] “Alkenyl” refers to substituted or unsubstituted hydrocarbon groups, including linear and branched alkenyl groups, containing at least one double bond. An alkenyl group may contain from two to twelve carbon atoms (e.g., C2-12alkenyl), such as two to eight carbon atoms (C2-8alkenyl) or two to six carbon atoms (C2-6alkenyl). Exemplary alkenyl groups include ethenyl (i.e., vinyl), prop-l -enyl, but-l-enyl, pent-l-enyl, penta- 1,4-dienyl, and the like. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted by one or more substituents such as those substituents described herein.

[0075]

[0035] “Alkynyl” refers to substituted or unsubstituted hydrocarbon groups, including linear and branched alkynyl groups, containing at least one triple bond. An alkynyl group may contain from two to twelve carbon atoms (e.g., C2-12alkynyl), such as two to eight carbon atoms (C2-8alkynyl) or two to six carbon atoms (C2-6alkynyl). Exemplary alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted by one or more substituents such as those substituents described herein.

[0076]

[0036] “Alkylene” or “alkylene chain” refers to substituted or unsubstituted divalent saturated hydrocarbon groups, including linear alkylene and branched alkylene groups, that contain from one to twelve carbon atoms (e.g., C1-12alkylene), such as one to eight carbon atoms (C1-8alkylene) or one to six carbon atoms (C1-6alkylene). Exemplary alkylene groups include methylene, ethylene, propylene, and n-butylene. Similarly, “alkenylene” and “alkynylene” refer to alkylene groups, as defined above, which comprise one or more carbon-carbon double or triple bonds, respectively. The points of attachment of the alkylene, alkenylene or alkynylene chain to the rest of the molecule can be through one carbon or any two carbons of the chain. Unless stated otherwise specifically in the specification, an alkylene, alkenylene, or alkynylene group is optionally substituted by one or more substituents such as those substituents described herein.

[0077]

[0037] “Heteroalkyl”, “heteroalkenyl” and “heteroalkynyl” refer to substituted or unsubstituted alkyl, alkenyl and alkynyl groups, respectively, in which one or more, such as 1, 2 or 3, of the carbon atoms are replaced with a heteroatom, such as O, N, P, Si, S, or combinations thereof. Any nitrogen, phosphorus, and sulfur heteroatoms present in the chain may optionally be oxidized, and any nitrogen heteroatoms may optionally be quatemized. If given, a numerical range refers to the chain length in total. For example, a 3- to 8-membered heteroalkyl group has a chain length of 3 to 8 atoms. Connection to the rest of the molecule may be through either a heteroatom or a carbon in the heteroalkyl, heteroalkenyl, or heteroalkynyl chain. Unless stated otherwise specifically in the specification, a heteroalkyl, hetero alkenyl, or heteroalkynyl group is optionally substituted by one or more substituents such as those substituents described herein.

[0078]

[0038] “Hetero alkylene”, “hetero alkenylene” and “heteroalkynylene” refer to substituted or unsubstituted alkylene, alkenylene and alkynylene groups, respectively, in which one or more, such as 1, 2 or 3, of the carbon atoms are replaced with a heteroatom, such as O, N, P, Si, S, or combinations thereof. Any nitrogen, phosphorus, and sulfur heteroatoms present in the chain may optionally be oxidized, and any nitrogen heteroatoms may optionally be quatemized. If given, a numerical range refers to the chain length in total. For example, a 3- to 8- membered hetero alkylene group has a chain length of 3 to 8 atoms. The points of attachment of the heteroalkylene, hetero alkenylene or heteroalkynylene chain to the rest of the molecule can be through either one heteroatom or one carbon, or any two heteroatoms, any two carbons, or any one heteroatom and any one carbon in the heteroalkylene, hetero alkenylene or heteroalkynylene chain. Unless stated otherwise specifically in the specification, a heteroalkylene, heteroalkenylene, or heteroalkynylene group is optionally substituted by one or more substituents such as those substituents described herein.

[0079]

[0039] “Carbocycle” refers to a saturated, unsaturated or aromatic ring in which each atom of the ring is a carbon atom. Carbocycle may include C3-10monocyclic rings, C5-12bicyclic rings, C5-18polycyclic rings, C5-12spirocyclic rings, and C5-12bridged rings. Each ring of a bicyclic or polycyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings. A polycyclic carbocycle contains a number or rings equal to the minimum number of scissions required to convert the carbocycle into an acyclic skeleton (e.g., bicyclic, tricyclic, tetracyclic, etc.). In some embodiments, the carbocycle is a C6-12aryl group, such as C6-10aryl. In some embodiments, the carbocycle is a C3-12cycloalkyl group. In some embodiments, the carbocycle is a C5-12cycloalkenyl group. In an exemplary embodiment, an aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated and aromatic rings, as valence permits, are included in the definition of carbocycle. A carbocycle may comprise a fused ring, a bridged ring, a spirocyclic ring, a saturated ring, an unsaturated ring, an aromatic ring, or any combination thereof. Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantly, phenyl, indanyl, and naphthyl. Unless state otherwise specifically in the specification, a carbocycle is optionally substituted by one or more substituents such as those substituents described herein.

[0080]

[0040] “Heterocycle” refers to a saturated, unsaturated or aromatic ring comprising one or more heteroatoms, for example 1, 2, 3, or 4 heteroatoms selected from O, S, P, and N. Heterocycle may include 3- to 10-membered monocyclic rings, 5- to 12-membered bicyclic rings, 5- to 18-membered polycyclic rings, 5- to 12-membered spirocyclic rings, and 5- to 12-membered bridged rings. Each ring of a bicyclic or polycyclic heterocycle may be selected from saturated, unsaturated, and aromatic rings. A polycyclic heterocycle contains a number or rings equal to the minimum number of scissions required to convert the heterocycle into an acyclic skeleton (e.g., bicyclic, tricyclic, tetracyclic, etc.). The heterocycle may be attached to the rest of the molecule through any atom of the heterocycle, valence permitting, such as a carbon or nitrogen atom of the heterocycle. In some embodiments, the heterocycle is a 5- to 10-membered heteroaryl group, such as 5- or 6-membered heteroaryl. In some embodiments, the heterocycle is a 3- to 12-membered heterocycloalkyl group. A heterocycle may comprise a fused ring, a bridged ring, a spirocyclic ring, a saturated ring, an unsaturated ring, an aromatic ring, or any combination thereof. In an exemplary embodiment, a heterocycle, e.g., pyridyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Exemplary heterocycles include pyrrolidinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, piperidinyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiophenyl, oxazolyl, thiazolyl, morpholinyl, indazolyl, indolyl, benzothienyl, benzoxazolyl, and quinolinyl. Unless stated otherwise specifically in the specification, a heterocycle is optionally substituted by one or more substituents such as those substituents described herein.

[0081]

[0041] “Heteroaryl” refers to an aromatic ring that comprises at least one heteroatom, for example 1, 2, 3, or 4 heteroatoms selected from O, S and N. Heteroaryl may include 5- to 10-membered monocyclic rings, 6- to 12- membered bicyclic rings, 6- to 18-membered polycyclic rings, 5- to 12-membered spirocyclic rings, and 6- to 12- membered bridged rings. As used herein, the heteroaryl ring may be selected from monocyclic, bicyclic, or polycyclic — including fused, spirocyclic and bridged ring systems — wherein at least one of the rings in the ring system is aromatic and comprises at least one heteroatom. A polycyclic heteroaryl contains a number or rings equal to the minimum number of scissions required to convert the heteroaryl into an acyclic skeleton (e.g., bicyclic, tricyclic, tetracyclic, etc.). The heteroatom(s) in the heteroaryl may optionally be oxidized. One or more nitrogen atoms, if present, are optionally quatemized. The heteroaryl may be attached to the rest of the molecule through any atom of the heteroaryl, valence permitting, such as a carbon or nitrogen atom of the heteroaryl. Examples of heteroaryl groups include, but are not limited to, azepinyl, benzimidazolyl, benzisothiazolyl, benzisoxazolyl, benzofuranyl, benzothiazolyl, benzothiophenyl, benzoxazolyl, furanyl, imidazolyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, purinyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl, pyridazolyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydroquinolinyl, thiadiazolyl, thiazolyl, and thienyl groups. Unless stated otherwise specifically in the specification, a heteroaryl is optionally substituted by one or more substituents such as those substituents described herein.

[0082]

[0042] Unless stated otherwise, hydrogen atoms are implied in structures depicted herein as necessary to satisfy the valence requirement.

[0083]

[0043] A waved line drawn across or at the end of a bond or a dashed bond are used interchangeably herein to denote where a bond disconnection or attachment occurs. For example, in the structure if R7 is 2-fluoro-6-hydroxyphenyl as in then R7may be depicted as

[0084]

[0044] The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons or heteroatoms of the structure. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, heteroatoms such as nitrogen may have any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.

[0085]

[0045] A compound disclosed herein, such as a compound of Formula (I), (I-a), (I-b), or (I-c), is optionally substituted by one or more — such as 1, 2 or 3 — substituents selected from: halogen, oxo, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3. 12 carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), -OR22, -SR22, -N(R22)(R23), =NR22, =C(R21)2, -C(O)OR22, -OC(O)N(R22)(R23), - N(R22)C(O)N(R22)(R23), -N(R22)C(O)OR22, -N(R22)S(O)2R22, -C(O)R22, -S(O)R22, -OC(O)R22, -C(O)N(R22)(R23), - C(O)C(O)N(R22)(R23), -N(R22)C(O)R22, -S(O)2R22, -S(O)(NR22)R22, -S(O)2N(R22)(R23)-, and - S(=O)(=NR22)N(R22)(R23); wherein two substituents attached to the same or adjacent atoms optionally join to form C3-12carbocycle or 3- to 12-membered heterocycle; wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalky l)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), C3-12carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, -OR22, -SR22, -N(R22)(R23), =NR22, =C(R21)2, -C(O)OR22, -OC(O)N(R22)(R23), - N(R22)C(O)N(R22)(R23), -N(R22)C(O)OR22, -N(R22)S(O)2R22, -C(O)R22, -S(O)R22, -OC(O)R22, -C(O)N(R22)(R23), - C(O)C(O)N(R22)(R23), -N(R22)C(O)R22, -S(O)2R22, -S(O)(NR22)R22, -S(O)2N(R22)(R23), and - S(=O)(=NR22)N(R22)(R23);

[0086] R21is independently selected at each occurrence from hydrogen, halogen, C1-6alkyl, C1-6haloalkyl, -C0-6alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle), or two R21are taken together with the carbon atom to which they are attached to form C3-12carbocycle or 3- to 12-membered heterocycle, each of which is optionally substituted with one, two, or three substituents independently selected from halogen, C1-3alkyl, C1-3haloalkyl, and -OH;

[0087] R22is independently selected at each occurrence from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, -C0-6alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle), wherein -C0-6alkyl-(C3-12carbocycle) and -C0-6alkyl-(3- to 12-membered heterocycle) are optionally substituted with one, two, or three groups independently selected from halogen and C1-6alkyl; and

[0088] R23is independently selected at each occurrence from hydrogen and C1-6alkyl; or R22and R23attached to the same nitrogen atom form 3- to 10 membered heterocycle.

[0089]

[0046] In some embodiments, a compound disclosed herein, such as a compound of Formula (I), (I-a), (I-b), or (I- c), is optionally substituted by one or more — such as 1, 2 or 3 — substituents selected from: halogen, oxo, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3. 12 carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), -OR22, -SR22, -N(R22)(R23), =NR22, =C(R21)2, -C(O)OR22, -OC(O)N(R22)(R23), - N(R22)C(O)N(R22)(R23), -N(R22)C(O)OR22, -N(R22)S(O)2R22, -C(O)R22, -OC(O)R22, -C(O)N(R22)(R23), - C(O)C(O)N(R22)(R23), -N(R22)C(O)R22, -S(O)2R22, -S(O)(NR22)R22, and -S(O)2N(R22)(R23)-, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalky l)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), C3-12carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, -OR22, -SR22, -N(R22)(R23), =NR22, and =C(R21)2;

[0090] R21is independently selected at each occurrence from hydrogen, halogen, C1-6alkyl, and C1-6haloalkyl;

[0091] R22is independently selected at each occurrence from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, -C0-6alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle), wherein -C0-6alkyl-(C3-12carbocycle) and -C0-6alkyl-(3- to 12-membered heterocycle) are optionally substituted with one, two, or three groups independently selected from halogen and C1-6alkyl;

[0092] R23is independently selected at each occurrence from hydrogen and C1-6alkyl; or R22and R23attached to the same nitrogen atom form 3- to 10 membered heterocycle.

[0093]

[0047] In some embodiments, a compound disclosed herein, such as a compound of Formula (I), (I-a), (I-b), or (I- c), is optionally substituted by one or more — such as 1 , 2 or 3 — substituents selected from halogen, oxo, =NH, -CN, -NO2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, -CH2-(C3-IO carbocycle), 3- to 10-membered heterocycle, -CH2-(3- to 10-membered heterocycle), -OH, -OCH3, -OCH2CH3, -NH2, -NHCH3, and -NHCH2CH3, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocycle, -CH2-(C3-IO carbocycle), 3- to 10-membered heterocycle, and -CH2-(3- to 10-membered heterocycle) are optionally substituted with one, two, or three groups independently selected from halogen, oxo, =NH, -CN, -NO2, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -OH, -OCH3, - OCH2CH3, -NH2, -NHCH3, and -NHCH2CH3.

[0094]

[0048] It will be understood by those skilled in the art that substituents can themselves be substituted, if appropriate. Unless specifically stated as “unsubstituted”, references to chemical moieties herein are understood to include substituted variants. For example, reference to a “heteroaryl” group or moiety implicitly includes both substituted and unsubstituted variants.

[0095]

[0049] Where bivalent substituent groups are specified herein by their conventional chemical formulae, written from left to right, they are intended to encompass the isomer that would result from writing the structure from right to left, e.g., -CH2O- is also intended to encompass -OCH2-.

[0096]

[0050] “Optional” or “optionally” means that the subsequently described event or circumstances may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, an “optionally substituted” group may be either unsubstituted or substituted.

[0097]

[0051] Compounds of the present disclosure also include crystalline and amorphous forms of those compounds, pharmaceutically acceptable salts, and active metabolites having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, amorphous forms of the compounds, and mixtures thereof.

[0098]

[0052] The compounds described herein may exhibit their natural isotopic abundance, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure. For example, hydrogen has three naturally occurring isotopes, denoted1H (protium),2H (deuterium), and3H (tritium). Protium is the most abundant isotope of hydrogen in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increased in vivo half-life and / or exposure, or may provide a compound useful for investigating in vivo routes of drug elimination and metabolism. Examples of isotopes that may be incorporated into compounds of the present disclosure include, but are not limited to,2H,3H,11C,14C,15N,18O,17O,35S,36Cl, and18F. Of particular interest are compounds of Formula (I), (I-a), (I-b), or (I-c) enriched in tritium or carbon- 14, which can be used, for example, in tissue distribution studies; compounds of the disclosure enriched in deuterium — especially at a site of metabolism — resulting, for example, in compounds having greater metabolic stability; and compounds of Formula (I), (I-a), (I-b), or (I-c) enriched in a positron emitting isotope, such as11C,18F,15O and13N, which can be used, for example, in Positron Emission Topography (PET) studies. Isotopically-enriched compounds may be prepared by conventional techniques well known to those skilled in the art.

[0099]

[0053] As used herein, the phrase “of the formula”, “having the formula” or “having the structure” is not intended to be limiting and is used in the same way that the term “comprising” is commonly used. For example, if one structure is depicted, it is understood that all stereoisomer and tautomer forms are encompassed, unless stated otherwise.

[0100]

[0054] Certain compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms, the asymmetric centers of which can be defined, in terms of absolute stereochemistry, as (R)- or (S)-. In some embodiments, in order to optimize the therapeutic activity of the compounds of the disclosure, e.g., to treat cancer, it may be desirable that the carbon atoms have a particular configuration (e.g., (R,R), (S,S), (S,R), or (R,S)) or are enriched in a stereoisomeric form having such configuration. The compounds of the disclosure may be provided as racemic mixtures. Accordingly, the disclosure relates to racemic mixtures, pure stereoisomers (e.g., enantiomers and diastereomers), stereoisomer-enriched mixtures, and the like, unless otherwise indicated. When a chemical structure is depicted herein without any stereochemistry, it is understood that all possible stereoisomers are encompassed by such structure. Similarly, when a particular stereoisomer is shown or named herein, it will be understood by those skilled in the art that minor amounts of other stereoisomers may be present in the compositions of the disclosure unless otherwise indicated, provided that the utility of the composition as a whole is not eliminated by the presence of such other isomers. Individual stereoisomers may be obtained by numerous methods that are known in the art, including preparation using chiral synthons or chiral reagents, resolution using chiral chromatography using a suitable chiral stationary phase or support, or by chemically converting them into diastereomers, separating the diastereoisomers by conventional means such as chromatography or recrystallization, then regenerating the original stereoisomer.

[0101]

[0055] Additionally, where applicable, all cis-trans or E / Z isomers (geometric isomers), tautomeric forms and topoisomeric forms of the compounds described herein are included with the scope of the disclosure unless otherwise specified.

[0056] The term “pharmaceutically acceptable” refers to a material that is not biologically or otherwise unacceptable when used in the subject compositions and methods. For example, the term “pharmaceutically acceptable carrier” refers to a material — such as an adjuvant, excipient, glidant, sweetening agent, diluent, preservative, dye, colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent or emulsifier — that can be incorporated into a composition and administered to a patient without causing unacceptable biological effects or interacting in an unacceptable manner with other components of the composition. Such pharmaceutically acceptable materials typically have met the required standards of toxicological and manufacturing testing, and include those materials identified as suitable inactive ingredients by the U.S. Food and Drug Administration.

[0102]

[0057] The terms “salt” and “pharmaceutically acceptable salt” refer to a salt prepared from a base or an acid. Pharmaceutically acceptable salts are suitable for administration to a patient, such as a mammal (for example, salts having acceptable mammalian safety for a given dosage regime). Salts can be formed from inorganic bases, organic bases, inorganic acids and organic acids. In addition, when a compound contains both a basic moiety, such as an amine, pyridine or imidazole, and an acidic moiety, such as a carboxylic acid or tetrazole, zwitterions may be formed and are included within the term “salt” as used herein. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0103]

[0058] “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxy lie acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc., and include, for example, acetic acid, trifluoro acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (see, for example, Berge S.M. et al., “Pharmaceutical Salts,” Journal of Pharmaceutical Science, 66: 1-19 (1997)). Acid addition salts of basic compounds are, in some embodiments, prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt according to methods and techniques with which a skilled artisan is familiar.

[0104]

[0059] “Pharmaceutically acceptable base addition salt” refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Pharmaceutically acceptable base addition salts are, in some embodiments, formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, A,A-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, V-methy Iglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, V-ethylpiperidme. poly amine resins and the like. See Berge et al., supra.

[0105]

[0060] The term “effective amount” or “therapeutically effective amount” refers to the amount of an agent that is sufficient to effect beneficial or desired results. The therapeutically effective amount may vary depending upon one or more of: the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. An effective amount of an active agent may be administered in a single dose or in multiple doses. A component may be described herein as having at least an effective amount, or at least an amount effective, such as that associated with a particular goal or purpose, such as any described herein. The term “effective amount” also applies to a dose that will provide an image for detection by an appropriate imaging method. The specific dose may vary depending on one or more of: the particular agent chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, the tissue to be imaged, and the physical delivery system in which it is carried.

[0106]

[0061] As used herein, “treating” or “treatment” refers to an approach for obtaining beneficial or desired results with respect to a disease, disorder, or medical condition (such as cancer) in a subject, including but not limited to the following: (a) ameliorating the disease or medical condition, e.g., eliminating or causing regression of the disease or medical condition in a subject; (b) suppressing the disease or medical condition, e.g., slowing or arresting the development of the disease or medical condition in a subject; or (c) alleviating symptoms of the disease or medical condition in a subject. For example, “treating cancer” would include preventing cancer from reoccurring, ameliorating cancer, suppressing cancer, and alleviating the symptoms of cancer. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder.

[0107]

[0062] A “therapeutic effect”, as that term is used herein, encompasses a therapeutic benefit and / or prophylactic benefit as described above. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

[0108]

[0063] The terms “antagonist” and “inhibitor” are used interchangeably, and they refer to a compound having the ability to inhibit a biological function (e.g., activity, expression, binding, protein-protein interaction) of a target protein (e.g., K-Ras). Accordingly, the terms “antagonist” and “inhibitor” are defined in the context of the biological role of the target protein. While preferred antagonists herein specifically interact with (e.g., bind to) the target, compounds that inhibit a biological activity of the target protein by interacting with other members of the signal transduction pathway of which the target protein is a member are also specifically included within this definition.

[0064] The term “selective inhibition” or “selectively inhibit” refers to the ability of a biologically active agent to preferentially reduce the target signaling activity as compared to off-target signaling activity, via direct or indirect interaction with the target.

[0109]

[0065] The terms “subject” and “patient” refer to an animal, such as a mammal, for example a human. The methods described herein can be useful in both human therapeutics and veterinary applications. In some embodiments, the subject is a mammal, such as a human. “Mammal” includes humans and both domestic animals such as laboratory animals and household pets (e.g., cats, dogs, swine, cattle, sheep, goats, horses, rabbits), and nondomestic animals such as wildlife and the like.

[0110]

[0066] The terms “therapeutic agent”, “therapeutic capable agent” or “treatment agent” are used interchangeably and refer to a molecule or compound that confers some beneficial effect upon administration to a subject. The beneficial effect includes enablement of diagnostic determinations; amelioration of a disease, symptom, disorder, or pathological condition; reducing or preventing the onset of a disease, symptom, disorder or condition; and generally counteracting a disease, symptom, disorder or pathological condition.

[0111]

[0067] The terms “polypeptide”, “peptide” and “protein” are used interchangeably herein to refer to polymers of amino acids of any length. The polymer may be linear or branched, it may comprise modified amino acids, and it may be interrupted by non-amino acids. The terms also encompass an amino acid polymer that has been modified; for example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation, such as conjugation with a labeling component. As used herein the term “amino acid” refers to either natural and / or unnatural or synthetic amino acids, including glycine and both the D or L optical isomers, and amino acid analogs and peptidomimetics.

[0112]

[0068] The terms “polynucleotide”, “nucleotide sequence”, “nucleic acid” and “oligonucleotide” are used interchangeably. They refer to a polymeric form of nucleotides of any length, either deoxyribonucleotides or ribonucleotides, or analogs thereof. Polynucleotides may have any three-dimensional structure, and may perform any function, known or unknown. The following are non-limiting examples of polynucleotides: coding or noncoding regions of a gene or gene fragment, loci (locus) defined from linkage analysis, exons, introns, messenger RNA (mRNA), transfer RNA, ribosomal RNA, short interfering RNA (siRNA), short-hairpin RNA (shRNA), micro-RNA (miRNA), ribozymes, cDNA, recombinant polynucleotides, branched polynucleotides, plasmids, vectors, isolated DNA of any sequence, isolated RNA of any sequence, nucleic acid probes, and primers. A polynucleotide may comprise one or more modified nucleotides, such as methylated nucleotides and nucleotide analogs, such as peptide nucleic acid (PNA), morpholino and locked nucleic acid (LNA), glycol nucleic acid (GNA), threose nucleic acid (TNA), 2 ’-fluoro, 2’-OMe, and phosphorothiolated DNA. If present, modifications to the nucleotide structure may be imparted before or after assembly of the polymer. The sequence of nucleotides may be interrupted by non-nucleotide components. A polynucleotide may be further modified after polymerization, such as by conjugation with a labeling component or other conjugation target.

[0113]

[0069] As used herein, “expression” refers to the process by which a polynucleotide is transcribed from a DNA template (such as into an mRNA or other RNA transcript) and / or the process by which a transcribed mRNA is subsequently translated into peptides, polypeptides, or proteins. Transcripts and encoded polypeptides may be collectively referred to as “gene product.” If the polynucleotide is derived from genomic DNA, expression may include splicing of the mRNA in a eukaryotic cell.

[0114]

[0070] An “antigen” is a moiety or molecule that contains an epitope, and, as such, also specifically binds to an antibody. An “antigen binding unit” may be whole or a fragment (or fragments) of a full-length antibody, a structural variant thereof, a functional variant thereof, or a combination thereof. A full-length antibody may be, for example, a monoclonal, recombinant, chimeric, deimmunized, humanized and human antibody. Examples of a fragment of a full-length antibody may include, but are not limited to, variable heavy (VH), variable light (VL), a heavy chain found in camelids, such as camels, llamas, and alpacas (VHH or VHH), a heavy chain found in sharks (V-NAR domain), a single domain antibody (sdAb, e.g., “nanobody”) that comprises a single antigen-binding domain, Fv, Fd, Fab, Fab', F(ab')2, and “r IgG” (or half antibody). Examples of modified fragments of antibodies may include, but are not limited to scFv, di-scFv or bi(s)-scFv, scFv-Fc, scFv-zipper, scFab, Fab2, Fab3, diabodies, single chain diabodies, tandem diabodies (Tandab's), tandem di-scFv, tandem tri-scFv, minibodies (e.g., (VH-VL- CH3)2, (scFv-CH3)2, ((scFv)2-CH3+CH3), ((scFv)2-CH3) or (scFv-CH3-scFv)2), and multibodies (e.g., tnabodies or tetrabodies).

[0115]

[0071] The terms “antibody” and “antibodies” encompass any antigen binding units, including without limitation: monoclonal antibodies, human antibodies, humanized antibodies, camelised antibodies, chimeric antibodies, and any other epitope -binding fragments. Antibodies can come in different varieties known as isotypes or classes In humans there are five antibody classes known as IgA, IgD, IgE, IgG, and IgM, which are further subdivided into subclasses such as IgA1, IgA2.

[0116]

[0072] The term “in vivo” refers to an event that takes place in a subject’s body. The term “ex vivo” refers to an event that first takes place outside of the subject’s body for a subsequent in vivo application into a subject’s body. For example, an ex vivo preparation may involve preparation of cells outside of a subject’s body for the purpose of introduction of the prepared cells into the same or a different subject’s body. The term “in vitro” refers to an event that takes place outside of a subject’s body. For example, an in vitro assay encompasses any assay run outside of a subject’s body. In vitro assays encompass cell-based assays in which cells alive or dead are employed. In vitro assays also encompass a cell-free assay in which no intact cells are employed.

[0117]

[0073] The disclosure is also meant to encompass the in vivo metabolic products of the disclosed compounds. Such products may result from, for example, the oxidation, reduction, hydrolysis, amidation, esterification, and the like of the administered compound, primarily due to enzymatic processes. Accordingly, the disclosure includes compounds produced by a process comprising administering a compound disclosed herein to a mammal for a period of time sufficient to yield a metabolic product thereof. Such products are typically identified by administering a radiolabeled compound of the disclosure in a detectable dose to an animal, such as rat, mouse, guinea pig, monkey, or to a human, allowing sufficient time for metabolism to occur, and isolating its conversion products from the urine, blood or other biological samples.

[0118]

[0074] The term “Ras” or “RAS” refers to a protein in the Rat sarcoma (Ras) superfamily of small GTPases, such as in the Ras subfamily. The Ras superfamily includes, but is not limited to, the Ras subfamily, Rho subfamily, Rab subfamily, Rap subfamily, Arf subfamily, Ran subfamily, Rheb subfamily, RGK subfamily, Rit subfamily, Miro subfamily, and Unclassified subfamily. In some embodiments, a Ras protein is selected from the group consisting of KRAS (also used interchangeably herein as K-Ras, K-ras, or Kras), HRAS (or H-Ras), NRAS (or N-Ras), MRAS (or M-Ras), ERAS (or E-Ras), RRAS2 (or R-Ras2), RALA (or RalA), RALB (or RalB), RIT1, and any combination thereof, such as from KRAS, HRAS, NRAS, RALA, RALB, and any combination thereof.

[0119]

[0075] The terms “mutant Ras” and “Ras mutant”, as used interchangeably herein, refer to a Ras protein with one or more amino acid mutations, such as with respect to a common reference sequence such as a wild-type (WT) sequence. In some embodiments, a mutant Ras is selected from a mutant KRAS, mutant HRAS, mutant NRAS, mutant MRAS, mutant ERAS, mutant RRAS2, mutant RALA, mutant RALB, mutant RIT 1 , and any combination thereof, such as from a mutant KRAS, mutant HRAS, mutant NRAS, mutant RALA, mutant RALB, and any combination thereof. In some embodiments, a mutation can be an introduced mutation, a naturally occurring mutation, or a non-naturally occurring mutation. In some embodiments, a mutation can be a substitution (e.g., a substituted amino acid), insertion (e.g., addition of one or more amino acids), or deletion (e.g., removal of one or more amino acids). In some embodiments, two or more mutations can be consecutive, non-consecutive, or a combination thereof. In some embodiments, a mutation can be present at any position of Ras. In some embodiments, a mutation can be present at position 12, 13, 62, 92, 95, 96 (e.g., Y96D), or any combination thereof of Ras relative to SEQ ID No. 1 when optimally aligned. In some embodiments, a mutant Ras may comprise about or at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, or more than 50 mutations. In some embodiments, a mutant Ras may comprise up to about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, or 50 mutations. In some embodiments, the mutant Ras is about or up to about 500, 400, 300, 250, 240, 233, 230, 220, 219, 210, 208, 206, 204, 200, 195, 190, 189, 188, 187, 186, 185, 180, 175, 174, 173, 172, 171, 170, 169, 168, 167, 166, 165, 160, 155, 150, 125, 100, 90, 80, 70, 60, 50, or fewer than 50 ammo acids in length. In some embodiments, an amino acid of a mutation is a proteinogenic, natural, standard, non-standard, non- canonical, essential, non-essential, or non-natural amino acid. In some embodiments, an amino acid of a mutation has a positively charged side chain, a negatively charged side chain, a polar uncharged side chain, a non-polar side chain, a hydrophobic side chain, a hydrophilic side chain, an aliphatic side chain, an aromatic side chain, a cyclic side chain, an acyclic side chain, a basic side chain, or an acidic side chain. In some embodiments, a mutation comprises a reactive moiety. In some embodiments, a substituted amino acid comprises a reactive moiety. In some embodiments, a mutant Ras can be further modified, such as by conjugation with a detectable label. In some embodiments, a mutant Ras is a full-length or truncated polypeptide. For example, a mutant Ras can be a truncated polypeptide comprising residues 1-169 or residues 11-183 (e.g., residues 11-183 of a mutant RALA or mutant RALB).

[0120]

[0076] As used herein, the term “corresponding to” or “corresponds to” as applied to an amino acid residue in a polypeptide sequence refers to the correspondence of such amino acid relative to a reference sequence when optimally aligned (e.g., taking into consideration of gaps, insertions and mismatches; wherein alignment may be primary sequence alignment or three-dimensional structural alignment of the folded proteins). For instance, the serine residue in a K-Ras G12S mutant refers to the serine corresponding to residue 12 of SEQ ID No. 4, which can serve as a reference sequence. For instance, the aspartate residue in a K-Ras G12D mutant refers to the aspartate corresponding to residue 12 of SEQ ID No. 2, which can serve as a reference sequence. When an amino acid of a mutant Ras protein corresponds to an amino acid position in the WT Ras protein, it will be understood that although the mutant Ras protein amino acid may be a different amino acid (e.g., G12D, wherein the wildtype G at position 12 is replaced by an aspartate at position 12 of SEQ ID. No. 1), the mutant amino acid is at the position corresponding to the wildtype amino acid (e.g., of SEQ ID No. 1). In embodiments, a modified Ras mutant protein disclosed herein may comprise truncations at the C-terminus, or truncations at the N-terminal end preceding the serine residue. The serine residue in such N-terminal truncated modified mutant is still considered corresponding to position 12 of SEQ ID No. 1. In addition, an aspartate residue at position 12 of SEQ ID No. 2 finds a corresponding residue in SEQ ID Nos. 6 and 8.

[0121]

[0077] The term “leaving group” is used herein in accordance with its well understood meaning in Chemistry and refers to an atom or group of atoms which breaks away from the rest of the molecule, taking with it the electron pair which used to be the bond between the leaving group and the rest of the molecule.

[0122] Conjugates

[0123]

[0078] Disclosed herein are conjugates that comprise an antigen binding unit and a KRAS inhibitor. A subject conjugate exhibits one or more advantageous properties as compared to the corresponding KRAS small molecule inhibitor in the conjugate. For example, a subject conjugate may possess intramolecular synergy mediated by the antigen binding unit targeting a first antigen and a KRAS inhibitor, both together synergistically reduce signaling output of the first antigen or KRAS. In another example, a subject conjugate possesses intramolecular synergy mediated by the antigen binding unit targeting a first antigen, and a KRAS inhibitor, both together synergistically reduce signaling output of the first antigen and KRAS. A conjugate may also improve cell permeability of a small molecule KRAS inhibitor by conjugating to an antibody or fragment thereof that is internalized into the cell upon specific binding to its antigen. A conjugate may also improve cell permeability of an antigen binding unit by conjugating to it a small molecule KRAS inhibitor. A conjugate may also improve tolerability or reduce toxicity of a small molecule KRAS inhibitor by conjugating the small molecule KRAS inhibitor to an antigen binding unit. A conjugate may also provide an enhanced overall therapeutic index via the intramolecular synergy, improved cell permeability of the KRAS inhibitor, reduced off-target toxicity mediated by the KRAS inhibitor, and / or enhance pharmacokinetics profile of the KRAS inhibitor when conjugated to an antigen binding unit. One or more desired advantageous properties of a subject conjugate may be greater than (i) the effect of the KRAS inhibitor alone, (ii) the effect of the antigen binding unit alone, and / or (iii) the sum of the effect the KRAS inhibitor and the antigen binding unit when administered individually (e.g., the sum of the individual effects). The effect of a subject conjugate can be at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 150%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, 1,000%, 5,000%, or more than (i) the effect of the KRAS inhibitor alone, (ii) the effect of the antigen binding unit alone, and / or (iii) the sum of individual effects. The effect can be any measurable effect including but not limited to an enhancement of a therapeutic effect of an individual component within the conjugate (e.g., the KRAS inhibitor or the antigen binding unit) or a reduction in a side effect of an individual component within the conjugate. The present disclosure encompasses conjugates that comprise an antigen binding unit and a KRAS inhibitor (e.g., a smallmolecule KRAS inhibitor), wherein the antigen binding unit targets a first antigen, and the KRAS inhibitor reduces signaling output of the KRAS protein. Where desired, the conjugation of the antigen binding unit and the KRAS inhibitor is constructed to be reversible or cleavable such that the KRAS inhibitor is released from the antigen binding unit inside a cell, following, e.g., internalization of the antigen binding unit by the cell.

[0124]

[0079] In some aspects, the antigen binding unit may be conjugated either directly or through a linker to the KRAS inhibitor to form a conjugate. Preferably, the antigen binding unit is conjugated to the KRAS inhibitor, optionally through a linker, by one or more covalent bonds. In some embodiments, the conjugate may comprise at least two molecules of the KRAS inhibitor per antigen binding unit, such as 2 to 10, 2 to 8, 2 to 6, 2 to 5, 2 to 4, 3 to 8, 3 to 6, or 3 to 4 molecules of the KRAS inhibitor per antigen binding unit, as a multi-payload ADC-conjugate.

[0125]

[0080] In certain aspects, the present disclosure provides a conjugate comprising an antigen binding unit exhibiting binding specificity for at least a first antigen that is not KRAS, wherein the antigen binding unit is covalently attached to a small-molecule KRAS inhibitor, optionally through a chemical linker, and wherein the antigen binding unit and the KRAS inhibitor in the conjugate synergistically inhibits signaling output of the first antigen or KRAS. In certain aspects, the present disclosure provides a conjugate comprising an antigen binding unit exhibiting binding specificity for at least a first antigen that is not KRAS, wherein the antigen binding unit is covalently attached to a small-molecule KRAS inhibitor, optionally through a chemical linker, and wherein the antigen binding unit and the KRAS inhibitor in the conjugate synergistically inhibits signaling output of the first antigen and KRAS. In some aspects, the present disclosure provides a conjugate comprising an antigen binding unit exhibiting binding specificity for at least a first antigen that is not KRAS, wherein the antigen binding unit is covalently attached to a small-molecule KRAS inhibitor, optionally through a chemical linker. The antigen binding unit may be conjugated either directly or through a linker to the KRAS inhibitor to form a conjugate. Preferably, the antigen binding unit is conjugated to the KRAS inhibitor by one or more covalent bonds. The conjugate may comprise at least two molecules of the KRAS inhibitor per antigen binding unit, such as 2 to 10, 2 to 8, 2 to 6, 2 to 5, 2 to 4, 3 to 8, 3 to 6, or 3 to 4 molecules of the KRAS inhibitor per antigen binding unit.

[0126]

[0081] A small-molecule KRAS inhibitor of the present disclosure typically has a molecular weight of less than 1000 daltons, such as less than 950 Da, less than 900 Da, less than 850 Da, less than 800 Da, less than 790 Da, less than 780 Da, less than 770 Da, less than 760 Da, less than 750 Da, less than 740 Da, less than 730 Da, less than 720 Da, less than 710 Da, less than 700 Da, less than 690 Da, less than 680 Da, less than 670 Da, less than 660 Da, less than 650 Da, less than 600 Da, less than 550 Da, less than 500 Da, less than 450 Da, less than 400 Da, less than 350 Da, less than 300 Da, less than 250 Da, or less than 200 Da. In some embodiments, the small molecule has a molecular weight of 100 to 1000 Da, such as 100 to 900 Da, 100 to 850 Da, 100 to 800 Da, 100 to 750 Da, 100 to 700 Da, 100 to 650 Da, 100 to 600 Da, 100 to 550 Da, 100 to 500 Da, 150 to 900 Da, 150 to 850 Da, 150 to 800 Da,

[0127] 150 to 750 Da, 150 to 700 Da, 150 to 650 Da, 150 to 600 Da, 150 to 550 Da, 150 to 500 Da, 200 to 900 Da, 200 to

[0128] 850 Da, 200 to 800 Da, 200 to 750 Da, 200 to 700 Da, 200 to 650 Da, 200 to 600 Da, 200 to 550 Da, 200 to 500 Da,

[0129] 250 to 900 Da, 250 to 850 Da, 250 to 800 Da, 250 to 790 Da, 250 to 780 Da, 250 to 770 Da, 250 to 760 Da, 250 to

[0130] 750 Da, 250 to 740 Da, 250 to 730 Da, 250 to 720 Da, 250 to 710 Da, 250 to 700 Da, 250 to 690 Da, 250 to 680 Da,

[0131] 250 to 670 Da, 250 to 660 Da, 250 to 650 Da, 250 to 600 Da, 250 to 550 Da, or 250 to 500 Da. In some embodiments, a small-molecule KRAS inhibitor has a molecular weight in the range of about 710 Da to about 750 Da. In some embodiments, a small-molecule KRAS inhibitor has a molecular weight in the range of about 550 Da to about 710 Da. In some embodiments, a small-molecule KRAS inhibitor has a molecular weight in the range of about 600 Da to about 700 Da. In some embodiments, a small -molecule KRAS inhibitor has a molecular weight in the range of about 600 Da to about 705 Da. In some embodiments, a small-molecule KRAS inhibitor has a molecular weight in the range of about 600 Da to about 710 Da. In some embodiments, a small -molecule KRAS inhibitor has a molecular weight in the range of about 600 Da to about 715 Da. In some embodiments, a small -molecule KRAS inhibitor has a molecular weight in the range of about 600 Da to about 720 Da. In some embodiments, a smallmolecule KRAS inhibitor has a molecular weight in the range of about 600 Da to about 725 Da. In some embodiments, a small-molecule KRAS inhibitor has a molecular weight in the range of about 600 Da to about 750 Da. In some embodiments, a small-molecule KRAS inhibitor has a molecular weight in the range of about 600 Da to about 800 Da.

[0132]

[0082] In some embodiments, the KRAS inhibitor is characterized by a PAMPA permeability (Pe) less than 1 x 10-6cm / s, such as less than 9 x 10-7, 8 x 10-7, 7 x 10-7, 6 x 10-7, 5 x 10-7, 4 x 10-7, 3 x 10-7, 2 x 10-7, 1 x 10-7, 1 x 10-8, or 1 x 10-9cm / s. In some embodiments, the KRAS inhibitor is characterized by a PAMPA permeability (Pe) greater than 1 x 10-6cm / s, such as greater than 2 x 10-6, 3 x 10-6, 4 x 10-6, 5 x 10-6, 6 x 10-6, 7 x 10-6, 8 x 10-6, 9 x 10-6, 1 x 10-5, 1 x 10-4, or 1 x 10-3cm / s.

[0133]

[0083] In some embodiments, the conjugate is characterized by an enhanced therapeutic efficacy. Enhanced therapeutic efficacy may be ascertained by the formula: wherein TIconjugate= TD50c / ED50c, wherein TD50cis the dose of conjugate required to produce a toxic effect in 50% of test subjects and ED50cis the dose of conjugate required to produce a therapeutic effect in 50% of test subjecLs: and wherein TIKRASI = TD50k / ED50k, wherein TD50kis the dose of KRAS inhibitor required to produce a toxic effect in 50% of test subjects and ED50kis the dose of KRAS inhibitor required to produce a therapeutic effect in 50% of the test subjects.

[0134] In some embodiments, TIconjugate / TlKRASiis greater than 1.1, such as greater than 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 10, 20, 30, 40, or 50. In some embodiments, TIconjugate / TlKRASiis greater than 2. In some embodiments, TIconjugate / TlKRASiis greater than 5. In some embodiments, TIconjugate / TlKRASiis between about 2 to about 5. In some embodiments, TIconjugate / TlKRASiis about 5 to about 10. In some embodiments, TIconjugate / TlKRASiis greater than 5.

[0135]

[0084] In some embodiments, the conjugate is characterized by reduced plasma concentration of the KRAS inhibitor. Reduced plasma concentration may be ascertained by the formula:

[0136] [KRASi]p-c / [KRASi]p-k< 1 wherein [KRASi]p-cis plasma concentration of the KRAS inhibitor at a first time -point following administration of the conjugate; and wherein [KRASi]p-kis plasma concentration of the KRAS inhibitor following administration of the KRAS inhibitor alone at an equivalent dose at the same time-point.

[0137] In some embodiments, [KRASi]p-c / [KRASi]p-kis less than 0.95, such as less than 0.9, 0.85, 0.8, 0.75, 0.7, 0.65, 0.6, 0.55, 0.5, 0.4, 0.3, 0.2, 0.1, 0.05, 0.01, 0.005, or 0.001. In some embodiments, [KRASi]p-c / [KRASi]p-kis less than 0.5. In some embodiments, [KRASi]p-c / [KRASi]p-kis less than 0.1. In some embodiments, the first time-point is 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 9 hours, 12 hours, 18 hours, 24 hours, 36 hours, or 48 hours after the administration. As used herein, the term “equivalent dose” refers to an amount of KRAS inhibitor that is approximately the same as the amount of KRAS inhibitor administered as a conjugate in a comparative study. For example, a conjugate comprising two molecules of the KRAS inhibitor per antigen binding unit administered at dose x would typically be compared to a dose of l / 2x of free KRAS inhibitor (the equivalent dose).

[0138]

[0085] In some embodiments, the conjugate is characterized by an increased concentration of the KRAS inhibitor in tumor tissue relative to plasma as ascertained by the formula:

[0139] ([KRASi]t-c / [KRASi]p-c) / ([KRASi]t-k / [KRASi]p-k) > 1 wherein [KRASi]t-cis concentration of the KRAS inhibitor in tumor tissue at a first time -point following administration of the conjugate; wherein [KRASi]p-cis plasma concentration of the KRAS inhibitor at the same time -point following the administration of the conjugate; wherein [KRASi]t-kis concentration of the KRAS inhibitor in tumor tissue following administration of the KRAS inhibitor alone at an equivalent dose at the same time-point; and wherein [KRASi]p-kis plasma concentration of the KRAS inhibitor at the same time-point following the administration of the KRAS inhibitor alone at the equivalent dose.

[0140] In some embodiments, ([KRASi]t-c / [KRASi]p-c) / ([KRASi]t-k / [KRASi]p-k) is greater than 1.1, such as greater than 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 10, 20, 30, 40, or 50. In some embodiments, ([KRASi]t-c / [KRASi]p-c) / ([KRASi]t-k / [KRASi]p-k) is greater than 2. In some embodiments, ([KRASi]t-c / [KRASi]p-c) / ([KRASi]t-k / [KRASi]p-k) is greater than 5. In some embodiments, the first time-point is 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 9 hours, 12 hours, 18 hours, 24 hours, 36 hours, or 48 hours after the administration.

[0141]

[0086] In some embodiments, the conjugate inhibits signaling output of the first antigen and KRAS in a cell that does not overexpress the first antigen relative to a control cell (e.g., a cancer cell that does not overexpress the first antigen relative to a control cell that is non-cancerous), optionally wherein the first antigen is a tumor antigen. For example, the cell does not overexpress the first antigen, wherein the first antigen is selected from AG7, B7-H3, BCMA, CAI 5-3, CD19, CD20, CD22, CD30, CD33, CD38, CD52, CD70, CD71, CD79B, CEA, CLDN18.2, EGFR, F0LR1, GCC, GPC1 , HER2, HER3, ICAM1, LeX, LeY, MET, MSLN, MUCl, NECTIN4, SLC44A4, TF, and Trop-2. In some embodiments, the first antigen is EGFR. In some embodiments, the conjugate inhibits signaling output of the first antigen and KRAS in a cell that overexpress the first antigen relative to a control cell (e.g., a cancer cell that does not overexpress the first antigen relative to a control cell that is non-cancerous), optionally wherein the first antigen is a tumor antigen. For example, a cell of interest overexpress the first antigen, wherein the first antigen is selected from AG7, B7-H3, BCMA, CA15-3, CD19, CD20, CD22, CD30, CD33, CD38, CD52, CD70, CD71, CD79B, CEA, CLDN18.2, EGFR, FOLR1, GCC, GPC1, HER2, HER3, ICAM1, LeX, LeY, MET, MSLN, MUCl, NECTIN4, SLC44A4, TF, and Trop-2. In some embodiments, the overexpressed first antigen is EGFR.

[0142]

[0087] In certain aspects, the present disclosure provides a conjugate of Formula (A): wherein:

[0143] AgB is an antigen binding unit;

[0144] L is a chemical linker;

[0145] D is independently selected at each occurrence from a small-molecule KRAS inhibitor, a cytotoxic small-molecule and a small-molecule agent that selectively modulates a non-KRAS target, wherein at least one D is a KRAS inhibitor; p is selected from 1 to 20; and q is selected from 1 to 20.

[0088] In some embodiments, p is selected from 1 to 10, such as 1 to 8, 1 to 6, 1 to 5, 1 to 4, 1 to 3, 2 to 8, 2 to 6, 2 to 5, 2 to 4, 3 to 8, 3 to 6, or 3 to 5. In some embodiments, p is 2, 3, 4, 5 or 6, such as p is 2, 3, or 4. In some embodiments, p is about 1, about 2, about 3, about 4, about 5, about 6, about 7, or about 8.

[0146]

[0089] In some embodiments, q is selected from 1 to 10, such as 1 to 8, 1 to 6, 1 to 5, 1 to 4, 1 to 3, 2 to 8, 2 to 6, 2 to 5, 2 to 4, 3 to 8, 3 to 6, or 3 to 5. In some embodiments, q is 1, 2, 3, 4, 5 or 6, such as q is 1 or 2. In some embodiments, q is 1. In some embodiments, p is 1 to 8 and q is 1 to 5. In some embodiments, p is 1 to 8 and q is 1. In some embodiments, p is 2 to 5 and q is 1.

[0147]

[0090] In some embodiments, D is a small-molecule KRAS inhibitor, such as a KRAS inhibitor described herein.

[0091] In some embodiments, the conjugate of Formula (A) is selected from:

[0148]

[0149]

[0092] In some embodiments, the conjugate of Formula (A) is selected from:

[0150]

[0151]

[0093] In some embodiments, the conjugate of Formula (A) is selected from:

[0152] wherein X, Z, A, R2, R3, R4, R6, R7, R8, R9, R10, R11, R22, n, and m are defined in the KRAS Inhibitors section below, for example, for a compound of Formula (I), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), or (I-g).

[0153] Antigen Binding Unit

[0154]

[0094] An antigen binding unit of a conjugate can contain one or more antigen binding domains (also referred to as binding domains). In some embodiments, an antigen binding unit has a first binding domain. In some embodiments, an antigen binding unit has a first and a second binding domain that bind to the same antigen. In some embodiments, an antigen binding unit has a first and a second binding domain that bind to different antigens. In some embodiments, an antigen binding unit has a first and second binding domain, and optionally a third or more binding domain.

[0155]

[0095] A binding domain typically recognizes a single antigen. An antigen binding unit of a conjugate can have binding domains that can recognize, for example, two, three, four, five, six, seven, eight, nine, ten, or more antigens. An antigen binding unit can comprise two binding domains in which each binding domain can recognize the same antigen. An antigen binding unit can comprise two binding domains in which each binding domain can recognize a different antigen. An antigen binding unit can comprise three binding domains in which each binding domain can recognize a different antigen. An antigen binding unit can comprise three binding domains in which two of the binding domains can recognize the same antigen and the third binding domain recognizes a different antigen. In some embodiments, an antigen binding unit is bivalent and mono-specific (i.e., having two binding domains that specifically bind to the same antigen). In embodiments in which an antigen binding unit is trivalent or greater, the antigen binding unit is typically bi-specific or greater. Antigen binding units having a third binding domain attached to the C-terminal end of a light chain and / or the C-terminal end of an Fc domain can be bi-specific, tri-specific or multi-specific.

[0156]

[0096] In some embodiments, an antigen binding unit can be a fusion protein, such as an Fc fusion protein, having a first binding domain and optionally a second binding domain. In some embodiments, two antigen binding domains and an Fc domain can be expressed as a fusion protein, optionally formed by expression of separate polypeptide chains.

[0157]

[0097] A binding domain can specifically bind to an antigen on a cell surface or to a fragment thereof. A binding domain can specifically bind an antigen on a cell surface, for example, a tumor antigen on a tumor cell, on an antigen presenting cell such as a dendritic cell or macrophage, or on another immune cell such as a T cell. In some embodiments, a binding domain can specifically bind to an antigen on a cell surface of a tumor cell or an antigen presenting cell (such as a dendritic cell or macrophage), but not on other immune cells such as T cells. In some embodiments, a binding domain can specifically bind to a tumor antigen. In some embodiments, a binding domain can specifically bind to an antigen on an antigen presenting cell. In some embodiments, a binding domain can be a cell surface receptor agonist, such as an agonistic antibody.

[0158]

[0098] A binding domain can be an antigen-binding portion of an antibody (an antigen binding domain) or an antigen binding antibody fragment. A binding domain can be one or more fragments of an antibody that can retain the ability to specifically bind to an antigen. A binding domain can be in a scaffold, in which a scaffold is a supporting framework for the binding domain. A binding domain, such as an antigen binding fragment of an antibody, can be in an antibody scaffold or antibody-like scaffold. A binding domain can be in a non-antibody scaffold.

[0159]

[0099] Antigen binding units can comprise a binding domain(s) that can specifically bind to a tumor antigen. A tumor antigen can be a tumor specific antigen and / or a tumor associated antigen. As described herein, a “tumor antigen” refers to a molecular marker that can be expressed on a neoplastic tumor cell and / or within a tumor microenvironment. The molecular marker can be a cell surface receptor. For example, a tumor antigen can be an antigen expressed on a cell associated with a tumor, such as a neoplastic cell, stromal cell, endothelial cell, fibroblast, or tumor-infiltrating immune cell. For example, the tumor antigen EGFR can be overexpressed by certain types of head and neck cancer. A tumor antigen can also be ectopically expressed by a tumor and contribute to deregulation of the cell cycle, reduced apoptosis, metastasis, and / or escape from immune surveillance. Tumor antigens are generally proteins or polypeptides derived therefrom, but can be glycans, lipids, or other small organic molecules. Additionally, a tumor antigen can arise through increases or decreases in post-translational processing exhibited by a cancer cell compared to a normal cell, for example, protein glycosylation, protein lipidation, protein phosphorylation, or protein acetylation.

[0160]

[0100] A binding domain of an antigen binding unit can bind to tumor cells, such as an antibody against a cell surface receptor or a tumor antigen. In certain embodiments, a binding domain can specifically bind to a tumor antigen, such as including but not limited to, AG7, CD5, CD19, CD20, CD22, CD25, CD37, CD30, CD33, CD38, CD45, CD52, CD70, CD71, CD79B, CAMPATH-1, BCMA, CS-1, PD-L1, B7-H3, B7-DC (PD-L2), HLA-DR, carcinoembryonic antigen (CEA), TAG-72, MUC1, MUC15, MUC16, folate-binding protein (FOLR1), A33, G250, prostate-specific membrane antigen (PSMA), GCC, GD2, GD3, GM2, ICAM1, LeX, LeY, sLe, sLe(a), polysialic acid, fucosyl GM1, GM3, BM3, GloboH, CA15-3, CA-125, CA19-9, epidermal growth factor, HER2, IL -2 receptor, EGFRvIII (de2-7 EGFR), EGFR, fibroblast activation protein (FAP), a tenascin, a metalloproteinase, endosialin, vascular endothelial growth factor, avp3, WT1, LMP2, HPV E6, HPV E7, p53 nonmutant, NY-ESO-1, GLP-3, MelanA / MARTl, Ras mutant, gplOO, p53 mutant, PR1, bcr-abl, tyrosinase, survivin, PSA, hTERT, STn, STN1, TNC, a Sarcoma translocation breakpoint fusion protein, EphA2, EphB2, PAP, ML-IAP, AFP, ERG, NA17, PAX3, ALK, androgen receptor, cyclin Bl, MYCN, RhoC, TRP-2, mesothehn (MSLN), PSCA, MAGE-A1, MAGE-A3, MET, CYP1B1, PLAV1, BORIS, Tn, TF, CSPG4, ETV6-AML, NY-BR-1, RGS5, SART3, Carbonic anhydrase IX, PAX5, OY-TES1, Sperm protein 17, LCK, MAGE-C2, MAGE-A4, GAGE, TRAIL 1, HMWMAA, AKAP-4, SSX2, XAGE 1, B7H3, Legumam, Tie 2, Tim 3, PAGE4, VEGFR2, MAD-CT- 1, PDGFR-B, MAD-CT-2, ROR2, CMET, HER3, EpCAM, CA6, NAPI2B, TROP2, Claudm-6 (CLDN6), Claudm-16 (CLDN16), CLDN18.2, RON, LY6E, LY6K, FRA, DLL3, PTK7, Uroplakm-IB (UPK1B), UPK2, LIV1, ROR1, GPC1, GPC3, ADAM12, LRRC15, CDH6, CDH3, TMEFF2, GPNMB, ALPPL2, LAMP-1, STEAP, ENPP3, Nectm4, LYPD3, GPA33, EFNA4, SLITRK6, HAVCR1, SLC44A4, STRA6, TMPRSS3, TMPRSS4, TMEM238, Clorfl86, Fos-related antigen 1, VEGFR1, endoglin, VTCN1 (B7-H4), VISTA, or a fragment thereof. In some embodiments, a binding domain specifically binds a target, such target may include but is not limited to, AG7, B7-H3, BCMA, CA15-3, CD19, CD20, CD22, CD30, CD33, CD38, CD52, CD70, CD71, CD79B, CEA, CLDN18.2, EGFR, FOLR1, GCC, GPC1, HER2, HER3, ICAM1, LeX, LeY, MET, MSLN, MUC1, NECTIN4, SLC44A4, TF, or Trop-2. In some embodiments, a binding domain specifically binds EGFR.

[0161]

[0101] EGFR (epidermal growth factor receptor) is a receptor tyrosine kinase that mediates normal cell growth and development. Phosphorylation of EGFR activates downstream signaling pathways, including the PI3K / AKT / mTOR, STAT, and RAS / MAPK pathways, that involve cell proliferation, angiogenesis, apoptosis, and metastasis. Overexpression of EGFR is frequently observed in a variety of tumors, including brain, breast, cervical, colorectal, esophageal, head and neck, kidney, lung, ovarian, and stomach cancers. EGFR mutations that result in constitutive activation of EGFR and downstream signaling pathways are associated with a number of cancers. Examples of antibodies that can target and inhibit EGFR include cetuximab, panitumumab, nimotuzumab, zalutumumab, matuzumab, and amivantamab. In some embodiments, the antigen binding unit is an anti-EGFR antibody, such as cetuximab.

[0162]

[0102] A binding domain of an antigen binding unit can be selected from any domain that specifically binds to an antigen, including a binding domain of an antibody or a non-antibody binding domain. A binding domain of an antibody can be a monoclonal antibody, a polyclonal antibody, a recombinant antibody, or an antigen binding fragment thereof, for example, a heavy chain variable domain (VH) and a light chain variable domain (VL). A binding domain of a non-antibody scaffold can be a lipocalin, an anticalin, ‘T-body ’, a peptide (e.g., a Bicycle™ peptide), an affibody, a peptibody, a DARPin, an affimer, an avimer, a knottin, a monobody, an affinity clamp, an ectodomain, a receptor ectodomain, a receptor, a cytokine, a ligand, an immunocytokine, a centryin, a T-cell receptor, or a recombinant T-cell receptor. In some embodiments, a binding domain of a non-antibody scaffold can be a lipocalin, an anticalin, ‘T- body’, an affibody, a peptide (e.g., a Bicycle™ peptide), a peptibody, a DARPin, an affimer, an avimer, a knottin, a monobody, a centryin or an affinity clamp.

[0163]

[0103] In some embodiments, a binding domain of an antigen binding unit is an antigen binding domain from a monoclonal antibody and can comprise a light chain and a heavy chain. In an embodiment, the monoclonal antibody binds to a tumor antigen and comprises the light chain of a tumor antigen antibody and the heavy chain of a tumor antigen antibody, which specifically bind to the tumor antigen. In another embodiment, the monoclonal antibody binds to an antigen present on the surface of an immune cell (immune cell antigen) and comprises the light chain of an anti-immune cell antigen antibody and the heavy chain of an anti-immune cell antigen antibody, which specifically bind to an immune cell antigen. In another embodiment, the monoclonal antibody specifically binds to an antigen present on the surface of an antigen presenting cell (APC antigen) and comprises the light chain of an anti-APC antigen antibody and the heavy chain of an anti-APC antigen antibody, which bind an APC antigen.

[0164]

[0104] In some embodiments, an antigen binding unit can comprise an antibody, such as a bivalent, mono-specific antibody. An antibody can consist of two identical light protein chains (light chains) and two identical heavy protein chains (heavy chains), all held together covalently by interchain disulfide linkages. The N-terminal regions of the light and heavy chains together can form the antigen recognition site of the antibody. Structurally, various functions of an antibody can be confined to discrete protein domains or regions. The portions that can recognize and can specifically bind to an antigen consist of three complementarity determining regions (CDRs) that he within the variable heavy chain regions and variable light chain regions at the N-terminal ends of the heavy and light chains. The constant domains provide the general framework of the antibody and may not be involved directly in binding the antibody to an antigen, but can be involved in various effector functions, such as participation of the antibody in antibody-dependent cellular cytotoxicity (ADCC).

[0165]

[0105] In some embodiments, an antigen binding unit comprises an antigen binding domain of an antibody that includes the light chain (LC) CDRs (LCDRs) and heavy chain (HC) CDRs (HCDRs) of the antibody. For example, an antigen binding domain of an antibody can comprise one or more of the following: a light chain complementary determining region 1 (LCDR1), a light chain complementary determining region 2 (LCDR2), or a light chain complementary determining region 3 (LCDR3). As another example, an antibody binding domain can comprise one or more of the following: a heavy chain complementary determining region 1 (HCDR1), a heavy chain complementary determining region 2 (HCDR2), or a heavy chain complementary determining region 3 (HCDR3). In some embodiments an antigen binding domain comprises all of the following: LCDR1, LCDR2, LCDR3, HCDR1, HCDR2 and HCDR3. Unless stated otherwise, the CDRs described herein are defined according to the IMGT (the international ImMunoGeneTics information system) or the Kabat numbering system. In some embodiments, an antigen binding domain can comprise only the heavy chain of an antibody (e.g., does not include the light chain(s)). In some embodiments, an antigen binding domain can comprise only the light chain of an antibody (e.g., does not include the heavy chain(s)). In some embodiments, an antigen binding domain can comprise only the variable region of the heavy chain of an antibody. In some embodiments, an antigen binding domain can comprise only the variable region of the light chain of an antibody.

[0166]

[0106] An antigen binding unit can also comprise any antigen binding fragment of an antibody or recombinant form thereof, including but not limited to an scFv, Fab, Fab’, Fab2, variable Fv fragment (Fv), domain antibody, and any other fragment thereof that can specifically bind to an antigen.

[0167]

[0107] An antibody used herein can be chimeric or “humanized”. Humanized forms of non-human (e.g., murine) antibodies can be chimeric immunoglobulins, immunoglobulin chains or fragments thereof (such as Fv, Fab, Fab’, F(ab’)2, scFv, variable Fv fragment (Fv), domain antibody or other antigen-binding subdomains of antibodies), that contain minimal sequences derived from non-human immunoglobulin (e.g., the CDRs). In general, a humanized antibody can comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDRs correspond to those of a non-human immunoglobulin and all or substantially all of the framework regions (FR) are those of a human immunoglobulin sequence. The humanized antibody can also comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin consensus sequence.

[0168]

[0108] An antibody also can be a human antibody. As used herein, “human antibodies” include antibodies having, for example, the amino acid sequence of a human immunoglobulin and include antibodies isolated from human immunoglobulin libraries or from animals transgenic for one or more human immunoglobulins that do not express endogenous immunoglobulins. Human antibodies can be produced using transgenic mice which are incapable of expressing functional endogenous immunoglobulins, but which can express human immunoglobulin genes. Completely human antibodies that recognize a selected epitope can be generated using guided selection. In this approach, a selected non-human monoclonal antibody, e.g., a mouse antibody, is used to guide the selection of a completely human antibody recognizing the same epitope.

[0169]

[0109] An antibody described herein can be a derivatized antibody. For example, derivatized antibodies can be modified by glycosylation, acetylation, pegylation, phosphorylation, amidation, derivatization by known protecting / blocking groups, proteolytic cleavage, and the like. An antibody can also be modified, such as by defucosylation or deglycosylation.

[0170] [HO] An antibody can be a bispecific antibody or a dual variable domain antibody (DVD). Bispecific and DVD antibodies are monoclonal, often human or humanized, antibodies that have binding specificities for at least two different antigens (e.g., bi-specific). An antigen binding unit described herein may comprise a first binding domain and a second binding domain or a third binding domain that specifically binds to a different antigen than the first binding domain. An antigen binding unit may comprise a second binding domain or a third binding domain that specifically binds to a tumor antigen or an immune cell.

[0171] [Ill] Conjugates comprising antigen binding units described herein may have a dissociation constant (Kd) that is less than 10 nM for the target of the binding domain. A conjugate comprising a bispecific antigen binding unit may have a dissociation constant (Kd) that is less than 10 nM for the target of the second binding domain. The conjugates or antigen binding units may have a dissociation constant (Kd) that is less than 1 nM, less than 100 pM, less than 10 pM, less than 1 pM, or less than 0. 1 pM.

[0172] Linkers

[0112] The conjugates described herein optionally include a linker or linkers that attach at least one KRAS inhibitor to an antigen binding unit. The linker may be a cleavable linker, such as a peptide linker, or a non- cleavable linker. A conjugate may comprise multiple linkers. These linkers can be the same linker or different linkers. In some embodiments, more than one payload, such as a KRAS inhibitor, is attached to a single linker. The payload may be the same or different.

[0173]

[0113] Typically, linkers of the present disclosure attach a KRAS inhibitor(s) to an antigen binding unit by forming a covalent linkage to the KRAS inhibitor at one location and a covalent linkage to the antigen binding unit of the conjugate at another. Covalent linkages can be formed by reaction between functional groups on the linker and functional groups on the KRAS inhibitor and antigen binding unit of the conjugate. As used herein, the expression “linker” includes linker presented in different context such as (i) unconjugated forms of the linker that comprise a functional group capable of forming a covalent bond with an antigen binding unit; (ii) partially conjugated forms of the linker covalently attached to a KRAS inhibitor, wherein the linker comprises a functional group capable of forming a covalent bond with an antigen binding unit; (iii) partially conjugated forms of the linker covalently attached to an antigen binding unit, wherein the linker comprises a functional group capable of forming a covalent bond with a KRAS inhibitor for generating a conjugate; and (iv) fully conjugated forms of the linker covalently attached to both a KRAS inhibitor and an antigen binding unit.

[0174]

[0114] In some embodiments, the present disclosure provides a conjugate formed by contacting an antigen binding unit with a linker attached to a KRAS inhibitor under conditions in which the linker covalently binds to the antigen binding unit. In some embodiments, the present disclosure provides a method of making a conjugate, comprising contacting an antigen binding unit with a linker attached to a KRAS inhibitor under conditions in which the linker covalently binds to the antigen binding unit, thereby forming the conjugate. In some embodiments, the linker comprises an electrophilic group that is capable of reacting with a nucleophilic group present on the antigen binding unit to form a covalent bond between the linker and the antigen binding unit. In some embodiments, the electrophilic group reacts with a sulfhydryl, hydroxyl, or amino functional group of the antigen binding unit. Suitable electrophilic groups include maleimides, haloacetamides, and NHS esters. In some embodiments, the linker comprises a nucleophilic group that is capable of reacting with an electrophilic group present in the antigen binding unit to form a covalent bond between the linker and the antigen binding unit. In some embodiments, the electrophilic group reacts with a hydrazide, hydroxylamine, amino, hydrazine, thiosemicarbazone, hydrazine carboxylate, or arylhydrazide functional group of the linker.

[0175]

[0115] As further described herein, a linker can be short, long, flexible, rigid, hydrophilic, or hydrophobic. A linker may contain segments having different characteristics, such as segments that are flexible or rigid. In some embodiments, a linker is chemically stable in extracellular environments, such as in the blood stream. In some embodiments, a linker or fragment thereof is not stable, such as a linker that undergoes cleavage and / or immolation or otherwise breaks down under certain physiological conditions, such as conditions found inside a tumor cell. In some embodiments, a linker is cleavable by one or more enzymes, such as a protease. A cleavable linker may be cleaved in vitro or in vivo. Cleavable linkers can include chemically or enzymatically unstable or degradable linkages. In some embodiments, cleavable linkers rely on processes inside the cell to liberate a KRAS inhibitor, such as reduction in the cytoplasm, exposure to acidic conditions in the lysosome, or cleavage by specific proteases or other enzymes within the cell. Cleavable linkers can incorporate one or more chemical bonds that are chemically or enzymatically cleavable, while the remainder of the linker may be non-cleavable.

[0176]

[0116] A linker may contain a chemically labile group such as a hydrazone or disulfide group. Linkers comprising chemically labile groups can exploit differential properties between the plasma and some cytoplasmic compartments. The intracellular conditions that can facilitate KRAS inhibitor release for hydrazine-containing linkers can be the acidic environment of endosomes and lysosomes, while disulfide-containing linkers can be reduced in the cytosol, which can contain high thiol concentrations (e.g., glutathione). The plasma stability of a linker containing a chemically labile group can be increased by introducing steric hindrance using substituents near the chemically labile group.

[0177]

[0117] Acid-labile groups, such as hydrazones, can remain intact during systemic circulation in the neutral pH of the blood (pH 7.3 -7.5) and can undergo hydrolysis and release a KRAS inhibitor once the conjugate is internalized into mildly acidic endosomal (pH 5.0-6.5) or lysosomal (pH 4.5-5.0) compartments of the cell. This pH dependent release mechanism can be associated with nonspecific release of the KRAS inhibitor. To increase the stability of the hydrazone group of the linker, the linker may be varied by chemical modification, e.g., substitution, allowing tuning to achieve more efficient release in the lysosome with minimal loss in circulation.

[0178]

[0118] Hydrazone-containing linkers can contain additional cleavage sites, such as additional acid-labile cleavage sites and / or enzymatically labile cleavage sites. Conjugates including hydrazone-containing linkers may include a

[0179]

[0119] In some embodiments, the linker is cleavable by a protease that is typically present in the disease microenvironment. The linker may contain a protease cleavage site for a protease that is overexpressed in the disease microenvironment. Cleavage of the protease cleavage site allows for the selective release of the KRAS inhibitor in the disease microenvironment while sparing normal cells or tissue from the KRAS inhibitor. In some embodiments, the linker contains a protease cleavage site for a protease selected from legumain, plasmin, TMPRSS3, TMPRSS4, TMPRSS6, MMP-1, MMP-2, MMP-3, MMP-8, MMP-9, MMP-14, MT1-MMP, CATHEPSIN D, CATHEPSIN K, CATHEPSIN S, ADAM10, ADAM12, ADAMTS, Caspase-1, Caspase-2, Caspase-3, Caspase-4, Caspase-5, Caspase-6, Caspase-7, Caspase-8, Caspase-9, Caspase-10, Caspase-11, Caspase- 12, Caspase-13, Caspase-14, TACE, a serine protease, a cysteine protease, human neutrophil elastase, beta- secretase, uPA, fibroblast associated protein, matriptase, PSMA, and PSA.

[0180]

[0120] In some embodiments, the linker is cleavable by a protease found in the extracellular microenvironment of the target cells, whereby cleavage of the protease cleavage site results in release of an active form of the KRAS inhibitor in the extracellular microenvironment. In some embodiments, the linker is cleavable by a protease found in the intracellular microenvironment of the target cells, whereby cleavage of the protease cleavage site results in release of an active form of the KRAS inhibitor in the intracellular microenvironment. In some embodiments, the protease is preferentially localized in the extracellular or intracellular microenvironment of the target cells. Preferential localization of a protease in an extracellular or intracellular microenvironment refers to the increased presence of an active or activatable form of the protease in the vicinity of the target cells associated with a disease to be treated, such that the protease can cleave the protease cleavage site and release an active form of the KRAS inhibitor upon or after antigen binding by the conjugate, as compared to the amount of protease in an extracellular or intracellular environment of normal cells (e.g., cells not associated with the disease).

[0121] A linker containing such a protease cleavage site may further comprise one or more components selected from pentafluorophenyl, succinimide, maleimide, and para-aminobenzoic acid (PABA). In some embodiments, the linker is a compound of the formula: (maleimidocaproyl)-(protease cleavage site)-(para-aminobenzyloxycarbonyl). The linker may comprise a maleimide at one end and a protease cleavage site at the other end. In some embodiments, the linker comprises a maleimide at one end, a protease cleavage site, and a self-immolative unit on the other end which is activated upon cleavage of the protease cleavage site. In some embodiments, the linker comprises a lysine residue, optionally having an acylated amine, and a protease cleavage site. In some embodiments, the linker is a compound of the formula Rx-SL-Pc-Iu, wherein Rxis a reactive moiety capable of forming a covalent bond with an antigen binding unit; SLis a stretcher unit, such as C1-10alkyl, PEG 1-5, or a combination thereof; Pcis a protease cleavage site, such as a dipeptide, tripeptide, or tetrapeptide described herein; and Iuis a self-immolative unit, such as p-aniinobenzyI carbamate.

[0181]

[0122] In some embodiments, the linker comprises a peptide, such as a dipeptide, tripeptide, or tetrapeptide. The peptide may comprise natural amino acids, unnatural amino acids, or combinations thereof. In some embodiments, the peptide comprises L-amino acids. In some embodiments, the linker comprises a component selected from Val- Cit, Cit-Val, Ala-Ala, Ala-Cit, Cit-Ala, Asn-Cit, Cit-Asn, Cit-Cit, Val-Glu, Glu-Val, Ser-Cit, Cit-Ser, Lys-Cit, Cit- Lys, Asp-Cit, Cit-Asp, Val-Ala, Ala-Vai, Val-Val, Val-Gly, Gly-Val, Phe-Lys, Lys-Phe, Val-Lys, Lys-Val, Ala- Lys, Lys-Ala, Phe-Cit, Cit-Phe, Leu-Cit, Cit-Leu, Ile-Cit, Cit-Ile, Phe-Arg, Arg-Phe, Cit-Trp, Trp-Cit, Gly-Gly, Gly- Cit, Cit-Gly, Ala-Pro, Pro-Ala, Ala-Ser, Ser-Ala, Glu-Val-Cit, Cit- Val-Glu, Glu-Gly-Cit, Cit-Gly-Glu, Asn-Ala-Ala, Ala-Ala-Asn, and Ala-Gly-Ala. In some embodiments, the linker comprises one or more components selected from Val-Cit, Glu-Val-Cit, Val-Ala, Val-Val, Val-Gly, Gly-Gly, Gly-Cit, Glu-Gly-Cit, Ala-Ala-Asn, Ala-Gly-Ala, Ala- Pro, Ala-Ser, and Phe-Lys. In some embodiments, the linker comprises a component selected from Val-Cit and Glu- Val-Cit.

[0182]

[0123] In some embodiments, the linker (L) consists of 10 to 500 atoms, such as 10 to 400 atoms or 10 to 300 atoms. In some embodiments, the linker consists of 30 to 400 atoms, such as 30 to 300 atoms. In some embodiments, the linker comprises one or more components independently selected from alkyl, alkene, alkyne, aryl, cycloalkyl, heterocycle, glycoside, silyl ether, hydroxy, ether, polyether, ketone, ester, polyester, carbonate, amide, polyamide, peptide, polypeptide, urea, carbamate, sulfide, disulfide, sulfate, sulfonamide, phosphate, hydrazone, and succinimide. In some embodiments, the linker comprises one or more components independently selected from alkyl, alkene, alkyne, aryl, cycloalkyl, heterocycle, glycoside, silyl ether, hydroxy, ether, ketone, ester, carbonate, amide, urea, carbamate, sulfide, disulfide, sulfate, sulfonamide, phosphate, hydrazone, and succinimide.

[0183]

[0124] A KRAS inhibitor that is directly attached to a peptide linker can be proteolytically released as an amino acid adduct of the KRAS inhibitor. Such adduct may be active in vivo, or the in vivo activity of the adduct relative to the KRAS inhibitor may be impaired. In some embodiments, a linker comprises a self-immolative spacer to separate the KRAS inhibitor from the site of proteolytic cleavage. Use of a self-immolative spacer can allow for the separation of the fully active, chemically unmodified KRAS inhibitor upon amide bond hydrolysis.

[0184]

[0125] Para-aminobenzyl alcohol is a self-immolative spacer that can be incorporated into a linker of the present disclosure. In particular, the amino group can form an amide bond with an amino acid residue of the linker, while an amine of the KRAS inhibitor can be connected to the benzylic alcohol through a carbamate group. Following cleavage of the amide bond in vivo (e.g., via proteolytic cleavage of a peptide linker), a 1 ,6-elimination reaction releases the KRAS inhibitor (D) as depicted in the following scheme:

[0185] Similarly, the same spacer may be used to connect KRAS inhibitors containing a phenol group to the remainder of the linker as a para-aminobenzyl ether (PABE). Self-immolative spacers that comprise a methylene carbamate unit suitable for conjugation with a KRAS inhibitor having a functional group such as a hydroxyl, thiol, amide, or amine are described in WO 2015 / 095755, which is hereby incorporated by reference in its entirety. Following cleavage of the amide bond in vivo, a 1 ,6-elimination reaction and subsequent decomposition releases the KRAS inhibitor (D) as depicted in the following simplified scheme:

[0186]

[0126] Cleavable linkers described herein may comprise non-cleavable portions or segments. Similarly, an otherwise non-cleavable linker may be modified to include a cleavable portion or segment to render it cleavable. By way of example only, polyethylene glycol (PEG) and related polymers can include cleavable groups in the polymer backbone. For example, a polyethylene glycol or polymer linker may include one or more protease cleavable groups.

[0187]

[0127] Maleimide groups may be used in the preparation of conjugates of the present disclosure due to their specificity for reacting with thiol groups of, for example, cysteine groups of the antigen binding unit of a conjugate. The reaction between a thiol group of an antigen binding unit and a linker comprising a maleimide group may proceed according to the following scheme: wherein indicates an attachment site to the remainder of the linker, optionally wherein the linker comprises the KRAS inhibitor.

[0188]

[0128] The reverse reaction leading to maleimide elimination from a thio-substituted succinimide may also take place. This reverse reaction is undesirable, as the maleimide group may subsequently react with another available thiol group such as other proteins in the body having available cysteine residues. Accordingly, the reverse reaction can undermine the specificity of a conjugate. One method of preventing the reverse reaction is to incorporate a basic group into the linking group as shown in the scheme below. Not wishing to be bound by any particular theory, the presence of the basic group may increase the nucleophilicity of nearby water molecules to promote ring-opening hydrolysis of the succinimide group. The hydrolyzed form of the succinimide is resistant to deconjugation in plasma. So called “self-stabilizing” linkers may provide conjugates with improved stability. A representative example is provided in the following scheme: wherein indicates an attachment site to the remainder of the linker, optionally wherein the linker comprises the KRAS inhibitor. Two possible isomers can result from the hydrolysis reaction even though a mechanism is only depicted for the formation of the first.

[0189]

[0129] The identity of the base as well as the distance between the base and the maleimide group can be modified to tune the rate of hydrolysis of the thio-substituted succinimide group. Bases suitable for inclusion in a linker described herein, e.g., any linker comprising a maleimide group prior to conjugating to an antigen binding unit, may facilitate hydrolysis of a nearby succinimide group formed after conjugation of the antigen binding unit to the linker. Bases may include, for example, amines (e.g., N(R12)(R13)), nitrogen-containing heterocycles (e.g., a 3- to 12- membered heterocycle comprising one or more nitrogen atoms), amidines, guanidines, and carbocycles or heterocycles substituted with one or more amine groups. A basic unit may be separated from a maleimide group by, for example, an alkylene chain, such as C1-10alkylene, wherein the alkylene is optionally substituted. A linker of the present disclosure that comprises a maleimide group may further comprise an electron withdrawing group, such as - C(O)R12, =O, -CN, -NO2, -CF3, -CBR3, -CC13, -CI3, halogen, -C(O)2R12, -C(O)N(R12)(R13), -C(O)R12, -C(O)F, - C(O)Br, -C(O)C1, -C(O)I, -SO2R12, -SO3R12, -SO2NHR12, -SO2N(R12)(R13), -PO3R12R13, -P(O)(CH3)NHR12, -NO, - N(R12)3+, -CR12=C(R12)2, and -C=CR12. Such linkers may also comprise an aryl group (e.g., phenyl) or heteroaryl group (e.g., pyridyl), each of which is optionally substituted with one or more electron withdrawing groups such as those described herein. Further examples of self-stabilizing linkers are provided in WO 2013 / 173337, which is incorporated herein by reference in its entirety. It will be understood that references herein to a linker comprising a maleimide group may equivalently describe a conjugate having a linker comprising a thio-substituted succinimide group or a hydrolyzed, ring-opened thio-substituted succinimide group, and vice versa. In some embodiments, a linker comprises a component selected from ,;wherein indicates an attachment site to the remainder of the linker, optionally wherein the linker comprises the KRAS inhibitor.

[0190]

[0130] A linker may bridge a pair of sulfhydryl groups derived from reduction of a native hinge disulfide bond found in an antigen binding unit. An advantage of this methodology is the ability to synthesize homogenous DAR4 conjugates (e.g., conjugates of Formula (A) wherein p is 4) by full reduction of IgGs to afford 4 pairs of sulfhydryls from interchain disulfide bonds followed by 4 equivalents of the conjugating agent. wherein indicates an attachment site to the remainder of the linker, optionally wherein the linker comprises the KRAS inhibitor. Similarly, a maleimide derivative may be used to bridge a pair of sulfhydryl groups: wherein indicates an attachment site to the remainder of the linker, optionally wherein the linker comprises the KRAS inhibitor.

[0191]

[0131] A linker may be polyvalent such that it covalently links more than one KRAS inhibitor to a single site on the antigen binding unit, or monovalent such that it covalently links a single KRAS inhibitor to a single site of the antigen binding unit. Exemplary polyvalent linkers that may be used to attach two or more KRAS inhibitors to an antigen binding unit of the conjugate include Fleximer® linkers. A Fleximer® linker utilizes a solubilizing poly acetal backbone to incorporate two or more KRAS inhibitors (D) via a sequence of ester bonds, for example, utilizing a linker comprising two or more units of the structure shown below. This methodology can render highly- loaded conjugates (e.g., DAR20 — conjugates of Formula (A) wherein q is 20).

[0192] An aliphatic alcohol may be present or introduced into a KRAS inhibitor to utilize this linker. In some embodiments, the alcohol moiety is then attached to an alanine moiety, which is then systematically incorporated into the Fleximer® linker. Liposomal processing of the conjugate in vitro releases the parent alcohol-containing drug. In some embodiment, the linker utilized for producing a subject conjugate may take on different formats. In some instances the linker, linker modified Kras inhibitor, or conjugate may take a form described below in this paragraph. In embodiments, the chemical linker is a chemical linker described in WO2020 / 236841, which is incorporated herein in its entirety. For example, the Linker- KRAS inhibitor may be a compound having the structure of Formula

[0193] (Xa), or a pharmaceutically acceptable salt thereof: wherein: R1is a reactive group; L1is a bridging spacer; Lp is a bivalent peptide spacer; G-L2-A is a self-immolative spacer; R2is a hydrophilic moiety; L2is a bond, a methylene, a neopentylene or a C2-C3alkenylene; A is a bond, ’-OC(=O)-*, -

[0194] OC(=O)N(CH3)CH2CH2N(CH3)C(=O)-* or -OC(=O)N(CH3)C(Ra)2C(Ra)2N(CH3)C(=O)-*, wherein each Rais independently selected from H, c1-6alkyl or a C3-8cycloalkyl and the * of A indicates the point of attachment to D; L3is a spacer moiety; and D is a KRAS inhibitor for generating a conjugate of the present disclosure comprising an N or an O, wherein D is connected to A via a direct bond from A to the N or the O of the KRAS inhibitor for generating a conjugate of the present disclosure. In embodiments, of the compound of Formula (Xa),Lp is a bivalent peptide spacer comprising one to four amino acid residues. In embodiments, is :wherein the * indicates the point of attachment to an N or a O of the KRAS inhibitor for generating a conjugate of the present disclosure, the *** indicates the point of attachment to Lp. In embodiments, the compound of Formula (Xa), has the formula (Xb): In embodiments, of the compound of Formula (Xa), R1is

[0195] NH2, -SH, -SR3, -SSR4, -S(=O)2(CH=CH2), -

[0196] (CH2)2S(=O)2(CH=CH2), -NHS(=O)2(CH=CH2), -NHC(=O)CH2Br, -NHC(=O)CH2I,

[0197] C(O)NHNH2,

[0198] L1is *-C(=O)(CH2)mO(CH2)m-**; *-

[0199] C(=O)((CH2)mO)t(CH2)n-**; *-C(=O)(CH2)m-**; *-C(=O)NH((CH2)mO)t(CH2)n-**; *-

[0200] C(=O)O(CH2)mSSC(R3)2(CH2)mC(=O)NR3(CH2)mNR3C(=O)(CH2)m-**; *-C(=O)O(CH2)mC(=O)NH(CH2)m-**; *- C(=O)(CH2)mNH(CH2)m-**; *-C(=O)(CH2)mNH(CH2)nC(=O)-**; *-C(=O)(CH2)mX1(CH2)m-**; *- C(=O)((CH2)mO)t(CH2)nX1(CH2)n-**; *-C(=O)(CH2)mNHC(=O)(CH2)n-**; *-

[0201] C(=O)((CH2)mO)t(CH2)nNHC(=O)(CH2)n-**; *-C(=O)(CH2)mNHC(=O)(CH2)nX1(CH2)n-**; *-

[0202] C(=O)((CH2)mO)t(CH2)nNHC(=O)(CH2)nX1(CH2)n-**; *-C(=O)((CH2)mO)t(CH2)nC(=O)NH(CH2)m-**; *- C(=O)(CH2)mC(R3)2-** or *-C(=O)(CH2)mC(=O)NH(CH2)m-**, where the * of L1indicates the point of attachment to Lp, and the ** of L1indicates the point of attachment to R1; R2is a hydrophilic moiety selected from polyethylene glycol, poly alkylene glycol, a sugar, an oligosaccharide, a polypeptide or C2-C6alkyl substituted with 1 to 3 groups; each R3is independently selected from H and C1-C6alkyl;R4is 2-pyridyl or 4-pyridyl; each

[0203] R5is independently selected from H, C1-C6alkyl, F, Cl, and-OH; each R6is independently selected from H, C1-C6alkyl, F, Cl, -NH2, -OCH3, - OCH2CH3, -N(CH3)2, -CN, -NO2and-OH; each R7is independently selected from H, C1-6alkyl, fluoro, benzyloxy substituted with-C(=O)OH, benzyl substituted with-C(=O)OH, C1-4alkoxy substituted with- C(=O)OH and C1-4alkyl substituted with-C(=O)OH; X1is is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; each n is independently selected from 1, 2, 3, 4, 5, 6, 7,

[0204] 8, 9 and 10; each t is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 and 30; Lp is a bivalent peptide spacer comprising an amino acid residue selected from glycine, valine, citrulline, lysine, isoleucine, phenylalanine, methionine, asparagine, proline, alanine, leucine, tryptophan, and tyrosine; A is a bond, -OC(=O)-*,

[0205] ' , -OC(=O)N(CH3)CH2CH2N(CH3)C(=O)-* or -OC(=O)N(CH3)C(Ra)2C(Ra)2N(CH3)C(=O)-*, wherein each Rais independently selected from H, C1-C6alkyl or a C3-C8cycloalkyl and the * of A indicates the point of attachment to KRAS inhibitor; L3 is a spacer moiety having the structure where (i) W is - CH2O-**, -CH2N(Rb)C(=O)O-**, -NHC(=O)C(Rb)2NHC(=O)O-**, - NHC(=O)C(Rb)2NH-**, NHC(=O)C(Rb)2NHC(=O)-**,-CH2N(X-R2)C(=O)O-**, -C(=O)N(X-R2)-**, -CH2N(X-R2)C(=O)-**, -C(=O)NRb- **, -C(=O)NH-**, -CHb2NRbC(=O)-**, -CH2NR C(=O)NH-**, -CH2NRbC(=O)NRb-**, -NHC(=O)-**, - NHC(=O)O-**, -NHC(=O)NH-**, -OC(=O)NH-**, -S(O)2NH-**, -NHS(O)2-**, -C(=O)-, -C(=O)O-** , -NH-, or - CH2N(Rb)C(=O)CH2-**, wherein each Rbis independently selected from H, C1-C6alkyl or C3-C8cycloalkyl and wherein the ** of W indicates the point of attachment to X; X is a bond, triazolyl or ***-CH2-triazolyl-*, wherein the *** of X indicates the point of attachment to W and the * of X indicates the point of attachment to R2; or (ii) W is -CH2O-**, -CH2N(Rb)C(=O)O-**, -NHC(=O)C(Rb)2NHC(=O)O-**, - NHC(=O)C(Rb)2NH-**, NHC(=O)C(Rb)2NHC(=O)-**, -CH2N(X-R2)C(=O)O-**, -C(=O)N(X-R2)-**, -CH2N(X-R2)C(=O)-**, -C(=O)NRb- **, -C(=O)NH-**, -CH2NRbC(=O)-**, -CH2NRbC(=O)NH-**, -CH2NRbC(=O)NRb-**, -NHC(=O)-**, - NHC(=O)O-**, -NHC(=O)NH-**, -OC(=O)NH-**, -S(O)2NH-**, -NHS(O)2-**, -C(=O)-, -C(=O)O-** or - NH-, wherein each Rbis independently selected from H, C1-C6alkyl or C3-C8cycloalkyl and wherein the ** of W indicates the point of attachment to X; X is ***-CH2-triazolyl-C1-4alkylene-OC(O)NHS(O)2NH-*, ***-C4-6cycloalkylene - OC(O)NHS(O)2NH-*, ***-(CH2CH2O)n- C(O)NHS(O)2NH-*, ***-(CH2CH2O)n-C(O)NHS(O)2NH-(CH2CH2O)n-*, or ***-CH2-triazolyl-C1-4alkylene-OC(O)NHS(O)2NH-(CH2CH2O)n-*, wherien each n independently is 1, 2, or 3, the *** of X indicates the point of attachment to W and the * of X indicates the point of attachment to R2; and the * of L3 indicates the point of attachment to R2; and KRAS inhibitor comprising an N or an O, wherein KRAS inhibitor is connected to A via a direct bond from A to the N or the O of the KRAS inhibitor. In embodiments, the conjugate is a conjugate described in WO2023102875, which is incorporated herein in its entirety. For example, the conjugate may have the formula (Xb): Ab-(L-(D)m)n, or a pharmaceutically acceptable salt thereof; wherein Ab is an antibody or antigen binding fragment thereof; L is a linker; D is a KRAS inhibitor moiety; m is an integer from 1 to 8; and n is any number from 1 to 10. In some embodiments, the L is selected from: a cleavable linker and a non-cleavable linker. In some embodiments, the L comprises cleavable peptide. In some embodiments, the cleavable peptide is cleavable by an enzyme. In some embodiments, the enzyme comprises Cathepsin B. In some embodiments, the cleavable peptide or L comprises an amino acid unit. In some embodiments, the amino acid unit comprises a dipeptide, tripeptide, tetrapeptide or pentapeptide. In some embodiments, the amino acid unit is selected from: Val- Cit, Val-Ala(VA), Glu-Val-Cit, Ala-Ala-Asn(AAN), Gly-Val-Cit, Gly-Gly-Gly(GGG)and Gly-Gly-Phe- Gly(GGFG). In some embodiments, the L comprises a spacer. In some embodiments, the spacer comprises self- immolative spacers. In some embodiments, the self-immolative spacer comprises p-aminobenzoxy carbonyl(PABC) or p-aminobenzyl(PAB). In some embodiments, the cleavable peptide is directly spliced to the spacer. In some embodiments, the L comprises: Val-Cit-PABC, Val-Ala-PABC, Glu-Val-Cit-PABC, Ala-Ala-Asn-PABC, Gly-Val- Cit-PABC, Gly-Gly-Gly-PABC, Gly-Gly-Phe-Gly-PABC, Val-Cit-PAB, Val-Ala-PAB, Glu-Val-Cit-PAB, Ala-Ala- Asn-PAB, Gly-Val-Cit-PAB, Gly-Gly-Gly-PAB or Gly-Gly-Phe-Gly-PAB. In some embodiments, the spacer comprises the structure shown in -NH-(CH2)n1-La-Lb-Lc-, where La denotes -O-or a single bond; Lb denotes - CR2(-CR3)-, or a single bond, where R2and R3each independently denote C1-C6alkyl, -(CH2)na-NH2, - (CH2)nb-COOH, or -(CH2)nC-OH, n1denotes an integer from 0 to 6, na, nband nceach independently denote an integer from 1 to 4, but R2and R3are not the same when nais 0, and Lc denotes -C(=O)-. In some embodiments, the spacer comprises -NH-(CH2)3-C(=O)-, -NH-CH2-O-CH2-C(=O)-or -NH-(CH2)2-O-CH2-C(=O)-. In some embodiments, the L comprises the structure shown in -L1-L 2-L 3-, where L 1 denotes -(succinimidyl-3-yl-N)- (CH2)n2-C(=O)-, -CH2-C(=O)-NH-(CH2)n3-C(=O)-or -C(=O)-(CH2)n4-C(=O)-, where n denotes an integer from 2 to 8, n3denotes an integer from 1 to 8, and n4denotes an integer from 1 to 8; L 2 denotes amino acid unit; L denotes the self-degradation spacer. In some embodiments, the L is selected from: -(succinimidyl-3-yl-N)-CH2CH2-C(=O)-

[0206] GGFG-PABC-; -(succinimidyl-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-PABC-; -(succinimidyl-3-yl-N)- CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-PABC-; -(succinimidyl-3-yl-N)-CH2CH2-C(=O)-NH-CH2CH2O- CH2CH2O-CH2CH2-C(=O)-GGFG-PABC-; -(succinimidyl-3-yl-N)-CH2CH2-C(=O)-NH-CH2CH2O-CH2CH2O- CH2CH2O-CH2CH2O-CH2CH2-C(=O)-GGFG-PABC-; -CH2-C(=O)-NH-CH2CH2-C(=O)-GGFG-PABC-; -C(=O)- CH2CH2CH2CH2CH2CH2-C(=O)-GGFG-PABC-; -(succinimidyl-3-yl-N)-CH2CH2-C(=O)-GGFG-NH-CH2CH2- C(=O)-; -(succinimidyl-3-yl-N)-CH2CH2-C(=O)-GGFG-NH-CH2CH2CH2-C(=O)-; -(succinimidyl-3-yl-N)- CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2CH2-C(=O)-; -(succinimidyl-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)- GGFG-NH-CH2CH2CH2-C(=O)-; -(succinimidyl-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-

[0207] CH2CH2CH2CH2CH2-C(=O)-; -(succinimidyl-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2-O-CH2-C(=O)- ; -(succinimidyl-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2CH2-O-CH2-C(=O)-; -(succinimidyl-3-yl-N)- CH2CH2-C(=O)-NH-CH2CH2O-CH2CH2O-CH2CH2-C(=O)-GGFG-NH-CH2CH2CH2-C(=O)-; -(succinimidyl-3-yl- N)-CH2CH2-C(=O)-NH-CH2CH2O-CH2CH2O-CH2CH2-C(=O)-GGFG-NH-CH2CH2-C(=O)-; -(succinimidyl-3-yl- N)-CH2CH2-C(=O)-NH-CH2CH2O-CH2CH2O-CH2CH2O-CH2CH2O-CH2CH2-C(=O)-GGFG-NH-CH2CH2CH2-

[0208] C(=O)-; -(succinimidyl-3-yl-N)-CH2CH2-C(=O)-NH-CH2CH2O-CH2CH2O-CH2CH2O-CH2CH2O-CH2CH2-C(=O)- GGFG-NH-CH2CH2-C(=O)-; -CH2-C(=O)-NH-CH2CH2-C(=O)-GGFG-NH-CH2CH2CH2-C(=O)-; -C(=O)- CH2CH2CH2CH2CH2CH2-C(=O)-GGFG-NH-CH2CH2CH2-C(=O)-; -(succinimidyl-3-yl-N)-CH2CH2-C(=O)-VA-

[0209] PABC-; -(succinimidyl-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-VA-PABC-; -(succinimidyl-3-yl-N)- CH2CH2CH2CH2CH2-C(=O)-VA-NH-PABC-; -(succinimidyl-3-yl-N)-CH2CH2-C(=O)-NH-CH2CH2O-CH2CH2O- CH2CH2-C(=O)-VA-PABC-; -(succinimidyl-3-yl-N)-CH2CH2-C(=O)-NH-CH2CH2o-CH2CH2O-CH2CH2O- CH2CH2O-CH2CH2-C(=O)-VA-PABC-; -CH2-C(=O)-NH-CH2CH2-C(=O)-VA-PABC-; -C(=O)- CH2CH2CH2CH2CH2CH2-C(=O)-VA-PABC-; -(succinimidyl-3-yl-N)-CH2CH2-C(=O)-VA-NH-CH2CH2-C(=O)-; - (succinimidyl-3-yl-N)-CH2CH2-C(=O)-VA-NH-CH2CH2CH2-C(=O)-; -(succinimidyl-3-yl-N)- CH2CH2CH2CH2CH2-C(=O)-VA-NH-CH2CH2-C(=O)-; -(succinimidyl-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-VA- NH-CH2CH2CH2-C(=O)-; -(succmimidyl-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-VA-NH-CH2CH2CH2CH2CH2- C(=O)-; -(succinimidyl-3-yl-N)-CH2CH2CH2CH2CH2-C(=O)-VA-NH-CH2-O-CH2-C(=O)-; -(succinimidyl-3-yl-N)- CH2CH2CH2CH2CH2-C(=O)-VA-NH-CH2CH2-O-CH2-C(=O)-; -(succinimidyl-3-yl-N)-CH2CH2-C(=O)-NH-

[0210] CH2CH2O-CH2CH2O-CH2CH2-C(=O)-VA-NH-CH2CH2CH2-C(=O)-; -(succinimidyl-3-yl-N)-CH2CH2-C(=O)-NH- CH2CH2O-CH2CH2O-CH2CH2-C(=O)-VA-NH-CH2CH2-C(=O)-; -(succinimidyl-3-yl-N)-CH2CH2-C(=O)-NH- CH2CH2O-CH2CH2O-CH2CH2O-CH2CH2O-CH2CH2-C(=O)-VA-NH-CH2CH2CH2-C(=O)-; -(succinimidyl-3-yl-N)- CH2CH2-C(=O)-NH-CH2CH2O-CH2CH2O-CH2CH2O-CH2CH2O-CH2CH2-C(=O)-VA-NH-CH2CH2-C(=O)-; -CH2- C(=O)-NH-CH2CH2-C(=O)-VA-NH-CH2CH2CH2-C(=O)-; and -C(=O)-CH2CH2CH2CH2CH2CH2-C(=O)-VA-NH- CH2CH2CH2-C(=O)-. In some embodiments, the p-aminobenzoxy carbonyl(PABC) or p-aminobenzyl(PAB) comprises a polysarcosine(poly-N-methylglycine) residue. In some embodiments, the L is selected from the following structure: wherein n5denotes an integer from 0 to 20. In some embodiments, the n5denotes an integer from 8 to 15. In embodiments, the chemical linker is a chemical linker described in WO2022 / 228494, which is incorporated herein in its entirety. For example, in one aspect, is provided a conjugate, or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein the conjugate includes a structure represented by formula (Xc):

[0211] ; wherein, Q1can be a linking group, L1can include -L1a-C(=O)-, L1acan be selected from the group consisting of optionally substituted alkylene groups, optionally substituted polyethylene glycol groups, optionally substituted alkenylene groups, optionally substituted alkynylene groups, optionally substituted aliphatic cyclylene groups, optionally substituted aliphatic heterocyclylene groups, optionally substituted arylene groups, and optionally substituted heteroarylene groups; L2can include an optionally substituted polypeptide residue, L3can include an optionally substituted spacer group. For example, the spacer group may have self- degrading ability. For example, the spacer group can include optionally substituted optionally substituted ’ wherein, L2and / or L3can include optionally substituted polysarcosine residues, T is a KRAS inhibitor, Ab is an antigen binding unit, and m is a number from 1 to 8. In another aspect, the compound, or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable salt, prodrug or solvate thereof, has the formula Xc; wherein, Q1can include a linker, L1can include -L1a-C(=O)-, wherein, L1acan be selected from the group consisting of optionally substituted alkylene groups, optionally substituted polyethylene glycol groups, optionally substituted alkenylene groups, optionally substituted alkynylene groups, optionally substituted aliphatic cyclylene groups, optionally substituted aliphatic heterocyclylene groups, optionally substituted arylene groups, and optionally substituted heteroarylene groups; L2can include an optionally substituted polypeptide residue, L3can include an optionally substituted spacer group. For example, wherein, the benzene ring of L3can be substituted with the optionally substituted structural unit -X. For example, the structural unit -X can be selected from the group consisting of optionally substituted

[0212] , wherein X1is selected from the group consisting of carbonyl, C1-C8alkyl, C1-C8alkoxy, C1-C6cycloalkyl, linear heteroalkyl comprising 1 -8 atoms, and linear-cyclic heteroalkyl comprising 1 -8 atoms, where the heteroalkyl comprises 1 -3 atoms selected from N, O or S; wherein X2 is selected from the group consisting of hydrogen, C1-C8alkyl, C1-C8alkoxy, C1-C6cycloalkyl, linear heteroalkyl comprising 1-8 atoms, and linear-cyclic heteroalkyl comprising 1-8 atoms, where the heteroalkyl comprises 1-3 atoms selected from N, O or S; wherein X3 is selected from the group consisting of hydrogen, C1-C8alkyl, C1-C8alkoxy, C1-C6cycloalkyl, linear heteroalkyl comprising 1 -8 atoms, and linear-cyclic heteroalkyl comprising 1 -8 atoms, where the heteroalkyl comprises 1 -3 atoms selected from N, O or S; the C1-C8alkyl, C1-C8alkoxy, C1-C6cycloalkyl, linear heteroalkyl comprising 1-8 atoms, and linear-cyclic heteroalkyl comprising 1 -8 atoms are each independently optionally substituted with one or more substituents selected from deuterium, halogen, cyano, nitro, amino, alkyl, carboxy, alkoxy, or cycloalkyl. For example, wherein, the benzene ring of L3 can be substituted with the optionally substituted structural unit -X. For example, the structural unit -X can include optionally substituted wherein X1is selected from the group consisting of C1-C8alkyl, C1-C8alkoxy, C1-C6cycloalkyl, linear heteroalkyl comprising 1-8 atoms, and linear-cyclic heteroalkyl comprising 1-8 atoms, where the heteroalkyl comprises 1-3 atoms selected from N, O or S, and the C1-C8alkyl, C1-C8alkoxy, C1-C6cycloalkyl, linear heteroalkyl comprising 1-8 atoms, and linear-cyclic heteroalkyl comprising 1 -8 atoms are each independently optionally substituted with one or more substituents selected from deuterium, halogen, cyano, nitro, amino, alkyl, carboxy, alkoxy, or cycloalkyl. In embodiments, the conjugate is a conjugate described in WO2013 / 173337, which is incorporated herein in its entirety. For example in some embodiments, the conjugate is represented by Formula Xd: or a salt thereof (e.g., pharmaceutically acceptable salts); L is a antigen binding unit; D' is a KRAS inhibitor; L° is the optional secondary linker assembly; and Lssis the self-stabilizing linker assembly, wherein M1is a succinimide ring or a hydrolyzed succinamide or together with BU forms a dilactam; BU is a Basic unit; HE is a hydrolysis enhancer comprising an electron withdrawing group; the circle represents a scaffold that can be C1-8alkylene, Ci.

[0213] 8 heteroalkylene, C6-10arylene, or C4-10heteroarylene, and optionally comprises a reactive site suitable for attachment to the optional secondary linker assembly or D'; the subscripts m, q and r are each 0 or 1 , and the sum of m + q + r is 0, 1 or 2 provided that if m + q + r is 0, the scaffold is a C6-10arylene or C4-10hetero arylene; the subscript a and b are each 0 or 1 , and the sum of a+b is 1; and the subscript p ranges from 1 to 20. In some aspects, when r is 1, HE does not comprise a carbonyl group, (i.e., C(=O)). In embodiments, r is zero, in some embodiments, a is 1 and b is zero. In other embodiments, a is zero and b is 1. In some embodiments m + q + r is 0. in such embodiments, the scaffold is a C6-10arylene or C4-10heteroarylene and acts as the electron withdrawing group. Exemplary aryls and heteroaryls include phenyl and pyridinyl. In some embodiments m + q + r is 1 or 2. In some embodiments, the conjugate is represented by Formula Xd or a salt thereof wherein a is 1 and r is zero. In some embodiments LOis present and is a releasable linker assembly, the circle represents a scaffold that is C1-8alkylene or C1-8heteroalkylene (preferably C1-4alkylene or C1-4hetero alkylene), a is 1, r is zero, and the sum of m+q is 1. In some such embodiments, the scaffold is C1-3alkylene or C1-3hetero alkylene. In some such embodiments, the alkylene is straight chain or branched. In some embodiments, LOis present and is a releasable linker assembly, the circle represents a scaffold that is C1-8alkylene or C1-8hetero alkylene (preferably C1-4alkylene or C1-

[0214] 4heteroalkylene), a is 1 , and m and r are zero. In some such embodiments, the scaffold is Ci alkylene or C1 -

[0215] 3heteroalkylene, in some such embodiments, the alkylene is straight chain or branched. In embodiments, M1is preferably a succinimide ring (i.e., non-hydrolyzed) or a hydrolyzed succinimide ring (also referred to herein as hydrolyzed succinimide). In some embodiments, the self-stabilizing linker assembly (Lss) is represented by Formula

[0216] Xdb: or a salt thereof (e.g., pharmaceutically acceptable salt) wherein the wavy lines indicate points for attachment of the optional secondary linker assembly to D' or D, and wherein / / indicates the point of attachment to a antigen binding unit. In the self-stabilizing linker assembly above, M1represents a succinimide ring or a hydrolyzed succinamide ring or a dilactam formed when the base reacts with the succinimide ring, BU is a Basic unit, HE is a hydrolysis enhancer comprising an electron withdrawing group, and the circle represents a scaffold that can be C1-8alkylene, C1-8heteroalkyiene, C6-10arylene, or C4-10heteroarylene, and optionally comprises a reactive site suitable for attachment to the optional secondary linker assembly, D!, or D; and the subscripts m, q and r are each 0 or 1 , and the sum of m + q + r is 0, 1 or 2 provided that if m + q + r is 0, the scaffold is a C6-10arylene or C4-10hetero arylene. In some embodiments, when r is 1 , HE does not comprise a carbonyl group, (i.e., C(=O)). In some embodiments, r is zero. In some embodiments m + q + r is 0. In such aspects, the C6-10arylene or C4-10heteroarylene act as the electron withdrawing group. Exemplary aryls and heteroaryls include phenyl and pyridinyl. In some embodiments m + q + r is 1 or 2. In some embodiments, the selfstabilizing linker assembly is represented by Formula 11 or a salt thereof wherein the circle represents a scaffold that is C1-8alkylene or C1-8heteroalkyiene (preferably C1-4alkylene or heteroalkyiene), r is zero, and the sum of m+q is 1. In some such aspects, the scaffold is C1-3alkylene or C1-3hetero alkylene. In some such aspects, the alkylene is a straight chain or branched alkylene. In some embodiments, the circle represents a scaffold that is C1-8alkylene or C1-8heteroalkyiene (preferably C1-4alkylene or heteroalkyiene) and m and r are zero. In some such aspects, the scaffold is C1-3alkylene or C1-3heteroalkyiene. In some such aspects, the alkylene is a straight chain or branched alkylene. In some embodiments, the circle represents a scaffold that is C1, C2, C3. or C4 straight or branched chain alkylene, r is zero, and the sum of m+q is 1. In some embodiments, the circle represents a scaffold that is C1, C2, C3. or C4 straight or branched chain alkylene, and m and r are zero. In embodiments of the conjugate having the Formula Xd: 1) m is 1 , and q and r are 0; 2) q is 1 , and m and r are 0; 3) r is 1 , and m and q are 0; 4) m is 1 , q and r are 0, and a is 1 ; 5) q is 1 , m and r are 0, and a is 1 ; 6) r is 1 , m and q are 0, and a is 1 ; 7) m is 1 , q and r are 0, and D' is a KRAS inhibitor; 8) q is 1. m and r are 0, and D' is a KRAS inhibitor; 9) r is 1 , m and q are 0, and D' is a KRAS inhibitor, D; 10) m is 3 , q and r are 0, a is 1, and D:is a Drug unit, D: 11) q is 1, m and r are 0, a is 1, and D' is a KRAS inhibitor; or 12) r is 1 , m and q are 0, a is 1 , and D' is a KRAS inhibitor. In embodiments, including those based on each of the selected embodiments of 1), 2) 3), 4), 5), 6), 7), 8), 9), 10), 11), and 12) above , the Basic unit (BU) comprises a primary, a secondary amine, or a tertiary amine. In still other selected embodiments, including those based on each of the selected embodiments of 1), 2) 3), 4), 5), 6), 7), 8), 9), 10), 11), and 12) above, the Basic unit is selected from the group consisting of-(C(R9)( R10))xNH2, -(C(R9)( R10))xNHRa, and -(C(R9)( R10))xNRa2, wherein x is an integer of from 0-4 (or from 1 to 4) and each Rais independently selected from the group consisting of C1-6alkyl and C1-6haloalkyl, or two Ragroups are combined with the nitrogen to which they are attached to form an azetidinyl, pyrrolidinyl or piperidinyl group, provided that if x is zero there are no less than 2 intervening atoms between the base of the Basic unit and the nitrogen atom of the succinimide (hydrolyzed or non-hydrolyzed) or dilactam, and each R9and R10are independently selected from H or C1-3alkyl. In still other selected embodiments, including those based on each of the selected embodiments of 1), 2) 3), 4), 5), 6), 7), 8), 9), 10), 11), and 12) above, the Basic unit is selected from the group consisting of -(CH2)xNH2, -(CH2)xNHRa, and -(CH2)xNRa2, wherein x is an integer of from 0 to 6 (preferably 0 to 4, or 1 to 4) provided that if x is zero there are no less than 2 intervening atoms between the base of the Basic unit and the nitrogen atom of the succinimide (hydrolyzed or non-hydrolyzed) or dilactam, and each Rais independently selected from the group consisting of C1-6alkyl and C1-6haloalkyl, or two Ragroups are combined with the nitrogen to which they are attached to form an azetidinyl, pyrrolidinyl or piperidinyl group. In yet other selected embodiments, x is an integer of from 1 to 4. In even other selected embodiments, including those based on each of the selected embodiments of 1), 2) 3), 4), 5), 6). 7), 8), 9), 10), 11), and 12) above, the Basic unit is NH2-CH2NH2, -CH2CH2NH2, - CH2CH2CH2NH2, or -CH2CH2CH2CH2NH2provided that if the Basic unit is -NH2, there are no less than 2 intervening atoms between the base and the nitrogen atom of the succinimide (hydrolyzed or non-hydrolyzed) or dilactam. In embodiments, the conjugate is a conjugate described in W02010 / 093395, which is incorporated herein in its entirety. For example, the conjugate may have the formula Xe, MAb-[L2]-[L l]-[AA]m- [A']-D; where MAb is a disease -targeting antibody; L2 is a component of the cross-linker comprising an antibodycoupling moiety and one or more of acetylene (or azide) groups; L 1 comprises a defined PEG with azide (or acetylene) at one end, complementary to the acetylene (or azide) moiety in L2, and a reactive group such as carboxylic acid or hydroxyl group at the other end; AA is an L-amino acid; m is an integer with values of 0, 1, 2, 3, or 4; and A' is an additional spacer, selected from the group of ethanolamine, 4-hydroxybenzyl alcohol, 4- aminobenzyl alcohol, or substituted or unsubstituted ethylenediamine. The L amino acids of 'AA' are selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. If the A' group contains hydroxyl, it is linked to the hydroxyl group or amino group of D in the form of a carbonate or carbamate, respectively. In a preferred embodiment of formula Xe, A' is a substituted ethanolamine derived from an L-amino acid, wherein the carboxylic acid group of the amino acid is replaced by a hydroxymethyl moiety. A' may be derived from any one of the following L-amino acids: alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. In embodiments, the conjugate is a conjugate described in WO2019081455, which is incorporated herein in its entirety. For example, the conjugate may have the formula Xf wherein D is KRAS inhibitor, X is an optional cleavable moiety for releasing D, Z is an optional spacer, and a is 1 or more, b is 1 or more and m is 1 or more; L is an orthogonal connector that allows for (HPSMW) to be in an orthogonal orientation with respect to (X-D), HPSMWresults from covalent binding to said orthogonal connector L, of a single molecular weight homopolymer having formula (Xfb) wherein n is one or more; R1and R2are different, and one of R1and R2is H or an inert group, the other one of R1and R2being a functionalized reactive group, said group being reactive for covalently binding a bindable group, in such reaction conditions that the inert group is non-reactive, Z1and Z2, identical or different, are optional spacers, and k is 2 or more. Further features of a conjugate of formula Xf, are given below, taken alone or in any combination. In embodiments, k is an integer which is at least 2, it is preferably 100 at most, more preferably 50 at most, and specifically 2-30, and more specifically 2-24, 6-24, or 12-24. In embodiments, said functionalized reactive group R1or R2may be selected from the following groups: carboxylic acid group, amino groups NRR" wherein R and R" are independently selected from H, (C1-C6) alkyl optionally interrupted by at least one heteroatom selected among O, N and S, hydroxyl group, halogen atoms, hydrazine (-NH2- NH2) group, nitro group, hydroxylamine group, azido group, (C2-C6) alkynyl group, (C2-C6) alkenyl group, thiol group, activated ester groups such as N-hydroxysuccinimide ester, perfluorinated esters, nitrophenyl esters, azabenzotriazole and benzotriazole activated esters, acylureas, boronic acid B(OR"")2groups, wherein R"" is a hydrogen atom or a C1-C6alkyl group, thiol-reactive groups such as maleimide, halomaleimides, haloacetyls, pyridyl disulfides, mesylate group, tosylate group, triflate group, aldehyde group, isocyanate or isothiocyanate group, chlorosulfonyl group, acrylate group. As mentioned above, spacers are optional, both Z1and Z2may be present, only one of Z1and Z2may be present, they also may not be present. In this latter case and when the homopolymer of the invention is a homopolymer of sarcosine, it has formula Xfc wherein R1, R2and k are as described above. In embodiments, R1may be H or an inert group and R2a functionalized reactive group or R1may be a functionalized reactive group and R2is H or an inert group. In embodiments, the functionalized reactive group R1or R2is a secondary amine and the inert group R1or R2is a carboxylic acid that remains unreacted and unbound on the final conjugate. In embodiments, R1is selected from OH and NH2, and when R1is OH, R2is COCH3and when R1is NH2, R2is CO— G— COOH, G being CH2CH2,

[0217] CH2CH2CH2, CH2CH2CH2CH2, CH2OCH2, CH2SCH2, CH2CH(CH3)CH2, CH2C(CH3)2CH2or CH2N(CH3)CH2. In embodiments, HPSMW wherein the wavy bond represents the attachment point to L or to a spacer Z, if present, k is 2 or more, preferably k is 2 to 50, and R4 is selected from -R', - O , -OR', -SR', -S-, -NR'2, -NR'3+, =NR', -CX3, -CN, -NRC(=O)R', -C(=O)R', -C(=O)NR'2, -SO3-, -SO3H, -S(=O)2R', -OS(=O)2OR', -S(=O)2NR', -S(=O)R', -OP(=O)(OR')2, -P(=O)(OR')2, -PO3, -PO3H2, -C(=O)X, -C(=S)R', -CO2R', - CO2, -C(=S)OR', C(=O)SR', C(=S)SR', C(=O)NR'2, C(=S)NR'2, or C(=NR')NR'2, where each X is independently a halogen: -F, -CI, -Br, or —I, and each R' is independently -H, -C1.20 alkyl, C6-C20 aryl, or C3-14 heterocycle.

[0218] Typically, R4 is -OR', -NR'2, or -C(=O)R'. In embodiments, the conjugate of formula Xf is wherein R6is —C1-C10alkylene-, — C1-C10heteroalkylene-, -C3-C8carbocyclo-, -O-

[0219] (C1- C8alkyl)-, -arylene-, — C1-C10alkylene-arylene-, -arylene-C1-C10alkylene-, — C1-C10alkylene-(C3-

[0220] C8carbocyclo)-, -(C3-C8carbocyclo)-C1-C10alkylene-, -C3-C8heterocyclo-, — C1-C10alkylene-(C3-C8heterocyclo)-, -(C3-C8heterocyclo)— C1-C10alkylene-, — C1-C10alkylene-C(=O)-, — C1-C10heteroalkylene-C(=O)-, -C3-

[0221] C8carbocyclo-C(=O)-, -O-(C1-C8alkyl)-C(=O)-, -arylene-C(=O)-, -C1-C10alkylene- arylene-C(=O)-, -arylene-C1- C10alkylene-C(=O)-, -C1-C10alkylene-(C3-C8carbocyclo)-C(=O)-, -(C3-C8carbocyclo)-C1-C10alkylene-C(=O)-, - C3-C8heterocyclo-C(=O)-, -C1-C10alkylene-(C3-C8heterocyclo)-C(=O)-, -(C3-C8heterocyclo)-C1-C10alkylene- C(=O)-, -C1-C10alkylene-NH-, -C1-C10heteroalkylene-NH-, -C3-C8carbocyclo-NH-, -O-(C1-C8alkyl)-NH-, - arylene -NH-, -C1-C10alkylene-arylene-NH-, -arylene-C1-C10alkylene-NH-, -C1-C10alkylene-(C3-C8carbocyclo)- NH-, -(C3-C8carbocyclo)-C1-C10alkylene-NH-, -C3-C8heterocyclo-NH-, -C1-C10alkylene-(C3-C8heterocyclo)-NH-, -(C3-C8heterocyclo)-C1-C10alkylene-NH-, -C1-C10alkylene-S-, -C1-C10heteroalkylene-S -, -C3-C8carbocyclo-S -, - O-(C1-C8alkyl)-)-S -, -arylene-S-, -C1-C10alkylene-arylene-S-, -arylene-C1-C10alkylene-S-, -C1-C10alkylene-(C3- C8carbocyclo)-S-, -(C3-C8carbocyclo)-C1-C10alkylene-S-, -C3-C8heterocyclo-S-, -C1-C10alkylene-(C3-

[0222] C8heterocyclo)-S-, -(C3-C8heterocyclo)-C1-C10alkylene-S-, — C1-C10alkylene-O-C(=O)-, -C3-C8carbocyclo-O- C(=O)-, -O-(C1-C8alkyl)-O-C(=O)-, -arylene-O-C(=O)-, -C1-C10alkylene-arylene-O-C(=O)-, -arylene-C1- C10alkylene-O-C(=O)-, -C1-Cio alkylene-(C3-C8carbocyclo)-O-C(=O)-,-(C3-C8carbocyclo)-C1-C10alkylene-O- C(=O)-, -C3-C8heterocyclo-O-C(=O)-, -C1-C10alkylene-(C3-C8heterocyclo)-O-C(=O)-, -(C3-C8heterocyclo)-C1- C10alkylene-O-C(=O)-; any of the R6group is optionally substituted with one or more of the substituents selected from : -X, -R, -O , -OR', =O, -SR', -S-, -NR'2, -NR'3+, =NR', -CX3, -CN, -OCN, -SCN, -N=C=O, -NCS, -NO, -NO2,

[0223] =N2, -N3, -NR'C(=O)R', -C(=O)R', -C(=O)NR'2, -SO3-, -SO3H, -S(=O)2R', -OS(=O)2OR', -S(=O)2NR', -S(=O)R', - OP(=O)(OR')2, -P(=O)(OR')2, -PO3, -PO3H2, -C(=O)X, -C(=S)R', -CO2R', -CO2, -C(=S)OR', C(=O)SR', C(=S)SR', C(=O)NR'2, C(=S)NR'2, and C(=NR')NR'2, where each X is independently a halogen: -F, -CI, -Br, or -I; and each R' is independently -H, -C1C20alkyl, -C6-C20aryl, or -C3-C14heterocycle; Z is an optional spacer; L is an orthogonal connector; X is an optional cleavable moiety for releasing D; D is KRAS inhibitor, a is 1 or more and b is 0, 1 or more, and HPSMWresults from covalent binding to said orthogonal connector L, of a single molecular weight homopolymer having formula (Xfb) above; wherein R1and R2are different, and one of R1and R2is H or an inert group, the other one of R1and R2being a functionalized reactive group, said group being reactive for covalently binding a bindable group, in such reaction conditions that the inert group is non-reactive, Z1and Z2, identical or different, are optional spacers, and n is 1 or more and k is 2 or more.

[0224]

[0132] In some embodiments, the linker comprises one or more components independently selected from polyethylene glycol, polysarcosine, a hydrazone, acetal, maleimide, succinimide, asparagine, aspartic acid, cysteine, glutamic acid, lysine, glutamine, arginine, serine, ornithine, threonine, valine, alanine, glycine, leucine, isoleucine, methionine, tryptophan, proline, histidine, citrulline, phenylalanine, carboxylate, p-aminobenzyloxy carbonyl, alkyl, alkene, alkyne, aryl, cycloalkyl, heterocycle, glycoside, silyl ether, hydroxy, ether, ketone, ester, carbonate, amide, urea, carbamate, sulfide, disulfide, sulfate, sulfonamide, phosphate, phenylboronic ester, phenylboronic acid, thioketal, tartaric acid, 1 ,2-diol acetonide, o-aminoalcohol, selenium, ortho-nitrobenzyl, phenacyl ester, sugar, glucoronide, trioxolane, oxime, acyl hydrazone, cyclobutyl, pyrophosphate, arylsulfate, heptamethine, cyanine fluorophore, o-nitrobenzyl, PC4AP, dsProc, 1,3-dioxane, triazole, piperazine, bis(vinylsulfonyl)piperazine, N- methyl-N-phenylvinylsulfonamide, and Pt.

[0225]

[0133] In some embodiments, the linker is a compound of the formula: wherein: indicates an attachment site to the antigen binding unit;

[0226] Z1is a product formed by reaction of the antigen binding unit with a reactive precursor of Z1;

[0227] Z2is absent or an optionally substituted spacer comprising one or more components independently selected from C1-6alkyl, (CH2CH2O)n2, and -C(O)NH-, or any combination thereof;

[0228] Z3is selected from Val-Cit, Cit-Val, Ala-Ala, Ala-Cit, Cit-Ala, Asn-Cit, Cit-Asn, Cit-Cit, Val-Glu, Glu- Val, Ser-Cit, Cit-Ser, Lys-Cit, Cit-Lys, Asp-Cit, Cit-Asp, Val-Ala, Ala-Vai, Val-Val, Val-Gly, Gly-Val, Phe-Lys, Lys-Phe, Val-Lys, Lys-Val, Ala-Lys, Lys-Ala, Phe-Cit, Cit-Phe, Leu-Cit, Cit-Leu, Ile-Cit, Cit-Ile, Phe-Arg, Arg- Phe, Cit-Trp, Trp-Cit, Gly-Gly, Gly-Cit, Cit-Gly, Ala-Pro, Pro-Ala, Ala-Ser, Ser-Ala, Glu- Val-Cit, Cit- Val-Glu, Glu-Gly-Cit, Cit-Gly-Glu, Asn-Ala-Ala, Ala-Ala-Asn, and Ala-Gly-Ala;

[0229] Rzis selected from hydrogen, -C1-4alkyl-On3-(C1-4alkylene)n4-Z4, -C1-4alkyl-N-[(C1-4alkylene)-Z4]2, -C2-4alkynyl-C1-4alkyl-On3-(C1-4alkylene)n4-Z4, and -C2-4alkynyl-C1-4alkyl-N-[(C1-4alkylene)-Z4]2;

[0230] Z4is selected from -SO3H, -CO2H, PEG 4-32, and a sugar moiety; n1, n3, and n4 are each independently 0 or 1 ; n2 is an integer from 1 to 6; and indicates an attachment site to the KRAS inhibitor.

[0231]

[0134] In some embodiments, the linker is a compound of the formula: wherein: indicates an attachment site to the antigen binding unit;

[0232] Z1is a product formed by reaction of the antigen binding unit with a reactive precursor of Z1;

[0233] Z2is absent or an optionally substituted spacer comprising one or more components independently selected from C1-6alkyl, (CH2CH2O)n2. -C(O)NH-, -C(O)NCH3-, (C(O)CH2N(CH3))n2, or any combination thereof;

[0234] Z3is selected from a bond, Val-Cit, Cit-Val, Ala-Ala, Ala-Cit, Cit-Ala, Asn-Cit, Cit-Asn, Cit-Cit, Val-Glu, Glu- Vai, Ser-Cit, Cit-Ser, Lys-Cit, Cit-Lys, Asp-Cit, Cit-Asp, Val-Ala, Ala- Vai, Val-Val, Val-Gly, Gly-Val, Phe- Lys, Lys-Phe, Val-Lys, Lys-Val, Ala-Lys, Lys-Ala, Phe-Cit, Cit-Phe, Leu-Cit, Cit-Leu, Ile-Cit, Cit-Ile, Phe-Arg, Arg-Phe, Cit-Trp, Trp-Cit, Gly-Gly, Gly-Cit, Cit-Gly, Ala-Pro, Pro-Ala, Ala-Ser, Ser-Ala, Glu-Val-Cit, Cit-Val- Glu, Glu-Gly-Cit, Cit-Gly-Glu, Asn-Ala-Ala, Ala-Ala-Asn, and Ala-Gly-Ala;

[0235] Rzis selected from hydrogen, Z4, -C1-4alkyl-On3-(C1-4alkylene)n4-Z4, -C1-4alkyl-N-[(C1-4alkylene)-Z4]2, - C2-4alkynyl-C1-4alkyl-On3-(C1-4alkylene)n4-Z4, and -C2-4alkynyl-C1-4alkyl-N-[(C1-4alkylene)-Z4]2;

[0236] Z4is selected from -SO3H, -CO2H, PEG 4-32, -(CH2N(CH3)C(O))n2CH3, and a sugar moiety; n1, n3, and n4 are each independently 0 or 1 : n2 is an integer from 1 to 20: and indicates an attachment site to the KRAS inhibitor.

[0237]

[0135] In some embodiments, a conjugate of the present disclosure comprises a linker selected from:

[0238] to the KRAS inhibitor and indicates an attachment site to the antigen binding unit.

[0239]

[0136] In some embodiments, a conjugate of the present disclosure comprises a linker selected from:

[0240]

[0241] wherein indicates an attachment site to the KRAS inhibitor and indicates an attachment site to the antigen binding unit.

[0242]

[0137] In some embodiments, the linker is a compound of the formula: wherein: indicates an attachment site to the antigen binding unit;

[0243] Z1is a product formed by reaction of the antigen binding unit with a reactive precursor of Z1;

[0244] Z2is absent, C1-6alkyl, (CH2CH2O)n2. -C(O)NH-, -C(O)NCH3-, (C(O)CH2N(CH3))n2, - ((CH2CH2O)n2(CH2CH2)C(O))N(CH2C(O)N(CH3)-(CH2CH2O)n2-(CH2CH2N(CH3)-(C(O)CH2N(CH3))n2- C(O)CH3)CH2-, -(C1-6alkyl)C(O)N(CH2C(O)N(CH3)-(CH2CH2O)n2-(CH2CH2N(CH3)-(C(O)CH2N(CH3))n2- C(O)CH3)CH2-, -(C1-6alkyl)C(O)N(CH2C(O)N(CH3)-(CH2CH2O)n2-(CH2CH2N(CH3)-(C(O)CH2N(CH3))n2- C(O)CH2N(H)C(O)CH3)CH2-, -((CH2CH2O)n2(CH2CH2)C(O))N((CH2CH2O)n2CH3)CH2-, -((C1-6alkyl)C(O))N((CH2CH2O)n2CH3)CH2-, -(C1-6alkyl)C(O))N((CH2C(O)N(CH3)-(CH2CH2O)n2CH3)CH2-, -((C1-6alkyl)C(O))N(CH2C(O)N((CH2CH2O)n2CH3)(CH2CH2O)n2CH3)CH2-, - ((CH2CH2O)n2(CH2CH2)C(O))N(CH2C(O)N((CH2CH2O)n2CH3)(CH2CH2O)n2CH3)CH2-, - ((CH2CH2O)n2(CH2CH2)C(O))N(CH2C(O)-(N(CH3)CH2C(O))n2-N(CH3)2)CH2-, -((C1-6alkyl)C(O))N(CH2C(O)- (N(CH3)CH2C(O))n2-N(CH3)2)CH2-, -(CH2CH2O)n2(CH2CH2)-, -(C1-6alkyl)-, - ((CH2CH2O)n2(CH2CH2)C(O)NH(CH2CH2)-, -(CH2CH2O)n2(CH2CH2)C(O)-(N(CH3)CH2C(O))n2-N(CH3)CH2)-, - (C1-6alkyl)C(O)-(N(CH3)CH2C(O))n2-N(CH3)CH2)-, -(Phenyl)-CH2C(O)NH(CH2CH2O)n2(CH2CH2)-, -(C1-6

[0245] Z3is selected from a bond, Val-Cit, Cit-Val, Ala-Ala, Ala-Cit, Cit-Ala, Asn-Cit, Cit-Asn, Cit-Cit, Val-Glu, Glu-Val, Ser-Cit, Cit-Ser, Lys-Cit, Cit-Lys, Asp-Cit, Cit-Asp, Val-Ala, Ala- Vai, Vai- Vai, Val-Gly, Gly-Val, Phe- Lys, Lys-Phe, Val-Lys, Lys-Val, Ala-Lys, Lys-Ala, Phe-Cit, Cit-Phe, Leu-Cit, Cit-Leu, Ile-Cit, Cit-Ile, Phe-Arg, Arg-Phe, Cit-Trp, Trp-Cit, Gly-Gly, Gly-Cit, Cit-Gly, Ala-Pro, Pro-Ala, Ala-Ser, Ser-Ala, Glu-Val-Cit, Cit-Val- Glu, Glu-Gly-Cit, Cit-Gly-Glu, Asn-Ala-Ala, Ala-Ala-Asn, and Ala-Gly-Ala;

[0246] Rzis selected from hydrogen, -CH2N(CH3)C(O)-(CH2CH2O)n2CH3, -CH2N(CH3)(C(O)CH2N(CH3))n2- C(O)CH3, -CH2N(CH3)C(O)-(CH2CH2O)n2-CH2CH2C(O)-(N(CH3)CH2C(O))n2-N(CH3)2, -SO3H, -CO2H, PEG 4-32, polysarcosine, -(CH2N(CH3)C(O))n2CH3, and a sugar moiety; n3, and n4 are each independently 0 or 1 ; n2 is independently an integer from 1 to 20; and indicates an attachment site to the KRAS inhibitor.

[0247]

[0138] In an aspect is provided a linker-(KRAS inhibitor) of Formula (B): wherein:

[0248] Z1ais a moiety capable of forming a covalent bond with an antigen binding unit;

[0249] Z2is absent or an optionally substituted spacer comprising one or more components independently selected from C1-6alkyl, (CH2CH2O)n2. -C(O)NH-, -C(O)NCH3-, (C(O)CH2N(CH3))n2, or any combination thereof;

[0250] Z3is selected from a bond, Val-Cit, Cit-Val, Ala-Ala, Ala-Cit, Cit-Ala, Asn-Cit, Cit-Asn, Cit-Cit, Val-Glu, Glu-Val, Ser-Cit, Cit-Ser, Lys-Cit, Cit-Lys, Asp-Cit, Cit-Asp, Val-Ala, Ala- Vai, Vai- Vai, Val-Gly, Gly-Val, Phe- Lys, Lys-Phe, Val-Lys, Lys-Val, Ala-Lys, Lys-Ala, Phe-Cit, Cit-Phe, Leu-Cit, Cit-Leu, Ile-Cit, Cit-Ile, Phe-Arg, Arg-Phe, Cit-Trp, Trp-Cit, Gly-Gly, Gly-Cit, Cit-Gly, Ala-Pro, Pro-Ala, Ala-Ser, Ser-Ala, Glu-Val-Cit, Cit-Val- Glu, Glu-Gly-Cit, Cit-Gly-Glu, Asn-Ala-Ala, Ala-Ala-Asn, and Ala-Gly-Ala;

[0251] Rzis selected from hydrogen, Z4, -C1-4alkyl-On3-(C1-4alkylene)n4-Z4, -C1-4alkyl-N-[(C1-4alkylene)-Z4]2, - C2-4alkynyl-C1-4alkyl-On3-(C1-4alkylene)n4-Z4, and -C2-4alkynyl-C1-4alkyl-N-[(C1-4alkylene)-Z4]2;

[0252] Z4is selected from -SO3H, -CO2H, PEG 4-32, -(CH2N(CH3)C(O))n2CH3, polysarcosine, and a sugar moiety; n1, n3, and n4 are each independently 0 or 1 ; n2 is independently an integer from 1 to 20; and the KRAS inhibitor is optionally a compound of Formula (I), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), or (I-g).

[0253]

[0139] In an aspect is provided a linker-(KRAS inhibitor) of Formula (B): wherein:

[0254] Z1ais a moiety capable of forming a covalent bond with an antigen binding unit (e.g., maleimide);

[0255] Z2is absent, C1-6alkyl, (CH2CH2O)n2. -C(O)NH-, -C(O)NCH3-, (C(O)CH2N(CH3))n2, - ((CH2CH2O)n2(CH2CH2)C(O))N(CH2C(O)N(CH3)-(CH2CH2O)n2-(CH2CH2N(CH3)-(C(O)CH2N(CH3))n2- C(O)CH3)CH2-, -(C1-6alkyl)C(O)N(CH2C(O)N(CH3)-(CH2CH2O)n2-(CH2CH2N(CH3)-(C(O)CH2N(CH3))n2- C(O)CH3)CH2-, -(C1-6alkyl)C(O)N(CH2C(O)N(CH3)-(CH2CH2O)n2-(CH2CH2N(CH3)-(C(O)CH2N(CH3))n2- C(O)CH2N(H)C(O)CH3)CH2-, -((CH2CH2O)n2(CH2CH2)C(O))N((CH2CH2O)n2CH3)CH2-, -((C1-6alkyl)C(O))N((CH2CH2O)n2CH3)CH2-, -(C1-6alkyl)C(O))N((CH2C(O)N(CH3)-(CH2CH2O)n2CH3)CH2-, -((C1-6alkyl)C(O))N(CH2C(O)N((CH2CH2O)n2CH3)(CH2CH2O)n2CH3)CH2-, - ((CH2CH2O)n2(CH2CH2)C(O))N(CH2C(O)N((CH2CH2O)n2CH3)(CH2CH2O)n2CH3)CH2-, - ((CH2CH2O)n2(CH2CH2)C(O))N(CH2C(O)-(N(CH3)CH2C(O))n2-N(CH3)2)CH2-, -((C1-6alkyl)C(O))N(CH2C(O)- (N(CH3)CH2C(O))n2-N(CH3)2)CH2-, -(CH2CH2O)n2(CH2CH2)-, -(C1-6alkyl)-, - ((CH2CH2O)n2(CH2CH2)C(O)NH(CH2CH2)-, -(CH2CH2O)n2(CH2CH2)C(O)-(N(CH3)CH2C(O))n2-N(CH3)CH2)-, -

[0256] (C1-6alkyl)C(O)-(N(CH3)CH2C(O))n2-N(CH3)CH2)-, -(Phenyl)-CH2C(O)NH(CH2CH2O)n2(CH2CH2)-, -(C1-6

[0257] Z3is selected from a bond, Val-Cit, Cit-Val, Ala-Ala, Ala-Cit, Cit-Ala, Asn-Cit, Cit-Asn, Cit-Cit, Val-Glu, Glu-Val, Ser-Cit, Cit-Ser, Lys-Cit, Cit-Lys, Asp-Cit, Cit-Asp, Val-Ala, Ala- Vai, Vai- Vai, Val-Gly, Gly-Val, Phe- Lys, Lys-Phe, Val-Lys, Lys-Val, Ala-Lys, Lys-Ala, Phe-Cit, Cit-Phe, Leu-Cit, Cit-Leu, Ile-Cit, Cit-Ile, Phe-Arg, Arg-Phe, Cit-Trp, Trp-Cit, Gly-Gly, Gly-Cit, Cit-Gly, Ala-Pro, Pro-Ala, Ala-Ser, Ser-Ala, Glu-Val-Cit, Cit-Val- Glu, Glu-Gly-Cit, Cit-Gly-Glu, Asn-Ala-Ala, Ala-Ala-Asn, and Ala-Gly-Ala:

[0258] Rzis selected from hydrogen, -CH2N(CH3)C(O)-(CH2CH2O)n2CH3, -CH2N(CH3)(C(O)CH2N(CH3))n2- C(O)CH3, -CH2N(CH3)C(O)-(CH2CH2O)n2-CH2CH2C(O)-(N(CH3)CH2C(O))n2-N(CH3)2, -SO3H, -CO2H, PEG 4-32, polysarcosine, -(CH2N(CH3)C(O))n2CH3, and a sugar moiety; nl, n3, and n4 are each independently 0 or 1 ; n2 is independently an integer from 1 to 20; and the KRAS inhibitor is optionally a compound of Formula (I), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), or (I-g).

[0259] KRAS Inhibitor for Generating Conjugates of the Present Disclosure (e.g., of Formula (A))

[0260]

[0140] In certain aspects, a KRAS inhibitor for generating a conjugate of the present disclosure is a compound of Formula (I): or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0261] X is selected from N and C(R6);

[0262] Z is selected from O, N, C(R5)2, C(O), S, S(O), and S(O)2;

[0263] R2, R5, R6, and R8are each independently selected at each occurrence from hydrogen, halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered hetero alky nyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalky l)-(C3-i2carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), -OR12, -SR12, - N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), -N(R12)C(O)N(R12)(R13), -N(R12)C(O)OR12, -N(R12)S(O)2R12, - C(O)R12, -S(O)R12, -OC(O)R12, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R12)C(O)R12, -S(O)2R12, - S(O)(NR12)R12, -S(O)2N(R12)(R13), -S(O)(NR12)N(R12)(R13), and -OCH2C(O)OR12, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered hetero alkynyl, -C0-6 alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle) are optionally substituted; optionally wherein two R5are taken together with the atom to which they are attached to form C3-8carbocycle or 3- to 8-membered heterocycle, each of which is optionally substituted; and further optionally wherein two R5are taken together to form =O, =NR12, or =C(R14)2;

[0264] R3is independently selected at each occurrence from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), -OR12, -SR12, -N(R12)(R13), -C(O)OR12, - OC(O)N(R12)(R13), -N(R12)C(O)N(R12)(R13), -N(R12)C(O)OR12, -N(R12)S(O)2R12, -C(O)R12, -S(O)R12, -0C(O)R12, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R12)C(O)R12, -S(O)2R12, -S(O)(NR12)R12, -S(O)2N(R12)(R13), - S(O)(NR12)N(R12)(R13), and -OCH2C(O)OR12, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalky l)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle) are optionally substituted; optionally wherein two R3are taken together with the atom or atoms to which they are attached to form C3-8carbocycle or 3- to 8-membered heterocycle, each of which is optionally substituted; optionally wherein two R3are taken together to form =O, =NR12, or =C(R14)2; and further optionally wherein one R3and R4are taken together with the atoms to which they are attached to form optionally substituted 3- to 10-membered heterocycle;

[0265] R4is selected from hydrogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalky l)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -C(O)OR12, -C(O)R12, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -S(O)2R12, - S(O)(NR12)R12, -S(O)2N(R12)(R13), and -S(=O)(=NR12)N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), and - (2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle) are optionally substituted;

[0266] R7is selected from C6-12aryl and 5- to 12-membered heteroaryl, each of which is optionally substituted; m is 0, 1, 2, or 3; n is 1 or 2;

[0267] R12is independently selected at each occurrence from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle) are optionally substituted;

[0268] R13is independently selected at each occurrence from hydrogen, C1-6alkyl, and C1-6haloalkyl; or R12and R13attached to the same nitrogen atom form optionally substituted 3- to 10-membered heterocycle; and

[0269] R14is independently selected at each occurrence from hydrogen, halogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle), or two R14are taken together with the carbon atom to which they are attached to form C3-12carbocycle or 3- to 12-membered heterocycle, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6alkyl-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), C3-12carbocycle, and 3- to 12-membered heterocycle are optionally substituted; wherein one hydrogen of the compound of Formula (I) is replaced with a bond to the antigen binding unit or the chemical linker.

[0270]

[0141] In embodiments, the chemical linker is covalently bonded to the antigen binding unit or the chemical linker is capable of covalently conjugating to the antigen binding unit.

[0271]

[0142] In embodiments, the compound of Formula (I) has the formula: wherein all variables are as described for Formula (I).

[0272]

[0143] In certain aspects, a KRAS inhibitor for generating a conjugate of the present disclosure is a compound of Formula (I): or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0273] X is selected from N and C(R6);

[0274] Z is selected from O, N, C(R5)2, C(O), S, S(O), and S(O)2;

[0275] R2, R5, R6, and R8are each independently selected at each occurrence from hydrogen, halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered hetero alky nyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalky l)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), -OR12, -SR12, - N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), -N(R12)C(O)N(R12)(R13), -N(R12)C(O)OR12, -N(R12)S(O)2R12, - C(O)R12, -S(O)R12, -OC(O)R12, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R12)C(O)R12, -S(O)2R12, - S(O)(NR12)R12, -S(O)2N(R12)(R13), -S(O)(NR12)N(R12)(R13), and -OCH2C(O)OR12, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered hetero alkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle) are optionally substituted with one or more R20; optionally wherein two R5are taken together with the atom to which they are attached to form C3-8carbocycle or 3- to 8-membered heterocycle, each of which is optionally substituted with one or more R20; and further optionally wherein two R5are taken together to form =O, =NR12, or =C(R14)2;

[0276] R3is independently selected at each occurrence from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), -OR12, -SR12, -N(R12)(R13), -C(O)OR12, - OC(O)N(R12)(R13), -N(R12)C(O)N(R12)(R13), -N(R12)C(O)OR12, -N(R12)S(O)2R12, -C(O)R12, -S(O)R12, -0C(O)R12, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R12)C(O)R12, -S(O)2R12, -S(O)(NR12)R12, -S(O)2N(R12)(R13), - S(O)(NR12)N(R12)(R13), and -OCH2C(O)OR12, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalky l)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted with one or more R20; optionally wherein two R3are taken together with the atom or atoms to which they are attached to form C3-8carbocycle or 3- to 8- membered heterocycle, each of which is optionally substituted with one or more R20; optionally wherein two R3are taken together to form =O, =NR12, or =C(R14)2; and further optionally wherein one R3and R4are taken together with the atoms to which they are attached to form 3- to 10-membered heterocycle optionally substituted with one or more R20;

[0277] R4is selected from hydrogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalky l)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -C(O)OR12, -C(O)R12, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -S(O)2R12, - S(O)(NR12)R12, -S(O)2N(R12)(R13), and -S(=O)(=NR12)N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), and - (2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle) are optionally substituted with one or more R20;

[0278] R7is selected from C6-12aryl and 5- to 12-membered heteroaryl, each of which is optionally substituted with one or more R20; m is 0, 1, 2, or 3; n is 1 or 2;

[0279] R12is independently selected at each occurrence from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle) are optionally substituted with one, two, or three R20;

[0280] R13is independently selected at each occurrence from hydrogen, C1-6alkyl, and C1-6haloalky I: or R12and R13attached to the same nitrogen atom form 3- to 10-membered heterocycle optionally substituted with one, two, or three R20;

[0281] R14is independently selected at each occurrence from hydrogen, halogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle), or two R14are taken together with the carbon atom to which they are attached to form C3-12carbocycle or 3- to 12-membered heterocycle, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6alkyl-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), C3-12carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one, two, or three R20;

[0282] R20is independently selected at each occurrence from halogen, oxo, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), -OR22, -SR22, -N(R22)(R23), =NR22, =C(R21)2, -C(O)OR22, -OC(O)N(R22)(R23), -N(R22)C(O)N(R22)(R23), -N(R22)C(O)OR22, -N(R22)S(O)2R22, -C(O)R22, -S(O)R22, -OC(O)R22, -C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), -N(R22)C(O)R22, -OS(O)2R22, -S(O)2R22, - S(O)(NR22)R22, -S(O)2N(R22)(R23)-, -S(O)(NR22)N(R22)(R23), and -OCH2C(O)OR22; wherein two R20attached to the same or adjacent atoms optionally join to form C3-12carbocycle or 3- to 12-membered heterocycle; wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalky l)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), C3-12carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, -OR22, -SR22, -N(R22)(R23), =NR22, =C(R21)2, -C(O)OR22, -OC(O)N(R22)(R23), -N(R22)C(O)N(R22)(R23), -N(R22)C(O)OR22, -N(R22)S(O)2R22, -C(O)R22, -S(O)R22, -OC(O)R22, -C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), -N(R22)C(O)R22, -OS(O)2R22, -S(O)2R22, - S(O)(NR22)R22, -S(O)2N(R22)(R23), and -S(O)(NR22)N(R22)(R23);

[0283] R21is independently selected at each occurrence from hydrogen, halogen, C1-6alkyl, C1-6haloalkyl, -C0-6alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle), or two R21are taken together with the carbon atom to which they are attached to form C3-12carbocycle or 3- to 12-membered heterocycle, each of which is optionally substituted with one, two, or three substituents independently selected from halogen, C1-3alkyl, C1-3haloalkyl, and -OH;

[0284] R22is independently selected at each occurrence from hydrogen, C1-6alkyl, C1-6haloalkyl, -C0-6alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle); and

[0285] R23is independently selected at each occurrence from hydrogen and C1-6alkyl; or R22and R23attached to the same nitrogen atom form 3- to 10 membered heterocycle; wherein one hydrogen of the compound of Formula (I) is replaced with a bond to the antigen binding unit or the chemical linker.

[0286]

[0144] In embodiments, the chemical linker is covalently bonded to the antigen binding unit or the chemical linker is capable of covalently conjugating to the antigen binding unit. In embodiments, the compound of

[0287] Formula (I) has the formula: wherein all variables are as described for Formula (I).

[0288]

[0145] In embodiments, the KRAS inhibitor for generating a conjugate is a compound of Formula (I-a): or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0289] X is selected from N and C(R6);

[0290] Z is selected from O, N, C(R5)2, C(O), S, S(O), and S(O)2;

[0291] A is 6-membered heteroaryl comprising one, two, or three ring nitrogen atoms;

[0292] R2, R5, R8, R9, and R10are each independently selected at each occurrence from hydrogen, halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6- membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalky l)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), -OR12, -

[0293] SR12, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), -N(R12)C(O)N(R12)(R13), -N(R12)C(O)OR12, -N(R12)S(O)2R12, -

[0294] C(O)R12, -S(O)R12, -OC(O)R12, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R12)C(O)R12, -S(O)2R12, -

[0295] S(O)(NR12)R12, -S(O)2N(R12)(R13), -S(O)(NR12)N(R12)(R13), and -OCH2C(O)OR12, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered hetero alky nyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle) are optionally substituted with one or more R20; optionally wherein two R5are taken together with the atom to which they are attached to form C3-8carbocycle or 3- to 8-membered heterocycle, each of which is optionally substituted with one or more R20; and further optionally wherein two R5are taken together to form =O, =NR12, or =C(R14)2; optionally wherein R9and R10, together with the atoms to which they are attached, form C4-8carbocycle or 4- to 8-membered heterocycle, each of which is optionally substituted with one or more R20; and further optionally wherein R3and R9, together with the atoms to which they are attached, form 4- to 8-membered heterocycle optionally substituted with one or more R20;

[0296] R3is independently selected at each occurrence from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), -OR12, -SR12, -N(R12)(R13), -C(O)OR12, - OC(O)N(R12)(R13), -N(R12)C(O)N(R12)(R13), -N(R12)C(O)OR12, -N(R12)S(O)2R12, -C(O)R12, -S(O)R12, -0C(O)R12, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R12)C(O)R12, -S(O)2R12, -S(O)(NR12)R12, -S(O)2N(R12)(R13), - S(O)(NR12)N(R12)(R13), and -OCH2C(O)OR12, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalky l)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle) are optionally substituted with one or more R20; optionally wherein two R3are taken together with the atom or atoms to which they are attached to form C3-8carbocycle or 3- to 8- membered heterocycle, each of which is optionally substituted with one or more R20; optionally wherein two R3are taken together to form =O, =NR12, or =C(R14)2;

[0297] R6is selected from hydrogen, halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalky l)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), -OR12, -SR12, -SF5, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), - N(R12)C(O)N(R12)(R13), -N(R12)C(O)OR12, -N(R12)S(O)2R12, -C(O)R12, -S(O)R12, -0C(O)R12, -C(O)N(R12)(R13), - C(O)C(O)N(R12)(R13), -N(R12)C(O)R12, -S(O)2R12, -S(O)(NR12)R12, -S(O)2N(R12)(R13), -S(O)(NR12)N(R12)(R13), and -OCH2C(O)OR12, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6- membered hetero alkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalky l)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)- (3- to 12-membered heterocycle) are optionally substituted with one or more R20; optionally wherein two R5are taken together with the atom to which they are attached to form C3-8carbocycle or 3- to 8-membered heterocycle, each of which is optionally substituted with one or more R20; and further optionally wherein two R5are taken together to form =O, =NR12, or =C(R14)2; optionally wherein R9and R10, together with the atoms to which they are attached, form C4-8carbocycle or 4- to 8-membered heterocycle, each of which is optionally substituted with one or more R20; and further optionally wherein R3and R9, together with the atoms to which they are attached, form 4- to 8-membered heterocycle optionally substituted with one or more R20;

[0298] R7is selected from C6-12aryl and 5- to 12-membered heteroaryl, each of which is optionally substituted with one or more R20; m is 0, 1, 2, or 3; n is 1 or 2;

[0299] R11is selected from hydrogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalky l)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)OR12, -C(O)OC(O)R12, -C(O)O-(C1-6alkyl)-OR15, -(C1-6alkyl)-OR15, -C(O)R12, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -S(O)2R12, -S(O)(NR12)R12, - S(O)2N(R12)(R13), and -S(O)(NR12)N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalky l)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle) are optionally substituted with one or more R20;

[0300] R12is independently selected at each occurrence from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle) are optionally substituted with one, two, or three R20;

[0301] R13is independently selected at each occurrence from hydrogen, C1-6alkyl, and C1-6haloalky I: or R12and R13attached to the same nitrogen atom form 3- to 10-membered heterocycle optionally substituted with one, two, or three R20;

[0302] R14is independently selected at each occurrence from hydrogen, halogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle), or two R14are taken together with the carbon atom to which they are attached to form C3-12carbocycle or 3- to 12-membered heterocycle, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6alkyl-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), C3-12carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one, two, or three R20;

[0303] R20is independently selected at each occurrence from halogen, oxo, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), -OR22, -SR22, -N(R22)(R23), =NR22, =C(R21)2, -SF5, =N-OR22, =N-N(R22)(R23), -P(O)(R22)(R23), -ON=R22, -C(O)OR22, -OC(O)N(R22)(R23), - N(R22)C(O)N(R22)(R23), -N(R22)C(O)OR22, -N(R22)S(O)2R22, -C(O)R22, -S(O)R22, -OC(O)R22, -C(O)N(R22)(R23), - C(O)C(O)N(R22)(R23), -N(R22)C(O)R22, -OS(O)2R22, -S(O)2R22, -S(O)(NR22)R22, -S(O)2N(R22)(R23)-, - S(O)(NR22)N(R22)(R23), and -OCH2C(O)OR22: wherein two R20attached to the same or adjacent atoms optionally join to form C3-12carbocycle or 3- to 12-membered heterocycle; wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), C3-12carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, -OR22, -SR22, -N(R22)(R23), =NR22, =C(R21)2, -SF5, =N-OR22, =N- N(R22)(R23), -P(O)(R22)(R23), -ON=R22, -C(O)OR22, -OC(O)N(R22)(R23), -N(R22)C(O)N(R22)(R23), - N(R22)C(O)OR22, -N(R22)S(O)2R22, -C(O)R22, -S(O)R22, -OC(O)R22, -C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), - N(R22)C(O)R22, -OS(O)2R22, -S(O)2R22, -S(O)(NR22)R22, -S(O)2N(R22)(R23), and -S(O)(NR22)N(R22)(R23); R21is independently selected at each occurrence from hydrogen, halogen, C1-6alkyl, C1-6haloalkyl, -C0-6alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle), or two R21are taken together with the carbon atom to which they are attached to form C3-12carbocycle or 3- to 12-membered heterocycle, each of which is optionally substituted with one, two, or three substituents independently selected from halogen, C1-3alkyl, C1-3haloalkyl, and -OH;

[0304] R22is independently selected at each occurrence from hydrogen, C1-6alkyl, C1-6haloalkyl, -C0-6alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle); and

[0305] R23is independently selected at each occurrence from hydrogen and C1-6alkyl; or R22and R23attached to the same nitrogen atom form 3- to 10 membered heterocycle; wherein one hydrogen of the compound is replaced with a bond to the antigen binding unit or the chemical linker.

[0306]

[0146] In embodiments, the chemical linker is covalently bonded to the antigen binding unit or the chemical linker is capable of covalently conjugating to the antigen binding unit. In embodiments, the compound of

[0307] Formula (I-a) has the formula: ; wherein all variables are as described for

[0308] Formula (I-a).

[0309]

[0147] In certain aspects, a KRAS inhibitor for generating a conjugate of the present disclosure is a compound of Formula (I-a): or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0310] X is selected from N and C(R6);

[0311] Z is selected from O, N, C(R5)2, C(O), S, S(O), and S(O)2;

[0312] A is 6-membered heteroaryl comprising one, two, or three ring nitrogen atoms;

[0313] R2, R5, R6, R8, R9, and R10are each independently selected at each occurrence from hydrogen, halogen, - CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6- membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalky l)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), -OR12, - SR12, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), -N(R12)C(O)N(R12)(R13), -N(R12)C(O)OR12, -N(R12)S(O)2R12, - C(O)R12, -S(O)R12, -OC(O)R12, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R12)C(O)R12, -S(O)2R12, - S(O)(NR12)R12, -S(O)2N(R12)(R13), -S(O)(NR12)N(R12)(R13), and -OCH2C(O)OR12, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle) are optionally substituted with one or more R20; optionally wherein two R5are taken together with the atom to which they are attached to form C3-8 carbocycle or 3- to 8-membered heterocycle, each of which is optionally substituted with one or more R20; and further optionally wherein two R5are taken together to form =O, =NR12, or =C(R14)2; optionally wherein R9and R10, together with the atoms to which they are attached, form C4-8carbocycle or 4- to 8-membered heterocycle, each of which is optionally substituted with one or more R20; and further optionally wherein R3and R9, together with the atoms to which they are attached, form 4- to 8-membered heterocycle optionally substituted with one or more R20;

[0314] R3is independently selected at each occurrence from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), -OR12, -SR12, -N(R12)(R13), -C(O)OR12, - OC(O)N(R12)(R13), -N(R12)C(O)N(R12)(R13), -N(R12)C(O)OR12, -N(R12)S(O)2R12, -C(O)R12, -S(O)R12, -OC(O)R12, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R12)C(O)R12, -S(O)2R12, -S(O)(NR12)R12, -S(O)2N(R12)(R13), - S(O)(NR12)N(R12)(R13), and -OCH2C(O)OR12, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalky l)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle) are optionally substituted with one or more R20; optionally wherein two R3are taken together with the atom or atoms to which they are attached to form C3-8carbocycle or 3- to 8- membered heterocycle, each of which is optionally substituted with one or more R20; optionally wherein two R3are taken together to form =O, =NR12, or =C(R14)2;

[0315] R7is selected from C6-12aryl and 5- to 12-membered heteroaryl, each of which is optionally substituted with one or more R20; m is 0, 1, 2, or 3; n is 1 or 2;

[0316] R11is selected from hydrogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalky l)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)OR12, -C(O)OC(O)R12, -C(O)O-(C1-6alkyl)-OR15, -(C1-6alkyl)-OR15, -C(O)R12, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -S(O)2R12, -S(O)(NR12)R12, - S(O)2N(R12)(R13), and -S(O)(NR12)N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalky l)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle) are optionally substituted with one or more R20;

[0317] R12is independently selected at each occurrence from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle) are optionally substituted with one, two, or three R20;

[0318] R13is independently selected at each occurrence from hydrogen, C1-6alkyl, and C1-6haloalky I: or R12and R13attached to the same nitrogen atom form 3- to 10-membered heterocycle optionally substituted with one, two, or three R20;

[0319] R14is independently selected at each occurrence from hydrogen, halogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle), or two R14are taken together with the carbon atom to which they are attached to form C3-12carbocycle or 3- to 12-membered heterocycle, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6alkyl-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), C3-12carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one, two, or three R20;

[0320] R20is independently selected at each occurrence from halogen, oxo, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), -OR22, -SR22, -N(R22)(R23), =NR22, =C(R21)2, -C(O)OR22, -OC(O)N(R22)(R23), -N(R22)C(O)N(R22)(R23), -N(R22)C(O)OR22, -N(R22)S(O)2R22, -C(O)R22, -S(O)R22, -OC(O)R22, -C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), -N(R22)C(O)R22, -OS(O)2R22, -S(O)2R22, - S(O)(NR22)R22, -S(O)2N(R22)(R23)-, -S(O)(NR22)N(R22)(R23), and -OCH2C(O)OR22; wherein two R20attached to the same or adjacent atoms optionally join to form C3-12carbocycle or 3- to 12-membered heterocycle; wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalky l)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), C3-12carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, -OR22, -SR22, -N(R22)(R23), =NR22, =C(R21)2, -C(O)OR22, -OC(O)N(R22)(R23), -N(R22)C(O)N(R22)(R23), -N(R22)C(O)OR22, -N(R22)S(O)2R22, -C(O)R22, -S(O)R22, -OC(O)R22, -C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), -N(R22)C(O)R22, -OS(O)2R22, -S(O)2R22, - S(O)(NR22)R22, -S(O)2N(R22)(R23), and -S(O)(NR22)N(R22)(R23);

[0321] R21is independently selected at each occurrence from hydrogen, halogen, C1-6alkyl, C1-6haloalkyl, -C0-6alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle), or two R21are taken together with the carbon atom to which they are attached to form C3-12carbocycle or 3- to 12-membered heterocycle, each of which is optionally substituted with one, two, or three substituents independently selected from halogen, C1-3alkyl, C1-3haloalkyl, and -OH;

[0322] R22is independently selected at each occurrence from hydrogen, C1-6alkyl, C1-6haloalkyl, -C0-6alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle); and

[0323] R23is independently selected at each occurrence from hydrogen and C1-6alkyl; or R22and R23attached to the same nitrogen atom form 3- to 10 membered heterocycle; wherein one hydrogen of the compound of Formula (I-a) is replaced with a bond to the antigen binding unit or the chemical linker.

[0324]

[0148] In embodiments, the chemical linker is covalently bonded to the antigen binding unit or the chemical linker is capable of covalently conjugating to the antigen binding unit. In embodiments, the compound of

[0325] Formula (I-a) has the formula: ; wherein all variables are as described for

[0326] Formula (I-a).

[0327]

[0149] In certain aspects, a KRAS inhibitor for generating a conjugate of the present disclosure is a compound of Formula (I-a): or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0328] X is selected from N and C(R6);

[0329] Z is selected from O, N, C(R5)2, C(O), S, S(O), and S(O)2;

[0330] A is 6-membered heteroaryl comprising one, two, or three ring nitrogen atoms;

[0331] R2, R5, R6, and R8are each independently selected at each occurrence from hydrogen, halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered hetero alky nyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalky l)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), -OR12, -SR12, - N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), -N(R12)C(O)N(R12)(R13), -N(R12)C(O)OR12, -N(R12)S(O)2R12, - C(O)R12, -S(O)R12, -OC(O)R12, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R12)C(O)R12, -S(O)2R12, - S(O)(NR12)R12, -S(O)2N(R12)(R13), -S(O)(NR12)N(R12)(R13), and -OCH2C(O)OR12, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered hetero alkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle) are optionally substituted with one or more R20; optionally wherein two R5are taken together with the atom to which they are attached to form C3-8carbocycle or 3- to 8-membered heterocycle, each of which is optionally substituted with one or more R20; and further optionally wherein two R5are taken together to form =O, =NR12, or =C(R14)2;

[0332] R3is independently selected at each occurrence from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), -OR12, -SR12, -N(R12)(R13), -C(O)OR12, - OC(O)N(R12)(R13), -N(R12)C(O)N(R12)(R13), -N(R12)C(O)OR12, -N(R12)S(O)2R12, -C(O)R12, -S(O)R12, -0C(O)R12, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R12)C(O)R12, -S(O)2R12, -S(O)(NR12)R12, -S(O)2N(R12)(R13), - S(O)(NR12)N(R12)(R13), and -OCH2C(O)OR12, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalky l)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle) are optionally substituted with one or more R20; optionally wherein two R3are taken together with the atom or atoms to which they are attached to form C3-8carbocycle or 3- to 8- membered heterocycle, each of which is optionally substituted with one or more R20; optionally wherein two R3are taken together to form =O, =NR12, or =C(R14)2;

[0333] R7is selected from C6-12aryl and 5- to 12-membered heteroaryl, each of which is optionally substituted with one or more R20; m is 0, 1, 2, or 3; n is 1 or 2;

[0334] R9and R10are independently selected from hydrogen, halogen, oxo, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6 alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), -OR22, -SR22, -N(R22)(R23), =NR22, =C(R21)2, -C(O)OR22, -OC(O)N(R22)(R23), -N(R22)C(O)N(R22)(R23), -N(R22)C(O)OR22, -N(R22)S(O)2R22, -C(O)R22, -S(O)R22, -OC(O)R22, -C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), -N(R22)C(O)R22, -OS(O)2R22, -S(O)2R22, - S(O)(NR22)R22, -S(O)2N(R22)(R23)-, -S(O)(NR22)N(R22)(R23), and -OCH2C(O)OR22; wherein R9and R10optionally join to form C3-12carbocycle or 3- to 12-membered heterocycle; wherein C1-6alkyl, C2.6 alkenyl, C2.6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), C3-12carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, -OR22, -SR22, -N(R22)(R23), =NR22, =C(R21)2, -C(O)OR22, - OC(O)N(R22)(R23), -N(R22)C(O)N(R22)(R23), -N(R22)C(O)OR22, -N(R22)S(O)2R22, -C(O)R22, -S(O)R22, -OC(O)R22, - C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), -N(R22)C(O)R22, -OS(O)2R22, -S(O)2R22, -S(O)(NR22)R22, - S(O)2N(R22)(R23), and -S(O)(NR22)N(R22)(R23);

[0335] R11is selected from hydrogen, C1-6alkyl, C1-6haloalkyl, -C0-6alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle);

[0336] R12is independently selected at each occurrence from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle) are optionally substituted with one, two, or three R20;

[0337] R13is independently selected at each occurrence from hydrogen, C1-6alkyl, and C1-6haloalkyl; or R12and R13attached to the same nitrogen atom form 3- to 10-membered heterocycle optionally substituted with one, two, or three R20;

[0338] R14is independently selected at each occurrence from hydrogen, halogen, C1-6alkyl, C2.6 alkenyl, C2.6 alkynyl, -C0-6alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle), or two R14are taken together with the carbon atom to which they are attached to form C3-12carbocycle or 3- to 12-membered heterocycle, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6alkyl-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), C3-12carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one, two, or three R20;

[0339] R20is independently selected at each occurrence from halogen, oxo, -CN, C1-6alkyl, C2.6 alkenyl, C2.6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), -OR22, -SR22, -N(R22)(R23), =NR22, =C(R21)2, -C(O)OR22, -OC(O)N(R22)(R23), -N(R22)C(O)N(R22)(R23), -N(R22)C(O)OR22, -N(R22)S(O)2R22, -C(O)R22, -S(O)R22, -OC(O)R22, -C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), -N(R22)C(O)R22, -OS(O)2R22, -S(O)2R22, - S(O)(NR22)R22, -S(O)2N(R22)(R23)-, -S(O)(NR22)N(R22)(R23), and -OCH2C(O)OR22; wherein two R20attached to the same or adjacent atoms optionally join to form C3-12carbocycle or 3- to 12-membered heterocycle; wherein C1-6alkyl, C2-6alkenyl, C2.6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalky l)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), C3-12carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, -OR22, -SR22, -N(R22)(R23), =NR22, =C(R21)2, -C(O)OR22, -OC(O)N(R22)(R23), -N(R22)C(O)N(R22)(R23), -N(R22)C(O)OR22, -N(R22)S(O)2R22, -C(O)R22, -S(O)R22, -OC(O)R22, -C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), -N(R22)C(O)R22, -OS(O)2R22, -S(O)2R22, - S(O)(NR22)R22, -S(O)2N(R22)(R23), and -S(O)(NR22)N(R22)(R23);

[0340] R21is independently selected at each occurrence from hydrogen, halogen, C1-6alkyl, C1-6haloalkyl, -C0-6alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle), or two R21are taken together with the carbon atom to which they are attached to form C3-12carbocycle or 3- to 12-membered heterocycle, each of which is optionally substituted with one, two, or three substituents independently selected from halogen, C1-3alkyl, C1-3haloalkyl, and -OH;

[0341] R22is independently selected at each occurrence from hydrogen, C1-6alkyl, C1-6haloalkyl, -C0-6alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle); and

[0342] R23is independently selected at each occurrence from hydrogen and C1-6alkyl; or R22and R23attached to the same nitrogen atom form 3- to 10 membered heterocycle; wherein one hydrogen of the compound of Formula (I-a) is replaced with a bond to the antigen binding unit or the chemical linker.

[0343]

[0150] In embodiments, the chemical linker is covalently bonded to the antigen binding unit or the chemical linker is capable of covalently conjugating to the antigen binding unit. In embodiments, the compound of

[0344] Formula (I-a) has the formula: ; wherein all variables are as described for

[0345] Formula (I-a).

[0346]

[0151] In certain aspects, a KRAS inhibitor for generating a conjugate of the present disclosure is a compound of Formula (I-b): or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0347] R2, R6, and R8are each independently selected at each occurrence from hydrogen, halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered hetero alky nyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalky l)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), -OR12, -SR12, - N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), -N(R12)C(O)N(R12)(R13), -N(R12)C(O)OR12, -N(R12)S(O)2R12, - C(O)R12, -S(O)R12, -OC(O)R12, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R12)C(O)R12, -S(O)2R12, - S(O)(NR12)R12, -S(O)2N(R12)(R13), -S(O)(NR12)N(R12)(R13), and -OCH2C(O)OR12, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered hetero alkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle) are optionally substituted with one or more R20;

[0348] R3is independently selected at each occurrence from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), -OR12, -SR12, -N(R12)(R13), -C(O)OR12, - OC(O)N(R12)(R13), -N(R12)C(O)N(R12)(R13), -N(R12)C(O)OR12, -N(R12)S(O)2R12, -C(O)R12, -S(O)R12, -OC(O)R12, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R12)C(O)R12, -S(O)2R12, -S(O)(NR12)R12, -S(O)2N(R12)(R13), - S(O)(NR12)N(R12)(R13), and -OCH2C(O)OR12, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalky l)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle) are optionally substituted with one or more R20; optionally wherein two R3are taken together with the atom or atoms to which they are attached to form C3-8carbocycle or 3- to 8- membered heterocycle, each of which is optionally substituted with one or more R20; and optionally wherein two R3are taken together to form =O, =NR12, or =C(R14)2; m is 0, 1, 2, or 3; n is 1 or 2;

[0349] R12is independently selected at each occurrence from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle) are optionally substituted with one, two, or three R20;

[0350] R13is independently selected at each occurrence from hydrogen, C1-6alkyl, and C1-6haloalky I: or R12and R13attached to the same nitrogen atom form 3- to 10-membered heterocycle optionally substituted with one, two, or three R20;

[0351] R14is independently selected at each occurrence from hydrogen, halogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle), or two R14are taken together with the carbon atom to which they are attached to form C3-12carbocycle or 3- to 12-membered heterocycle, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6alkyl-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), C3-12carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one, two, or three R20;

[0352] R20is independently selected at each occurrence from halogen, oxo, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), -OR22, -SR22, -N(R22)(R23), =NR22, =C(R21)2, -C(O)OR22, -OC(O)N(R22)(R23), -N(R22)C(O)N(R22)(R23), -N(R22)C(O)OR22, -N(R22)S(O)2R22, -C(O)R22, -S(O)R22, -OC(O)R22, -C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), -N(R22)C(O)R22, -OS(O)2R22, -S(O)2R22, - S(O)(NR22)R22, -S(O)2N(R22)(R23)-, -S(O)(NR22)N(R22)(R23), and -OCH2C(O)OR22; wherein two R20attached to the same or adjacent atoms optionally join to form C3-12carbocycle or 3- to 12-membered heterocycle; wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalky l)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), C3-12carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, -OR22, -SR22, -N(R22)(R23), =NR22, =C(R21)2, -C(O)OR22, -OC(O)N(R22)(R23), -N(R22)C(O)N(R22)(R23), -N(R22)C(O)OR22, -N(R22)S(O)2R22, -C(O)R22, -S(O)R22, -OC(O)R22, -C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), -N(R22)C(O)R22, -OS(O)2R22, -S(O)2R22, - S(O)(NR22)R22, -S(O)2N(R22)(R23), and -S(O)(NR22)N(R22)(R23);

[0353] R21is independently selected at each occurrence from hydrogen, halogen, C1-6alkyl, C1-6haloalkyl, -C0-6alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle), or two R21are taken together with the carbon atom to which they are attached to form C3-12carbocycle or 3- to 12-membered heterocycle, each of which is optionally substituted with one, two, or three substituents independently selected from halogen, C1-3alkyl, C1-3haloalkyl, and -OH;

[0354] R22is independently selected at each occurrence from hydrogen, C1-6alkyl, C1-6haloalkyl, -C0-6alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle); and

[0355] R23is independently selected at each occurrence from hydrogen and C1-6alkyl; or R22and R23attached to the same nitrogen atom form 3- to 10 membered heterocycle; wherein one hydrogen of the compound of Formula (I-b) is replaced with a bond to the antigen binding unit or the chemical linker.

[0356]

[0152] In embodiments, the chemical linker is covalently bonded to the antigen binding unit or the chemical linker is capable of covalently conjugating to the antigen binding unit.

[0357]

[0153] In some embodiments, the compound of Formula (I-b), is a compound of Formula (I-c): or a pharmaceutically acceptable salt or solvate thereof.

[0358]

[0154] In some embodiments of Formula (I-a), (i) X is N; and / or (ii) R3is independently selected at each occurrence from C2-6alkenyl, C2-6alkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)- (C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), wherein C2-6alkenyl, C2-6alkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6- membered heteroalky l)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), and -(2- to 6- membered heteroalky l)-(3- to 12-membered heterocycle) are optionally substituted with one, two, or three R20; wherein two R3are optionally taken together with the atom or atoms to which they are attached to form C3-8carbocycle or 3- to 8-membered heterocycle, each of which is optionally substituted with one, two, or three R20; and further wherein two R3are optionally taken together to form =O, =NR12, or =C(R14)2; and / or (iii) R9is selected from C1-6alkyl, C2-6alkenyl and C2-6alkynyl, wherein C1-6alkyl is substituted with =N-OR22, =N-N(R22)(R23), or -ON=R22, and wherein C2-6alkenyl and C2-6alkynyl are optionally substituted with one, two, or three R20; and / or (iv) R6is selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, - C0-6alkyl-(C3-12carbocycle), -OR12, -SR12, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), - N(R12)C(O)N(R12)(R13), -N(R12)C(O)OR12, -N(R12)S(O)2R12, -C(O)R12, -S(O)R12, -OC(O)R12, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R12)C(O)R12, -S(O)2R12, -S(O)(NR12)R12, -S(O)2N(R12)(R13), - S(O)(NR12)N(R12)(R13), -OCH2C(O)OR12, and -SF5, wherein C2-6alkenyl and C2-6alkynyl are optionally substituted with one, two, or three R20; and wherein C1-6alkyl and -C0-6alkyl-(C3-12carbocycle) are each substituted with one, two, or three R20.

[0359]

[0155] In certain aspects, the present disclosure provides a compound of Formula (I-d) applicable for generating a subject conjugate: or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0360] X is selected from C(R6) and N;

[0361] A is 6-membered heteroaryl comprising one, two, or three ring nitrogen atoms;

[0362] R2, R8, R9, and R10are each independently selected at each occurrence from hydrogen, halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered hetero alky nyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalky l)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), -OR12, -SR12, - N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), -N(R12)C(O)N(R12)(R13), -N(R12)C(O)OR12, -N(R12)S(O)2R12, - C(O)R12, -S(O)R12, -OC(O)R12, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R12)C(O)R12, -S(O)2R12, - S(O)(NR12)R12, -S(O)2N(R12)(R13), -S(O)(NR12)N(R12)(R13), and -OCH2C(O)OR12, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered hetero alkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle) are optionally substituted with one or more R20; optionally wherein two R5are taken together with the atom to which they are attached to form C3-8carbocycle or 3- to 8-membered heterocycle, each of which is optionally substituted with one or more R20; and further optionally wherein two R5are taken together to form =O, =NR12, or =C(R14)2; optionally wherein R9and R10, together with the atoms to which they are attached, form C4-8carbocycle or 4- to 8-membered heterocycle, each of which is optionally substituted with one or more R20; and further optionally wherein R3and R9, together with the atoms to which they are attached, form 4- to 8-membered heterocycle optionally substituted with one or more R20;

[0363] R3is independently selected at each occurrence from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), -OR12, -SR12, -N(R12)(R13), -C(O)OR12, - OC(O)N(R12)(R13), -N(R12)C(O)N(R12)(R13), -N(R12)C(O)OR12, -N(R12)S(O)2R12, -C(O)R12, -S(O)R12, -0C(O)R12, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R12)C(O)R12, -S(O)2R12, -S(O)(NR12)R12, -S(O)2N(R12)(R13), - S(O)(NR12)N(R12)(R13), and -OCH2C(O)OR12, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalky l)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle) are optionally substituted with one or more R20; optionally wherein two R3are taken together with the atom or atoms to which they are attached to form C3-8carbocycle or 3- to 8- membered heterocycle, each of which is optionally substituted with one or more R20; optionally wherein two R3are taken together to form =O, =NR12, or =C(R14)2;

[0364] R6is selected from hydrogen, halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalky l)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), -OR12, -SR12, -SF5, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), - N(R12)C(O)N(R12)(R13), -N(R12)C(O)OR12, -N(R12)S(O)2R12, -C(O)R12, -S(O)R12, -0C(O)R12, -C(O)N(R12)(R13), - C(O)C(O)N(R12)(R13), -N(R12)C(O)R12, -S(O)2R12, -S(O)(NR12)R12, -S(O)2N(R12)(R13), -S(O)(NR12)N(R12)(R13), and -OCH2C(O)OR12, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6- membered hetero alkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalky l)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)- (3- to 12-membered heterocycle) are optionally substituted with one or more R20;

[0365] R7is selected from C6-12aryl and 5- to 12-membered heteroaryl, each of which is optionally substituted with one or more R20; m is 0, 1, 2, or 3; n is 1 or 2;

[0366] R11is selected from hydrogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalky l)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)OR12, -C(O)OC(O)R12, -C(O)O-(C1-6alkyl)-OR15, -(C1-6alkyl)-OR15, -C(O)R12, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -S(O)2R12, -S(O)(NR12)R12, - S(O)2N(R12)(R13), and -S(O)(NR12)N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalky l)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle) are optionally substituted with one or more R20; m is 0, 1, 2, or 3; n is 1 or 2;

[0367] R12is independently selected at each occurrence from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle) are optionally substituted with one, two, or three R20;

[0368] R13is independently selected at each occurrence from hydrogen, C1-6alkyl, and C1-6haloalky I: or R12and R13attached to the same nitrogen atom form 3- to 10-membered heterocycle optionally substituted with one, two, or three R20;

[0369] R14is independently selected at each occurrence from hydrogen, halogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle), or two R14are taken together with the carbon atom to which they are attached to form C3-12carbocycle or 3- to 12-membered heterocycle, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6alkyl-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), C3-12carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one, two, or three R20; R20is independently selected at each occurrence from halogen, oxo, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), -OR22, -SR22, -N(R22)(R23), =NR22, =C(R21)2, -SF5, =N-OR22, =N-N(R22)(R23), -P(O)(R22)(R23), -ON=R22, -C(O)OR22, -OC(O)N(R22)(R23), - N(R22)C(O)N(R22)(R23), -N(R22)C(O)OR22, -N(R22)S(O)2R22, -C(O)R22, -S(O)R22, -OC(O)R22, -C(O)N(R22)(R23), - C(O)C(O)N(R22)(R23), -N(R22)C(O)R22, -OS(O)2R22, -S(O)2R22, -S(O)(NR22)R22, -S(O)2N(R22)(R23)-, - S(O)(NR22)N(R22)(R23), and -OCI PC(O)OR22: wherein two R20attached to the same or adjacent atoms optionally join to form C3-12carbocycle or 3- to 12-membered heterocycle; wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), C3-12carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, -OR22, -SR22, -N(R22)(R23), =NR22, =C(R21)2, -SF5, =N-OR22, =N- N(R22)(R23), -P(O)(R22)(R23), -ON=R22, -C(O)OR22, -OC(O)N(R22)(R23), -N(R22)C(O)N(R22)(R23), - N(R22)C(O)OR22, -N(R22)S(O)2R22, -C(O)R22, -S(O)R22, -OC(O)R22, -C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), - N(R22)C(O)R22, -OS(O)2R22, -S(O)2R22, -S(O)(NR22)R22, -S(O)2N(R22)(R23), and -S(O)(NR22)N(R22)(R23);

[0370] R21is independently selected at each occurrence from hydrogen, halogen, C1-6alkyl, C1-6haloalkyl, -C0-6alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle), or two R21are taken together with the carbon atom to which they are attached to form C3-12carbocycle or 3- to 12-membered heterocycle, each of which is optionally substituted with one, two, or three substituents independently selected from halogen, C1-3alkyl, C1-3haloalkyl, and -OH;

[0371] R22is independently selected at each occurrence from hydrogen, C1-6alkyl, C1-6haloalkyl, -C0-6alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle); and

[0372] R23is independently selected at each occurrence from hydrogen and C1-6alkyl; or R22and R23attached to the same nitrogen atom form 3- to 10 membered heterocycle; wherein one hydrogen of the compound is replaced with a bond to the antigen binding unit or the chemical linker.

[0373]

[0156] In embodiments, the chemical linker is covalently bonded to the antigen binding unit or the chemical linker is capable of covalently conjugating to the antigen binding unit.

[0374]

[0157] In certain aspects, the present disclosure provides a compound of Formula (I-e) applicable for generating a subject conjugate,: or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0375] A is 6-membered heteroaryl comprising one, two, or three ring nitrogen atoms; R2, R8, and R10are each independently selected at each occurrence from hydrogen, halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered hetero alky nyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalky l)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), -OR12, -SR12, - N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), -N(R12)C(O)N(R12)(R13), -N(R12)C(O)OR12, -N(R12)S(O)2R12, - C(O)R12, -S(O)R12, -OC(O)R12, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R12)C(O)R12, -S(O)2R12, - S(O)(NR12)R12, -S(O)2N(R12)(R13), -S(O)(NR12)N(R12)(R13), and -OCH2C(O)OR12, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered hetero alkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle) are optionally substituted with one or more R20;

[0376] R9is selected from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalky l)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -OR12, -SR12, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), -N(R12)C(O)N(R12)(R13), - N(R12)C(O)OR12, -N(R12)S(O)2R12, -C(O)R12, -S(O)R12, -OC(O)R12, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), - N(R12)C(O)R12, -S(O)2R12, -S(O)(NR12)R12, -S(O)2N(R12)(R13), -S(O)(NR12)N(R12)(R13), and -OCH2C(O)OR12, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted with one or more R20; optionally wherein R9and R10, together with the atoms to which they are attached, form C4-8carbocycle or 4- to 8-membered heterocycle, each of which is optionally substituted with one or more R20; and further optionally wherein R3and R9, together with the atoms to which they are attached, form 4- to 8-membered heterocycle optionally substituted with one or more R20;

[0377] R3is independently selected at each occurrence from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), -OR12, -SR12, -N(R12)(R13), -C(O)OR12, - OC(O)N(R12)(R13), -N(R12)C(O)N(R12)(R13), -N(R12)C(O)OR12, -N(R12)S(O)2R12, -C(O)R12, -S(O)R12, -OC(O)R12, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R12)C(O)R12, -S(O)2R12, -S(O)(NR12)R12, -S(O)2N(R12)(R13), - S(O)(NR12)N(R12)(R13), and -OCH2C(O)OR12, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalky l)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle) are optionally substituted with one or more R20; optionally wherein two R3are taken together with the atom or atoms to which they are attached to form C3-8carbocycle or 3- to 8- membered heterocycle, each of which is optionally substituted with one or more R20; optionally wherein two R3are taken together to form =O, =NR12, or =C(R14)2;

[0378] R6is selected from hydrogen, halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalky l)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), -OR12, -SR12, -SF5, -N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), - N(R12)C(O)N(R12)(R13), -N(R12)C(O)OR12, -N(R12)S(O)2R12, -C(O)R12, -S(O)R12, -OC(O)R12, -C(O)N(R12)(R13), - C(O)C(O)N(R12)(R13), -N(R12)C(O)R12, -S(O)2R12, -S(O)(NR12)R12, -S(O)2N(R12)(R13), -S(O)(NR12)N(R12)(R13), and -OCH2C(O)OR12, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6- membered hetero alkenyl, 3- to 6-membered hetero alkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalky l)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)- (3- to 12-membered heterocycle) are optionally substituted with one or more R20;

[0379] R7is selected from C6-12aryl and 5- to 12-membered heteroaryl, each of which is optionally substituted with one or more R20; m is 0, 1, 2, or 3; n is 1 or 2;

[0380] R11is selected from hydrogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalky l)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl, -C(O)OR12, -C(O)OC(O)R12, -C(O)O-(C1-6alkyl)-OR15, -(C1-6alkyl)-OR15, -C(O)R12, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -S(O)2R12, -S(O)(NR12)R12, - S(O)2N(R12)(R13), and -S(O)(NR12)N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalky l)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle) are optionally substituted with one or more R20; m is 0, 1, 2, or 3; n is 1 or 2;

[0381] R12is independently selected at each occurrence from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle) are optionally substituted with one, two, or three R20;

[0382] R13is independently selected at each occurrence from hydrogen, C1-6alkyl, and C1-6haloalky I: or R12and R13attached to the same nitrogen atom form 3- to 10-membered heterocycle optionally substituted with one, two, or three R20;

[0383] R14is independently selected at each occurrence from hydrogen, halogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle), or two R14are taken together with the carbon atom to which they are attached to form C3-12carbocycle or 3- to 12-membered heterocycle, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6alkyl-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), C3-12carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one, two, or three R20;

[0384] R20is independently selected at each occurrence from halogen, oxo, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), -OR22, -SR22, -N(R22)(R23), =NR22, =C(R21)2, -SF5, =N-OR22, =N-N(R22)(R23), -P(O)(R22)(R23), -ON=R22, -C(O)OR22, -OC(O)N(R22)(R23), - N(R22)C(O)N(R22)(R23), -N(R22)C(O)OR22, -N(R22)S(O)2R22, -C(O)R22, -S(O)R22, -OC(O)R22, -C(O)N(R22)(R23), - C(O)C(O)N(R22)(R23), -N(R22)C(O)R22, -OS(O)2R22, -S(O)2R22, -S(O)(NR22)R22, -S(O)2N(R22)(R23)-, - S(O)(NR22)N(R22)(R23), and -OCH2C(O)OR22: wherein two R20attached to the same or adjacent atoms optionally join to form C3-12carbocycle or 3- to 12-membered heterocycle; wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), C3-12carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, -OR22, -SR22, -N(R22)(R23), =NR22, =C(R21)2, -SF5, =N-OR22, =N- N(R22)(R23), -P(O)(R22)(R23), -ON=R22, -C(O)OR22, -OC(O)N(R22)(R23), -N(R22)C(O)N(R22)(R23), - N(R22)C(O)OR22, -N(R22)S(O)2R22, -C(O)R22, -S(O)R22, -OC(O)R22, -C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), - N(R22)C(O)R22, -OS(O)2R22, -S(O)2R22, -S(O)(NR22)R22, -S(O)2N(R22)(R23), and -S(O)(NR22)N(R22)(R23);

[0385] R21is independently selected at each occurrence from hydrogen, halogen, C1-6alkyl, C1-6haloalkyl, -C0-6alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle), or two R21are taken together with the carbon atom to which they are attached to form C3-12carbocycle or 3- to 12-membered heterocycle, each of which is optionally substituted with one, two, or three substituents independently selected from halogen, C1-3alkyl, C1-3haloalkyl, and -OH;

[0386] R22is independently selected at each occurrence from hydrogen, C1-6alkyl, C1-6haloalkyl, -C0-6alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle); and

[0387] R23is independently selected at each occurrence from hydrogen and C1-6alkyl; or R22and R23attached to the same nitrogen atom form 3- to 10 membered heterocycle; wherein one hydrogen of the compound is replaced with a bond to the antigen binding unit or the chemical linker.

[0388]

[0158] In embodiments, the chemical linker is covalently bonded to the antigen binding unit or the chemical linker is capable of covalently conjugating to the antigen binding unit.

[0389]

[0159] In some embodiments, for a compound of Formula (I-e) applicable for generating a subject conjugate, R10is halogen. In some embodiments, for a compound of Formula (I-e), R10is -F. In some embodiments, for a compound of Formula (I-e), R10is -Cl. In some embodiments, for a compound of Formula (I-e), R10is -Br. In some embodiments, for a compound of Formula (I-e), R10is C1-6alkyl optionally substituted with one, two, or three R20. In some embodiments, for a compound of Formula (I-e), R10is C1-6alkyl optionally substituted with one, two, or three halogen. In some embodiments, for a compound of Formula (I-e), R10is C1-6alkyl optionally substituted with one, two, or three -F. In some embodiments, for a compound of Formula (I-e), R10is unsubstituted methyl. In some embodiments, for a compound of Formula (I-e), R10is unsubstituted C1-6alkyl. In some embodiments, for a compound of Formula (I-e), R10is -CF3. In some embodiments, for a compound of Formula (I-e), R10is -CHF2. In some embodiments, for a compound of Formula (I-e), R10is -OH. In some embodiments, the substituents (for example, R2, R3, R6, R7, R8, R9, and R10) of formula (I-e) are the same as the corresponding substituents in Formula

[0390] (I), (I-a), (I-b), (I-c), and / or (I-d). In some embodiments, for a compound of Formula (I-e), is selected compound of Formula (I-e), is selected from

[0391]

[0160] In some embodiments, for a compound of Formula (I) or (I-a) applicable for generating a subject conjugate, X is C(R6), such as C(Cl). In some embodiments, X is N. In some embodiments, X is C(R6); and R6and R8are independently selected from hydrogen, halogen, and C1-3haloalkyl. In some embodiments, X is C(R6); R6is selected from chlorine and -CF3: and R8is fluorine. In some embodiments, X is N; and R8is selected from hydrogen, halogen, and C1-3haloalkyl. In some embodiments, X is N; and R8is fluorine. In some embodiments, X is C(R6); and Z is selected from O and C(R5)2. In some embodiments, X is C(R6); and Z is selected from O and CH2. In some embodiments, X is C(R6); Z is selected from O and C(R5)2: and R6and R8are independently selected from hydrogen, halogen, and C1-3haloalkyl. In some embodiments, X is C(R6); Z is selected from O and C(R5)2: R6is selected from chlorine and -CF3: and R8is fluorine. In some embodiments, X is C(R6); Z is selected from O and CH2: and R6and R8are independently selected from hydrogen, halogen, and C1-3haloalkyl. In some embodiments, X is C(R6); Z is selected from O and CH2: R6is selected from chlorine and -CF3; and R8is fluorine. In some embodiments, X is N; Z is selected from O and CH2: and R8is selected from hydrogen, halogen, and C1-3haloalkyl. In some embodiments, X is N; Z is selected from O and CH2: and R8is selected from hydrogen, halogen, and C1-3haloalkyl. In some embodiments, X is N; Z is selected from O and CH2: and R8is fluorine. In some embodiments, X is N; Z is selected from O and CH2: and R8is fluorine.

[0392]

[0161] In some embodiments, for a compound of Formula (I) applicable for generating a subject conjugate, R4is selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle), each of which is optionally substituted with one or more R20. In some embodiments, R4is selected from C1-6alkyl and -C0-6alkyl-(3- to 12-membered heterocycle), each of which is optionally substituted with one or more R20. In some embodiments, R4is -C1-3alkyl-(3- to 9-membered heterocycle) optionally substituted with one or more R20, and further optionally wherein the 3- to 9-membered heterocycle is selected from azetidinyl, thietanyl,

[0393] 1,1 -dioxide, imidazolyl, thiazolyl, isothiazolyl, triazolyl, pyrazolyl, pyrazinyl, pyidonyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrrolopyridinyl, and pyrazolopyridinyl. In some embodiments, the 3- to 9-membered heterocycle is selected from pyrazolyl, pyridonyl, pyridinyl, pyrimidinyl, and pyridazinyl. In some embodiments, the 3- to 9- membered heterocycle is pyridinyl. In some embodiments, R4is -C1-3alkyl-(pyridine) optionally substituted with one or more R20. In some embodiments, R4is -C1-3alkyl-(3- to 9-membered heterocycle), wherein the 3- to 9- membered heterocycle is substituted with -NH2. In some embodiments, R4is -C1-3alkyl-(pyridine), wherein the pyridine is substituted with -NH2.

[0394]

[0162] In some embodiments, for a compound of Formula (I-a) applicable for generating a subject conjugate, A is 6-membered heteroaryl comprising one or two ring nitrogen atoms. In some embodiments, A is selected from pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl. In some embodiments, A is selected from pyridin-3-yl, pyridazin- 4-yl, pyrimidin-5-yl, and pyrazin-2-yl. In some embodiments, A is pyridinyl. In some embodiments, A is pyridin-3- yl.

[0395]

[0163] In some embodiments, for a compound of Formula (I-a) applicable for generating a subject conjugate, R9is selected from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, -C0-6alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), -OR12, and -N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalky 1)- (C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12- membered heterocycle) are optionally substituted with one, two, or three R20; or R9and R10, together with the atoms to which they are attached, form C4-8carbocycle or 4- to 8-membered heterocycle, each of which is optionally substituted with one, two, or three R20; or R3and R9, together with the atoms to which they are attached, form 4- to 8-membered heterocycle optionally substituted with one, two, or three R20. In some embodiments, R9is selected from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), -OR12, and -N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalky 1)- (C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12- membered heterocycle) are optionally substituted with one, two, or three R20. In some embodiments, R9and R10, together with the atoms to which they are attached, form C4-8carbocycle or 4- to 8-membered heterocycle, each of which is optionally substituted with one, two, or three R20. In some embodiments, R3and R9, together with the atoms to which they are attached, form 4- to 8-membered heterocycle optionally substituted with one, two, or three R20. In some embodiments, R9is C1-3alkyl optionally substituted with one, two, or three R20; or R9and R10, together with the atoms to which they are attached, form C4-8carbocycle or 4- to 8-membered heterocycle, each of which is optionally substituted with one, two, or three R20. In some embodiments, R9is C1-3alkyl optionally substituted with one, two, or three R20. In some embodiments, R9is C1-6alkyl substituted with -N(R12)C(O)R12, such as -NHC(O)(C2-6alkenyl). In some embodiments, R9is C1-3alkyl substituted with -N(R12)C(O)R12, such as -NHC(O)(C2-6alkenyl). In some embodiments, R9is C1-6alkyl substituted with -N(R22)C(O)R22, such as -NHC(O)(C2-6alkenyl). In some embodiments, R9is C1-3alkyl substituted with -N(R22)C(O)R22, such as -NHC(O)(C2-6alkenyl). In some embodiments, R9is C1-6alkyl substituted with -NHC(O)CHCH2. In some embodiments, R9is C1-3haloalkyl, such as -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, or -CH2CF3. In some embodiments, R9is selected from -CH3, -CHF2, - CH2CH3, and CH2CHF2. In some embodiments, R9is C1-3alkyl. In some embodiments, R9is CH3. In some

[0396]

[0164] In some embodiments, for a compound of Formula (I-a) applicable for generating a subject conjugate, R9is selected from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), -OR22, and -N(R22)(R23), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalky 1)- (C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12- membered heterocycle) are optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, -OR22, -SR22, -N(R22)(R23), =NR22, =C(R21)2, -C(O)OR22, -OC(O)N(R22)(R23), -N(R22)C(O)N(R22)(R23), -N(R22)C(O)OR22, -N(R22)S(O)2R22, -C(O)R22, -S(O)R22, -OC(O)R22, -C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), -N(R22)C(O)R22, -OS(O)2R22, -S(O)2R22, - S(O)(NR22)R22, -S(O)2N(R22)(R23), and -S(O)(NR22)N(R22)(R23). In some embodiments, R9is C1-3alkyl optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, -OR22, -SR22, -N(R22)(R23), =NR22, =C(R21)2, -C(O)OR22, -OC(O)N(R22)(R23), - N(R22)C(O)N(R22)(R23), -N(R22)C(O)OR22, -N(R22)S(O)2R22, -C(O)R22, -S(O)R22, -OC(O)R22, -C(O)N(R22)(R23), - C(O)C(O)N(R22)(R23), -N(R22)C(O)R22, -OS(O)2R22, -S(O)2R22, -S(O)(NR22)R22, -S(O)2N(R22)(R23), and - S(O)(NR22)N(R22)(R23).

[0397]

[0165] In embodiments, R9is selected from C2-6alkenyl and C2-6alkynyl, wherein C2-6alkenyl and C2-6alkynyl are optionally substituted with one, two, or three substituents selected from halogen, and C3-6carbocycle. In embodiments, R9is selected from C2-4alkenyl and C2-4alkynyl, wherein C2-4alkenyl and C2-4alkynyl are optionally substituted with one, two, or three substituents selected from F and cyclopropyl. In embodiments, R9is selected

[0398]

[0166] In embodiments, R9is selected from -C1-6alkyl-(C3-6carbocycle), -(2- to 6-membered heteroalkyl)-(C3-6carbocycle), -C1-6alkyl-(3- to 6-membered heterocycle), and -(2- to 6-membered heteroalky l)-(3- to 6-membered heterocycle), wherein -C1-6alkyl-(C3-6carbocycle), -(2- to 6-membered heteroalkyl)-(C3-6carbocycle), -C1-6alkyl-(3- to 6-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 6-membered heterocycle) are each optionally substituted with one, two, or three substituents selected from oxo, -OR22, and C1-6alkyl optionally substituted with one or more substituents independently selected from oxo, -OR22, and -N(R22)(R23). In embodiments, R9is selected from -C1-3alkyl-(C3-6carbocycle), -(2- to 3 -membered heteroalky l)-(C3-6carbocycle), - C1-3alkyl-(4- to 6-membered heterocycle), and -(2- to 3-membered heteroalkyl)-(4- to 6-membered heterocycle), wherein -C1-3alkyl-(C3-6carbocycle), -(2- to 3-membered heteroalkyl)-(C3-6carbocycle), -C1-3alkyl-(4- to 6- membered heterocycle), and -(2- to 3 -membered heteroalky l)-(4- to 6-membered heterocycle) are each optionally substituted with one, two, or three substituents selected from oxo, -OCH3, and C1-6alkyl optionally substituted with one or more substituents independently selected from oxo and -NH2. In embodiments, R9is selected from -C1-3alkyl-(C3-6saturated carbocycle), -(2- to 3-membered heteroalkyl)-(C3-6saturated carbocycle), -C1-3alkyl-(4- to 6- membered saturated heterocycle), -(2- to 3-membered hetero alkyl) -(4- to 6-membered saturated heterocycle), -C1-3alkyl-(5- to 6-membered heteroaryl), and -(2- to 3-membered heteroalkyl)-(5- to 6-membered heteroaryl), wherein - C1-3alkyl-(C3-6saturated carbocycle), -(2- to 3-membered heteroalkyl)-(C3-6saturated carbocycle), -C1-3alkyl-(4- to 6-membered saturated heterocycle), -(2- to 3 -membered hetero alkyl) -(4- to 6-membered saturated heterocycle), -C1-3alkyl-(5- to 6-membered heteroaryl), and -(2- to 3-membered heteroalkyl)-(5- to 6-membered heteroaryl) are each optionally substituted with one, two, or three substituents selected from oxo, -OCH3, -CH3, C(O)CH3, C(O)C(NH2)(CH(CH3)2. In embodiments, R9is selected from

[0399]

[0167] In embodiments, R9is C1-6alkyl optionally substituted with one, two, or three substituents selected from halogen, oxo, -OR22, -N(R22)(R23), -S(O)R22, -C(O)N(R22)(R23), -N(R22)C(O)R22, -S(O)2R22, -P(O)(R22)(R23), and

[0400] =N-OR22. In embodiments, R9is C1-6alkyl optionally substituted with one, two, or three substituents selected from

[0401] F, -NH2, -N(CH3)2, -N(CH2CH3)2, OXO, -OH, -OCH3, -OCHF2, -OCF3, -S(O)CH3, -C(O)N(H)(CH3), - N(CH3)C(O)CH3, -S(O)2CH3, -P(O)(CH3)2, and =N-OCH2CH3. In embodiments, R9is selected from

[0402]

[0403]

[0168] In some embodiments, for a compound of Formula (I-a) applicable for generating a subject conjugate, R10is selected from hydrogen, halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, -OR12, and -N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, and 2- to 6-membered heteroalkyl are optionally substituted with one, two, or three R20; or R9and R10, together with the atoms to which they are attached, form C4-8carbocycle or 4- to 8-membered heterocycle, each of which is optionally substituted with one, two, or three R20. In some embodiments, R10is selected from hydrogen, halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6- membered heteroalkyl, -OR12, and -N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, and 2- to 6-membered heteroalkyl are optionally substituted with one, two, or three R20. In some embodiments, R9and R10, together with the atoms to which they are attached, form C4-8carbocycle or 4- to 8-membered heterocycle, each of which is optionally substituted with one, two, or three R20. In some embodiments, R10is selected from hydrogen and halogen; or R9and R10, together with the atoms to which they are attached, form C4-8carbocycle or 4- to 8-membered heterocycle, each of which is optionally substituted with one, two, or three R20. In some embodiments, R10is selected from hydrogen and halogen. In some embodiments, R10is hydrogen.

[0404]

[0169] In some embodiments, for a compound of Formula (I-a) applicable for generating a subject conjugate, R10is selected from hydrogen, halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, -OR22, and -N(R22)(R23), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, and 2- to 6-membered heteroalkyl are optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, -OR22, -SR22, -N(R22)(R23), =NR22, =C(R21)2, -C(O)OR22, -OC(O)N(R22)(R23), - N(R22)C(O)N(R22)(R23), -N(R22)C(O)OR22, -N(R22)S(O)2R22, -C(O)R22, -S(O)R22, -OC(O)R22, -C(O)N(R22)(R23), - C(O)C(O)N(R22)(R23), -N(R22)C(O)R22, -OS(O)2R22, -S(O)2R22, -S(O)(NR22)R22, -S(O)2N(R22)(R23), and - S(O)(NR22)N(R22)(R23). In some embodiments, R10is selected from hydrogen and halogen.

[0405]

[0170] In some embodiments, for a compound of Formula (I-a) applicable for generating a subject conjugate, R11is selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6alkyl-(C3-12carbocycle), -C0-6alkyl-(3- to 12- membered heterocycle), -C(O)R12, and -C(O)N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6alkyl- (C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle) are optionally substituted with one, two, or three R20. In some embodiments, R11is selected from hydrogen, C1-6alkyl, and -C(O)R12. In some embodiments, R11is hydrogen. In some embodiments, R11is C1-6alkyl, such as -CH3. In some embodiments, R11is -C(O)R12. In some embodiments, R11is selected from hydrogen, C1-6alkyl, C1-6haloalkyl, -C0-6alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle). In some embodiments, R11is a bond to the antigen binding unit or the chemical linker.

[0406]

[0171] In some embodiments, for a compound of Formula (I-a) applicable for generating a subject conjugate,

[0407]

[0173] In some embodiments, is selected from ’

[0408]

[0409]

[0174] In some embodiments, for a compound of Formula (I) or (I-a) applicable for generating a subject conjugate, R7is selected from C6-12aryl and 5- to 12-membered heteroaryl, each of which is optionally substituted with one or more R20. In some embodiments, R7is selected from C10aryl and 9-membered heteroaryl, each of which is optionally substituted with one or more R20. In some embodiments, R7is selected from naphthalenyl and benzothiophenyl, each of which is optionally substituted with one or more R20. In some embodiments, R7is selected from C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more R20. In some embodiments, R7is selected from bicyclic C4-10cycloalkyl, bicyclic 4- to 10-membered heterocycloalkyl, bicyclic C7-10 aryl, and bicyclic 7- to 10-membered heteroaryl, each of which is optionally substituted with one or more R20. In some embodiments, R7is selected from bridged bicyclic C4-10cycloalkyl, bridged bicyclic 4- to 10-membered heterocycloalkyl, bridged bicyclic C7-10 aryl, and bridged bicyclic 7- to 10-membered heteroaryl, each of which is optionally substituted with one or more R20. In some embodiments, R7is selected from fused bicyclic C4-10cycloalkyl, fused bicyclic 4- to 10-membered heterocycloalkyl, fused bicyclic C7-10 aryl, and fused bicyclic 7- to 10-membered heteroaryl, each of which is optionally substituted with one or more R20. In some embodiments, R7is selected from C6-10aryl and 5- to 10- membered heteroaryl, each of which is optionally substituted with one, two, three, four, or five R20. In some embodiments, R7is selected from naphthyl, isoquinolinyl, indazolyl, benzothiazolyl, benzothiophenyl, phenyl, and pyridinyl, each of which is optionally substituted with one or more R20. In some embodiments, R7is naphthyl, optionally substituted with one or more R20. In some embodiments, R7is benzothiophenyl, optionally substituted with one or more R20. In some embodiments, R7is phenyl, optionally substituted with one or more R20. In some embodiments, R7is pyridinyl, optionally substituted with one or more R20. In some embodiments, R7is substituted with one, two, three, or four substituents independently selected from halogen, -CN, C1-3alkyl, C1-3haloalky 1, C2-3alkenyl, C2-3alkynyl, -OR22, -N(R22)(R23), and C3-6cycloalkyl. In some embodiments, R7is selected from C6aryl and 6-membered heteroaryl, each of which is substituted with one, two, three, four, or five R20. In some embodiments, R7is optionally substituted with one or more R20, such as one, two, three, four, five, six, or seven R20. In some embodiments, R7is selected from benzothiophenyl, thienopyridinyl, furopyridinyl, and naphthalenyl: wherein each is optionally substituted with one, two, three, four, or five R20.

[0410]

[0175] In some embodiments, for a compound of Formula (I), (I-a), (I-d), or (I-e) applicable for generating a subject conjugate, R7is selected from: wherein:

[0411] Q1, Q3, and Q5are independently selected from N and C(R1a);

[0412] Q4and Q6are independently selected from O, S, C(R1a)2, and N(R1b);

[0413] X4, X5, X6, X9, and X10are independently selected from C(R1a) and N;

[0414] X7and X8are independently selected from C(R1a), C(R1a)2, N, and N(R1b); X13is selected from a bond, C(R1a), N, C(O), C(R1a)2, C(O)C(R1a)2, C(R1 a)2C(R1a)2, C(R1a)2N(R1b), and

[0415] N(R1b);

[0416] X14, X15, X17, and X18are independently selected from C(O), C(R1a), N, C(R1a)2, and N(R1b);

[0417] X16is selected from C, N, and C(R1a); each R1ais independently selected from hydrogen, halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), -OR12, -SR12, -N(R12)(R13), -C(O)OR12, - OC(O)N(R12)(R13), -N(R12)C(O)N(R12)(R13), -N(R12)C(O)OR12, -N(R12)S(O)2R12, -C(O)R12, -S(O)R12, -OC(O)R12, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R12)C(O)R12, -S(O)2R12, -S(O)(NR12)R12, -S(O)2N(R12)(R13), and - S(=O)(=NR12)N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6- membered hetero alkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalky l)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)- (3- to 12-membered heterocycle) are optionally substituted with one, two, or three R20; or two R1abonded to the same carbon are joined to form 3- to 10-membered heterocycle or C3-10carbocycle, wherein 3- to 10-membered heterocycle and C3-10carbocycle are optionally substituted with one, two, or three R20; or two R1abonded to adjacent atoms are joined to form 3- to 10-membered heterocycle or C3-10carbocycle, wherein 3- to 10-membered heterocycle and C3-10carbocycle are optionally substituted with one, two, or three R20; or one R1aand one R1bare joined to form 3- to 10-membered heterocycle or C3-10carbocycle, wherein 3- to 10-membered heterocycle and C3-10carbocycle are optionally substituted with one, two, or three R20; each R1bis independently selected from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 3- to 10-membered heterocycle, and C3-10carbocycle, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 3- to 10-membered heterocycle, and C3-10carbocycle are optionally substituted with one, two, or three R20; and indicates a single or double bond such that all valences are satisfied.

[0418]

[0176] In some embodiments, for a compound of Formula (I), (I-a), (I-d), or (I-e) applicable for generating a subject conjugate, R7is selected from

[0419]

[0420]

[0421]

[0177] In some embodiments, for a compound of Formula (I), (I-a), (I-d), or (I-e) applicable for generating a subject conjugate, R7is benzothiophenyl optionally substituted with one or more R20. In some embodiments, R7is benzothiophenyl optionally substituted with one, two, three, or four R20. In some embodiments, R7is benzothiophenyl substituted with three R20. In some embodiments, R7is benzo [b]thiophen-4-yl optionally substituted with one, two, three, or four R20. In some embodiments, R7is benzo [b]thiophen-4-yl substituted with three R20. In some embodiments, R7is selected from

[0422]

[0423]

[0178] In some embodiments, for a compound of Formula (I), (I-a), (I-d), or (I-e) applicable for generating a subject conjugate, R7is selected from

[0424]

[0179] In some embodiments, for a compound of Formula (I), (I-a), (I-d), or (I-e) applicable for generating a subject conjugate, R7is substituted with one, two, three, or four substituents independently selected from halogen, - CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, -OR22, -SR22, and -N(R22)(R23), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, and C3-6cycloalkyl are optionally substituted with one, two, or three substituents independently selected from halogen, C1-6alkyl, C1-6haloalkyl, and -OR22. In some embodiments, R7is substituted with one, two, three, or four substituents independently selected from halogen, -CN, C1-3alkyl, C2-3alkenyl, C2-3alkynyl, -OR22, and -N(R22)(R23). In some embodiments, R7is substituted with one, two, three, or four substituents independently selected from halogen, -CN, -CH3, -C=CH, -OH, and -NH2. In some embodiments, R7is substituted with -F, -CN, and -NH2. In some embodiments, R7is substituted with -F, -C=CH, and -OH. In some embodiments, R7is substituted with -CF3, -CH3, and -NH2. In some embodiments, R7is substituted with -CF3and -NH2. In some embodiments, R7is substituted with -CF3, -CH3, -F, and -NH2. In some embodiments, R7is substituted with -CF3, - F, and -NH2. In some embodiments, R7is substituted with one, two, three, or four substituents independently selected from halogen, -CN, -CH3, -CH2CH3, -CH=CH2, -CF3, -C=CH, -OH, -NH2, and -cyclopropyl. In some embodiments, R7is substituted with one, two, or three substituents independently selected from halogen, -CN, and - N(R22)(R23). In some embodiments, R7is substituted with one, two, or three substituents independently selected from fluorine, chlorine, -CN, and -NH2.

[0425]

[0180] In some embodiments, for a compound of Formula (I) applicable for generating a subject conjugate:

[0426] X is selected from C(R6) and N;

[0427] Z is selected from O and C(R5)2;

[0428] R2, R3, R6, and R8are each independently selected at each occurrence from hydrogen, halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C3-8carbocycle, 3- to 8-membered heterocycle, -OR12, -N(R12)(R13), -C(O)OR12, - N(R12)C(O)N(R12)(R13), -C(O)R12, -OC(O)R12, -C(O)N(R12)(R13), and -N(R12)C(O)R12, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C3-8carbocycle, and 3- to 8-membered heterocycle are optionally substituted with one, two, or three R20; wherein two R3are optionally taken together with the atom or atoms to which they are attached to form C3-8carbocycle or 3- to 8-membered heterocycle, each of which is optionally substituted with one, two, or three R20; and further wherein two R3are optionally taken together to form =O, =NR12, or =C(R14)2;

[0429] R7is selected from naphthyl, benzothiophenyl, phenyl, and pyridinyl, each of which is optionally substituted with one or more R20; m is 0 or 1 ; and n is 1 or 2.

[0430]

[0181] In some embodiments, for a compound of Formula (I) applicable for generating a subject conjugate:

[0431] X is selected from C(R6) and N;

[0432] Z is selected from O, CH2, and CI I(CI F,): R2is -OR12;

[0433] R3is independently selected at each occurrence from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8carbocycle, and 3- to 8-membered heterocycle, each of which is optionally substituted with one, two, or three R20;

[0434] R6and R8are independently selected from hydrogen, halogen, and C1-3haloalkyl;

[0435] R7is selected from naphthyl, benzothiophenyl, phenyl, and pyridinyl, each of which is optionally substituted with one or more R20; m is 0 or 1 ; and n is 1 or 2.

[0436]

[0182] In some embodiments, for a compound of Formula (I-a) applicable for generating a subject conjugate:

[0437] X is selected from C(R6) and N;

[0438] Z is selected from O and C(R5)2;

[0439] A is selected from pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl;

[0440] R2, R3, R6, R8, and R10are each independently selected at each occurrence from hydrogen, halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C3-8carbocycle, 3- to 8-membered heterocycle, -OR12, -N(R12)(R13), - C(O)OR12, -N(R12)C(O)N(R12)(R13), -C(O)R12, -OC(O)R12, -C(O)N(R12)(R13), and -N(R12)C(O)R12, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C3-8carbocycle, and 3- to 8-membered heterocycle are optionally substituted with one, two, or three R20; wherein two R3are optionally taken together with the atom or atoms to which they are attached to form C3-8carbocycle or 3- to 8-membered heterocycle, each of which is optionally substituted with one, two, or three R20; and further wherein two R3are optionally taken together to form =O, =NR12, or =C(R14)2;

[0441] R7is selected from naphthyl, benzothiophenyl, phenyl, and pyridinyl, each of which is optionally substituted with one or more R20;

[0442] R9is C1-3alkyl optionally substituted with one, two, or three R20;

[0443] R11is hydrogen; m is 0 or 1 ; and n is 1 or 2.

[0444]

[0183] In some embodiments, for a compound of Formula (I-a) applicable for generating a subject conjugate:

[0445] X is C(R6);

[0446] A is selected from pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl;

[0447] R11is hydrogen;

[0448] R2, R6, R8, and R10are each independently selected at each occurrence from hydrogen, halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C3-8carbocycle, 3- to 8-membered heterocycle, -OR12, -N(R12)(R13), -C(O)OR12, - N(R12)C(O)N(R12)(R13), -C(O)R12, -OC(O)R12, -C(O)N(R12)(R13), and -N(R12)C(O)R12, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C3-8carbocycle, and 3- to 8-membered heterocycle are optionally substituted with one, two, or three R20;

[0449] R3is independently selected at each occurrence from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, - C3-8carbocycle, 3- to 8-membered heterocycle, -OR12, -N(R12)(R13), -C(O)OR12, -N(R12)C(O)N(R12)(R13), -C(O)R12, -OC(O)R12, -C(O)N(R12)(R13), and -N(R12)C(O)R12, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C3-8carbocycle, and 3- to 8-membered heterocycle are optionally substituted with one, two, or three R20; wherein two R3are optionally taken together with the atom or atoms to which they are attached to form C3-8carbocycle or 3- to 8- membered heterocycle, each of which is optionally substituted with one, two, or three R20; and further wherein two R3are optionally taken together to form =O, =NR12, or =C(R14)2;

[0450] R7is benzo [b]thiophen-4-yl optionally substituted with one, two, three, or four R20;

[0451] R9is C1-3alkyl optionally substituted with one, two, or three R20; m is 0 or 1 ; and n is 1 or 2.

[0452]

[0184] In some embodiments, for a compound of Formula (I-a) applicable for generating a subject conjugate:

[0453] X is N;

[0454] A is selected from pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl;

[0455] R11is hydrogen;

[0456] R2, R6, R8, and R10are each independently selected at each occurrence from hydrogen, halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C3-8carbocycle, 3- to 8-membered heterocycle, -OR12, -N(R12)(R13), -C(O)OR12, - N(R12)C(O)N(R12)(R13), -C(O)R12, -OC(O)R12, -C(O)N(R12)(R13), and -N(R12)C(O)R12, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C3-8carbocycle, and 3- to 8-membered heterocycle are optionally substituted with one, two, or three R20;

[0457] R3is independently selected at each occurrence from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, - C3-8carbocycle, 3- to 8-membered heterocycle, -OR12, -N(R12)(R13), -C(O)OR12, -N(R12)C(O)N(R12)(R13), -C(O)R12, -OC(O)R12, -C(O)N(R12)(R13), and -N(R12)C(O)R12, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C3-8carbocycle, and 3- to 8-membered heterocycle are optionally substituted with one, two, or three R20; wherein two R3are optionally taken together with the atom or atoms to which they are attached to form C3-8carbocycle or 3- to 8- membered heterocycle, each of which is optionally substituted with one, two, or three R20; and further wherein two R3are optionally taken together to form =O, =NR12, or =C(R14)2;

[0458] R7is selected from naphthyl, phenyl, and pyridinyl, each of which is optionally substituted with one or more R20;

[0459] R9is C1-3alkyl optionally substituted with one, two, or three R20; m is 0 or 1 ; and n is 1 or 2.

[0460]

[0185] In some embodiments, for a compound of Formula (I-a) applicable for generating a subject conjugate:

[0461] A is selected from pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl;

[0462] R2is selected from hydrogen, C1-3alkyl, -OR12, and 3- to 10-membered heterocycle, wherein C1-3alkyl and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R20;

[0463] R3is independently selected at each occurrence from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8carbocycle, and 3- to 8-membered heterocycle, each of which is optionally substituted with one, two, or three R20;

[0464] R6and R8are independently selected from hydrogen, halogen, and C1-3haloalkyl;

[0465] R9is C1-3alkyl optionally substituted with one, two, or three R20;

[0466] R11is hydrogen; and m is 0 or 1.

[0467]

[0186] In some embodiments, for a compound of Formula (I), (I-a), (I-b) or (I-c) applicable for generating a subject conjugate:

[0468] R2, R3, R6, and R8are each independently selected at each occurrence from hydrogen, halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C3-8carbocycle, 3- to 8-membered heterocycle, -OR12, -N(R12)(R13), -C(O)OR12, - N(R12)C(O)N(R12)(R13), -C(O)R12, -OC(O)R12, -C(O)N(R12)(R13), and -N(R12)C(O)R12, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C3-8carbocycle, and 3- to 8-membered heterocycle are optionally substituted with one, two, or three R20; wherein two R3are optionally taken together with the atom or atoms to which they are attached to form C3-8carbocycle or 3- to 8-membered heterocycle, each of which is optionally substituted with one, two, or three R20; and further wherein two R3are optionally taken together to form =O, =NR12, or =C(R14)2; and m is 0 or 1.

[0469]

[0187] In some embodiments, for a compound of Formula (I), (I-a), (I-b), (I-c), (I-d), or (I-e) applicable for generating a subject conjugate:

[0470] R2is selected from hydrogen, C1-3alkyl, -OR12, and 3- to 10-membered heterocycle, wherein C1-3alkyl and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R20;

[0471] R3is independently selected at each occurrence from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8carbocycle, and 3- to 8-membered heterocycle, each of which is optionally substituted with one, two, or three R20;

[0472] R6and R8are independently selected from hydrogen, halogen, and C1-3haloalkyl; and m is 0 or 1.

[0473]

[0188] In some embodiments, for a compound of Formula (I), (I-a), (I-b), (I-c), (I-d), or (I-e) applicable for generating a subject conjugate:

[0474] R2is -OR12;

[0475] R3is independently selected at each occurrence from C1-6alkyl optionally substituted with one, two, or three R20; m is 0 or 1 ;

[0476] R6is selected from chlorine and -CF3; and

[0477] R8is fluorine.

[0478]

[0189] In some embodiments, for a compound of Formula (I), (I-a), (I-b), (I-c), (I-d), or (I-e) applicable for generating a subject conjugate:

[0479] R3is independently selected at each occurrence from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8carbocycle, and 3- to 8-membered heterocycle, each of which is optionally substituted with one, two, or three substituents independently selected from halogen, -CN, -OH, and -OCH3; m is 0 or 1 ;

[0480] R6is selected from chlorine and -CF3; and

[0481] R8is fluorine.

[0482]

[0190] In some embodiments, for a compound of Formula (I), (I-a), (I-b), (I-c), (I-d), or (I-e) applicable for generating a subject conjugate :

[0483] R3is independently selected at each occurrence from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8carbocycle, and 3- to 8-membered heterocycle, each of which is optionally substituted with one, two, or three substituents independently selected from halogen, -CN, -OH, and -OCH3; m is 0 or 1 ;

[0484] R6is selected from chlorine and -CF3;

[0485] R8is fluorine; and n is 1.

[0191] In some embodiments, for a compound of Formula (I) or (I-a) applicable for generating a subject conjugate:

[0486] X is C(R6);

[0487] Z is O;

[0488] R2is

[0489] R3is independently selected at each occurrence from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8carbocycle, and 3- to 8-membered heterocycle, each of which is optionally substituted with one, two, or three substituents independently selected from halogen, -CN, -OH, and -OCH3; m is 0 or 1 ;

[0490] R6is selected from chlorine and -CF3:

[0491] R7is pyridinyl optionally substituted with one or more R20;

[0492] R8is fluorine; and n is 1.

[0493]

[0192] In some embodiments, for a compound of Formula (I) or (I-a) applicable for generating a subject conjugate: X is N;

[0494] Z is selected from O and C(R5)2;

[0495] R2is

[0496] R3is independently selected at each occurrence from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8carbocycle, and 3- to 8-membered heterocycle, each of which is optionally substituted with one, two, or three substituents independently selected from halogen, -CN, -OH, and -OCH3; m is 0 or 1 ;

[0497] R7is naphthyl optionally substituted with one or more R20;

[0498] R8is fluorine; and n is 1 or 2.

[0499]

[0193] In some embodiments, the compound of Formula (I) or (I-a) applicable for generating a subject conjugate, is selected from:

[0500] or a pharmaceutically acceptable salt or solvate thereof.

[0501]

[0194] In some embodiments, the compound of Formula (I) or (I-a) applicable for generating a subject conjugate, is selected from:

[0502]

[0503]

[0195] In some embodiments, for a compound of Formula (I), (I-a), (I-b), (I-c), (I-d), or (I-e) applicable for generating a subject conjugate , R2is selected from hydrogen, C1-6alkyl, C2-6alkenyl, C3-10carbocycle, 3- to 10- membered heterocycle, -OR12, and -N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C3-10carbocycle, and 3- to 10- membered heterocycle are optionally substituted with one, two, or three R20. In some embodiments, R2is selected from hydrogen, -(C0-3alkylene)-O-(C0-3alkylene)-R20, C1-3alkyl, and 3- to 10-membered heterocycle, wherein each C0-3alkylene, C1-3alkyl, and 3- to 10-membered heterocycle is optionally substituted with one, two, or three R20. In some embodiments, R2is selected from hydrogen, C1-3alkyl, -OR12, and 3- to 10-membered heterocycle, wherein C1-3alkyl and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R20. In some embodiments, R2is OR12. In some embodiments, R2is -O(C1-3alkylene)(4- to 10-membered heterocycle), wherein

[0504] 4- to 10-membered heterocycle is optionally substituted with one, two, or three substituents independently selected from halogen, C1-3alkyl, C1-3haloalkyl, and =C(R21)2, wherein R21is independently selected at each occurrence from hydrogen, halogen, and C1-3alkyl. In some embodiments, R2is -OCH2(hexahydro-lH-pyrrolizine) optionally substituted with one, two, or three R20. In some embodiments, R2is -OCH2(hexahydro-lH-pyrrolizine) optionally substituted with one, two, or three substituents independently selected from halogen, C1-3alkyl, C1-3haloalkyl, and =C(R21)2, wherein R21is independently selected at each occurrence from hydrogen, halogen, and C1-3alkyl.

[0505]

[0196] In some embodiments, for a compound of Formula (I), (I-a), (I-b), (I-c), (I-d), or (I-e) applicable for

[0506]

[0507]

[0197] In some embodiments, for a compound of Formula (I), (I-a), (I-b), (I-c), (I-d), or (I-e) applicable for generating a subject conjugate, R2is substituted with one, two, three, or four substituents independently selected from halogen, oxo, C1-6alkyl, -OR22, -N(R22)(R23), =C(R21)2, and -OC(O)N(R22)(R23), wherein C1-6alkyl is optionally substituted with one or more substituents independently selected from halogen, -CN, -OR22, -N(R22)(R23), and -OC(O)N(R22)(R23). In some embodiments, R2is substituted with one, two, three, or four substituents independently selected from halogen, C1-3alkyl, C1-3haloalkyl, and =C(R21)2, wherein R21is independently selected at each occurrence from hydrogen, halogen, and C1-3alkyl. In some embodiments, R2is substituted with one, two, three, or four substituents independently selected from halogen, C1-3alkyl, C1-3haloalkyl, =CH2, =CHF, and =CF2. In some embodiments, R2is substituted with =C(R21)2, such as =CF2. In some embodiments, R2is substituted with halogen, such as fluorine.

[0508]

[0198] In some embodiments, for a compound of Formula (I), (I-a), (I-b), (I-c), (I-d), or (I-e) applicable for generating a subject conjugate, R3is independently selected at each occurrence from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered hetero alky nyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalky l)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), -OR12, -SR12, - N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), -N(R12)C(O)N(R12)(R13), -N(R12)C(O)OR12, -N(R12)S(O)2R12, - C(O)R12, -S(O)R12, -OC(O)R12, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R12)C(O)R12, -S(O)2R12, - S(O)(NR12)R12, -S(O)2N(R12)(R13), -S(O)(NR12)N(R12)(R13), and -OCH2C(O)OR12, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered hetero alkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle) are optionally substituted with one, two, or three R20; wherein two R3are optionally taken together with the atom or atoms to which they are attached to form C3-8carbocycle or 3- to 8-membered heterocycle, each of which is optionally substituted with one, two, or three R20; and further wherein two R3are optionally taken together to form =O, =NR12, or =C(R14)2. In some embodiments, two R3are taken together with the atom or atoms to which they are attached to form C3-8carbocycle or 3- to 8-membered heterocycle, each of which is optionally substituted with one, two, or three R20. In some embodiments, two R3are taken together with the atom to which they are attached to form C3-8carbocycle or 3- to 8- membered heterocycle, each of which is optionally substituted with one, two, or three R20. In some embodiments, two R3attached to adjacent atoms are taken together with the atoms to which they are attached to form C3-8carbocycle or 3- to 8-membered heterocycle, each of which is optionally substituted with one, two, or three R20. In some embodiments, two R3are taken together to form =O, =NR12, or =C(R14)2.

[0509]

[0199] In some embodiments, for a compound of Formula (I), (I-a), (I-b), (I-c), (I-d), or (I-e) applicable for generating a subject conjugate, R3is independently selected at each occurrence from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6alkyl-(C3-6carbocycle), -(2- to 6-membered heteroalkyl)-(C3-e carbocycle), -C0-6alkyl-(3- to 6-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 6-membered heterocycle), -OR12, and - N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6alkyl-(C3-e carbocycle), -(2- to 6-membered heteroalky l)-(C3-6carbocycle), -C0-6alkyl-(3- to 6-membered heterocycle), and -(2- to 6-membered heteroalky l)-(3- to 6-membered heterocycle) are optionally substituted with one, two, or three R20; wherein two R3are optionally taken together with the atom or atoms to which they are attached to form C3-8carbocycle or 3- to 8-membered heterocycle, each of which is optionally substituted with one, two, or three R20; and further wherein two R3are optionally taken together to form =O, =NR12, or =C(R14)2. In some embodiments, R3is independently selected at each occurrence from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8carbocycle, and 3- to 8-membered heterocycle, each of which is optionally substituted with one, two, or three R20. In some embodiments, R3is independently selected at each occurrence from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8carbocycle, and 3- to 8-membered heterocycle, each of which is optionally substituted with one, two, or three substituents independently selected from halogen, -CN, - OH, and -OCH3. In some embodiments, R3is C2-3alkenyl. In some embodiments, R3is C2-3alkynyl. In some embodiments, R3is C1-3haloalkyl. In some embodiments, R3is selected from -CHCH2, -CCH, -CH2CN, and -CHF2.

[0510]

[0200] In some embodiments, for a compound of Formula (I), (I-a), (I-b), (I-c), (I-d), or (I-e) applicable for generating a subject conjugate, m is 0, 1, or 2. In some embodiments, m is 0 or 1. In some embodiments, m is 1 or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3.

[0511]

[0201] In some embodiments, for a compound of Formula (I), (I-a), (I-b), (I-c), (I-d), or (I-e) applicable for generating a subject conjugate, Z is selected from O, N, C(R5)2, and C(O). In some embodiments, Z is selected from S, S(O), and S(O)2. In some embodiments, Z is selected from O and C(R5)2. In some embodiments, Z is selected from O, CH2, and CH(CH3). In some embodiments, Z is O. In some embodiments, Z is CH2. In some embodiments, Z is CH(CH3).

[0512]

[0202] In some embodiments, for a compound of Formula (I), (I-a), (I-b), (I-c), (I-d), or (I-e) applicable for generating a subject conjugate, R6is selected from hydrogen, halogen, -CN, C1-6alkyl, 2- to 6-membered heteroalkyl, -C0-6alkyl-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -OR12, and -N(R12)(R13), wherein C1-6alkyl, 2- to 6-membered heteroalkyl, -C0-6alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle) are optionally substituted with one or more R20. In some embodiments, R6is selected from hydrogen, halogen, C1-3alkyl. In some embodiments, R6is selected from hydrogen, halogen, and C1-3haloalkyl. In some embodiments, R6is selected from halogen and C1-3haloalkyl. In some embodiments, R6is selected from hydrogen and halogen. In some embodiments, R6is hydrogen. In some embodiments, R6is halogen, such as fluorine. In some embodiments, R6is chlorine. In some embodiments, R6is C1-3haloalkyl, such as -CHF2. In some embodiments, R6is -CF3. In some embodiments, R6is -CH2CN. In some embodiments, R6is -NH2. In some embodiments, R6is -

[0513] N( C1 [3)2. In some embodiments, R6is -N(CH2CH3)2. In some embodiments, R6is -SF5.

[0514]

[0203] In some embodiments, for a compound of Formula (I), (I-a), (I-b), (I-c), (I-d), or (I-e) applicable for generating a subject conjugate, R8is selected from hydrogen, halogen, -CN, C1-6alkyl, 2- to 6-membered heteroalkyl, -C0-6alkyl-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -OR12, and -N(R12)(R13), wherein C1-6alkyl, 2- to 6-membered heteroalkyl, -C0-6alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle) are optionally substituted with one or more R20. In some embodiments, R8is selected from hydrogen, halogen, and C1-3alkyl. In some embodiments, R8is selected from hydrogen and halogen. In some embodiments, R8is hydrogen. In some embodiments, R8is halogen, such as chlorine. In some embodiments, R8is fluorine. In some embodiments, R6and R8are independently selected from hydrogen, halogen, and C1-3haloalkyl. In some embodiments, R6and R8are independently selected from C1-3haloalky 1 and halogen. In some embodiments, R6and R8are independently selected from hydrogen, halogen, and -CF3. In some embodiments, R6and R8are independently selected from -Cl, -F, and -CF3. In some embodiments, R6and R8are independently selected from hydrogen and halogen.

[0515]

[0204] In some embodiments, for a compound of Formula (I), (I-a), (I-b), (I-c), (I-d), or (I-e) applicable for generating a subject conjugate, n is 0, 1, 2, or 3. In some embodiments, n is 1. In some embodiments, n is 2.

[0516]

[0205] In some embodiments, for a compound of Formula (I), (I-a), (I-b), (I-c), (I-d), or (I-e) applicable for generating a subject conjugate:

[0517] R2is selected from hydrogen, C1-3alkyl, -OR12, and 3- to 10-membered heterocycle, wherein C1-3alkyl and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R20;

[0518] R3is independently selected at each occurrence from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8carbocycle, and 3- to 8-membered heterocycle, each of which is optionally substituted with one, two, or three R20; m is 0 or 1 ; and

[0519] R6and R8are independently selected from hydrogen, halogen, and CF3.

[0520]

[0206] In some embodiments, for a compound of Formula (I), (I-a), (I-b), (I-c), (I-d), or (I-e) applicable for generating a subject conjugate:

[0521] R2is selected from hydrogen, C1-3alkyl, -OR12, and 3- to 10-membered heterocycle, wherein C1-3alkyl and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R20;

[0522] R3is independently selected at each occurrence from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8carbocycle, and 3- to 8-membered heterocycle, each of which is optionally substituted with one, two, or three R20; m is 0 or 1 ;

[0523] R6and R8are independently selected from hydrogen, halogen, and -CF3: and n is 1.

[0524]

[0207] In some embodiments, for a compound of Formula (I), (I-a), (I-b), (I-c), (I-d), or (I-e) applicable for generating a subject conjugate:

[0525] R2is selected from hydrogen, C1-3alkyl, -OR12, and 3- to 10-membered heterocycle, wherein C1-3alkyl and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R20;

[0526] R3is independently selected at each occurrence from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8carbocycle, and 3- to 8-membered heterocycle, each of which is optionally substituted with one, two, or three R20; m is 0 or 1 ;

[0527] R6is selected from chlorine and -CTT and

[0528] R8is fluorine.

[0529]

[0208] In some embodiments, for a compound of Formula (I), (I-a), (I-b), (I-c), (I-d), or (I-e) applicable for generating a subject conjugate:

[0530] R2is selected from hydrogen, C1-3alkyl, -OR12, and 3- to 10-membered heterocycle, wherein C1-3alkyl and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R20;

[0531] R3is independently selected at each occurrence from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8carbocycle, and 3- to 8-membered heterocycle, each of which is optionally substituted with one, two, or three R20; m is 0 or 1 ;

[0532] R6is selected from chlorine and -CTT

[0533] R8is fluorine; and n is 1.

[0534]

[0209] In some embodiments, for a compound of Formula (I), (I-a), (I-b), (I-c), (I-d), or (I-e) applicable for generating a subject conjugate:

[0535] R2is

[0536] R3is independently selected at each occurrence from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8carbocycle, and 3- to 8-membered heterocycle, each of which is optionally substituted with one, two, or three substituents independently selected from halogen, -CN, -OH, and -OCH3; m is 0 or 1 ;

[0537] R6is selected from chlorine and -CF3: and

[0538] R8is fluorine.

[0539]

[0210] In some embodiments, for a compound of Formula (I), (I-a), (I-b), (I-c), (I-d), or (I-e) applicable for generating a subject conjugate:

[0540] R2is

[0541] R3is independently selected at each occurrence from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8carbocycle, and 3- to 8-membered heterocycle, each of which is optionally substituted with one, two, or three substituents independently selected from halogen, -CN, -OH, and -OCH3; m is 0 or 1 ;

[0542] R6is selected from chlorine and -CF3:

[0543] R8is fluorine; and n is 1.

[0544]

[0211] In some embodiments, a compound of Formula (I), (I-a), (I-b), or (I-c) applicable for generating a subject conjugate, has the formula: wherein:

[0545] Ring A is 6-membered heteroaryl comprising one or two ring nitrogen atoms;

[0546] R2is selected from -O-CH2-(8- to 10-membered saturated heterocycle) and -O-CH2-(cyclopropylene)-CH2- (5- to 8-membered saturated heterocycle); wherein -O-CH2-(8- to 10-membered saturated heterocycle) and -O-CH2- (cyclopropylene)-CH2-(5- to 8-membered saturated heterocycle) are optionally substituted with one or more substituents independently selected from -F, =CF2, =CH2, and =CHF;

[0547] R9is selected from C1-3alkyl, C2-4alkenyl, C2-3alkynyl, -C1-2alkyl-(C3-4saturated carbocycle), and -C1-2alkyl-(5- to 6-membered saturated heterocycle); wherein C1-3alkyl, C2-4alkenyl, C2-3alkynyl, -C1-2alkyl-(C3-4saturated carbocycle), and -C1-2alkyl-(5- to 6-membered saturated heterocycle) are each optionally substituted with one or more halogen, R10is selected from hydrogen and halogen;

[0548] R6is selected from halogen and -CF3;

[0549] R7is benzothiophenyl optionally substituted with one or more substituents independently selected from -

[0550] NH2, -CN, and -F;

[0551] R8is halogen; and wherein one hydrogen of the compound is replaced with a bond to the antigen binding unit or the chemical linker.

[0552]

[0212] In embodiments, the chemical linker is covalently bonded to the antigen binding unit or the chemical linker is capable of covalently conjugating to the antigen binding unit.

[0553]

[0213] In embodiments of a compound of Formula (I-f) applicable for generating a subject conjugate, R6is -CF3. In embodiments of a compound of Formula (I-f) applicable for generating a subject conjugate, R5is halogen. In embodiments of a compound of Formula (I-f) applicable for generating a subject conjugate, R8is -F. In some embodiments, the substituents (for example, R2, R6, R7, R8, R9, and R10) of formula (I-f) are the same as the corresponding substituents in Formula (I), (I-a), (I-b), and / or (I-c), including in embodiments thereof. In embodiments, a compound of Formula (I-f) is a compound of Formula (I), (I-a), (I-b), and / or (I-c),.

[0554]

[0214] In some embodiments, a compound of Formula (I), (I-a), (I-b), or (I-c) applicable for generating a subject conjugate, has the formula: wherein:

[0555] R2is selected from -O-CH2-(8- to 10-membered saturated heterocycle) and -O-CH2-(cyclopropylene)-CH2- (5- to 8-membered saturated heterocycle); wherein -O-CH2-(8- to 10-membered saturated heterocycle) and -O-CH2- (cyclopropylene)-CH2-(5- to 8-membered saturated heterocycle) are optionally substituted with one or more substituents independently selected from -F, =CF2, =CH2, and =CHF;

[0556] R9is selected from C1-3alkyl, C2-4alkenyl, C2-3alkynyl, -C1-2alkyl-(C3-4saturated carbocycle), and -C1-2alkyl-(5- to 6-membered saturated heterocycle); wherein C1-3alkyl, C2-4alkenyl, C2-3alkynyl, -C1-2alkyl-(C3-4saturated carbocycle), and -C1-2alkyl-(5- to 6-membered saturated heterocycle) are each optionally substituted with one or more -F,

[0557] R6is selected from -Cl and -CF3;

[0558] R7is benzothiophenyl optionally substituted with one or more substituents independently selected from - NH2, -CN, and -F;

[0559] R8is -F ; and wherein one hydrogen of the compound is replaced with a bond to the antigen binding unit or the chemical linker.

[0560]

[0215] In embodiments, the chemical linker is covalently bonded to the antigen binding unit or the chemical linker is capable of covalently conjugating to the antigen binding unit.

[0561]

[0216] In embodiments of a compound of Formula (I-f) applicable for generating a subject conjugate, R6is -CF3. In some embodiments, the substituents (for example, R2, R6, R7, R8, R9, and R10) of formula (I-f) are the same as the corresponding substituents in Formula (I), (I-a), (I-b), or (I-c), including in embodiments thereof. In embodiments, a compound of Formula (I-d) applicable for generating a subject conjugate is a compound of Formula (I), (I-a), (I-b), or (I-c).

[0562]

[0217] In some embodiments, a compound of Formula (I), (I-a), (I-b), or (I-c), applicable for generating a subject conjugate, has the formula:

[0563] CH3;

[0564] R6is selected from -Cl and -CF3; R7is selected from

[0565] R8is -F ; and wherein one hydrogen of the compound is replaced with a bond to the antigen binding unit or the chemical linker.

[0566]

[0218] In embodiments, the chemical linker is covalently bonded to the antigen binding unit or the chemical linker is capable of covalently conjugating to the antigen binding unit.

[0567]

[0219] In embodiments of a compound of Formula (I-f) applicable for generating a subject conjugate, R6is -CF3.

[0568] In some embodiments, the substituents (for example, R2, R6, R7, R8, R9, and R10) of formula (I-f) are the same as the corresponding substituents in Formula (I), (I-a), (I-b), or (I-c), including in embodiments thereof. In embodiments, a compound of Formula (I-f) applicable for generating a subject conjugate is a compound of Formula (I), (I-a), (I-b), or (I-c). In some embodiments of the formulae above, some embodiments of the formulae above, R2is embodiments of the formulae above, R2is In some embodiments of the formulae above, R9is formulae above, R9is . In some embodiments of the formulae above, R9is -CH3. In some embodiments of the formulae above, R9is -CH2CH3. In some embodiments of the formulae above, R6is -Cl. In some embodiments of the formulae above, R6is -CF3. In some embodiments of the formulae above, R7is embodiments of the formulae above, R7is In some embodiments of the formulae above, R7is

[0569] In some embodim ents, one embodiment of each of , Ring A, R2, R6, R7, R8, R9, and R10is combined with a formulae above to generate a single compound.

[0570]

[0220] In some embodiments, a compound of Formula (I), (I-a), (I-b), or (I-c), applicable for generating a subject conjugate, has the formula:

[0571] CH3;

[0572] R5is selected from hydrogen and halogen; wherein one hydrogen of the compound of Formula (I-g) is replaced with a bond to the antigen binding unit or the chemical linker. In embodiments, R9is -CH3and R10is hydrogen. In embodiments, R9is and R10is hydrogen. In embodiments, R9is -CH3and R10is halogen. In embodiments, R9is -CH2CH3and R10is halogen. In embodiments,

[0573] R9is -CH3and R10is -F. In embodiments, R9is selected from formulae above, R2is . In some embodiments of the formulae above, R2is

[0574] In some embodiments, the substituents (for example, R2, R6, R7, R8, R9, and R10) of formula (I-g) are the same as the correspondi...

Claims

CLAIMSWHAT IS CLAIMED IS:

1. A conjugate comprising an antigen binding unit exhibiting binding specificity for at least a first antigen that is not KRAS, wherein the antigen binding unit is covalently attached to a small-molecule KRAS inhibitor, optionally through a chemical linker, and wherein the antigen binding unit and the KRAS inhibitor in the conjugate synergistically inhibits signaling output of the first antigen and KRAS.

2. A conjugate comprising an antigen binding unit exhibiting binding specificity for at least a first antigen that is not KRAS, wherein the antigen binding unit is covalently attached to a small-molecule KRAS inhibitor, optionally through a chemical linker, and wherein the KRAS inhibitor selectively inhibits KRAS or a mutant thereof relative to HRAS and NRAS.

3. The conjugate of claim 1 or 2, wherein the KRAS inhibitor is characterized by a PAMPA permeability (Pe) less than 1 x 10-6cm / s.

4. The conjugate of any one of the preceding claims, wherein the conjugate is characterized by an enhanced therapeutic efficacy as ascertained by the formula:wherein TIconjugate= TD50c / ED50c, wherein TD50cis the dose of conjugate required to produce a toxic effect in 50% of test subjects and ED50cis the dose of conjugate required to produce a therapeutic effect in 50% of test subjects; and wherein TIKRASI = TD50k / ED50k, wherein TD50kis the dose of KRAS inhibitor required to produce a toxic effect in 50% of test subjects and ED50kis the dose of KRAS inhibitor required to produce a therapeutic effect in 50% of the test subjects.

5. The conjugate of any one of the preceding claims, wherein the conjugate is characterized by reduced plasma concentration of the KRAS inhibitor as ascertained by the formula:[KRASi]p-c / [KRASi]p-k< 1 wherein [KRASi]p-cis plasma concentration of the KRAS inhibitor at a first time -point following administration of the conjugate; and wherein [KRASi]p-kis plasma concentration of the KRAS inhibitor following administration of the KRAS inhibitor alone at an equivalent dose at the same time-point.

6. The conjugate of any one of the preceding claims, wherein the conjugate is characterized by an increased concentration of the KRAS inhibitor in tumor tissue relative to plasma as ascertained by the formula:([KRASi]t-c / [KRASi]p-c) / ([KRASi]t-k / [KRASi]p-k) > 1 wherein [KRASi]t-cis concentration of the KRAS inhibitor in tumor tissue at a first time -point following administration of the conjugate; wherein [KRASi]p-cis plasma concentration of the KRAS inhibitor at the same time -point following the administration of the conjugate; wherein [KRASi]t-kis concentration of the KRAS inhibitor in tumor tissue following administration of the KRAS inhibitor alone at an equivalent dose at the same time-point; and wherein [KRASi]p-kis plasma concentration of the KRAS inhibitor at the same time-point following theadministration of the KRAS inhibitor alone at the equivalent dose.

7. A conjugate of Formula (A):wherein:AgB is an antigen binding unit;L is a chemical linker;D is independently selected at each occurrence from a small-molecule KRAS inhibitor, a cytotoxic smallmolecule and a small-molecule agent that selectively modulates a non-KRAS target, wherein at least one D is a KRAS inhibitor; p is selected from 1 to 20; and q is selected from 1 to 20.

8. The conjugate of any one of the preceding claims, wherein the antigen binding unit is an antibody or an antigen-binding fragment thereof.

9. The conjugate of any one of the preceding claims, wherein the antigen binding unit is selected from a monoclonal antibody, a Fab, a Fab’, an F(ab’), an Fv, a disulfide linked Fc, an scFv, a single domain antibody, a diabody, a bi-specific antibody, and a multi-specific antibody.

10. The conjugate of any one of the preceding claims, wherein the antigen binding unit is a monoclonal antibody.

11. The conjugate of any one of the preceding claims, wherein the antigen binding unit specifically binds a target selected from AG7, B7-H3, BCMA, CA15-3, CD19, CD20, CD22, CD30, CD33, CD38, CD52, CD70, CD71, CD79B, CEA, CLDN18.2, EGFR, FOLR1, GCC, GPC1, HER2, HER3, ICAM1, LeX, LeY, MET, MSLN, MUCl, NECTIN4, SLC44A4, TF, and Trop-2.

12. The conjugate of any one of the preceding claims, wherein the antigen binding unit is selected from cetuximab, bevacizumab, paitumumab, ofatumumab, inotuzumab, gemtuzumab, alemtuzumab, and trastuzumab.

13. The conjugate of any one of claims 1 to 11, wherein the antigen binding unit is an anti -EGFR antibody.

14. The conjugate of claim 13, wherein the anti-EGFR antibody is cetuximab.

15. The conjugate of any one of the preceding claims, wherein the linker comprises one or more components independently selected from alkyl, alkene, alkyne, aryl, cycloalkyl, heterocycle, glycoside, silyl ether, hydroxy, ether, ketone, ester, carbonate, amide, urea, carbamate, sulfide, disulfide, sulfate, sulfonamide, phosphate, hydrazone, and succinimide.

16. The conjugate of any one of the preceding claims, wherein the linker comprises one or more components independently selected from alkyl, polyethylene glycol, a hydrazone, maleimide, succinimide, asparagine, aspartic acid, cysteine, glutamic acid, lysine, glutamine, arginine, serine, ornithine, threonine, valine, alanine, glycine,leucine, isoleucine, methionine, tryptophan, proline, histidine, citrulline, phenylalanine, carboxylate, and p- aminobenzyloxy carbonyl.

17. The conjugate of any one of the preceding claims, wherein the linker comprises one or more components selected from Val-Cit, Glu-Val-Cit, Val-Ala, Val-Val, Val-Gly, Gly-Gly, Gly-Cit, Glu-Gly-Cit, Ala-Ala-Asn, Ala- Gly-Ala, Ala-Pro, Ala-Ser, and Phe-Lys.

18. The conjugate of any one of claims 7 to 17, wherein p is selected from 2 to 8.

19. The conjugate of any one of claims 7 to 18, wherein q is selected from 1 to 4.

20. The conjugate of any one of claims 7 to 19, wherein D is a small-molecule KRAS inhibitor.

21. The conjugate of any one of the preceding claims, wherein the KRAS inhibitor is a compound of Formula (I):or a pharmaceutically acceptable salt or solvate thereof, wherein:X is selected from N and C(R6);Z is selected from O, N, C(R5)2, C(O), S, S(O), and S(O)2;R2, R5, R6, and R8are each independently selected at each occurrence from hydrogen, halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered hetero alky nyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalky l)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), -OR12, -SR12, - N(R12)(R13), -C(O)OR12, -OC(O)N(R12)(R13), -N(R12)C(O)N(R12)(R13), -N(R12)C(O)OR12, -N(R12)S(O)2R12, - C(O)R12, -S(O)R12, -OC(O)R12, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R12)C(O)R12, -S(O)2R12, - S(O)(NR12)R12, -S(O)2N(R12)(R13), -S(O)(NR12)N(R12)(R13), and -OCH2C(O)OR12, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered hetero alkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle) are optionally substituted with one or more R20; optionally wherein two R5are taken together with the atom to which they are attached to form C3-8carbocycle or 3- to 8-membered heterocycle, each of which is optionally substituted with one or more R20; and further optionally wherein two R5are taken together to form =O, =NR12, or =C(R14)2;R3is independently selected at each occurrence from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), -OR12, -SR12, -N(R12)(R13), -C(O)OR12, - OC(O)N(R12)(R13), -N(R12)C(O)N(R12)(R13), -N(R12)C(O)OR12, -N(R12)S(O)2R12, -C(O)R12, -S(O)R12, -0C(O)R12, - C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -N(R12)C(O)R12, -S(O)2R12, -S(O)(NR12)R12, -S(O)2N(R12)(R13), - S(O)(NR12)N(R12)(R13), and -OCH2C(O)OR12, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-memberedheteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalky l)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle) are optionally substituted with one or more R20; optionally wherein two R3are taken together with the atom or atoms to which they are attached to form C3-8carbocycle or 3- to 8- membered heterocycle, each of which is optionally substituted with one or more R20; optionally wherein two R3are taken together to form =O, =NR12, or =C(R14)2; and further optionally wherein one R3and R4are taken together with the atoms to which they are attached to form 3- to 10-membered heterocycle optionally substituted with one or more R20;R4is selected from hydrogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalky l)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), -C(O)OR12, -C(O)R12, -C(O)N(R12)(R13), -C(O)C(O)N(R12)(R13), -S(O)2R12, - S(O)(NR12)R12, -S(O)2N(R12)(R13), and -S(=O)(=NR12)N(R12)(R13), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), and - (2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle) are optionally substituted with one or more R20;R7is selected from C6-12aryl and 5- to 12-membered heteroaryl, each of which is optionally substituted with one or more R20; m is 0, 1, 2, or 3; n is 1 or 2;R12is independently selected at each occurrence from hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle), wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle) are optionally substituted with one, two, or three R20;R13is independently selected at each occurrence from hydrogen, C1-6alkyl, and C1-6haloalky I: or R12and R13attached to the same nitrogen atom form 3- to 10-membered heterocycle optionally substituted with one, two, or three R20;R14is independently selected at each occurrence from hydrogen, halogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle), or two R14are taken together with the carbon atom to which they are attached to form C3-12carbocycle or 3- to 12-membered heterocycle, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6alkyl-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), C3-12carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one, two, or three R20;R20is independently selected at each occurrence from halogen, oxo, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), -OR22, -SR22, -N(R22)(R23), =NR22, =C(R21)2, -C(O)OR22, -OC(O)N(R22)(R23), -N(R22)C(O)N(R22)(R23), -N(R22)C(O)OR22, -N(R22)S(O)2R22, -C(O)R22, -S(O)R22, -OC(O)R22, -C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), -N(R22)C(O)R22, -OS(O)2R22, -S(O)2R22, - S(O)(NR22)R22, -S(O)2N(R22)(R23)-, -S(O)(NR22)N(R22)(R23), and -OCH2C(O)OR22; wherein two R20attached to the same or adjacent atoms optionally join to form C3-12carbocycle or 3- to 12-membered heterocycle; wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalky l)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), C3-12carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, -OR22, -SR22, -N(R22)(R23), =NR22, =C(R21)2, -C(O)OR22, -OC(O)N(R22)(R23), -N(R22)C(O)N(R22)(R23), -N(R22)C(O)OR22, -N(R22)S(O)2R22, -C(O)R22, -S(O)R22, -OC(O)R22, -C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), -N(R22)C(O)R22, -OS(O)2R22, -S(O)2R22, - S(O)(NR22)R22, -S(O)2N(R22)(R23), and -S(O)(NR22)N(R22)(R23);R21is independently selected at each occurrence from hydrogen, halogen, C1-6alkyl, C1-6haloalkyl, -C0-6alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle), or two R21are taken together with the carbon atom to which they are attached to form C3-12carbocycle or 3- to 12-membered heterocycle, each of which is optionally substituted with one, two, or three substituents independently selected from halogen, C1-3alkyl, C1-3haloalkyl, and -OH;R22is independently selected at each occurrence from hydrogen, C1-6alkyl, C1-6haloalkyl, -C0-6alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle); andR23is independently selected at each occurrence from hydrogen and C1-6alkyl; or R22and R23attached to the same nitrogen atom form 3- to 10 membered heterocycle; wherein one hydrogen of the compound of Formula (I) is replaced with a bond to the antigen binding unit or the chemical linker.

22. The conjugate of claim 21, wherein the KRAS inhibitor is a compound of Formula (I-a):or a pharmaceutically acceptable salt or solvate thereof, wherein:A is 6-membered heteroaryl comprising one, two, or three ring nitrogen atoms;R9and R10are independently selected from hydrogen, halogen, oxo, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), -OR22, -SR22, -N(R22)(R23), =NR22, =C(R21)2, -C(O)OR22, -OC(O)N(R22)(R23), -N(R22)C(O)N(R22)(R23), -N(R22)C(O)OR22, -N(R22)S(O)2R22, -C(O)R22, -S(O)R22, -OC(O)R22, -C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), -N(R22)C(O)R22, -OS(O)2R22, -S(O)2R22, - S(O)(NR22)R22, -S(O)2N(R22)(R23)-, -S(O)(NR22)N(R22)(R23), and -OCH2C(O)OR22; wherein R9and R10optionally join to form C3-12carbocycle or 3- to 12-membered heterocycle; wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered hetero alkenyl, 3- to 6-membered heteroalkynyl, -C0-6alkyl-(C3-12carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12carbocycle), -C0-6alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalky l)-(3- to 12-membered heterocycle), C3-12carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one or more substituents independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, -OR22, -SR22, -N(R22)(R23), =NR22, =C(R21)2, -C(O)OR22, -OC(O)N(R22)(R23), -N(R22)C(O)N(R22)(R23), -N(R22)C(O)OR22, -N(R22)S(O)2R22, -C(O)R22, -S(O)R22, -OC(O)R22, - C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), -N(R22)C(O)R22, -OS(O)2R22, -S(O)2R22, -S(O)(NR22)R22, - S(O)2N(R22)(R23), and -S(O)(NR22)N(R22)(R23); andR11is selected from hydrogen, C1-6alkyl, C1-6haloalkyl, -C0-6alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle).

23. The conjugate of claim 22, wherein A is selected from pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

24. The conjugate of claim 22 or 23, wherein A is pyridinyl.

25. The conjugate of any one of claims 22 to 24, wherein R11is hydrogen.

26. The conjugate of any one of claims 22 to 25, wherein R10is selected from hydrogen and halogen; or R9andR10, together with the atoms to which they are attached, form C4-8carbocycle or 4- to 8-membered heterocycle, each of which is optionally substituted.

27. The conjugate of any one of claims 22 to 26, wherein R10is hydrogen.

28. The conjugate of any one of claims 22 to 27, wherein29. The conjugate of any one of claims 22 to 28, wherein R9is optionally substituted C1-3alkyl.

30. The conjugate of any one of claims 22 to 29, wherein R9is CH3.

31. The conjugate of claim 21, wherein R4is selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C0-6alkyl-(C3-12carbocycle), and -C0-6alkyl-(3- to 12-membered heterocycle), each of which is optionally substituted with one or more R20.

32. The conjugate of claim 31, wherein R4is selected from C1-6alkyl and -C0-6alkyl-(3- to 12-membered heterocycle), each of which is optionally substituted with one or more substituents independently selected from halogen, -CH3, -NH2, -NHCH3, and -N(CH3)2.

33. The conjugate of any one of claims 21 to 32, wherein X is C(R6).

34. The conjugate of any one of claims 21 to 32, wherein X is N.

35. The conjugate of any one of claims 21 to 34, wherein Z is O.

36. The conjugate of any one of claims 21 to 35, wherein R7is selected from naphthyl, isoquinolinyl, indazolyl, benzothiazolyl, benzothiophenyl, phenyl, and pyridinyl, each of which is optionally substituted with one, two, three, or four R20.

37. The conjugate of any one of claims 21 to 36, wherein R7is benzothiophenyl optionally substituted with one, two, three, or four R20.

38. The conjugate of any one of claims 21 to 37, wherein R7is substituted with one, two, three, or four substituents independently selected from halogen, -CN, C1-3alkyl, C1-3haloalkyl, C2-3alkenyl, C2-3alkynyl, -OR22, - N(R22)(R23), and C3-6cycloalkyl.

39. The conjugate of any one of claims 21 to 38, wherein R7is substituted with one, two, three, or four substituents independently selected from halogen, -CN, -CH3, -CH2CH3, -CH=CH2, -CF3, -C=CH, -OH, -NH2, and - cyclopropyl.

40. The conjugate of any one of claims 21 to 39, wherein R7 is selected from41. The conjugate of any one of claims 21 to 40, wherein R7is42. The conjugate of claim 22, wherein:X is C(R6);A is selected from pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl;R2, R6, and R8are each independently selected at each occurrence from hydrogen, halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C3-8carbocycle, 3- to 8-membered heterocycle, -OR12, -N(R12)(R13), -C(O)OR12, - N(R12)C(O)N(R12)(R13), -C(O)R12, -OC(O)R12, -C(O)N(R12)(R13), and -N(R12)C(O)R12, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C3-8carbocycle, and 3- to 8-membered heterocycle are optionally substituted with one, two, or three R20;R3is independently selected at each occurrence from halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, - C3-8carbocycle, 3- to 8-membered heterocycle, -OR12, -N(R12)(R13), -C(O)OR12, -N(R12)C(O)N(R12)(R13), -C(O)R12, -OC(O)R12, -C(O)N(R12)(R13), and -N(R12)C(O)R12, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C3-8carbocycle, and 3- to 8-membered heterocycle are optionally substituted with one, two, or three R20; wherein two R3are optionally taken together with the atom or atoms to which they are attached to form C3-8carbocycle or 3- to 8- membered heterocycle, each of which is optionally substituted with one, two, or three R20; and further wherein two R3are optionally taken together to form =O, =NR12, or =C(R14)2;R7is benzo [b]thiophen-4-yl optionally substituted with one, two, three, or four R20;R9is C1-3alkyl optionally substituted with one, two, or three R20;R10is selected from hydrogen, halogen, -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8carbocycle, 3- to 8- membered heterocycle, -OR22, -N(R22)(R23), -C(O)OR22, -N(R22)C(O)N(R22)(R23), -C(O)R22, -OC(O)R22, - C(O)N(R22)(R23), and -N(R22)C(O)R22, wherein C1-6alkyl, C2-6alkenyl, C2-6alkynyl, -C3-8carbocycle, and 3- to 8-membered heterocycle are optionally substituted with one, two, or three substituents independently selected from halogen, oxo, -CN, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, -OR22, -SR22, -N(R22)(R23), =NR22, =C(R21)2, -C(O)OR22, -OC(O)N(R22)(R23), -N(R22)C(O)N(R22)(R23), -N(R22)C(O)OR22, -N(R22)S(O)2R22, -C(O)R22, -S(O)R22, -OC(O)R22, -C(O)N(R22)(R23), -C(O)C(O)N(R22)(R23), -N(R22)C(O)R22, -OS(O)2R22, -S(O)2R22, - S(O)(NR22)R22, -S(O)2N(R22)(R23), and -S(O)(NR22)N(R22)(R23);R11is hydrogen; m is 0 or 1 ; and n is 1 or 2.

43. The conjugate of claim 22, wherein the KRAS inhibitor is a compound of Formula (I-b):or a pharmaceutically acceptable salt or solvate thereof.

44. The conjugate of claim 43, wherein the KRAS inhibitor is a compound of Formula (I-c):or a pharmaceutically acceptable salt or solvate thereof.

45. The conjugate of any one of claims 21 to 44, wherein R2is selected from hydrogen, C1-3alkyl, -OR12, and 3- to 10-membered heterocycle, wherein C1-3alkyl and 3- to 10-membered heterocycle are optionally substituted with one, two, or three R20.

46. The conjugate of any one of claims 21 to 45, wherein R2is -OR12.

47. The conjugate of any one of claims 21 to 46, wherein R2is -O(C1-3alkyl)(4- to 10-membered heterocycle) optionally substituted with one, two, or three substituents independently selected from halogen, C1-3alkyl, C1-3haloalkyl, and =C(R21)2, wherein R21is independently selected at each occurrence from hydrogen, halogen, and C1-3alkyl.

48. The conjugate of any one of claims 21 to 47, wherein R2is selected from:

49. The conjugate of any one of claims 21 to 48, wherein R2is50. The conjugate of any one of claims 21 to 49, wherein R3is independently selected at each occurrence from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8carbocycle, and 3- to 8-membered heterocycle, each of which is optionally substituted with one, two, or three R20.

51. The conjugate of any one of claims 21 to 50, wherein R3is independently selected at each occurrence from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-8carbocycle, and 3- to 8-membered heterocycle, each of which is optionally substituted with one, two, or three substituents independently selected from halogen, -CN, -OH, and -OCH3.

52. The conjugate of any one of claims 21 to 51, wherein m is 0 or 1.

53. The conjugate of any one of claims 21 to 52, wherein m is 0.

54. The conjugate of any one of claims 21 to 53, wherein R6and R8are independently selected from hydrogen, halogen, and C1-3haloalkyl.

55. The conjugate of any one of claims 21 to 54, wherein R6is selected from chlorine and -CF3.

56. The conjugate of any one of claims 21 to 55, wherein R8is fluorine.

57. The conjugate of any one of claims 21 to 56, wherein n is 1.

58. A pharmaceutical composition comprising the conjugate of any one of claims 1 to 57, or a salt thereof, and a pharmaceutically acceptable excipient.

59. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a conjugate of any one of claims 1 to 57, or a salt thereof.

60. A method of treating cancer in a subject comprising a Ras mutant protein, the method comprising: inhibiting the Ras mutant protein of said subject by administering to said subject a conjugate of any one of claims 1 to 57, or a salt thereof.

61. The method of claim 59 or 60, wherein the cancer is a solid tumor or a hematological cancer.

62. The method of any one of claims 59 to 61, wherein the cancer comprises a K-Ras G12C, G12D, G12S, or G12V mutant protein.

63. A method of modulating signaling output of a Ras protein, comprising contacting a Ras protein with an effective amount of a conjugate of any one of claims 1 to 57, or a salt thereof, thereby modulating the signaling output of the Ras protein.

64. A method of inhibiting cell growth, comprising administering an effective amount of a conjugate of any one of claims 1 to 57, or a salt thereof, to a cell expressing a Ras protein, thereby inhibiting growth of said cells.

65. The method of any one of claims 59 to 64, comprising administering an additional agent.

66. A method of delivering a small-molecule KRAS inhibitor that exhibits low permeability as characterized by a PAMPA assay, comprising contacting a tumor cell with a conjugate of any one of claims 1 to 57, or a salt thereof, wherein the KRAS inhibitor exhibits a PAMPA permeability (Pe) value less than 1 x 10-6cm / s.

67. A method of enhancing therapeutic efficacy of a small -molecule KRAS inhibitor, comprising providing a conjugate of any one of claims 1 to 57 to a subject, wherein enhanced therapeutic efficacy is ascertained by the formula:wherein TIconjugate= TD50c / ED50c, wherein TD50cis the dose of conjugate required to produce a toxic effect in 50% of test subjects and ED50cis the dose of conjugate required to produce a therapeutic effect in 50% of test subjects; and wherein TIKRASI = TD50k / ED50k, wherein TD50kis the dose of KRAS inhibitor required to produce a toxic effect in 50% of test subjects and ED50kis the dose of KRAS inhibitor required to produce a therapeutic effect in 50% of the test subjects.

68. A method of reducing plasma concentration of a small-molecule KRAS inhibitor, comprising providing a conjugate of any one of claims 1 to 57 to a subject, wherein reduced plasma concentration is ascertained by the formula:[KRASi]p-c / [KRASi]p-k< 1 wherein [KRASi]p-cis plasma concentration of the KRAS inhibitor at a first time -point following administration of the conjugate; and wherein [KRASi]p-kis plasma concentration of the KRAS inhibitor following administration of the KRAS inhibitor alone at an equivalent dose at the same time-point.

69. A method of increasing concentration of a small-molecule KRAS inhibitor in tumor tissue, comprising providing a conjugate of any one of claims 1 to 57 to a subject, wherein increased tumor tissue concentration is ascertained by the formula:([KRASi]t-c / [KRASi]p-c) / ([KRASi]t-k / [KRASi]p-k) > 1 wherein [KRASi]t-cis concentration of the KRAS inhibitor in tumor tissue at a first time -point following administration of the conjugate; wherein [KRASi]p-cis plasma concentration of the KRAS inhibitor at the same time -point following the administration of the conjugate; wherein [KRASi]t.kis concentration of the KRAS inhibitor in tumor tissue following administration of the KRAS inhibitor alone at an equivalent dose at the same time-point; and wherein [KRASi]p-kis plasma concentration of the KRAS inhibitor at the same time-point following the administration of the KRAS inhibitor alone at the equivalent dose.

70. A method of delivering a small-molecule KRAS inhibitor to the central nervous system of a subject, comprising administering a conjugate of any one of claims 1 to 57 to the subject, wherein the KRAS inhibitor is released from the conjugate after entering the CNS of the subject.

71. A method of generating a slow-release form of a small-molecule KRAS inhibitor, the method comprising conjugating an antigen binding unit to a small-molecule KRAS inhibitor through a chemical linker, wherein the small-molecule inhibitor is released from the conjugate upon introducing the conjugate into a subject or a cell.

72. The method of any one of claims 59 to 71, wherein efficacy of the conjugate is greater than efficacy of a combination of the antigen binding unit and the KRAS inhibitor when each is administered at a comparable concentration.

73. The method of any one of claims 59 to 72, wherein toxicity of the conjugate is less than toxicity of a combination of the antigen binding unit and the KRAS inhibitor when each is administered at a comparable concentration.

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