FAP-activated camptothecin conjugates and uses thereof

Abstract

Provided herein are compounds, including compounds of Formula (I''), (I'), and (I), and a pharmaceutically acceptable salts thereof, which comprise a fibroblast activating protein (FAP)-cleavable moiety and are capable of delivering a camptothecin to FAP-expressing tissues (eg., cancers). Also provided herein are pharmaceutical compositions and kits comprising the same, as well as methods of using the same.

Description

[0001] FAP-ACTIVATED CAMPTOTHECIN CONJUGATES AND USES THEREOF

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] [1] This application claims the benefit under 35 U.S.C. § 119(e) of U.S. provisional application number 63 / 703,510, filed October 4, 2024, U.S. provisional application number 63 / 755,760, filed February 7, 2025, U.S. provisional application number 63 / 766,868, filed March 4, 2025, and U.S. provisional application number 63 / 794,219, filed April 24, 2025, each of which is incorporated by reference herein in its entirety.

[0004] BACKGROUND

[0005] [2] Prodrugs that can be specifically activated within the tumor microenvironment offer a powerful approach to cancer therapy by providing enhanced selectivity and reducing off-target effects. These prodrugs remain inert in the body until they encounter the unique physiological conditions of the tumor, such as acidic pH, high enzymatic activity, or specific reductive environments. This targeted activation ensures that the therapeutic agent is released directly at the tumor site, minimizing damage to healthy tissues and reducing systemic toxicity. Moreover, tumor-specific activation can improve drug efficacy, as the active form of the drug is concentrated where it is most needed, potentially allowing for higher doses to be used safely. This strategy enhances treatment precision and can overcome some of the challenges associated with traditional chemotherapy.

[0006] SUMMARY

[0007] [3] Provided herein are compounds comprising a fibroblast activating protein (FAP)-cleavable moiety that are capable of delivering a camptothecin to FAP-expressing tissues (e.g., cancers). Also provided herein are pharmaceutical compositions comprising the compounds provided herein, and kits comprising the same.

[0008] [4] In one aspect, provided herein are compounds of Formula (I"), (F), or (I): and pharmaceutically acceptable salts thereof, wherein R1, L1, X, R2A, R3A, n, R2, R3, R4, m, L2, and CAM are as described herein.

[0009] [5] In certain embodiments, for example, a compound described herein (e.g., a compound of Formula (I"), (F), or (I)) is selected from those recited in Tables Al, Al.l, A2, and A3 (infra), and pharmaceutically acceptable salts thereof.

[0010] [6] In another aspect, provided herein are pharmaceutical compositions comprising a compound described herein (e.g., a compound of Formula (I"), (F), or (I)) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In certain embodiments, a pharmaceutical composition provided herein comprises an effective amount (e.g., therapeutically effective amount) of a compound described herein (e.g, a compound of Formula (I"), (F), or (I)), or a pharmaceutically acceptable salt thereof.

[0011] [7] As described, compounds and pharmaceutical compositions provided herein can deliver a camptothecin to FAP -expressing tissues (e.g. , cancers) and are therefore useful for treating diseases characterized by fibroblast activation protein upregulation in a subject.

[0012] [8] In other aspects, provided herein are methods and uses of the compounds and pharmaceutical compositions provided herein, including, but not limited to, the following:

[0013] (a) Methods of treating a disease characterized by fibroblast activation protein upregulation (e.g., cancer, fibrosis, or inflammation) in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound described herein (e.g. , a compound of Formula (I"), (I'), or (I)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0014] (b) Methods of treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound described herein (e.g. , a compound of Formula (I"), (I'), or (I)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0015] (c) Methods of administering to a subject a compound described herein (e.g. , a compound of Formula (I"), (I'), or (I)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0016] [9] In another aspect, provided herein are compounds (e.g., of Formula (I"), (I'), or (I)), and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, for use in any of the methods provided herein.

[0017]

[0010] In another aspect, provided herein are uses of compounds (e.g., of Formula (I"), (I'), or (I)), and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, as medicaments and / or in the preparation of medicaments.

[0018]

[0011] The details of certain embodiments of the disclosure are set forth in the Detailed Description, as described below. Other embodiments of the disclosure will be apparent from the Drawings, Definitions, Examples, Abstract, and Claims.

[0019] BRIEF DESCRIPTION OF THE DRAWINGS

[0020]

[0012] Non-limiting embodiments of the present disclosure will be described by way of example with reference to the accompanying figures, which are schematic and are not intended to be drawn to scale. In the figures, each identical or nearly identical component illustrated is typically represented by a single numeral. For purposes of clarity, not every component is labeled in every figure, nor is every component of each embodiment of the disclosure shown where illustration is not necessary to allow those of ordinary skill in the art to understand the disclosure. In the figures:

[0013] FIG. 1 shows the concentration of parent Example compounds or released Exatecan in non-FAP expressing HEK293T cells (HEK-parental) and HEK293T cells which have been engineered to express high levels of FAP (HEK-FAP) following treatment with 40 nm of the parent Example compound.

[0021]

[0014] FIG. 2 shows the maximum tolerated dose of Example compounds as compared to that of conventional Exatecan in non-tumor bearing NMRI nu / nu mice treated either once daily (QD) or biweekly (BIW).

[0022]

[0015] FIGs. 3A-3E show the concentration of parent Example compound or released Exatecan in tumor or plasma following dosing with the parent Example compound in a high FAP expressing patient derived xenograft (PDX) model of Melanoma. FIG. 3 A shows tumor uptake data for Example 90 dosed at 15 mg / kg subcutaneously. FIG. 3B shows tumor uptake data for Example 117 dosed at 15 mg / kg subcutaneously. FIG. 3C shows tumor uptake data for Example 56 dosed at 10 mg / kg subcutaneously. FIG. 3D shows tumor uptake data for Example 122 dosed at 15 mg / kg subcutaneously. FIG. 3E shows tumor uptake data for Example 6 dosed at 15 mg / kg subcutaneously.

[0023]

[0016] FIGs. 4A-4C show change in tumor volume following inoculation with vehicle, Example compound, or Exatecan in a cell-line derived xenograft (CDX) model of HEK-FAP (HEK293T engineered to over-express FAP). FIG. 4A shows change in tumor volume in animals from the Example 56 and Exatecan cohorts removed from treatment at day 46 and monitored for tumor regrowth, until day 70 at which point the study was terminated. FIG. 4B shows change in tumor volume in animals from the Example 90, Example 116, Example 98, and Exatecan cohorts removed from treatment on days 31 (QW groups) or 34 (BIW groups) and monitored for tumor regrowth. FIG. 4C shows change in tumor volume in animals from the Example 117 and Exatecan cohorts.

[0024]

[0017] FIG. 5 shows change in tumor volume following inoculation with vehicle, Example compound, or Exatecan in a patient derived xenograft (PDX) model of Sarcoma.

[0025]

[0018] FIG. 6 shows change in tumor volume following inoculation with vehicle, Example compound, or Exatecan in a cell-line derived xenograft (CDX) model of LS174T cells engineered to express FAP.

[0026]

[0019] FIG. 7 shows the concentration of parent Example compound or released Exatecan in tumor or plasma following dosing with the parent Example compound in a high FAP expressing patient derived xenograft (PDX) model of Sarcoma. FIG. 7 shows tumor uptake data for Example 90 dosed at 10 mg / kg subcutaneously.

[0027]

[0020] FIGs. 8A-8B show Example compound killing of MDA-MB-231 tumor spheroids in the presence or absence of FAP-expressing primary human mammary fibroblasts as a monoculture (FIG. 8A) or coculture (FIG. 8B).

[0028]

[0021] FIG. 9 shows the concentration of parent Example compound or released Exatecan in tumor or plasma following dosing with the parent Example compound in a high FAP expressing patient derived xenograft model of LS174T colorectal cancer. FIG. 9 shows tumor uptake data for Example 90 dosed at 40 mg / kg subcutaneously.

[0029]

[0022] FIG. 10A shows the concentration of parent Example compound or released Exatecan in tumor or plasma following dosing with the parent Example compound in a high FAP expressing patient derived xenograft model of HEK293T. FIG. 10A shows tumor uptake data for Example 90 dosed at 40 mg / kg subcutaneously. FIG. 10B shows PK curves of tumor and plasma concentration of exatecan, Example 90, and exatecan released from Example 90 after a single s.c dose. Plotted values are the mean concentration from N=3 mice.

[0030]

[0023] FIG. 11 shows change in tumor volume following injection with vehicle, Example compound, or Exatecan in a patient-derived xenograft (PDX) model of gastric cancer.

[0031]

[0024] FIG. 12 shows change in tumor volume following injection with vehicle, Example compound, or Exatecan in a patient-derived xenograft (PDX) model of pancreatic carcinoma.

[0032]

[0025] FIGs. 13A-13B show Example 90 compound killing of LS174T tumor cells only when FAP expressing primary human fibroblasts and / or recombinant hFAP are present. FIG. 13A shows compound killing in a 2D LS174T mono-culture. FIG. 13B shows compound killing in a 2D LS174T / HcoF coculture.

[0033]

[0026] FIGs. 14A-14D show the effect of Example 90 in a 3D co-culture model with MDA-MB-231 triple negative breast cancer cells (FAP-negative, GFP-positive) and primary human mammary fibroblasts at various tumor: fibroblast ratios (0 to 75% fibroblasts). FIG. 14A shows Example compound killing of MDA-MB-231 tumor spheroids in co-culture with primary human mammary fibroblasts at various tumor to fibroblast (F) percentages. FIG. 14B shows FAP activity in MDA-MB-231 tumor spheroids in coculture with primary human mammary fibroblasts at various tumor to fibroblast (F) percentages. FIGs. 14C-14D show correlation of FAP activity and Example 90 tumor killing IC50 (FIG. 14C) or % killing at top concentration (FIG. 14D) in MDA-MB-231 tumor spheroid cocultures with primary human mammary fibroblasts at various FAP activities.

[0034]

[0027] FIG. 15 shows plasma concentration of Example 90, exatecan released from Example 90, or exatecan releasted from exatecan mesylate dihydrate.

[0035]

[0028] FIG. 16 shows Western blot analysis of PD biomarkers on LS174T-FAP CDX tumors treated with a single dose of Example 90 (s.c, 40mg / kg).

[0036]

[0029] FIG. 17 shows that FAP expression correlates with SLFN 11 expression across multiple tumor types. Scatter plots show the relationship between FAP and SLFN11 mRNA expression (log2(TPM+l)) in small cell lung cancer, pancreatic cancer, cervical cancer and gastric cancer. Each dot represents a tumor sample. Light grey (far left) indicates FAP negative patients, dark gray (bottom) indicates FAP positive, low SLFN11 expressing patients, and medium gray (top right) indicates FAP positive high SLFN11 patients. Linear regression analysis with correlation coefficients (R) and p-values are overlaid.

[0037]

[0030] FIG. 18 shows a tumor uptake model with Example 90 in a FAP -positive tumor model of pancreatic cancer.

[0038]

[0031] FIG. 19 shows change in tumor volume following injection with vehicle, Example compound, or Exatecan in a patient-derived xenograft (PDX) model of colorectal cancer. DETAILED DESCRIPTION

[0039]

[0032] FAP is a post-prolyl cleaving serine protease that can cleave on the C-terminal side of an internal proline residue. Provided herein are compounds comprising a FAP-cleavable moiety that are capable of delivering a camptothecin to FAP-expressing tissues (e.g., cancers). Also provided herein are pharmaceutical compositions comprising the compounds provided herein, and kits comprising the same.

[0040] General Definitions

[0041]

[0033] The following definitions are general terms used throughout the present disclosure.

[0042]

[0034] The term “camptothecin” includes a compound (or a radical thereof) belonging to the class of compounds considered to be camptothecins, camptothecin analogs, camptothecin derivatives or camptothecin conjugates. In some embodiments, the term “camptothecin” refers to a compound (or a radical thereof) derived from the camptothecin five-ring backbone: optionally with one or more modifications or substituents. Camptothecins may exist in the lactone or carboxylate forms, and the term “camptothecin” includes either or both alternatives. Examples of camptothecins include, but are not limited to, irinotecan (7-ethyl-10-[4-(l-piperidino)-l-piperidino]- carbonyloxycamptothecin), belotecan, Dxd (N-((lS,9S)-9-Ethyl-5-fluoro-9-hydroxy-4-methyl-10,13- dioxo-2,3,9,10,13,15-hexahydro-lH,12H-benzo[de]pyrano[3',4':6,7]indolizino[l,2-b]quinolin-l-yl)-2- hydroxyacetamide), SN-38 ((4 S)-4, 11 -Diethyl -4, 9-dihydroxy- 1 ,4-dihydro-3H, 14H- pyrano[3 ’,4’ :6,7]indolizino[l,2-b]quinoline-3, 14-dione), topotecan ((S)-9-N,N-dimethylaminoethyl-10- hydroxycamptothecin), 10-aminocamptothecin, 9-aminocamptothecin (9-amino-20(S)-camptothecin), 9- nitrocamptothecin (rubitecan), lurtotecan (7-(4-methylpiperazinomethylene)- 10,11 -ethylenedioxy-20(S)- camptothecin), exatecan, karenitecin, homocamptothecin, 10-hydroxycamptothecin, 9- hydroxycamptothecin, 9-hydroxy-10-dimethylaminomethyl camptothecin, 10,11- methylendioxy camptothecin, 9-chloro-10,l 1-methylenedioxy-camptothecin, 7 -ethyl- 10- hydroxycamptothecin, 7-ethylcamptothecin, silatecan, TAS 103, 9-amino-10,l l- methylenedioxycamptothecin, 7-(2-N-isopropylamino)ethyl)-(20S)-camptothecin, (7-(4- methylpiperadinomethylene)-10,ll-ethylenedioxy-20(S)-camptothecin, 7-(4- methylpiperadinomethylene)-10,ll-methylenedioxy-20-camptothecin, and stereoisomers thereof.

[0043]

[0035] The term “self-immolative linker” or “self-eliminating linker” includes a temporary extender, spacer, or placeholder unit attaching two or more molecules together by chemical bonds that are cleaved under defined conditions to release the two molecules. In general, a self-immolative or self-eliminating linker may be linear or branched, and may link two or more of the same molecules together, or may link two or more different molecules together. The self-immolative or self-eliminating linker may degrade, decompose, or fragment under, for example, physiological conditions, acidic conditions, basic conditions, or in the presence of specific chemical agents. Examples of self-eliminating linkers include, but are not limited to, p-aminobenzyloxycarbonyl (PABC) and 2,4-bis(hydroxymethyl)aniline. In certain embodiments, the self-immolative linker includes one or more moieties that are hydrolyzed under physiological conditions to reveal the desired molecule (e.g., a camptothecin). In other embodiments, the self-immolative linker is cleaved by an enzymatic activity of the host animal.

[0044]

[0036] As used herein, the term “salt” includes any and all salts and encompasses pharmaceutically acceptable salts. Salts include ionic compounds that result from the neutralization reaction of an acid and a base. A salt is composed of one or more cations (positively charged ions) and one or more anions (negative ions) so that the salt is electrically neutral (without a net charge). The term “pharmaceutically acceptable salt” includes those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethane sulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3 -phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N+(CI-4 alkyl )y salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0045]

[0037] Throughout the present disclosure, references to “the compound” and “a compound” provided herein are intended to encompass the compound or group of compounds, and also pharmaceutically acceptable salts, stereoisomers, tautomers, solvates (e.g, hydrates), and isotopically labeled derivatives thereof.

[0038] The term “amino acid” or “amino acid residue” encompasses all compounds, whether natural or synthetic, which include both an amino functionality and an acid functionality, including amino acid analogues and derivatives. In certain embodiments, the amino acids contemplated in the present invention are those naturally occurring amino acids found in proteins, or the naturally occurring anabolic or catabolic products of such amino acids, which contain amino and carboxyl groups. Naturally occurring amino acids are identified throughout by the conventional three- letter and / or one-letter abbreviations, corresponding to the trivial name of the amino acid, in accordance with the following list. The abbreviations are accepted in the peptide art and are recommended by the IUPAC-IUB commission in biochemical nomenclature. The term “amino acid residue” further includes analogues, derivatives, and congeners of any specific amino acid referred to herein, as well as C-terminal or N-terminal protected amino acid derivatives (e.g., modified with an N-terminal or C-terminal protecting group).

[0046]

[0039] The terms “composition” and “formulation” are used interchangeably.

[0047]

[0040] A “subject” to which administration is contemplated includes a human (z.e., male or female of any age group, e.g., pediatric subject (e.g., infant, child, or adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult)) or non-human animal. In certain embodiments, the non-human animal is a mammal (e.g., primate (e.g., cynomolgus monkey or rhesus monkey), commercially relevant mammal (e.g., cattle, pig, horse, sheep, goat, cat, or dog), or bird (e.g., commercially relevant bird, such as chicken, duck, goose, or turkey)). In some embodiments, the non-human animal is a fish, reptile, or amphibian. The non-human animal may be a male or female at any stage of development. The non- human animal may be a transgenic animal or genetically engineered animal. The term “patient” includes a human subject in need of treatment of a disease or condition.

[0041] The term “administer,” “administering,” or “administration” includes injecting, implanting, providing or otherwise introducing a compound described herein, or a composition thereof, in, to or on a subject.

[0048]

[0042] The terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of the disease have developed or have been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease. For example, treatment may be administered to a susceptible subject prior to the onset of symptoms (e.g. , in light of a history of symptoms and / or in light of exposure to a pathogen). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.

[0049]

[0043] The terms “condition,” “disease,” and “disorder” are used interchangeably.

[0050]

[0044] An “effective amount” of a compound described herein includes an amount sufficient to elicit the desired biological response. An effective amount of a compound described herein may vary depending on such factors as the desired biological endpoint, severity of side effects, disease, or disorder, the identity, pharmacokinetics, and pharmacodynamics of the particular compound, the condition being treated, the mode, route, and desired or required frequency of administration, the species, age and health or general condition of the subject. In certain embodiments, an effective amount is a therapeutically effective amount. In certain embodiments, an effective amount is the amount of a compound described herein in a single dose. In certain embodiments, an effective amount is the combined amounts of a compound described herein in multiple doses. In certain embodiments, an effective amount is an amount sufficient for delivering a camptothecin to a FAP-expressing tissue. In certain embodiments, an effective amount is an amount sufficient for delivering a camptothecin to the site of a cancer.

[0051]

[0045] A “therapeutically effective amount” of a compound described herein is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition, alone or in combination with other therapies. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms, signs, or causes of the condition, and / or enhances the therapeutic efficacy of another therapeutic agent. In certain embodiments, a therapeutically effective amount is an amount sufficient for treating a disease characterized by FAP upregulation. In certain embodiments, a therapeutically effective amount is an amount sufficient for treating cancer, fibrosis, or inflammation.

[0052]

[0046] The term “fibroblast activating protein” or “FAP” refers to fibroblast activation protein alpha (FAPa, or simply FAP; EC 3.4.21.-), also known as seprase or 170 kDa melanoma membrane -bound gelatinase. FAP is a homodimeric integral membrane protein belonging to the serine protease family and to the dipeptidyl peptidase (DPP-IV)-like subfamily.

[0053]

[0047] The term “target tissue” includes any biological tissue of a subject (including a group of cells, a body part, or an organ) or a part thereof, including blood and / or lymph vessels, which is the object to which a compound, particle, and / or composition of the present disclosure is delivered. A target tissue may be an abnormal or unhealthy tissue, which may need to be treated. A target tissue may also be a normal or healthy tissue that is under a higher than normal risk of becoming abnormal or unhealthy, which may need to be prevented. In certain embodiments, the target tissue is the liver. In certain embodiments, the target tissue is the lung. A “non-target tissue” is any biological tissue of a subject (including a group of cells, a body part, or an organ) or a part thereof, including blood and / or lymph vessels, which is not a target tissue. In certain embodiments, a target tissue is a tissue that expresses FAP.

[0054] Chemical Definitions

[0055]

[0048] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Michael B. Smith, March ’s Advanced Organic Chemistry, 7thEdition, John Wiley & Sons, Inc., New York, 2013; Richard C. Larock, Comprehensive Organic Transformations, John Wiley & Sons, Inc., New York, 2018; and Carruthers, Some Modern Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987.

[0056]

[0049] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer, or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al. , Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw- Hill, NY, 1962); and Wilen, S.H., Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ, of Notre Dame Press, Notre Dame, IN 1972). The present disclosure additionally encompasses compounds as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0057]

[0050] When a range of values (“range”) is listed, it encompasses each value and sub-range within the range. A range is inclusive of the values at the two ends of the range unless otherwise provided. For example, “C1-6 alkyl” encompasses, C1, C2, C3, C4, C5, C6, C1-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6 alkyl.

[0058]

[0051] Use of the phrase “at least one instance” refers to 1, 2, 3, 4, or more instances, but also encompasses a range, e.g., for example, from 1 to 4, from 1 to 3, from 1 to 2, from 2 to 4, from 2 to 3, or from 3 to 4 instances, inclusive.

[0059]

[0052] Affixing the suffix “-ene” to a group indicates the group is a divalent moiety, e.g., alkylene is the divalent moiety of alkyl, alkenylene is the divalent moiety of alkenyl, alkynylene is the divalent moiety of alkynyl, heteroalkylene is the divalent moiety of heteroalkyl, heteroalkenylene is the divalent moiety of heteroalkenyl, heteroalkynylene is the divalent moiety of heteroalkynyl, carbocyclylene is the divalent moiety of carbocyclyl, heterocyclylene is the divalent moiety of heterocyclyl, arylene is the divalent moiety of aryl, and heteroarylene is the divalent moiety of heteroaryl.

[0060]

[0053] The term “halo” or “halogen” refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).

[0061]

[0054] The term “alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C1.20 alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“C1.12 alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“CMO alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1.9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C1-8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1.7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1-6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C1.4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C1 alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-6 alkyl”). Examples of C1-6 alkyl groups include methyl (C1), ethyl (C2), propyl (C3) (e.g., / 7-propyl. isopropyl), butyl (C4) (e.g., w-butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C5) (e.g., / 7-pcntyl. 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tert- amyl), and hexyl (C6) (e.g.. n-hcxyl). Additional examples of alkyl groups include / 7-hcptyl (C7), w-octyl (C8), n-dodecyl (C12), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents (e.g., halogen, such as F). In certain embodiments, the alkyl group is an unsubstituted C1.12 alkyl (such as unsubstituted C1-6 alkyl, e.g., -CH3 (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n7-propyl (zr-Pr). unsubstituted isopropyl (z-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted / 7-biityl (n-Bu). unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec- Bu or s-Bu), unsubstituted isobutyl (z-Bu)). In certain embodiments, the alkyl group is a substituted C1.12 alkyl (such as substituted CM alkyl, e g., -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, or benzyl (Bn)).

[0062]

[0055] The term “haloalkyl” is a substituted alkyl group, wherein one or more of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo. “Perhaloalkyl” is a subset of haloalkyl and refers to an alkyl group wherein all of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo. In some embodiments, the haloalkyl moiety has 1 to 20 carbon atoms (“C1-20 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 10 carbon atoms (“C O haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 9 carbon atoms (“C1-9 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 8 carbon atoms (“C1-8 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 7 carbon atoms (“C1-7 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 6 carbon atoms (“C1-6 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 5 carbon atoms (“C1-5 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 4 carbon atoms (“C1-4 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 3 carbon atoms (“C1-3 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 2 carbon atoms (“C1-2 haloalkyl”). In some embodiments, all of the haloalkyl hydrogen atoms are independently replaced with fluoro to provide a “perfluoroalkyl” group. In some embodiments, all of the haloalkyl hydrogen atoms are independently replaced with chloro to provide a “perchloroalkyl” group. Examples of haloalkyl groups include -CHF2, -CH2F, -CF3, -CH2CF3, -CF2CF3, -CF2CF2CF3, -CC13, -CFC12, -CF2C1, and the like.

[0063]

[0056] The term “heteroalkyl” refers to an alkyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, sulfur, silicon, boron, and phosphorous within (e.g., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, the heteroalkyl group is an alkyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, and sulfur within (e.g., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 20 carbon atoms and 1 or more heteroatoms within the parent chain (“C1-20 heteroalkyl”). In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 12 carbon atoms and 1 or more heteroatoms within the parent chain (“C1-i2heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 11 carbon atoms and 1 or more heteroatoms within the parent chain (“C1-11 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 10 carbon atoms and 1 or more heteroatoms within the parent chain (“C1-10 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1 or more heteroatoms within the parent chain (“C1-9 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1 or more heteroatoms within the parent chain (“C1-8 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1 or more heteroatoms within the parent chain (“C1.7 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms within the parent chain (“C1-6 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms within the parent chain (“C1.5 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms within the parent chain (“C1.4 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain (“C1.3heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain (“C1-2 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“C1 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms within the parent chain (“C2.6 heteroalkyl”). Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an “unsubstituted heteroalkyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents.

[0064]

[0057] The term “alkenyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds). In some embodiments, an alkenyl group has 2 to 20 carbon atoms (“C2-20 alkenyl”). In some embodiments, an alkenyl group has 2 to 12 carbon atoms (“C2-12 alkenyl”). In some embodiments, an alkenyl group has 2 to 11 carbon atoms (“C2-11 alkenyl”). In some embodiments, an alkenyl group has 2 to 10 carbon atoms (“C2-10 alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms (“C2-9 alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2-8 alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C2-7 alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2-6 alkenyl”). In some embodiments, an alkenyl group has 2 to

[0065] 5 carbon atoms (“C2-5 alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C2-4 alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2-3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atom (“C2 alkenyl”). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C2-4 alkenyl groups include ethenyl (C2), 1 -propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents. In an alkenyl group, a C=C double bond for which the stereochemistry is not specified (e.g., -CH=CHCH3or ) may be in the ( / ■.)- or (Z)- configuration.

[0066]

[0058] The term “heteroalkenyl” refers to an alkenyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, sulfur, silicon, boron, and phosphorous within (e.g., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, the heteroalkenyl group is an alkenyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, and sulfur within (e.g., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 20 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“C2-20 heteroalkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 12 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“C2-12 heteroalkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 11 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“C2-11 heteroalkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“C2-10 heteroalkenyl”). In some embodiments, a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1 or more heteroatoms within the parent chain (“C2-9 heteroalkenyl”). In some embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“C2-8 heteroalkenyl”). In some embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“C2-7 heteroalkenyl”). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“C2-6 heteroalkenyl”). In some embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“C2-5 heteroalkenyl”). In some embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“C2-4 heteroalkenyl”). In some embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“C2-3 heteroalkenyl”). In some embodiments, a heteroalkenyl group has 2 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“C2 heteroalkenyl”). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“C2-6 heteroalkenyl”). Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an “unsubstituted heteroalkenyl”) or substituted (a “substituted heteroalkenyl”) with one or more substituents.

[0067]

[0059] The term “alkynyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (“C2-20 alkynyl”). In some embodiments, an alkynyl group has 2 to 10 carbon atoms (“C2-10 alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C2-9 alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C2-8 alkynyl”). In some embodiments, an alkynyl group has 2 to 7 carbon atoms (“C2-7 alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C2-6 alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C2-5 alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C2-4 alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C2-3 alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C2 alkynyl”). The one or more carbon-carbon triple bonds can be internal (such as in 2- butynyl) or terminal (such as in 1-butynyl). Examples of C2-4 alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkynyl groups as well as pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents.

[0068]

[0060] The term “heteroalkynyl” refers to an alkynyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, sulfur, silicon, boron, and phosphorous within (e.g., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, the heteroalkynyl group is an alkynyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, and sulfur within (e.g., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkynyl group refers to a group having from 2 to 20 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“C2-20 heteroalkynyl”). In certain embodiments, a heteroalkynyl group refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“C2-10 heteroalkynyl”). In some embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“C2-9 heteroalkynyl”). In some embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“C2-8 heteroalkynyl”). In some embodiments, a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“C2-7 heteroalkynyl”). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“C2-6 heteroalkynyl”). In some embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“C2-5 heteroalkynyl”). In some embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and lor 2 heteroatoms within the parent chain (“C2-4 heteroalkynyl”). In some embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“C2-3 heteroalkynyl”). In some embodiments, a heteroalkynyl group has 2 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“C2 heteroalkynyl”). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“C1-6 heteroalkynyl”). Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an “unsubstituted heteroalkynyl”) or substituted (a “substituted heteroalkynyl”) with one or more substituents.

[0069]

[0061] The term “carbocyclyl” or “carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms (“C3-14 carbocyclyl”) and zero heteroatoms in the non- aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 14 ring carbon atoms (“C3-14 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 13 ring carbon atoms (“C3-13 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 12 ring carbon atoms (“C3-12 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 11 ring carbon atoms (“C3-11 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (“C3-10 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C3-8 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C3-7 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms (“C4-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C5-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10 carbocyclyl”). Exemplary C3-6 carbocyclyl groups include cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C3-8 carbocyclyl groups include the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C3-10 carbocyclyl groups include the aforementioned C3-8 carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro- 1 H-indcny I (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like. Exemplary C3-8 carbocyclyl groups include the aforementioned C3-10 carbocyclyl groups as well as cycloundecyl (C11), spiro[5.5]undecanyl (C11), cyclododecyl (C12), cyclododecenyl (C12), cyclotridecane (C13), cyclotetradecane (C14), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and can be saturated or can contain one or more carbon-carbon double or triple bonds. “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents. In certain embodiments, the carbocyclyl includes 0, 1, or 2 C=C double bonds in the carbocyclic ring system, as valency permits.

[0070]

[0062] “Cycloalkyl” refers to a saturated carbocyclyl group. In some embodiments, a cycloalkyl group has from 3 to 14 ring carbon atoms (“C3-14 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms (“C3-10 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C3-8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 7 ring carbon atoms (“C3-7 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms (“C4-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C5-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C5-10 cycloalkyl”). Examples of C5-6 cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3-6 cycloalkyl groups include the aforementioned C5-6 cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-8 cycloalkyl groups include the aforementioned C3-6 cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents.

[0071]

[0063] The term “heterocyclyl” or “heterocyclic” refers to a radical of a 3- to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, silicon, boron, and phosphorous (“3-14 membered heterocyclyl”). In certain embodiments, the heterocyclyl group is a radical of a 3 - to 14-membered non- aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. The point of attachment can be either to a ring carbon atom or a ring heteroatom of the heterocyclyl group, as valency permits. For example, in heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g. , a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”)), and can be saturated or can contain one or more carbon-carbon double or triple bonds. Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents. In certain embodiments, the heterocyclyl is substituted or unsubstituted, 3- to 8-membered, monocyclic heterocyclyl, wherein 1, 2, or 3 atoms in the heterocyclic ring system are independently oxygen, nitrogen, or sulfur, as valency permits.

[0072]

[0064] In some embodiments, a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0073]

[0065] Exemplary 3 -membered heterocyclyl groups containing 1 heteroatom include azirdinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing 1 heteroatom include tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2, 5-dione. Exemplary 5-membered heterocyclyl groups containing 2 heteroatoms include dioxolanyl, oxathiolanyl and dithiolanyl. Exemplary 5 -membered heterocyclyl groups containing 3 heteroatoms include triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6- membered heterocyclyl groups containing 1 heteroatom include piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing 3 heteroatoms include triazinyl. Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include azocanyl, oxecanyl and thiocanyl. Exemplary bicyclic heterocyclyl groups include indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro- 1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, lH-benzo[e][l,4]diazepinyl, 1,4,5,7-tetrahydro- pyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7- dihydro-4H-thieno[2,3-c]pyranyl, 2,3-dihydro-lH-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3- b]pyridinyl, 4,5,6,7-tetrahydro-lH-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, l,2,3,4-tetrahydro-l,6-naphthyridinyl, and the like.

[0074]

[0066] The term “aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6-14 aryl”). In some embodiments, an aryl group has 6-10 ring carbon atoms (“C6-io aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“C6 aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms (“C1 aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms (“C14 aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl group is independently unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents.

[0075]

[0067] The term “heteroaryl” refers to a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 it electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, silicon, boron, and phosphorous (“5-14 membered heteroaryl”). In certain embodiments, the heteroaryl group is a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 7t electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. The point of attachment can be either to a ring carbon atom or a ring heteroatom of the heteroaryl group, as valency permits. For example, in heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl / heteroaryl) ring system. Polycyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, e.g. , either the ring bearing a heteroatom (e.g. , 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl). In certain embodiments, the heteroaryl is substituted or unsubstituted, 5- or 6-membered, monocyclic heteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur. In certain embodiments, the heteroaryl is substituted or unsubstituted, 9- or 10-membered, bicyclic heteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur.

[0076]

[0068] In some embodiments, a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents.

[0077]

[0069] Exemplary 5 -membered heteroaryl groups containing 1 heteroatom include pyrrolyl, furanyl, and thiophenyl. Exemplary 5 -membered heteroaryl groups containing 2 heteroatoms include imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5 -membered heteroaryl groups containing 3 heteroatoms include triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5 -membered heteroaryl groups containing 4 heteroatoms include tetrazolyl. Exemplary 6-membered heteroaryl groups containing 1 heteroatom include pyridinyl. Exemplary 6-membered heteroaryl groups containing 2 heteroatoms include pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing 3 or 4 heteroatoms include triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing 1 heteroatom include azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6- bicyclic heteroaryl groups include indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl.

[0078]

[0070] The term “acyl” refers to a non-cyclic group comprising a C=O, C=N, or C=S moiety. Exemplary acyl groups include aldehydes (-CHO), carboxylic acids (-CO2H), ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas.

[0079]

[0071] A group is optionally substituted unless expressly provided otherwise. The term “optionally substituted” refers to being substituted or unsubstituted. In general, the term “substituted” when referring to a chemical group means that at least one hydrogen present on the group is replaced with a permissible substituent, e.g, a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position. The invention is not limited in any manner by the exemplary substituents described herein.

[0080]

[0072] In certain embodiments, exemplary substituents include halogen, -CN, -NO2, -N3, -SO2H, -SO3H, - OH, -ORaa, -0N(Rbb)2, -N(Rbb)2, -N(Rbb)3+X , -N(0Rcc)Rbb, -SH, -SRaa, -SCN, -SSRCC, -C(=O)Raa, -CO2H, -CHO, -C(ORCC)2, -CO2Raa, -OC(=O)Raa, -OCO2Raa, -C(=O)N(Rbb)2, -OC(=O)N(Rbb)2, -NRbbC(=O)Raa, - NRbbCO2Raa, -NRbbC(=O)N(Rbb)2, -C(=NRbb)Raa, -C(=NRbb)ORaa, -OC(=NRbb)Raa, -OC(=NRbb)ORaa, - C(=NRbb)N(Rbb)2, -OC(=NRbb)N(Rbb)2, -NRbbC(=NRbb)N(Rbb)2, -C(=O)NRbbSO2Raa, -NRbbSO2Raa, - SO2N(Rbb)2, -SO2Raa, -SO2ORaa, -OSO2Raa, -S(=O)Raa, -OS(=O)Raa, -Si(Raa)3, -OSi(Raa)3-C(=S)N(Rbb)2, - C(=O)SRaa, -C(=S)SRaa, -SC(=S)SRaa, -SC(=O)SRaa, -OC(=O)SRaa, -SC(=O)ORaa, -SC(=O)Raa, - P(=O)(Raa)2, -P(=O)(ORCC)2, -OP(=O)(Raa)2, -OP(=O)(ORCC)2, -P(=O)(N(Rbb)2)2, -OP(=O)(N(Rbb)2)2, - NRbbP(=O)(Raa)2, -NRbbP(=O)(ORcc)2, -NRbbP(=O)(N(Rbb)2)2, -P(RCC)2, -P(ORCC)2, -P(RCC)3+X , - P(ORCC)3+X , -P(RCC)4, -P(ORCC)4, -OP(RCC)2, -OP(RCC)3+X , -OP(ORCC)2, -OP(ORCC)3X , -OP(RCC)4, - OP(ORCC)4, -B(Raa)2, -B(ORCC)2, -BRaa(ORcc), C1-20 alkyl, C1-20 haloalkyl, C2-20 alkenyl, C2-20 alkynyl, C1-20 heteroalkyl, C2-20 heteroalkenyl, C2-20 heteroalkynyl, C3.i4carbocyclyl, 3-14 membered heterocyclyl, C6-i4aryl, and 5-14 membered heteroaryl, wherein X- is a counterion; or two geminal hydrogens on a carbon atom are replaced with the group =0, =S, =NN(Rbb)2, =NNRbbC(=0)Raa, =NNRbbC(=0)0Raa, =NNRbbS(=O)2Raa, =NRbb, or =NORCC; each instance of Raais, independently, selected from C1-20 alkyl, C1-20 haloalkyl, C2-20 alkenyl, C2- 20 alkynyl, C1-20 heteroalkyl, C2-20 heteroalkenyl, C2-20 heteroalkynyl, C3.i4carbocyclyl, 3-14 membered heterocyclyl, C6-i4aryl, and 5-14 membered heteroaryl, or two Raagroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring; each instance of Rbbis, independently, selected from hydrogen, -OH, -ORaa, -N(RCC)2, -CN, - C(=O)Raa, -C(=0)N(RCC)2, -CO2Raa, -SO2Raa, -C(=NRcc)0Raa, -C(=NRCC)N(RCC)2, -SO2N(RCC)2, -SO2RCC, - SO2ORCC, -SORaa, -P(=O)(Raa)2, -P(=O)(ORCC)2, -P(=O)(N(RCC)2)2, C1 20 alkyl, C1 20 haloalkyl, C2-20 alkenyl, C2-20 alkynyl, C1-20 heteroalkyl, C2-20 heteroalkenyl, C2-20 heteroalkynyl, C3-14 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two Rbbgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring; and each instance of Rccis, independently, selected from hydrogen, C1-20 alkyl, C1-20 haloalkyl, C2-20 alkenyl, C2-20 alkynyl, C1-20 heteroalkyl, C2-20 heteroalkenyl, C2-20 heteroalkynyl, C3-14 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two Rccgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring.

[0081]

[0073] In certain embodiments, the molecular weight of a substituent (e.g., carbon atom substituent) is lower than 250, lower than 200, lower than 150, lower than 100, or lower than 50 g / mol. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, nitrogen, and / or silicon atoms. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, and / or nitrogen atoms. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, and / or iodine atoms. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, and / or chlorine atoms.

[0082]

[0074] In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, -ORaa, -SRaa, -SCN, -N(Rbb)2, -CN, - NO2, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, -OC(=O)Raa, -OCO2Raa, -OC(=O)N(Rbb)2, -NRbbC(=O)Raa, - NRbbCO22Raa, or -NRbbC(=O)N(Rbb)2. In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1O alkyl, -ORaa, -SRaa, -N(Rbb)2, -CN, -NO2, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, -OC(=O)Raa, -OCO2Raa, - OC(=O)N(Rbb)2, -NRbbC(=O)Raa, -NRbbCO2Raa, or -NRbbC(=O)N(Rbb)2, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, / -Bn. Bn, allyl, acetyl, pivaloyl, or benzoyl) when attached to an oxygen atom, or a sulfur protecting group (e.g., acetamidomethyl, / -Bn. 3- nitro-2 -pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl) when attached to a sulfur atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1.6 alkyl, or a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts).

[0083]

[0075] In certain embodiments, each nitrogen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, -C(=O)Raa, -CCER13, -C(=O)N(Rbb)2, or a nitrogen protecting group. In certain embodiments, each nitrogen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, -C(=O)Raa, -CO2R33, - C(=O)N(Rbb)2, or a nitrogen protecting group, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, or an oxygen protecting group when attached to an oxygen atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, or a nitrogen protecting group. In certain embodiments, each nitrogen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl or a nitrogen protecting group.

[0076] In certain embodiments, the substituent present on the nitrogen atom is a nitrogen protecting group. Nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference. Non-limiting examples of nitrogen protecting groups include benzyl (Bn), tert-butyloxycarbonyl (BOC), carbobenzyloxy (Cbz), 9-flurenylmethyloxycarbonyl (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl (Ac), benzoyl (Bz),p-methoxybenzyl (PMB), 3,4- dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), 2,2,2-trichloroethyloxycarbonyl (Troc), triphenylmethyl (Tr), tosyl (Ts), brosyl (Bs), nosyl (Ns), mesyl (Ms), triflyl (Tf), or dansyl (Ds). In certain embodiments, at least one nitrogen protecting group is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts.

[0084]

[0077] In certain embodiments, each oxygen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, -C(=O)Raa, -CC>2Raa, -C(=O)N(Rbb)2, or an oxygen protecting group. In certain embodiments, each oxygen atom substituents is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, -C(=O)Raa, -CC>2Raa, - C(=O)N(Rbb)2, or an oxygen protecting group, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, or an oxygen protecting group when attached to an oxygen atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, or a nitrogen protecting group. In certain embodiments, each oxygen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl or an oxygen protecting group.

[0085]

[0078] In certain embodiments, the substituent present on an oxygen atom is an oxygen protecting group. Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference. In certain embodiments, an oxygen protecting group is a silyl group. Non-limiting examples of oxygen protecting groups include / -butyldiphenylsilyl (TBDPS), t- butyldimethylsilyl (TBDMS), triisoproylsilyl (TIPS), triphenylsilyl (TPS), triethylsilyl (TES), trimethylsilyl (TMS), triisopropylsiloxymethyl (TOM), acetyl (Ac), benzoyl (Bz), allyl carbonate, 2,2,2- trichloroethyl carbonate (Troc), 2-trimethylsilylethyl carbonate, methoxymethyl (MOM), 1 -ethoxyethyl (EE), 2-methyoxy-2-propyl (MOP), 2,2,2-trichloroethoxyethyl, 2-methoxyethoxymethyl (MEM), 2- trimethylsilylethoxymethyl (SEM), methylthiomethyl (MTM), tetrahydropyranyl (THP), tetrahydrofuranyl (THF), p-methoxyphenyl (PMP), triphenylmethyl (Tr), methoxytrityl (MMT), dimethoxytrityl (DMT), allyl, p-methoxybenzyl (PMB), / -butyl, benzyl (Bn), allyl, or pivaloyl (Piv). In certain embodiments, at least one oxygen protecting group is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, / -Bn. Bn, allyl, acetyl, pivaloyl, or benzoyl.

[0086]

[0079] In certain embodiments, each sulfur atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, or a sulfur protecting group. In certain embodiments, each sulfur atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, -C(=O)Raa, -CO2Raa, -C(=O)N(Rbb)2, or a sulfur protecting group, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, or an oxygen protecting group when attached to an oxygen atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, or a nitrogen protecting group. In certain embodiments, each sulfur atom substituent is independently substituted (e.g. , substituted with one or more halogen) or unsubstituted C1-6 alkyl or a sulfur protecting group.

[0087]

[0080] In certain embodiments, the substituent present on a sulfur atom is a sulfur protecting group. Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference. In certain embodiments, a sulfur protecting group is acetamidomethyl, / -Bn. 3-nitro- 2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl.

[0088]

[0081] A “counterion” or “anionic counterion” is a negatively charged group associated with a positively charged group in order to maintain electronic neutrality. An anionic counterion may be monovalent (e.g., including one formal negative charge). An anionic counterion may also be multivalent (e.g., including more than one formal negative charge), such as divalent ortrivalent. Exemplary counterions include halide ions (e.g., F , Cl’, Br , I ), NOs’, CIO4 , OH-, H2PO4 , HCO3 , HSO4 , sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate, naphthalene- 1 -sulfonic acid-5 -sulfonate, ethan-1 -sulfonic acid-2- sulfonate, and the like), carboxylate ions (e.g., acetate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, and the like), BF4 , PF4 , PFe , AsFe’, SbFe’, B[3,5-(CF3)2C6H3]4]’, BfCeFs^ , BPl , A1(OC(CF3)3)4 , and carborane anions (e.g., CB11H12 or (HCBnMesBre) ). Exemplary counterions which may be multivalent include CO2. HPO42, PO4 B4O72’. SO42, S2O32, carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like), and carboranes.

[0089]

[0082] The term “amino acid sidechain” refers to that portion of an amino acid other than -CH(NH2)COOH, as defined by K. D. Kopple, "Peptides and Amino Acids", W. A. Benjamin Inc., New York and Amsterdam, 1966, as defined on pages 2 and 33. For the most part, the amino acids used in the application of this disclosure are those naturally occurring amino acids found in proteins, or the naturally occurring anabolic or catabolic products of such amino acids which contain amino and carboxyl groups. Amino acid sidechains include side chains selected from those of the following amino acids: glycine, alanine, valine, cysteine, leucine, iso leucine, serine, threonine, methionine, glutamic acid, aspartic acid, glutamine, asparagine, lysine, arginine, proline, histidine, phenylalanine, tyrosine, and tryptophan, and those amino acids and amino acid analogs which have been identified as constituents of peptidylglycan bacterial cell walls. Amino acid residues having “basic sidechains” include Arg, Lys and His. Amino acid residues having “acidic sidechains” include Glu and Asp. Amino acid residues having “neutral polar sidechains” include Ser, Thr, Asn, Gin, Cys and Tyr. Amino acid residues having “neutral non-polar sidechains” include Gly, Ala, Vai, He, Leu, Met, Pro, Trp and Phe. Amino acid residues having “non-polar aliphatic sidechains” include Gly, Ala, Vai, He and Leu. Amino acid residues having “hydrophobic sidechains” include Ala, Vai, He, Leu, Met, Phe, Tyr and Trp. Amino acid residues having “small hydrophobic sidechains” include Ala and

[0090] Vai. Amino acid residues having “aromatic sidechains” include Tyr, Trp and Phe.

[0091]

[0083] These and other exemplary substituents are described in more detail in the Detailed Description, Drawings, Examples, and Claims. The embodiments provided herein are not limited in any manner by the above exemplary listing of substituents.

[0092] Compounds

[0093]

[0084] As described herein, provided herein are compounds comprising a camptothecin conjugated to a FAP -cleavable moiety.

[0094]

[0085] In one aspect, provided herein are compounds of Formula (I"): and pharmaceutically acceptable salts thereof, wherein:

[0095] CAM is a camptothecin;

[0096] L1is a bond, C3-10 carbocyclylene, C6-io arylene, 3- to 10-membered heterocyclylene, or 5- to 10- membered heteroarylene, wherein the carbocyclylene, arylene, heterocyclylene, or heteroarylene is optionally substituted, including optionally substituted with one or more instances of R1A;

[0097] R1is hydrogen, R1A, C1-30 alkyl, C1-30 haloalkyl, C1-30 heteroalkyl, C2-30 alkenyl, C2-30 heteroalkenyl, C2-30 alkynyl, C2-30 heteroalkynyl, C3-10 carbocyclyl, 3- to 10-membered heterocyclyl, C6-io aryl, 5- to 10-membered heteroaryl, polyethylene glycol (PEG), polysarcosine (PSar), or any combination thereof, wherein each alkyl, haloalkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, PEG, or PSar is independently optionally substituted, including optionally with one or more instances of R1A; each instance of R1Ais independently C1-6 alkyl, C3-15 carbocyclyl, -OR0, -CO2R0, -N(RN)2, -C(=O)N(RN)2, PEG, or PSar;

[0098] R2and each instance of R2Aare independently hydrogen or optionally substituted C1-C6 alkyl; or optionally wherein R1and R2are joined together, or R1and R2Aare joined together, with the intervening atoms to form a 5- to 10-membered heterocyclic ring, wherein the heterocyclic ring is optionally substituted, including optionally with one or more instances of R1A;

[0099] R3is hydrogen or optionally substituted C1-6 alkyl; each instance of R3Ais hydrogen, optionally substituted C1-6 alkyl, or an amino acid sidechain; each instance of R4is independently halogen, C1-6 alkyl, C1-6 haloalkyl, -OR0, or -N(RN)2, wherein the alkyl or haloalkyl is optionally substituted; or two instances of R4are taken together to form =0; m is 0, 1, 2, 3, 4, 5, 6, or 7; n is 0, 1, or 2; X is a bond, -C(=O)-, -OC(=O)-, -N(RN)C(=O)-, -S(=O)2-, or -S(=O)-;

[0100] L2is a bond, or -N(H)-L2- is a bond or a self-immolative linker; each instance of R° is independently H, optionally substituted C1-6 alkyl, optionally substituted C1-6 haloalkyl, optionally substituted C3-7 carbocyclyl, or optionally substituted C1-6 acyl; and each instance of RNis independently H, optionally substituted C1-6 alkyl, optionally substituted C3-7 carbocyclyl, or optionally substituted C1-6 acyl, or two RNbonded to the same nitrogen are joined together to form optionally substituted 3-7 membered heterocyclyl.

[0101]

[0086] In one aspect, provided herein are compounds of Formula (F): and pharmaceutically acceptable salts thereof, wherein:

[0102] CAM is a camptothecin;

[0103] L1is a bond, C3-10 carbocyclylene, C6-io arylene, 3- to 10-membered heterocyclylene, or 5- to 10- membered heteroarylene, wherein the carbocyclylene, arylene, heterocyclylene, or heteroarylene is optionally substituted, including optionally substituted with one or more instances of R1A;

[0104] R1is hydrogen, R1A, C1-30 alkyl, C1-30 haloalkyl, C1-30 heteroalkyl, C2-30 alkenyl, C2-30 heteroalkenyl, C2-30 alkynyl, C2-30 heteroalkynyl, C3-10 carbocyclyl, 3- to 10-membered heterocyclyl, C6-io aryl, 5- to 10-membered heteroaryl, polyethylene glycol (PEG), polysarcosine (PSar), or any combination thereof, wherein each alkyl, haloalkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, PEG, or PSar is independently optionally substituted, including optionally with one or more instances of R1A; each instance of R1Ais independently C1-6 alkyl, C3-15 carbocyclyl, -OR0, -CO2R0, -N(RN)2, -C(=O)N(RN)2, PEG, or PSar;

[0105] R2and each instance of R2Aare independently hydrogen or optionally substituted C1-C6 alkyl; or optionally wherein R1and R2are joined together, or R1and R2Aare joined together, with the intervening atoms to form a 5- to 10-membered heterocyclic ring, wherein the heterocyclic ring is optionally substituted, including optionally with one or more instances of R1A;

[0106] R3is hydrogen or optionally substituted C1-6 alkyl; each instance of R3Ais hydrogen, optionally substituted C1-6 alkyl, or an amino acid sidechain; each instance of R4is independently halogen, C1-6 alkyl, C1-6 haloalkyl, -OR0, or -N(RN)2, wherein the alkyl or haloalkyl is optionally substituted; m is 0, 1, 2, 3, 4, 5, 6, or 7; n is 0, 1, or 2;

[0107] X is a bond, -C(=O)-, -OC(=O)-, -N(RN)C(=O)-, -S(=O)2-, or -S(=O)-;

[0108] L2is a bond, or -N(H)-L2- is a bond or a self-immolative linker; each instance of R° is independently H, optionally substituted C1-6 alkyl, optionally substituted C1-6 haloalkyl, optionally substituted C3-7 carbocyclyl, or optionally substituted C1-6 acyl; and each instance of RNis independently H, optionally substituted C1-6 alkyl, optionally substituted C3-7 carbocyclyl, or optionally substituted C1-6 acyl, or two RNbonded to the same nitrogen are joined together to form optionally substituted 3-7 membered heterocyclyl.

[0109]

[0087] In one aspect, provided herein are compounds of Formula (I): and pharmaceutically acceptable salts thereof, wherein:

[0110] CAM is a camptothecin;

[0111] L1is a bond, C3-10 carbocyclylene, C6-io arylene, 3- to 10-membered heterocyclylene, or 5- to 10- membered heteroarylene, wherein the carbocyclylene, arylene, heterocyclylene, or heteroarylene is optionally substituted, including optionally substituted with one or more instances of R1A;

[0112] R1is hydrogen, R1A, C1-30 alkyl, C1-30 haloalkyl, C1-30 heteroalkyl, C2-30 alkenyl, C2-30 heteroalkenyl, C2-30 alkynyl, C2-30 heteroalkynyl, C3-10 carbocyclyl, 3- to 10-membered heterocyclyl, C6-io aryl, 5- to 10-membered heteroaryl, polyethylene glycol (PEG), or any combination thereof, wherein each alkyl, haloalkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, or PEG is independently optionally substituted, including optionally with one or more instances of R1A; each instance of R1Ais independently C1-6 alkyl, C3-15 carbocyclyl, -OR0, -CO2R0, -N(RN)2, -C(=O)N(RN)2, or PEG;

[0113] R2and each instance of R2Aare independently hydrogen or optionally substituted C1-C6 alkyl; or optionally wherein R1and R2are joined together, or R1and R2Aare joined together, with the intervening atoms to form a 5- to 10-membered heterocyclic ring, wherein the heterocyclic ring is optionally substituted, including optionally with one or more instances of R1A;

[0114] R3is hydrogen or optionally substituted C1-6 alkyl; each instance of R3Ais hydrogen, optionally substituted C1-6 alkyl, or an amino acid sidechain; each instance of R4is independently halogen, C1-6 alkyl, C1-6 haloalkyl, -OR0, or -N(RN)2, wherein the alkyl or haloalkyl is optionally substituted; m is 0, 1, 2, 3, 4, 5, 6, or 7; n is 0, 1, or 2;

[0115] X is a bond, -C(=O)-, -OC(=O)-, -N(RN)C(=O)-, -S(=O)2-, or -S(=O)-;

[0116] L2is a bond, or -N(H)-L2- is a bond or a self-immolative linker; each instance of R° is independently H, optionally substituted C1-6 alkyl, optionally substituted C1-6 haloalkyl, optionally substituted C3-7 carbocyclyl, or optionally substituted C1-6 acyl; and each instance of RNis independently H, optionally substituted C1-6 alkyl, optionally substituted C3-7 carbocyclyl, or optionally substituted C1-6 acyl, or two RNbonded to the same nitrogen are joined together to form optionally substituted 3-7 membered heterocyclyl.

[0117]

[0088] In certain embodiments, the compound of Formula (I"), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I') or (I), or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula (I'), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0118]

[0089] In certain embodiments, the compound is of Formula (I-A) : or a pharmaceutically acceptable salt thereof.

[0119]

[0090] In certain embodiments, the compound is of Formula (I-B) : or a pharmaceutically acceptable salt thereof, wherein -N(H)-L2- is a bond or a self-immolative linker.

[0120]

[0091] In certain embodiments, the compound is of Formula (I-C) : or a pharmaceutically acceptable salt thereof, wherein -N(H)-L2- is a bond or a self-immolative linker.

[0092] In certain embodiments, the compound is of Formula (I-D): or a pharmaceutically acceptable salt thereof.

[0121]

[0093] In certain embodiments, the compound is of Formula (I-E): or a pharmaceutically acceptable salt thereof.

[0122]

[0094] In certain embodiments, the compound is of Formula (I-F): or a pharmaceutically acceptable salt thereof.

[0095] In certain embodiments, the compound is of Formula (I-G): or a pharmaceutically acceptable salt thereof.

[0123]

[0096] In certain embodiments, the compound is of Formula (I-H): or a pharmaceutically acceptable salt thereof, wherein -N(H)-L2- is a bond or a self-immolative linker.

[0124]

[0097] In certain embodiments, the compound is of Formula (I-I): or a pharmaceutically acceptable salt thereof, wherein -N(H)-L2- is a bond or a self-immolative linker.

[0098] In certain embodiments, the compound is of Formula (I-J): or a pharmaceutically acceptable salt thereof.

[0125]

[0099] In certain embodiments, the compound is of Formula (I-K): or a pharmaceutically acceptable salt thereof.

[0126] Camptothecin (CAM)

[0127]

[0100] As generally defined herein, CAM is a camptothecin. In certain embodiments, CAM is any camptothecin provided herein. In certain embodiments, CAM is exatecan, SN-38, Dxd, belotecan, or topotecan. In certain embodiments, CAM is exatecan, SN-38, Dxd, or belotecan. In certain embodiments,

[0128]

[0129] L2

[0130]

[0101] As generally defined herein, L2is a bond, or -N(H)-L2- is a bond or a self-immolative linker. In certain embodiments, L2is a bond, or -N(H)-L2- is a bond. In certain embodiments, L2is a bond, or - N(H)-L2- is a self-immolative linker. In certain embodiments, -N(H)-L2- is a bond or a self-immolative linker. In certain embodiments, L2is a bond. In certain embodiments, -N(H)-L2- is a bond. In certain embodiments, -N(H)-L2- is a self-immolative linker. In certain embodiments, the self-immolative linker is cleaved to release CAM.

[0131]

[0102] In certain embodiments, -N(H)-L2- is of the formula: , wherein:

[0132] * denotes the point of attachment to CAM; r is 0, 1, 2, or 3; each instance of Ring A is independently 5- or 6-membered heterocyclyl, 5- or 6-membered heteroaryl, or phenyl; each instance of Y is independently a bond, optionally substituted C1-8 alkylene, or optionally substituted C1-8 heteroalkylene; each instance of R5is independently halogen, C1-20 alkyl, C1-20 haloalkyl, C1-20 heteroalkyl, C1-20 alkenyl, C1-20 alkynyl, C3-10 carbocyclyl, -OR0, -CO2R°, -N(RN)2, -C(=O)N(RN)2, -CN, PEG, PSar, -L5- R5A, or -C(=O)-L5-R5A, or two instances of R5are are joined together with the intervening atoms to form an optionally substituted 5- to 6-membered heterocyclic ring fused to an aryl ring; wherein the alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, carbocyclyl, PEG, PSar, or heterocyclyl is optionally substituted, including optionally with one or more instances of R5A;

[0133] L5is a bond, C1-20 alkylene, C1-20 haloalkylene, C1-20 heteroalkylene, PEG, or PSar wherein the alkylene, haloalkylene, or heteroalkylene is optionally substituted; each instance of R5Ais independently C1-6 alkyl, -OR0, -CO2R°, -N(RN)2, -C(=O)N(RN)2, PEG, or PSar; and p is 0, 1, 2, 3, or 4 as permited by valency.

[0134]

[0103] In certain embodiments, -N(H)-L2- is of the formula: , wherein:

[0135] * denotes the point of atachment to CAM; r is 0, 1, 2, or 3; each instance of Ring A is independently 5- or 6-membered heterocyclyl, 5- or 6-membered heteroaryl, or phenyl; each instance of Y is independently a bond, optionally substituted C1-8 alkylene, or optionally substituted C1-8 heteroalkylene; each instance of R5is independently halogen, C1-20 alkyl, C1-20 haloalkyl, C1-20 heteroalkyl, C1-20 alkenyl, C1-20 alkynyl, -OR0, -CO2R°, -N(RN)2, -C(=O)N(RN)2, PEG, PSar, -L5-R5A, or -C(=O)-L5-R5A, wherein the alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, PEG, or PSar is optionally substituted, including optionally with one or more instances of R5A;

[0136] L5is a bond, C1-20 alkylene, C1-20 haloalkylene, C1-20 heteroalkylene, PEG, or PSar wherein the alkylene, haloalkylene, or heteroalkylene is optionally substituted; each instance of R5Ais independently C1-6 alkyl, -OR0, -CO2R°, -N(RN)2, -C(=O)N(RN)2, PEG, or PSar; and p is 0, 1, 2, 3, or 4 as permited by valency.

[0104] In certain embodiments, -N(H)-L2- is of the formula: wherein:

[0137] * denotes the point of attachment to CAM; r is 0, 1, 2, or 3; each instance of Ring A is independently 5- or 6-membered heterocyclyl, 5- or 6-membered heteroaryl, or phenyl; each instance of Y is independently a bond, optionally substituted Cus alkylene, or optionally substituted C1-8 heteroalkylene; each instance of R5is independently halogen, C1-20 alkyl, C1-20 haloalkyl, C1-20 heteroalkyl, C1-20 alkenyl, C1-20 alkynyl, -OR0, -CO2R°, -N(RN)2, -C(=O)N(RN)2, PEG, -L5-R5A, or -C(=O)-L5-R5A, wherein the alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, or PEG is optionally substituted, including optionally with one or more instances of R5A;

[0138] L5is a bond, C1-20 alkylene, C1-20 haloalkylene, C1-20 heteroalkylene, or PEG, wherein the alkylene, haloalkylene, or heteroalkylene is optionally substituted; each instance of R5Ais independently C1-6 alkyl, -OR0, -CO2R°, -N(RN)2, -C(=O)N(RN)2, or PEG; and p is 0, 1, 2, 3, or 4 as permitted by valency.

[0139]

[0105] As generally defined herein, each instance of Ring A is independently 5- or 6-membered heterocyclyl, 5- or 6-membered heteroaryl, or phenyl. In certain embodiments, each instance of Ring A is independently 5- or 6-membered heterocyclyl or 5- or 6-membered heteroaryl. In certain embodiments, each instance of Ring A is independently 5- or 6-membered heteroaryl or phenyl. In certain embodiments, at least one instance of Ring A is phenyl. In certain embodiments, at least one instance of Ring A is 5- or 6-membered heteroaryl. In certain embodiments, at least one instance of Ring A is 5- or 6- membered N-heteroaryl. In certain embodiments, at least one instance of Ring A is pyridyl, pyrrolyl, or thiazolyl. In certain embodiments, at least one instance of Ring A is 5- to 6-membered heterocyclyl. In certain embodiments, at least one instance of Ring A is 5- to 6-membered N-heterocyclyl. In certain embodiments, at least one instance of Ring A is pyrrolidinyl.

[0140]

[0106] As generally defined herein, r is 0, 1, 2, or 3. In certain embodiments, r is 1 or 2. In certain embodiments, r is 1. In certain embodiments, r is 2.

[0141]

[0107] As generally defined herein, each instance of Y is independently a bond, optionally substituted Cus alkylene, or optionally substituted C1-8 heteroalkylene. In certain embodiments, each instance ofY is optionally substituted C1-8 alkylene or optionally substituted C1-8 heteroalkylene. In certain embodiments, each instance ofY is optionally substituted C1.4 alkylene or optionally substituted C1-4 heteroalkylene. In certain embodiments, each instance ofY is C1.4 alkylene or C1.4 heteroalkylene, wherein the alkylene or heteroalkylene is optionally substituted with acyl. In certain embodiments, Y comprises one or more instances of -N(Me)-, -N(H)-, -C(=0)-, -C02-, -0-, -S(=0)2-, -P(=O)(OH)O-, -P(=O)(OMe)O-, -P(=O)(OEt)O-, -C(Me)H-, or -CH2-. In certain embodiments, Y comprises one or more instances of -N(Me)-, -N(H)-, -CO2-, -O-, -S(=O)2-, -P(=O)(OH)O-, -P(=O)(OMe)O-, -P(=O)(OEt)O-, -C(Me)H-, or -CH2-. In certain embodiments, Y comprises one or more instances of -N(H)-, -C(=O)-, -CO2-, -P(=O)(OEt)O-, -C(Me)H-, or -CH2-. In certain embodiments, Y comprises one or more instances of -N(H)-, -CO2-, -P(=O)(OEt)O-, -C(Me)H-, or -CH2-. In certain embodiments, at least one instance of Y is a bond. In certain embodiments, at least one instance of Y is -CH2-. In certain embodiments, at least one instance ofY is -CO2CH2-. In certain embodiments, at least one instance ofY is -C(=O)OCH2-. In certain embodiments, at least one instance ofY is -C(=O)-. In certain embodiments, at least one instance ofY is -N(RN)CC>2CH2-. In certain embodiments, at least one instance ofY is -N(H)CC>2CH2-. In certain embodiments, at least one instance ofY is -N(H)C(=O)OCH2-. In certain embodiments, at least one instance ofY is -CH2N(RN)CO2CH2-. In certain embodiments, at least one instance ofY is -CH2N(Me)CO2CH2-. In certain embodiments, at least one instance ofY is -CH2N(Me)C(=O)OCH2-. In certain embodiments, at least one instance ofY is -P(=O)(OEt)O-C(Me)H-. In certain embodiments, at least one instance ofY is -P(=O)(OEt)O-CH2-. In certain embodiments, at least one instance ofY is

[0142] -CO2-CH(C(=O)N(RN)2)-. In certain embodiments, Y is

[0143]

[0108] In certain embodiments, -N(H)-L2- is of the formula: , wherein * denotes the point of attachment to CAM. In certain embodiments, -N(H)-L2- is of the formula: , wherein * denotes the point of attachment to CAM.

[0144]

[0109] In certain embodiments, -N(H)-L2- is of the formula:

[0145] , or , wherein * denotes the point of attachment to CAM. In certain embodiments, -N(H)-L2- is of the formula: or wherein * denotes the point of attachment to CAM. In certain embodiments, -N(H)-L2- is of the formula: or wherein * denotes the point of attachment to CAM. In certain embodiments,

[0146] -N(H)-L2- is of the formula: , wherein * denotes the point of attachment to

[0147] CAM. In certain embodiments, -N(H)-L2- is of the formula: , wherein * denotes the point of attachment to CAM.

[0148] [HO] In certain embodiments, -N(H)-L2- is of the formula:

[0149] , wherein * denotes the point of attachment to CAM.

[0150] [Hl] In certain embodiments, -N(H)-L2- is of the formula: , wherein * denotes the point of attachment to CAM. In certain embodiments, -N(H)-L2- is of the formula : wherein * denotes the point of attachment to CAM.

[0112] In certain embodiments, -N(H)-L2- is of the formula: wherein * denotes the point of attachment to CAM. In certain embodiments, -N(H)-L2- is of the formula: wherein * denotes the point of attachment to CAM. In certain embodiments, -N(H)-L2- is of the formula: , wherein * denotes the point of attachment to CAM.

[0151]

[0113] In certain embodiments, -N(H)-L2- is of the formula: the point of attachment to CAM and each of R6aand R6bis independently hydrogen or optionally substituted C1-6 alkyl. In certain embodiments, -N(H)-L2- is of the formula: wherein * denotes the point of attachment to CAM and each of R6aand R6bis independently hydrogen or optionally substituted C1-6 alkyl, and wherein at least one instance of R5is PEG or PSar. In certain embodiments, -N(H)-L2- is of the formula: , wherein * denotes the point of attachment to CAM and each of R6aand R6bis independently hydrogen or optionally substituted C1-6 alkyl. In certain embodiments, -N(H)-L2- is of the formula: denotes the point of attachment to CAM, one of R6aand R6bis hydrogen, and the other of R6aand R6bis hydrogen or optionally substituted C1-6 alkyl. In certain embodiments, -N(H)-L2- is of the formula: , wherein * denotes the point of attachment to CAM, one of R6aand R6bis hydrogen, and the other of R6aand R6bis optionally substituted C1-6 alkyl. In certain embodiments, -

[0152] N(H)-L2- is of the formula: , wherein * denotes the point of attachment to

[0153] CAM. In certain embodiments, -N(H)-L2- is of the formula: denotes the point of attachment to CAM.

[0154]

[0114] In certain embodiments, -N(H)-L2- is of the formula: wherein * denotes the point of attachment to CAM. In certain embodiments, -N(H)-L2- is of the formula: , wherein * denotes the point of attachment to CAM, and wherein at least one instance of R5is PEG or PSar. In certain embodiments, -N(H)-L2- is of the formula: , wherein * denotes the point of attachment to CAM. In certain embodiments, -N(H)-L2- is of the formula: wherein * denotes the point of attachment to CAM. In certain embodiments, -N(H)-L2- is of the formula: , wherein * denotes the point of attachment to CAM. In certain embodiments,

[0155] -N(H)-L2- is of the formula: wherein * denotes the point of attachment to

[0156] CAM. In certain embodiments, -N(H)-L2- is of the formula: denotes the point of attachment to CAM. In certain embodiments, -N(H)-L2- is of the formula: , wherein * denotes the point of attachment to CAM. In certain embodiments,

[0157] -N(H)-L2- is of the formula: , wherein * denotes the point of attachment to

[0158] CAM. In certain embodiments, -N(H)-L2- is of the formula: denotes the point of attachment to CAM. In certain embodiments, -N(H)-L2- is of the formula: denotes the point of attachment to CAM. In certain embodiments, -N(H)-L2- is of the formula: CAM. In certain embodiments, -N(H)-L2- is of the formula: , wherein * denotes the point of attachment to CAM. In certain embodiments, -N(H)-L2- is of the formula: denotes the point of attachment to CAM. In certain embodiments, -N(H)-L2- is of the formula: , wherein * denotes the point of attachment to CAM. In certain embodiments, -N(H)-L2- is of the formula: , wherein * denotes the point of attachment to CAM. In certain embodiments, -N(H)-L2- is of the formula: , wherein * denotes the point of attachment to

[0159] CAM. In certain embodiments, -N(H)-L2- is of the formula: , wherein * denotes the point of atachment to CAM. In certain embodiments, -N(H)-L2- is of the formula: , wherein * denotes the point of atachment to CAM. In certain embodiments, -N(H)-L2- is of the formula: , wherein * denotes the point of atachment to CAM. In certain embodiments, -N(H)-L2- is of the formula: , wherein * denotes the point of atachment to CAM. In certain embodiments, -N(H)-L2- is of the formula: , wherein * denotes the point of atachment to

[0160] CAM. In certain embodiments, -N(H)-L2- is of the formula: of atachment to CAM. In certain embodiments, -N(H)-L2- is of the formula: denotes the point of atachment to CAM. In certain embodiments, -N(H)-L2- is of the formula: , wherein * denotes the point of attachment to CAM. In certain embodiments, -N(H)-L2- is

[0161]

[0115] In certain embodiments, -N(H)-L2- is of the formula: , wherein * denotes the point of attachment to CAM, and

[0162] RNis independently H, optionally substituted C1-6 alkyl, optionally substituted C3-7 carbocyclyl, or optionally substituted C1-6 acyl. In certain embodiments, -N(H)-L2- is of the formula: , wherein * denotes the point of attachment to CAM.

[0116] In certain embodiments, -N(H)-L2- is of the formula: wherein * denotes the point of attachment to CAM, and RNis independently H, optionally substituted C1-

[0163] 6 alkyl, optionally substituted C3-7 carbocyclyl, or optionally substituted C1-6 acyl. In certain embodiments, -N(H)-L2- is of the formula: point of attachment to CAM.

[0164]

[0117] In certain embodiments, -N(H)-L2- is of the formula: wherein * denotes the point of attachment to CAM, and RNis independently H, optionally substituted C1- e alkyl, optionally substituted C3-7 carbocyclyl, or optionally substituted C1-6 acyl. In certain embodiments, -N(H)-L2- is of the formula: the point of attachment to CAM.

[0165]

[0118] As generally defined herein, p is 0, 1, 2, 3, or 4. In certain embodiments, p is 0, 1, 2, or 3. In certain embodiments, p is 0, 1, or 2. In certain embodiments, p is 0. In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, p is 3. In certain embodiments, p is 4.

[0166]

[0119] As generally defined herein, each instance of R5is independently halogen, C1-20 alkyl, C1-20 haloalkyl, C1-20 heteroalkyl, C1-20 alkenyl, C1-20 alkynyl, C3-10 carbocyclyl, -OR0, -CO2R0, -N(RN)2, -C(=O)N(RN)2, -CN, PEG, PSar, -L5-R5A, or -C(=O)-L5-R5A, or two instances of R5are joined together with the intervening atoms to form an optionally substituted 5- to 6-membered heterocyclic ring fused to an aryl ring; wherein the alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, carbocyclyl, PEG, PSar, or heterocyclyl is optionally substituted, including optionally with one or more instances of R5A. In certain embodiments, each instance of R5is independently halogen, C1-20 alkyl, C1-20 haloalkyl, C1-20 heteroalkyl, C1-20 alkenyl, C1-20 alkynyl, -OR0, -CO2R°, -N(RN)2, -C(=O)N(RN)2, PEG, PSar, -L5-R5A, or -C(=O)-L5- R5A, wherein the alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, PEG, or PSar is optionally substituted, including optionally with one or more instances of R5A. In certain embodiments, each instance of R5is independently halogen, C1-20 alkyl, C1-20 haloalkyl, C1-20 heteroalkyl, C1-20 alkenyl, C1-20 alkynyl, -OR0, -CO2R°, -N(RN)2, -C(=O)N(RN)2, PEG, -L5-R5A, or -C(=O)-L5-R5A, wherein the alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, or PEG is optionally substituted, including optionally with one or more instances of R5A.

[0167]

[0120] In certain embodiments, at least one instance of R5is halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 heteroalkyl, C1-6 alkenyl, C1-6 alkynyl, C3-7 carbocyclyl, -OR0, -CO2R0, -N(RN)2, -C(=O)N(RN)2, or -CN. In certain embodiments, at least one instance of R5is halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 heteroalkyl, C1-6 alkenyl, C1-6 alkynyl, -OR0, -CO2R0, -N(RN)2, or -C(=O)N(RN)2. In certain embodiments, at least one instance of R5is halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 heteroalkyl, C3-7 carbocyclyl, -OR0, -CO2R0, -N(RN)2, -C(=O)N(RN)2, or -CN. In certain embodiments, at least one instance of R5is halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 heteroalkyl, -OR0, -CO2R0, -N(RN)2, or -C(=O)N(RN)2. In certain embodiments, at least one instance of R5is -Br, -Cl, -F, unsubstituted C1.4 alkyl, -CF3, -CH2OH, -CFEOMc. -CFEOEt. -OH, -OMe, -OEt, -CO2H, -CO2Me, -CO2Et, -CH2NH2, -CH2NHMe, -CH2NMe2, -NH2, -NHMe, -NMe2, em o men s, a eas one ns ance o s - , - , - 3, - 3, - e,

[0168] 0 . In certain embodiments, at least one instance of R5is -Me, -F, -CH3,

[0169]

[0121] In certain embodiments, at least one instance of R5is C1-20 alkyl, C1-20 haloalkyl, C1-20 heteroalkyl, C1-20 alkenyl, C1-20 alkynyl, PEG, -L5-R5A, or -C(=O)-L5-R5A. In certain embodiments, at least one instance of R5is C1-20 alkyl, C1-20 haloalkyl, C1-20 heteroalkyl, PEG, -L5-R5A, or -C(=O)-L5-R5A. In certain embodiments, at least one instance of R5is PEG, -L5-R5A, or -C(=O)-L5-R5A. In certain embodiments, at least one instance of R5is PEG. In certain embodiments, at least one instance of R5is of the formula: , wherein ql is an integer from 1-25, inclusive, and R° is H, optionally substituted C1- e alkyl, optionally substituted C1-6 haloalkyl, optionally substituted C3-7 carbocyclyl, or optionally substituted C1.6 acyl. In certain embodiments, at least one instance of R5is of the formula: , wherein ql is an integer from 1-25, inclusive, and each instance of RNis independently H, optionally substituted C1-6 alkyl, optionally substituted C3-7 carbocyclyl, or optionally substituted C1.6 acyl, or two RNbonded to the same nitrogen are joined together to form optionally substituted 3-7 membered heterocyclyl.

[0170]

[0122] In certain embodiments, R5is -L5-R5Aor -C(=O)-L5-R5A. In certain embodiments, R5is -L5-R5A. In certain embodiments, R5is -C(=O)-L5-R5A.

[0171]

[0123] In certain embodiments, two instances of R5are joined together with the intervening atoms to form an optionally substituted 5- to 6-membered heterocyclic ring fused to an aryl ring. In certain embodiments, two instances of R5are joined together with the intervening atoms to form an optionally substituted 5 -membered heterocyclic ring fused to an aryl ring. In certain embodiments, two instances of R5are joined together with the intervening atoms to form an optionally substituted 6-membered heterocyclic ring fused to an aryl ring. In certain embodiments, two instances of R5are joined together with the intervening atoms to form a 2,3-dihydrobenzo[b][l,4]dioxine ring system.

[0172]

[0124] As generally defined herein, L5is a bond, C1-20 alkylene, C1-20 haloalkylene, C1-20 heteroalkylene, PEG, or PSar, wherein the alkylene, haloalkylene, or heteroalkylene is optionally substituted. In certain embodiments, L5is a bond, C1-20 alkylene, C1-20 haloalkylene, C1-20 heteroalkylene, or PEG, wherein the alkylene, haloalkylene, or heteroalkylene is optionally substituted. In some embodiments, L5is a bond. In some embodiments, L5is CMO alkylene, C O haloalkylene, CMO heteroalkylene, or PEG. In some embodiments, L5is of the formula: , wherein ql is an integer from 1-

[0173] 25, inclusive. In some embodiments, L5is C1-6 heteroalkylene. In some embodiments, L5or -C(=O)-L5- is

[0174]

[0125] As generally defined herein, each instance of R5Ais independently C1-6 alkyl, -OR0, -CO2R0, - N(RN)2, -C(=O)N(RN)2, PEG, or PSar. In certain embodiments, each instance of R5Ais independently C1-6 alkyl, -OR0, -CO2R0, -N(RN)2, -C(=O)N(RN)2, or PEG. In certain embodiments, at least one instance of R5Ais C1-6 alkyl, -OR0, -CO2R0, -N(RN)2, or -C(=O)N(RN)2. In certain embodiments, at least one instance of R5Ais Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, -OH, -OMe -OEt, -CO2H, -CO2Me, -CO2Et, -NH2, -NHMe, -NMe2, -C(=O)NH2, -C(=O)NHMe, or -C(=O)NMe2. In certain embodiments, at least one instance of R5Ais PEG. In certain embodiments, at least one instance of R5Ais of the formula: , wherein ql is an integer from 1-25, inclusive, and R° is H, optionally substituted C1- e alkyl, optionally substituted C1-6 haloalkyl, optionally substituted C3-7 carbocyclyl, or optionally substituted C1.6 acyl. In certain embodiments, at least one instance of R5Ais of the formula: , wherein ql is an integer from 1-25, inclusive, and each instance of RNis independently H, optionally substituted C1-6 alkyl, optionally substituted C3-7 carbocyclyl, or optionally substituted C1.6 acyl, or two RNbonded to the same nitrogen are joined together to form optionally substituted 3-7 membered heterocyclyl.

[0175]

[0126] In certain embodiments, at least one instance of R5is of the formula:

[0176] , wherein ql is an integer from 1-25, inclusive. In certain embodiments, at least one instance of R5is of , wherein ql is an integer from 1-25, inclusive. In certain embodiments, at least one instance of R5is of the formula: integer from 1-25, inclusive. In certain embodiments, at least one instance of R5is of the formula: inclusive. In certain embodiments, at least one instance of R5is of the formula: , wherein ql is an integer from 1-15, inclusive. In certain

[0177] V^O\ / ^OMe embodiments, at least one instance of R5is of the formula:q1or , wherein ql is an integer from 1-15, inclusive. In certain embodiments, at least one instance of R5is . In certain embodiments, at least one instance of R5is . In certain embodiments, at least one of R5is

[0178]

[0127] In certain embodiments, at least one instance of R5is PSar. In certain embodiments, at least one instance of R5is of the formula , wherein q3 is an integer from 1-25, inclusive, and each instance of RNis H, optionally substituted C1-6 alkyl, optionally substituted C3-7 carbocyclyl, optionally substituted C1-6 acyl, or two RNbonded to the same nitrogen are joined together to form optionally substituted 3-7 membered heterocyclyl. at least one instance of R5is of the formula wherein q3 is an integer from 1-25, inclusive, and each instance of RNis H, optionally substituted C1-6 alkyl, optionally substituted C3-7 carbocyclyl, optionally substituted C1-6 acyl, or two RNbonded to the same nitrogen are joined together to form optionally substituted 3-7 membered heterocyclyl. at least one instance of R5is of the formula , wherein q3 is an integer from 1-10, inclusive, at least one instance of R5is of the formula

[0179] R4, m

[0180]

[0128] As generally defined herein, m is 0, 1, 2, 3, 4, 5, 6, or 7. In certain embodiments, m is 0, 1, 2, 3, 4, 5, or 6. In certain embodiments, m is 0, 1, 2, 3, 4, or 5. In certain embodiments, m is 0, 1, 2, 3, or 4. In certain embodiments, m is 0, 1, 2, or 3. In certain embodiments, m is 0, 1, or 2. In certain embodiments, m is 0 or 1. In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is 3. In certain embodiments, m is 4. In certain embodiments, m is 5. In certain embodiments, m is 6. In certain embodiments, m is 7.

[0181]

[0129] As generally defined herein, each instance of R4is independently halogen, C1-6 alkyl, C1-6 haloalkyl, -OR0, or -N(RN)2, wherein the alkyl or haloalkyl is optionally substituted; or two instances of R4are taken together to form =0. In some embodiments, each instance of R4is independently halogen, C1-6 alkyl, C1-6 haloalkyl, -OR0, or -N(RN)2, wherein the alkyl or haloalkyl is optionally substituted. In certain embodiments, at least one instance of R4is Br, Cl, F, Me, Et, -CF3, -OEt, -OMe, -OH, -NMe2, - NHMe, or -NH2. In certain embodiments, at least one instance of R4is optionally substituted C1-4 alkyl. In certain embodiments, at least one instance of R4is Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, or t-Bu. In certain embodiments, at least one instance of R4is Me or Et. In certain embodiments, at least one instance of R4is optionally substituted C1-4 haloalkyl. In certain embodiments, at least one instance of R4is -CF3. In certain embodiments, at least one instance of R4is halogen. In certain embodiments, at least one instance of R4is Br, Cl, or F. In certain embodiments, at least one instance of R4is F. In some embodiments, two instances of R4are taken together to form =0.

[0182]

[0130] In certain embodiments, each instance of R4is the same. In certain embodiments, at least one instance of R4is different. In certain embodiments, each instance of R4is different.

[0183]

[0131] As generally defined herein, X is a bond, -C(=O)-, -OC(=O)-, -N(RN)C(=O)-, -S(=O)2-, or -S(=O)-. In certain embodiments, X is -C(=O)-, -OC(=O)-, -N(RN)C(=O)-, -S(=O)2-, or -S(=O)-. In certain embodiments, X is -C(=O)- or -S(=O)2-. In certain embodiments, X is a bond. In certain embodiments, X is -C(=O)- or -OC(=O)-. In certain embodiments, X is -S(=O)2- or -S(=O)-. In certain embodiments, X is -S(=O)2- or -C(=O)-. In certain embodiments, X is -C(=O)-. In certain embodiments, X is -OC(=O)-. In certain embodiments, X is -N(RN)C(=O)-. In certain embodiments, X is -S(=O)2-. In certain embodiments, X is -S(=O)-.

[0184] L1, R1, R1A

[0185]

[0132] As generally defined herein, L1is a bond, C3-10 carbocyclylene, C6-io arylene, 3- to 10-membered heterocyclylene, or 5- to 10-membered heteroarylene, wherein the carbocyclylene, arylene, heterocyclylene, or heteroarylene is optionally substituted, including optionally substituted with one or more instances of R1A. In certain embodiments, L1is a bond. In certain embodiments, L1is C3-10 carbocyclylene, C6-io arylene, 3- to 10-membered heterocyclylene, or 5- to 10-membered heteroarylene, wherein the carbocyclylene, arylene, heterocyclylene, or heteroarylene is optionally substituted, including optionally substituted with one or more instances of R1A. In certain embodiments, L1is C3-10 carbocyclylene or C6-io arylene, wherein the carbocyclylene or arylene are optionally substituted, including optionally substituted with one or more instances of R1A. In certain embodiments, L1is C3-10 carbocyclylene or 3- to 10-membered heterocyclylene, wherein the carbocyclylene or heterocyclylene are optionally substituted, including optionally substituted with one or more instances of R1A. In certain embodiments, L1is C6-io arylene or 5- to 10-membered heteroarylene, wherein the arylene or heteroarylene are optionally substituted, including with one or more instances of R1A. In certain embodiments, L1is 5- to 10-membered heteroarylene or 5- to 6-membered heterocyclylene, wherein the heteroarylene or heterocyclylene are optionally substituted, including optionally substituted with one or more instances of R1A. In certain embodiments, L1is phenylene, wherein the phenylene is optionally substituted, including with one or more instances of R1A. In certain embodiments, L1is naphthylene, wherein the naphthyleneis optionally substituted, including with one or more instances of R1A. In certain embodiments, L1is C3-C7 carbocyclylene, wherein the carbocyclylene is optionally substituted, including with one or more instances of R1A. In certain embodiments, L1is 5- or 6-membered heteroarylene, wherein the heteroarylene is optionally substituted, including with one or more instances of R1A. In certain embodiments, L1is 5-membered heteroarylene, wherein the heteroarylene is optionally substituted, including with one or more instances of R1A. In certain embodiments, L1is 5-membered heteroarylene comprising at least one nitrogen atom, wherein the heteroarylene is optionally substituted, including with one or more instances of R1A. In certain embodiments, L1is 5-membered heteroarylene comprising at least one sulfur atom, wherein the heteroarylene is optionally substituted, including with one or more instances of R1A. In certain embodiments, L1is thiazolyl, wherein the thiazolyl is optionally substituted, including with one or more instances of R1A. In certain embodiments, L1is 6-membered heteroarylene, wherein the heteroarylene is optionally substituted, including with one or more instances of R1A. In certain embodiments, L1is 6-membered heteroarylene comprising at least one nitrogen atom, wherein the heteroarylene is optionally substituted, including with one or more instances of R1A. In certain embodiments, L1is pyridinyl, wherein the pyridinyl is optionally substituted, including with one or more instances of R1A. In certain embodiments, L1is 3- to 7-membered heterocyclylene, wherein the heterocyclylene is optionally substituted, including with one or more instances of R1A.

[0186]

[0133] In certain embodiments, -L'-R1is of the formula: . In certain embodiments, -L'-R1is of the formula: certain embodiments, -L'-R1is of the formula: . In certain embodiments, -L'-R1is of the formula: . In certain embodiments, -L'-R1is

[0187] R1of the formula: . In certain embodiments, -L'-R1is of the formula: . In certain embodiments, -L'-R1is of the formula: . In certain embodiments, -L'-R1is of the formula:

[0188] R1 . In certain embodiments, -L'-R1is of the formula: . In certain embodiments, -

[0189] L'-R1is of the formula: certain embodiments, -L'-R1is of the formula: certain embodiments, -L’-R1is of the formula: . In certain embodiments, -L'-R1is of the certain embodiments, -L'-R1is of the formula: embodiments, -L'-R1is of the formula: . In certain embodiments, -L'-R1is of the formula: R1 . In certain embodiments, -L'-R1is of the formula: . In certain embodiments, -

[0190] L'-R1is of the formula: . In certain embodiments, -L'-R1is of the formula: . In certain embodiments, -L’-R1is of the formula: . In certain embodiments, -L'-R1is of the , each of which is independently optionally substituted, including optionally substituted with one or more instances of R1A. In certain embodiments, - independently optionally substituted, including optionally substituted with one or more instances of R1A.

[0191]

[0192]

[0135] In certain embodiments, -L1is a bond, or -L’-R1is of the formula:

[0193]

[0136] As generally defined herein, R1is hydrogen, R1A, C1-30 alkyl, C1-30 haloalkyl, C1-30 heteroalkyl, C2-30 alkenyl, C2-30 heteroalkenyl, C2-30 alkynyl, C2-30 heteroalkynyl, C3-10 carbocyclyl, 3- to 10-membered heterocyclyl, C6-io aryl, 5- to 10-membered heteroaryl, polyethylene glycol (PEG), polysarcosine (Psar), or any combination thereof, wherein each alkyl, haloalkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, PEG, or PSar is independently optionally substituted, including optionally with one or more instances of R1A; or optionally wherein R1and R2are joined together, or R1and R2Aare joined together, with the intervening atoms to form a 5- to 10- membered heterocyclic ring, wherein the heterocyclic ring is optionally substituted, including optionally with one or more instances of R1A. In certain embodiments, R1is hydrogen, R1A, C1-30 alkyl, C1-30 haloalkyl, C1-30 heteroalkyl, C2-30 alkenyl, C2-30 heteroalkenyl, C2-30 alkynyl, C2-30 heteroalkynyl, C3-10 carbocyclyl, 3- to 10-membered heterocyclyl, C6-io aryl, 5- to 10-membered heteroaryl, polyethylene glycol (PEG), or any combination thereof, wherein each alkyl, haloalkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, or PEG is independently optionally substituted, including optionally with one or more instances of R1A; or optionally wherein R1and R2are joined together, or R1and R2Aare joined together, with the intervening atoms to form a 5- to 10-membered heterocyclic ring, wherein the heterocyclic ring is optionally substituted, including optionally with one or more instances of R1A. In certain embodiments, R1is hydrogen, R1A, C1-30 alkyl, C1-30 haloalkyl, C1-30 heteroalkyl, C2-30 alkenyl, C2-30 heteroalkenyl, C2-30 alkynyl, C2-30 heteroalkynyl, C3-10 carbocyclyl, 3- to 10-membered heterocyclyl, C6-io aryl, 5- to 10- membered heteroaryl, PEG, PSar, or any combination thereof, wherein each alkyl, haloalkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, or PEG is independently optionally substituted, including optionally with one or more instances of R1A. In certain embodiments, R1is hydrogen, R1A, C1-30 alkyl, C1-30 haloalkyl, C1-30 heteroalkyl, C2-30 alkenyl, C2-30 heteroalkenyl, C2-30 alkynyl, C2-30 heteroalkynyl, C3-10 carbocyclyl, 3- to 10-membered heterocyclyl, C6-io aryl, 5- to 10-membered heteroaryl, polyethylene glycol (PEG), or any combination thereof, wherein each alkyl, haloalkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, or PEG is independently optionally substituted, including optionally with one or more instances of R1A. In certain embodiments, R1is hydrogen, R1A, C1-20 alkyl, C1-20 haloalkyl, C1-20 heteroalkyl, C2-20 alkenyl, C2-20 alkynyl, polyethylene glycol (PEG), wherein the alkyl, haloalkyl, heteroalkyl, alkenyl, or alkynyl, is optionally substituted, including optionally with one or more instances of R1A. In certain embodiments, R1is R1A, C1-20 alkyl, C1-20 haloalkyl, C1-20 heteroalkyl, C2-20 alkenyl, C2- 20 alkynyl, PEG, or PSar, wherein the alkyl, haloalkyl, heteroalkyl, alkenyl, or alkynyl, is optionally substituted, including optionally with one or more instances of R1A. In certain embodiments, R1is R1A, C1-20 alkyl, C1-20 haloalkyl, C1-20 heteroalkyl, C2-20 alkenyl, C2-20 alkynyl, polyethylene glycol (PEG), wherein the alkyl, haloalkyl, heteroalkyl, alkenyl, or alkynyl, is optionally substituted, including optionally with one or more instances of R1A. In certain embodiments, R1is C1-20 alkyl, C1-20 haloalkyl, C1.20 heteroalkyl, C2-20 alkenyl, C2-20 alkynyl, PEG, PSar, wherein the alkyl, haloalkyl, heteroalkyl, alkenyl, or alkynyl, is optionally substituted, including optionally with one or more instances of R1A. In certain embodiments, R1is C1-20 alkyl, C1-20 haloalkyl, C1-20 heteroalkyl, C2-20 alkenyl, C2-20 alkynyl, polyethylene glycol (PEG), wherein the alkyl, haloalkyl, heteroalkyl, alkenyl, or alkynyl, is optionally substituted, including optionally with one or more instances of R1A. In certain embodiments, R1is hydrogen or R1A. In certain embodiments, R1is hydrogen. In certain embodiments, R1is R1A.

[0194]

[0137] In certain embodiments, R1is C1-30 alkyl, wherein the alkyl is optionally substituted, including optionally with one or more instances of R1A. In certain embodiments, R1is C1-10 alkyl, wherein the alkyl is optionally substituted, including optionally with one or more instances of R1A. In certain embodiments, R1is methylene, wherein the methylene is optionally substituted, including optionally with one or more F instances of R1A. In certain embodiments, R1i In certain embodiments, R1is '

[0138] In certain embodiments, R1is C1-20 heteroalkyl, wherein the heteroalkyl is optionally substituted, including optionally with one or more instances of R1A. In certain embodiments, R1is C1-w heteroalkyl, wherein the heteroalkyl is optionally substituted, including optionally with one or more instances of R1A. In certain embodiments, R1is C1-30 heteroalkyl comprising one or more oxygen atoms, wherein the heteroalkyl is optionally substituted, including optionally with one or more instances of R1A. In certain embodiments, R1is optionally substituted alkoxy, including optionally with one or more instances of R1A.

[0195] In certain embodiments, R1is -0-CH2-R1A. In certain embodiments, certain embodiments, R1is C1-w heteroalkyl comprising one or more nitrogen atoms, wherein the heteroalkyl is optionally substituted, including optionally with one or more instances of R1A. In certain embodiments,

[0196]

[0139] In certain embodiments, R1is C2-30 alkenyl, wherein the alkenyl is optionally substituted, including optionally with one or more instances of R1A. In certain embodiments, R1is C2-10 alkenyl, wherein the alkenyl is optionally substituted, including optionally with one or more instances of R1A. In certain r embodiments, R1is '

[0197]

[0140] In certain embodiments, R1is C2-30 alkynyl, wherein the alkynyl is optionally substituted, including optionally with one or more instances of R1A. In certain embodiments, R1is C2-10 alkynyl, wherein the alkynyl is optionally substituted, including optionally with one or more instances of R1A. In certain embodiments,

[0198]

[0141] In certain embodiments, R1is C3-10 carbocyclyl, wherein the carbocyclyl is optionally substituted, including optionally substituted with one or more instances of R1A. In certain embodiments, R1is C3-7 carbocyclyl, wherein the carbocyclyl is optionally substituted, including optionally substituted with one

[0199]

[0143] In certain embodiments, at least one of R1or R1Ais PEG or PSar.

[0200]

[0144] In certain embodiments, R1is PEG or PSar. In certain embodiments, R1is PEG. In certain embodiments, R1is or , wherein ql is an integer from 1-25, inclusive, and R° is H, optionally substituted C1-6 alkyl, optionally substituted C1-6 haloalkyl, optionally substituted C3-7 carbocyclyl, or optionally substituted C1-6 acyl. In certain embodiments, R1is , wherein ql is an integer from 1-25, inclusive, and each instance of RNis H, optionally substituted C1-6 alkyl, optionally substituted C3-7 carbocyclyl, optionally substituted C1-6 acyl, or two RNbonded to the same nitrogen are joined together to form optionally substituted 3-7 membered heterocyclyl. In certain embodiments, R1is . wherein ql is an integer from 1-10, inclusive. In certain embodiments, R1is of the ql is an integer from 1-25, inclusive. In certain embodiments, R1is of the formula: wherein ql is an integer from 1-25, inclusive. In certain embodiments, R1is of the formula: , wherein ql is an integer from 1-10, inclusive. In certain embodiments, R1is . In certain embodiments, R1is In certain emb odiments, R1is . In certain embodiments, R1is . In certain embodiments, R1is In certain

[0201] O embodiments, R1is In certain embodiments, at least one instance of R1Ais of the e formula: wherein ql is an integer from 1-25, inclusive. In e certain embodiments, R1is of the formula: or , wherein ql is an integer f rom 1-10, inclusive. In certain embodiments, R1i In certain

[0202] L Me

[0203] C X embodiments, R1is . In certain embodiments, R1Ais ' '7.TIn certain embodiments, R1Ais . In certain embodi t R1Ai o. Me

[0204] O'

[0205] . In certain embodiments, R1is of the formula: or

[0206] O

[0207] ^NMe2q1wherein ql is an integer from 1 25, inclusive. In certain embodiments, R1is of the formula , wherein ql is an integer from 1-10, inclusive.

[0208] In certain embodiments, R1is

[0209]

[0145] In certain embodiments, R1is PSar. In certain embodiments, R1is of the formula wherein q3 is an integer from 1-25, inclusive, and each instance of RNis H, optionally substituted C1-6 alkyl, optionally substituted C3-7 carbocyclyl, optionally substituted C1-6 acyl, or two RNbonded to the same nitrogen are joined together to form optionally substituted 3-7 membered heterocyclyl. In certain embodiments, R1is of the formula , wherein q3 is an integer from 1-25, inclusive, and each instance of RNis H, optionally substituted C1-6 alkyl, optionally substituted C3-7 carbocyclyl, optionally substituted C1-6 acyl, or two RNbonded to the same nitrogen are joined together to form optionally substituted 3-7 membered heterocyclyl. In certain embodiments, R1is of the formula , wherein q3 is an integer from 1-10, inclusive. In certain embodiments, R1is of the formula

[0210]

[0146] In certain embodiments, R1is of the formula: , wherein q2 is an integer from 0-25. In

[0211] O certain embodiments, R1is of the formula: , wherein q2 is an integer from 0-25. In certain embodiments, R1is of the formula: , wherein q2 is an integer from 1-20. In certain embodiments, R1is of the formula: , wherein q2 is an integer from 1-5. In certain

[0212] O embodiments, R1is . In some embodiments, R1is R1A, and R1Ais -CO2H.

[0213]

[0147] As generally defined herein, each instance of R1Ais independently C1-6 alkyl, C3-15 carbocyclyl, - OR0, -CO2R0, -N(RN)2, -C(=O)N(RN)2, PEG, or PSar. In certain embodiments, each instance of R1Ais independently C1-6 alkyl, C3-15 carbocyclyl, -OR0, -CO2R0, -N(RN)2, -C(=O)N(RN)2, or PEG. In certain embodiments, each instance of R1Ais independently C1-6 alkyl, C3-15 carbocyclyl, -OR0,

[0214] -CO2R0, -N(RN)2, or -C(=O)N(RN)2. In certain embodiments, at least one instance of R1Ais Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, -OH, -OMe, -CO2OH, -CO2OMe, -NH2, -NHMe, -NMe2, -C(=O)NH2, - C(=O)NHMe, or -C(=O)NMe2. In certain embodiments, at least one instance of R1Ais -Me, -OMe, or - CO2H. In certain embodiments, at least one instance of R1Ais -CO2H. In certain embodiments, at least one instance of R1Ais C3-15 carbocyclyl. In certain embodiments, at least one instance of R1Ais C7-15 carbocyclyl, wherein the carbocyclyl is fused with one or more aryl or heteroaryl groups. In certain embodiments, at least one instance of R1Ais C9-15 carbocyclyl, wherein the carbocyclyl is fused with one or more aryl groups. In certain embodiments, at least one instance

[0215]

[0148] In certain embodiments, at least one instance of R1Ais PEG or PSar. In certain embodiments, at least one instance of R1Ais PEG. In certain embodiments, at least one instance of R1Ais , wherein ql is an integer from 1-25, inclusive, and R° is H, optionally substituted C1-6 alkyl, optionally substituted C1-6 haloalkyl, optionally substituted C3-7- carbocyclyl, or optionally substituted C1-6 acyl. In certain embodiments, at least one instance of R1Ais of the formula: , or , wherein ql is an integer from 1-25, inclusive. In certain embodiments, R1Ais of the formula: , wherein ql is an integer from 1-10. In certain embodiments, R1Ais .In certain embodiments,

[0216] R1Ais . In certain embodiments, R1Ais . In certain embodiments, R1Ais . In certain embodiments, at least one instance of R1Ais of the formula: or , wherein ql is an integer from 1-25, inclusive. In certain embodiments, at least one instance of R1Ais of the formula: or , wherein ql is an integer from 1-10, inclusive. In certain embodiments, at least one instance of R1Ais . In certain embodiments, at least one instance of R1Ais Me . In certain embodiments, at least one instance of R1Ais

[0217]

[0149] In certain embodiments, at least one instance of R1Ais PSar. In certain embodiments, R1Ais of the formul , wherein q3 is an integer from 1-25, inclusive, and each instance of RNis H, optionally substituted C1-6 alkyl, optionally substituted C3-7 carbocyclyl, optionally substituted C1-6 acyl, or two RNbonded to the same nitrogen are joined together to form optionally substituted 3-7 membered heterocyclyl. In certain embodiments, R1Ais of the formula wherein q3 is an integer from 1-25, inclusive, and each instance of RNis H, optionally substituted C1-6 alkyl, optionally substituted C3-7 carbocyclyl, optionally substituted C1-6 acyl, or two RNbonded to the same nitrogen are joined together to form optionally substituted 3-7 membered heterocyclyl. In certain embodiments, R1Ais of the formula , wherein q3 is an integer from 1-10, inclusive. In certain embodiments,

[0218] R1Ais of the formula certain embodiments, R1Ais of the formula wherein q3 is an integer from 1-25, inclusive, and each instance of RNis H, optionally substituted C1-6 alkyl, optionally substituted C3-7 carbocyclyl, optionally substituted C1-6 acyl, or two RNbonded to the same nitrogen are joined together to form optionally substituted 3-7 membered heterocyclyl. In certain embodiments, R1Ais of the formula , wherein q3 is an integer from 1-25, inclusive, and each instance of RNis H, optionally substituted C1-6 alkyl, optionally substituted C3-7 carbocyclyl, optionally substituted C1-6 acyl, or two RNbonded to the same nitrogen are joined together to form optionally substituted 3-7 membered heterocyclyl. In certain embodiments, R1Ais of the formula , wherein q3 is an integer from 1-10, inclusive. In certain embodiments, R1Ais of the formula

[0219]

[0150] As generally defined herein, ql is an integer from 1-25, inclusive. In certain embodiments, ql is an integer from 1-20, inclusive. In certain embodiments, ql is an integer from 1-15, inclusive. In certain embodiments, ql is an integer from 1-15, inclusive. In certain embodiments, ql is an integer from 1-10, inclusive. In certain embodiments, ql is an integer from 1-5, inclusive. In certain embodiments, ql is an integer from 2-25, inclusive. In certain embodiments, ql is an integer from 2-20, inclusive. In certain embodiments, ql is an integer from 2-15, inclusive. In certain embodiments, ql is an integer from 2-10, inclusive. In certain embodiments, ql is an integer from 2-5, inclusive. In certain embodiments, ql is an integer from 5-25, inclusive. In certain embodiments, ql is an integer from 5-20, inclusive. In certain embodiments, ql is an integer from 5-15, inclusive. In certain embodiments, ql is an integer from 5-10, inclusive. In certain embodiments, ql is 1. In certain embodiments, ql is 2. In certain embodiments, ql is 3. In certain embodiments, ql is 4. In certain embodiments, ql is 5. In certain embodiments, ql is 6. In certain embodiments, ql is 7. In certain embodiments, ql is 8. In certain embodiments, ql is 9. In certain embodiments, ql is 10.

[0220]

[0151] As generally defined herein, q2 is an integer from 0-25, inclusive. In certain embodiments, q2 is an integer from 0-20, inclusive. In certain embodiments, q2 is an integer from 0-15, inclusive. In certain embodiments, q2 is an integer from 0-10, inclusive. In certain embodiments, q2 is an integer from 0-5, inclusive. In certain embodiments, q2 is an integer from 1-25, inclusive. In certain embodiments, q2 is an integer from 1-20, inclusive. In certain embodiments, q2 is an integer from 1-15, inclusive. In certain embodiments, q2 is an integer from 1-15, inclusive. In certain embodiments, q2 is an integer from 1-10, inclusive. In certain embodiments, q2 is an integer from 1-5, inclusive. In certain embodiments, q2 is an integer from 2-25, inclusive. In certain embodiments, q2 is an integer from 2-20, inclusive. In certain embodiments, q2 is an integer from 2-15, inclusive. In certain embodiments, q2 is an integer from 2-10, inclusive. In certain embodiments, q2 is an integer from 2-5, inclusive. In certain embodiments, q2 is 1. In certain embodiments, q2 is 2. In certain embodiments, q2 is 3. In certain embodiments, q2 is 4. In certain embodiments, q2 is 5. In certain embodiments, q2 is 6. In certain embodiments, q2 is 7. In certain embodiments, q2 is 8. In certain embodiments, q2 is 9. In certain embodiments, q2 is 10.

[0221]

[0152] As generally defined herein, q3 is is an integer from 1-25, inclusive. In certain embodiments, q3 is an integer from 1-20, inclusive. In certain embodiments, q3 is an integer from 1-15, inclusive. In certain embodiments, q3 is an integer from 1-15, inclusive. In certain embodiments, q3 is an integer from 1-10, inclusive. In certain embodiments, q3 is an integer from 1-5, inclusive. In certain embodiments, q3 is an integer from 2-25, inclusive. In certain embodiments, q3 is an integer from 2-20, inclusive. In certain embodiments, q3 is an integer from 2-15, inclusive. In certain embodiments, q3 is an integer from 2-10, inclusive. In certain embodiments, q3 is an integer from 2-5, inclusive. In certain embodiments, q3 is an integer from 5-25, inclusive. In certain embodiments, q3 is an integer from 5-20, inclusive. In certain embodiments, q3 is an integer from 5-15, inclusive. In certain embodiments, q3 is an integer from 5-10, inclusive. In certain embodiments, q3 is 1. In certain embodiments, q3 is 2. In certain embodiments, q3 is 3. In certain embodiments, q3 is 4. In certain embodiments, q3 is 5. In certain embodiments, q3 is 6. In certain embodiments, q3 is 7. In certain embodiments, q3 is 8. In certain embodiments, q3 is 9. In certain embodiments, q3 is 10. R2, R2A, R3, R3A, n

[0222]

[0153] As generally defined herein, R2is hydrogen or optionally substituted C1-C6 alkyl; or optionally wherein R1and R2are joined together, with the intervening atoms to form a 5- to 10-membered heterocyclic ring, wherein the heterocyclic ring is optionally substituted, including optionally with one or more instances of R1A. In certain embodiments, R2is hydrogen or optionally substituted C1-C6 alkyl. In certain embodiments, R2is H. In certain embodiments, R2is optionally substituted C1-4 alkyl. In certain embodiments, R2is Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, or t-Bu. In certain embodiments, R2is -(CH2)2NMe2.

[0223]

[0154] In certain embodiments, R1and R2are joined together with the intervening atoms to form a 5- to 10-membered heterocyclic ring, wherein the heterocyclic ring is optionally substituted, including optionally with one or more instances of R1A. In certain embodiments, R1and R2are joined together with the intervening atoms to form an optionally 5- to 6-membered heterocyclyl ring. In certain embodiments, R1and R2are joined together with the intervening atoms to form an optionally substituted 5- to 6- membered heterocyclic ring fused to an aryl ring. In certain embodiments, R1and R2are joined together with the intervening atoms to form optionally substituted isoindolinyl. In certain embodiments, R1and R2are joined together with the intervening atoms to form

[0224]

[0155] As generally defined herein, R3is hydrogen or optionally substituted C1-6 alkyl. In certain embodiments, R3is hydrogen or unsubstituted C1-6 alkyl. In certain embodiments, R3is hydrogen or optionally substituted C1-4 alkyl. In certain embodiments, R3is Me, Et, n-Pr, i- Pr, n-Bu, i-Bu, or t-Bu. In certain embodiments, R3is H, Me, or Et. In certain embodiments, R3is Et or Me. In certain embodiments, R3is H or Me. In certain embodiments, R3is H. In certain embodiments, R3is Me.

[0225]

[0156] As generally defined herein, n is 0, 1, or 2. In certain embodiments, n is 0 or 1. In certain embodiments, n is 1 or 2. In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2.

[0226]

[0157] As generally defined herein, each instance of R2Ais independently hydrogen or optionally substituted C1-C6 alkyl; or optionally wherein R1and R2Aare joined together, with the intervening atoms to form a 5- to 10-membered heterocyclic ring, wherein the heterocyclic ring is optionally substituted, including optionally with one or more instances of R1A. In certain embodiments, each instance of R2Ais independently hydrogen or optionally substituted C1-C6 alkyl. In certain embodiments, at least one instance of R2Ais H. In certain embodiments, at least one instance of R2Ais optionally substituted C1-4 alkyl. In certain embodiments, at least one instance of R2Ais Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, or t-Bu. In certain embodiments, at least one instance of R2Ais -(CH2)2NMe2.

[0227]

[0158] In certain embodiments, R1and R2Aare joined together with the intervening atoms to form a 5- to 10-membered heterocyclic ring, wherein the heterocyclic ring is optionally substituted, including optionally with one or more instances of R1A. In certain embodiments, R1and R2Aare joined together with the intervening atoms to form an optionally 5- to 6-membered heterocyclyl ring. In certain embodiments, R1and R2Aare joined together with the intervening atoms to form an optionally substituted 5- to 6-membered heterocyclic ring fused to an aryl ring. In certain embodiments, R1and R2Aare joined together with the intervening atoms to form optionally substituted isoindolinyl. In certain embodiments,

[0228] R1and R2Aare joined together with the intervening atoms to form

[0229]

[0159] As generally defined herein, each instance of R3Ais hydrogen, optionally substituted C1-6 alkyl, or an amino acid sidechain. In certain embodiments, each instance of R3Ais hydrogen or an amino acid side chain. In certain embodiments, each instance of R3Ais optionally substituted C1-6 alkyl or an amino acid side chain. In certain embodiments, at least one instance of R3Ais an amino acid side chain. In certain embodiments, at least one instance of R3Ais a basic amino acid sidechain. In certain embodiments, at least one instance of R3Ais an acidic amino acid sidechain. In certain embodiments, at least one instance of R3Ais a neutral amino acid sidechain. In certain embodiments, at least one instance of R3Ais a hydrophobic amino acid sidechain. In certain embodiments, each instance of R3Ais hydrogen or optionally substituted C1-6 alkyl. In certain embodiments, at least one instance of R3Ais hydrogen or optionally substituted C1-4 alkyl. In certain embodiments, at least one instance of R3Ais Me, Et, n-Pr, i- Pr, n-Bu, i-Bu, or t-Bu. In certain embodiments, at least one instance of R3Ais H, Me, or -CH2OR0. In certain embodiments, at least one instance of R3Ais H, Me, or -CH2OH. In certain embodiments, at least one instance of R3Ais H, Me, or Et. In certain embodiments, at least one instance of R3Ais Et or Me. In certain embodiments, at least one instance of R3Ais H or Me. In certain embodiments, at least one instance of R3Ais -CH2OR0or Me. In certain embodiments, at least one instance of R3Ais -CH2OH or Me. In certain embodiments, at least one instance of R3Ais H. In certain embodiments, at least one instance of R3Ais Me. In certain embodiments, at least one instance of R3Ais -CH2OR0. In certain embodiments, at least one instance of R3Ais -CH2OH.

[0230] R°, RN

[0231]

[0160] As generally defined herein, each instance of R° is independently H, optionally substituted C1-6 alkyl, optionally substituted C1-6 haloalkyl, optionally substituted C3-7 carbocyclyl, or optionally substituted C1-6 acyl. In certain embodiments, at least one instance of R° is H. In certain embodiments, each instance of R° is H. In certain embodiments, at least one instance of R° is optionally substituted C1-6 alkyl. In certain embodiments, at least one instance of R° is optionally substituted C3-7 carbocyclyl. In certain embodiments, at least one instance of R° is optionally substituted C1-6 acyl.

[0232]

[0161] As generally defined herein, each instance of RNis independently H, optionally substituted C1-6 alkyl, optionally substituted C3-7 carbocyclyl, or optionally substituted C1-6 acyl, or two RNbonded to the same nitrogen are joined together to form optionally substituted 3-7 membered heterocyclyl. In certain embodiments, at least one instance of RNis H. In certain embodiments, each instance of RNis H. In certain embodiments, at least one instance of RNis optionally substituted C1-6 alkyl. In certain embodiments, at least one instance of RNis Me. In certain embodiments, each instance of RNis Me. In certain embodiments, at least one instance of RNis optionally substituted C8-vcarbocyclyl. In certain embodiments, at least one instance of RNis optionally substituted C1-6 acyl. In certain embodiments, two RNbonded to the same nitrogen are taken together to form optionally substituted 3-7 membered heterocyclyl.

[0233] Compound Species

[0234]

[0162] In certain embodiments, the compound is selected from those in Table Al.

[0235] Table Al

[0236]

[0237]

[0238]

[0239]

[0240]

[0241]

[0242]

[0243]

[0244]

[0245]

[0246] and pharmaceutically acceptable salts thereof.

[0247]

[0163] In certain embodiments, the compound is selected from those in Table Al.1.

[0248] Table Al.1

[0249]

[0250]

[0251]

[0252]

[0253]

[0254]

[0255]

[0164] In certain embodiments, the compound is selected from those in Table A2.

[0256] Table A2

[0257]

[0258]

[0259]

[0260]

[0261]

[0262]

[0263]

[0264] and pharmaceutically acceptable salts thereof.

[0265]

[0165] In certain embodiments, the compound is selected from those in Table A3.

[0266] Table A3

[0267]

[0268]

[0269]

[0270]

[0271]

[0272]

[0273]

[0274]

[0275]

[0276]

[0277]

[0278]

[0279]

[0280]

[0281]

[0282]

[0283]

[0284]

[0285] Pharmaceutical Compositions, Kits, and Administration

[0286]

[0166] The present disclosure provides pharmaceutical compositions comprising a compound described herein (e.g. , a compound of Formula (I"), (I'), or (I)) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers and / or excipients. In one aspect, provided herein is a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In certain embodiments, a compound described herein is provided in an effective amount in the pharmaceutical composition. In certain embodiments, the effective amount is a therapeutically effective amount.

[0287]

[0167] Pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include bringing the compound described herein (z.e., the “active ingredient”) into association with a carrier or excipient, and / or one or more other accessory ingredients, and then, if necessary and / or desirable, shaping, and / or packaging the product into a desired single- or multi -dose unit.

[0288]

[0168] Pharmaceutical compositions can be prepared, packaged, and / or sold in bulk, as a single unit dose, and / or as a plurality of single unit doses. A “unit dose” is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and / or a convenient fraction of such a dosage, such as one-half or one-third of such a dosage.

[0289]

[0169] Relative amounts of the active ingredient, the pharmaceutically acceptable carrier or excipient, and / or any additional ingredients in a pharmaceutical composition described herein will vary, depending upon the identity, size, and / or condition of the subject treated and further depending upon the route by which the composition is to be administered.

[0170] Pharmaceutically acceptable carriers / excipients used in the manufacture of provided pharmaceutical compositions include inert diluents, solvents, dispersing and / or granulating agents, surface active agents and / or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, oils, butters, and / or waxes. Excipients such as coloring agents, coating agents, sweetening agents, flavoring agents, and fragrances may also be present in the composition.

[0290]

[0171] The compounds and compositions provided herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, intradermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and / or drops), mucosal, nasal, buccal, sublingual; by intratracheal instillation, bronchial instillation, and / or inhalation; and / or as an oral spray, nasal spray, and / or aerosol. Specifically contemplated non-limiting routes of administration include intravenous administration (e.g., systemic intravenous injection) and direct intra-tumoral administration. In general, the most appropriate route of administration will depend upon a variety of factors including the nature of the agent (e.g. , its stability in the environment of the gastrointestinal tract), and / or the condition of the subject (e.g., whether the subject is able to tolerate oral administration).

[0291]

[0172] Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and / or perform such modification with ordinary experimentation.

[0292]

[0173] Compounds provided herein are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions described herein will be decided by a physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific composition employed; the age, body weight, general health, sex, and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.

[0293]

[0174] The exact amount of a compound required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound, mode of administration, and the like. An effective amount may be included in a single dose (e.g., single oral dose) or multiple doses (e.g., multiple oral doses). In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, any two doses of the multiple doses include different or substantially the same amounts of a compound described herein.

[0175] A compound or composition, as described herein, can be administered in combination with one or more additional pharmaceutical agents (e.g., therapeutically and / or prophy tactically active agents). The compounds or compositions can be administered in combination with additional pharmaceutical agents that improve their activity (e.g., activity (e.g., potency and / or efficacy) in treating a disease in a subject in need thereof, in preventing a disease in a subject in need thereof, in reducing the risk to develop a disease in a subject in need thereof), improve bioavailability, improve safety, reduce drug resistance, reduce and / or modify metabolism, inhibit excretion, and / or modify distribution in a subject or cell. It will also be appreciated that the therapy employed may achieve a desired effect for the same disorder, and / or it may achieve different effects. In certain embodiments, the additional agent is a chemotherapeutic agent.

[0294]

[0176] Also encompassed by the disclosure are kits (e.g., pharmaceutical packs). The kits provided may comprise a pharmaceutical composition or compound described herein and a container (e.g. , a vial, ampule, bottle, syringe, and / or dispenser package, or other suitable container). In some embodiments, provided kits may optionally further include a second container comprising a pharmaceutical excipient for dilution or suspension of a pharmaceutical composition or compound described herein.

[0295]

[0177] In certain embodiments, a kit described herein further includes instructions for using the kit. A kit described herein may also include information as required by a regulatory agency such as the U.S. Food and Drug Administration (FDA). In certain embodiments, the information included in the kits is prescribing information. In certain embodiments, the kits provide instructions for treating a disease (e.g., cancer) in a subject in need thereof. A kit described herein may include one or more additional pharmaceutical agents described herein as a separate composition.

[0296] Methods of Treatment and Uses

[0297]

[0178] As described herein, compounds provided herein can deliver a camptothecin to FAP-expressing tissues (e.g., cancers).

[0298]

[0179] In one aspect, provided herein are methods of treating a disease characterized by fibroblast activation protein (FAP) upregulation in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein (e.g. , a compound of Formula (I"), (F), or (I)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Also provided are compounds described herein (e.g, compounds of Formula (I"), (F), and (I)), and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, for use in treating a disease characterized by fibroblast activation protein (FAP) upregulation in a subject in need thereof. Also provided herein uses of compounds described herein (e.g., compounds of Formula (I"), (F), and (I)), and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, as medicaments and / or in the preparation of medicaments (e.g., for treating a disease characterized by fibroblast activation protein (FAP) upregulation in a subject in need thereof).

[0299]

[0180] In another aspect, provided herein are methods of treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Also provided are compounds described herein (e.g., compounds of Formula (I"), (F), and (I)), and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, for use in treating cancer in a subject in need thereof. Also provided herein uses of compounds described herein (e.g., compounds of Formula (I"), (I'), and (I)), and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, as medicaments and / or in the preparation of medicaments (e.g., for treating cancer).

[0300]

[0181] In another aspect, provided herein are methods comprising administering to a subject a compound described herein (e.g., compounds of Formula (I"), (I'), and (I)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the subject has a disease characterized by FAP upregulation. In some embodiments, the subject has cancer.

[0301]

[0182] In some embodiments, the compound, pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof, is administered by intravenous injection.

[0302]

[0183] In some embodiments, the disorder characterized by FAP upregulation is cancer, fibrosis, or inflammation. In some embodiments, the disorder characterized by FAP upregulation is cancer. In some embodiments, the cancer is selected from head and neck cancer, soft tissue sarcoma, breast cancer, lung cancer, gastric cancer, colorectal cancer, pancreatic cancer, uterine cancer, ovarian cancer, cervical cancer, sarcoma, and melanoma. In some embodiments, the cancer is selected from head and neck cancer, soft tissue sarcoma, breast cancer, lung cancer, gastric cancer, colorectal cancer, pancreatic cancer, uterine cancer, ovarian cancer, and cervical cancer. In some embodiments, the cancer is selected from breast cancer, lung cancer, gastric cancer, pancreatic cancer, uterine cancer, ovarian cancer, and cervical cancer. In some embodiments, the cancer is triple -negative breast cancer (TNBC), gastric cancer, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), uterine cancer, ovarian cancer, pancreatic cancer, or cervical cancer. In some embodiments, the cancer is selected from head and neck cancer, soft tissue sarcoma, breast cancer, lung cancer, gastric cancer, colorectal cancer, and pancreatic ductal adenocarcinoma. In some embodiments, the cancer is head and neck cancer. In some embodiments, the head and neck cancer is salivary gland cancer. In some embodiments, the cancer is sarcoma. In some embodiments, the cancer is soft tissue sarcoma. In some embodiments, the soft tissue sarcoma is undifferentiated pleomorphic sarcoma or dedifferentiated liposarcoma. In some embodiments, the cancer is breast cancer. In some embodiments, the breast cancer is triple -negative breast cancer (TNBC). In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the pancreatic cancer is pancreatic ductal adenocarcinoma. In some embodiments, the cancer is lung cancer. In some embodiments, the lung cancer is small cell lung cancer or non-small lung cell cancer. In some embodiments, the cancer is small cell lung cancer (SCLC). In some embodiments, the cancer is non-small cell lung cancer (NSCLC). In certain embodiments, the cancer is gastric cancer. In some embodiments, the cancer is uterine cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is cervical cancer. In some embodiments, the cancer is melanoma.

[0184] The term “cancer” includes a class of diseases characterized by the development of abnormal cells that proliferate uncontrollably and have the ability to infdtrate and destroy normal body tissues. In certain embodiments, the cancer is a solid cancer. In certain embodiments, the cancer is a hematopoietic cancer (z.e., hematological cancer).

[0303]

[0185] In certain embodiments, the cancer is a hematopoietic cancer (e.g., leukemia (e.g., acute lymphocytic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myelocytic leukemia (AML) (e.g., B- cell AML, T-cell AML), chronic myelocytic leukemia (CML) (e.g., B-cell CML, T-cell CML), chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL)); lymphoma (e.g., Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL)), non-Hodgkin lymphoma (NHL) (e.g., B-cell NHL such as diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma)), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphomas (e.g., mucosa-associated lymphoid tissue (MALT) lymphomas, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (z.e., Waldenstrom’s macroglobulinemia), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B -lymphoblastic lymphoma and primary central nervous system (CNS) lymphoma, T-cell NHL such as precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sezary syndrome)), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplastic large cell lymphoma); heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease); a myeloproliferative disorder (MPD) (e.g., polycythemia vera (PV), essential thrombocytosis (ET), agnogenic myeloid metaplasia (AMM) a.k.a. myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)); multiple myeloma (MM); plasma cell neoplasia; familiar hypereosinophilia; inflammatory myofibroblastic tumors; immunocytic amyloidosis). In certain embodiments, the cancer is leukemia. In certain embodiments, the cancer is acute lymphoblastic leukemia (ALL). In certain embodiments, the cancer is early T-cell precursor (ETP)-acute lymphoblastic leukemia (ALL).

[0304]

[0186] In certain embodiments, the cancer is musculoskeletal cancer (e.g., bone cancer (e.g., osteosarcoma, osteoid osteoma, malignant fibrous histiocytoma, Ewing’s sarcoma, chordoma, malignant giant cell tumor chordoma, chondrosarcoma osteochondroma, benign chondroma, chondroblastoma chondromyxofibroma, myelodysplastic syndrome (MDS)), muscle cancer (e.g., rhabdomyosarcoma, rhabdomyoma), connective tissue cancer, synovioma).

[0305]

[0187] In certain embodiments, the cancer is a nervous system cancer (e.g., brain cancer (e.g., astrocytoma, medulloblastoma, glioma (e.g., astrocytoma, oligodendroglioma), glioblastomas, glioblastoma multiform, medulloblastoma, ependymoma, germinoma (z.e., pinealoma), oligodendroglioma, schwannoma, retinoblastoma, congenital tumors, craniopharyngioma), spinal cord cancer, neurofibroma (e.g., neurofibromatosis (NF) type 1 or type 2, schwannomatosis), neuroblastoma, primitive neuroectodermal tumors (PNT), meningeal cancer (e.g., meningioma, meningiosarcoma, gliomatosis), skull cancer, acoustic neuroma, ependymoma, hemangioblastoma, ocular cancer (e.g., intraocular melanoma, retinoblastoma)).

[0306]

[0188] In certain embodiments, the cancer is selected from endocrine / exocrine cancers (e.g, thyroid cancer (e.g., papillary thyroid carcinoma, follicular thyroid carcinoma; medullary thyroid carcinoma, multiple endocrine neoplasia type 2A, multiple endocrine neoplasia type 2B, familial medullary thyroid cancer, pheochromocytoma, paraganglioma), pancreatic cancer (e.g., pancreatic andenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), Islet cell tumors, ductal adenocarcinoma, insulinoma, glucagonoma, vipoma), adrenal gland cancer, neuroendocrine cancer (e.g., gastroenteropancreatic neuroendocrine tumor (GEP-NET), carcinoid tumor), sebaceous gland carcinoma, sweat gland carcinoma). In certain embodiments, the cancer is sweat gland cancer (e.g., sweat gland carcinoma).

[0307]

[0189] In certain embodiments, the cancer is liver cancer (e.g., hepatocellular cancer (HCC) (e.g, hepatocellular carcinoma, hepatoblastoma, hepatocellular adenoma), malignant hepatoma, hemangiomas, biliary cancer (e.g., cholangiocarcinoma)).

[0308]

[0190] In certain embodiments, the cancer is head and neck cancer (e.g., squamous cell carcinoma of the head and neck (SCCHN), adenoid cystic carcinoma). In certain embodiments, the cancer is oral cancer (e.g., buccal cavity cancer, lip cancer, tongue cancer, mouth cancer, pharynx cancer, hypopharynx cancer (e.g., hypopharyngeal carcinoma), throat cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer), salivary gland cancer). In certain embodiments, the cancer is esophageal cancer (e.g., esophageal squamous cell carcinoma, esophageal adenocarcinoma, Barrett’s adenocarcinoma, esophageal leiomyosarcoma).

[0309]

[0191] In certain embodiments, the cancer is gastrointestinal cancer (e.g., anal cancer, colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma), gall bladder cancer, gastric cancer (e.g., stomach cancer (e.g., stomach adenocarcinoma)), gastrointestinal stromal tumor (GIST), small bowel cancer (e.g., appendix cancer, small bowel carcinoma, e.g., small bowel adenocarcinoma), small intestine cancer, large bowel cancer, large intestine cancer).

[0310]

[0192] In certain embodiments, the cancer is cardiovascular cancer (e.g., primary cardiac tumors, angiosarcoma (e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, hemangiosarcoma), endotheliosarcoma (e.g., Kaposi’s sarcoma, multiple idiopathic hemorrhagic sarcoma), cardiac myxoma, cardiac rhabdomyoma).

[0311]

[0193] In certain embodiments, the cancer is lung cancer (e.g., bronchus cancer (e.g., bronchogenic carcinoma, bronchial adenoma), alveolar carcinoma, mesothelioma, small cell lung cancer (SCLC), nonsmall cell lung cancer (NSCLC), lung adenocarcinoma, chondromatous hamartoma, papillary adenocarcinoma) .

[0312]

[0194] In certain embodiments, the cancer is a genitourinary cancer (e.g., bladder cancer (e.g., urothelial carcinoma), urethral cancer, kidney cancer (e.g., nephroblastoma a.k.a. Wilms’ tumor, renal cell carcinoma), clear cell renal cell carcinoma, chromophobe renal cell carcinoma, papillary renal cell carcinoma, renal medullary cancer, nephroblastom), testicular cancer (e.g., seminoma, testicular embryonal carcinoma), germ cell cancer, prostate cancer (e.g., prostate adenocarcinoma), penile cancer (e.g., Paget’s disease of the penis and scrotum)).

[0313]

[0195] In certain embodiments, the cancer is a gynecological cancer (e.g., endometrial cancer (e.g., uterine cancer (e.g., uterine sarcoma, choriocarcinoma), endometrial carcinoma), cervical cancer (e.g., cervical adenocarcinoma), ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma), germ cell cancer, vulvar cancer (e.g., Paget’s disease of the vulva) vaginal cancer, fallopian tube cancer).

[0314]

[0196] In certain embodiments, the cancer is breast cancer (e.g. , adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast, triple negative breast cancer, HER-2 positive breast cancer, HER2 -negative breast cancer).

[0315]

[0197] In certain embodiments, the cancer is skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC), dermatofribroma).

[0316]

[0198] In certain embodiments, the cancer is a soft tissue cancer (e.g., intraepithelial neoplasms, epithelial carcinomas, epithelial sarcomas, adenocarcinomas, adenomas, fibrosarcomas, fibromas, liposarcomas, lipomas, myxomas, teratomas).

[0317]

[0199] The terms “tumor” and “neoplasm” are used interchangeably and refer to an abnormal mass of tissue wherein the growth of the mass surpasses and is not coordinated with the growth of a normal tissue. A tumor or neoplasm may be “benign” or “malignant,” depending on the following characteristics: degree of cellular differentiation (including morphology and functionality), rate of growth, local invasion, and metastasis. A “benign neoplasm” is generally well differentiated, has characteristically slower growth than a malignant neoplasm, and remains localized to the site of origin. In addition, a benign neoplasm does not have the capacity to infiltrate, invade, or metastasize to distant sites. Exemplary benign neoplasms include, but are not limited to, lipoma, chondroma, adenomas, acrochordon, senile angiomas, seborrheic keratoses, lentigos, and sebaceous hyperplasia. In some cases, certain “benign” tumors may later give rise to malignant neoplasms, which may result from additional genetic changes in a subpopulation of the tumor’s neoplastic cells, and these tumors are referred to as “pre -malignant neoplasms.” An exemplary pre-malignant neoplasm is a teratoma. In contrast, a “malignant neoplasm” is generally poorly differentiated (anaplasia) and has characteristically rapid growth accompanied by progressive infiltration, invasion, and destruction of the surrounding tissue. Furthermore, a malignant neoplasm generally has the capacity to metastasize to distant sites. The term “metastasis,” “metastatic,” or “metastasize” includes the spread or migration of cancerous cells from a primary or original tumor to another organ or tissue and is typically identifiable by the presence of a “secondary tumor” or “secondary cell mass” of the tissue type of the primary or original tumor and not of that of the organ or tissue in which the secondary (metastatic) tumor is located.

[0318]

[0200] In certain embodiments, "treating a cancer" includes preventing the development of a cancer, reducing the symptoms of cancer, and / or inhibiting the growth of an established cancer or tumor. As used herein the term “inhibit” or “inhibition” in the context of cancer or tumor growth, for example, includes a reduction in the rate of growth (z.e., reduction in the rate of proliferation of the cancer or tumor’s cells). In some embodiments, the term refers to a reduction in the rate of cancer or tumor growth to a level that is statistically significantly lower than an initial rate (e.g. , the rate of tumor growth before administration or application of a compound provided herein). In some embodiments, the term refers to a reduction in the rate of cancer or tumor growth to a rate that is less than 75%, less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0. 1%, less than 0.01%, less than 0.001%, or less than 0.0001% of an initial rate (e.g., the rate of cancer or tumor growth before administration or application of a compound provided herein).

[0319]

[0201] In certain embodiments, treating cancer can result in a reduction in size or volume of a tumor. For example, after treatment, tumor size is reduced by 5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or greater) relative to its size prior to treatment. Size of a tumor may be measured by any reproducible means of measurement. The size of a tumor may be measured as a diameter of the tumor or by any reproducible means of measurement. In certain embodiments, the tumor size is reduced by at least 25% relative to its size prior to treatment.

[0320]

[0202] In certain embodiments, treating cancer may further result in a decrease in number of tumors. For example, after treatment, tumor number is reduced by 5% or greater (e.g. , 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or greater) relative to number prior to treatment. Number of tumors may be measured by any reproducible means of measurement. The number of tumors may be measured by counting tumors visible to the naked eye or at a specified magnification (e.g., 2x, 3x, 4x, 5x, lOx, or 50x).

[0321]

[0203] In certain embodiments, treating cancer can result in a decrease in number of metastatic nodules in other tissues or organs distant from the primary tumor site. For example, after treatment, the number of metastatic nodules is reduced by 5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or greater) relative to number prior to treatment. The number of metastatic nodules may be measured by any reproducible means of measurement. The number of metastatic nodules may be measured by counting metastatic nodules visible to the naked eye or at a specified magnification (e.g., 2x, lOx, or

[0322] 5 Ox).

[0323]

[0204] The term “inflammation” includes inflammation caused by or resulting from an inflammatory disease or inflammatory condition. Inflammatory diseases and conditions include those diseases, disorders or conditions that are characterized by signs of pain (dolor, from the generation of noxious substances and the stimulation of nerves), heat (calor, from vasodilatation), redness (rubor, from vasodilatation and increased blood flow), swelling (tumor, from excessive inflow or restricted outflow of fluid), and / or loss of function (functio laesa, which can be partial or complete, temporary or permanent. Inflammation takes on many forms and includes, but is not limited to, acute, adhesive, atrophic, catarrhal, chronic, cirrhotic, diffuse, disseminated, exudative, fibrinous, fibrosing, focal, granulomatous, hyperplastic, hypertrophic, interstitial, metastatic, necrotic, obliterative, parenchymatous, plastic, productive, proliferous, pseudomembranous, purulent, sclerosing, seroplastic, serous, simple, specific, subacute, suppurative, toxic, traumatic, and / or ulcerative inflammation. The term “inflammatory disease” may also refer to a dysregulated inflammatory reaction that causes an exaggerated response by macrophages, granulocytes, and / or T-lymphocytes leading to abnormal tissue damage and / or cell death. An inflammatory disease can be either an acute or chronic inflammatory condition and can result from infections or non-infectious causes. Inflammatory diseases include, without limitation, atherosclerosis, arteriosclerosis, autoimmune disorders, multiple sclerosis, systemic lupus erythematosus, polymyalgia rheumatica (PMR), gouty arthritis, degenerative arthritis, tendonitis, bursitis, psoriasis, cystic fibrosis, arthrosteitis, rheumatoid arthritis, inflammatory arthritis, Sjogren’s syndrome, giant cell arteritis, progressive systemic sclerosis (scleroderma), ankylosing spondylitis, polymyositis, dermatomyositis, pemphigus, pemphigoid, diabetes (e.g., Type I), myasthenia gravis, Hashimoto’s thyroiditis, Graves’ disease, Goodpasture’s disease, mixed connective tissue disease, sclerosing cholangitis, inflammatory bowel disease, Crohn’s disease, ulcerative colitis, pernicious anemia, inflammatory dermatoses, usual interstitial pneumonitis (UIP), asbestosis, silicosis, bronchiectasis, berylliosis, talcosis, pneumoconiosis, sarcoidosis, desquamative interstitial pneumonia, lymphoid interstitial pneumonia, giant cell interstitial pneumonia, cellular interstitial pneumonia, extrinsic allergic alveolitis, Wegener’s granulomatosis and related forms of angiitis (temporal arteritis and polyarteritis nodosa), inflammatory dermatoses, hepatitis, delayed-type hypersensitivity reactions (e.g., poison ivy dermatitis), pneumonia, respiratory tract inflammation, Adult Respiratory Distress Syndrome (ARDS), encephalitis, immediate hypersensitivity reactions, asthma, hayfever, allergies, acute anaphylaxis, rheumatic fever, glomerulonephritis, pyelonephritis, cellulitis, cystitis, chronic cholecystitis, ischemia (ischemic injury), reperfusion injury, allograft rejection, host-versus-graft rejection, appendicitis, arteritis, blepharitis, bronchiolitis, bronchitis, cervicitis, cholangitis, chorioamnionitis, conjunctivitis, dacryoadenitis, dermatomyositis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, gingivitis, ileitis, iritis, laryngitis, myelitis, myocarditis, nephritis, omphalitis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, pharyngitis, pleuritis, phlebitis, pneumonitis, proctitis, prostatitis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, testitis, tonsillitis, urethritis, urocystitis, uveitis, vaginitis, vasculitis, vulvitis, vulvovaginitis, angitis, chronic bronchitis, osteomyelitis, optic neuritis, temporal arteritis, transverse myelitis, necrotizing fasciitis, and necrotizing enterocolitis. An ocular inflammatory disease includes, but is not limited to, post-surgical inflammation.

[0324]

[0205] Additional exemplary inflammatory conditions include, but are not limited to, inflammation associated with acne, anemia (e.g., aplastic anemia, hemolytic autoimmune anemia), asthma, arteritis (e.g., polyarteritis, temporal arteritis, periarteritis nodosa, Takayasu’s arteritis), arthritis (e.g., crystalline arthritis, osteoarthritis, psoriatic arthritis, gouty arthritis, reactive arthritis, rheumatoid arthritis and Reiter’s arthritis), ankylosing spondylitis, amylosis, amyotrophic lateral sclerosis, autoimmune diseases, allergies or allergic reactions, atherosclerosis, bronchitis, bursitis, chronic prostatitis, conjunctivitis, Chagas disease, chronic obstructive pulmonary disease, cermatomyositis, diverticulitis, diabetes (e.g., type I diabetes mellitus, Type II diabetes mellitus), a skin condition (e.g., psoriasis, eczema, bums, dermatitis, pruritus (itch)), endometriosis, Guillain-Barre syndrome, infection, ischemic heart disease, Kawasaki disease, glomerulonephritis, gingivitis, hypersensitivity, headaches (e.g., migraine headaches, tension headaches), ileus (e.g., postoperative ileus and ileus during sepsis), idiopathic thrombocytopenic purpura, interstitial cystitis (painful bladder syndrome), gastrointestinal disorder (e.g., selected from peptic ulcers, regional enteritis, diverticulitis, gastrointestinal bleeding, eosinophilic gastrointestinal disorders (e.g., eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, eosinophilic colitis), gastritis, diarrhea, gastroesophageal reflux disease (GORD, or its synonym GERD), inflammatory bowel disease (IBD) (e.g., Crohn’s disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischemic colitis, diversion colitis, Behcet’s syndrome, indeterminate colitis) and inflammatory bowel syndrome (IBS)), lupus, multiple sclerosis, morphea, myasthenia gravis, myocardial ischemia, nephrotic syndrome, pemphigus vulgaris, pernicious anemia, peptic ulcers, polymyositis, primary biliary cirrhosis, neuroinflammation associated with brain disorders (e.g., Parkinson’s disease, Huntington’s disease, and Alzheimer’s disease), prostatitis, chronic inflammation associated with cranial radiation injury, pelvic inflammatory disease, reperfusion injury, regional enteritis, rheumatic fever, systemic lupus erythematosus, scleroderma, sarcoidosis, spondyloarthopathies, Sjogren’s syndrome, thyroiditis, transplantation rejection, tendonitis, trauma or injury (e.g., frostbite, chemical irritants, toxins, scarring, bums, physical injury), vasculitis, vitiligo and Wegener’s granulomatosis. In certain embodiments, the inflammatory disorder is selected from arthritis (e.g., rheumatoid arthritis), inflammatory bowel disease, inflammatory bowel syndrome, asthma, psoriasis, endometriosis, interstitial cystitis and prostatitis. In certain embodiments, the inflammatory condition is an acute inflammatory condition (e.g., for example, inflammation resulting from infection). In certain embodiments, the inflammatory condition is a chronic inflammatory condition (e.g., conditions resulting from asthma, arthritis and inflammatory bowel disease). The compounds may also be useful in treating inflammation associated with trauma and non-inflammatory myalgia. The compounds disclosed herein may also be useful in treating inflammation associated with cancer.

[0325]

[0206] The term “fibrosis” includes the development of fibrous connective tissue as a reparative response to injury or damage, including the pathological state of excessive production or excessive deposition of fibrous tissue, contraction of the extracellular matrix, and / or abnormalities of cells, fibronectin, and / or collagen. The term “fibrosis” includes fibrosis of organs or tissues of the body, for example, of the heart, kidney, liver, joint, lung, pleural tissue, peritoneal tissue, skin, cornea, retina, musculoskeletal, or gastrointestinal tract. Fibrosis may occur as a result of various etiologies, including, for example, idiopathic pulmonary fibrosis (IPF), cystic fibrosis, iatrogenic drug-induced fibrosis, occupation-induced fibrosis, environment-induced fibrosis, diffuse parenchymal lung disease, granulomatous disease (sarcoidosis, hypersensitivity pneumonia), collagen vascular disease, alveolar proteinosis, Langerhans cell granulomatosis, lymphangioleiomyomatosis, hereditary disease (Hermansky Pudlac) Syndrome, tuberous sclerosis, neurofibromatosis, metabolic accumulation disease, familial interstitial lung disease), radiation-induced fibrosis, chronic obstructive pulmonary disease (COPD), scleroderma, bleomycin- induced lung fiber Disease, chronic asthma, silicosis, asbestos-induced pulmonary fibrosis, acute respiratory distress syndrome (ARDS), renal fibrosis, tubulointerstitial fibrosis, glomerulonephritis, focal segmental glomerulosclerosis, IgA nephropathy Hypertension, alport, intestinal fibrosis, liver fibrosis, cirrhosis, alcohol-induced liver fibrosis, drug-induced liver fibrosis, hemochromatosis, non-alcoholic steatohepatitis (NASH), bile duct injury, primary biliary cirrhosis, infection-induced liver fibrosis, virus- induced liver fibrosis, autoimmune hepatitis, corneal scarring, hypertrophic scarring, Dupuytren’s disease, keloid, dermal fibrosis, cutaneous scleroderma, systemic sclerosis, spinal cord injury or fibrosis, myelofibrosis, vascular restenosis, atherosclerosis Arteriosclerosis, Wegener's granulomatosis, or Peyronie’s disease.

[0326]

[0207] In certain embodiments, treating a disease characterized by fibroblast activation protein (FAP) upregulation (e.g., cancer, fibrosis, or inflammation) can result in an increase in average survival time of a population of subjects treated according to the present disclosure in comparison to a population of untreated subjects. For example, the average survival time is increased by more than 30 days (more than 60 days, 90 days, or 120 days). An increase in average survival time of a population may be measured by any reproducible means. An increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with the compound of the present disclosure. An increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with the compound of the present disclosure.

[0327]

[0208] In certain embodiments, treating a disease characterized by fibroblast activation protein (FAP) upregulation (e.g., cancer, fibrosis, or inflammation) can also result in a decrease in the mortality rate of a population of treated subjects in comparison to an untreated population. For example, the mortality rate is decreased by more than 2% (e.g., more than 5%, 10%, or 25%). A decrease in the mortality rate of a population of treated subjects may be measured by any reproducible means, for example, by calculating for a population the average number of disease-related deaths per unit time following initiation of treatment with the compound of the present disclosure. A decrease in the mortality rate of a population may also be measured, for example, by calculating for a population the average number of disease- related deaths per unit time following completion of a first round of treatment with the compound of the present disclosure.

[0328]

[0209] In certain embodiments, treating a disease characterized by fibroblast activation protein (FAP) upregulation (e.g., cancer, fibrosis, or inflammation) can also result in an increased average progression- free survival time of a population of treated subjects in comparison to an untreated population. For example, the average progression-free survival time is increased by more than 30 days (more than 60 days, 90 days, or 120 days). An increase in average progression-free survival time of a population may be measured by any reproducible means. An increase in average progression-free survival time of a population may be measured, for example, by calculating for a population the average length of progression-free survival following initiation of treatment with the compound of the present disclosure. An increase in average progression-free survival time of a population may also be measured, for example, by calculating for a population the average length of progression-free survival following completion of a first round of treatment with the compound of the present disclosure. “Progression-free survival” as used herein includes the length of time during and after medication or treatment during which the disease being treated (e.g., a disease characterized by fibroblast activation protein (FAP) upregulation (e.g., cancer, fibrosis, or inflammation)) does not get worse.

[0329]

[0210] In certain embodiments, upon cleavage of the FAP -cleavable moiety, the camptothecin is released in its active for or in a form that is readily metabolized to its active form. In certain embodiments, a compound described here (e.g., a compound of Formula (I"), (F), or (I)), or a pharmaceutically acceptable salt thereof, has less than 50%, less than 60%, less than 70%, less than 80%, less than 90%, less than 95%, or less than 98% of the therapeutic activity of the active form of the camptothecin.

[0330] [2H] In certain embodiments, the FAP -cleavable moiety has a kcat / Kmfor cleavage by FAP at least 10- fold greater than for cleavage by prolyl endopeptidase (EC 3.4.21.26; PREP). In certain embodiments, the FAP-cleavable moiety has a kcat / Kmfor cleavage by FAP at least 100-fold, 1000-fold, 5000-fold, or 10,000-fold greater kcat / Km.

[0331]

[0212] In certain embodiments, a compound described herein (e.g., a compound of Formula (I"), (F), or (I)), or a pharmaceutically acceptable salt thereof, the compound, or a pharmaceutically acceptable salt thereof, has a therapeutic index that is at least 2 times greater than the therapeutic index of the camptothecin alone. In certain embodiments, a compound described herein (e.g., a compound of Formula (I"), (F), or (I)), or a pharmaceutically acceptable salt thereof, the compound, or a pharmaceutically acceptable salt thereof, has a therapeutic index that is at least at least 5, 10, 50, 100, 250, 500, 1000, 5000, or even 10,000 times greater of the camptothecin alone.

[0332]

[0213] In certain embodiments, a larger percentage of the camptothecin is localized in a target tissue (e.g. , tissue expressing FAP), relative to the administration of the camptothecin alone, when compared on an equivalent dose basis. In certain embodiments, the ratio of camptothecin localized to the target tissue relative to other tissue (e.g. , blood, liver or heart) is at least 2 times greater for an equivalent dose of the compound described herein (e.g., a compound of Formula (I"), (F), or (I)), or a pharmaceutically acceptable salt thereof, relative to the camptothecin alone. In certain embodiments, the ratio of camptothecin localized to the target tissue relative to other tissue (e.g., blood, liver or heart) is at least 5, 10, 100, or 1,000 times greater for an equivalent dose of the compound described herein (e.g., a compound of Formula (I"), (F), or (I)), or a pharmaceutically acceptable salt thereof, relative to the camptothecin alone.

[0333]

[0214] In certain embodiments, the maximum tolerated dose of a compound described herein (e.g., a compound of Formula (I"), (F), or (I)), or a pharmaceutically acceptable salt thereof, is at least 2 times greater than the maximum tolerated dose of the camptothecin alone. In certain embodiments, the maximum tolerated dose of a compound described herein (e.g., a compound of Formula (I"), (F), or (I)), or a pharmaceutically acceptable salt thereof, is at least 5, 10, 100, or 1000 times greater than the maximum tolerated dose of the camptothecin alone.

[0334]

[0215] In certain embodiments, a compound described herein (e.g., a compound of Formula (I"), (I'), or (I)), or a pharmaceutically acceptable salt thereof, has less than 10% activity relative to the free or active camptothecin derived or released therefrom. In an embodiment, a compound described herein (e.g., a compound of Formula (I"), (I'), or (I)), or a pharmaceutically acceptable salt thereof, has less than 5% activity relative to the free or active camptothecin derived or released therefrom. In an embodiment, a compound described herein (e.g, a compound of Formula (I"), (I'), or (I)), or a pharmaceutically acceptable salt thereof, has less than 1% activity relative to the free or active camptothecin derived or released therefrom.

[0335]

[0216] In certain embodiments, the cell permeability of a compound described herein (e.g, a compound of Formula (I"), (F), or (I)), or a pharmaceutically acceptable salt thereof, is at least 50% less than the cell permeability of the camptothecin. In certain embodiments, the cell permeability of a compound described herein (e.g. , a compound of Formula (I"), (F), or (I)), or a pharmaceutically acceptable salt thereof, is at least 60% less, 70% less, 80% less, 90% less, 95% less, 98% less, 99% less, or 99.9% less than the cell permeability of the camptothecin.

[0336]

[0217] In certain embodiments, the circulating half-life of a compound described herein (e.g., a compound of Formula (I"), (F), or (I)), or a pharmaceutically acceptable salt thereof, is at least 25% longer than the circulating half-life of the camptothecin alone. In certain embodiments, the circulating half-life of a compound described herein (e.g., a compound of Formula (I"), (F), or (I)), or a pharmaceutically acceptable salt thereof, is at least 50%, 75%, 100%, 150%, 200%, 500%, 750%, or even 1000% longer than the circulating half-life of the camptothecin alone.

[0337] EXAMPLES

[0338]

[0218] In order that the present disclosure may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting in their scope.

[0339]

[0219] The examples provided below include procedures, intermediates, and characterization data useful, e.g., for the preparation of compounds provided herein. All synthetic steps, procedures, compounds (e.g., synthetic intermediates), reaction conditions, reaction mixtures, reagents, etc. are included herein as aspects of the present disclosure.

[0340] Synthesis of Compounds

[0341]

[0220] Exemplary methods and general procedures that may be used to provide the compounds of the present disclosure are shown below.

[0342] Abbreviations

[0343] Aq. aqueous

[0344] Boc tert-butyloxycarbonyl d days dba dibenzylideneacetone

[0345] DCM dichloromethane

[0346] Dess Martin I. l . l -Tris(acctyloxy)- l . l -dihydro- l.2-bcnziodoxol-3-( IH)-onc periodinane DIEA diisopropylethylamine

[0347] DMAP 4-dimethylaminopyridine

[0348] DMF dimethylformamide

[0349] Dppf 1, l'-bis(diphenylphosphino)ferrocene

[0350] DSC AA'-disiiccini idyl carbonate

[0351] EEDQ ethyl -2 -ethoxyquinoline- 1 (2H) -carboxylate

[0352] EtOAc ethyl acetate

[0353] Exatecan ( IS, 95)- 1 -amino-9-ethyl-5 -fluoro-9-hydroxy-4-methyl- 1,2, 3, 9, 12, 15 -hexahydro-

[0354] 1 OH, 13H benzo [de]pyrano [3 ',4' : 6,7]indolizino [ 1 ,2- b] quinoline- 10, 13 -dione

[0355] Fmoc fluorenyhnethyloxycarbonyl

[0356] H hours

[0357] HATU hexafluorophosphate azabenzotriazole tetramethyl uranium

[0358] HOBt hydroxybenzotriazole

[0359] HPLC high performance liquid chromatography

[0360] IPA isopropanol

[0361] MeCN acetonitrile min minutes

[0362] NBS A-bromosiiccinimidc

[0363] NCS A-chlorosiiccinimidc

[0364] NMI 1 -methyl - IH-imidazole

[0365] NMR nuclear magnetic resonance

[0366] PEG polyethylene glycol rt room temperature sat. saturated

[0367] T3P propylphosphonic anhydride

[0368] TBAF tetrabutyl aluminium fluoride

[0369] TBME tert-butyl methyl ether

[0370] TBS tert-butyl di-methyl silyl

[0371] TCFH X-(chloro(dimethylamino)methylene)-N-methylmethanaminium hexafluorophosphate(V)

[0372] THF tetrahydrofuran

[0373] TLC thin layer chromatography

[0374] XantPhos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene

[0375] Examples and Intermediate Compounds

[0376] Experimental Methods

[0377]

[0221] All reagents were commercial grade and were used as received without further purification, unless otherwise specified. Reagent grade solvents were used, unless otherwise specified. Reactions were conducted at room temperature unless otherwise specified. Manual normal phase column chromatography was carried out using glass columns over silica gel (200-300 mesh, SANPONT, Yucheng Chemical (Shanghai) Co., Ltd.). Automated normal phase column chromatography was carried out using a Teledyne Isco Combiflash Nextgen300+, Lumen or Lumen+ equipped with Redisep Silver or Buchi Flashpure columns. Alternatively, a Biotage Isolera equipped with WelFlash, SiCL LS Irregular, 40-63 pm, 60 A, (40 g, 120 g, 220 g, 330 g) cartridges was used. Reverse phase column chromatography was carried out using a Biotage Isolera equipped with SiliaSep C18 Flash cartridges. Preparative TLC was carried out using 20 cm x 20 cm silica gel F254 pre-coated plates, supplied by SANPONT, Yucheng Chemical (Shanghai) Co., Ltd. Preparative reverse phase HPLC was performed using a Waters HClass (binary solvent pump) and an acidic, (ACQUITY UPLC® CSH C18, 130A, 1.7 pm, 2.1 x 30 mm at 40 °C, UV at 210 - 400 nm unless otherwise indicated, MS by electrospray ionisation, 98% water + 0. 1% formic acid / 2% MeCN to 100% MeCN), basic (ACQUITY UPLC® BEH Cl 8, 130 A. 1.7 pm, 2.1 x 30 mm at 40 °C, UV at 210 - 400 nm unless otherwise indicated, MS by electrospray ionisation, 98% water + 0.1% ammonia / 2% MeCN to 100% MeCN) or neutral method (ACQUITY UPLC® CSH C18, BOA, 1.7 pm, 2.1 x 30 mm at 40 °C, UV at 210 - 400 nm unless otherwise indicated, MS by electrospray ionisation, 98% 10 mM NFLOAc in water / 2% MeCN to 100% MeCN). Alternatively, a Shimadzu LC- 20AP system with a quaternary solvent pump and diode array detector with Agilent 10 Prep-C18, 250 x 21.2mm, 10 pm or Boston Prep-C18, 250 x 21.2mm, 10 pm columns were utilised.

[0378]

[0222] Compound analysis was performed by LC-MS and NMR. LC-MS data was collected using an Aglient 1260 or 1290 with either an acidic (Cortecs C18, 90A, 2.7 pM, 30 x 2.1 mm at 40 °C, UV at 260nm + / - 90nm unless otherwise indicated, MS by electrospray ionisation, 98% water + 0.1% formic acid / 2% MeCN to 100% MeCN) or basic (Kinetex Evo C18, 100A, 2.6 pM, 30 x 2. 1 mm at 40 °C, UV at 260nm + / - 90nm unless otherwise indicated, MS by electrospray ionisation, 98% water + 0.1% ammonia / 2% MeCN to 100% MeCN) method. Alternatively a Shimadzu LC-MS2020 (Shimadzu LC- 20XR series, Binary Pump, Diode Array Detector) system was utilised.vNMR spectra were recorded using a Bruker 500MHz Avance III HD spectrometer equipped with a Bruker 5mm SmartProbe™ or Q.One Instruments, Quantum-I Plus 400 MHz spectrometer. Spectra were measured at 298 K, unless indicated otherwise, and were referenced relative to the solvent resonance. The chemical shifts are reported in parts per million. Data were acquired using Bruker TopSpin software and processed using MestreNova software. Compounds were typically dried using a lyophiliser. The compounds prepared were named using IUPAC nomenclature.

[0379]

[0223] Experimental Procedures

[0380]

[0224] INTERMEDIATE A

[0381]

[0225] Tert-butyl l-hydroxy-3,6,9,12,15,18,21-heptaoxatetracosan-24-oate

[0226] To a solution of 3,6,9,12,15,18-hexaoxaicosane-l,20-diol (4.00 g, 12.3 mmol) in DCM (40 mL) was added Na (56.4 mg, 2.5 mmol) in pieces at 0 °C under N2. The mixture was stirred at 0 °C for 30 mins. tert-Butyl acrylate (1.25 g, 9.8 mmol) in DCM (10 mL) was added slowly and the reaction mixture was stirred at rt for 16 h. The mixture was diluted with water (100 mL) and extracted with DCM (30 mL x 4). The combined organic layers were washed with brine, dried over Na2SC>4 and concentrated under vacuum. The residue was purified by column chromatography to afford the title compound (1.80 g, 32.7%) as a colourless oil. LC-MS m / z = 455.20 [M+H]+; ’H NMR (400 MHz, DMSO-cL) 5 4.56 (t, J= 5.5 Hz, 1H), 3.60 - 3.40 (m, 30H), 2.41 (t, J= 6.2 Hz, 2H), 1.39 (s, 9H).

[0382]

[0227] INTERMEDIATE B

[0383]

[0228] 2,5,8,ll,14,17,20,23-octaoxapentacosan-25-yl 4-methylbenzenesulfonate

[0384]

[0229] To a solution of 2,5,8,ll,14,17,20,23-octaoxapentacosan-25-ol (500 mg, 1.30 mmol), TEA (0.27 mL, 1.95 mmol) and DMAP (32.0 mg, 0.26 mmol) in DCM (10 mL) was added TsCl (372 mg, 1.95 mmol) at 0 °C. The reaction mixture was stirred at rt for 2h. The mixture was poured into water (80 mL) and extracted with DCM (40 mL x 3). The combined organic layers were washed with brine, dried over Na2SC>4 and concentrated under vacuum to give the title compound (1.10 g, crude) as an oil. LC-MS m / z = 539.20 [M+H]+.

[0385]

[0230] Intermediates C - F were prepared in a similar manner to intermediate B by sulfonate protection of a primary alcohol. See table 1 below.

[0386]

[0231] Table 1: Protection of primary alcohol

[0387]

[0232] INTERMEDIATE G

[0388]

[0233] Methyl 3-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)isonicotinate

[0389]

[0234] To a solution of methyl 3-hydroxyisonicotinate (100 mg, 0.65 mmol) in DMF (2.0 mL) was added CS2CO3 (424 mg, 1.30 mmol) and l-bromo-2-(2-(2-methoxyethoxy)ethoxy)ethane (222 mg, 0.98 mmol) The reaction mixture was stirred at rt for 16 h. The mixture was diluted with water (40 mL) and extracted with 3: 1 DCM / IPA (20 mL x 3). The combined organic layers were washed with brine, dried over Na2SC>4, fdtered and concentrated under vacuum. The mixture was purified by Prep-TLC to afford the title compound (120 mg, 88%) as a yellow oil. LC-MS m / z = 300.10 [M+H]+; 'H NMR (400 MHz, DMSO-6) 5 8.59 (s, 1H), 8.31 (d, J= 4.8 Hz, 1H), 7.54 (d, J= 4.8 Hz, 1H), 4.33 - 4.28 (m, 2H), 3.83 (s, 3H), 3.78 - 3.73 (m, 2H), 3.63 - 3.58 (m, 2H), 3.54 - 3.48 (m, 4H), 3.44 - 3.39 (m, 2H), 3.22 (s, 3H).

[0390]

[0235] Intermediates H - J was prepared in a similar manner to intermediate G via PEGylation of methyl 3-hydroxyisonicotinate. See table 2 below.

[0391]

[0236] Table 2: PEGylation of methyl 3-hydroxyisonicotinate

[0392]

[0237] INTERMEDIATE K

[0393]

[0238] tert- Butyl 2-bromoquinoline-4-carboxylate

[0394]

[0239] To a solution of 2-bromoquinoline-4-carboxylic acid (200 mg, 0.79 mmol) and DMAP (48.5 mg, 0.40 mmol) in THF (8.0 mL) was added BOC2O (450 mg, 2.06 mmol) slowly at 0 °C. The reaction mixture was stirred at rt for 16 h. The mixture was diluted with water (80 mL) and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SC>4, filtered and concentrated under vacuum. The residue was purified by column chromatography to afford the title compound (250 mg, 83%) as a white solid. LC-MS m / z = 309.95 [M+H]+; ’H NMR (400 MHz, DMSO- d6) 5 8.47 (dd, J= 8.6, 1.6 Hz, 1H), 8.06 (dd, J= 8.6, 1.2 Hz, 1H), 7.98 (s, 1H), 7.93 - 7.87 (m, 1H), 7.82 - 7.76 (m, 1H), 1.64 (s, 9H).

[0395]

[0240] INTERMEDIATE L

[0396]

[0241] / er / - Butyl 2-(4-bromopyridin-2-yl)acetate

[0397]

[0242] To a solution of 4-bromo-2-methylpyridine (2.00 g, 11.6 mmol) in THF (20 mL) was added LDA (1.0 M in THF, 34.9 mL, 34.9 mmol) at -78 °C and stirred at -78 °C for 1 h. BOC2O (5.07 g, 23.3 mmol) was added and the reaction mixture was stirred at -78 °C for 2 h and then at rt for 16 h. The mixture was quenched with sat. aq. NH4CI and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine, dried over Na2SC>4, filtered and concentrated under vacuum. The residue was purified by column chromatography to afford the title compound (1.00 g, 32%) as a yellow solid. LC-MS m / z = 272.0 and 274.0 [M+H]+; 'H NMR (400 MHz, DMSO-r / 4) 8 8.38 (d, J= 5.3 Hz, 1H), 7.63 (d, J = 1.9 Hz, 1H), 7.57 - 7.54 (m, 1H), 3.75 (s, 2H), 1.39 (s, 9H).

[0398]

[0243] INTERMEDIATE M

[0399]

[0244] Methyl 2-(2-( / er / -butoxy)-2-oxoethyl)isonicotinate

[0400]

[0245] A mixture of intermediate L (900 mg, 3.31 mmol), DIEA (1.73 mL 9.92 mmol) and

[0401] Pd(dppf)C12 DCM (270 mg, 0.33 mmol) in MeOH (10 mL) was stirred at 50 °C under CO atmosphere for 16 h. The mixture was diluted with water (80 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, fdtered and concentrated under vacuum. The residue was purified by column chromatography to afford the title compound (900 mg, 98%) as a brown oil. LC-MS m / z = 252.1 [M+H]+; 'H NMR (400 MHz, DMSO-tL) 5 8.72 - 8.65 (m, 1H), 7.81 - 7.67 (m, 2H), 3.90 (s, 3H), 3.86 (s, 2H), 1.39 (s, 9H).

[0402]

[0246] Intermediate N was prepared in a similar manner to intermediate M via carbonylation. See table 3 below.

[0403]

[0247] Table 3: Carbonylation of aryl bromide

[0404]

[0248] INTERMEDIATE O

[0405]

[0249] Ethyl 6-morpholinoquinoline-4-carboxylate

[0406]

[0250] A mixture of ethyl 6-bromoquinoline-4-carboxylate (250 mg, 892 pmol), morpholine (390 pL, 4.46 mmol) and CS2CO3 (582 mg, 1.78 mmol) in Dioxane (15 mL) was purged with nitrogen for 10 min.

[0407] RuPhos Pd G4 (75.9 mg, 89.2 pmol) was added and the reaction mixture was stirred at 100 °C for 16 h under N2. The reaction mixture was concentrated under vacuum. The residue was dissolved in EtOAc (30 mL), washed with water (30 mL) and brine (30 mL), dried over MgSO4, filtered and concentrated under vacuum. The residue was purified by column chromatography to afford the title compound (225 mg, 85 %,) as a yellow solid. LC-MS m / z = 287.2 [M+H]+;1H NMR (500 MHz, DMSO) 5 8.77 (d, J = 4.5 Hz, 1H), 7.96 (d, J = 9.3 Hz, 1H), 7.92 (d, J = 2.8 Hz, 1H), 7.85 (d, J = 4.4 Hz, 1H), 7.73 (dd, J = 9.4, 2.8 Hz, 1H), 4.43 (q, J = 7.1 Hz, 2H), 3.82 - 3.78 (m, 4H), 3.31 - 3.27 (m, 4H), 1.39 (t, J = 7.1 Hz, 3H).

[0408]

[0251] INTERMEDIATE P

[0409]

[0252] 2-(3,4-Dichlorophenyl)ethanethioamide

[0410]

[0253] A solution of 2-(3,4-dichlorophenyl)acetamide (1.00 g, 4.90 mmol) and Lawesson's reagent (2.18 g, 5.39 mmol) in THF (30 mL) was stirred at 80 °C for 16 h. Sat. aq. NaHCOs (40 mL) was added and the reaction mixture extracted with EtOAc (40 mL x 3). The combined organic layers were dried over MgSC>4, fdtered and concentrated under vacuum. The residue was purified by column chromatography to afford the title compound (864 mg, 76%) as a beige solid. LC-MS m / z = 220.0 [M+H]+.

[0411]

[0254] INTERMEDIATE Q

[0412]

[0255] Ethyl 2-(3,4-dichlorobenzyl)thiazole-4-carboxylate

[0413]

[0256] A solution of intermediate P (864 mg, 3.73 mmol) and ethyl 3-bromo-2-oxopropanoate (468 pL, 3.73 mmol) in EtOH (25 mL) was stirred at 80 °C for 2 h. The reaction mixture was concentrated under vacuum and the residue was triturated with MTBE to afford the title compound (883 mg, 71%) as a white solid. LC-MS m / z = 316.0 [M+H]+; 'H NMR (500 MHz, DMSO) 5 8.41 (s, 1H), 7.67 (d, J= 2.1 Hz, 1H), 7.62 (d, J= 8.3 Hz, 1H), 7.35 (dd, J= 8.3, 2.1 Hz, 1H), 4.42 (s, 2H), 4.28 (q, J= 7.I Hz, 2H), 1.29 (t, J= 7.1 Hz, 3H).

[0414]

[0257] INTERMEDIATE R

[0415]

[0258] Methyl 2-(N-acetylsulfamoyl)isonicotinate

[0416]

[0259] To a solution of methyl 2-sulfamoylisonicotinate (200 mg, 925 pmol) and DMAP (113 mg, 925.0 pmol) in DCM (1.00 mL) was added TEA (774 pL, 5.55 mmol) and acetyl chloride (0.20 mL, 2.78 mmol) and the reaction mixture was stirred at rt for 48 h. The reaction mixture was concentrated under vacuum and the residue was purified by column chromatography to afford the title compound (240 mg, 64%) as a yellow solid. LC-MS m / z = 259.0 [M+H]+; ’H NMR (500 MHz, DMSO) 5 9.43 (s, 1H), 8.94 (dd, J= 4.9, 0.9 Hz, 1H), 8.36 (dd, J= 1.6, 0.8 Hz, 1H), 8.10 (dd, J= 4.9, 1.6 Hz, 1H), 3.95 (s, 3H), 1.92 (s, 3H).

[0417]

[0260] INTERMEDIATE S

[0261] 2-(2-( / e / 7-Butoxy)-2-oxoethyl)isonicotinic acid

[0418]

[0262] To a solution of intermediate M (200 mg, 0.79 mmol) in 4: 1 THF / water (5.0 mL) was added LiOHH2O (66.8 mg, 1.59 mmol) at 0 °C. and the reaction mixture was stirred at rt for 1 h. The mixture was acidified to pH 3 with IN HC1 solution. The mixture was diluted with water (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under vacuum to afford the title compound (120 mg, 63.5 %) as a white solid. LC-MS m / z = 238.1 [M+H]+; 'HNMR (400 MHz, DMSO-tL) 5 13.64 (s, 1H), 8.67 (d, J= 5.1 Hz, 1H), 7.82 - 7.65 (m, 2H), 3.85 (s, 2H), 1.40 (s, 9H).

[0419]

[0263] Intermediates T - AA were prepared in a similar manner to intermediate S, via ester hydrolysis. See table 4 below.

[0420]

[0264] Table 4: Ester hydrolysis of heterocyclic acids

[0421]

[0265] INTERMEDIATE AB

[0422]

[0266] 1 -( / er / - Butyl) 2-methyl (A)-4-methylenepyrrolidine-l,2-dicarboxylate

[0423]

[0267] To a solution of methyltriphenylphosphonium bromide (8.81 g, 24.7 mmol) in THF (20 mL) was added tBuOK (2.77 g, 24.7 mmol) at 0 °C and the reaction mixture was stirred at 0 °C for 2 h. l-(tert- Butyl) 2-methyl (.S)-4-oxopyrrolidinc- L2-dicarboxylatc (3.00 g, 12.33 mmol) in THF (30 mL) was added and the reaction mixture was stirred at rt for 2 h. The mixture was diluted with water (200 mL) and extracted with EtOAc (60 mL x 3). The combined organic layers were washed with brine, dried over Na2SC>4, filtered and concentrated under vacuum. The residue was purified by column chromatography to afford the title compound (600 mg, 20%) as a colourless oil. LC-MS m / z = 186.10 [M-Thi+H]+; 'H NMR (400 MHz, DMSO-d6) 5 5.03 - 4.98 (m, 2H), 4.40 - 4.31 (m, 1H), 3.99 - 3.90 (m, 2H), 3.66 - 3.61 (m, 3H), 3.06 - 2.95 (m, 1H), 2.58 - 2.51 (m, 1H), 1.41 - 1.33 (m, 9H).

[0424]

[0268] INTERMEDIATE AC

[0425]

[0269] 1 -(tert- Butyl) 2-methyl (2A)-4-hydroxy-4-(trifluoromethyl)pyrrolidine-l,2-dicarboxylate

[0426]

[0270] To a solution of 1 -(tert-butyl) 2-methyl (.S')-4-oxopyrrolidinc- 1,2-dicarboxylate (4.00 g, 16.4 mmol) in THF (50 mL) at 0 °C was added CFsSiMes (34.2 g, 264 mmol) and TBAF (IM in THF, 0.09 mL, 0.09 mmol) and the reaction mixture was stirred at rt for 16 h. The reaction mixture was quenched with sat. aq. NH4C1 (30 mL) and TBAF (IM in THF, 17 mL, 16.9 mmol) and stirred at rt for 20 min. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (60 mL x 3). The combined organic layers were washed with brine, dried over Na2SC>4, filtered and concentrated under vacuum. The residue was purified by column chromatography to afford the title compound (1.50 g, 29%) as a yellow oil. LC- MS m / z = 258.00 [M-'Bu+H] ; H NMR (400 MHz, DMSO-tL) 5 6.57 (s, 1H), 4.52 - 4.41 (m, 1H), 3.67 - 3.63 (m, 3H), 3.62 - 3.47 (m, 2H), 2.65 - 2.55 (m, 1H), 2.15 - 2.08 (m, 1H), 1.42 - 1.34 (m, 9H).

[0427]

[0271] INTERMEDIATE AD

[0428]

[0272] l-(tert-Butyl) 2-methyl (A)-4-(trifluoromethyl)-2,3-dihydro-l / 7-pyrrole-l,2-dicarboxylate

[0429]

[0273] To a solution of intermediate AC (1.50 g, 4.79 mmol) in pyridine (44 mL) was added SOCL (4.4 mL) under N2 and the reaction mixture was stirred at 115 °C for 20 mins. The mixture was poured into ice water, extracted with EtOAc (50 mL x 3). washed with brine, dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by column chromatography to afford the title compound (680 mg, 60%) as a yellow oil. LC-MS m / z = 240.00 [M-Thi+H]+; ’HNMR (400 MHz, DMSO-d6) 5 6.72 - 6.66 (m, 1H), 5.21 - 5.13 (m, 1H), 4.35 - 4.29 (m, 2H), 3.73 - 3.68 (m, 3H), 1.44 - 1.35 (m, 9H).

[0430]

[0274] INTERMEDIATE AE

[0431]

[0275] l-(tert-Butyl) 2-methyl (2A)-4-methylpyrrolidine-l,2-dicarboxylate

[0432]

[0276] To a solution of intermediate AB (550 mg, 2.25 mmol) in MeOH (5 mL) was added 10% Pd / C

[0433] (120 mg, 0.11 mmol) and the reaction mixture was stirred at rt for 2 h under H2. The reaction mixture was filtered and concentrated under vacuum to afford the title compound (500 mg, 91%) as a white solid. LC- MS m / z = 188.10 [M-'Bu+H] ; 'HNMR (400 MHz, DMSO-;L) 5 4.18 - 4.10 (m, 1H), 3.68 - 3.49 (m, 4H), 2.87 - 2.76 (m, 1H), 2.41 - 2.31 (m, 1H), 2.27 - 1.92 (m, 2H), 1.39 - 1.30 (m, 9H), 1.03 - 0.93 (m, 3H).

[0434]

[0277] Intermediate AF was prepared in a similar manner to intermediate AE, via hydrogenation. See table 5 below.

[0435]

[0278] Table 5: Hydrogenation of alkene

[0436]

[0279] INTERMEDIATE AG

[0437]

[0280] Methyl (2A)-4-methylpyrrolidine-2-carboxylate

[0438]

[0281] To a solution of intermediate AE (500 mg, 2.05 mmol) in DCM (12 mb) was added 4 M HC1 in dioxane (6 mb) at 0 °C and the reaction mixture was stirred at rt for 2 h. The mixture was concentrated under vacuum to afford the title compound (300 mg, 92%) as a yellow oil. LC-MS m / z = 144.10 [M+H]+.

[0439]

[0282] Intermediate AH was prepared in a similar manner to intermediate AG , via Boc deprotection. See table 6 below.

[0440]

[0283] Table 6: Boc deprotection of proline derivatives

[0441]

[0284] INTERMEDIATE Al

[0285] To a solution of isonicotinic acid (3.40 g, 27.64 mmol), tert-butyl D-alaninate (5.02 g, 27.6 mmol) in DMF (40 mL) was added DIEA (14.3 g, 111 mmol) and HATU (10.50 g, 27.6 mmol) at 0 °C. The reaction mixture was stirred at rt for 2h. The mixture was diluted with water (400 mL) and extracted with DCM (80 mL x 3). The combined organic layers were washed with brine, dried over Na2SC>4, fdtered and concentrated under vacuum. The residue was purified by column chromatography to afford the tile compound (5.50 g, 79%) as yellow oil. LC-MS m / z = 251.1 [M+H]+; ’H NMR (400 MHz, DMSO-t / e) 5 8.96 (d, J= 7.0 Hz, 1H), 8.76 - 8.70 (m, 2H), 7.80 - 7.75 (m, 2H), 4.40 - 4.29 (m, 1H), 1.41 (s, 9H), 1.40 - 1.37 (m, 3H).

[0442]

[0286] INTERMEDIATE AJ

[0443]

[0287] To a solution of intermediate Al (5.50 g, 22.0 mmol) in H2O (20 mL) was added 4N HC1 (60 mL) dropwise at 0 °C. The reaction mixture was stirred at rt for 16 h. The reaction mixture was concentrated under vacuum to afford the title compound (4.80 g, 90%) as yellow oil. LC-MS m / z = 195.05 [M+H]+; ’H NMR (400 MHz, DMSO-6) 5 9.41 (d, J= 7.2 Hz, 1H), 9.00 - 8.95 (m, 2H), 8.26 - 8.19 (m, 2H), 4.45 (p, J = 7.4 Hz, 1H), 1.43 (d, J = 7.4 Hz, 3H).

[0444]

[0288] INTERMEDIATE AK

[0445]

[0289] Methyl (tert-butoxycarbonyl)-Z)-alanyl-Z-prolinate

[0446]

[0290] A solution of (tert-butoxycarbonyl)-D-alanine (1.00 g, 5.285 mmol), HATU (3.01 g, 7.92 mmol) and DIEA (3.68 mL, 21.1 mmol) in DMF (15 mL) was stirred at rt for 30 min. Methyl Z-prolinate (875 mg, 5.29 mmol) was added and the reaction mixture was stirred at rt for 3 h. The mixture was diluted with water (200 ml) and extracted with EtOAc (50 ml x 3). The combined organic layers were washed with brine, dried over Na2SC>4 and concentrated under vacuum. The residue was purified by column chromatography to afford the title compound (1.25 g, 63%) as a white solid. LC-MS m / z = 201.1 [M+H- 100]+ 'H NMR (400 MHz, DMSO-6) 5 7.23 - 6.50 (m, 1H), 4.35 - 4.22 (m, 1H), 3.71 - 3.33 (m, 5H), 2.23 - 1.77 (m, 4H), 1.37 (d, J = 8.8 Hz, 9 H), 1.18 - 1.04 (m, 3H).

[0447]

[0291] Intermediates AL - AS were synthesised in a similar manner to intermediate AJ, see table 7 below.

[0292] Table 7 : Amide coupling with (tert-butoxycarbonyl)-D-alanine or glycine

[0448]

[0293] INTERMEDIATE AT

[0449]

[0294] Methyl Z>-alanyl-Z-prolinate

[0450]

[0295] To a solution of intermediate AK (1.25 g, 4.16 mmol) in DCM (18 mL) was added 4 M HC1 in dioxane (9 mL) dropwise and the reaction mixture was stirred at rt for 2 hours. The mixture was concentrated under vacuum to afford the title compound (833 mg, 99%) as a yellow solid. LC- MS m / z = 201.1 / 401.2 [M+H]+; 'HNMR (400 MHz, DMSO-6) 5 8.42 - 8.19 (m, 2H), 4.39 - 4.13 (m, 1H), 3.76 - 3.68 (m, 1H), 3.64 - 3.55 (m, 3H), 3.54 - 3.45 (m, 2H), 2.25 - 1.70 (m, 4H), 1.38 - 1.21 (m, 3H).

[0451]

[0296] INTERMEDIATE AU

[0452]

[0297] Methyl (6-methoxyquinoline-4-carbonyl)-Z>-alanyl-Z-prolinate

[0453]

[0298] To a solution of 6-methoxyquinoline-4-carboxylic acid (913 mg, 4.50 mmol), HATU (2.56 g, 6.74 mmol) and DIEA (3.91 mL, 22.5 mmol) in DMF (15 mL) was added and intermediate AT (900 mg, 4.50 mmol) in DMF (3 mL). The reaction mixture was stirred at rt for 1 h. The reaction mixture was diluted with water (80 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SC>4 and concentrated under vacuum. The residue was purified by column chromatography to afford the title compound (800 mg, 46%) as a yellow solid. LC-MS m / z = 386.2 [M+H]+; 'H NMR (400 MHz, DMSO-6) 5 9.23 - 8.93 (m, 1H), 8.80 - 8.75 (m, 1H), 8.00 - 7.93 (m, 1H), 7.71 - 7.53 (m, 1H), 7.51 - 7.41 (m, 2H), 5.16 - 4.86 (m, 1H), 4.56 - 4.30 (m, 1H), 3.92 - 3.82 (m, 4H), 3.71 - 3.55 (m, 4H), 2.25 - 2.14 (m, 1H), 2.03 - 1.83 (m, 3H), 1.40 - 1.29 (m, 3H).

[0454]

[0299] Intermediates AV - BA were prepared similarly to intermediate AU by amide formation with the appropriate acid, see table 8 below.

[0455]

[0300] Table 8: Amide coupling with methyl D-alanyl-L-prolinate derivatives

[0456]

[0301] INTERMEDIATE BB

[0457]

[0302] Methyl (2A,4 / ?)- l-(( / e / 7-butoxycarbonyl)-D-alanyl)-4-((tert- butyldimethylsilyl)oxy)pyrrolidine-2-carboxylate

[0458]

[0303] To a solution of intermediate AQ (1.80 g, 5.68 mmol) and imidazole (1.16 g, 17.0 mmol) in DMF (20 mL) was added TBSC1 (1.29 g, 8.53 mmol) slowly at 0 °C and the reaction mixture was stirred at rt for 16 h. The mixture was diluted with water (200 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with water and brine, dried over Na2SC>4, filtered and concentrated under vacuum. The residue was purified by column chromatography to afford the title compound (2.20 g, 90%) as a colourless oil. LC-MS m / z = 431.1 [M+H]+. 'HNMR (400 MHz, DMSO-6) 5 7.22 - 6.88 (m, 1H), 4.59 - 4.48 (m, 1H), 4.32 - 4.19 (m, 2H), 3.77 - 3.66 (m, 1H), 3.63 - 3.57 (m, 3H), 3.46 - 3.38 (m, 1H), 2.26 - 1.91 (m, 2H), 1.42 - 1.34 (m, 9H), 1.18 - 1.08 (m, 3H), 0.90 - 0.78 (m, 9H), 0.14 - 0.03 (m, 6H).

[0459]

[0304] INTERMEDIATE BC

[0460]

[0305] Methyl (2A,47?)-l-(isonicotinoyl-Z>-alanyl)-4-((methylsulfonyl)oxy)pyrrolidine-2-carboxylate

[0461]

[0306] To a solution of intermediate AS (1.00 g, 3.11 mmol) and TEA (1.30 mL, 9.33 mmol) in DCM (10 mL) were added MsCl (0.36 mL, 4.66 mmol) slowly at 0 °C and the reaction mixture was stirred at rt for 1 h. The reaction mixture was diluted with water (100 mL) and extracted with DCM (50 mL x 3). The combined organic layers were washed with brine, dried over Na2SC>4 and concentrated under vacuum to afford the title compound (864 mg, 70%) as a yellow oil. LC-MS m / z = 400. 1 [M+H]+.

[0307] INTERMEDIATE BD

[0462]

[0308] Methyl (2A,4A)-4-azido-l-(isonicotinoyl-Z>-alanyl)pyrrolidine-2-carboxylate

[0463]

[0309] A solution of intermediate BC (864 mg, 2.16 mmol) and NaN; (703 mg, 10.8 mmol) in DMF (10 mL) was stirred at 90 °C for 3 h. The reaction mixture was diluted with water (60 mL) and extracted with 3: 1 DCM / IPA (20 mL x 3). The combined organic layers were dried over Na2SC>4 and concentrated under vacuum. The residue was purified by column chromatography to afford the title compound (647 mg, 86%) as a yellow oil. LC-MS m / z = 347.2 [M+H]+. ’H NMR (400 MHz, DMSO-tL) 5 9.18 - 8.93 (m, 1H), 8.76 - 8.68 (m, 2H), 7.95 (s, 1H), 7.83 - 7.75 (m, 2H), 5.34 - 4.78 (m, 1H), 4.56 - 4.40 (m, 2H), 4.00 - 3.53 (m, 5H), 2.59 - 2.51 (m, 1H), 2.05 - 1.87 (m, 1H), 1.38 - 1.30 (m, 3H).

[0464]

[0310] INTERMEDIATE BE

[0465]

[0311] Methyl (2A,4A)-4-((tert-butoxycarbonyl)amino)-l-(isonicotinoyl-Z>-alanyl)pyrrolidine-2- carboxylate

[0466]

[0312] To a solution of intermediate BD (647 mg, 1.86 mmol) and BOC2O (1.22 g, 5.60 mmol) in IPA (20 mL) was added 10% Pd / C (130 mg, 0.12 mmol) and the reaction mixture was stirred at rt under H2for 2 h. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by column chromatography to afford the title compound (280 mg, 36%) as a white solid. LC-MS m / z = 421.3 [M+H]+. ’H NMR (400 MHz, DMSO- e) 5 9.15 - 8.86 (m, 1H), 8.77 - 8.66 (m, 2H), 7.84 - 7.73 (m, 2H), 7.15 - 6.84 (m, 1H), 5.13 - 4.69 (m, 1H), 4.44 - 4.21 (m, 1H), 4.17 - 4.03 (m, 1H), 3.95 - 3.68 (m, 2H), 3.65 - 3.55 (m, 3H), 2.46 - 2.34 (m, 1H), 1.80 - 1.63 (m, 1H), 1.40 - 1.28 (m, 12H).

[0467]

[0313] INTERMEDIATE BF

[0468]

[0314] (6-Methoxyquinoline-4-carbonyl)-Z>-alanyl-Z-proline

[0469]

[0315] To a solution of intermediate AU (700 mg, 2.08 mmol) in THF (15 mL) and water (3.0 mL) was added LiOHH2O (174 mg, 4.15 mmol). The reaction mixture was stirred at rt for 2 h. The reaction mixture was acidified with 1 M HC1 (6 mL) to pH ~ 5, and then extracted with 3: 1 DCM / IPA (30 mL x 10). The organic layers was concentrated under vacuum to afford the title compound (600 mg, 92%) as a yellow solid. LC-MS m / z = 372.05 [M+H]+; 'H NMR (400 MHz, DMSO-6) 5 12.45 (s, br, 1H), 9.21 - 8.93 (m, 1H), 8.82 - 8.75 (m, 1H), 8.03 - 7.91 (m, 1H), 7.69 - 7.35 (m, 3H), 5.05 - 4.86 (m, 1H), 4.60 -

[0470] 4.20 (m, 1H), 3.96 - 3.82 (m, 3H), 3.84 - 3.40 (m, 2H), 2.27 - 2.13 (m, 1H), 2.03 - 1.80 (m, 3H), 1.37 -

[0471] 1.21 (m, 3H).

[0472]

[0316] Intermediates BG - BU were prepared similarly to intermediate BF by methyl ester hydrolysis, see table 9 below.

[0473]

[0317] Table 9: Methyl ester hydrolysis

[0474]

[0475]

[0318] EXAMPLE 1

[0476]

[0319] JV-((7?)-l-((iS)-2-(((liS,9iS)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15- hexahydro-l / / ,12 / / -benzo[de|pyrano[3',4':6,7|indolizino[l,2- / >|quinolin-l-yl)carbamoyl)pyrrolidin- l-yl)-l-oxopropan-2-yl)isonicotinamide

[0477]

[0320] To a solution of intermediate BO (75.0 mg ,0.13 mmol), exatecan (73.1 mg, 0.13 mmol) and DIEA

[0478] (0.11 mL, 0.64 mmol) in DMF (2.0 mL) was added HATU (49.0 mg, 15.0 mmol). The reaction mixture was stirred at rt for 1 h under N2. The mixture was diluted with water (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by prep-HPLC to afford the title compound (37.2 mg, 41%) as a yellow solid. LC-MS m / z = 709.60 [M+H]+; ’HNMR (400 MHz, DMSO-t / e) 59.13 - 8.95 (m, 1H), 8.78 - 8.37 (m, 2H), 7.94 - 7.69 (m, 2H), 7.33 - 7.09 (m, 1H), 6.96 (d, J= 4.4 Hz, 1H), 5.61 -

[0479] 5.50 (m, 1H), 5.42 - 5.34 (m, 2H), 5.29 - 5.20 (m, 1H), 5.09 - 4.84 (m, 1H), 4.53 - 4.42 (m, 2H), 3.84 -

[0480] 3.78 (m, 1H), 3.61 - 3.58 (m, 1H), 3.20 - 3.09 (m, 2H), 2.40 - 2.35 (m, 3H), 2.26 - 1.75 (m, 9H), 1.33 -

[0481] 1.19 (m, 4H), 0.88 - 0.80 (m, 3H).

[0482]

[0321] INTERMEDIATE BY

[0483]

[0322] Methyl 3-(pyridin-4-ylthio)propanoate

[0484]

[0323] A mixture of 4-bromopyridine HC1 (1.50 g, 17.7 mmol), methyl 3-mercaptopropanoate (940 pL, 8.49 mmol), DIEA (4.03 mL, 23.1 mmol) and XantPhos (223 mg, 386 pmol) in toluene (20 mL) was purged with N2 for 10 min. Pd(dba)2 (177 mg, 193 pmol) was added and the reaction mixture was stirred at reflux for 3 h. The reaction mixture was diluted with toluene (20 mL), washed with sat. aq. NaHCCf (40 mL), brine (40 mL), dried over MgSCL, filtered and concentrated under vacuum. The residue was purified by silica column chromatography to afford the title compound (1.43 g, 87%) as an orange oil. LC-MS m / z = 198.0 [M+H]+; 'H NMR (500 MHz, DMSO-6) 5 8.37 (d, J= 6.3 Hz, 2H), 7.28 (d, J= 6.3 Hz, 2H), 3.62 (s, 3H), 3.28 (t, J= 7.0 Hz, 2H), 2.72 (t, J= 7.0 Hz, 2H).

[0485]

[0324] INTERMEDIATE BW

[0486]

[0325] Methyl 3-(pyridin-4-ylsulfonyl)propanoate

[0487]

[0326] To a solution of intermediate BV (1.24 g, 5.85 mmol) in MeCN (100 mL) was added KMnCE (2.77 g,17.5 mmol) and iron(III) chloride (284 mg, 1.75 mmol). The reaction mixture was stirred at rt for 5 h. The reaction mixture was filtered through a celite plug and rinsed with MeCN. The mixture was concentrated under vacuum and the remaining residue partitioned between EtOAc (30 mL) and brine (20 mL). Sat. aq. Na2S20s was added until decolorization and the mixture was filtered through a celite plug. The aqueous layer was extracted with EtOAc (20 mL x 2), the organics layers combined and concentrated under vacuum to afford the title compound (782 mg, 58%) as a white solid. LC-MS m / z =

[0488] 230.2 [M+H]+; 'HNMR (500 MHz, DMSO-6) 5 8.97 - 8.92 (m, 2H), 7.89 - 7.86 (m, 2H), 3.70 (t, J =

[0489] 7.2 Hz, 2H), 3.54 (s, 3H), 2.67 (t, J= 7.2 Hz, 2H).

[0490]

[0327] INTERMEDIATE BX

[0491]

[0328] tert- Butyl (pyridin-4-ylsulfonyl)-Z>-alanyl-Z-prolinate

[0492]

[0329] To a solution of intermediate BW (395 mg, 1.55 mmol) in THF (8.0 mL) was added NaOEt (578 mg, 1.78 mmol) and stirred at rt for 2 h. The reaction mixture was concentrated under vacuum. The residue was suspended in THF (20 mL), cooled to 0 °C and tert-butyl D-alaninate HC1 (282 mg, 1.55 mmol), DIEA (540 pL, 3.10 mmol) were added. NBS (276 mg, 1.55 mmol) and DMF (3.0 mL) were added and the reaction mixture was stirred at rt for 40 h. The reaction mixture was concentrated under vacuum and the residue purified by column chromatography to afford the title compound (434 mg, 90%) as an orange oil. LC-MS m / z = 287.2 [M+H]+; 'H NMR (500 MHz, DMSO-6) 5 11.05 (s, 1H), 8.85 - 8.80 (m, 2H), 7.73 - 7.68 (m, 2H), 3.90 - 3.79 (m, 1H), 1.23 (s, 9H), 1.20 (d, J= 7.2 Hz, 3H).

[0493]

[0330] INTERMEDIATE BY

[0494]

[0331] tert- Butyl ((tetrahydro-2 / / -pyran-4-yl)sulfonyl)- / )-alaninate

[0495]

[0332] A solution of tetrahydro-2H-pyran-4-sulfonyl chloride (0.28 g, 1.5 mmol) in DCM (2.0 mL) was added to a solution of tert-butyl D-alaninate, HC1 (0.25 g, 1.4 mmol) and DIEA (0.96 mL, 5.5 mmol) in DCM (5.0 mL) at 0 °C. The reaction mixture was stirred at rt for 18 h. The reaction mixture was purified by column chromatography to afford the title compound (63.0 mg, 16%) as a colourless oil.

[0496]

[0333] INTERMEDIATE BZ

[0497]

[0334] tert-Butyl / V-isonicotinoyl- / V-methyl- / )-alaninate

[0498]

[0335] To a solution of isonicotinoyl chloride HCl (1.00 g, 5.62 mmol) in DCM (10 mL) at 0 °C was added tert-butyl methyl-D-alaninate HC1 (1.00 g, 5.11 mmol) and DIEA (3.56 mL, 20.4 mmol). The reaction mixture was stirred at rt for 2 h. The reaction mixture was diluted with DCM (20 mL), washed with sat. aq. NH4C1 (20 mL x 2), sat. aq. NaHCOs solution (20 mL x 2) and brine (20 mL), dried over MgSO4. filtered and concentrated under vacuum to afford the title compound (1.22 g, 88%) as an orange oil. LC-MS m / z = 265.2 [M+H]+; 'H NMR (500 MHz, DMSO-6) 5 8.72 - 8.65 (m, 2H), 7.38 - 7.29 (m, 2H), 4.86 - 4.09 (m, 1H), 2.87 - 2.76 (m, 3H), 1.45 - 1.29 (m, U ). Mixture of two rotamers.

[0499]

[0336] Intermediate CA - CB were prepared in a similar manner to intermediate BZ, via amide coupling. See table 10 below.

[0500]

[0337] Table 10: Amide coupling with D-Alaninate derivatives

[0339] Tert-butyl 2-methyl-5,8,ll,14,17,20,23-heptaoxa-2-azahexacosan-26-oate

[0501]

[0340] Intermediate E (270 mg, 0.5 mmol) was treated with dimethylamine (2 M in THF, 2.8 mL, 5.6 mmol). The reaction mixture was stirred at rt for 16 h. The mixture was concentrated under vacuum and the residue purified by column chromatography to afford the title compound (70.0 mg, 29%) as a yellow oil. LC-MS m / z = 482.20 [M+H]+; 'H NMR (400 MHz, DMSO-tL) 5 3.60 - 3.48 (m, 28H), 2.60 (t, J = 5.9 Hz, 2H), 2.41 (t, J= 6.2 Hz, 2H), 2.30 (s, 3H), 2.30 (s, 3H), 1.40 (s, 9H).

[0502]

[0341] Intermediate CD was synthesised in a similar manner to intermediate CC via nucleophilic substitution. See table 11 below.

[0503]

[0342] Table 11: Nucleophilic substitution with an amine

[0504]

[0343] INTERMEDIATE CE

[0505]

[0344] (7?)-2-(l-Oxoisoindolin-2-yl)propanoic acid

[0506]

[0345] A solution of D-alanine (1.20 g, 13.4 mmol) and phthalaldehyde (2.00 g, 14.9 mmol) in MeCN (60 mL) was stirred at 82 °C for 16 h. The resulting precipitate was filtered, washed with MeCN (15 mL) and concentrated under vacuum to afford the title compound (2.17 g, 78%) as a yellow solid. LC-MS m / z = 206.2 [M+H]+; 'HNMR (500 MHz, DMSO-6) 5 12.91 (s, 1H), 7.73 - 7.68 (m, 1H), 7.66 - 7.59 (m, 2H), 7.55 - 7.46 (m, 1H), 4.84 (q, J= 7.5 Hz, 1H), 4.57 - 4.45 (m, 2H), 1.51 (d, J = 7.5 Hz, 3H).

[0507]

[0346] INTERMEDIATE CF

[0508]

[0347] tert- Butyl (( ?)-2-(l-oxoisoindolin-2-yl)propanoyl)-Z-prolinate

[0509]

[0348] To intermediate CE (2.17 g, 10.6 mmol) in EtOAc (35 mL) was added DIEA (11 mL, 63.4 mmol) and the reaction mixture stirred at rt for 10 min. T3P (50% wt in EtOAc, 9.44 mL, 15.9 mmol) was added and the reaction mixture was stirred at rt for 5 min. / - Butyl Z-prolinate (1.81 g, 10.6 mmol) was added and reaction was stirred at rt for 3 h. The reaction mixture was diluted with 1 M HC1 (50 mL) and EtOAc (50 mL), and the layers separated. The organic layer was washed with 2 M NaOH (50 mL), brine (50 mL), dried over MgSCE, fdtered and concentrated under vacuum to afford the title compound (3.62 g, 91%) as a yellow oil. LC-MS m / z = 359.2 [M+H]+; 'H NMR (500 MHz, DMSO-6) 5 7.75 - 7.66 (m, 1H), 7.66 - 7.58 (m, 2H), 7.55 - 7.46 (m, 1H), 5.22 (q, J= 6.8 Hz, 1H), 4.58 - 4.49 (m, 1H), 4.43 (d, J = 17.6 Hz, 1H), 4.19 (dd, J= 8.6, 5.4 Hz, 1H), 3.63 (dt, J= 10.2, 6.6 Hz, 1H), 3.44 - 3.32 (m, 1H), 3.30 -

[0510] 3.21 (m, 1H), 2.20 - 2.05 (m, 1H), 1.89 - 1.75 (m, 2H), 1.75 - 1.65 (m, 1H), 1.48 (s, 1H), 1.45 - 1.34 (m,

[0511] 1H), 1.30 (d, J= 4.8 Hz, 9H).

[0512]

[0349] INTERMEDIATE CG

[0513]

[0350] ((7?)-2-(l-Oxoisoindolin-2-yl)propanoyl)-Z-proline

[0514]

[0351] To intermediate CF (3.62 g, 10.1 mmol) in 1,4-dioxane (10 mL) was added 4M HC1 in dioxane (13 mL, 50.5 mmol). The reaction mixture was stirred at rt for 18 h and then concentrated under vacuum.

[0515] The residue was suspended in toluene and concentrated under vacuum to afford the title compound (3.26 g, 94%) as a yellow solid. LC-MS m / z = 303.2 [M+H]+; 'H NMR (500 MHz, DMSO-6) 5 12.48 (s, 1H), 7.72 (d, J= 7.6 Hz, 1H), 7.64 - 7.57 (m, 2H), 7.54 - 7.47 (m, 1H), 5.22 (q, J= 6.8 Hz, 1H), 4.47 (s, 2H), 4.25 (dd, J= 8.6, 5.3 Hz, 1H), 3.63 (dt, J= 10.1, 6.5 Hz, 1H), 3.21 (dt, J= 10.2, 6.8 Hz, 1H), 2.20 - 2.10 (m, 1H), 1.94 - 1.66 (m, 3H), 1.36 (d, J= 6.9 Hz, 1H), 1.29 (d, J= 6.8 Hz, 2H).

[0516]

[0352] Intermediates CH - CN were prepared in a similar manner to intermediate CG by tert-butyl ester hydrolysis. See table 12 below.

[0517]

[0353] Table 12: Tert-butyl ester hydrolysis

[0518]

[0354] INTERMEDIATE CO

[0519]

[0355] 2,2,5-Trimethyl-4-oxo-3,8,ll,14,17-pentaoxa-5-azaicosan-20-oic acid

[0520]

[0356] To a mixture of intermediate CN (160 mg, 0.298 mmol) and TEA (0. 12 mL, 0.89 mmol) in DCM (3.0 mL) were added (Boc)O (98.0 mg, 0.44 mmol) slowly at 0 °C. The reaction mixture was stirred at rt for 2 h. The mixture was concentrated under vacuum to afford the title compound (285 mg, crude) as a yellow oil. LC-MS m / z = 380.15 [M+H]+

[0521]

[0357] INTERMEDIATE CP

[0522]

[0358] tert- Butyl (2-(5-amino-2-(hydroxymethyl)benzamido)ethyl)carbamate

[0359] To a solution of 6-aminoisobenzofuran-l(327)-one (500 mg, 3.35 mmol) in MeOH (10 mL) was added tert-butyl (2-aminoethyl)carbamate (1.08 g, 6.71 mmol). The reaction mixture was stirred at 100 °C for 16 h. The mixture was concentrated under vacuum, diluted with water (80 mL) and extracted with

[0523] DCM (40 mL x 3). The combined organic layers were washed with brine, dried over Na2SC>4, filtered and concentrated under vacuum. The residue was purified by column chromatography to afford the title compound (900 mg, 87%) as a yellow oil. LC-MS m / z = 310.15 [M+H]+; ’H NMR (400 MHz, DMSO- <76) 5 8.30 (t, J= 5.5 Hz, 1H), 7.06 (d, J= 8.1 Hz, 1H), 6.87 - 678 (m, 1H), 6.67 (d, J= 2.4 Hz, 1H), 6.58 (dd, J= 8.1, 2.4 Hz, 1H), 5.14 (s, 2H), 4.99 (t, J= 5.7 Hz, 1H), 4.34 (d, J= 5.6 Hz, 2H), 3.26 - 3.21 (m,

[0524] 2H), 3.09 - 3.03 (m, 2H), 1.38 (s, 9H).

[0525]

[0360] INTERMEDIATE CQ

[0526]

[0361] 2-(Hydroxymethyl)-JV-methyl-5-nitrobenzamide

[0527]

[0362] A mixture of 6-nitroisobenzofuran-l(327)-one (500 mg, 2.79 mmol) and methanamine (2M in THF, 4.88 mL, 9.77 mmol) was stirred at 75 °C for 16 h. The mixture was concentrated under vacuum to afford the title compound (550 mg, 94%) as a yellow solid. LC-MS m / z = 211.05 [M+H]+; 'H NMR (400 MHz, DMSO- e) 5 8.65 - 8.47 (m, 1H), 8.36 - 8.26 (m, 1H), 8.20 (d, J= 2.4 Hz, 1H), 7.86 (d, J= 8.6 Hz, 1H), 5.54 (s, 1H), 4.79 - 4.64 (m, 2H), 2.78 (d, J= 4.6 Hz, 3H).

[0528]

[0363] INTERMEDIATE CR

[0529]

[0364] (2-((Methylamino)methyl)-4-nitrophenyl)methanol

[0530]

[0365] To a solution of intermediate CQ (3.52 g, 16.8 mmol) in THF (35 mL) was added borane-methyl sulfide complex (10 M, 8.4 mL, 83.8 mmol,) dropwise at 0 °C. The reaction mixture was stirred at rt for 16 h under N2 . The mixture was quenched with MeOH at 0 °C and concentrated under vacuum to afford the title compound (3.29 g, crude) which was used directly in the next step. LC-MS m / z = 197.10 [M+H]+

[0531]

[0366] INTERMEDIATE CS

[0532]

[0367] tert-butyl (2-(hydroxymethyl)-5-nitrobenzyl)(methyl)carbamate

[0368] To a solution of intermediate CR (3.29 g, 16.8 mmol) in THF (50 mL) was added BOC2O (19.3 mL, 83.8 mmol) and the reaction mixture was stirred at rt for 16 h under N2. The reaction mixture was concentrated under vacuum, and purified by silica column chromatography to afford the title compound (1.80 g, crude) as an orange solid. LC-MS m / z = 197.05 [M-Boc+H]+

[0533]

[0369] INTERMEDIATE CT

[0534]

[0370] 3-Bromo-4-(((ter / -butyldimethylsilyl)oxy)methyl)aniline

[0535]

[0371] To a solution of (4-amino-2-bromophenyl)methanol (3.56 g, 17.6 mmol) and imidazole (3.60 g, 52.9 mmol) in DMF (40 mL) was added TBSC1 (3.72 g, 24.7 mmol) at 0 °C and the reaction mixture was stirred at rt for 16 h. The mixture was diluted with water (120 mL) and extracted with EtOAc (60 mL x 3). The combined organic layers were washed with brine, dried overNa2SC>4, and concentrated under vacuum. The residue was purified by column chromatography to afford the title compound (4.00 g, 71%) as a yellow oil. LC-MS m / z = 315.95 & 317.95 [M+H]+.

[0536]

[0372] INTERMEDIATE CU

[0537]

[0373] Methyl 2-cyclopropyl-4-nitrobenzoate

[0538]

[0374] To a solution of methyl 2-bromo-4-nitrobenzoate (2.00 g, 7.7 mmol), cyclopropylboronic acid (2.00 g, 23.1 mmol) and K3PO4 (8.20 g, 38.5 mmol) in toluene (80 mL) and water (8 mL) was added Pd(dppf)C12 (570 mg, 0.77 mmol) and the reaction mixture was stirred at 100 °C for 16 h under N2. The mixture was concentrated under vacuum and purified by column chromatography to give the title compound as a green oil. (1.00 g, 58%). 'H NMR (400 MHz, DMSO-6) 5 10.41 - 9.57 (m, 1H), 9.30 (d, J= 6.6 Hz, 1H), 8.79 - 8.74 (m, 1H), 8.53 - 8.44 (m, 1H), 8.20 - 8.14 (m, 1H), 8.07 - 7.93 (m, 2H), 7.78

[0539] - 7.60 (m, 4H), 7.41 - 7.30 (m, 3H), 6.53 - 6.47 (m, 1H), 5.46 - 5.40 (m, 2H), 5.29 - 5.26 (m, 2H), 5.10

[0540] - 5.05 (m, 2H), 5.03 - 4.40 (m, 2H), 3.80 - 3.48 (m, 3H), 3.22 - 3.08 (m, 2H), 2.37 (s, 3H), 2.24 - 2.10 (m, 3H), 1.99 - 1.82 (m, 5H), 1.39 - 1.24 (m, 3H), 0.87 (t, J= 7.4 Hz, 3H).

[0541]

[0375] Intermediate CV was prepared in a similar manner to intermediate CU via palladium-catalysed cross-coupling. See table 13 below.

[0376] Table 13: Palladium-catalysed cross-coupling

[0542]

[0377] INTERMEDIATE CW

[0543]

[0378] 3-((2,5,8,ll-Tetraoxatridecan-13-yl)oxy)-4-nitrobenzaldehyde

[0544]

[0379] To a solution of 3-hydroxy-4-nitrobenzaldehyde (270 mg, 1.62 mmol) in DMF (6.0 mL) was added K2CO3 (446 mg, 2.23 mmol) and 13-bromo-2,5,8,ll-tetraoxatridecane (438 mg, 1.62 mmol). The reaction mixture was stirred at 95 °C for 3 h. The reaction mixture was diluted with water (60 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SC>4, filtered and concentrated under vacuum. The residue was purified by Prep-TLC to afford the title compound (230 mg, 40%) as a yellow oil. LC-MS m / z = 375. 10 [M+H]+; 'H NMR (400 MHz, DMSO- e) 5 10.06 (s, 1H), 8.05 (d, J= 8.I Hz, 1H), 7.87 (s, 1H), 7.65 (dd, J= 8.2, 1.4 Hz, 1H), 4.39 (t, J = 4.5 Hz, 2H), 3.80 - 3.75 (m, 2H), 3.61 - 3.56 (m, 2H), 3.53 - 3.47 (m, 8H), 3.42 - 3.38 (m, 2H), 3.22 (s, 3H).

[0545]

[0380] INTERMEDIATE CX

[0546]

[0381] l-(4-methylpiperazin-l-yl)-2-(4-nitrophenyl)ethane-l, 2-dione

[0547]

[0382] To a suspension of 2-(4-nitrophenyl)-2-oxoacetic acid (1.00 g, 5.12 mmol), 1 -methylpiperazine (616 mg, 6.15 mmol) and NMI (1.43 mL, 17.9 mmol) in MeCN (12 mL) was added TCFH (1.87 g, 6.66 mmol) at 0 °C. The reaction mixture was stirred at rt for 18 h. The reaction mixture was concentrated under vacuum and the residue dissolved in EtOAc (50 mL). The reaction mixture was washed with sat. aq. NaHCOs (40 mL x 2) and brine (40 mL), dried over MgSO4 and concentrated under vacuum to afford the title compound (1.52 g, 86%) as an orange solid. LC-MS m / z = 278.20 [M+H]+; 'HNMR (500 MHz, DMSO-d6) 5 8.45 - 8.39 (m, 2H), 8.20 - 8.11 (m, 2H), 3.68 - 3.64 (m, 2H), 3.34 (dd, J= 5.8, 4.3 Hz, 2H), 2.54 - 2.51 (m, 2H), 2.37 (t, J= 5.1 Hz, 2H), 2.27 (s, 3H).

[0383] Intermediate CY was prepared in a similar manner to intermediate CX, via amide coupling. See table 14 below.

[0548]

[0384] Table 14: Amide coupling with 2-(4-nitrophenyl)-2-oxoacetic acid

[0549]

[0385] INTERMEDIATE CZ

[0550]

[0386] 5-Amino-2-(hydroxymethyl)-A-methylbenzamide

[0551]

[0387] To a solution of intermediate CQ (550 mg, 2.62 mmol) in MeOH (5.0 mL) was added 20% Pd(OH)2 / C (84.6 mg, 0.13 mmol). The reaction mixture was stirred at rt under H2 for 2 h. The reaction mixture was filtered and concentrated under vacuum. The residue was purified by column chromatography to afford the title compound (110 mg, 23%) as a white solid. LC-MS m / z = 181.15 [M+H]+;1H NMR (400 MHz, DMSO-6) 5 8.23 (d, J= 5.1 Hz, 1H), 7.06 (d, J= 8.1 Hz, 1H), 6.66 (d, J = 2.4 Hz, 1H), 6.58 (dd, J= 8.2, 2.4 Hz, 1H), 5.15 (s, 2H), 5.01 (t, J= 5.7 Hz, 1H), 4.33 (d, J= 5.7 Hz, 2H), 2.73 (d, J = 4.6 Hz, 3H).

[0552]

[0388] Intermediates DA - DE were prepared similarly to intermediate CZ by nitro reduction; see table 15 below.

[0553]

[0389] Table 15: Nitro reduction to aniline

[0554]

[0390] INTERMEDIATE DF

[0555]

[0391] (3-((2,5,8,ll-Tetraoxatridecan-13-yl)oxy)-4-aminophenyl)methanol

[0556]

[0392] To a solution of intermediate DC (200 mg, 0.61 mmol) in MeOH (4.0 mL) was added NaBEE (92.6 mg, 2.45 mmol). The reaction mixture was stirred at rt for 2 h. The mixture was diluted with water (50 mL) and extracted with 3: 1 DCM / IPA (30 mL x 3). The combined organic layers were concentrated under vacuum to afford the title compound (200 mg, 80%) as a brown oil. LC-MS m / z = 330. 10 [M+H]+; ' H NMR (400 MHz, DMSO-6) 5 6.77 (d, J= 1.7 Hz, 1H), 6.64 (dd, J= 7.9, 1.7 Hz, 1H), 6.58 (d, J= 7.8 Hz, 1H), 4.82 (t, J= 5.7 Hz, 1H), 4.56 (s, 2H), 4.31 (d, J= 5.6 Hz, 2H), 4.05 - 4.01 (m, 2H), 3.75 - 3.72 (m, 2H), 3.62 - 3.58 (m, 2H), 3.56 - 3.50 (m, 8H), 3.44 - 3.41 (m, 2H), 3.23 (s, 3H).

[0557]

[0393] INTERMEDIATE DG

[0558]

[0394] (3-Aminopyridin-2-yl)methanol

[0559]

[0395] To a solution of methyl 3 -aminopicolinate (1.00 g, 6.57 mmol) in THF (30 mL) was slowly added LiAlEL in THF (2.4 M, 9.58 mL, 23.0 mmol) at 0 °C. The reaction mixture was stirred for 10 min then warmed up to rt and stirred for 2 h. The reaction was cooled to 0 °C and water (0.9 mL), 15% aq. NaOH (0.9 mL) and water (0.9 mL) were slowly added to the reaction mixture. The resulting mixture was stirred for 15 min at rt. MgSCL was added and the reaction mixture was fdtered and washed with TBME (30 mL). The filtrate was concentrated under vacuum to afford the title compound (658 mg, 79%) as a yellow oil. LC-MS m / z = 125.50 [M+H]+

[0560]

[0396] Intermediate DH - DI was prepared in a similar manner to intermediate DG, via ester reduction. See table 16 below.

[0561]

[0397] Table 16: Ester reduction to alcohol

[0562]

[0398] INTERMEDIATE DJ

[0563]

[0399] tert- Butyl (( ?)-l-((5)-2-((4-(hydroxymethyl)phenyl)carbamoyl)pyrrolidin-l-yl)-l-oxopropan- 2-yl)carbamate

[0564]

[0400] To a solution of intermediate BG (2.00 g, 6.99 mmol) (4-aminophenyl)methanol (860 mg, 6.99 mmol) and DIEA (4.87 mL, 28.0 mmol) in DMF (40 mL) was added HATU (2.66 g, 6.99 mmol). The reaction mixture was stirred at rt for 1 h. The mixture was diluted with water (200 mL) and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SC>4 and concentrated under vacuum. The residue was purified by column chromatography to afford the title compound ( 1.70 g, 62%) as a yellow solid. LC-MS m / z = 392.15 [M+H]+; ’H NMR (400 MHz, DMSO-t / e) 5 10.22 - 9.51 (m, 1H), 7.57 - 7.50 (m, 2H), 7.27 - 7.20 (m, 2H), 7.12 - 6.97 (m, 1H), 5.13 - 5.05 (m, 1H), 4.45 - 4.09 (m, 4H), 3.73 - 3.41 (m, 2H), 2.30 - 1.76 (m, 4H), 1.36 (s, 9H), 1.20 - 0.99 (m, 3H).

[0565]

[0401] Intermediates DK - EY were prepared similarly to intermediate DJ by amide coupling with the appropriate aniline; see table 17 below.

[0402] Table 17: Amide coupling of D-alanyl-L-proline and analogues

[0566]

[0403] INTERMEDIATE EZ

[0567]

[0404] 2-(2-(((ter / -Butoxycarbonyl)(methyl)amino)methyl)phenyl)acetic acid

[0568]

[0405] To a solution of 2-(2-((( / ert-butoxycarbonyl)amino)methyl)phenyl)acetic acid (1.00 g , 3.77 mmol) in THF (10 mL) was added sodium hydride (452 mg, 60% wt, 11.3 mmol) at 0 °C. The reaction mixture was stirred for 10 min at 0 °C. Methyl iodide (707 pL. 11.3 mmol) was added and the reaction mixture was stirred at rt for 16 h. The reaction mixture was diluted with DCM (25 mL), washed with 1 M HC1 (25 mL x 2) and brine (10 mL). The organic layer was dried over MgSO . filtered and concentrated under vacuum to afford the title compound (1.16 g, 100%) as an orange oil. LC-MS m / z = 278.20 [M-H]-; ’H NMR (500 MHz, DMSO-tL) 5 12.32 (s, 1H), 7.29 - 7.20 (m, 3H), 7.09 (d, J= 7.4 Hz, 1H), 4.41 (s, 2H), 3.63 (d, J= 1.7 Hz, 2H), 2.68 (d, J= 1.8 Hz, 3H), 1.40 (d, J= 24.6 Hz, 9H).

[0569]

[0406] INTERMEDIATE FA

[0407] Methyl 2-(2-((( / e / 7-butoxycarbonyl)(methyl)amino)methyl)phenyl)acetate

[0570]

[0408] To a solution of intermediate EZ (1.16 g, 4.15 mmol) in DMF (10 mL) was added K2CO3 (600 mg, 4.34 mmol) and the reaction was stirred at rt for 10 min. Methyl iodide (779 pL, 12.5 mmol) was added and the reaction was stirred for 4 h. The reaction mixture was diluted with EtOAc (50 mL), washed with

[0571] 1 M HC1 (50 mL) and 1: 1 brine / water (25 mL x 4). The organic layer was dried over MgSCL, fdtered and concentrated under vacuum to afford the title compound (1.13 g, 93%) as an orange oil . LC-MS m / z = 194.20 [M-Boc+H]+

[0572]

[0409] INTERMEDIATE FB

[0573]

[0410] Methyl 2-(2-((methylamino)methyl)phenyl)acetate hydrochloride

[0574] [4H] To intermediate FA (1.13 g, 3.85 mmol) was added 4M HC1 in dioxane (9.63 mL, 38.5 mmol) and the reaction mixture was stirred at rt for 30 min. The reaction mixture was concentrated under vacuum to afford the title compound as a yellow solid (885 mg, 95%). LC-MS m / z = 194.20 [M+H]+; 'H NMR (500 MHz, DMSO-d6) 5 9.15 (s, 2H), 7.63 - 7.56 (m, 1H), 7.40 - 7.33 (m, 2H), 7.33 - 7.27 (m, 1H), 4.12 (s,

[0575] 2H), 3.92 (s, 2H), 3.63 (s, 3H), 2.58 (s, 3H).

[0576]

[0412] INTERMEDIATE FC

[0577]

[0413] Methyl 2-((((4-((S)-l-(isonicotinoyl-Z>-alanyl)pyrrolidine-2- carboxamido)benzyl)oxy)carbonyl)(methyl)amino)benzoate

[0578]

[0414] To a suspension of intermediate EC (250 mg, 568 pmol) and bis(2,5-dioxopyrrolidin-l-yl) carbonate (582 mg, 2.27 mmol) in DCM (30 mL) was added pyridine (184 pL, 2.27 mmol) and the reaction was stirred at rt for 16 h. The reaction mixture was washed with sat. aq. NH4CI (25 mL), sat. aq. NaHCOs (25 mL) and brine (25 mL), dried over MgSCLand fdtered. The resulting solution was added to a mixture of methyl 2-((methylamino)methyl)benzoate HCl (147 mg, 681 pmol) and DMAP (277 mg, 2.27 mmol) in DCM (4.0 mL). The reaction mixture was stirred at rt for 16 h. The mixture was washed with sat. aq. NH4CI (25 mL), sat. aq. NaHCOs (25 mL) and brine (25 mL), dried over MgSCL, fdtered and concentrated under vacuum. The crude product was purified by column chromatography to afford the title compound (363 mg, 92%) as a light brown oil. LC-MS m / z = 602.2 [M+H]+

[0579]

[0415] Intermediate FD was prepared in a similar manner to intermediate FC via carbamate formation. See table 18 below.

[0580]

[0416] Table 18: Carbamate formation with N-methyl benzoate derivatives

[0581]

[0417] INTERMEDIATE FE

[0582]

[0418] 2-((((4-((iS)-l-(isonicotinoyl-Z>-alanyl)pyrrolidine-2- carboxamido)benzyl)oxy)carbonyl)(methyl)amino)benzoic acid

[0583]

[0419] To intermediate FC (363 mg, 525 pmol) was dissolved in 2: 1: 1 THF / MeOH / water (8.0 mL) was added LiOHTEO (28.6 mg, 682 pmol) and the reaction mixture was stirred at rt for 16 h. The reaction was quenched with 1 M HC1 until pH 6 reached and concentrated under vacuum. The residue was coevaporated with toluene (2x) and DCM (2x) to afford the title compound (316 mg, 75 %) as a beige solid. LC-MS m / z = 588.2 [M+H]+

[0584]

[0420] Intermediate FF was prepared in a similar manner to intermediate FE via ester hydrolysis. See table 19 below.

[0585]

[0421] Table 19: Methyl ester hydrolysis

[0586]

[0422] INTERMEDIATE FG

[0587]

[0423] 4-((A)-l-(Isonicotinoyl-Z>-alanyl)pyrrolidine-2-carboxamido)benzyl (2-({{tert- butyldimethylsilyl)oxy)methyl)phenyl)carbamate

[0588]

[0424] To a solution of triphosgene (50.0 mg, 168.5 pmol) in DCM (3.0 mL) at 0 °C was added 2-(((tert- butyldimethylsilyl)oxy)methyl)aniline (100 mg, 421 pmol) and pyridine (40.7 pL, 505 pmol) in DCM (3.0 mL). The reaction mixture was stirred at 0 °C for 1 h. A suspension of intermediate EC (167 mg, 421 pmol), DMAP (56.6 mg, 463 pmol) and TEA (117 pL, 842 pmol) in 3: 1 DCM / DMF (4.0 mL) was added and the reaction mixture was stirred at rt for 16 h. The reaction mixture was purified by column chromatography to afford the title compound (198 mg, 69 %) as a pink solid. LC-MS m / z = 660.2 [M+H]+;1H NMR (500 MHz, DMSO-6) 5 9.64 (s, 1H), 9.10 - 9.03 (m, 1H), 8.83 (s, 1H), 8.76 - 8.70 (m, 2H), 7.84 - 7.78 (m, 2H), 7.68 - 7.60 (m, 2H), 7.51 - 7.41 (m, 1H), 7.39 - 7.30 (m, 3H), 7.24 (t, J = 7.7 Hz, 1H), 7.17 - 7.10 (m, 1H), 5.07 (d, 2H), 4.80 (p, J= 6.8 Hz, 1H), 4.68 (d, J= 7.3 Hz, 2H), 4.48 - 4.42 (m, 1H), 3.80 - 3.57 (m, 1H), 3.29 (s, 2H), 2.03 - 1.91 (m, 2H), 1.90 - 1.72 (m, 1H), 1.35 (d, J = 6.9 Hz, 2H), 1.23 (d, J = 6.9 Hz, 1H), 0.86 (s, 9H), 0.03 (s, 6H).

[0589]

[0425] Intermediate FH was prepared in a similar manner to intermediate FG via carbamate formation, see table 20 below.

[0590]

[0426] Table 20: Carbamate formation with silyl ether benzoate derivatives

[0591]

[0427] INTERMEDIATE FI

[0592]

[0428] tert- Butyl (( ?)-l-((A)-2-((3-cyano-4-(hydroxymethyl)phenyl)carbamoyl)pyrrolidin-l-yl)-l- oxopropan-2-yl)carbamate

[0593]

[0429] To a solution of intermediate DQ (300 mg, 566 pmol) in THF (15 mL) was added TBAF (1 M in THF, 0.9 mL) at 0 °C. The reaction mixture was stirred at rt for 1 h. The mixture was diluted with water (100 mL) and extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine, dried over Na2SC>4 and concentrated under vacuum. The residue was purified by column chromatography to afford the title compound (131 mg, 55%) as a colourless oil. LC-MS m / z = 417.10 [M+H]+; ’H NMR (400 MHz, DMSO-d6) 5 10.54-9.83 (m, 1H), 8.03 - 7.78 (m, 2H), 7.59-7.54 (m, 1H), 7.15-7.02 (m, 1H), 5.51 - 5.49 (m, 1H), 4.59-4.58 (m, 2H), 4.41 - 4.25 (m, 1H), 3.75 - 3.43 (m, 3H), 2.16 - 2.05 (m, 2H), 1.95 - 1.81 (m, 2H), 1.36 (s, 9H), 1.18 - 1.02 (m, 3H).

[0594]

[0430] Intermediate FJ - FK was prepared in a similar manner to intermediate FI, via silyl ether deprotection. See table 21 below.

[0595]

[0431] Table 21: Silyl ether deprotection

[0596] Int. Structure Intermediate, Form, Yield, LC-MS, NMR

[0597]

[0432] INTERMEDIATE FL

[0598]

[0433] tert- Butyl ((7?)-l-((A)-2-((4-((((4- nitrophenoxy)carbonyl)oxy)methyl)phenyl)carbamoyl)pyrrolidin-l-yl)-l-oxopropan-2- yl)carbamate

[0599]

[0434] A solution of intermediate DJ (700 mg, 1.79 mmol) and DIEA (0.47 mL, 2.69 mmol) in DMF (8.0 mL) was stirred at 0 °C for 20 min. Bis(4-nitrophenyl) carbonate (817 mg, 2.69 mmol) in DMF (2.0 mL) was added and the reaction mixture was stirred at rt for 2h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine, dried over Na2SC>4, filtered and concentrated. The residue was purified by column chromatography to afford the title compound (900 mg, 48%) as a yellow solid. LC-MS m / z = 557. 10 [M+H]+; 'H NMR (400 MHz, DMSO- e) 5 10.35 - 9.63 (m, 1H), 8.11 - 8.01 (m, 1H), 7.79 - 7.55 (m, 3H), 7.45 - 7.25 (m, 3H), 7.15 - 6.90 (m, 1H), 6.53 - 6.48 (m, 1H), 5.44 (s, 2H), 5.36 - 5.19 (m, 3H), 5.08 (s, 2H), 4.43 - 4.28 (m, 1H), 3.71 - 3.43 (m, 2H), 3.31 - 3.05 (m, 2H), 2.36 (d, J= 1.8 Hz, 3H), 2.25 - 2.02 (m, 3H), 2.02 - 1.76 (m, 5H), 1.39 - 1.32 (m, 9H), 1.21 - 1.00 (m, 3H), 0.88 (t, J= 7.3 Hz, 3H).

[0600]

[0435] Intermediates FM - GZ were prepared similarly to intermediate FL by carbonate formation; see table 22 below.

[0601]

[0436] Table 22: Carbonate Formation

[0602]

[0437] INTERMEDIATE HA

[0603]

[0438] re / 7- Butyl (( ?)-l-((A)-2-((4-(((((lA,9A)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo- 2,3,9,10,13,15-hexahydro-LH,12 / f-benzo[de]pyrano[3',4':6,7]indolizino[l,2-Z>]quinolin-l- yl)carbamoyl)oxy)methyl)phenyl)carbamoyl)pyrrolidin-l-yl)-l-oxopropan-2-yl)carbamate

[0604]

[0439] To a solution of intermediate FL (100 mg, 0.14 mmol) in DMF (2.0 mL) and pyridine (0.5 mL) was added HOBt (38.8 mg, 0.29 mmol), exatecan (81.6 mg, 0.14 mmol) and DIEA (0.10 mL, 0.57 mmol). The reaction mixture was stirred at rt for 16 h. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine, dried over Na2SC>4 and concentrated under vacuum. The residue was purified by column chromatography to afford the title compound (130 mg, 85%) as a yellow solid. LC-MS m / z = 853.25 [M+H]+. 'H NMR (400 MHz, DMSO- e) 5 10.35 - 9.63 (m, 1H), 8.11 - 8.01 (m, 1H), 7.79 - 7.55 (m, 3H), 7.45 - 7.25 (m, 3H), 7.15 - 6.90 (m, 1H), 6.53 - 6.48 (m, 1H), 5.44 (s, 2H), 5.36 - 5.19 (m, 3H), 5.08 (s, 2H), 4.43 - 4.28 (m, 1H), 3.71 - 3.43 (m, 2H), 3.31 - 3.05 (m, 2H), 2.36 (d, J= 1.8 Hz, 3H), 2.25 - 2.02 (m, 3H), 2.02 - 1.76 (m, 5H), 1.39 - 1.32 (m, 9H), 1.21 - 1.00 (m, 3H), 0.88 (t, J= 7.3 Hz, 3H).

[0605]

[0440] Example 2 - 15 and intermediates HB - IA were prepared similarly to intermediate HA by carbamate formation with Exatecan; see tables 23 and 24 below.

[0606]

[0441] Table 23: Installation of Exatecan via carbamate formation

[0607] Ex. Structure Intermediate, Form, Yield, LC-MS, NMR

[0608]

[0442] Table 24: Installation of Exatecan via carbamate formation

[0609]

[0443] EXAMPLE 16

[0610]

[0444] 4-((ASSl1(isonicotinoyl-Z>-alanyl)pyrrolidine-2-carboxamido)benzyl (2-(((l1S1SS)-9-ethyl-5- fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-LH,12 / H- benzo[de]pyrano[3',4':6,7]indolizino[l,2-b]quinolin-l-yl)carbamoyl)phenyl)(methyl)carbamate

[0611]

[0445] To a solution of exatecan (50.0 mg, 115 pmol), intermediate FE (75.1 mg, 126 pmol) and NMI (31.9 pL, 402 pmol) in DMF (2.0 mL) was added TCFH (38.7 mg, 138 pmol) and the reaction was stirred at rt for 2 d. The reaction mixture was concentrated under vacuum. The residue dissolved in DMSO (3.0 mL), filtered and purified by prep-HPLC to afford the title compound (27.2 mg, 24%) as a white solid. LC-MS m / z = 1005.2 [M+H]+'H NMR (500 MHz, DMSO-td3 5 9.98 (dd, J= 379.9, 21.2 Hz, 1H), 9.04 (d, J= 8.7 Hz, 2H), 8.75 - 8.66 (m, 2H), 7.88 - 7.09 (m, 12H), 6.52 (s, 1H), 5.74 (s, 1H), 5.51 - 3.34 (m, 12H), 3.31 - 3.10 (m, 3H), 2.85 (s, 3H), 2.49 - 1.73 (m, 9H), 1.41 - 1.15 (m, 4H), 0.86 (t, J= 7.3 Hz, 3H).

[0612]

[0446] Example 17 was prepared in a similar manner to example 16, see table 25 below.

[0613]

[0447] Table 25: Installation of Exatecan via carbamate formation

[0614]

[0448] EXAMPLE 18

[0615]

[0449] (3-((iS)-l-(isonicotinoyl-Z>-alanyl)pyrrolidine-2-carboxamido)pyridin-2-yl)methyl ((1IS,9IS)-9- ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-l / / ,12 / / - benzo[de]pyrano[3',4':6,7]indolizino[l,2-b]quinolin-l-yl)carbamate

[0450] To a suspension of exatecan (47.0 mg, 88.6 pmol) and DIEA (309 pL, 1.77 mmol) in 1,4-dioxane (5 mL) was added triphosgene (10.5 mg, 35.4 pmol) in 1,4-dioxane (1.0 mL) The reaction mixture was stirred at 100 °C for 1 h. The reaction was cooled to rt and a solution of intermediate EW (40.8 mg, 97.4 pmol) and dibutyltin dilaurate (10.0 pL, 16.9 pmol) in toluene (5.0 mL) was added. The reaction mixture was stirred at 100 °C for 3 h. The reaction mixture was concentrated under vacuum and the residue dissolved in DMSO (1.0 mL) and fdtered. The residue was purified by prep-HPLC to afford the title compound (1.1 mg, 1%) as a white solid. LC-MS m / z = 859.60 [M+H]+.

[0616]

[0451] EXAMPLE 19

[0617]

[0452] 4-((A)-l-((7?)-2-(l-oxoisoindolin-2-yl)propanoyl)pyrrolidine-2-carboxamido)benzyl ((lA,9A)-9- ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-LH,12 / 7- benzo[de]pyrano[3',4':6,7]indolizino[l,2-Z>]quinolin-l-yl)carbamate

[0618]

[0453] To a solution of intermediate EP (62.4 mg, 138 pmol) in DCM (5.0 mL) was added pyridine (37.1 pL, 459 pmol) and bis(2,5-dioxopyrrolidin-l-yl) carbonate (118 mg, 459 pmol). The reaction was stirred at rt for 16 h. The reaction mixture was diluted with DCM (3.0 mL), washed with sat. aq. NH4CI (5.0 mL), sat. aq. NaHCOs (5.0 mL) and brine (5.0 mL), dried over MgSCL, and filtered. To the mixture was added Exatecan (50.0 mg, 115 pmol) and DMAP (56.1 mg, 459 pmol) in DCM (12 mL). The reaction was stirred at rt for 3 d. The reaction mixture was concentrated under vacuum and the remaining residue dissolved in DMSO, filtered and purified by Prep HPLC to afford the title compound (42.7 mg, 43%) as a beige solid. LC-MS m / z = 869.2 [M+H]+; 'H NMR (500 MHz, DMSO-6) 5 10.43 - 10.05 (m, 1H), 8.09 - 8.00 (m, 1H), 7.80 - 7.27 (m, 10H), 6.51 (s, 1H), 5.47 - 4.41 (m, 10H), 3.74 - 3.59 (m, 1H), 3.29 - 3.06 (m, 3H), 2.43 - 2.31 (m, 3H), 2.25 - 1.73 (m, 8H), 1.36 - 1.22 (m, 3H), 0.87 (t, J= 7.4 Hz, 3H).

[0619] Mixture of retainers.

[0620]

[0454] Intermediate IB was prepared similarly to example 19 by carbamate formation; see table 26 below.

[0621]

[0455] Table 26: Carbamate formation

[0622]

[0456] INTERMEDIATE IC

[0623]

[0457] 4-((5)-pyrrolidine-2-carboxamido)benzyl ((lA,9A)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13- dioxo-2,3,9,10,13,15-hexahydro-l / / ,12 / / -benzo[de|pyrano[3',4':6,7|indolizino[l,2- / >|quinolin-l- yl)carbamate

[0624]

[0458] To a solution of intermediate IB (623 mg, 689 pmol) in DMF (5.0 mL) was added piperidine (681 pL, 6.89 mmol). The reaction was stirred at rt for 16 h. The reaction mixture was purified by silica column chromatography. The residue was stirred in toluene (10 mL) at 60°C for 30 min, cooled and the precipitate filtered and dried to afford the title compound (135 mg, 18%) as a brown solid. LC-MS m / z = 682.2 [M+H]+

[0625]

[0459] INTERMEDIATE ID

[0626]

[0460] 4-((iS)-l-(Z>-Alanyl)pyrrolidine-2-carboxamido)benzyl ((lA,9A)-9-ethyl-5-fluoro-9-hydroxy-4- methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-l / / ,12 / / -benzo[6 / |pyrano[3',4':6,7|indolizino[l,2-

[0627] Z>] quinolin-l-yl)carbamate

[0628]

[0461] To a solution of intermediate HA (50.0 mg, 0.06 mmol) in DCM (0.9 mL) was added TFA (0.3 mL) at 0 °C. The reaction mixture was stirred at rt for 1 h. The mixture was basified with sat. aq. NaHCCE to pH 9 and extracted with 3: 1 DCM / IPA (20 mL x 3). The combined organic layers were washed with brine, dried over Na2SC>4 and concentrated under vacuum to afford the title compound (43.0 mg, 98%) as a yellow solid. LC-MS m / z = 753. 15 [M+H]+

[0629]

[0462] Intermediates IE - IV were prepared similarly to intermediate ID by Boc deprotection, see table 27 below.

[0463] Table 27 : Boc deprotection

[0630]

[0464] EXAMPLE 20

[0631]

[0465] 4-((iS)-l-(JV-Isonicotinoyl- / V-methyl-Z)-alanyl)pyrrolidine-2-carboxamido)benzyl ((lS,9S)-9- ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-lH,12H- benzo[t / e]pyrano[3',4':6,7]indolizino[l,2-Z>]quinolin-l-yl)carbamate

[0632]

[0466] To a suspension of intermediate IC (40.0 mg, 52.2 pmol) and intermediate CH (12.1 mg, 57.4 pmol) and NMI (14.5 pL, 183 pmol) in DMF (2.0 mL) was added TCFH (17.6 mg, 62.7 pmol) and the reaction mixture was stirred at rt for 16 h. The reaction mixture was concentrated under vacuum. The residue was dissolved in DMSO, filtered and purified by Prep HPLC to afford the title compound (2.70 mg, 5.8 %) as a white solid. LC-MS m / z = 872.2 [M+H]+

[0633]

[0467] Examples 21 - 25 were prepared in a similar manner to example 20 via amide formation, see table 28 below.

[0634]

[0468] Table 28: Amide coupling with intermediate IC derivatives

[0635]

[0469] EXAMPLE 26

[0636]

[0470] 4-((iS)-l-(pyridazin-4-yl-Z)-alanyl)pyrrolidine-2-carboxamido)benzyl ((liS,9X)-9-ethyl-5- fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-l / f,12Ef- benzo[de]pyrano[3',4':6,7]indolizino[l,2-Z>]quinolin-l-yl)carbamate

[0637]

[0471] To a solution of intermediate ID (43.0 mg, 0.06 mmol) and DIEA (0.04 mL, 0.23 mmol) in DMF (2.0 mL) was added HATU (32.6 mg, 0.09 mmol). The reaction mixture was stirred at rt for 1 h. The reaction mixture was purified by prep-HPLC to afford the title compound (11.3 mg, 23%) as a yellow solid. LC-MS m / z = 859.15 [M+H]+; ’H NMR (400 MHz, DMSO-J6) 5 10.40 - 9.69 (m, 1H), 9.58 - 9.53 (m, 1H), 9.45 - 9.40 (m, 1H), 9.36 - 9.29 (m, 1H), 8.10 - 8.02 (m, 2H), 7.77 (d, J= 10.9 Hz, 1H), 7.67 - 7.59 (m, 2H), 7.41 - 7.30 (m, 3H), 6.54 - 6.47 (m, 1H), 5.45 - 5.39 (m, 2H), 5.33 - 5.24 (m, 3H), 5.10 - 4.82 (m, 3H), 4.50 - 4.41 (m, 1H), 3.78 - 3.48 (m, 2H), 3.21 - 3.10 (m, 1H), 2.37 (s, 3H), 2.19 - 1.83 (m, 9H), 1.39 - 1.29 (m, 3H), 0.89 - 0.85 (m, 3H).

[0638]

[0472] Examples 27 - 84 and intermediates IW - JR were prepared similarly to example 26 by amide coupling with the appropriate acid; see tables 29 and 30 below.

[0639]

[0473] Table 29: Amide coupling between terminal amino group and acid

[0640]

[0474] Table 30: Intermediates derived from amide coupling between terminal amino group and acid

[0641]

[0475] INTERMEDIATE JS

[0642]

[0476] 5-(2,5,8,ll,14,17,20,23-octaoxapentacosan-25-yl) ethanethioate

[0643]

[0477] To a solution of intermediate B (1.10 g, 1.30 mmol) in DMF (8 mL) was added potassium ethanethioate (742 mg, 6.50 mmol) and the reaction mixture was stirred at rt for 16 h. The reaction mixture was poured into water (80 mL) and extracted with EtOAc (50 mL x 3). The organic layers were washed with brine, dried over Na2SC>4 and concentrated under vacuum. The residue was purified by silica column chromatography to afford the title compound (510 mg, 89%) as an oil. LC-MS m / z = 443.2 [M+H]+; 'H NMR (400 MHz, Chloroform-d) 5 3.66 - 3.57 (m, 30H), 3.56 - 3.52 (m, 2H), 3.37 (s, 3H), 3.09 (t, J= 6.5 Hz, 2H), 2.33 (s, 3H).

[0644]

[0478] INTERMEDIATE JT

[0645]

[0479] 2,5,8,ll,14,17,20,23-octaoxapentacosane-25-sulfonyl chloride

[0646]

[0480] To a solution of intermediate JS (200 mg, 0.45 mmol) in MeCN (4 mb) was added 2 M HC1 solution (0.23 mb, 0.45 mmol) and NCS (240 mg, 1.80 mmol) at 0 °C. The mixture was stirred at 0 °C under N2 for 2 h. The mixture was poured into water (50 mb) and extracted with EtOAc (20 mb x 3). The organic layers were washed with brine, dried over Na2SC>4 and concentrated under vacuum to give the title compound (210 mg, crude) as an oil. ’H NMR (400 MHz, Chloroform-d) 5 4.09 (t, J= 5.8 Hz, 2H), 4.00 (t, J= 5.7 Hz, 2H), 3.73 - 3.68 (m, 2H), 3.67 - 3.60 (m, 24H), 3.57 - 3.52 (m, 2H), 3.37 (s, 3H).

[0647]

[0481] EXAMPLE 85

[0648]

[0482] 4-((iS)-l-((pyridin-3-ylsulfonyl)-Z)-alanyl)pyrrolidine-2-carboxamido)benzyl ((lA,9iS)-9-ethyl- 5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-LH,12Ef- benzo[t / e]pyrano[3',4':6,7]indolizino[l,2-b]quinolin-l-yl)carbamate

[0649]

[0483] To a solution of intermediate ID (80.0 mg, 0.06 mmol) and DIEA (30 pL, 0.17 mmol) in DCM (5 mb) was added pyridine-3 -sulfonyl chloride (12.2 mg, 0.07 mmol) and the reaction was stirred at rt for 16 h. The reaction mixture was concentrated under vacuum. The residue was dissolved in DMSO, filtered and purified by prep HPLC. The clean fractions were lyophilised to afford the title compound (2.60 mg, 5.0%) as a white solid. LC-MS m / z = 894.40 [M+H]+; 'H NMR (400 MHz, DMSO-d6) 5 10.42 - 9.88 (m, 1H), 8.96 - 7.25 (m, 10H), 6.56 - 6.50 (m, 2H), 5.50 - 3.48 (m, 9H), 3.30 - 3.08 (m, 3H), 2.63 (s, 1H), 2.42 - 2.34 (m, 4H), 2.25 - 1.80 (m, 5H), 1.33 - 0.98 (m, 6H), 0.87 (m, 3H).

[0650]

[0484] Examples 86 - 89 were prepared in a similar manner to example 85 by sulfonamide formation; see table 31 below.

[0485] Table 31: Sulfonamide formation

[0651]

[0487] 4-(((7?)-l-((A)-2-((4-(((((liS,9iS)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo- 2,3,9,10,13,15-hexahydro-l / / ,12 / / -benzo[< / e|pyrano[3',4':6,7|indolizino[l ,2- / >|quinolin-l- yl)carbamoyl)oxy)methyl)phenyl)carbamoyl)pyrrolidin-l-yl)-l-oxopropan-2- yl)carbamoyl)picolinic acid

[0652]

[0488] To a solution of intermediate JA (55.0 mg, 0.06 mmol) in 1: 1 THF / H2O (2.0 mL) was added LiOHH2O (5.00 mg, 0.12 mmol) and The reaction mixture was stirred at rt for 1 h. The reaction mixture was acidified with 1 M HC1 to -pH 6 and purified by prep-HPLC to give the title compound (20.0 mg, 36%) as a yellow solid. LC-MS m / z = 902. 15 [M+H]+;1H NMR (400 MHz, DMSO-J6) 5 10.43 - 9.53 (m, 1H), 9.38 - 8.77 (m, 2H), 8.59 - 7.30 (m, 9H), 6.56 - 6.44 (m, 1H), 5.47 - 5.41 (m, 2H), 5.32 - 5.24 (m, 3H), 5.11 - 5.05 (m, 2H), 4.86 - 4.39 (m, 2H), 3.86 - 3.58 (m, 3H), 2.42 - 1.78 (m, 13H), 1.39 - 1.25 (m, 3H), 0.87 (t, J= 7.3 Hz, 3H).

[0653]

[0489] Examples 91 - 106 were prepared similarly to example 90 by basic hydrolysis; see table 32 below.

[0654]

[0490] Table 32: Example compounds obtained from basic hydrolysis of terminal methyl ester

[0655]

[0491] EXAMPLE 107

[0656]

[0492] 2-Fluoro-4-((iS)-l-((piperidine-4-carbonyl)-Z)-alanyl)pyrrolidine-2-carboxamido)benzyl ((liS,9iS)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-l / f,12Ef- benzo[de]pyrano[3',4':6,7]indolizino[l,2-Z>]quinolin-l-yl)carbamate

[0657]

[0493] A solution of intermediate JK (70.0 mg, 0.07 mmol) and formic acid (2.0 mL) in DCM (2.0 mL) was stirred at rt for 2 h. The reaction mixture was concentrated under vacuum and purified by prep- HPLC to afford the title compound (15.7 mg, 25.24%) as a yellow solid. LC-MS m / z = 864.20 [M+H]+;

[0658] 1H NMR (400 MHz, DMSO-J6) 5 10.54 - 9.47 (m, 1H), 8.36 (s, 1H), 8.28 - 8.00 (m, 2H), 7.85 - 7.22 (m, 7H), 5.46 - 5.05 (m, 8H), 3.14 - 3.09 (m, 3H), 2.73 - 2.59 (m, 3H), 2.40 - 2.32 (m, 5H), 2.25 - 2.10 (m, 4H), 1.97 - 1.81 (m, 6H), 1.74 - 1.55 (m, 5H), 1.20 - 1.07 (m, 3H), 0.88 (t, J= 7.4 Hz, 3H).

[0659]

[0494] Examples 108 - 114 and intermediates JU - JW were prepared similarly to example 107 by Boc deprotection; see tables 33 and 34 below.

[0495] Table 33: Final compounds derived from Boc deprotection

[0660]

[0496] Table 34: Boc-Deprotection

[0661]

[0662]

[0498] 2-((2,2-Dimethyl-4,20-dioxo-3,8,ll,14,17-pentaoxa-5,21-diazatricosan-23-yl)carbamoyl)-4- ((iS)-l-(isonicotinoyl-Z>-alanyl)pyrrolidine-2-carboxamido)benzyl ((lS,9S)-9-ethyl-5-fluoro-9- hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-l / / ,12 / / - benzo[t / e]pyrano[3',4':6,7]indolizino[l,2-b]quinolin-l-yl)carbamate

[0663]

[0499] To a solution of example 109 (100 mg, 0.11 mmol), 2,2-dimethyl-4-oxo-3,8,ll,14,17-pentaoxa-5- azaicosan-20-oic acid (38.7 mg, 0.11 mmol) in DMF (2.0 mL) was added DIEA (0.11 mL, 0.70 mmol) and HATU (40.3 mg, 0.11 mmol). The resulting mixture was stirred at rt for 1 h under N2. The reaction mixture was diluted with water (40 mL) and extracted with 3: 1 DCM / IPA (20 mL x 3). The combined organic layers were concentrated under vacuum. The residue was purified by silica column chromatography to afford the title compound (120 mg, 79%) as a brown oil. LC-MS m / z = 1291.35 [M+H]+; 'H NMR (400 MHz, DMSO-6) 5 10.58 - 9.60 (m, 1H), 9.06 (d, J= 6.5 Hz, 1H), 8.74 - 8.65 (m, 2H), 8.40 - 8.31 (m, 1H), 8.10 - 8.02 (m, 1H), 7.96 - 7.88 (m, 1H), 7.81 - 7.73 (m, 4H), 7.37 - 7.18

[0664] (m, 3H), 6.76 - 6.69 (m, 1H), 6.68 - 6.60 (m, 1H), 6.52 - 6.49 (m, 1H), 5.44 - 5.19 (m, 9H), 5.06 - 4.76

[0665] (m, 1H), 4.53 - 4.39 (m, 2H), 4.25 - 4.18 (m, 1H), 4.00 - 3.94 (m, 1H), 3.87 - 3.75 (m, 2H), 3.62 - 3.46

[0666] (m, 18H), 3.08 - 2.98 (m, 2H), 2.38 (s, 3H), 2.20 - 2.15 (m, 2H), 2.01 - 1.96 (m, 5H), 1.90 - 1.83 (m,

[0667] 1H), 1.35 - 1.33 (m, 12H), 0.85 - 0.83 (m, 3H).

[0668]

[0500] Examples 115 - 121 and intermediates JY - KA were prepared in a similar manner to intermediate JX via amide coupling, see tables 35 and 36 below.

[0501] Table 35: Example compounds derived from amide coupling on the terminal amine linker

[0669]

[0502] Table 36: Intermediates derived from amide coupling on the linker substituent

[0670]

[0503] EXAMPLE 122

[0504] 2-((l-Amino-15-oxo-3,6,9,12-tetraoxa-16-azaoctadecan-18-yl)carbamoyl)-4-((A)-l- (isonicotinoyl-Z>-alanyl)pyrrolidine-2-carboxamido)benzyl ((lA,9A)-9-ethyl-5-fluoro-9-hydroxy-4- methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-l / / ,12 / / -benzo[de|pyrano[3',4':6,7|indolizino[l,2- Z>]quinolin-l-yl)carbamate

[0671]

[0505] To a solution of intermediate JY (120 mg, 0.08 mmol) in MeCN (3.0 mL) was added 4M HC1- dioxane (2.0 mL) at 0 °C. The reaction mixture was stirred at 0 °C for Ih. The reaction mixture was concentrated under vacuum and purified by Prep-HPLC to afford the title compound (12.5 mg, 13%) as a white solid. LC-MS m / z = 1191.35 [M+H]+; 'H NMR (400 MHz, DMSO-6) 5 10.58 - 9.71 (m, IH), 9.11 - 9.02 (m, IH), 8.74 - 8.65 (m, 2H), 8.41 - 8.35 (m, IH), 8.06 (d, J= 8.7 Hz, IH), 7.99 - 7.89 (m, IH), 7.82 - 7.70 (m, 5H), 7.51 - 7.43 (m, IH), 7.32 - 7.29 (m, IH), 5.48 - 5.38 (m, 2H), 5.34 - 5.18 (m, 5H), 5.07 - 4.74 (m, IH), 4.48 - 4.42 (m, IH), 3.81 - 3.51 (m, 18H), 3.30 - 3.03 (m, 9H), 2.94 - 2.75 (m, 2H), 2.37 (s, 3H), 2.34 - 1.77 (m, 10H), 1.38 - 1.23 (m, 3H), 0.87 (t, J= 7.3 Hz, 3H).

[0672]

[0506] Examples 123 - 127 were prepared in a similar manner to example 122, by Boc deprotection. See table 37 below.

[0673]

[0507] Table 37: Final compounds derived from Boc deprotection

[0674]

[0508] EXAMPLE 128

[0675]

[0509] 4-(((iS)-l-(((7?)-l-((iS)-2-((4-(((((liS,9iS)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo- 2,3,9,10,13,15-hexahydro-LH,12 / 7-benzo[t / e]pyrano[3',4':6,7]indolizino[l,2-b]quinolin-l- yl)carbamoyl)oxy)methyl)phenyl)carbamoyl)pyrrolidin-l-yl)-l-oxopropan-2-yl)amino)-3-hydroxy- l-oxopropan-2-yl)amino)-4-oxobutanoic acid

[0676]

[0510] To a solution of intermediate JV (90.0 mg, 0.11 mmol) and succinic acid (15.0 mg, 0.11 mmol) in DCM (1.5 mL) was added TEA (0.06 mL, 0.54 mmol) and HATU (42.0 mg, 0.11 mmol). The reaction mixture was stirred at rt for 2 h under N2. The mixture was concentrated under vacuum and purified by Prep-HPLC to give the title compound (6.20 mg, 6.0%) as a yellow solid. LC-MS m / z = 940.15 [M+H]+; 1H NMR (400 MHz, DMSO-J6) 5 12.00 (s, 1H), 10.33 - 9.61 (m, 1H), 8.15 - 7.84 (m, 3H), 7.77 (d, J = 10.9 Hz, 1H), 7.67 - 7.33 (m, 4H), 7.31 (s, 1H), 6.51 (s, 1H), 5.44 (s, 2H), 5.33 - 5.22 (m, 3H), 5.14 - 5.02 (m, 2H), 4.93 - 4.46 (m, 2H), 4.45 - 4.18 (m, 2H), 3.76 - 3.65 (m, 1H), 3.61 - 3.49 (m, 3H), 3.21 - 3.03 (m, 2H), 2.43 - 1.79 (m, 17H), 1.22 - 1.06 (m, 3H), 0.88 (t, J= 7.3 Hz, 3H).

[0511] Example 129 was prepared similarly to example 128 by amide coupling with succinic acid; see table 38 below.

[0677]

[0512] Table 38: Amide coupling with succinic acid

[0678]

[0513] EXAMPLE 130

[0679]

[0514] (10iS,23iS)-10-ethyl-18-fluoro-10-hydroxy-19-methyl-5,9-dioxo-8-oxa-4,15- diazahexacyclo[14.7.1.02,14.04,13.06,11.020,24]tetracosa-l,6(ll),12,14,16,18,20(24)-heptaen-23-yl {p-[(X)- l-[(7?)-2-isonicotinoylaminopropionyl]-2-pyrrolidinylcarbonylamino]phenyl}[7V-2-(3,6,9,12,15- pentaoxahexadecylcarbonylamino)ethylcarbamoyl]methanecarbamate

[0680]

[0515] To intermediate HY (116 mg, 111 pmol) was added 4M HC1 (2.0 m , 8.00 mmol) in dioxane (2.0 m ) and the reaction mixture was stirred at rt for 2 h. The reaction mixture was concentrated under vacuum. To the residue was added TCPH (27.5 mg, 97.9 pmol) 2,5,8,l l,14-pentaoxaheptadecan-17-oic acid (23.2 ph, 91.8 pmol) and NMI (17.0 ph, 214 pmol) in DMb (2.0 mb) and the reaction was stirred at rt for 18 h. The reaction mixture was concentrated under vacuum and the residue purified by prep-HPEC to afford the title compound as a white solid (2.00 mg, 3%). EC-MS m / z = 603.8 [M+2H]2+; ’H NMR (500 MHz, DMSO-d6) 5 9.68 - 8.12 (m, 6H), 7.99 - 7.21 (m, 6H), 6.86 - 6.25 (m, 4H), 5.87 - 4.02 (m, 6H), 3.84 - 3.44 (m, 20H), 3.24 - 2.97 (m, 11H), 2.40 - 2.37 (m, 3H), 2.30 - 2.12 (m, 2H), 2.08 (s, 3H), 2.00 - 1.77 (m, 4H), 1.38 - 1.00 (m, 4H), 0.92 - 0.82 (m, 3H).

[0681]

[0516] EXAMPLE 131

[0682]

[0517] 4-((2S,4S)-4-hydroxy-l-(isonicotinoyl-D-alanyl)pyrrolidine-2-carboxamido)benzyl ((lS,9S)-9- ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-lH,12H- benzo[de]pyrano[3',4':6,7]indolizino[l,2-b]quinolin-l-yl)carbamate

[0683]

[0518] To a solution of intermediate JI (223 mg, 0.23 mmol) in DCM (9.0 mL) was added TFA (3.0 mL) slowly at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. The mixture was basified with sat. aq. Na2COs to pH ~8 and extracted with 3: 1 DCM / IPA (20 mL x 3). The combined organic layers were dried over Na2SC>4 and concentrated in vacuum. The residue was purified by prep-HPLC to afford the title compound (9.50 mg, 19%) as a yellow solid. LC-MS m / z = 874.3 [M+H]+; ’H NMR (400 MHz, DMSO- d6) 5 10.49 - 9.65 (m, 1H), 9.12 - 8.66 (m, 3H), 8.08 - 7.57 (m, 6H), 7.45 - 7.26 (m, 3H), 6.50 (s, 1H), 5.43 (s, 2H), 5.34 - 5.17 (m, 4H), 5.13 - 5.03 (m, 2H), 4.83 - 4.72 (m, 1H), 4.55 - 4.45 (m, 1H), 4.42 - 4.28 (m, 1H), 3.75 - 3.66 (m, 1H), 3.60 - 3.49 (m, 1H), 3.25 - 3.02 (m, 2H), 2.36 (s, 3H), 2.28 - 2.08 (m, 3H), 2.04 - 1.78 (m, 3H), 1.39 - 1.19 (m, 3H), 0.87 (t, J= 7.2 Hz, 3H).

[0684]

[0519] EXAMPLE 132

[0685]

[0520] 4-((A)-l-(isonicotinoyl-Z>-alanyl)-4-oxopyrrolidine-2-carboxamido)benzyl ((lA,9A)-9-ethyl-5- fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-lH,12H- benzo[de]pyrano[3',4':6,7]indolizino[l,2-b]quinolin-l-yl)carbamate

[0686]

[0521] To a solution of example 131 (79 mg, 0.09 mmol) in 1: 1 MeCN / DCM (16 mL) was added Dess- Martin periodinane (383 mg, 0.90 mmol) slowly at rt. The reaction mixture was stirred at rt for 2 h. Sat. aq. (Na2CC>3) was added to reach ~ pH 8 and the mixture was extracted with 3: 1 DCM / IPA (20 mL x 3). The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The residue was purified by prep-HPLC to afford the title compound (10.5 mg, 13%) as a yellow solid. LC-MS m / z = 872.3 [M+H]+, 'H NMR (400 MHz, DMSO-tL) 5 10.71 - 10.06 (m, 1H), 9.22 - 9.04 (m, 1H), 8.80 - 8.42 (m, 2H), 8.05 (d, J= 8.8 Hz, 1H), 7.86 - 7.72 (m, 3H), 7.68 - 7.54 (m, 2H), 7.45 - 7.26 (m, 3H), 6.51 (s, 1H), 5.53 - 5.39 (m, 2H), 5.35 - 5.21 (m, 3H), 5.15 - 4.96 (m, 3H), 4.90 - 4.68 (m, 1H), 4.27 (d, J= 18.0 Hz, 1H), 4.15 - 4.03 (m, 1H), 3.27 - 3.01 (m, 3H), 2.69 - 2.54 (m, 1H), 2.42 - 2.30 (m, 3H), 2.25 - 2.09 (m, 2H), 1.94 - 1.79 (m, 2H), 1.40 - 1.21 (m, 3H), 0.86 (t, J= 7.4 Hz, 3H).

[0687] Biological Data

[0688] Table 39: FAP Enabled Cytotoxicity (CFPAC-1) and kcatI KM data for example compounds of the invention.

[0689]

[0522] The cytotoxicity of each of the example compounds was measured against CFPAC- 1 cells and pIC50values calculated. The experiment was repeated in the presence of human FAP (+hFAP) and in the presence of a FAP inhibitor (+FAPi).

[0690] Table 39

[0691]

[0692] FAP Enabled Cytotoxicity - : pIC8o (+hFAP) - pIC8o (+FAPi) < 0.5; + : 0.5 < pIC8o (+hFAP) - pIC8o (+FAPi) < 1.5, ++ : pIC5o (+hFAP) - pIC5o (+FAPi) > 1.5 keat / KM + : >100 M-1s'1; ++ > 1000 M-1s'1; +++ > 10000 M-1s'1; ++++ > 100000 AF's'1; ND = not measured

[0693] Additional In Vitro and In Vivo Data

[0694] Cell Uptake Data

[0695]

[0523] To determine the cellular uptake of Example compounds, an experiment was performed to quantify the concentrations of the parent Example compound and released exatecan warhead within the cells. In this cell uptake experiment, non-FAP expressing HEK293T cells (HEK-parental) and HEK293T cells which have been engineered to express high levels of FAP (HEK-FAP) were treated with 40 nM of Example 56, and LC-MS used to assess the intracellular levels of the parent Example compound (indicated as “Example XX”) or released Exatecan (indicated as “Exatecan”) (FIG. 1). C6lls were sampled at timepoints shown in FIG. 1.

[0696] Tolerability Data

[0697]

[0524] In order to determine the maximum tolerated dose (MTD) of Example compounds and conventional Exatecan, non-tumor bearing NMRI nu / nu mice were treated either once daily (QD) or biweekly (BIW). Individual body weights were measured daily, as well as signs of distress or discomfort that may be caused by toxicity. Tolerated compounds showed body weight maintenance or increase (>10%), whereas those that were not tolerated showed mild (>10%) to moderate (>15%) body weight loss (BWL), with animals being terminated if they displayed severe (>20%) body weight loss.

[0698]

[0525] Daily and biweekly tolerability of Example 56, and Exatecan. Once daily dosing for Exatecan and Example 56, and biweekly dosing for Exatecan demonstrated weight loss, and therefore was taken as established MTD (FIG. 2). However, no weight loss was observed with biweekly (50 mg / kg) dosing of Example 56, and therefore no MTD could be established (FIG. 2).

[0699] Tumor Uptake Data

[0700]

[0526] Melanoma or Sarcoma Tumor Uptake. To quantify the levels of parent Example compound and released exatecan warhead in the tumor and plasma following dosing, high FAP expressing patient derived xenograft (PDX) models of Melanoma (Mell3281) or Sarcoma were used. Tumor fragments were subcutaneously implanted into the left flank of mice and were allowed to develop to a size of 250 mm3- 400 mm3before commencing with dosing. Animals were subcutaneously dosed once and sampled at either 4 hr, 24 hr, or 36 hr post-dosing (n=3 per timepoint). LC-MS was used to quantify the concentration of parent Example compound (indicated as “Example XX”) or released Exatecan (indicated as “Exatecan”) in plasma and tumor samples (Melanoma, FIGs. 3A-3E; Sarcoma, FIG. 7).

[0701]

[0527] LS174T-FAP Tumor Uptake. To quantify the levels of parent compound and released exatecan warhead, in the tumor and plasma following dosing, a cell-line derived xenograft (CDX) model of LS174T-FAP (LS174T colorectal cancer cells engineered to over-express FAP) was used. C6lls from growing cultures were implanted subcutaneously into the left flank of mice, and were allowed to develop to a size of 250mm3-400mm3before commencing with dosing. Animals were subcutaneously dosed once with Example 90 (40mg / kg), and sampled at either 4 hr, or 24 hr post-dosing (n=3 per timepoint). LC / MS was used to quantify the concentration of parent compound (indicated as “Example XX”) or released Exatecan (indicated as “Exatecan”), in plasma and tumor samples (FIG. 9).

[0702]

[0528] HEK-FAP Tumor Uptake. A cell-line derived xenograft (CDX) model of HEK-FAP (HEK293T engineered to over-express FAP) was also used in a tumor uptake study. C6lls from growing cultures were implanted subcutaneously into the left flank of mice, and were allowed to develop to a size of 250 mm3-400 mm3before commencing with dosing. Animals were subcutaneously dosed once, and sampled at either 4 hr, 16 hr, 24 hr, 30 hr, or 36 hr post-dosing (n=3 per timepoint). LC / MS was used to quantify the concentration of parent compound (indicated as “Example XX”) or released Exatecan (indicated as “Exatecan”), in plasma and tumor samples (FIG. 10A). PK modeling of tumor and plasma concentration following Compound 57 dosing suggests prolonged tumor exposure (FIG. 10B).

[0703]

[0529] Pancreatic Tumor Uptake. Tumor uptake of Compound 57 was evaluated in a FAP -positive tumor model of pancreatic cancer (FIG. 18).

[0704] Efficacy Data

[0705]

[0530] HEK-FAP CDX Efficacy. A cell-line derived xenograft (CDX) model of HEK-FAP (HEK293T engineered to over-express FAP) was used in the below efficacy studies. C6lls from growing cultures were implanted subcutaneously into female NOG mice. At palpable tumor sizes (of -100 mm3) the test compounds (indicated as “Example XX”) or conventional Exatecan (indicated as “Exatecan”) were injected subcutaneously once weekly (QW) or twice weekly (BIW). Tumor growth was monitored twice weekly and at humane endpoints, the studies were terminated.

[0706]

[0531] HEK-FAP CDX efficacy with Example 56 and Exatecan. Animals from the Example 56 and Exatecan cohorts were removed from treatment at day 46 and monitored for tumor regrowth, until day 70 at which point the study was terminated (FIG. 4A).

[0707]

[0532] HEK-FAP CDX efficacy with Example 90, Example 116, Example 98, and Exatecan.

[0708] Remaining animals from the Example 90, Example 116, Example 98, and Exatecan cohorts were removed from treatment on days 31 (QW groups) or 34 (BIW groups) and monitored for tumor regrowth (FIG. 4B). Vehicle, Example 90, Example 116, and Exatecan QW cohorts were dosed on days 10, 17, 24 and 31, and the BIW cohorts were dosed on days 10, 14, 17, 20, 24, 28, 31, and 34. For Example 98, QW cohorts were dosed on days 10, 17, and 24, and the BIW cohorts were dosed on days 10, 14, 17, 28, and 31.

[0709]

[0533] HEK-FAP CDX efficacy with Example 117, and Exatecan. Tumor growth was monitored (FIG. 4C).

[0710]

[0534] Sarcoma PDX efficacy with Example 90, Example 117, and Exatecan. A patient derived xenograft (PDX) model of Sarcoma was used in this efficacy study. Tumor fragments were subcutaneously implanted into the left flank of mice and were allowed to develop to a size of -100 mm3before commencing with dosing. Test compounds (indicated as “Example XX”) or conventional Exatecan (indicated as “Exatecan”) were injected subcutaneously once weekly (QW). Tumor growth was monitored twice weekly and at humane endpoints, the studies were terminated (FIG. 5).

[0711]

[0535] LS174T-FAP CDX efficacy with Example 90, Example 45, Example 98, Example 117, and Exatecan. A cell-line derived xenograft (CDX) model of LS174T cells engineered to express FAP was used in this efficacy study. C6lls from growing cultures were implanted subcutaneously into female NOG mice. At palpable tumor sizes (of -100 mm3) the test compounds (indicated as “Example XX”) or conventional Exatecan (indicated as “Exatecan”) were injected subcutaneously once weekly (QW). Tumor growth was monitored twice weekly and at humane endpoints, the studies were terminated (FIG. 6). Vehicle, Example 45, Example 117, and Exatecan QW cohorts were dosed on days 4, 11, and 18, and the Example 90 cohort was dosed on days 4, 18, and 25.

[0712]

[0536] Example 90 dosing was also lowered from 50 mg / kg for its first dose, down to 40 mg / kg for its subsequent doses.

[0713]

[0537] Gastl3765A PDX Efficacy with Example 90 and Exatecan. A patient derived xenograft (PDX) model of gastric cancer was used in this efficacy study. Tumor fragments were subcutaneously implanted into the left flank of mice and were allowed to develop to a size of -100-120 mm3before commencing with dosing. Test compound (indicated as “Example 90”) or conventional Exatecan (indicated as “Exatecan”) were injected subcutaneously once weekly (QW) for 3 weeks. Tumou growth was monitored twice weekly and at humane endpoints, the studies were terminated (FIG. 11). Terminal tumor volumes continued until termination of last animal in the group. All animals were dose on days 9, 16, and 23. Remaining animals were removed from treatment on day 23 and monitored for tumor regrowth.

[0714]

[0538] Pancl2532 PDX Efficacy with Example 90 and Exatecan. A patient derived xenograft (PDX) model of pancreatic carcinoma was used in the below efficacy study. Tumor fragments were subcutaneously implanted into the left flank of mice and were allowed to develop to a size of -100-120 mm3before commencing with dosing. Test compound (indicated as “Example 90”) or conventional Exatecan (indicated as “Exatecan”) were injected subcutaneously once weekly (QW) for 3 weeks. Tumor growth was monitored twice weekly and at humane endpoints, the studies were terminated (FIG. 12). Terminal tumor volumes continued until termination of last animal in the group. All animals were dose on days 9, 16, and 23. Remaining animals were removed from treatment on day 23 and monitored for tumor regrowth.

[0539] Co6044 PDX Efficacy with Example 90 and Exatecan. A patient derived xenograft (PDX) model of colorectal cancer was used in the below efficacy study. Tumor fragments were subcutaneously implanted into the left flank of mice and were allowed to develop to a size of -100- 120mm3before commencing with dosing. Test compound (indicated as “Example 90”) or conventional Exatecan (indicated as “Exatecan”) were injected subcutaneously once weekly (QW) for 3 weeks. Tumor growth was monitored twice weekly and at humane endpoints, the studies were terminated (FIG. 19). Terminal tumour volumes continued until termination of last animal in the group. All animals were dosed on days 9, 16, and 23. Remaining animals were removed from treatment on day 23 and monitored for tumor regrowth.

[0715] Co-culture Data

[0716]

[0540] 2D Co-culture Data. LS174T-GFP colorectal cancer cell line and primary human colonic fibroblasts (HCoF) were cultured in EMEM + 10% fetal bovine serum and DMEM + 10% fetal bovine serum, respectively. Both the LS 174T-GFP tumor cells and HCoF cells were then harvested, strained, washed, and the required cell number adjusted in serum-free MammoCult™ medium (Stem C6ll Technologies, #05620). In the LS174T-GFP mono-culture condition, 7,500 cells / well were seeded into a 96-well microplate. In the co-culture condition, 2,500 LS174T-GFP and 7,500 HCoF cells / well were seeded into a 96-well microplate. After 24 h incubation at 37 deg C with 5% CO2, cells were pre-treated with recombinant FAP (hFAP, final 10 nM) or FAP inhibitor (FAPi, final 10 pM) for 15 minutes prior to the addition of compound titrations. The plates were imaged on the IncuCyte® for 5 days. LS174T-GFP tumor kill was measured as loss of GFP+ tumor cells.

[0717]

[0541] The cytotoxic activity and bystander effect of Example 90 compounds are demonstrated in a 2D in- vitro assay with FAP -positive primary human colonic fibroblasts (HCoF) and FAP-negative colorectal tumor cells (LS174T-GFP). Example 90 is capable of killing FAP-negative tumor cells only when FAP- positive fibroblasts are present or when recombinant FAP is added. In mono-cultures (FIG. 13 A), Example 90 is mostly inert with an IC50 of 55 nM, similar to +FAPi condition of 61 nM. Addition of 10 nM recombinant FAP as positive control to the mono-culture increases Example 90 cytotoxicity to levels similar as the warhead, with IC50 of 0.093 and 0.141 nM, respectively. In the co-culture conditions (FIG. 13B), Example 90 cytotoxicity (IC50 of 0.409 nM) is within 4-fold to the warhead (0.110 nM) due to FAP expressed on the HCoF. Addition of recombinant FAP to the co-culture conditions further enhances Example 90 cytotoxicity (IC50 of 0.066 nM). Example 90 cytotoxicity in co-culture is FAP dependent as pre -incubation with a specific FAP inhibitor abrogates Example 90 cytotoxicity. The 2D co-culture assay demonstrates that Example 90 kills tumor cells in a FAP dependent manner.

[0718] Table 40.

[0719]

[0542] Compound killing of MDA-MB-231 tumor spheroids in the presence or absence of FAP- expressing primary human mammary fibroblasts. MDA-MB-231 -GFP breast cancer cell line and primary human mammary fibroblasts (HMF) were cultured in DMEM + 10% fetal bovine serum. MDA- MB-231-GFP tumor cells were harvested, washed, and the required cell number was adjusted in mamocult medium (Stem C6ll Technologies, #05620) and 12.5 pg / ml collagen I. The cell suspension was seeded into a 384-well ultra-low-attachment (ULA) microplate at 5,000 cells / well in 15 pl. The plate was centrifuged at 200 g for 4 min, rotated and centrifuged again, before incubation at 37 °C. After 24 h incubation, for the coculture condition 15,000 HMF cells / well in 15 pl mamocult media were added into the 384-well plate, while 15 pl mamocult media only with no additional cells was added to the monoculture condition. The plate was centrifuged at 200 g for 4 min, rotated and centrifuged again, before incubation at 37 °C. After another 24 h incubation, cells were pre-treated with 5 pl of 8X concentration of recombinant FAP (hFAP) (final 10 nM), 8X FAP inhibitor (FAPi) (final 10 pM), or control mamocult media for at least 10 minutes, before addition of 5 pl of 8X concentration of compound titration. The plate was imaged on the Incucyte for 5 days. MDA-MB-231-GFP tumor kill was measured as loss of GFP+ tumor spheroid fluorescence at Day 5.

[0720]

[0543] The cytotoxic activity and bystander effect of Example compounds were demonstrated in an in- vitro study with FAP-positive primary human mammary fibroblasts (HMF) and FAP -negative triplenegative breast tumor cells (MDA-MB-231) cultured as 3D spheroids (FIGs. 8A-8B). Example 90 is capable of killing FAP -negative tumor cells only when FAP-positive fibroblasts are present. In monocultures, in the absence of fibroblasts, Example 90 is mostly inert with an IC50 of >10pM (FIG. 8A). As a control, addition of recombinant FAP (hFAP) to monocultures increases Example 90 cytotoxicity to levels seen with Exatecan warhead. In cocultures, Example 90 cytotoxicity is similar to Exatecan warhead (-0.06 pM) due to presence of FAP on primary fibroblasts (FIG. 8B). Addition of recombinant FAP to cocultures does not further increase Example 90 cytotoxicity as FAP on fibroblasts is sufficient to lead to full release of warhead. Example 90 cytotoxicity in cocultures is FAP dependent as pre-incubation with a specific FAP inhibitor (FAPi) abrogates Example 90 cytotoxicity. The 3D coculture spheroid assay demonstrates that Example 90 kills tumor cells only when FAP+ fibroblasts are present. Table 41: IC50 for Example compound killing of MDA-MB-231 tumor spheroids in the presence or absence of FAP-expressing primary human mammary fibroblasts as a monoculture or co-culture

[0544] 3D Ratio Co-culture Data. To determine activity of Example compound in tumors with low fibroblast content and low FAP setting, Example 90 was tested in a 3D co-culture model with MDA-MB- 231 triple negative breast cancer cells (FAP-negative, GFP -positive) and primary human mammary fibroblasts at various tumor: fibroblast ratios (0 to 75% fibroblasts). 3D spheroids of MDA-MB-231-GFP cells alone or cocultures with fibroblasts were generated by seeding 5,000 MDA-MB-231-GFP cells / well in 384-well ultra-low-attachment microplates. After 24 h incubation at 37 °C, fibroblasts were added to achieve 75% to 4% fibroblasts in cocultures. Following another 24 h incubation, monocultures and cocultures were treated with Exatecan warhead or Example compound ± 10 pM FAP inhibitor for 120 h. C6lls were imaged on Incucyte, and tumor cell death was analyzed as % reduction in GFP intensity relative to vehicle control. FAP enzymatic activity was measured by lysing 3D spheroids and quantifying FAP enzyme activity in cell lysates. Specifically, FAP activity was measured by measuring the cleavage of a synthetic Anorogenic FAP-specific peptide substrate, N-(quinoline-4-carbonyl)-D-Ala-L-Pro-AMC (3144-AMC), where AMC is the Anorogenic leaving group, providing a means for the specific measurement of FAP enzymatic activity in biological samples (Keane et al., 2013, doi: 10.1016 / j.fob.2013.12.001).

[0721]

[0545] Example 90 showed little activity in cultures with 0% fibroblasts due to the absence of FAP (FIG. 14A). In cocultures containing 75% fibroblasts, Example 90 exhibited cytotoxicity comparable to that of exatecan warhead alone. This cytotoxicity was sustained even with reduced fibroblast ratios. Notably, enhanced cytotoxicity was observed in cocultures with fibroblast percentages as little as 4-10%, compared to cultures with 0% fibroblasts. The cytotoxicity was FAP-dependent, as it was reversed with a FAP inhibitor. FAP activity in the co-culture model correlated with fibroblast percentage (FIG. 14B, Table 42) and cytotoxicity (FIGs. 14C-14D), suggesting that FAP activity as low as 300-500 pmol / min / mg is sufficient for Example 90 to exhibit significant cytotoxicity. This level of FAP activity is anticipated in human tumors. Accordingly, provided compounds such as Example 90 can be used to treat patients with relatively low fibroblast content and relatively low FAP expression.

[0722] Table 42. IC8o for Example compound killing of MDA-MB-231 tumor spheroids in co-culture with primary human mammary fibroblasts at various tumor to fibroblast (F) percentages.

[0723] Pharmacokinetics

[0724]

[0546] A PK study was conducted to assess the pharmacokinetics of Example 90 and “Example 90- released exatecan”, the exatecan released via FAP-mediated cleavage of Example 90. This study was conducted in male ICR mice (N = 3), each dosed with a single iv dose of Example 90 (10 mg / kg). Plasma samples were collected from each mouse at 0 hr, 0.083 hr, 0.25 hr, 0.5 hr, 1 hr, 2 hr, 4 hr, 8 hr and 24 hr timepoints and the concentration of Example 90 and exatecan quantified using LC-MS.

[0725]

[0547] Following iv administration, the mean maximum plasma concentration (Cmax) of Example 90 was 12400 ng / mL. This was observed at the first sampling time of 5 minutes post-dose. The Cmaxof released exatecan was 141 ng / mL.

[0726]

[0548] The elimination half-life of Example 90 was 3.40 hours. This is significantly longer than the elimination half-life observed for released exatecan (1.89 hours). The exposure of Example 90 was 90- fold higher than that for released exatecan, with AUC values of 6090 ng.h / mL and 67.1 ng.h / mL respectively. This is also reflected in the much larger Cmaxobserved for Example 90 than exatecan.

[0727]

[0549] A PK study was also conducted to examine the pharmacokinetics of exatecan alone. This study was conducted in male ICR mice (N = 3), each dosed with a single iv dose of exatecan mesylate dihydrate (5 mg / kg). Plasma samples were collected from each mouse at 0 hr, 0.083 hr, 0.25 hr, 0.5 hr, 1 hr, 2 hr, 4 hr, 8 hr and 24 hr timepoints and the concentration of exatecan quantified using LC-MS.

[0728]

[0550] Following iv administration, the mean maximum plasma concentration (Cmax) of exatecan was 2230 ng / mL. This was observed at the first sampling time of 5 minutes post-dose. This is 15.8-fold greater than the Cmaxfor Example 90-released exatecan. The AUC for exatecan alone was 1440 ng.h / mL, 21.5-fold greater than for Example 90-released exatecan. The table below shows selected PK parameters for exatecan, Example 90 and exatecan released from Example 90. Values presented are the mean of N = 3 animals.

[0729] Table 43. Pharmacokinetic parameters.

[0730] PD Biomarker Analysis

[0731]

[0551] To quantify the expression of DNA damage response DNA damage repair, apoptosis, and cell cycle markers in tumor following administration of Example 90, western blot analysis was performed on tumor lysates and were probed for common markers of the above. Tumor samples were obtained from a tumor uptake experiment, in which a cell-line derived xenograft (CDX) model of LS174T-FAP (LS174T colorectal cancer cells engineered to over-express FAP) was employed. C6lls from growing cultures were implanted subcutaneously into the left flank of mice, and were allowed to develop to a size of 250 mm3- 400 mm3before commencing with dosing. Animals were subcutaneously dosed once with Example 90 (40 mg / kg), and sampled at either 4 hr, or 24 hr post-dosing (n=3 per timepoint).

[0732]

[0552] Tumor samples were homogenized and lysates were prepared for protein quantification via a BCA assay. Equal concentrations of each sample were then analysed by western blot, stained with the respective primary and secondary antibodies, and imaged via chemiluminescence (FIG. 16).

[0733]

[0553] yH2AX expression was found to increase at both the 4 hr and 24 hr post-Example 90 dosed tumors compared to the vehicle treated tumors. p21 levels also increased compared to vehicle following Example 90 administration, where levels at 24 hr were slightly higher than levels at 4hr post-dosing. This was also true for pKAP 1 levels, with increased at both the 4 hr and 24 hr timepoints compared to vehicle- treated tumors. pCHK2 again showed a similar pattern, where no staining was observed in vehicle -treated tumors, but at 4 hr and 24 hr, the levels observed were further increased.

[0734] Correlation of FAP and SLFN11 expression as a predictive biomarker for pre\CISION®-enabled therapeutics

[0735] Introduction

[0736]

[0554] Fibroblast activation protein is a post-proline protease highly expressed on cancer-associated fibroblasts (CAFs) in the tumor stroma of many solid tumors. The pre|CISION® platform leverages FAP enzymatic activity to release cytotoxic agents specifically within the tumor, minimizing systemic toxicity and enhancing intratumoral drug concentrations.

[0737]

[0555] Schlafen 11 (SLFN 11), is a DNA / RNA helicase-like protein and has emerged as a potential predictive biomarker of tumor sensitivity to DNA-damaging therapies, including topoisomerase I inhibitors, platinum agents and PARP inhibitors. SLFN 11 expression leads to replication fork destabilization and impaired DNA repair, making SLFN 11 -positive tumors more susceptible to insult from DNA-damaging agents. The clinical utility of SLFN 11 has been demonstrated in several studies

[0556] A potential synergy emerges when FAP and SLFN 11 expression profiles are considered together as tumors co-expressing high levels of FAP and SLFN11 are most likely to respond to pre|CISION®- enabled DNA-damaging agents. In these tumors, high FAP expression enables efficient localisation and cleavage of pre|CISION® compounds, while SLFN11 expression enhances tumor cell susceptibility to the DNA damaging inducing payload. Identifying tumor types where this co-expression exists could allow for rational patient stratification and biomarker-driven clinical development.

[0738] Methodology

[0739]

[0557] To explore the potential utility of FAP and SLFN 11 as complementary predictive biomarkers, mRNA expression data were analyzed from Tempus Al’s LENS platform, a large-scale multi-omics database encompassing over 160,000 solid tumor samples profiled by RNA sequencing. The analysis focused on 30 tumor indications and select subtypes, including pancreatic, breast, lung and colorectal cancer. Expression values were normalized and presented as log2(TPM+l).

[0740]

[0558] To assess co-expression, FAP and SLFN11 expression levels were extracted for each tumor samples and visualized using scatter plots. To enhance interpretation, vertical and horizontal dashed lines were used to define biologically relevant expression cutoffs for both FAP and SLFN11. These thresholds delineated samples into quadrants representing combinations of negative, weak or strong FAP expression and low or high SLFN 11 expression.

[0741]

[0559] The proportion of samples in each quadrant was calculated and displayed directly on the plot, enabling quantification of prevalence of potentially targetable subgroups (strong FAP - high SLFN 11 expression). A linear regression trendline was applied to assess the overall relationship between FAP and SLFN11 expression. Pearson’s R and the corresponding p-value were calculated and overlaid on each plot to evaluate the strength and statistical significance of the correlation.

[0742] Results

[0743]

[0560] FAP mRNA expression was found to significantly correlate with SLFN11 expression across select solid tumor indications. In small-cell lung cancer (SCLC) 30.5% of samples had strong FAP - high SLFN 11 expression while 67.8% of pancreatic cancer samples had strong FAP - high SLFN 11 expression. 58.3% of cervical cancer samples demonstrated strong FAP - high SLFN11 expression and 47.2% of gastric samples (FIG. 9). Collectively, these findings support the hypothesis that co-expression of FAP and SLFN 11 can be leveraged for patient selection strategies, particularly in indications like pancreatic cancer. Compounds disclosed herein possess DNA damage -inducing payloads. The FAP- SLFN 11 correlation could act as a predictive biomarker for the stratification of patients receiving compounds disclosed herein.

[0744] Table 44-1. FAP-SLFN11 Correlation Summary Table 44-11. FAP-SLFN11 Correlation Summary

[0745] EQUIVALENTS AND SCOPE

[0746]

[0561] In the claims, articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The present disclosure includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The present disclosure includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.

[0747]

[0562] Furthermore, the present disclosure encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the present disclosure, or aspects of the present disclosure, is / are referred to as comprising particular elements and / or features, certain embodiments of the present disclosure or aspects of the present disclosure consist, or consist essentially of, such elements and / or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms “comprising” and “containing” are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub-range within the stated ranges in different embodiments of the present disclosure, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0748]

[0563] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present disclosure that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the present disclosure can be excluded from any claim, for any reason, whether or not related to the existence of prior art.

[0749]

[0564] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present disclosure, as defined in the following claims.

Claims

CLAIMSWhat is claimed is:

1. A compound of Formula (I"):and pharmaceutically acceptable salts thereof, wherein:CAM is a camptothecin;L1is a bond, C3-10 carbocyclylene, C6-io arylene, 3- to 10-membered heterocyclylene, or 5- to 10- membered heteroarylene, wherein the carbocyclylene, arylene, heterocyclylene, or heteroarylene is optionally substituted, including optionally substituted with one or more instances of R1A;R1is hydrogen, R1A, C1-30 alkyl, C1-30 haloalkyl, C1-30 heteroalkyl, C2-30 alkenyl, C2-30 heteroalkenyl, C2-30 alkynyl, C2-30 heteroalkynyl, C3-10 carbocyclyl, 3- to 10-membered heterocyclyl, C6-io aryl, 5- to 10-membered heteroaryl, polyethylene glycol (PEG), polysarcosine (PSar), or any combination thereof, wherein each alkyl, haloalkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, PEG, or PSar is independently optionally substituted, including optionally with one or more instances of R1A; each instance of R1Ais independently C1-6 alkyl, C3-15 carbocyclyl, -OR0, -CO2R0, -N(RN)2, -C(=O)N(RN)2, PEG, or PSar;R2and each instance of R2Aare independently hydrogen or optionally substituted C1-C6 alkyl; or optionally wherein R1and R2are joined together, or R1and R2Aare joined together, with the intervening atoms to form a 5- to 10-membered heterocyclic ring, wherein the heterocyclic ring is optionally substituted, including optionally with one or more instances of R1A;R3is hydrogen or optionally substituted C1-6 alkyl; each instance of R3Ais hydrogen, optionally substituted C1-6 alkyl, or an amino acid sidechain; each instance of R4is independently halogen, C1-6 alkyl, C1-6 haloalkyl, -OR0, or -N(RN)2, wherein the alkyl or haloalkyl is optionally substituted; or two instances of R4are taken together to form =0; m is 0, 1, 2, 3, 4, 5, 6, or 7; n is 0, 1, or 2;X is a bond, -C(=O)-, -OC(=O)-, -N(RN)C(=O)-, -S(=O)2-, or -S(=O)-;L2is a bond, or -N(H)-L2- is a bond or a self-immolative linker; each instance of R° is independently H, optionally substituted C1-6 alkyl, optionally substituted C1-6 haloalkyl, optionally substituted C3-7 carbocyclyl, or optionally substituted C1-6 acyl; and each instance of RNis independently H, optionally substituted C1-6 alkyl, optionally substituted C3-7- carbocyclyl, or optionally substituted C1-6 acyl, or two RNbonded to the same nitrogen are joined together to form optionally substituted 3-7 membered heterocyclyl.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (I):or a pharmaceutically acceptable salt thereof, wherein:CAM is a camptothecin;L1is a bond, C3-10 carbocyclylene, C6-io arylene, 3- to 10-membered heterocyclylene, or 5- to 10- membered heteroarylene, wherein the carbocyclylene, arylene, heterocyclylene, or heteroarylene is optionally substituted, including optionally substituted with one or more instances of R1A;R1is hydrogen, R1A, C1-30 alkyl, C1-30 haloalkyl, C1-30 heteroalkyl, C2-30 alkenyl, C2-30 heteroalkenyl, C2-30 alkynyl, C2-30 heteroalkynyl, C3-10 carbocyclyl, 3- to 10-membered heterocyclyl, C6-io aryl, 5- to 10-membered heteroaryl, polyethylene glycol (PEG), or any combination thereof, wherein each alkyl, haloalkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, or PEG is independently optionally substituted, including optionally with one or more instances of R1A; each instance of R1Ais independently C1-6 alkyl, C3-15 carbocyclyl, -OR0, -CO2R0, -N(RN)2, -C(=O)N(RN)2, or PEG;R2and each instance of R2Aare independently hydrogen or optionally substituted C1-C6 alkyl; or optionally wherein R1and R2are joined together, or R1and R2Aare joined together, with the intervening atoms to form a 5- to 10-membered heterocyclic ring, wherein the heterocyclic ring is optionally substituted, including optionally with one or more instances of R1A;R3is hydrogen or optionally substituted C1-6 alkyl; each instance of R3Ais hydrogen, optionally substituted C1-6 alkyl, or an amino acid sidechain; each instance of R4is independently halogen, C1-6 alkyl, C1-6 haloalkyl, -OR0, or -N(RN)2, wherein the alkyl or haloalkyl is optionally substituted; m is 0, 1, 2, 3, 4, 5, 6, or 7; n is 0, 1, or 2;X is a bond, -C(=O)-, -OC(=O)-, -N(RN)C(=O)-, -S(=O)2-, or -S(=O)-;L2is a bond, or -N(H)-L2- is a bond or a self-immolative linker; each instance of R° is independently H, optionally substituted C1-6 alkyl, optionally substituted C1-6 haloalkyl, optionally substituted C3-7 carbocyclyl, or optionally substituted C1-6 acyl; and each instance of RNis independently H, optionally substituted C1-6 alkyl, optionally substituted C3-7 carbocyclyl, or optionally substituted C1-6 acyl, or two RNbonded to the same nitrogen are joined together to form optionally substituted 3-7 membered heterocyclyl.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is ofFormula (I-A):

4. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein CAM is exatecan, SN-38, Dxd, belotecan, or topotecan.

5. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein CAM is exatecan.

6. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (I-B):wherein -N(H)-L2- is a bond or a self-immolative linker.

7. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (I-C):wherein -N(H)-L2- is a bond or a self-immolative linker.

8. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein n is i.

9. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein n is 0.

10. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (I-H):wherein -N(H)-L2- is a bond or a self-immolative linker.

11. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (I-I):wherein -N(H)-L2- is a bond or a self-immolative linker.

12. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein L2is a bond or -N(H)-L2- is a bond.

13. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (I-D):

14. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (I-E):

15. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein -N(H)-L2- is a self-immolative linker.

16. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein -N(H)-L2- is of the formula:, wherein:* denotes the point of attachment to CAM; each instance of R5is independently halogen, C1-20 alkyl, C1-20 haloalkyl, C1-20 heteroalkyl, C1-20 alkenyl, C1-20 alkynyl, C3-10 carbocyclyl, -OR0, -CO2R0, -N(RN)2, -C(=0)N(RN)2, -CN, PEG, PSar, -L5- R5A, or -C(=O)-L5-R5A, or two instances of R5are are joined together with the intervening atoms to form an optionally substituted 5- to 6-membered heterocyclic ring fused to an aryl ring; wherein the alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, carbocyclyl, PEG, PSar, or heterocyclyl is optionally substituted, including optionally with one or more instances of R5A;L5is a bond, C1-20 alkylene, C1-20 haloalkylene, C1-20 heteroalkylene, PEG, or PSar, wherein the alkylene, haloalkylene, or heteroalkylene is optionally substituted; each instance of R5Ais independently C1-6 alkyl, -OR0, -CO2R0, -N(RN)2, -C(=O)N(RN)2, PEG, or PSar; p is 0, 1, 2, 3, or 4.

17. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (I-F):

18. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (I-G):

19. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein the -N(H)-L2- is of the formula:wherein * denotes the point of attachment to CAM.

20. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (I- J):

21. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (I-K):

22. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, or 2.

23. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein the -N(H)-L2- is of the formula:, wherein * denotes the point of attachment to CAM.

24. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein at least one instance of R5is -CN, -F, -CF3, -CH3, -OMe,25. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof,26. The compound of any one of the preceding claims, wherein R1and R2are joined together with the intervening atoms to form an optionally substituted 5- to 6-membered heterocyclic ring fused to an aryl ring.

27. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein L1is a bond.

28. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein L1is 5- to 10-membered heteroarylene or 5- to 6-membered heterocyclylene, wherein the heteroarylene or heterocyclylene are optionally substituted with one or more instances of R1A.

29. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein -L’-R1is of the formula:

30. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof,with one or more instances of R1A.

31. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof,instances of R1A.

32. The compound of any one of the preceding claims, wherein R1is hydrogen, R1A, C1-20 alkyl, C1-20 haloalkyl, C1-20 heteroalkyl, C2-20 alkenyl, C2-20 alkynyl, PEG, or PSar, wherein the alkyl, haloalkyl, heteroalkyl, alkenyl, or alkynyl, is optionally substituted, including optionally with one or more instances of R1A.

33. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R1is of the formula:wherein ql is an integer from 1-25.

34. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R1is of the formula:, wherein q2 is an integer from 1-20.

35. The compound of any one of the preceding claims, wherein R1is36. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein at least one instance of R1Ais -Me, -OMe, or -CO2H.

37. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein at least one instance of R1Ais of the formula:wherein ql is an integer from 1-25, inclusive.

38. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein X is -C(=O)- or -S(=O)2-.

39. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein X is -C(=O)-.

40. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein at least one instance of R2Ais H.

41. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein at least one instance of R3Ais Me.

42. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R2is H.

43. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R3is H or Me.

44. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, or 2.

45. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein at least one instance of R4is halogen.

46. The compound of claim 1 or 2, wherein the compound is selected from those in Table Al and pharmaceutically acceptable salts thereof.

47. The compound of claim 1, wherein the compound is selected from those in Table Al.l and pharmaceutically acceptable salts thereof.

48. The compound of claim 1, wherein the compound is selected from those in Table A2 and pharmaceutically acceptable salts thereof.

49. The compound of claim 1, wherein the compound is selected from those in Table A3 and pharmaceutically acceptable salts thereof.

50. A pharmaceutical composition comprising a compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

51. A method of treating a disease characterized by fibroblast activation protein (FAP) upregulation in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

52. The method of claim 48, wherein the disorder characterized by FAP upregulation is cancer, fibrosis, or inflammation.

53. A method of treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

54. A method comprising administering to a subject a compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

55. The method of claim 51, wherein the subject has a disease characterized by FAP upregulation.

56. The method of claim 51 or 52, wherein the subject has cancer.

57. The method of any one of claims 49, 50, or 53, wherein the cancer is selected from head and neck cancer, soft tissue sarcoma, breast cancer, lung cancer, gastric cancer, colorectal cancer, pancreatic cancer, uterine cancer, ovarian cancer, and cervical cancer.

58. The method of claim 54, wherein the head and neck cancer is salivary gland cancer.

59. The method of claim 54, wherein the soft tissue sarcoma is undifferentiated pleomorphic sarcoma or dedifferentiated liposarcoma.

60. The method of claim 54, wherein the breast cancer is triple -negative breast cancer.

61. The method of claim 54, wherein the lung cancer is small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC).

62. The method of claim 54, wherein the pancreatic cancer is pancreatic ductal adenocarcinoma.

63. The method of any one of claims 48-56, wherein the compound, pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof, is administered by intravenous injection.

64. The method of any one of claims 48-56, wherein the compound, pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof, is administered by direct intra-tumoral administration.

65. A compound of any of the preceding claims, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in treating a disorder characterized by FAP upregulation in a subject.

66. Use of a compound of any of the preceding claims, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as a medicament.

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