Methods and compositions for targeted protein degradation

Abstract

Provided are chaperone retention effect drug conjugates (CREDCs) comprised of an exatecan-like portion, a linker, and a chemical moiety that binds HSP90 protein. Pharmaceutical compositions comprising the disclosed CREDCs and their use in treating cancer and related conditions are also provided.

Description

This application claims priority to PCT Application No. PCT / CN2024 / 083433, filed on March 23, 2024. The entire contents of the foregoing application are expressly incorporated herein by reference. BACKGROUND Despite advances, treatment of cancer with chemotherapeutic agents remains disappointing. Cancer patients treated with chemotherapeutic agents endure debilitating regimens and often a poor prognosis. This is because the effectiveness and / or application of chemotherapeutic agents containing toxic moieties is reduced by unwanted side effects due to off target or systemic toxicity. The ability to concentrate chemotherapeutics agents in tumor tissue while reducing normal tissue exposure may greatly reduce off target toxicity and improve overall clinical outcomes. Cancer is characterized by aberrant protein expression and activity. HSP90 (heat shock protein 90 kDa) is a molecular chaperone that facilitates the 3-dimensional folding and maintenance of a significant portion of the proteins that signal for cellular growth including many oncogenes (Trepel J. et al, Nat Rev Cancer. 2010, 10:537-49; Birbo B. et al, Int J Mol Sci., 2021, 22:10317). Cancer cells exist in tumor microenvironments characterized by reduced blood flow, high interstitial pressure, hypoxia and acidosis. To mitigate these conditions that negatively affect overall protein stability, cancer cells overexpress HSP90 and even secrete it extracellularly (Lang BJ et al, Int J Mol Sci. 2019, 20:4507; Taha EA et al, Int J Mol Sci. 2019, 20:4588). Moreover, HSP90 chaperone activity is greatly enhanced in cancer cells due to the abundance of mutated or misfolded proteins (Lacey T, Lacey H, Cancer Treat Res Commun. 2021, 28:100400). Cancer specific post-translational modification and protein-protein interaction states also affect HSP90 chaperone activity (Backe SJ et al, J Biol Chern. 2020, 295:11099-11117). In cancer cells this elevated expression and enhanced chaperone activity results in increased binding of HSP90 to small molecule drugs that target its N-terminal ATP-binding. This is in contrast to normal, non-proliferating cells that do not possess elevated levels of HSP90 expression or activity (Kamal A et al., Nature. 2003 425:407-10; Moulick K et al, Nat Chern Biol. 2011, 7:818-26). Due to these differences, HSP90 drugs exhibit a chaperone retention effect by concentrating in tumor tissue, while cleared from normal tissue. Camptothecin analogs such as irinotecan, exatecan and SN-38 are antineoplastic agents that inhibit DNA topoisomerase I (Topo I) activity and prevent the relaxation of supercoiled DNA during DNA replication and RNA transcription (Pommier Y, Nat Rev Cancer. 2006, 6:789-802). These agents are commonly used in chemotherapeutic regimen to treat colorectal, pancreatic, small lung and gastric cancers along with pediatric sarcomas (Fujita K et al, World J Gastroenterol. 2015, 21:12234—12248; Rubinson DA et al, Hematol Oncol Clin North Am. 2015, 29:761-776; Levy B et al, JNCCN. 2013, 11:780-787; Mahipal A et al, JNCCN. 2015, 13:1281-1291; Yohe ME et al, Cancer Treat Res Commun. 2021, 28:100400). However, these agents present problems with bioavailability and off target toxicity (Venditto VJ, Simanek ES, Mol Pharm. 2010, 7:307-49). Accordingly, the need exists for chaperone retention effect drug conjugates (CREDCs) that effectively target and concentrate antineoplastic agents such as camptothecin analogs into tumor tissue. SUMMARY Provided herein are CREDCs comprising an exatecan-like portion, a linker, and a chemical moiety that binds HSP90 protein. Such compounds include those having the Formula I: and pharmaceutically acceptable salts thereof. Compositions comprising the disclosed compounds of Formula I as well as methods for their manufacture and their biochemical activity are also provided. DETAILED DESCRIPTION 1. General Description of Compounds Provided herein are CREDC compounds having the Formula I: or a pharmaceutically acceptable salt thereof, wherein L is a linker and A is a chemical moiety that binds HSP90 protein 2. Definitions As used herein, the articles “a” and “an” refer to one or more than one, e.g., to at least one, of the grammatical object of the article. The use of the words "a" or "an" when used in conjunction with the term "comprising" herein may mean "one," but it is also consistent with the meaning of "one or more," "at least one," and "one or more than one." As used herein, “about” and “approximately” generally mean an acceptable degree of error for the quantity measured given the nature or precision of the measurements. Exemplary degrees of error are within 20 percent (%), typically, within 10%, and more typically, within 5% of a given range of values. The term “substantially” means more than 50%, preferably more than 80%, and most preferably more than 90% or 95%. As used herein the term "comprising" or "comprises" are used in reference to compositions, methods, and respective component(s) thereof, that are present in a given embodiment, yet open to the inclusion of unspecified elements. As used herein, the term "alkyl" means a saturated straight chain or branched non-cyclic hydrocarbon having, unless specified otherwise, from 1 to 10 carbon atom e.g., (Ci-Cejalkyl or (Ci-C4)alkyl. Representative straight chain alkyls include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl and n-decyl; while saturated branched alkyls include isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, 2-methylbutyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylpentyl, 2,2-dimethylhexyl, 3,3-dimethylpentyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylpentyl, 3-ethylpentyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, 2-methyl-4-ethylpentyl, 2-methyl-2- ethylhexyl, 2-methyl-3-ethylhexyl, 2-methyl-4-ethylhexyl, 2,2-diethylpentyl, 3,3-diethylhexyl, 2,2-diethylhexyl, 3,3-diethylhexyl and the like. As used herein, the term "alkynyl" means a saturated straight chain or branched non-cyclic hydrocarbon having, unless specified otherwise, from 2 to 10 carbon atoms (e.g., (C2-Ce)alkynyl or (C2-C4)alkynyl) and having at least one carbon-carbon triple bond. Representative straight chain and branched alkynyls include acetylenyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-butynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 5-hexynyl, 1-heptynyl, 2-heptynyl, 6-heptynyl, 1-octynyl, 2-octynyl, 7-octynyl, 1-nonynyl, 2-nonynyl, 8-nonynyl, 1-decynyl, 2-decynyl, 9-decynyl, and the like. As used herein, the term “alkenyl” as used herein, denotes a straight or branched chain hydrocarbon radical containing one or more double bonds and typically from 2 to 20 carbon atoms. For example, “(C2-C6)alkenyl” contains from two to six carbon atoms. Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, 1 methyl 2 buten 1 yl, heptenyl, octenyl and the like. As used herein, the term “cycloalkyl" means a saturated, monocyclic alkyl radical having from e.g., 3 to 10 carbon atoms (e.g., from 4 to 6 carbon atoms). Representative cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecanyl. The term “oxo” refers to the group =0. As used herein, the term "haloalkyl" means and alkyl group in which one or more (including all) the hydrogen radicals are replaced by a halo group, wherein each halo group is independently selected from -F, -Cl, -Br, and -I. Representative haloalkyl groups include trifluoromethyl, bromomethyl, 1,2-dichloroethyl, 4-iodobutyl, 2-fluoropentyl, and the like. “Alkoxy” means an alkyl radical attached through an oxygen linking atom, represented by -O-alkyL For example, “(Ci-C4)alkoxy” includes methoxy, ethoxy, proproxy, and butoxy. “Haloalkoxy” is a haloalkyl group which is attached to another moiety via an oxygen atom such as, e.g., -OCHF2 or -OCF3. As used herein, the term "heterocyclyl" means a 4- to 12-membered monocyclic or polycyclic saturated or partially unsaturated heterocyclic ring (e.g., bridged bicyclic) containing 1 to 4 heteroatoms independently selected from N, O, and S. The heterocycle may be attached via any heteroatom or carbon atom, as valency permits. Representative heterocycles include morpholinyl, thiomorpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, oxiranyl, dioxanyl, oxetanyl, dihydrofuranyl, dihydropyranyl, isoindolinyl, dihydropyridinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrindinyl, tetrahydropyrimidinyl, diazabicyclooctanyl, hexahydropyrrolizinyl, 2-azaspiro[3.3]heptanyl, 2,7-diazaspiro[3.5]nonanyl, 2-azaspiro[3.5]nonanyl, 3-azabicyclo[3.1.0]hexanyl, 8-azabicyclo[3.2.1]octanyl, 3,8-diazabicyclo[3.2.1]octanyl, 3,6-diazabicyclo[3.1.1]heptanyl, octahydro-lH-pyrrolo[2,3-c]pyridinyl, and the like. Optional substituents on a heterocyclyl group may be present on any substitutable position and, include, e.g., the position at which the heterocyclyl is attached, valence permitting. As used herein, the term "heteroaryl" means a 5- to 12-membered aromatic radical containing 1-4 heteroatoms selected from N, O, and S. A heteroaryl group may be mono- or bicyclic. The heteroaryl may be attached via any heteroatom or carbon atom, as valency permits. Representative heteroaryl groups include pyridyl, furanyl, thienyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, quinolinyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, triazolyl, thiadiazolyl, isoquinolinyl, indazolyl, benzoxazolyl, benzofuryl, indolizinyl, imidazopyridyl, tetrazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl, indolyl, tetrahydroindolyl, azaindolyl, imidazopyridyl, quinazolinyl, purinyl, benzothienyl, and the like. Optional substituents on a heteroaryl group may be present on any substitutable position and, include, e.g., the position at which the heteroaryl is attached, valence permitting. As used herein, the term "halogen" or "halo" means F, Cl, Br or I. The term "linker" or "tether," used interchangeably, refers to a chemical moiety that joins two other moieties (e.g., a therapeutic moiety and a binding moiety). A linker can covalently join a therapeutic moiety (e.g., exatecan) and a binding moiety (e.g., chemical moiety which binds HSP90 protein. In one aspect, the linker is uncleavable in vivo. In one aspect, the linker comprises one or more cyclic ring systems. In another aspect, the linker comprises an alkyl chain optionally substituted by and / or interrupted with one or more chemical groups. In one aspect, the linker comprises optimal spatial and chemical properties to effectuate optimal therapeutic activity. The term “HSP90” refers collectively, individually or in various combinations to the protein products of members of the heat shock protein 90 (90 kDa) gene family, including: HSP90AA1 (HSP90-alpha or HSP900C), HSP90AB1 (HSP90-beta or HSP90p), HSP90B1 (GRP94) and TRAP1. When used in connection to describe a chemical group that may have multiple points of attachment, a hyphen (-) designates the point of attachment of that group to the variable to which it is defined. For example, -NH(Ci-C4)alkyl\means that the point of attachment for this group occurs on the nitrogen atom. A hash bond as in “    ” represents the point at which the depicted group is attached to the defined variable. The compounds described herein may have chiral centers and / or geometric centers (E- and Z- isomers). It will be understood that the present disclosure encompasses all stereoisomers and geometric isomers. Tautomeric forms of the compounds described herein are also part of the present disclosure. When the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight pure relative to all of the other stereoisomers. Percent by weight pure relative to all of the other stereoisomers is the ratio of the weight of one stereoisomer over the weight of the depicted stereoisomer plus the weight of the other stereoisomers. For use in medicines, the pharmaceutically acceptable salts of the disclosed compounds refer to non-toxic “pharmaceutically acceptable salts.” Pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic / anionic or basic / cationic salts. Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include e.g., salts of inorganic acids (such as hydrochloric acid, hydrobromic, phosphoric, nitric, and sulfuric acids) and of organic acids (such as, acetic acid, benzenesulfonic, benzoic, methanesulfonic, and p-toluenesulfonic acids). Compounds of the present teachings with acidic groups such as carboxylic acids can form pharmaceutically acceptable salts with pharmaceutically acceptable base(s). Suitable pharmaceutically acceptable basic salts include e.g., ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth metal salts (such as magnesium and calcium salts). Compounds with a quaternary ammonium group also contain a counteranion such as chloride, bromide, iodide, acetate, perchlorate and the like. Other examples of such salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, benzoates and salts with amino acids such as glutamic acid. The term “pharmaceutically acceptable carrier” refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat. Any compositions or methods provided herein can be combined with one or more of any of the other compositions and methods provided herein. As used herein, the term "subject" refers to human and non-human animals, including veterinary subjects. The term "non-human animal" includes all vertebrates, e.g., mammals and non-mammals, such as non-human primates, mice, rabbits, sheep, dog, cat, horse, cow, chickens, amphibians, and reptiles. In a preferred embodiment, the subject is a human and may be referred to as a patient. As used herein, the terms "treat," "treating" or "treatment" refer, preferably, to an action to obtain a beneficial or desired clinical result including, but not limited to, alleviation or amelioration of one or more signs or symptoms of a disease or condition, diminishing the extent of disease, stability (i.e., not worsening) of the state of disease, amelioration or palliation of the disease state, diminishing rate of or time to progression, and remission (whether partial or total). "Treatment" can also mean prolonging survival as compared to expected survival in the absence of treatment. Treatment does not need to be curative. A "therapeutically effective amount" is that amount sufficient to treat a disease in a subject. A therapeutically effective amount can be administered in one or more administrations. In one aspect, a therapeutically effective amount refers to a dosage of from about 0.01 to about 100 mg / kg body weight / day. The terms "administer," "administering" or "administration" include any method of delivery of a pharmaceutical composition or agent into a subject's system or to a particular region in or on a subject. In certain embodiments of the invention, an agent is administered intravenously, intramuscularly, subcutaneously, intradermally, intranasally, orally, transcutaneously, or mucosally. In a preferred embodiment, an agent is administered intravenously. In another preferred embodiment, an agent is administered orally. Administering an agent can be performed by a number of people working in concert. Administering an agent includes, for example, prescribing an agent to be administered to a subject and / or providing instructions, directly or through another, to take a specific agent, either by self-delivery, e.g., as by oral delivery, subcutaneous delivery, intravenous delivery through a central line, etc.; or for delivery by a trained professional, e.g., intravenous delivery, intramuscular delivery, intratumoral delivery, etc. 3. Compounds In a first embodiment, the compound of Formula I is of the Formula II or III: or a pharmaceutically acceptable salt thereof, wherein L and A are as described above for Formula I. In a second embodiment, A in the compound of Formula I or II is selected from and W is 5- or 6-membered heteroaryl optionally substituted with 1 to 3 groups selected from R2; R1 is halo, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, or halo(Ci-C4)alkoxy; R2 is (Ci-C4)alkyl, halo(Ci-C4)alkyl, (C2-C6)alkenyl, halo(C2-C6)alkenyl, (C2-C6)alkynyl, halo(C2-C6)alkynyl, CN, -Ci-4alkylORa, -ORa, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -C(O)NRa(Ci-4alkylene)ORa, -C(O)NRa(Ci-4alkylene)NRaRb, -C(O)NRa(Ci-4alkylene)OR, -NRaRb, -O(Ci-4alkylene)NRaRb, -SH, -S(Ci-4alkyl), -Ci-4alkylNRaRb, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -SO2NRaRb, -NRa(Ci-4alkyl)ORa, -NRa(Ci-4alkyl)NRaRb, -Ci-6alkylC(O)NRaRb, phenyl or monocyclic heteroaryl, wherein said phenyl and monocyclic heteroaryl are each optionally and independently substituted with 1 to 3 groups selected from R4; Ra and Rb are each independently selected from hydrogen and (Ci-C4)alkyl, wherein said (Ci-C4)alkyl is optionally substituted with one or more halo or a monocyclic heterocyclyl, or both; R3 and R4 are each independently hydrogen, halo, -NRaRb, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, or halo(Ci-C4)alkoxy; Q and U are each independently selected from phenyl, mono or bicyclic heteroaryl, mono or bicyclic heterocyclyl, and cycloalkyl, each of which being optionally substituted with 1 to 3 groups selected from R2; V is phenyl or mono or bicyclic heteroaryl optionally substituted with 1 to 3 groups selected from R3; R10, R11, R13, and R14 are each independently selected from hydrogen, halo, -CN, (Ci-C4)alkyl, halo(Ci-C4)alkyl, and -C(O)NRaRb; and R15 is hydrogen, (Ci-C4)alkyl, or halo(Ci-C4)alkyl, wherein the remaining variables are as described above for Formula I. Alternatively, as part of a second embodiment, A in the R3 is hydrogen, halo, -NRaRb, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, or halo(Ci-C4)alkoxy; Ra and Rb are each independently selected from hydrogen and (Ci-C4)alkyl, wherein said (Ci-C4)alkyl is optionally substituted with one or more halo or a monocyclic heterocyclyl, or both; and R14 is (Ci-C4)alkyl, wherein the remaining variables are as described above for Formula I. In another alternative, as part of a second embodiment, A in the compound of HO Formula I or II is * v , wherein R1 is halo, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, or halo(Ci-C4)alkoxy; W is 5- or 6-membered heteroaryl optionally substituted with 1 to 3 groups selected from R2; V is phenyl or mono or bicyclic heteroaryl optionally substituted with 1 to 3 groups selected from R3; R2 is (Ci-C4)alkyl, halo(Ci-C4)alkyl, (C2-C6)alkenyl, halo(C2-C6)alkenyl, (C2-C6)alkynyl, halo(C2-C6)alkynyl, CN, -Ci-4alkylORa, -ORa, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -C(O)NRa(Ci-4alkylene)ORa, -C(O)NRa(Ci-4alkylene)NRaRb, -C(O)NRa(Ci-4alkylene)OR, -NRaRb, -O(Ci-4alkylene)NRaRb, -SH, -S(Ci-4alkyl), -Ci-4alkylNRaRb, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -SO2NRaRb, -NRa(Ci-4alkyl)ORa, -NRa(Ci-4alkyl)NRaRb, -Ci-6alkylC(O)NRaRb, phenyl or monocyclic heteroaryl, wherein said phenyl and monocyclic heteroaryl are each optionally and independently substituted with 1 to 3 groups selected from R4; R3 and R4 are each independently hydrogen, halo, -NRaRb, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, or halo(Ci-C4)alkoxy; and Ra and Rb are each independently selected from hydrogen and (Ci-C4)alkyl, wherein said (Ci-C4)alkyl is optionally substituted with one or more halo or a monocyclic heterocyclyl, or both, wherein the remaining variables are as described above for Formula I. In another Z is N or CH (preferably CH); R1 is halo, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, or halo(Ci-C4)alkoxy; 10           R2 is (Ci-C4)alkyl, halo(Ci-C4)alkyl, (C2-C6)alkenyl, halo(C2-C6)alkenyl, (C2- C6)alkynyl, halo(C2-C6)alkynyl, CN, -Ci-4alkylORa, -ORa, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -C(O)NRa(Ci-4alkylene)ORa, -C(O)NRa(Ci-4alkylene)NRaRb, -C(O)NRa(Ci-4alkylene)OR, -NRaRb, -O(Ci-4alkylene)NRaRb, -SH, -S(Ci-4alkyl), -Ci-4alkylNRaRb, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -SO2NRaRb, -NRa(Ci-4alkyl)ORa, -NRa(Ci-4alkyl)NRaRb, - Ci-6alkylC(0)NRaRb, phenyl or monocyclic heteroaryl, wherein said phenyl and monocyclic heteroaryl are each optionally and independently substituted with 1 to 3 groups selected from R4; R3 and R4 are each independently hydrogen, halo, -NRaRb, (Ci-C4)alkyl, halo(Ci-5 C4)alkyl, (Ci-C4)alkoxy, or halo(Ci-C4)alkoxy; and Ra and Rb are each independently selected from hydrogen and (Ci-C4)alkyl, wherein said (Ci-C4)alkyl is optionally substituted with one or more halo or a monocyclic heterocyclyl, or both, wherein the remaining variables are as described above for Formula I. R1 is halo, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, or halo(Ci-C4)alkoxy; R2 is (Ci-C4)alkyl, halo(Ci-C4)alkyl, (C2-C6)alkenyl, halo(C2-C6)alkenyl, (C2- C6)alkynyl, halo(C2-C6)alkynyl, CN, -Ci-4alkylORa, -ORa, -C(O)Ra, -C(O)ORa, - 15 C(O)NRaRb, -C(O)NRa(Ci-4alkylene)ORa, -C(O)NRa(Ci-4alkylene)NRaRb, -C(O)NRa(Ci-4alkylene)OR, -NRaRb, -O(Ci-4alkylene)NRaRb, -SH, -S(Ci-4alkyl), -Ci-4alkylNRaRb, -SRa, - S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -SO2NRaRb, -NRa(Ci-4alkyl)ORa, -NRa(Ci-4alkyl)NRaRb, -Ci-6alkylC(O)NRaRb, phenyl or monocyclic heteroaryl, wherein said phenyl and monocyclic heteroaryl are each optionally and independently substituted with 1 to 3 groups selected from R4; R3 and R4 are each independently hydrogen, halo, -NRaRb, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, or halo(Ci-C4)alkoxy; and Ra and Rb are each independently selected from hydrogen and (Ci-C4)alkyl, wherein said (Ci-C4)alkyl is optionally substituted with one or more halo or a monocyclic heterocyclyl, or both, wherein the remaining variables are as described above for Formula I. R1 is halo, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, or halo(Ci-C4)alkoxy; R2 is (Ci-C4)alkyl, halo(Ci-C4)alkyl, (C2-C6)alkenyl, halo(C2-C6)alkenyl, (C2-C6)alkynyl, halo(C2-C6)alkynyl, CN, -Ci-4alkylORa, -ORa, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -C(O)NRa(Ci-4alkylene)ORa, -C(O)NRa(Ci-4alkylene)NRaRb, -C(O)NRa(Ci-4alkylene)OR, -NRaRb, -O(Ci-4alkylene)NRaRb, -SH, -S(Ci-4alkyl), -Ci-4alkylNRaRb, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -SO2NRaRb, -NRa(Ci-4alkyl)ORa, -NRa(Ci-4alkyl)NRaRb, -Ci-6alkylC(O)NRaRb, phenyl or monocyclic heteroaryl, wherein said phenyl and monocyclic heteroaryl are each optionally and independently substituted with 1 to 3 groups selected from R4; R3 and R4 are each independently hydrogen, halo, -NRaRb, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, or halo(Ci-C4)alkoxy; and Ra and Rb are each independently selected from hydrogen and (Ci-C4)alkyl, wherein said (Ci-C4)alkyl is optionally substituted with one or more halo or a monocyclic heterocyclyl, or both, wherein the remaining variables are as described above for Formula I. In another alternative, A in the compound of Formula I or II is R1 is halo, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, or halo(Ci-C4)alkoxy; R2 is (Ci-C4)alkyl, halo(Ci-C4)alkyl, (C2-C6)alkenyl, halo(C2-C6)alkenyl, (C2-C6)alkynyl, halo(C2-C6)alkynyl, CN, -Ci-4alkylORa, -ORa, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -C(O)NRa(Ci-4alkylene)ORa, -C(O)NRa(Ci-4alkylene)NRaRb, -C(O)NRa(Ci-4alkylene)OR, -NRaRb, -O(Ci-4alkylene)NRaRb, -SH, -S(Ci-4alkyl), -Ci-4alkylNRaRb, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -SO2NRaRb, -NRa(Ci-4alkyl)ORa, -NRa(Ci-4alkyl)NRaRb, -Ci-6alkylC(O)NRaRb, phenyl or monocyclic heteroaryl, wherein said phenyl and monocyclic heteroaryl are each optionally and independently substituted with 1 to 3 groups selected from R4; R4 is hydrogen, halo, -NRaRb, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, or halo(Ci-C4)alkoxy; and Ra and Rb are each independently selected from hydrogen and (Ci-C4)alkyl, wherein said (Ci-C4)alkyl is optionally substituted with one or more halo or a monocyclic heterocyclyl, or both, wherein the remaining variables are as described above for Formula I. In yet another alternative, A in the compound of Formula I or II is HO wherein R1 is halo, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, or halo(Ci-C4)alkoxy; R2 is (Ci-C4)alkyl, halo(Ci-C4)alkyl, (C2-C6)alkenyl, halo(C2-C6)alkenyl, (C2-C6)alkynyl, halo(C2-C6)alkynyl, CN, -Ci-4alkylORa, -ORa, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -C(O)NRa(Ci-4alkylene)ORa, -C(O)NRa(Ci-4alkylene)NRaRb, -C(O)NRa(Ci-4alkylene)OR, -NRaRb, -O(Ci-4alkylene)NRaRb, -SH, -S(Ci-4alkyl), -Ci-4alkylNRaRb, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -SO2NRaRb, -NRa(Ci-4alkyl)ORa, -NRa(Ci-4alkyl)NRaRb, -Ci-6alkylC(O)NRaRb, phenyl or monocyclic heteroaryl, wherein said phenyl and monocyclic heteroaryl are each optionally and independently substituted with 1 to 3 groups selected from R4; R4 is hydrogen, halo, -NRaRb, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, or halo(Ci-C4)alkoxy; and Ra and Rb are each independently selected from hydrogen and (Ci-C4)alkyl, wherein said (Ci-C4)alkyl is optionally substituted with one or more halo or a monocyclic heterocyclyl, or both, wherein the remaining variables are as described above for Formula I. In a third embodiment, each R3 is independently selected from hydrogen, halo, and halo(Ci-C4)alkyl, wherein the remaining variables are as described above for Formula I or II5or the second embodiment. In a fourth embodiment, R1 is selected from halo and (Ci-C4)alkyl, wherein the remaining variables are as described above for Formula I or II / k the second or third embodiment. Alternatively, as part of a fourth embodiment, R1 is selected from chloro, isopropyl, methyl, propyl, and ethyl, wherein the remaining variables are as described above for Formula I or II / k the second or third embodiment. In another alternative, as part of a fourth embodiment, R1 is selected from isopropyl and ethyl, wherein the remaining variables are as described above for Formula I or I^or the second or third embodiment. In a fifth embodiment, R2 is selected from -ORa, -SRa, -C(O)NRaRb, and -C(O)NRa(Ci-4alkylene)NRaRb, wherein the remaining variables are as described above for Formula I or II / k the second, third, or fourth embodiment. In a sixth embodiment, Ra and Rb are each independently selected from hydrogen and (Ci-C4)alkyl, wherein said (Ci-C4)alkyl is optionally substituted with 1 to 3 halo or a 6membered heterocyclyl, wherein the remaining variables are as described above for Formula I or II / k the second, third, fourth, or fifth embodiment. In a seventh embodiment, R2 is selected from OH, -C(O)NHCH2CF3, -C(O)NHCH2CH3, -C(O)NHCH(CH3)2, -C(O)NH(CH2CH3)2, -C(O)NHCH(CH3)CF3, -C(O)NHcyclopropyl, -C(O)NHmethylcyclopropyl, C(O)NH2, and -C(O)NH(CH2)2piperidinyl, wherein the remaining variables are as described above for Formula I or I^or the second, third, fourth, fifth, or sixth embodiment. Alternatively, as part of a seventh embodiment, R2 is selected from -C(O)NHCH2CF3 and OH, wherein the remaining variables are as described above for Formula I or I^or the second, third, fourth, fifth, or sixth embodiment. In another alternative, as part of a seventh embodiment, R2 is OH, wherein the remaining variables are as described above for Formula I or I^or the second, third, fourth, fifth, or sixth embodiment. In an eighth embodiment, L in the compound of Formula I or II is selected from -(CH2)r-HET1-X1-HET2-(CH2)s-OC(O)-, -(CH2)r-HET1-X1-(CH2)q-HET2-(CH2)s-OC(O)-, -(CH2)r-HET1-X1-HET2-(CH2)s-C(O)O-(CH2)m-X2-,     -(CH2)r-HET1-HET2-(CH2)s-C(O)- (CH2)m-X2-, -(CH2)yOC(O)-, -(CH2)r-HET1-(CH2)w-S-S-HET2-(CH2)s-OC(O)-, -(CH2)r-HET1-X1-(CH2)s-OC(O)-, -(CH2)r-HET1-X1-HET2-(CH2)s-NHC(O)O-(CH2)m-X2-, -(CH2)r-HET1-C(O)O-(CH2)m-X2-, -(CH2)rNRf(CH2)v-HET2-X1-HET1-(CH2)s-OC(O)-, -(CH2)rNRf(CH2)v-HET2-X1-HET1-(CH2)s-C(O)O-(CH2)m-X2-, -(CH2)rNRf(CH2)v-HET2-(CH2)s-NHC(O)O-(CH2)m-X2-, -(CH2)r-HET3-OC(O)-, -(CH2)r-HET2-X1-HET3-OC(O)-, -(CH2)r-HET3-X1-(CH2)s-OC(O)-, -(CH2)r-HET3-X1-HET2-OC(O)-, -X^HE^-OCCO)-, -X1-HET3-X2-(CH2)s-OC(O)-,   -(CH2)r-HET1-HET2-(CH2)s-OC(O)-,   -(CH2)r-HET1-(CH2)q- HET2-(CH2)s-OC(O)-, -(CH2)r-HET1-X1-(CH2)w-S-S-HET2-(CH2)s-OC(O)-, -(CH2)r-HET1-HET2-(CH2)s-NHC(O)O-(CH2)m-X2-,      -(CH2)r-HET1-NHC(O)O-(CH2)m-X2-,      - (CH2)rNRf(CH2)v-HET2-X1-(CH2)q-HET1-(CH2)s-OC(O)-, -(CH2)rNRf(CH2)v-HET2-HET1-(CH2)s-C(O)O-(CH2)m-X2-, -(CH2)rNRf(CH2)v-OC(O)-, -(CH2)rNRf(CH2)v-HET2-(CH2)w-S-S-HET1-(CH2)s-OC(O)-, -(CH2)rNRf(CH2)v-HET2-X1-(CH2)s-OC(O)-, -(CH2)rNRf(CH2)v-HET2-X1-HET1-(CH2)s-NHC(O)O-(CH2)m-X2-, -(CH2)rNRf(CH2)v-HET2-C(O)O-(CH2)m-X2-,   -(CH2)rNRf(CH2)v-HET2-X1-(CH2)s-OC(O)-, -(CH2)rNRf(CH2)v-HET2-X1-(CH2)s- C(O)-(CH2)m-X2-, -(CH2)rNRf(CH2)v-HET2-X1-(CH2)q-HET1-(CH2)s-NHC(O)O-(CH2)m-X2-, -(CH2)rNRf(CH2)v-HET2-X1-(CH2)s-NHC(O)O-(CH2)m-X2-, -(CH2)rNRf(CH2)v-HET2-X1-HET1-(CH2)s-NHC(O)O-(CH2)m-X2-(CH2)m-X2-, -(CH2)rNRf(CH2)v-HET2-X1-(CH2)s-NHC(O)O-(CH2)m-X2-, -(CH2)r-HET1-X1-(CH2)q-HET3-(CH2)s-OC(O)-, -(CH2)r-HET1-X1-HET3-(CH2)s-C(O)O-(CH2)m-X2-, -(CH2)r-HET1-HET3-(CH2)s-C(O)-(CH2)m-X2-, -(CH2)r-HET1-(CH2)w-S-S-HET3-(CH2)s-OC(O)-, -(CH2)r-HET1-X1-HET3-(CH2)s-NHC(O)O-(CH2)m-X2-, -(CH2)r-HET3-C(O)O-(CH2)m-X2-, -(CH2)rNRf(CH2)v-HET2-X1-HET3-(CH2)s-OC(O)-, -(CH2)rNRf(CH2)v-HET3-X1-HET1-(CH2)s-C(O)O-(CH2)m-X2-, -(CH2)rNRf(CH2)v-HET3-(CH2)s-NHC(O)O-(CH2)m-X2-,                 -C(O)NH-CRR’ -C(O)NH-CRR’ - C(O)NHCRR’C(O)NH(CH2)m-X2-, and -C(O)NH-CRR’-C(O)NH-CRR’-C(O)NH-HET2-(CH2)s-OC(O)-. m, q, r, s, v, w, and y are each independently 0 to 4; Rf is selected from hydrogen and (Ci-C4)alkyl; X1 and X2 are each independently selected from CO and -CH2-; HET1, HET2, and HET3 are each independently selected from monocyclic heterocyclyl, bicyclic heterocyclyl, monocyclic cycloalkyl, and phenyl; and R’ and R” are each independently selected from hydrogen and (Ci-C4)alkyl, wherein said (Ci-C4)alkyl is optionally substituted with phenyl or NHC(O)NH2, wherein the remaining variables are as described above for the second, third, fourth, fifth, sixth, or seventh embodiment. Alternatively, as part of an eighth embodiment, L is selected from -(CH2)r-HET1-X1-HET2-(CH2)s-OC(O)-, -(CH2)r-HET1-X1-(CH2)q-HET2-(CH2)s-OC(O)-, -(CH2)r-HET1-X1-HET2-(CH2)s-C(O)O-(CH2)m-X2-,     -(CH2)r-HET1-HET2-(CH2)s-C(O)- (CH2)m-X2-, -(CH2)yOC(O)-, -(CH2)r-HET1-(CH2)w-S-S-HET2-(CH2)s-OC(O)-, -(CH2)r-HET1-X1-(CH2)s-OC(O)-, -(CH2)r-HET1-X1-HET2-(CH2)s-NHC(O)O-(CH2)m-X2-, -(CH2)r-HET1-C(O)O-(CH2)m-X2-, -(CH2)rNRf(CH2)v-HET2-X1-HET1-(CH2)s-OC(O)-, -(CH2)rNRf(CH2)v-HET2-X1-HET1-(CH2)s-C(O)O-(CH2)m-X2-, -(CH2)rNRf(CH2)v-HET2-(CH2)s-NHC(O)O-(CH2)m-X2-, -(CH2)r-HET3-OC(O)-, -(CH2)r-HET2-X1-HET3-OC(O)-, -(CH2)r-HET3-X1-(CH2)s-OC(O)-, -(CH2)r-HET3-X1-HET2-OC(O)-, -X^HET^OQO)-, -X1-HET3-X2-(CH2)s-OC(O)-, -C(O)NH-CRR’-C(O)NH-CRR’-C(O)NHCRR’C(O)NH(CH2)m-X2-, and -C(O)NH-CRR’-C(O)NH-CRR’-C(O)NH-HET2-(CH2)s-OC(O)-, m, q, r, s, v, w, and y are each independently 0 to 4; Rf is selected from hydrogen and (Ci-C4)alkyl; X1 and X2 are each independently selected from CO and -CH2-; HET1, HET2, and HET3 are each independently selected from monocyclic heterocyclyl, bicyclic heterocyclyl, monocyclic cycloalkyl, and phenyl; and R’ and R” are each independently selected from hydrogen and (Ci-C4)alkyl, wherein said (Ci-C4)alkyl is optionally substituted with phenyl or NHC(O)NH2, wherein the remaining variables are as described above for the second, third, fourth, fifth, sixth, or seventh embodiment. In a ninth embodiment, HET1 is monocyclic heterocyclyl, wherein the remaining variables are as described above for the second, third, fourth, fifth, sixth, seventh, or eighth embodiment. In a tenth embodiment, HET1 is selected from piperazinyl, azetindinyl, and piperidinyl, wherein the remaining variables are as described above for the second, third, fourth, fifth, sixth, seventh, eighth, or ninth embodiment. In an eleventh embodiment, HET2 is selected from monocyclic heterocyclyl, monocyclic cycloalkyl, and phenyl, wherein the remaining variables are as described above for the second, third, fourth, fifth, sixth, seventh, eighth, ninth, or tenth embodiment. In a twelfth embodiment, HET2 is selected from cyclohexyl, piperidinyl, cyclopropyl, and phenyl, wherein the remaining variables are as described above for the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh embodiment. In a thirteenth embodiment, HET3 is bicyclic heterocyclyl, wherein the remaining variables are as described above for the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, or twelfth embodiment. In a fourteenth embodiment, HET3 is selected from 2-azaspiro[3.3]heptanyl, 2,7-diazaspiro[3.5]nonanyl, 2-azaspiro[3.5]nonanyl, 3-azabicyclo[3.1.0]hexanyl, 8-azabicyclo[3.2.1]octanyl, 3,8-diazabicyclo[3.2.1]octanyl, 3,6-diazabicyclo[3.1.1]heptanyl, and octahydro-lH-pyrrolo[2,3-c]pyridinyl, wherein the remaining variables are as described above for the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, or thirteenth embodiment. In a fifteenth embodiment, r is 1, wherein the remaining variables are as described above for the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, or fourteenth embodiment. In a sixteenth embodiment, s is 0, 1,2, or 3, wherein the remaining variables are as described above for the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, or fifteenth embodiment. In a seventeenth embodiment, q is 1, wherein the remaining variables are as described above for the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, or sixteenth embodiment. In an eighteenth embodiment, m is 1, wherein the remaining variables are as described above for the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, or seventeenth embodiment. In a nineteenth embodiment, y is 1 to 4, wherein the remaining variables are as described above for the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, or eighteenth embodiment. In a twentieth embodiment, w is 1 to 4, wherein the remaining variables are as described above for the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, or ninteenth embodiment. In a twenty-first embodiment, v is 1, wherein the remaining variables are as described above for the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, or twentieth embodiment. L is selected from In a twenty-second embodiment, wherein * indicates the point of attachment to A and wherein the remaining variables are as described above for the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, or twenty-first embodiment. Compounds having the Formula I or II are further disclosed in the Exemplification and are included in the present disclosure. Pharmaceutically acceptable salts thereof as well as the neutral forms are included. 4. Uses, Formulation and Administration Compounds and compositions described herein are generally useful as anticancer therapies. The terms "cancer" or "tumor" are well known in the art and refer to the presence, e.g., in a subject, of cells possessing characteristics typical of cancer-causing cells, such as uncontrolled proliferation, immortality, metastatic potential, rapid growth and proliferation rate, decreased cell death / apoptosis, and certain characteristic morphological features. Cancer cells are often in the form of a solid tumor. However, cancer also includes non-solid tumors, e.g., blood tumors, e.g., leukemia, wherein the cancer cells are derived from bone marrow. As used herein, the term "cancer" includes pre-malignant as well as malignant cancers. Cancers include, but are not limited to, acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic (granulocytic) leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, Burkitt's lymphoma, dysproliferative changes (dysplasias and metaplasias), embryonal carcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen-receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, heavy chain disease, hemangioblastoma, hepatoma, hepatocellular cancer, hormone insensitive prostate cancer, leiomyosarcoma, liposarcoma, lung cancer, lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin and non-Hodgkin), malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovaries, pancreas, prostate, skin, and uterus, lymphoid malignancies of T-cell or B-cell origin, leukemia, lymphoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid tumors (carcinomas and sarcomas), small cell lung cancer, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer, and Wilms' tumor. Other cancers include primary cancer, metastatic cancer, oropharyngeal cancer, hypopharyngeal cancer, liver cancer, gall bladder cancer, bile duct cancer, small intestine cancer, urinary tract cancer, kidney cancer, urothelium cancer, female genital tract cancer, uterine cancer, gestational trophoblastic disease, male genital tract cancer, seminal vesicle cancer, testicular cancer, germ cell tumors, endocrine gland tumors, thyroid cancer, adrenal cancer, pituitary gland cancer, hemangioma, sarcoma arising from bone and soft tissues, Kaposi's sarcoma, nerve cancer, ocular cancer, meningial cancer, glioblastomas, neuromas, neuroblastomas, Schwannomas, solid tumors arising from hematopoietic malignancies such as leukemias, metastatic melanoma, recurrent or persistent ovarian epithelial cancer, fallopian tube cancer, primary peritoneal cancer, gastrointestinal stromal tumors, colorectal cancer, gastric cancer, melanoma, glioblastoma multiforme, non-squamous non-small-cell lung cancer, malignant glioma, epithelial ovarian cancer, primary peritoneal serous cancer, metastatic liver cancer, neuroendocrine carcinoma, refractory malignancy, triple negative breast cancer, HER2- amplified breast cancer, nasopharageal cancer, oral cancer, biliary tract, hepatocellular carcinoma, squamous cell carcinomas of the head and neck (SCCHN), non-medullary thyroid carcinoma, recurrent glioblastoma multiforme, neurofibromatosis type 1, CNS cancer, liposarcoma, leiomyosarcoma, salivary gland cancer, mucosal melanoma, acral / lentiginous melanoma, paraganglioma, pheochromocytoma, advanced metastatic cancer, solid tumor, triple negative breast cancer, colorectal cancer, sarcoma, melanoma, renal carcinoma, endometrial cancer, thyroid cancer, rhabdomysarcoma, multiple myeloma, ovarian cancer, glioblastoma, gastrointestinal stromal tumor, mantle cell lymphoma, and refractory malignancy. "Solid tumor," as used herein, is understood as any pathogenic tumor that can be palpated or detected using imaging methods as an abnormal growth having three dimensions. A solid tumor is differentiated from a blood tumor such as leukemia. However, cells of a blood tumor are derived from bone marrow; therefore, the tissue producing the cancer cells is a solid tissue that can be hypoxic. "Tumor tissue” or “tumorous tissue" are understood as cells, extracellular matrix, and other naturally occurring components associated with the solid tumor. A specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound described herein in the composition will also depend upon the particular compound in the composition. EXEMPLIFICATION Chemical Synthesis The representative examples that follow are intended to help illustrate the present disclosure, and are not intended to, nor should they be construed to, limit the scope of the invention. General starting materials used were obtained from commercial sources or prepared in other examples, unless otherwise noted. Preparation of Compounds The compounds claimed herein were prepared following the procedures outlined in the following protocols. Example 1: Compound 018 synthesis A representative synthesis scheme for compound 018 is shown in below. Specific synthesis routes of intermediates are also shown. Intermediate 3: 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-hydroxy-2-methylpropanamide To a solution of compound 2 (30 mg, 0.28 mmol) in DMF (2 mL) were added HOSu (33 mg, 0.28 mmol) and EDCI (54 mg, 0.28 mmol) at room temperature. The mixture was stirred for 1 h at room temperature. It was added to a solution of compound 1 (100 mg, 0.19 mmol) and EhN (0.03 mL, 0.25 mmol) in DMF (2 mL). Then the reaction mixture was stirred at room temperature for 15 hours. It was diluted with H2O, and extracted with EtOAc (10 mL*2). The combined organic layers was washed with H2O and brine. It was dried (Na2SO4 anhydrous), filtered and concentrated. The residue was purified by column chraomatography on silica gel (PE:EA = 5:1) to afford intermediate 3 (100 mg) as a pink solid. Intermediate 5: l-(((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)amino)-2-methyl-l-oxopropan-2-yl (4-nitrophenyl) carbonate To a stirred solution of intermediate 3 (80 mg, 0.15 mmol) in pyridine (4 mL) was added 4-nitrophenyl carbonochloridate (53 mg, 0.26 mmol) in portions at room temperature. The mixture was stirred at room temperature overnight. Then 4-nitrophenyl carbonochloridate (150 mg, 0.74 mmol) was added and the reaction mixture was stirred at room temperature overnight. Another batch of 4-nitrophenyl carbonochloridate (150 mg, 0.74 mmol) was added and the reaction mixure was stirred at room temperature overnight. It was diluted with H2O, and extracted with EtOAc (10 mL*2). The combined organic layers was washed with H2O and brine. It was dried (Na2SO4 anhydrous), filtered and concentrated to give crude intermediate 5 (380 mg) as a gray solid which was used without further purification. Compound 018 l-(((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)amino)-2-methyl-l-oxopropan-2-yl 4-((4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-l,2,4-triazol-4-yl)benzyl)piperidin-l-yl)methyl)piperidine-l-carboxylate To a solution of intermediate 6 in DMF (4 mL) were added intermediate 5 (133 mg, 0.19 mmol) and EhN (0.26 mL, 1.84 mmol) at room temperature. Then the reaction mixture was stirred at room temperature overnight. It was poured into water, the precipitated solid was collected by filtration and purified by pre-TLC(DCM / MeOH=10:l) to afford compound 018 (2.57 mg) as a yellow solid. ’H NMR (400 MHz, CD3OD) 5 7.64( d, J= 10.8 Hz, 1H), 7.31-7.27 (m, 3H), 7.21-7.20 (m, 2H), 6.68-6.66 (m, 1H), 6.28 (s, 1H), 5.61-5.59 (m, 1H), 5.57-5.55 (m, 2H), 5.50-5.46 (m, 1H), 5.35-5.18 (m, 1H), 4.88-4.60 (m, 2H), 4.35-4.30 (m, 1H), 4.10-4.09 (m, 1H), 3.95-3.85 (m, 1H), 3.31-3.30 (m, 2H), 3.183.12 (m, 3H), 2.60-2.59 (m, 2H), 2.57-2.54 (m, 3H), 2.42-2.33 (m, 4H), 2.31-2.23 (m, 5H), 2.20-2.16 (m, 2H), 2.09-2.04 (m, 2H), 2.03-2.00 (m, 3H), 1.76-1.59 (m, 3H), 1.04-1.00 (m, 3H), 0.90-0.88 (m, 6H). LCMS (ESI): RT = 1.113 min, m / z found 1053.3 [M+H]+. The following additional compounds were made according to the general procedure above using the appropriate starting materials. Compound 001 cf3cooh 4-(2-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-l, 2,4-triazol-4-yl)benzyl)piperazin-l-yl)-2-oxoethyl)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 trifluoroacetic acid. H NMR (400 MHz, DMSO-d6) 5 8.12 (d, 7=8.8 Hz, 1H), 7.87-7.81 (m, 1H), 7.67-7.63 (m, 1H), 7.49 (m, 1H), 7.41 (s, 1H), 7.36 (s, 1H), 7.29 (s, 1H), 6.89 (d, 7=9.2 Hz, 2H), 6.82 (s 1H), 5.61-5.56 (m, 1H), 5.41-5.34 (m, 2H), 5.26-5.20 (m, 2H), 4.20 (m, 1H), 3.83 (s, 1H), 3.64 (m, 1H), 3.48(s, 1H), 3.13 (s, 1H), 2.43 (s, 3H), 2.19 (m, 3H), 2.01-1.85 (m, 4H), 1.60 (m, 1H), 1.01-0.96 (m,6H), 0.90 (m, 3H). LCMS (ESI): Rt = 1.160 min, m / z found 1019.2 [M+H]+. Compound 002 OH F cf3cooh 3-(4-(3-(2,4-dihydroxy-5-methylphenyl)-5-hydroxy-4H-l,2,4-triazol-4-yl)phenyl)propyl ((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 trifluoroacetic acid. ’H NMR (400 MHz, DMSO-76) 5 7.63 (s, 2H), 7.29 (m, 2H), 7.15 (m, 2H), 6.77 (s, 1H), 6.21 (s, 1H), 5.54 (m, 1H), 5.38-5.33 (m, 3H), 4.89 (m, 1H), 4.22-4.07 (m, 2H), 2.81-2.77 (m, 2H), 2.43 (s, 3H), 2.05-2.02 (m, 4H), 1.97-1.94 (m, 5H), 1.03-0.984 (m, 3H). LCMS (ESI): RT = 1.460 min, m / z found 803.2 [M+H]+. Compound 003 o cf3cooh 4-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-l, 2,4-triazol-4-yl)benzyl)piperazine-l-carbonyl)cyclohexyl (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 trifluoroacetic acid. H NMR (400 MHz, DMSO-d6) 5 9.75 (s, 1H), 9.47 (s, 1H), 8.80 (d, J =8.8 Hz, 1H), 7.83 (d, J =10.8 Hz, 1H), 7.48 (m, 2H), 7.33 (s, 1H), 7.30 (m, 2H), 7.10-6.97 (m, 1H), 6.55 (s, 1H), 6.23 (s, 1H), 5.665.64 (m, 1H), 5.47-5.35 (m, 4H), 4.35-4.29 (m, 3H), 3.79 (s, 1H), 3.22-3.16 (m, 6H), 3.102.97 (m, 4H), 2.44-2.28 (m, 7H), 1.89-1.32 (m, 6H), 1.47-1.31 (m, 5H), 1.04-0.99 (m, 6H), 0.86 (t, J =7.2 Hz, 3H). LCMS (ESI): Rt = 1.157 min, m / z found 997.4 [M+H]+. Compound 004 HCOOH 2-(((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)amino)-2-oxoethyl 4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-l,2,4-                triazol-4- yl)benzyl)piperazine-l-carboxylate, formate. ’H NMR (400 MHz, DMSO-<L>) 5 11.92 (s, 1H), 9.63 (s, 1H), 9.61 (s, 1H), 8.58-8.56 (d, J = 8.4 Hz, 1H), 8.31 (s, 2H), 7.83-7.80 (d, J = 10.8 Hz, 1H), 7.31-7.29 (m, 3H), 7.15-7.13 (d, J = 8.4 Hz, 2H), 6.77(s, 1H), 6.52 (s, 1H), 6.27 (s, 1H), 5.59-5.55 (m, 1H), 5.42 (s, 1H), 5.26 (q, J= 5.6 Hz, 2H), 4.47(m, 2H), 3.55 (s, 2H), 3.45 (s, 3H), 3.18 (s, 3H), 3.00-2.93 (m, 1H), 2.41 (s, 4H), 2.31 (s, 4H), 2.22-2.11 (m, 1H), 1.91-1.82 (m, 1H), 0.94 (d, J = 6.8 Hz, 7H), 0.86 (t, J = 7.2 Hz, 4H). LCMS (ESI): RT = 1.080 min, m / z found 929.3 [M+H]+. Compound 005 3-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-l, 2,4-triazol-4-yl)benzyl)piperazin-l-yl)-3-oxopropyl (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, trifluoroacetic acid. H NMR (400 MHz, DMSO-tfc) 5 9.98 (s, 1H), 9.75 (s, 1H), 9.48 (s, 1H), 8.79 (d, J = 8.0 Hz, 1H), 7.84-7.81 (m, 1H), 7.48-7.45 (m, 2H), 7.33-7.26 (m, 3H), 7.03 (s, 1H), 6.55 (s, 1H), 6.23 (s, 1H), 5.67-5.65 (m, 2H), 5.425.34 (m, 4H), 4.50-4.05 (m, 4H), 3.64-3.61 (m, 2H), 3.30-3.21 (m, 5H), 3.02-2.97 (m, 4H), 2.41-2.30 (m, 7H), 1.88-1.83 (m, 2H), 1.00 (m, 6H), 0.86 (d, J= 14.8 Hz, 3H). LCMS (ESI): Rt = 1.444 min, m / z found 1055.0 [M-H]+. Compound 006 (4-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-l, 2,4-triazol-4- yl)benzyl)piperazine-l-carbonyl)cyclohexyl)methyl(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. 1H NMR (400 MHz, DMSO-tfc) 5 9.73 (s, 1H), 9.49 (s, 1H), 8.80 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.32-7.29 (m, 3H), 7.16-7.14 (m, 2H), 6.95 (s, 1H), 6.24 (s, 1H), 5.74 (m, 1H), 5.42-5.41 (m, 4H), 4.38 (m, 1H), 3.44- 3.39 (m, 3H), 3.32-3.29 (m, 2H), 2.15 (m, 1H), 2.41-2.23 (m, 10H), 1.89 (m, 2H), 1.55-1.23 (m, 13H), 0.98 (t, J = 9.0 Hz, 3H), 0.86 (t, J = 9.0 Hz, 3H). LCMS (ESI): Rt = 1.447 min, m / z found 1011.5 [M+H]+. Compound 007 o 2-(((lS,9S)-9-ethyl-5-fhioro-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)amino)-2-oxoethyl 4-((4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-l,2,4             -triazol-4- yl)benzyl)piperidin-l-yl)methyl)piperidine-l-carboxylate. H NMR (400 MHz, DMSO-d6) 5 11.92 (s, 1H), 9.62 (s, 1H), 9.43 (s, 1H), 8.57 (s, 1H), 7.80 (d, J= 4.0 Hz, 2H), 7.31 (s, 1H), 7.17-7.11 (m, 4H), 6.75 (s, 1H), 6.54 (s, 1H), 6.28 (s, 1H), 5.57 (s, 1H), 5.43 (s, 1H), 5.31-5.17 (m, 2H), 4.44 (m, 2H), 3.93 (m, 2H), 3.18 (m, 2H), 2.96-2.67 (m, 9H), 2.41 (s, 3H), 1.99-1.68 (m, 16H), 0.93 (d, J = 6.7 Hz, 6H), 0.87 (m, 3H). LCMS (ESI): Rt = 1.127 min, m / z found 1025.3 [M+H]+. Compound 008 2-(((lS,9S)-9-ethyl-5-fhioro-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)amino)-2-oxoethyl (4-((4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-((2,2,2-trifluoroethyl) carbamoyl)-4H- l,2,4-triazol-4-yl)benzyl)piperidin-l-yl)methyl)benzyl)carbamate. H NMR (400 MHz, DMSO-d6) 5 10.54 (s, 1H), 9.59 (s, 1H), 8.59 (s, 1H), 7.81 (s, 2H), 7.32-7.19 (m, 10H), 6.60-6.54 (m, 2H), 6.34 (s, 1H), 5.60 (s, 1H), 5.43 (s, 1H), 5.27 (m, 2H), 4.46 (m, 2H), 4.17 (m, 2H), 3.58 (m, 2H), 3.18 (m, 2H), 2.89 (m, 2H), 2.74 (m, 2H), 2.41 (s, 3H), 2.16 (m, 5H), 1.84 (m, 5H), 1.54 (m, 4H), 0.86 (s, 3H), 0.80 (d, J= 6.7 Hz, 6H). LCMS (ESI): Rt = 1.200 min, m / z found 1156.3 [M+H]+. Compound 009 1-(4-(((4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-l,2,4-triazol-4-yl)benzyl) (methyl)amino)methyl)benzyl)piperidin-4-yl(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. ’H NMR (400 MHz, CD3OD) 5 7.68-7.60 (m, 2H), 7.527.35 (m, 7H), 7.28 (d, J= 8.4 Hz, 2H), 6.87 (s, 1H), 6.23 (s, 1H), 5.79-5.70 (m, 1H), 5.645.49 (m, 2H), 5.39-5.24 (m, 2H), 4.21-4.10 (m, 2H), 3.89 (s, 1H), 3.58 (s, 4H), 3.09-2.96 (m, 4H), 2.57-2.47 (m, 1H), 2.44-2.37 (m, 4H), 2.20 (s, 3H), 2.00-1.90 (m, 4H), 1.83-1.69 (m, 2H), 1.33-1.31 (m, 4H), 1.30-1.27 (m, 3H), 1.01-0.95 (m, 3H), 0.92-0.87 (m, 6H). LCMS (ESI): Rt = 1.394 min, m / z found 1020.1 [M+H]+. Compound 010 cf3cooh l-(4-(((4-(3-carbamoyl-5-(2,4-dihydroxy-5-isopropylphenyl)-4H-l,2,4-triazol-4-yl)benzyl)(methyl)amino)methyl)benzyl)piperidin-4-yl(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, trifluoroacetic acid. H NMR (400 MHz, CD3OD) 5 7.71-7.64 (m, 3H), 7.61-7.55 (m, 6H), 7.49 (d, J = 8.4 Hz, 2H), 7.22 (s, 1H), 6.70 (s, 1H), 5.55-5.35 (m, 5H), 5.24-5.14 (m, 2H), 4.43-4.24 (m, 5H), 4.10-3.75 (m, 1H), 3.52-3.42 (m, 2H), 3.09-2.95 (m, 2H), 2.72 (s, 3H), 2.47-2.40 (m, 4H), 2.32-2.21 (m, 1H), 2.16-2.05 (m, 1H), 2.03-1.86 (m, 5H), 1.76-1.57 (m, 1H), 1.11 (dd, J = 6.8, 2.4 Hz, 6H), 1.02 (t, J= 7.2 Hz, 3H). LCMS (ESI): Rt = 1.348 min, m / z found 1046.4 [M+H]+. Compound Oil CF3C00H 1-(4-(((4-(3-(2,4-dihydroxy-5-methylphenyl)-5-hydroxy-4H-l,2,4-triazol-4-yl)benzyl) (methyl)amino)methyl)benzyl)piperidin-4-yl (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, trifluoroacetic acid. H NMR (400 MHz, CD3OD) 5 7.72-7.56(m, 7H), 7.52 (d, J= 8.8 Hz, 2H), 7.41 (d, J= 8.4 Hz, 2H), 7.10 (s, 1H), 6.13 (s, 1H), 5.78-5.72 (m, 1H), 5.68-5.54 (m, 2H), 5.39-5.29 (m, 2H), 4.52-4.25 (m, 6H), 4.10-3.75 (m, 1H), 3.53-3.46 (m, 1H), 3.14-3.05 (m, 1H), 2.72 (s, 3H), 2.57-2.49 (m, 1H), 2.48-2.33 (m, 5H), 2.21-2.08 (m, 1H), 2.04-1.86 (m, 8H), 1.76-1.61 (m, 1H), 1.44-1.16 (m, 1H), 1.00 (t, J= 7.2 Hz, 3H). LCMS (ESI): Rt = 1.341min, m / z found 991.3 [M+H]+. Compound 012 cf3cooh 2-(((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)amino)-2-oxoethyl 4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-l,2,4-triazol           -4-yl)-2- (trifluoromethyl)benzyl)piperazine-l-carboxylate, trifluoroacetic acid. ’H NMR (400 MHz, DMSO-J6) 5 12.04 (s, 1H), 9.65 (s, 1H), 9.38 (s, 1H), 8.64-8.56 (m, 1H), 7.83-7.77 (m, 2H), 7.56-7.46 (m, 2H), 7.31 (s, 1H), 6.94 (s, 1H), 6.66-6.46 (s, 1H), 6.24 (s, 1H), 5.67-5.50 (m, 1H), 5.42 (s, 2H), 5.24 (q, J= 19.2 Hz, 2H), 4.52-4.44 (m, 2H), 3.31-2.90 (m, 6H), 2.72-2.57 (m, 2H), 2.45-2.34 (m, 6H), 2.26-2.02 (m, 4H), 1.94-1.77 (m, 2H), 1.02 (d, J = 8.0 Hz, 6H), 0.86 (t, J = 8.0 Hz, 3H). LCMS (ESI): Rt = 1.420 min, m / z found 997.9 [M+H]+. Compound 013 cfjcooh 2-(((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)amino)-2-oxoethyl 4-(4-(((4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H            -l,2,4-triazol-4- yl)benzyl)(methyl)amino)methyl)benzyl)piperidine-l-carboxylate, trifluoroacetic acid. ’H NMR (400 MHz, DMSO-J6) 5 11.98 (s, 1H), 9.69 (d, J= 64 Hz, 2H), 9.33 (s, 1H), 8.56 (d, J = 8.0 Hz, 1H), 7.82 (d, J = 12.0 Hz, 1H), 7.50 (d, J = 8.0 Hz, 2H), 7.41(d, J = 7.6 Hz, 2H), 7.34-7.23 (m, 5H), 6.90 (s, 1H), 6.55 (s, 1H), 6.23 (s, 1H), 5.63-5.52 (m, 1H), 5.455.37 (m, 2H), 5.23 (dd, J= 40.0, 19.2 Hz, 2H), 4.45-4.34 (m, 4H), 4.27-4.09 (m, 3H), 3.073.87 (m, 4H), 3.22-3.12 (m, 2H), 3.08-2.95 (m, 1H), 2.81-2.60 (s, 2H), 2.45-2.38 (m, 4H), 2.25-2.02 (m, 4H), 1.92-1.79 (s, 2H), 1.78-1.67 (m, 1H), 1.57-1.48 (m, 2H), 1.26-1.10 (m, 1H), 1.01 (d, J = 6.8 Hz, 6H), 0.86 (t, J = 7.2 Hz, 4H). LCMS (ESI): Rt = 1.160 min, m / z found 1061.3 [M+H]+. Compound 014 2-(((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)amino)-2-oxoethyl 4- (4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy- 4H-l,2,4-triazol-4-yl)-2- (trifluoromethyl)benzyl)piperazin-l-yl)piperidine-l-carboxylate, trifluoroacetic acid. ’H NMR (400 MHz, DMSO-J6) 5 12.03 (s, 1H), 9.61 (s, 1H), 9.38 (s, 1H), 8.58 (s, 1H), 7.82-7.74 (m, 2H), 7.49-7.41 (m, 2H), 7.31 (s, 1H), 6.91 (s, 1H), 6.54 (s, 1H), 6.25 (s, 1H), 5.57 (s, 1H), 5.43 (s, 2H), 5.28-5.20 (m, 2H), 4.51-4.39 (m, 2H), 4.00 (s, 1H), 4.56 (s, 2H), 3.23-3.13 (m, 2H), 3.07-2.69 (m, 3H), 2.50-2.40 (m, 10H), 2.21-1.97 (m, 5H), 1.95-1.62 (m, 5H), 1.01(d, J= 4.0 Hz, 6H), 0.91-0.82 (m, 3H). LCMS (ESI): Rt = 1.120 min, m / z found 1080.2 [M+H]+ Compound 015 2-(((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)amino)-2-oxoethyl 4-(4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-        l,2,4-triazol-4-yl)-2- fluorobenzyl)piperazin-l-yl)piperidine-l-carboxylate. H NMR (400 MHz, DMSO-tfc) 5 12.00 (s, 1H), 9.66 (s, 1H), 9.36 (s, 1H), 9.11 (s, 1H), 8.68 (d, J = 8.0 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.70 (s, 1H), 7.32 (s, 1H), 7.12 (d, J= 12.0 Hz, 1H), 7.03-6.97 (m, 1H), 6.92 (s, 1H), 6.30 (s, 1H), 5.58 (s, 1H), 5.43 (s, 2H), 5.30-5.16 (m, 2H), 4.56-4.41 (m, 2H), 4.274.01 (m, 2H), 3.82-3.63 (m, 2H), 3.23-2.64 (m, 12H), 2.41 (s, 3H), 2.23-1.98 (m, 5H), 1.941.79 (m, 3H), 1.86-1.45 (m, 2H), 1.03 (d, J= 8.0 Hz, 6H), 0.90-0.83 (m, 3H). LCMS (ESI): Rt = 1.107 min, m / z found 1030.3 [M+H]+. Compound 016 cf3cooh 2-(((lS,9S)-9-ethyl-5-fhioro-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)amino)-2-oxoethyl (4-(((4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-l,2,4-               triazol-4- yl)benzyl)(methyl)amino)methyl)benzyl)carbamate, trifluoroacetic acid. H NMR (400 MHz, DMSO-d6) 5 11.98 (s, 1H), 9.89-9.73 (m, 1H), 9.61 (s, 1H), 9.33(s, 1H), 8.64-8.58 (m, 1H), 8.15-7.90 (m, 1H), 7.82 (d, J = 10.8 Hz, 1H), 7.55-7.49 (m, 2H), 7.48-7.42 (m, 2H), 7.70-7.34 (m, 2H), 7.32 (s, 1H), 7.29-7.22 (m, 2H), 6.94 (s, 1H), 6.55 (s, 1H), 6.23 (s, 1H), 5.59 (s, 1H), 5.42 (s, 2H), 5.35-5.15 (m, 2H), 4.51-4.37 (m, 4H), 4.29-4.13 (m, 4H), 3.213.15 (m, 2H), 3.04-2.93 (m, 1H), 2.54 (s, 3H), 2.41 (s, 3H), 2.23-2.07 (m, 2H), 1.96-1.79 (m, 2H), 1.01 (d, J = 6.8 Hz, 6H), 0.86 (t, J = 7.2 Hz, 3H). LCMS (ESI): Rt = 1.089 min, m / z found 993.3 [M+H]+. Compound 017 cf3cooh l-(((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)amino)-2-methyl-l-oxopropan-2-yl (4-((4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5 -((2,2,2-trifluoroethyl) carbamoyl)-4H-l,2,4-triazol-4-yl)benzyl)piperidin-l-yl) methyl) benzyl) carbamate, trifluoroacetic acid. *H NMR (400 MHz, CD3OD) 5 7.67-7.64 (m, 2H), 7.54-7.52 (m, 2H), 7.25-7.24 (m, 3H), 6.56 (s, 1H), 6.27 (s, 1H), 5.55-5.54 (m, 1H), 5.37-5.33 (m, 1H), 5.115.02 (m, 3H), 4.88-4.81 (m, 2H), 4.26-4.24 (m, 2H), 3.97-3.95 (m, 2H), 3.31-3.30 (m, 2H), 3.24-3.21 ( m,2H), 2.89-2.88 (m ,2H), 2.74-2.72 (m, 2H), 2.51-2.40 (m ,3H), 2.38 (s, 3H), 2.18-2.14 (m, 2H), 1.86-1.83 (m, 3H), 1.61 (s, 3H), 1.47 (s, 3H), 0.96-0.92 (m, 3H), 0.810.79 (m, 6H). LCMS (ESI): Rt = 1.236 min, m / z found 1184.2 [M+H]+. Compound 018 l-(((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)amino)-2-methyl-l-oxopropan-2-yl 4-((4-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5- hydroxy-4H-1,2,4-triazol-4-yl)benzyl)piperidin-l-yl)methyl)piperidine-l-carboxylate. H NMR (400 MHz, CD3OD) 5 7.64 ( d, J= 10.8 Hz, 1H), 7.31-7.27 (m, 3H), 7.21-7.20 (m, 2H), 6.68-6.66 (m, 1H), 6.28 (s, 1H), 5.61-5.59 (m, 1H), 5.57-5.55 (m, 2H), 5.50-5.46 (m, 1H), 5.35-5.18 (m, 1H), 4.88-4.60 (m, 2H), 4.35-4.30 (m, 1H), 4.10-4.09 (m, 1H), 3.95-3.85 (m, 1H), 3.31-3.30 (m, 2H), 3.18-3.12 (m, 3H), 2.60-2.59 (m, 2H), 2.57-2.54 (m, 3H), 2.42-2.33 (m, 4H), 2.312.23 (m, 5H), 2.20-2.16 (m, 2H), 2.09-2.04 (m, 2H), 2.03-2.00 (m, 3H), 1.76-1.59 (m, 3H), 1.04-1.00 (m, 3H), 0.90-0.88 (m, 6H). LCMS (ESI): RT = 1.113 min, m / z found 1053.3 [M+H]+. Compound 019 cf3cooh 2-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-l, 2,4-triazol-4-yl)benzyl)-2-azaspiro[3.3]heptan-6-yl((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, trifluoroacetic acid. ’H NMR (400 MHz, DMSO-<7>) 5 11.94 (s, 1H), 10.11 (s, 1H), 9.59 (s, 1H), 9.31 (s, 1H), 7.98 (d, 7 = 9.2 Hz, 1H), 7.78 (d, J= 11.2 Hz, 1H), 7.44-7.42 (m, 2H), 7.32 (s, 6H), 7.25-7.23 (m, 2H), 6.88 (s, 2H), 6.52 (s, 1H), 6.24 (s, 1H), 5.42-5.41 (m, 2H), 5.23-5.18 (m, 3H), 4.88-4.86 (m, 1H), 4.32-4.30 (m, 2H), 4.18-4.02 (m, 4H), 3.32-3.31 (m, 1H), 3.01-3.00 (m, 1H), 2.75-7.70 (m, 1H), 2.50-2.49 (m, 5H), 2.38-2.36 (m, 3H), 2.15-2.12 (m, 1H), 1.88-1.85 (m, 2H), 1.02 (d, J = 6.8 Hz, 6H), 0.88 (t, J= 7.2 Hz, 3H).LCMS (ESI): Rt = 1.078 min, m / z found 898.3 [M+H]+. Compound 020 CF3C00H 2-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-l, 2,4-triazol-4-yl)benzyl)-2-azaspiro[3.3]heptan-6-yl((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, trifluoroacetic acid. ’H NMR (400 MHz, DMSO-dd) 5 11.94 (s, 1H), 10.11 (s, 1H), 9.59 (s, 1H), 9.31 (s, 1H), 7.98 (d, 7 = 9.2 Hz, 1H), 7.78 (d,7= 11.2 Hz, 1H), 7.44-7.42 (m, 2H), 7.32 (s, 6H), 7.25-7.23 (m, 2H), 6.88 (s, 2H), 6.52 (s, 1H), 6.24 (s, 1H), 5.42-5.41 (m, 2H), 5.23-5.18 (m, 3H), 4.88-4.86 (m, 1H), 4.32-4.30 (m, 2H), 4.18-4.02 (m, 4H), 3.32-3.31 (m, 1H), 3.01-3.00 (m, 1H), 2.75-7.70 (m, 1H), 2.50-2.49 (m, 5H), 2.38-2.36 (m, 3H), 2.15-2.12 (m, 1H), 1.88-1.85 (m, 2H), 1.02 (d, J = 6.8 Hz, 6H), 0.88 (t, J= 7.2 Hz, 3H). LCMS (ESI): Rt = 1.093 min, m / z found 898.3 [M+H]+. Compound 021 cf3cooh 1-(7-(4-(3-(2,4-dihydroxy-5-methylphenyl)-5-hydroxy-4H-l, 2,4-triazol-4-yl)benzyl)-2,7-diazaspiro[3.5]nonan-2-yl)-2-methyl-l-oxopropan-2-yl((lS,9S)-9-ethyl-5-fhioro-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, trifluoroacetic acid. H NMR (400 MHz, DMSO-tfc) 5 11.95 (s, 1H), 9.57 (s, 1H), 9.55-9.53 (m, 1H), 9.29 (s, 1H), 8.08-8.04 (m, 1H), 7.80 (d, J= 8.0 Hz, 1H), 7.48-7.47 (m, 2H), 7.32-7.23 (m, 4H), 6.95 (s, 1H), 6.53 (s, 1H), 6.22 (s, 1H), 5.43-5.41 (m, 2H), 5.29-5.25 (m, 3H), 4.29-4.27 (m, 2H), 4.05-3.98 (m, 2H), 3.62-3.59 (m, 2H), 3.25-3.00 (m, 4H), 2.50 (s, 3H), 2.33-1.85 (m, 13H), 1.55-1.52 (m, 3H), 1.48 (s, 3H), 0.86 (t, J = 7.2 Hz, 3H). LCMS (ESI): Rt = 1.038 min, m / z found 969.3 [M+H]+. Compound 022 1-(7-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-l, 2,4-triazol-4-yl)benzyl)-2,7-diazaspiro[3.5]nonan-2-yl)-2-methyl-l-oxopropan-2-yl((lS,9S)-9-ethyl-5-fhioro-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, trifluoroacetic acid. H NMR (400 MHz, DMSO-tfc) 8 11.97 (s, 1H), 9.59 (s, 1H), 9.55-9.53 (m, 1H), 9.34 (s, 1H), 8.08-8.04 (m, 1H), 7.80 (d, J= 8.0 Hz, 1H), 7.48-7.47 (m, 2H), 7.32-7.23 (m, 3H), 6.86 (s, 1H), 6.52 (s, 1H), 6.25 (s, 1H), 5.43-5.41 (m, 2H), 5.29-5.25 (m, 3H), 4.29-4.27 (m, 2H), 4.05-3.98 (m, 2H), 3.62-3.59 (m, 2H), 3.25-3.00 (m, 5H), 2.51 (s, 3H), 2.33-1.85 (m, 10H), 1.55-1.52 (m, 3H), 1.48 (s, 3H), 1.01 (t, J = 6.8 Hz, 3H), 0.86 (t, J = 7.2 Hz, 3H). LCMS (ESI): Rt = 1.123 min, m / z found 997.3 [M+H]+. Compound 023 cf3cooh 1-(7-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-l, 2,4-triazol-4-yl)benzyl)-2,7-diazaspiro[3.5]nonane-2-carbonyl)cyclopropyl((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, trifluoroacetic acid. H NMR (400 MHz, DMSO-tfc) 8 11.97 (s, 1H), 9.60 (s, 1H), 9.55-9.53 (m, 1H), 9.34 (s, 1H), 8.17-8.15 (m, 1H), 7.80 (d, J= 8.0 Hz, 1H), 7.48 (d, J= 8.0 Hz, 2H), 7.32-7.23 (m, 3H), 6.86 (s, 1H), 6.52 (s, 1H), 6.26 (s, 1H), 5.43-5.41 (m, 2H), 5.25-5.21 (m, 3H), 4.29-4.27 (m, 2H), 4.15-4.13 (m, 1H), 4.02-4.00 (m, 1H), 3.74-3.67 (m, 2H), 3.35-3.33 (m, 6H), 2.97-2.93 (m, 3H), 2.51 (s, 3H), 2.37-2.35 (m, 3H), 1.87-1.85 (m, 4H), 1.49-1.05 (m, 3H), 1.01 (t, J= 6.8 Hz, 3H), 0.86 (t, J = 7.2 Hz, 3H). LCMS (ESI): Rt = 1.074 min, m / z found 995.3 [M+H]+. Compound 024 cf3cooh 1-(7-(4-(3-(2,4-dihydroxy-5-methylphenyl)-5-hydroxy-4H-l, 2,4-triazol-4-yl)benzyl)-2,7-diazaspiro[3.5]nonane-2-carbonyl)cyclopropyl((lS,9S)-9-ethyl-5-fhioro-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, trifluoroacetic acid. H NMR (400 MHz, DMSO-tfc) 5 11.94 (s, 1H), 9.58 (s, 1H), 9.55 (s, 1H), 9.30 (s, 1H), 8.17-8.15 (m, 1H), 7.80 (d, J= 8.0 Hz, 1H), 7.47 (d, J= 8.0 Hz, 2H), 7.32-7.23 (m, 3H), 6.95 (s, 1H), 6.52 (s, 1H), 6.23 (s, 1H), 543-5.41 (m, 2H), 5.25-5.21 (m, 3H), 4.29-4.27 (m, 2H), 4.15-4.13 (m, 1H), 4.02-4.00 (m, 1H), 3.74-3.67 (m, 2H), 3.35-3.33 (m, 3H), 2.97-2.93 (m, 2H), 2.51 (s, 3H), 2.37-2.35 (m, 3H), 1.97 (s, 3H), 1.87-1.85 (m, 4H), 1.49-1.05 (m, 6H), 0.86 (t, J= 7.2 Hz, 3H). LCMS (ESI): Rt = 1.031 min, m / z found 967.2 [M+H]+. Compound 025 2-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-2-azaspiro[3.3]heptan -6-yl((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, trifluoroacetic acid. ‘H NMR (400 MHz, DMSO-d6) 5 10.33-10.02 (m, 2H), 9.66 (s, 1H), 8.00 (d, J= 8.9 Hz, 1H), 7.79 (d, J = 10.7 Hz, 1H), 7.43-7.35 (m, 2H), 7.33 (s, 1H), 7.137.00 (m, 1H), 6.54 (s, 1H), 6.41 (s, 1H), 5.42 (s, 2H), 5.30-5.16 (m, 3H), 5.05-4.73 (m, 6H), 4.33 (s, 2H), 4.25-4.01 (m, 4H), 3.17-3.06 (m, 3H), 2.78-2.64 (m, 2H), 2.38 (s, 3H), 2.28- 2.18 (m, 2H), 2.13-2.08 (m, 2H), 1.91-1.86 (m, 2H), 1.14 (d, J = 6.9 Hz, 6H), 0.88 (t, J = 7.3 Hz, 3H). LCMS (ESI): Rt = 1.077 min, m / z found 884.3 [M-CF3COOH+H]+. Compound 026 2-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-2-azaspiro[3.3]heptan -6-yl((9S)-9-ethyl-5-fhioro-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, trifluoroacetic acid. ’H NMR (400 MHz, DMSO-J6) 5 10.25-10.02 (m, 2H), 9.66 (s, 1H), 8.00 (d, J= 8.9 Hz, 1H), 7.79 (d, J = 10.7 Hz, 1H), 7.43-7.35 (m, 2H), 7.33 (s, 1H), 7.137.00 (m, 1H), 6.54 (s, 1H), 6.41 (s, 1H), 5.42 (s, 2H), 5.30-5.16 (m, 3H), 5.05-4.73 (m, 6H), 4.33 (s, 2H), 4.25-4.01 (m, 4H), 3.17-3.06 (m, 3H), 2.78-2.64 (m, 2H), 2.38 (s, 3H), 2.282.18 (m, 2H), 2.13-2.08 (m, 2H), 1.91-1.86 (m, 2H), 1.14 (d, J = 6.9 Hz, 6H), 0.88 (t, J = 7.3 Hz, 3H). LCMS (ESI): Rt = 5.347 min, m / z found 884.3 [M-CF3COOH+H]+. Compound 027 2-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-l, 2,4-triazol-4-yl)benzyl)-2-azaspiro[3.5]nonan-7-yl((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, trifluoroacetic acid. ’H NMR (400 MHz, DMSO-cL): 5 11.94 (s, 1H), 10.16 (s, 1H), 9.60 (s, 1H), 9.33 (s, 1H), 7.90 (d, J= 7.6 Hz, 1H), 7.77 (d, J = 10.9 Hz, 1H), 7.48 (d, J= 7.9 Hz, 2H), 7.31 (s, 1H), 7.25 (d, J= 8.3 Hz, 2H), 6.88 (s, 1H), 6.51 (s, 1H), 6.24 (s, 1H), 5.42 (s, 2H), 5.31-5.11 (m, 3H), 4.65 (s, 1H), 4.38 (s, 2H), 3.97-3.75 (m, 4H), 3.25-3.21 (m, 1H), 3.16-3.06 (m, 1H), 3.05-2.97 (m, 1H), 2.38 (s, 3H), 2.27-2.17 (m, 1H), 2.16-2.06 (m, 1H), 2.04-1.93 (m, 2H), 1.91-1.80 (m, 3H), 1.68 (s, 2H), 1.54-1.40 (m, 2H), 1.01 (d, J= 6.8 Hz, 6H), 0.88 (t, J= 7.0 Hz, 3H). LCMS (ESI): Rt = 5.157 min, m / z found 926.2 [M-CF3COOH+H]+. Compound 028 cf3cooh 2-(4-(3-(5-ethyl-2,4-dihydroxyphenyl)-5-hydroxy-4H-l,2,4-triazol-4-yl)benzyl)-2-azaspiro[3.3]heptan-6-yl((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, trifluoroacetic acid. ’H NMR (400 MHz, DMSO-de): 6 11.93 (s, 1H), 10.14 (s, 1H), 9.57 (s, 1H), 9.30 (s, 1H), 7.98 (d, J= 9.0 Hz, 1H), 7.78 (d, J = 0.9 Hz, 1H), 7.43 (d, J= 8.3 Hz, 2H), 7.32 (s, 1H), 7.24 (d, J= 8.2 Hz, 2H), 6.91 (s, 1H), 6.52 (s, 1H), 6.24 (s, 1H), 5.42 (s, 2H), 5.26-5.10 (m, 3H), 4.91-4.81 (m, 1H), 4.32 (s, 2H), 4.24-3.98 (m, 4H), 3.14-3.11 (m, 1H), 2.69-2.64 (m, 1H), 2.41-2.35 (m, 7H), 2.24-2.17 (m, 2H), 2.14-2.06 (m, 1H), 2.04-1.96 (m, 1H), 1.91-1.82 (m, 2H), 1.02 (t, J= 7.5 Hz, 3H), 0.88 (t, J= 7.3 Hz, 3H). LCMS (ESI): Rt = 1.120 min, m / z found 884.2 [M-CF3COOH+H]+. Compound 029 CF3C00H 2-(4-(3-(5-ethyl-2,4-dihydroxyphenyl)-5-hydroxy-4H-l,2,4-triazol-4-yl)benzyl)-2-azaspiro[3.3]heptan-6-yl((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, trifluoroacetic acid. ’H NMR (400 MHz, DMSO-<L>) 5 11.93 (s, 1H), 10.17-10.06 (m, 1H), 9.57 (s, 1H), 9.30 (s, 1H), 7.98 (d, J= 8.5 Hz, 1H), 7.78 (d, J= 11.0 Hz, 1H), 7.43 (d, J= 8.4 Hz, 2H), 7.32 (s, 1H), 7.24 (d, J= 8.2 Hz, 2H), 6.91 (s, 1H), 6.51 (s, 1H), 6.24 (s, 1H), 5.42 (d, J= 4.7 Hz, 2H), 5.26-5.17 (m, 3H), 4.90-4.83 (m, 1H), 4.344.29 (m, 2H), 4.21-4.01 (m, 4H), 3.13-3.10 (m, 1H), 2.69-2.62 (m, 1H), 2.40-2.35 (m, 7H), 2.25-2.17 (m, 2H), 2.14-2.09 (m, 1H), 2.04-1.96 (m, 1H), 1.91-1.83 (m, 2H), 1.02 (t, J= 7.5 Hz, 3H), 0.87 (t, J = 7.5 Hz, 3H). LCMS (ESI): Rt = 1.120 min, m / z found 884 [M-CF3COOH+H]+. Compound 030 cf3cooh 3-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-l, 2,4-triazol-4-yl)benzyl)-3-azabicyclo[3.1.0]hexan-6-yl((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, trifluoroacetic acid. ’H NMR (400 MHz, DMSO-t / d) 5 11.96 (s, 1H), 9.73 (s, 1H), 9.59 (s, 1H), 9.31 (s, 1H), 8.16 (d, J= 8.7 Hz, 1H), 7.78 (d, J = 10.8 Hz, 1H), 7.547.42 (m, 2H), 7.32 (s, 1H), 7.25 (d, J= 7.6 Hz, 2H), 6.89 (s, 1H), 6.52 (s, 1H), 6.25 (s, 1H), 5.42 (s, 2H), 5.29-5.11 (m, 3H), 4.42-4.21 (m, 3H), 3.77 (s, 1H), 3.54-3.50 (m, 2H), 3.153.10 (m, 1H), 3.03-2.99 (m, 1H), 2.40-2.31 (m, 5H), 2.28-2.07 (m, 4H), 1.92-1.83 (m, 2H), 1.02 (d, J = 6.8 Hz, 6H), 0.88 (t, J = 7.3 Hz, 3H). LCMS (ESI): Rt = 1.140 min, m / z found 884 [M-CF3COOH+H]+. Compound 031 CF3C00H 3-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-l, 2,4-triazol-4-yl)benzyl)-3-azabicyclo[3.1.0]hexan-6-yl((9S)-9-ethyl-5-fhioro-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, trifluoroacetic acid. ’H NMR (400 MHz, DMSO-cL): 5 11.95 (s, 1H), 9.74 (s, 1H), 9.59 (s, 1H), 9.31 (s, 1H), 8.16 (s, 1H), 7.79 (d, J= 10.9 Hz, 1H), 7.58-7.41 (m, 2H), 7.32 (s, 1H), 7.25 (d, J = 7.4 Hz, 2H), 6.89 (s, 1H), 6.52 (s, 1H), 6.25 (s, 1H), 5.43 (s, 2H), 5.31-5.14 (m, 3H), 4.33 (d, J= 23.1 Hz, 3H), 3.77 (s, 1H), 3.51 (s, 2H), 3.16-3.14 (m, 1H), 3.01-2.99 (t, J= 8 Hz 1H), 2.38 (s, 5H), 2.28-2.10 (m, 4H), 1.92-1.84 (m, 2H), 1.02 (d, J = 6.8 Hz, 6H), 0.87 (t, J = 7.3 Hz, 3H). LCMS (ESI): Rt = 1.160 min, m / z found 884.2 [M-CF3COOH+H]+. Compound 032 2-(4-(3-(2,4-dihydroxy-5-methylphenyl)-5-hydroxy-4H-l, 2,4-triazol-4-yl)benzyl)-2-azaspiro[3.5]nonan-7-yl((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 2,2,2-trifluoroacetate, trifluoroacetic acid. H NMR (400 MHz, DMSO-d6): 5 11.92 (s, 1H), 10.40 (s, 1H), 9.61 (s, 1H), 9.31 (s, 1H), 7.91 (d, J = 8.7 Hz, 1H), 7.77 (d, J = 10.8 Hz, 1H), 7.47 (d, J = 8.3 Hz, 2H), 7.31 (s, 1H), 7.25 (t, J = 8.5 Hz, 2H), 6.95 (s, 1H), 6.53 (d, J= 11.1 Hz, 1H), 6.24 (s, 1H), 5.42 (s, 2H), 5.32-5.11 (m, 3H), 4.64 (s, 1H), 4.37 (s, 2H), 3.84 (d, J= 26.0 Hz, 4H), 3.29-3.18 (m, 2H), 3.11 (s, 1H), 2.35 (d, J= 16.6 Hz, 3H), 2.21 (s, 1H), 2.07 (s, 1H), 1.97 (s, 4H), 1.92-1.81 (m, 3H), 1.68 (s, 2H), 1.47 (s, 2H), 1.30-1.12 (m, 1H), 0.87 (t, J = 7.3 Hz, 3H). LCMS (ESI): Rt = 1.100 min, m / z found 898.2 [M-CF3COOH+H]+. Compound 033 CF3COOH      F 2-(4-(3-(2,4-dihydroxy-5-methylphenyl)-5-hydroxy-4H-l, 2,4-triazol-4-yl)benzyl)-2-azaspiro[3.5]nonan-7-yl((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, trifluoroacetic acid. ’H NMR (400 MHz, DMSO-tfc) 5 11.92 (s, 1H), 10.32 (s, 1H), 9.60 (s, 1H), 9.30 (s, 1H), 7.90 (d, 7=8.4 Hz, 1H), 7.77 (d, J= 11.0 Hz, 1H), 7.48 (d, J= 8.0 Hz, 2H), 7.31 (s, 1H), 7.24 (d, J= 8.2 Hz, 2H), 6.94 (d, J= 10.8 Hz, 1H), 6.51 (s, 1H), 6.23 (s, 1H), 5.42 (s, 2H), 5.30-5.11 (m, 3H), 4.65 (s, 1H), 4.37 (s, 2H), 3.993.72 (m, 4H), 3.23-3.19 (m, 1H), 3.17-3.05 (m, 2H), 2.38 (s, 3H), 2.26-2.19 (m, 1H), 2.152.06 (m, 1H), 1.97 (s, 4H), 1.91-1.82 (m, 3H), 1.73-1.64 (m, 2H), 1.57-1.40 (m, 2H), 1.311.15 (m, 1H), 0.88 (t, J = 7.2 Hz, 3H). LCMS (ESI): Rt = 1.120 min, m / z found 898.2 [M-CF3COOH+H]+. Compound 034 2-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-2-azaspiro[3.5]nonan-7-yl((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, trifluoroacetic acid. ’H NMR (400 MHz, CD3OD) 5 7.69 (s, 1H), 7.56-7.42 (m, 5H), 7.16 (s, 1H), 6.37 (s, 1H), 5.52 (s, 1H), 5.34-5.20 (m, 5H), 4.94 (d, J = 7.7 Hz, 4H), 4.42 (s, 1H), 3.97 (d, J= 13.2 Hz, 4H), 3.21-3.09(m, 2H), 2.35 (s, 4H), 2.17-2.03 (m, 6H), 1.94 (d, J = 7.4 Hz, 6H), 1.33-1.29 (m, 1H), 1.20 (d, J = 7.0 Hz, 6H), 0.99 (t, J = 7.3 Hz, 3H). LCMS (ESI): Rt = 1.268 min, m / z found 912.4 [M-CF3COOH+H]+. Compound 035 2-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-2-azaspiro[3.5]nonan-7-yl((9S)-9-ethyl-5-fhioro-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, trifluoroacetic acid. 1H NMR (400 MHz, CD3OD) 5 7.59-7.45 (m, 5H), 7.34 (d, J = 10.9 Hz, 1H), 7.16 (s, 1H), 6.37 (s, 1H), 5.50 (s, 2H), 5.39-5.21 (m, 5H), 4.94 (d, J= 8.1 Hz, 4H), 4.43 (s, 1H), 4.01 (d, J= 12.7 Hz, 4H), 3.24-3.03 (m, 2H), 2.35 (s, 4H), 1.91-1.66 (m, 11H), 1.31-1.28 (m, 1H), 1.20 (d, J = 6.9 Hz, 6H), 0.97 (t, J = 7.3 Hz, 3H). LCMS (ESI): Rt = 1.276 min, m / z found 912.3 [M-CF3COOH+H]+. Compound 036 2-(4-(3-(5-ethyl-2,4-dihydroxyphenyl)-5-hydroxy-4H-l,2,4-triazol-4-yl)benzyl)-2-azaspiro[3.5]nonan-7-yl((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, trifluoroacetic acid. 1H NMR (400 MHz, DMSO-cL) 5 11.93 (s, 1H), 10.25 (s, 1H), 9.59 (s, 1H), 9.32 (s, 1H), 7.90 (d, J= 8.5 Hz, 1H), 7.77 (d, J= 10.9 Hz, 1H), 7.47 (d, J= 8.1 Hz, 2H), 7.31 (s, 1H), 7.24 (d, J= 8.1 Hz, 2H), 6.91 (s, 1H), 6.55-6.51 (m, 1H), 6.24 (s, 1H), 5.42 (s, 2H), 5.27-5.13 (m, 3H), 4.64 (s, 1H), 4.37 (s, 2H), 3.99-3.73 (m, 4H), 3.24-3.20 (m, 1H), 3.15-3.07 (m, 1H), 2.40-2.33 (m, 5H), 2.27-2.18 (m, 1H), 2.17-2.07 (m, 1H), 2.03-1.94 (m, 2H), 1.92-1.80 (m, 3H), 1.76-1.66 (m, 2H), 1.56-1.43 (m, 2H), 1.291.15 (m, 1H), 1.01 (t, J= 7.5 Hz, 3H), 0.88 (t, J= 7.3 Hz, 3H). LCMS (ESI): Rt = 1.120 min, m / z found 912.2 [M-CF3COOH+H]+. Compound 037 2-(4-(3-(5-ethyl-2,4-dihydroxyphenyl)-5-hydroxy-4H-l,2,4-triazol-4-yl)benzyl)-2-azaspiro[3.5]nonan-7-yl((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, trifluoroacetic acid.. 1H NMR (400 MHz, DMSO-6fc) 311.93 (s, 1H), 10.25 (s, 1H), 9.59 (s, 1H), 9.32 (s, 1H), 7.90 (d, J= 8.5 Hz, 1H), 7.77 (d, J= 10.9 Hz, 1H), 7.47 (d, J= 8.1 Hz, 2H), 7.31 (s, 1H), 7.24 (d, J= 8.1 Hz, 2H), 6.91 (s, 1H), 6.55-6.51 (m, 1H), 6.24 (s, 1H), 5.42 (s, 2H), 5.27-5.13 (m, 3H), 4.64 (s, 1H), 4.37 (s, 2H), 3.99-3.73 (m, 4H), 3.24-3.20 (m, 1H), 3.15-3.07 (m, 1H), 2.40-2.33 (m, 5H), 2.27-2.18 (m, 1H), 2.17-2.07 (m, 1H), 2.03-1.94 (m, 2H), 1.92-1.80 (m, 3H), 1.76-1.66 (m, 2H), 1.56-1.43 (m, 2H), 1.291.15 (m, 1H), 1.01 (t, J= 7.5 Hz, 3H), 0.88 (t, J= 7.3 Hz, 3H). LCMS (ESI): Rt = 1.140 min, m / z found 912.2 [M-CF3COOH+H]+. Compound 038 cf3cooh 3-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-3-azabicyclo   [3.1.0] hexan-6-yl((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, trifluoroacetic acid. 1H NMR (400 MHz, DMSO-dd): 5 10.03 (s, 1H), 9.72 (s, 1H), 9.64 (s, 1H), 8.21-8.10 (m, 1H), 7.82-7.75 (m, 1H), 7.41 (s, 3H), 7.35-7.29 (m, 1H), 7.04 (s, 1H), 6.53 (s, 1H), 6.41 (s, 1H), 5.42 (s, 2H), 5.30-5.16 (m, 3H), 4.81 (s, 4H), 4.444.26 (m, 3H), 3.87-3.76 (m, 1H), 3.53-3.50 (m, 2H), 3.18-3.01 (m, 4H), 2.38 (s, 3H), 2.352.32 (m, 1H), 2.25-2.06 (m, 3H), 1.87 (t, J = 9.0 Hz, 2H), 1.14 (d, J= 6.9 Hz, 6H), 0.87 (t, J = 7.4 Hz, 3H). LCMS (ESI): Rt = 1.160 min, m / z found 870.3 [M-CF3COOH+H]+. Compound 039 cf3cooh 3-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-3-azabicyclo[3.1.0] hexan-6-yl((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, trifluoroacetic acid. 1H NMR (400 MHz, DMSO-tfc): 5 10.03 (s, 1H), 9.76 (s, 1H), 9.64 (s, 1H), 8.27-8.12 (m, 1H), 7.79 (d, J= 11.1 Hz, 1H), 7.54-7.37 (m, 3H), 7.32 (s, 1H), 7.04 (s, 1H), 6.60-6.49 (m, 1H), 6.41 (s, 1H), 5.43 (s, 2H), 5.31-5.16 (m, 3H), 4.82 (s, 4H), 4.45-4.25 (m, 3H), 3.85-3.77 (m, 1H), 3.72-3.61 (m, 2H), 3.20-3.03 (m, 4H), 2.38 (s, 3H), 2.35-2.28 (m, 1H), 2.24-2.09 (m, 3H), 1.90-1.83 (m, 2H), 1.14 (d, J = 6.8 Hz, 6H), 0.87 (t, J = 7.4 Hz, 3H). LCMS (ESI): Rt = 1.160 min, m / z found 870.2 [M-CF3COOH+H]+. Compound 040 cf3cooh (lS,5S)-3-(4-(3-(5-ethyl-2,4-dihydroxyphenyl)-5-hydroxy-4H-l,2,4-triazol-4-yl)benzyl)-3-azabicyclo[3.1.0]hexan-6-yl((9S)-9-ethyl-5-fhioro-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, trifluoroacetic acid. ’H NMR (400 MHz, DMSO-t / d) 5 11.94 (s, 1H), 9.72 (s, 1H), 9.57 (s, 1H), 9.30 (s, 1H), 8.20-8.12 (m, 1H), 7.79 (d, J = 10.9 Hz, 1H), 7.53-7.41 (m, 2H), 7.32 (s, 1H), 7.28-7.21 (m, 2H), 6.95-6.90 (m, 1H), 6.52 (s, 1H), 6.23 (s, 1H), 5.42 (s, 2H), 5.29-5.16 (m, 3H), 4.43-4.24 (m, 3H), 3.85-3.73 (m, 1H), 3.53-3.50 (m, 2H), 3.163.01 (m, 3H), 2.42-2.36 (m, 6H), 2.25-2.10 (m, 3H), 1.93-1.82 (m, 2H), 1.02 (t, J= 7.5 Hz, 3H), 0.88 (t, J = 7.2 Hz, 3H). LCMS (ESI): Rt = 1.100 min, m / z found 870.2 [M-CF3COOH+H]+. Compound 041 cf3cooh (lS,5S)-3-(4-(3-(5-ethyl-2,4-dihydroxyphenyl)-5-hydroxy-4H-l,2,4-triazol-4-yl)benzyl)-3-azabicyclo[3.1.0]hexan-6-yl((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, trifluoroacetic acid. ’H NMR (400 MHz, DMSO-tfc) 5 11.98-11.89 (m, 1H), 9.75 (s, 1H), 9.57 (s, 1H), 9.30 (s, 1H), 8.20-8.13 (m, 1H), 7.79 (d, J = 11.0 Hz, 1H), 7.53-7.40 (m, 2H), 7.32 (s, 1H), 7.28-7.21 (m, 2H), 6.92 (s, 1H), 6.52 (s, 1H), 6.24 (s, 1H), 5.43 (s, 2H), 5.29-5.15 (m, 3H), 4.41-4.20 (m, 3H), 3.77 (s, 1H), 3.51 (s, 2H), 3.17-2.99 (m, 3H), 2.41-2.35 (m, 6H), 2.23-2.08 (m, 3H), 1.91-1.82 (m, 2H), 1.02 (t, J= 7.4 Hz, 3H), 0.87 (t, J= 7.3 Hz, 3H). LCMS (ESI): Rt = 1.120 min, m / z found 870.1 [M-CF3COOH+H]+. Compound 042 3-(4-(3-(2,4-dihydroxy-5-methylphenyl)-5-hydroxy-4H-l, 2,4-triazol-4-yl)benzyl)-3-azabicyclo[3.1.0]hexan-6-yl((9S)-9-ethyl-5-fhioro-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, trifluoroacetic acid. ’H NMR (400 MHz, DMSO-tfc): 5 11.94 (s, 1H), 9.81 (s, 1H), 9.59 (s, 1H), 9.28 (s, 1H), 8.15 (s, 1H), 7.78 (d, J= 10.6 Hz, 1H), 7.53-7.42 (m, 2H), 7.32 (s, 1H), 7.24 (d, J = 8.2 Hz, 2H), 6.97 (s, 1H), 6.53 (s, 1H), 6.23 (s, 1H), 5.42 (s, 2H), 5.27-5.17 (m, 3H), 4.40-4.25 (m, 3H), 3.79 (s, 1H), 3.51 (s, 2H), 3.14-3.03 (m, 3H), 2.38 (s, 3H), 2.33 (s, 1H), 2.25-2.12 (m, 3H), 1.98 (s, 3H), 1.92-1.83 (m, 2H), 0.88 (t, J = 7.3 Hz, 3H).LCMS (ESI): Rt = 1.060 min, m / z found 856.2 [M-CF3COOH+H]+. Compound 043 3-(4-(3-(2,4-dihydroxy-5-methylphenyl)-5-hydroxy-4H-l, 2,4-triazol-4-yl)benzyl)-3-azabicyclo[3.1.0]hexan-6-yl((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, trifluoroacetic acid. ’H NMR (400 MHz, DMSO-tfc): 5 11.94 (s, 1H), 9.73 (s, 1H), 9.58 (s, 1H), 9.28 (s, 1H), 8.16 (s, 1H), 7.79 (d, J= 11.0 Hz, 1H), 7.53-7.40 (m, 2H), 7.32 (s, 1H), 7.25 (s, 2H), 6.97 (s, 1H), 6.52 (s, 1H), 6.23 (s, 1H), 5.43 (s, 2H), 5.325.12 (m, 3H), 4.45-4.21 (m, 3H), 3.78 (s, 1H), 3.52 (s, 2H), 3.08 (d, J= 48.1 Hz, 3H), 2.38 (s, 3H), 2.36-2.33 (m, 1H), 2.16 (d, J= 37.5 Hz, 3H), 1.98 (s, 3H), 1.91-1.83 (m, 2H), 0.87 (t, J= 7.3 Hz, 3H). LCMS (ESI): Rt = 1.080 min, m / z found 856.2 [M-CF3COOH+H]+. Compound 044 cf3cooh 2-(7-(4-(3-(2,4-dihydroxy-5-methylphenyl)-5-hydroxy-4H-l, 2,4-triazol-4-yl)benzyl)-2,7-diazaspiro[3.5]nonan-2-yl)-2-oxoethyl((9S)-9-ethyl-5-fhioro-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, trifluoroacetic acid, H NMR (400 MHz, DMSO-tfc) 5 11.94 (s, 1H), 9.58-9.45 (m, 2H), 9.29 (s, 1H), 8.19 (s, 1H), 7.79 (d, J= 10.9 Hz, 1H), 7.497.42 (m, 2H), 7.32 (d, J = 2.1 Hz, 1H), 7.26 (d, J= 7.9 Hz, 2H), 6.95 (s, 1H), 6.51 (s, 1H), 6.22 (s, 1H), 5.42 (s, 2H), 5.25 (d, J= 10.3 Hz, 3H), 4.53 (d, J= 7.0 Hz, 2H), 4.27 (s, 2H), 4.01 f(s, 1H), 3.92 (s, 1H), 3.79-3.60 (m, 3H), 3.15 (s, 3H), 2.95 (s, 2H), 2.39 (s, 3H), 2.19 (s, 2H), 2.08 (s, 2H), 1.97 (s, 3H), 1.86 (dd, J = 15.0, 7.7 Hz, 4H), 0.88 (t, J = 7.3 Hz, 3H). LCMS (ESI): Rt = 1.040 min, m / z found 941.1 [M-CF3COOH+H]+. Compound 045 CF3C00H 2-(7-(4-(3-(2,4-dihydroxy-5-methylphenyl)-5-hydroxy-4H-l,2,4-triazol-4-yl)benzyl)- 2,7-diazaspiro[3.5]nonan-2-yl)-2-oxoethyl((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, trifluoroacetic acid. H NMR (400 MHz, DMSO-tfc) 5 11.97 (s, 1H), 9.62-9.32 (m, 3H), 8.21 (s, 1H), 7.80 (d, J= 10.7 Hz, 1H), 7.47 (d, 7 = 7.9 Hz, 2H), 7.34 (s, 1H), 7.27 (d, J= 8.3 Hz, 2H), 7.07 (d, J= 51.0 Hz, 1H), 6.96 (s, 1H), 6.54 (s, 1H), 6.24 (s, 1H), 5.43 (s, 2H), 5.28 (s, 3H), 4.54 (s, 2H), 4.27 (s, 2H), 4.01 (s, 2H), 3.753.70 (m, 3H), 3.07-3.05 (m, 3H) 2.94 (d, J= 6.9 Hz, 2H), 2.40 (s, 3H), 2.20 (s, 2H), 1.98 (s, 3H), 1.89-1.79 (m, 4H), 0.88 (t, J= 7.5 Hz, 3H). LCMS (ESI): Rt = 1.060 min, m / z found 941.1 [M-CF3COOH+H]+. Compound 046 4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-l,2,4-triazol-4-yl)-N-(2-((2-(((S)-l-((2-(((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)amino)-2-oxoethyl)amino)-l-oxo-3-phenylpropan-2-yl)amino)-2-oxoethyl)amino)-2-oxoethyl)benzamide, trifluoroacetic acid. 1H NMR (400 MHz, CD3OD): 5 8.30-8.25 (m, 1H), 8.13-8.07 (m, 1H), 7.77 (d, J= 8.4 Hz, 2H), 7.58-7.55 (m, 2H), 7.25-7.14 (m, 7H), 6.90 (s, 1H), 6.17 (s, 1H), 5.57-5.52 (m, 2H), 5.34-5.31 (m, 1H), 5.20-5.15 (m, 1H), 4.954.88 (m, 1H), 4.45-4.36 (m, 1H), 3.93-3.47 (m, 6H), 3.17-2.96 (m, 4H), 2.37 (s, 3H), 2.252.18 (m, 1H), 1.95-1.87 (m, 2H), 1.05 (d, J= 6.8 Hz, 6H), 0.97 (t, J = 7.2 Hz, 3H). LCMS: (ESI) Rt = 0.933 min, m / z found 546.8 [M / 2+H]+. Compound 047 0 CF3C00H (trans)-8-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-l,2,4-triazol-4-yl)benzoyl)-8-azabicyclo[3.2.1]octan-3-yl((lS,9S)-9-ethyl-5-fhioro-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, trifluoroacetic acid. H NMR (400 MHz, DMSO-de): 5 12.03 (s, 1H), 9.65 (s, 1H), 9.40 (s, 1H), 8.03-7.98 (m, 1H), 7.90-7.76 (m, 1H), 7.55-7.50 (m, 2H), 7.32-7.25 (m, 4H), 6.88 (s, 1H), 6.56-6.52 (m, 1H), 6.27 (s, 1H), 5.45 (s, 2H), 5.23-5.17 (m, 4H), 4.70-4.66 (m, 1H), 4.10-4.07 (m, 1H), 3.26-3.23 (m, 1H), 3.12-3.00 (m, 2H), 2.39 (s, 3H), 2.21-1.80 (m, 12H), 1.05-0.95 (m, 6H), 0.92-0.87 (m, 3H). LCMS: (ESI) Rt = 1.019 min, m / z found 927.2 [M+H]+. Compound 048 2-((lS,4S)-5-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-l,2,4-triazol-4-yl)benzoyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl((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, trifluoroacetic acid. 'H NMR (400 MHz, DMSO-J6) 511.99 (s, 1H), 9.63-9.61 (m, 1H), 9.38-9.36 (m, 1H), 8.22-8.18 (m, 1H), 7.81-7.79 (m, 1H), 7.56-7.54 (m, 2H), 7.30-7.23 (m, 4H), 6.94-6.92 (m, 1H), 6.57-6.50 (m, 1H), 6.27-6.25 (m, 1H), 5.45-5.43 (m, 2H), 5.29-5.27 (m, 3H), 4.80-4.33 (m, 4H), 3.78-3.58 (m, 3H), 3.27-3.03 (m, 4H), 2.40 (s, 3H), 2.22-2.20 (m, 2H), 1.90-1.87 (m, 4H), 1.06-1.02 (m, 6H), 0.90-0.88 (m, 3H). LCMS (ESI): Rt = 0.699 min, m / z found 955.0 [M+H]+. Compound 049 cf3cooh (lR,3R,5S)-8-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-l,2,4-triazol-4-yl)benzoyl)-8-azabicyclo[3.2.1]octan-3-yl((lS,9S)-9-ethyl-5-fhioro-9-hydroxy-4-methyl-10,13-dioxo-l,2,3,9,10,12,13,15-octahydrobenzo[de]pyrano[3',4':6,7]indolizino[l,2-b]quinolin-l-yl)carbamate, trifluoroacetic acid. H NMR (400 MHz, DMSO-tfc): 512.02 (s, 1H), 9.65 (s, 1H), 9.42 (s, 1H), 7.99-7.95 (m, 1H), 7.81-7.78 (m, 1H), 7.56-7.48 (m, 2H), 7.32-7.25 (m, 3H), 6.89 (s, 1H), 6.68-6.44 (m, 1H), 6.29 (s, 1H), 5.49-5.39 (m, 2H), 5.295.07 (m, 4H), 4.65-4.60 (m, 1H), 3.97-3.95 (m, 1H), 3.25-3.21 (m, 1H), 3.17-3.00 (m, 2H), 2.40 (s, 3H), 2.21-1.82 (m, 12H), 1.08-1.00 (m, 6H), 0.91-0.88 (m, 3H). LCMS (ESI): Rt = 1.016 min, m / z found 927.2 [M+H]+. Compound 050 2-((lR,5S)-3-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-l,2,4-triazol-4-yl)benzoyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-oxoethyl((lS,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-l,2,3,9,10,12,13,15-octahydrobenzo[de]pyrano [3',4':6,7]indolizino[l,2-b]quinolin-l-yl)carbamate, trifluoroacetic acid. H NMR (400 MHz, DMSO-J6): 512.01 (s, 1H), 9.65 (s, 1H), 9.42 (s, 1H), 8.23-8.19 (m, 1H), 7.81-7.79 (m, 1H), 7.57-7.36 (m, 2H), 7.33 (s, 1H), 7.28-7.22 (m, 3H), 6.89 (s, 1H), 6.72-6.65 (m, 1H), 6.28 (s, 1H), 5.43 (s, 2H), 5.33-5.26 (m, 3H), 4.79-4.19 (m, 3H), 3.29-2.99 (m, 7H), 2.40 (s, 3H), 2.25-2.18 (m, 2H), 1.93-1.42 (m, 6H), 1.04-1.01 (m, 6H), 0.91-0.87 (m, 3H) LCMS (ESI): Rt = 0.649 min, m / z found 970.6 [M+H]+. Compound 051 2-(3-(4-(3-(2,4-dihydroxy-5-methylphenyl)-5-hydroxy-4H-l, 2,4-triazol-4-yl)benzyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)-2-oxoethyl((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, trifluoroacetic acid. H NMR (400 MHz, DMSO-tfc): 5 11.96 (s, 1H), 10.66 (br s, 1H), 9.62 (br s, 1H), 9.32 (br s, 1H), 8.47-8.31 (m, 1H), 7.86-7.75 (m, 1H), 7.73-7.49 (m, 2H), 7.39-7.19 (m, 5H), 7.01-6.93 (m, 1H), 6.58-6.50 (m, 1H), 6.24 (s, 1H), 5.44-5.22 (m, 6H), 4.74-4.38 (m, 8H), 2.41 (s, 3H), 2.30-2.05 (m, 4H), 1.98 (s, 3H), 1.93-1.79 (m, 4H), 0.95-0.88 (m, 3H). LCMS: (ESI) Rt = 0.770 min, m / z found 914.1 [M+H]+. Compound 052 2-((lR,5S)-3-(4-(3-(2,4-dihydroxy-5-methylphenyl)-5-hydroxy-4H-l,2,4-triazol-4-yl)benzyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-oxoethyl((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, trifluoroacetic acid. H NMR (400 MHz, DMSO-Je) 5 11.95 (s, 1H), 9.62 (br s, 1H), 9.30 (s, 1H), 8.25-8.19 (m, 1H), 7.83-7.80 (m, 1H), 7.58-7.44 (m, 1H), 7.35-7.25 (m, 3H), 6.97 (s, 1H), 6.68-6.42 (m, 1H), 6.24 (s, 1H), 5.44 (s, 2H), 5.35-5.24 (m, 3H), 4.80-4.11 (m, 4H), 3.41-2.93 (m, 8H), 2.42 (s, 3H), 2.32- 2.05 (m, 3H), 1.99 (s, 3H), 1.95-1.79 (m, 6H), 0.91 (t, J= 7.2 Hz, 3H). LCMS: (ESI) Rt = 0.792 min, m / z found 927.9 [M+H]+. Compound 053 cf3cooh 2-((lR,5S)-8-(4-(3-(2,4-dihydroxy-5-methylphenyl)-5-hydroxy-4H-l,2,4-triazol-4-yl)benzyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-oxoethyl((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, trifluoroacetic acid. H NMR (400 MHz, DMSO-( / 6) 6 11.97 (s, 1H), 10.10 (br s, 1H), 9.63 (s, 1H), 9.32 (s, 1H), 8.27-8.17 (m, 1H), 7.79 (d, J = 10.8 Hz, 1H), 7.61-7.47 (m, 2H), 7.36-7.21 (m, 3H), 6.97 (s, 1H), 6.605.50 (m, 1H), 6.23 (s, 1H), 5.41 (s, 2H), 5.35-5.17 (m, 4H), 5.07-4.92 (m, 1H), 4.75-4.62 (m, 1H), 4.34-4.11 (m, 3H), 3.93-3.78 (m, 3H), 3.57-3.50 (m, 1H), 3.25-3.05 (m, 3H), 2.38 (s, 3H), 2.32-1.97 (m, 5H), 1.98 (s, 3H), 1.88-1.81 (m, 2H), 0.88 (t, J= 7.2 Hz, 3H). LCMS: (ESI) Rt = 0.762 min, m / z found 927.9 [M+H]+. Compound 054 CF3C00H (S)-l-((lS,4S)-5-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)-l-oxopropan-2-yl((lS,9S)-9-ethyl-5-fluoro-9-hydroxy- 4-methyl-10,13-dioxo-l,2,3,9,10,12,13,15-octahydrobenzo[de]pyrano[3',4':6,7] indolizino[l,2-b]quinolin-l-yl)carbamate, trifluoroacetic acid. H NMR (400 MHz, DMSO-Je): 510.19-9.95 (m, 1H), 9.75-9.61 (m, 1H), 8.32-8.18 (m, 1H), 7.80-7.78 (m, 1H), 7.61-7.42 (m, 2H), 7.32 (s,lH), 7.11-6.96 (m, 1H), 6.71-6.33 (m, 1H), 5.50-5.40 (m, 2H), 5.32-5.08 (m, 4H), 5.01-4.70 (m, 5H), 4.65-4.27 (m, 2H), 3.89-3.51 (m, 4H), 3.30-2.98 (m, 6H), 2.40-2.28 (m, 4H), 2.28-1.98 (m, 3H), 1.95-1.75 (m, 2H), 1.50-1.32 (m, 3H), 1.19-1.03 (m, 6H), 1.00-0.82 (m, 3H). LCMS (ESI): Rt = 0.613 min, m / z found 942.6 [M+H]+. Compound 055 2-((lS,4S)-5-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-l,2,4-triazol-4-yl)benzyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl((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, trifluoroacetic acid. ’H NMR (400 MHz, DMSO-J6): 5 11.93 (s, 1H), 9.58 (m, 1H), 9.31 (s, 1H), 8.21-8.19 (m, 1H), 7.77-7.74 (m, 1H), 7.54-7.52 (m, 2H), 7.29 (s, 1H), 7.25-7.22 (m, 2H), 6.87-6.84 (m, 1H), 6.51-6.49 (m, 1H), 6.22 (s, 1H), 5.38 (s, 2H), 5.28-5.25 (m, 3H), 4.76-4.72 (m, 2H), 4.53-4.27 (m, 3H), 3.70-3.62 (m, 1H), 3.43-3.33 (m, 3H), 3.25-3.20 (m, 2H), 3.15-3.02 (m, 1H), 2.53-2.51 (m, 4H), 2.41-2.37 (m, 3H), 2.19-2.16 (m, 2H), 1.98-1.96 (m, 2H), 0.99-0.95 (m, 6H), 0.85 (t, J = 7.2 Hz, 3H). LCMS (ESI): Rt = 0.598 min, m / z found 941.6 [M+H]+. Compound 056 2-((3aS,7aR)-6-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-l,2,4-triazol-4-yl)benzyl)octahydro-lH-pyrrolo[2,3-c]pyridin-l-yl)-2-oxoethyl((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, trifluoroacetic acid. H NMR (400 MHz, DMSO-d6) 5 11.94 (s, 1H), 9.58-9.57 (m, 1H), 9.30-9.28 (m, 1H), 8.178.11 (m, 1H), 7.76-7.74 (m, 1H), 7.46-7.44 (m, 2H), 7.30-7.20 (m, 3H), 6.84-6.78 (m, 1H), 6.55-6.47 (m, 1H), 6.21-6.20 (m, 1H), 5.38 (s, 2H), 5.27-5.24 (m, 3H), 4.67-4.55 (m, 1H), 4.33-4.23 (m, 2H), 3.60-3.58 (m, 2H), 3.36-3.34 (m, 4H), 3.30-3.15 (m, 2H), 2.96-2.94 (m, 2H), 2.50-2.44 (m, 4H), 2.35 (s, 3H), 2.19-1.75 (m, 7H), 0.99-0.95 (m, 6H), 0.85-0.84 (m, 3H). LCMS (ESI): Rt = 0.607 min, m / z found 969.6 [M+H]+. Compound 057 2-((1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methyl)-2-azaspiro[3.3]heptan-6-yl((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, trifluoroacetic acid. H NMR (400 MHz, DMSO-dd) 5 10.21-10.04 (m, 1H), 9.73-9.68 (m, 1H), 8.08-8.03 (m, 1H), 7.81-7.78 (m, 1H), 7.54-7.49 (m, 4H), 7.33 (s, 1H), 7.28 (s, 1H), 7.15 (s, 1H), 7.08-7.03 (m, 2H), 6.64-6.43 (m, 1H), 5.43 (s, 2H), 5.29-5.13 (m, 3H), 4.91-4.83 (m, 6H), 4.28-4.11 (m, 6H), 3.13-3.10 (m, 6H), 2.812.77 (m, 3H), 2.39 (s, 3H), 2.17-2.07 (m, 2H), 1.90-1.85 (m, 4H), 1.81-1.72 (m, 2H), 1.44- 1.37 (m, 2H), 1.15 (d, J = 7.2 Hz, 6H), 0.90 (t, J = 7.2 Hz, 3H). LCMS (ESI): Rt = 0.764 min, m / z found 981.6 [M+H]+. Compound 058 cf3cooh 2-((lS,4S)-5-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl((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, trifluoroacetic acid. H NMR (400 MHz, DMSO-J6) 5 10.15-10.03 (m, 1H), 9.69 (s, 1H), 8.27-8.23 (m, 1H), 7.82-7.78 (m, 1H), 7.597.44 (m, 3H), 7.34-7.29 (m, 2H), 7.06 (s, 1H), 6.54 (s, 1H), 6.43 (s, 1H), 5.44-5.41 (m, 3H), 5.31-5.25 (m, 4H), 4.83-4.73 (m, 8H), 3.19-3.03 (m, 8H), 2.40 (s, 3H), 2.24-2.16 (m, 3H), 1.94-1.84 (m, 2H), 1.15 (d, J = 6.4 Hz, 6H), 0.90 (t, J = 6.4 Hz, 3H). LCMS (ESI): Rt = 0.648 min, m / z found 927.6 [M+H]+. Compound 059 CF3C00H 2-((lR,5S)-3-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-3,8- diazabicyclo[3.2.1]octan-8-yl)-2-oxoethyl((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, trifluoroacetic acid. H NMR (400 MHz, DMSO-tfc) 5 10.06 (s, 1H), 9.65 (s, 1H), 8.25-8.25 (m, 1H), 7.82-7.79 (m, 1H), 7.65-7.34 (m, 3H), 7.087.04 (m, 1H), 6.41 (s, 1H), 5.44 (s, 2H), 5.31-5.24 (m, 3H), 4.82-4.73 (m, 6H), 4.62-4.35 (m, 2H), 3.37-3.07 (m, 10H), 2.41 (s, 3H), 2.25-2.17 (m, 3H), 2.03-1.85 (m, 7H), 1.14 (d, J = 6.8 Hz, 6H), 0.90 (t, J = 6.8 Hz, 3H). LCMS (ESI): Rt = 0.648 min, m / z found 941.6 [M+H]+. Compound 060 F CF3COOH 2-((1-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)azetidin-3-yl)methyl)-2-azaspiro[3.3]heptan-6-yl((lS,9S)-9-ethyl-5-fhioro-9-hydroxy-4-methyl-10,13-dioxo-l,2,3,9,10,12,13,15-octahydrobenzo[de]pyrano[3',4':6,7]indolizino[l,2-b]quinolin-l-yl)carbamate, trifluoroacetic acid. H NMR (400 MHz, DMSO-t / e) 8 10.5110.28 (m, 1H), 10.10-1.05 (m, 1H), 9.68 (s, 1H), 8.03 (d, J= 8.8 Hz, 1H), 7.80 (d, J= 10.8 Hz, 1H), 7.53-7.33 (m, 4H), 7.05 (s, 1H), 6.56 (s, 1H), 6.42 (s, 1H), 5.43 (s, 2H), 5.32-5.09 (m, 3H), 4.92-4.81 (m, 5H), 4.44-3.88 (m, 10H), 3.50-3.44 (m, 2H), 3.30-2.65 (m, 7H), 2.40 (s, 3H), 2.31-1.98 (m, 3H), 1.94-1.83 (m, 2H), 1.15 (d, J = 6.8 Hz, 6H), 0.90 (t, J = 7.2 Hz, 3H). LCMS (ESI): Rt = 1.460 min, m / z found 952.6 [M+H]+. Compound 061 CF3COOH 2-((1-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-l, 2,4-triazol-4-yl)benzoyl)azetidin-3-yl)methyl)-2-azaspiro[3.3]heptan-6-yl((lS,9S)-9-ethyl-5-fhioro-9-hydroxy-4-methyl-10,13-dioxo-l,2,3,9,10,12,13,15-octahydrobenzo[de]pyrano [3',4':6,7]indolizino[l,2-b]quinolin-l-yl)carbamate, trifluoroacetic acid. H NMR (400 MHz, DMSO-Je) 5 12.20 (s, 1H), 9.90-9.80 (m, 2H), 9.55 (s, 1H), 8.21 (d, J= 8.8 Hz, 1H), 7.99 (d, J = 10.8 Hz, 1H), 7.82 (d, J = 8.4 Hz, 2H), 7.53 (s, 1H), 7.46 (d, J = 8.4 Hz, 2H), 7.12 (s, 1H), 6.77-6.73 (m, 1H), 6.46 (s, 1H), 5.64 (s, 2H), 5.54-5.27 (m, 3H), 5.10-5.07 (m, 1H), 4.65-5.20 (m, 1H), 4.46-4.23 (m, 6H), 4.08-3.95 (m, 1H), 3.53-3.19 (m, 5H), 3.10-2.94 (m, 2H), 2.87-2.80 (m, 1H), 2.61-2.55 (m, 4H), 2.51-2.24 (m, 3H), 2.14-2.02 (m, 2H), 1.24 (d, J= 6.8 Hz, 6H), 1.09 (t, J= 7.2 Hz, 3H). LCMS (ESI): Rt = 1.201 min, m / z found 980.6 [M+H]+. Compound 062 cf3cooh 2-((lR,4R)-5-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl((lS,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-l,2,3,9,10,12,13,15-octahydrobenzo[de]pyrano[3',4':6,7] indolizino[l,2-b]quinolin-l-yl)carbamate, trifluoroacetic acid. H NMR (400 MHz, DMSO-6?6) 5 10.37-9.95 (m, 1H), 9.75-9.53 (m, 2H), 8.37-8.16 (m, 1H), 7.81 (d, J = 10.8 Hz, 1H), 7.65-7.41 (m, 3H), 7.34 (s, 1H), 7.05 (s, 1H), 6.58-6.54 (m, 1H), 6.42 (s, 1H), 5.44 (s, 2H), 5.35-5.21 (m, 3H), 4.97-4.02 (m, 11H), 3.68 (s, 2H), 3.31-3.07 (m, 5H), 2.40 (s, 3H), 2.27-2.07 (m, 3H), 1.98-1.80 (m, 2H), 1.15 (d, J = 6.8 Hz, 6H), 0.90 (t, J= 7.2 Hz, 3H). LCMS (ESI): Rt = 0.640 min, m / z found 927.7 [M+H]+. Compound 063 2-((lS,4S)-5-(4-(3-(2,4-dihydroxy-5-methylphenyl)-5-hydroxy-4H-l,2,4-triazol-4-yl)benzyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl((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, trifluoroacetic acid. H NMR (400 MHz, DMSO-de) 5 10.10 (s, 1H), 9.68 (s, 1H), 8.25-8.23 (m, 1H), 7.82-7.80 (m, 1H), 7.597.51 (m, 2H), 7.34 (s, 1H), 7.07-7.00 (m, 1H), 6.56-6.44 (m, 1H), 6.43 (s, 1H), 5.43 (s, 2H), 5.31-5.28 (m, 3H), 5.00-4.86 (m, 1H), 4.86-4.75 (m, 4H), 4.73-4.70 (m, 1H), 4.24-4.00 (m, 2H), 3.97-3.88 (m, 2H), 3.80-3.66 (m, 1H), 3.60-3.46 (m, 4H), 3.29-3.15 (m, 2H), 3.12-3.09 (m, 2H), 2.54-2.47 (m, 3H), 2.41 (s, 3H), 2.14-2.02 (m, 3H), 1.89-1.75 (m, 2H), 1.16 (d, J = 6.8 Hz, 6H), 0.90 (t, J = 7.2 Hz, 3H). LCMS (ESI): Rt = 1.061 min, m / z found 940.6 [M+H]+. Compound 064 2-(3-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-l, 2,4-triazol-4-yl)benzyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)-2-oxoethyl((lS,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-l,2,3,9,10,12,13,15-octahydrobenzo[de]pyrano[3',4':6,7] indolizino[l,2-b]quinolin-l-yl)carbamate, trifluoroacetic acid. H NMR (400 MHz, DMSO-d6): 5 11.97 (s, 1H), 10.45-10.35 (m, 1H), 9.61 (s,lH), 9.34 (s, 1H), 8.47-8.30 (m, 1H), 7.85-7.75 (m, 1H), 7.71-7.41 (m, 2H), 7.38-7.21 (m, 3H), 6.98-6.86 (m, 1H), 6.60-6.50 (m, 1H), 6.24 (s, 1H), 5.57-5.18 (m, 5H), 4.70-4.35 (m, 5H), 4.09-3.65 (m, 4H), 3.32-3.13 (m, 2H), 3.06-2.95 (m, 1H), 2.77-2.62 (m, 1H), 2.39 (s, 3H), 2.30-2.13 (m, 2H), 2.09-1.97 (m, 1H), 1.95-1.80 (m, 2H), 1.06-0.97 (m, 6H), 0.93-0.85 (m, 3H). LCMS (ESI): Rt = 0.890 min, m / z found 941.6 [M+H]+. Compound 065 2-((3aS,7aR)-6-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl) octahydro-lH-pyrrolo[2,3-c]pyridin-l-yl)-2-oxoethyl((lS,9S)-9-ethyl-5-fhioro-9-hydroxy-4-methyl-10,13-dioxo-l,2,3,9,10,12,13,15-octahydrobenzo[de]pyrano [3',4':6,7]indolizino[l,2-b]quinolin-l-yl)carbamate, trifluoroacetic acid. H NMR (400 MHz, DMSO-Je): 510.20-9.97 (m, 1H), 9.85-9.42 (m, 2H), 8.29-8.12 (m, 1H), 7.88-7.76 (m, 1H), 7.60-7.32 (m, 4H), 7.15-7.02 (m, 1H), 6.69-6.48 (m, 1H), 6.41 (s, 1H), 5.48-5.21 (m, 5H), 4.97-4.12 (m, 8H), 3.78-3.51 (m, 5H), 3.31-3.01 (m, 5H), 2.91-2.78 (m, 1H), 2.58-2.56 (m, 2H), 2.40 (s, 3H), 2.26-1.79 (m, 7H), 1.22-1.08 (m, 6H), 0.95-0.83 (m, 3H). LCMS (ESI): Rt = 1.011 min, m / z found 956.0 [M+H]+. Compound 066 2-((lR,5S)-8-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-l,2,4-triazol-4-yl)benzyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-oxoethyl((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, trifluoroacetic acid. H NMR (400 MHz, DMSO-d6) 5 12.00 (s, 1H), 10.15-1.08 (m, 1H), 9.65 (s, 1H), 9.37 (s, 1H), 8.27-8.23 (m, 1H), 7.82 (d, J = 10.8 Hz, 1H), 7.65-7.58 (m, 2H), 7.34-7.25 (m, 3H), 7.01-6.90 (m, 1H), 6.55 (s, 1H), 6.27 (s, 1H), 5.44 (s, 2H), 5.36-5.28 (m, 3H), 5.03-4.97 (m, 1H), 4.724.67 (m, 1H), 4.30-4.22 (m, 2H), 3.95-3.80 (m, 3H), 3.60-3.53 (m, 2H), 3.34-2.99 (m, 6H), 2.41 (s, 3H), 2.32-2.05 (m, 4H), 1.95-1.84 (m, 2H), 1.03 (d, J= 6.8 Hz, 6H), 0.90 (t, J= 7.2 Hz, 3H). LCMS (ESI): Rt = 0.981 min, m / z found 955.3 [M+H]+. Compound 067 cf3cooh 0 2-((lR,5S)-3-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-l,2,4-triazol-4-yl)benzyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-oxoethyl((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, trifluoroacetic acid. H NMR (400 MHz, DMSO-J6) 5 11.97 (s, 1H), 9.64 (s, 1H), 9.36 (s, 1H), 8.25-8.20 (m, 1H), 7.81 (d, J = 10.8 Hz, 1H), 7.48 (s, 2H), 7.34 (s, 1H), 7.26-7.23 (m, 2H), 6.87 (s, 1H), 6.27 (s, 1H), 5.44 (s, 2H), 5.34-5.24 (m, 3H), 4.83-4.72 (m, 2H), 4.59-3.72 (m, 5H), 3.30-3.13 (m, 4H), 3.072.96 (m, 2H), 2.62-2.52 (m, 2H), 2.41 (s, 3H), 2.24-2.18 (m, 2H), 2.05-1.78 (m, 6H), 1.01 (d, J= 6.8 Hz, 6H), 0.90 (t, J= 7.2 Hz, 3H). LCMS (ESI): Rt = 0.980 min, m / z found 955.4 [M+H]+. Compound 068 OH 0 2-((3aR,6aR)-5-(4-(3-(2,4-dihydroxy-5-methylphenyl)-5-hydroxy-4H-l,2,4-triazol-4-yl)benzyl)hexahydropyrrolo[3,4-b]pyrrol-l(2H)-yl)-2-oxoethyl((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, trifluoroacetic acid. H NMR (400 MHz, DMSO-d6) 5 11.94 (s, 1H), 10.24-10.04 (m, 1H), 9.60 (s, 1H), 9.30 (s, 1H), 8.31-8.17 (m, 1H), 7.81-7.75 (m, 1H), 7.55-7.43 (m, 2H), 7.35-7.24 (m, 3H), 6.98-6.95 (m, 1H), 6.53 (s, 1H), 6.22 (s, 1H), 5.46-5.40 (m, 2H), 5.35-5.27 (m, 3H), 4.80-4.24 (m, 5H), 4.03-3.52 (m, 4H), 3.28-2.96 (m, 6H), 2.39 (s, 3H), 2.19 (s, 2H), 1.97-1.84 (m, 6H), 0.92-0.85 (m, 3H). LCMS (ESI): Rt = 0.911 min, m / z found 927.3 [M+H]+. Compound 069 (2S)-l-(3-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)-l-oxopropan-2-yl((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, trifluoroacetic acid. H NMR (400 MHz, DMSO-J6) 5 10.38-10.33 (m, 1H), 10.10-10.01 (m, 1H), 9.67 (s, 1H), 8.70-8.65 (m, 1H), 7.61-7.53 (m, 1H), 7.37-7.33 (m, 2H), 7.26 (s, 1H), 7.05 (s, 1H), 6.60-6.52 (m, 1H), 6.42 (s, 1H), 5.52-5.45 (m, 2H), 5.30-5.22 (m, 2H), 4.92-4.78 (m, 4H), 4.58 (s, 1H), 4.34-4.07 (m, 2H), 3.65-3.57 (m, 1H), 3.34-3.06 (m, 8H), 2.40-2.31 (m, 8H), 1.93-1.81 (m, 3H), 1.46-1.36 (m, 3H), 1.15 (d, J = 6.8 Hz, 6H), 0.89 (t, J = 6.8 Hz, 3H). LCMS (ESI): Rt = 0.665 min, m / z found 941.6 [M+H]+. Compound 070 CF,COOH 2-(3-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)-2-oxoethyl((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, trifluoroacetic acid. H NMR (400 MHz, DMSO-tfc) 8 10.52-10.42 (m, 1H), 10.15-10.05 (m, 1H), 9.68 (s, 1H), 8.45-8.40 (m, 1H), 7.83-7.00 (m, 5H), 6.64-6.42 (m, 1H), 5.45-5.21 (m, 3H), 4.84-4.39 (m, 6H), 3.25-3.05 (m, 9H), 2.41-1.90 (m, 15H), 1.26-1.14 (m, 6H), 0.99-0.87 (m, 3H). LCMS (ESI): Rt = 0.668 min, m / z found 927.6 [M+H]+. Compound 071 cf3cooh 2-((1-(4-(3-(2,4-dihydroxy-5-methylphenyl)-5-hydroxy-4H-l, 2,4-triazol-4-yl)benzyl)piperidin-4-yl)methyl)-2-azaspiro[3.3]heptan-6-yl((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, trifluoroacetic acid. H NMR (400 MHz, DMSO-J6) 8 11.98 (s, 1H), 10.13-9.85 (m, 1H), 9.72-9.62 (m, 1H), 9.36 (s, 1H), 8.04-7.97 (m, 1H), 7.81-7.76 (m, 1H), 7.50-7.45 (m, 2H), 7.34 (s, 1H), 7.30-7.26 (m, 2H), 6.96 (s, 1H), 6.68-6.44 (m, 1H), 6.26 (s, 1H), 5.44 (s, 2H), 5.35-5.13 (m, 3H), 4.93-4.86 (m, 1H), 4.36-4.08 (m, 6H), 3.39-3.24 (m, 4H), 3.16-3.06 (m, 3H), 2.97-2.63 (m, 3H), 2.48-2.39 (m, 5H), 2.31-2.23 (m, 2H), 2.15-2.03 (m, 2H), 1.95-1.86 (m, 4H), 1.82-1.74 (m, 2H), 1.431.34 (m, 2H), 0.90 (t, J = 7.2 Hz, 3H). LCMS (ESI): Rt = 0.948 min, m / z found 967.4 [M+H]+. Compound 072 cf3cooh 2-((1-(4-(3-(2,4-dihydroxy-5-methylphenyl)-5-hydroxy-4H-l, 2,4-triazol-4-yl)benzyl)azetidin-3-yl)methyl)-2-azaspiro[3.3]heptan-6-yl((lS,9S)-9-ethyl-5-fhioro-9-hydroxy-4-methyl-10,13-dioxo-l,2,3,9,10,12,13,15-octahydrobenzo[de]pyrano [3',4':6,7]indolizino[l,2-b]quinolin-l-yl)carbamate, trifluoroacetic acid. H NMR (400 MHz, DMSO-Je) 5 11.96 (s, 1H), 10.53-9.92 (m, 1H), 9.64 (s, 1H), 9.34 (s, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.80 (d, J = 10.8 Hz, 1H), 7.47-7.36 (m, 2H), 7.34 (s, 1H), 7.28-7.25 (m , 2H), 6.97 (s, 1H), 6.56 (s, 1H), 6.25 (s, 1H), 5.44 (s, 2H), 5.33-5.11 (m, 3H), 4.96-4.81 (m, 1H), 4.51-3.86 (m, 10H), 3.25-2.65 (m, 6H), 2.48-2.03 (m, 8H), 1.99 (s, 3H), 1.95-1.83 (m, 2H), 0.90 (t, J = 7.2 Hz, 3H). LCMS (ESI): Rt = 0.900 min, m / z found 938.6 [M+H]+. Compound 073 (S)-l-((lR,5S)-3-(4-(3-(2,4-dihydroxy-5-methylphenyl)-5-hydroxy-4H-l,2,4-triazol-4-yl)benzyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-l-oxopropan-2-yl((lS,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-l,2,3,9,10,12,13,15-octahydrobenzo[de]pyrano [3',4':6,7]indolizino[l,2-b]quinolin-l-yl)carbamate, trifluoroacetic acid. H NMR (400 MHz, DMSO-Je) 5 11.95-11.89 (m, 1H), 9.60 (s, 1H), 9.31 (s, 1H), 8.25-8.20 (m, 1H), 7.80 (d, J= 10.8 Hz, 1H), 7.61-7.09 (m, 5H), 7.03-6.86 (m, 1H), 6.60-5.50 (m, 1H), 6.24 (s, 1H), 5.44 (s, 2H), 5.38-5.17 (m, 4H), 4.86-4.01 (m, 3H), 3.43-3.04 (m, 8H), 2.40 (s, 3H), 2.262.07 (m, 3H), 2.05-1.76 (m, 9H), 1.46-1.32 (m, 3H), 0.89 (t, J= 7.2 Hz, 3H). LCMS (ESI): Rt = 0.896 min, m / z found 941.3 [M+H]+. Compound 074 (S)-l-((lR,5S)-3-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-l-oxopropan-2-yl((lS,9S)-9-ethyl-5-fhioro-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, trifluoroacetic acid. H NMR (400 MHz, DMSO-de) 5 10.30-10.01 (m, 1H), 9.65 (s, 1H), 8.33-8.20 (m, 1H), 7.86-7.78 (m, 1H), 7.507.34 (m, 3H), 7.08-7.05 (m, 1H), 6.68-6.38 (m, 1H), 5.44 (s, 2H), 5.37-5.18 (m, 3H), 4.824.52 (m, 5H), 4.31-3.50 (m, 8H), 3.30-3.06 (m, 3H), 2.67-2.52 (m, 4H), 2.39 (s, 3H), 2.282.10 (m, 2H), 2.05-1.77 (m, 5H), 1.44-1.33 (m, 3H), 1.16-1.06 (m, 6H), 0.89 (t, J= 7.2 Hz, 3H). LCMS (ESI): Rt = 0.985 min, m / z found 955.6 [M+H]+. Compound 075 (2S)-l-(3-(4-(3-(2,4-dihydroxy-5-methylphenyl)-5-hydroxy-4H-l,2,4-triazol-4-yl)benzyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)-l-oxopropan-2-yl((lS,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-l,2,3,9,10,12,13,15-octahydrobenzo[de] pyrano[3',4':6,7]indolizino[l,2-b]quinolin-l-yl)carbamate, trifluoroacetic acid. H NMR (400 MHz, DMSO-J6) 5 11.95 (s, 1H), 10.30-10.25 (s, 1H), 9.64-9.56 (m, 1H), 9.369.28 (m, 1H), 8.55-8.49 (m, 1H), 7.88-7.20 (m, 6H), 7.01-6.94 (m, 1H), 6.55 (s, 1H), 6.266.22 (m, 1H), 5.53-4.87 (m, 6H), 4.71-3.55 (m, 7H), 3.32-3.10 (m, 3H), 2.74-2.62 (m, 1H), 2.41-2.19 (m, 5H), 2.02-1.84 (m, 6H), 1.47-1.32 (m, 3H), 0.89 (t, J= 7.2 Hz , 3H). LCMS (ESI): Rt = 0.888 min, m / z found 927.3 [M+H]+. Compound 076 2-((1-((2-(2,4-dihydroxy-5-methylbenzoyl)isoindolin-5-yl)methyl)piperidin-4-yl)methyl)-2-azaspiro[3.3]heptan-6-yl((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, trifluoroacetic acid. H NMR (400 MHz, DMSO-tfc) 5 10.15 (s, 1H), 10.08-9.83 (m, 1H), 9.71 (s, 1H), 8.07-8.02 (m, 1H), 7.84-7.78 (m, 1H), 7.657.42 (m, 3H), 7.34 (s, 1H), 7.07 (s, 1H), 6.56 (s, 1H), 6.43 (s, 1H), 5.44 (s, 2H), 5.30-5.13 (m, 3H), 4.92-4.84 (m, 5H), 4.30-4.12 (m, 6H), 3.29-3.22 (m, 2H), 3.16-3.07 (m, 3H), 2.972.78 (m, 3H), 2.68-2.55 (m, 2H), 2.40 (s, 3H), 2.31-2.22 (m, 2H), 2.14-2.06 (m, 4H), 1.951.71 (m, 6H), 1.46-1.33 (m, 2H), 0.90 (t, J = 7.2 Hz, 3H). LCMS (ESI): Rt = 0.936 min, m / z found 953.4 [M+H]+. Compound 077 2-((lS,4S)-5-(4-(3-(2,4-dihydroxy-5-methylphenyl)-5-hydroxy-4H-l,2,4-triazol-4-yl)benzyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl((lS,9S)-9-ethyl-5-fhioro-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, trifluoroacetic acid. H NMR (400 MHz, DMSO-d6) 5 11.94 (s, 1H), 9.71-9.59 (m, 2H), 9.30-9.28 (m, 1H), 8.23-8.21 (m, 1H), 7.81-7.78 (m, 1H), 7.55-7.53 (m, 2H), 7.32 (s, 1H), 7.27-7.25 (m, 2H), 6.97-6.95 (m, 1H), 6.54-6.52 (m, 1H), 6.22 (s, 1H), 5.42 (s, 2H), 5.28-5.25 (m, 3H), 4.79-4.76 (m, 2H), 4.514.39 (m, 2H), 4.29-4.27 (m, 1H), 3.70-3.62 (m, 1H), 3.43-3.41 (m, 2H), 3.17-3.13 (m, 4H), 2.53-2.51 (m, 2H), 2.41-2.37 (m, 3H), 2.19-2.16 (m, 2H), 1.98-1.96 (m, 3H), 1.88-1.86 (m, 2H), 0.88 (t, J= 7.2 Hz, 3H). LCMS (ESI): Rt = 0.842 min, m / z found 913.2 [M+H]+. Compound 078 cf3cooh 2-((lR,4R)-5-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-l,2,4-triazol-4-yl)benzyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl((lS,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-l,2,3,9,10,12,13,15-octahydrobenzo[de]pyrano [3',4':6,7]indolizino[l,2-b]quinolin-l-yl)carbamate, trifluoroacetic acid. H NMR (400 MHz, DMSO-J6): 5 11.97 (s, 1H), 9.90-9.49 (m, 2H), 9.40-9.28 (m, 1H), 8.24-8.18 (m, 1H), 7.80-7.73 (m, 1H), 7.60-7.55 (s, 1H), 7.32-7.25 (m, 3H), 6.93-6.80 (m,lH), 6.52 (s, 1H), 6.28-6.19 (m, 1H), 5.41 (s, 2H), 5.35-5.14 (m, 3H), 4.89-4.20 (m, 6H), 3.86-3.58 (m, 4H), 3.28-2.79 (m, 6H), 2.38 (s, 3H), 2.29-2.10 (m, 2H), 1.92-1.82 (m, 2H), 1.05-1.90 (m, 6H), 0.92-0.85 (m, 3H). LCMS (ESI): Rt = 0.924 min, m / z found 941.4 [M+H]+. Compound 079 cf3cooh (S)-l-((lR,4R)-5-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-l,2,4-triazol-4-yl)benzyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-l-oxopropan-2-yl((lS,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-l,2,3,9,10,12,13,15-octahydrobenzo[de]pyrano [3',4':6,7]indolizino[l,2-b]quinolin-l-yl)carbamate, trifluoroacetic acid. H NMR (400 MHz, DMSO-tfc): 512.03-11.90 (m, 1H), 9.78-9.48 (m, 2H), 9.43-9.26 (m, 1H), 8.45-8.20 (m, 1H), 7.86-7.72 (m, 1H), 7.67-7.49 (m, 1H), 7.41-7.17 (m, 3H), 6.93-6.76 (m, 1H), 6.52 (s, 1H), 6.34-6.15 (m, 1H), 5.41 (s, 2H), 5.31-4.97 (m, 4H), 4.29-4.21 (m, 4H), 3.95-3.41 (m, 4H), 3.31-2.84 (m, 6H), 2.37 (s, 3H), 2.15-2.06 (m, 2H), 1.92-1.76 (m, 2H), 1.50-1.23 (m, 3H), 1.07-0.89 (m, 6H), 0.87-0.75 (m, 3H). LCMS (ESI): Rt = 0.920 min, m / z found 956.4 [M+H]+. Compound 080 cf3cooh 2-((3aR,6aR)-5-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-l,2,4-triazol-4-yl)benzyl)hexahydropyrrolo[3,4-b]pyrrol-l(2H)-yl)-2-oxoethyl((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, trifluoroacetic acid. H NMR (400 MHz, DMSO-J6) 5 11.96 (s, 1H), 10.23-10.00 (m, 1H), 9.60 (s, 1H), 9.34 (s, 1H), 8.31-8.17 (m, 1H), 7.81-7.78 (m, 1H), 7.60-7.41 (m, 2H), 7.34-7.32 (m, 1H), 7.27-7.25 (m, 2H), 6.89-6.87 (m, 1H), 6.53 (s, 1H), 6.26-6.24 (m, 1H), 5.43 (s, 2H), 5.29-5.26 (m, 3H), 4.77-4.66 (m, 2H), 4.63-4.37 (m, 2H), 3.81-3.78 (m, 1H), 3.52-3.48 (m, 2H), 3.24-3.18 (m, 4H), 3.06-2.94 (m, 2H), 2.53-2.51 (m, 3H), 2.42-2.39 (m, 3H), 2.20-2.18 (m, 2H), 1.89-1.86 (m, 3H), 1.01-0.99 (m, 6H), 0.89-0.86 (m, 3H). LCMS (ESI): Rt = 0.908 min, m / z found 955.4 [M+H]+. Compound 081 2-(cis)-5-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl) hexahydropyrrolo[3,4-b]pyrrol-l(2H)-yl)-2-oxoethyl((lS,9S)-9-ethyl-5-fhioro-9-hydroxy-4-methyl-10,13-dioxo-l,2,3,9,10,12,13,15-octahydrobenzo[de]pyrano [3',4':6,7]indolizino[l,2-b]quinolin-l-yl)carbamate, trifluoroacetic acid. H NMR (400 MHz, DMSO-de): 5 10.25-9.98 (m, 1H), 9.66 (s, 1H), 8.36-8.14 (m, 1H), 7.88-7.73 (m, 1H), 7.64-7.29 (m, 4H), 7.12-6.96 (m, 1H), 6.68-6.45 (m, 1H), 6.42 (s, 1H), 5.43 (s, 2H), 5.385.17 (m, 3H), 4.94-4.26 (m, 8H), 3.94-3.50 (m, 4H), 3.30-2.95 (m, 6H), 2.56-2.52 (m, 2H), 2.40 (s, 3H), 2.27-1.73 (m, 6H), 1.23-1.07 (m, 6H), 1.01-0.78 (m, 3H). LCMS (ESI): Rt = 1.010 min, m / z found 942.0 [M+H]+. Compound 082 (S)-l-((lR,5S)-8-(4-(3-(2,4-dihydroxy-5-methylphenyl)-5-hydroxy-4H-l,2,4-triazol-4-yl)benzyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-l-oxopropan-2-yl((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, trifluoroacetic acid. ’H NMR (400 MHz, DMSO-J6) 5 12.00 (s, 1H), 10.22-9.98 (m, 1H), 9.66 (s, 1H), 9.35 (s, 1H), 8.28-8.23 (m, 1H), 7.80 (d, J= 10.8 Hz, 1H), 7.59-7.56 (m, 2H), 7.34-7.29 (m, 3H), 6.99 (s, 1H), 6.68-6.45 (m, 1H), 6.25 (s, 1H), 5.54-5.44 (m, 3H), 5.35-5.17 (m, 4H), 4.40-4.87 (m, 8H), 3.16-3.03 (m, 2H), 2.40 (s, 3H), 2.32-2.11 (m, 5H), 2.00 (s, 3H), 1.931.85 (m, 2H), 1.44-1.32 (m, 3H), 0.89 (t, J= 7.2 Hz, 3H). LCMS (ESI): Rt = 1.365 min, m / z found 940.8 [M+H]+. Compound 083 (S)-l-((3aR,6aR)-5-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl) hexahydropyrrolo[3,4-b]pyrrol-l(2H)-yl)-l-oxopropan-2-yl((lS,9S)-9-ethyl-5-fhioro-9-hydroxy-4-methyl-10,13-dioxo-l,2,3,9,10,12,13,15-octahydrobenzo[de]pyrano [3',4':6,7]indolizino[l,2-b]quinolin-l-yl)carbamate, trifluoroacetic acid. H NMR(400 MHz, DMSO-de): 510.56-9.93 (m, 2H), 9.76-9.56 (m, 1H), 8.31-8.13 (m, 1H), 7.84-7.70 (m, 1H), 7.62-7.23 (m, 4H), 7.17-6.95 (m,lH), 6.63-6.45 (m, 1H), 6.40 (s, 1H), 5.41 (s, 2H), 5.35-5.14 (m, 4H), 4.91-4.69 (m, 3H), 4.60-4.24 (m, 3H), 4.01-3.51 (m, 5H), 3.28-2.84 (m, 6H), 2.37 (s, 3H), 2.20-1.76 (m, 6H), 1.40-1.24 (m, 3H), 1.23-1.07 (m, 6H), 0.95-0.78 (m, 3H). LCMS (ESI): Rt = 1.008 min, m / z found 956.4 [M+H]+. Compound 084 2-((lR,4R)-5-(4-(3-(2,4-dihydroxy-5-methylphenyl)-5-hydroxy-4H-l,2,4-triazol-4-yl)benzyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-oxoethyl((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, trifluoroacetic acid. H NMR (400 MHz, DMSO-tfc) 5 11.95 (s, 1H), 9.61 (s, 1H), 9.34-9.29 (m, 1H), 8.24-8.19 (m, 1H), 7.79 (d, J = 10.8 Hz, 1H), 7.64-7.54 (m, 2H), 7.32 (s, 1H), 7.27-7.24 (m, 2H), 6.98-6.96 (m, 1H), 6.53 (s, 1H), 6.25-6.22 (m, 1H), 5.42 (s, 2H), 5.27-5.20 (m, 3H), 4.84-3.4.69 (m, 2H), 4.654.4.49 (m, 2H), 4.40-4.15 (m, 2H), 3.75-3.43 (m, 4H), 3.28-3.09 (m, 4H), 2.39 (s, 3H), 2.19-2.02 (m, 3H), 1.97 (s, 3H), 1.93-1.82 (m, 2H), 0.88 (t, J = 7.2 Hz, 3H). LCMS (ESI): Rt = 0.853 min, m / z found 913.2 [M+H]+. Compound 085 (S)-l-((lR,4R)-5-(4-(3-(2,4-dihydroxy-5-methylphenyl)-5-hydroxy-4H-l,2,4-triazol-4-yl)benzyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-l-oxopropan-2-yl((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, trifluoroacetic acid. *H NMR (400 MHz, DMSO-d6) 5 11.95 (s, 1H), 9.67-9.58 (m, 1H), 9.32-9.26 (m, 1H), 8.38-8.20 (m, 1H), 7.78 (d, J= 10.8 Hz, 1H), 7.62-7.55 (m, 2H), 7.31-7.24 (m, 3H), 6.98-6.90 (m, 1H), 6.53 (s, 1H), 6.23-6.16 (m, 1H), 5.42-5.02 (m, 7H), 4.79-4.26 (m, 5H), 3.92-3.55 (m, 6H), 2.42-2.37 (m, 3H), 2.27-2.06 (m, 3H), 1.96 (s, 3H), 1.89-1.76 (m, 2H), 1.46-1.27 (m, 3H), 0.88 (t, J= 7.2 Hz, 3H). LCMS (ESI): Rt = 0.855 min, m / z found 927.3 [M+H]+. Compound 086 4-((S)-2-((S)-2-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-l,2,4-triazol-4-yl)benzamido)-3-methylbutanamido)-5-ureidopentanamido)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, trifluoroacetic acid. H NMR (400 MHz, DMSO-d6) 5 11.98 (s, 1H), 10.02 (s, 1H), 9.59 (s, 1H), 9.32 (s, 1H), 8.28 (d, J = 8.4 Hz, 1H), 8.19 (d, J = 7.6 Hz, 1H), 8.05 (d, J= 8.8 Hz, 1H), 7.87 (d, J= 8.8 Hz, 2H), 7.77 (d, J= 11.2 Hz, 1H), 7.60 (d, J= 8.4 Hz, 2H), 7.36 (d, J= 8.4 Hz, 2H), 7.31 (s, 1H), 7.23 (d, J = 8.8 Hz, 2H), 6.97 (s, 1H), 6.22 (s, 1H), 6.00 (br s, 1H), 5.44 (s, 2H), 5.325.27 (m, 3H), 5.08 (s, 2H), 4.43-4.38 (m, 1H), 4.32 (t, J= 8.0 Hz, 1H), 3.17-2.90 (m, 6H), 2.37 (s, 3H), 2.22-1.97 (m, 4H), 1.92-1.81 (m, 2H), 1.73-1.56 (m, 2H), 1.52-1.29 (m, 4H), 1.05 (d, J= 6.8 Hz, 6H), 0.93-0.85 (m, 9H). LCMS (ESI): Rt = 1.031 min, m / z found 1178.3 [M+H]+. Compound 087 cf3cooh (S)-l-((lR,4R)-5-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-l-oxopropan-2-yl((lS,9S)-9-ethyl-5-fhioro-9-hydroxy-4-methyl-10,13-dioxo-l,2,3,9,10,12,13,15-octahydrobenzo[de]pyrano [3',4':6,7] indolizino[l,2-b]quinolin-l-yl)carbamate, trifluoroacetic acid. H NMR (400 MHz, DMSO-tfc): 5 10.15-9.94 (m, 1H), 9.70-9.53 (m, 1H), 8.43-8.19 (m, 1H), 7.78 (d, J= 10.8 Hz, 1H), 7.60-7.39 (m, 3H), 7.31 (s, 1H), 7.10-6.97 (m, 1H), 6.52 (s, 1H), 6.40 (s, 1H), 5.50-4.92 (m, 7H), 4.87-4.75 (m, 4H), 4.71-4.22 (m, 4H), 3.90-3.45 (m, 4H), 3.29-2.96 (m, 4H), 2.42-2.32 (m, 3H), 2.24-2.04 (m, 3H), 1.95-1.77 (m, 2H), 1.42-1.30 (m, 3H), 1.21-1.02 (m, 6H), 0.87 (t, J = 7.2 Hz, 3H). LCMS (ESI): Rt = 1.015 min, m / z found 941.4 [M+H]+. Compound 088 (S)-l-((lR,5S)-8-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-l-oxopropan-2-yl((lS,9S)-9-ethyl-5-fhioro-9-hydroxy-4-methyl-10,13-dioxo-l,2,3,9,10,12,13,15-octahydrobenzo[de]pyrano [3',4':6,7]indolizino [l,2-b]quinolin-l-yl)carbamate. 1H NMR (400 MHz, DMSO-tfc): 5 10.08 (s, 1H), 9.63 (s, 1H), 8.18 (d, J= 8.8 Hz, 1H), 7.77 (d, J = 10.8 Hz, 1H), 7.49-7.28 (m, 3H), 7.05 (s, 1H), 6.52 (s, 1H), 6.40 (s, 1H), 5.58 -5.12 (m, 6H), 4.95-4.75 (m, 3H), 4.07 -3.43 (m, 6H), 3.29 -3.05 (m, 7H), 2.79-2.67 (m, 1H), 2.38 (s, 3H), 2.26-2.09 (m, 2H), 2.02 -1.71 (m, 5H), 1.391.27 (m, 3H), 1.14 (d, J= 6.8 Hz, 6H), 0.87 (t, J = 7.2 Hz, 3H). LCMS (ESI): Rt = 1.011 min, m / z found 955.4 [M+H]+. Compound 089 2-((1-((2-(2,4-dihydroxy-5-methylbenzoyl)isoindolin-5-yl)methyl)azetidin-3-yl)methyl)-2-azaspiro[3.3]heptan-6-yl((lS,9S)-9-ethyl-5-fhioro-9-hydroxy-4-methyl-10,13-dioxo-l,2,3,9,10,12,13,15-octahydrobenzo[de]pyrano[3',4':6,7]indolizino[l,2-b]quinolin-l-yl)carbamate, trifluoroacetic acid.1H NMR (400 MHz, DMSO-cL) 5 10.45-10.26 (m, 1H), 10.13 (s, 1H), 9.68 (s, 1H), 8.01 (d, J= 8.8 Hz, 1H), 7.78 (d, J= 10.8 Hz, 1H), 7.52-7.32 (m, 4H), 7.05 (s, 1H), 6.54 (br s, 1H), 6.40 (s, 1H), 5.41 (s, 2H), 5.32-5.09 (m, 3H), 4.91-4.76 (m, 5H),4.41-3.86 (m, 10H), 3.45-3.42 (m, 2H), 3.28-2.61 (m, 6H), 2.38 (s, 3H), 2.33-2.10 (m, 3H), 2.04 (s, 3H), 1.95-1.80 (m, 2H), 0.88 (t, J = 7.2 Hz, 3H). LCMS (ESI): Rt = 0.939 min, m / z found 925.4 [M+H]+. Compound 090 cf3cooh 4-((2-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-l-yl)ethyl)disulfanyl)benzyl((lS,9S)-9-ethyl-5-fhioro-9-hydroxy-4-methyl-10,13-dioxo-l,2,3,9,10,12,13,15-octahydrobenzo[de]pyrano[3',4':6,7]indolizino[l,2-b]quinolin-l-yl)carbamate trifluoroacetic acid.1H NMR (400 MHz, DMSO-tfe) 8 10.05 (s, 1H), 9.64 (s, 1H), 8.12 (d, J = 8.8 Hz, 1H), 7.78 (d, 7=10.8 Hz, 1H), 7.58 (d, J = 8.4 Hz, 2H), 7.51-7.27 (m, 6H), 7.03 (s, 1H), 6.73-6.46 (m, 1H), 6.40 (s, 1H), 5.44 (s, 2H), 5.27-5.10 (m, 5H), 4.85-4.71 (m, 4H), 4.29-3.96 (m, 2H), 3.27-2.70 (m, 16H), 2.38 (s, 3H), 2.26-2.12 (m, 2H), 1.95-1.82 (m, 2H), 1.13 (d, J = 6.8 Hz, 6H), 0.88 (t, J = 7.2 Hz, 3H). LCMS (ESI): Rt = 1.355 min, m / z found 1054.6 [M+H]+. Compound 091 2-((2-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-l-yl)ethyl)disulfaneyl)-2-methylpropyl((lS,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-lH,12Hbenzo[de]pyrano[3',4':6,7]indolizino[l,2-b]quinolin-l-yl)carbamate 2,2,2-trifluoroacetate. H NMR (400 MHz, DMSO) 8 10.04 (s, 1H), 9.63 (s, 1H), 8.06 (d, J= 8.8 Hz, 1H), 7.79 (d, J= 10.8 Hz, 1H), 7.48-7.31 (m, 4H), 7.04 (s, 1H), 6.67-6.39 (m, 2H), 5.41 (s, 2H), 5.28-5.20 (m, 3H), 4.83-4.73 (s, 4H), 4.334.26 (m, 2H), 4.16-4.02 (m, 4H), 3.35-2.81 (m, 14H), 2.38 (s, 3H), 2.24-2.11 (m, 2H), 1.941.76 (m, 2H), 1.31 (s, 6H), 1.13 (d, J= 6.8 Hz, 6H), 0.87 (t, J= 7.2 Hz, 3H). LCMS (ESI): Rt = 1.423 min, m / z found 1021.4 [M+H]+. Compound 092 (1-((2-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-l-yl)ethyl)disulfaneyl)cyclobutyl)methyl((lS,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-lH,12Hbenzo[de]pyrano[3',4':6,7]indolizino[l,2-b]quinolin-l-yl)carbamate 2,2,2-trifluoroacetate. H NMR (400 MHz, DMSO) 5 7.78 (d, J = 11.2 Hz, 1H), 7.50-7.34 (m, 4H), 7.04 (s, 1H), 6.41 (s, 1H), 5.45-5.37 (m, 2H), 5.305.20 (m, 3H), 4.85-4.75 (m, 4H), 4.28 (dd, J = 37.6, 11.6 Hz, 2H), 4.10 (s, 2H), 3.27-3.19 (m, 2H), 3.14-2.96 (m, 11H), 2.38 (s, 3H), 2.30-1.92 (m, 10H), 1.90-1.81 (m, 2H), 1.13 (d, J = 6.8 Hz, 6H), 0.88 (t, J = 7.2 Hz, 3H). LCMS (ESI): Rt = 1.183 min, m / z found 1033.3 [M+H]+. Compound 093 2-((2-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-l-yl)ethyl)disulfaneyl)ethyl((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 2,2,2-trifluoroacetate. ’H NMR (400 MHz, DMSO) 5 7.78-7.75 (m, 1H), 7.44-7.33 (m, 4H), 7.04 (s, 1H), 6.41 (s, 1H), 5.45-5.36 (m, 2H), 5.28-5.16 (m, 3H), 4.864.70 (m, 4H), 4.43-4.31 (m, 2H), 4.28-4.12 (m, 2H), 3.26-3.01 (m, 16H), 2.54-2.53 (m, 1H), 2.37-2.35 (m, 3H), 2.23-2.13 (m, 2H), 1.90-1.83 (m, 2H), 1.14 (d, J = 6.8 Hz, 6H), 0.88 (t, J = 7.2 Hz, 3H). LCMS (ESI): Rt = 1.057 min, m / z found 993.3 [M+H]+. Compound 094 N-((S)-10-benzyl-l-(((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)amino)-l,6,9,12,15-pentaoxo-3-oxa-5,8,ll,14-tetraazahexadecan-16-yl)-4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-l,2,4-triazol-4-yl)benzamide 2,2,2-trifluoroacetate 2,2,2-trifluoroacetate. 1H NMR (400 MHz, DMSO) 5 11.96 (s, 1H), 9.56 (s, 1H), 9.30 (s, 1H), 8.80-8.77 (m, 1H), 8.64-8.60 (m, 1H), 8.51-8.49 (m, 1H), 8.32-8.29 (m, 1H), 8.12-8.08 (m, 2H), 7.82-7.79 (m, 2H), 7.78-7.76 (m, 1H), 7.31 (s, 1H), 7.23-7.21 (m, 6H), 7.18-7.14 (m, 1H), 6.98 (s, 1H), 6.51 (s, 1H), 6.21 (s, 1H), 5.62-5.57 (m, 1H), 5.425.40 (m, 2H), 5.20 (s, 2H), 4.64-4.50 (m, 2H), 4.48-4.45 (m, 1H), 4.04-4.01 (m, 2H), 3.873.84 (m, 2H), 3.74-3.62 (m, 4H), 3.19-3.15 (m, 2H), 3.04-3.02 (m, 2H), 2.79-2.74 (m, 1H), 2.40-2.36 (m, 3H), 2.21-2.14 (m, 2H), 1.89-1.82 (m, 2H), 1.06 (d, J = 6.8 Hz, 6H), 0.86 (t, J = 7.2 Hz, 3H). LCMS (ESI): Rt = 0.932 min, m / z found 1179.4 [M+H]+. Compound 095 4-(((((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)carbamoyl)oxy)methyl)phenyl-4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazine-l-carboxylate 2,2,2-trifluoroacetate. H NMR (400 MHz, DMSO) 510.02 (s, 1H), 9.65 (s, 1H), 8.10 (d, J = 8.4 Hz, 1H), 7.78 (d, J = 10.8 Hz, 1H), 7.53-7.39 (m, 5H), 7.32 (s, 1H), 7.16 (d, J = 8.4 Hz, 2H), 7.04 (s, 1H), 6.53 (s, 1H), 6.41 (s, 1H), 5.485.39 (m, 2H), 5.34-5.23 (m, 3H), 5.18-5.11 (m, 2H), 4.89-4.71 (m, 4H), 4.44-4.30 (m, 2H), 4.23-4.01 (m, 2H), 3.34-3.02 (m, 9H), 2.38 (s, 3H), 2.26-2.11 (m, 2H), 1.94-1.80 (m, 2H), 1.14 (d, J = 6.8 Hz, 6H), 0.88 (t, J = 7.2 Hz, 3H). LCMS (ESI): Rt = 0.665 min, m / z found 941.6 [M+H]+. Compound 096 0 4-(((((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)carbamoyl)oxy)methyl)phenyl-4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazine-l-carboxylate 2,2,2-trifluoroacetate. H NMR (400 MHz, DMSO) 55 10.02 (s, 1H), 9.64 (s, 1H), 8.09 (d, J= 8.8 Hz, 1H), 7.78 (d, J= 10.8 Hz, 1H), 7.53-7.37 (m, 5H), 7.32 (s, 1H), 7.14 (d, J= 8.4 Hz, 2H), 7.04 (s, 1H), 6.52 (s, 1H), 6.41 (s, 1H), 5.465.42 (m, 2H), 5.26-5.23 (m, 3H), 5.18-5.10 (m, 2H), 4.89-4.74 (m, 4H), 4.48-4.32 (m, 2H), 4.25-4.01 (m, 2H), 3.31-3.02 (m, 9H), 2.38 (s, 3H), 2.25-2.13 (m, 2H), 1.94-1.80 (m, 2H), 1.13 (d, J = 6.8 Hz, 6H), 0.88 (t, J = 7.2 Hz, 3H). LCMS (ESI): Rt = 1.063 min, m / z found 941.6 [M+H]+. Compound 097 (1-((2-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piperazin-l-yl)ethyl)disulfaneyl)cyclopentyl)methyl-((lS,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-lH,12Hbenzo[de]pyrano[3',4':6,7]indolizino[l,2-b]quinolin-l-yl)carbamate 2,2,2-trifluoroacetate. H NMR (400 MHz, DMSO) 511.04 (s, 1H), 10.04 (s, 1H), 9.63 (s, 1H), 8.14-8.03 (m, 1H), 7.79 (d, J = 11.2 Hz, 1H), 7.41-7.32 (m, 4H), 7.04 (s, 1H), 6.40 (s, 1H), 5.41 (s, 2H), 5.30-5.24 (m, 3H), 4.88-4.70 (m, 8H), 4.254.05 (m, 4H), 3.27-3.20 (m, 2H), 3.17-3.09 (m, 4H), 3.06-2.97 (m, 6H), 2.38 (s, 3H), 2.222.12 (m, 2H), 1.91-1.81 (m, 4H), 1.71-1.51 (m, 6H), 1.13 (d, J = 6.8 Hz, 6H), 0.87 (t, J = 7.2 Hz, 3H). LCMS (ESI): Rt = 1.073 min, m / z found 1047.4 [M+H]+. Compound 098 2-((2-(2-hydroxy-5-isopropyl-4-(phosphonooxy)benzoyl)isoindolin-5-yl)methyl)-2-azaspiro[3.3]heptan-6-yl-((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 2,2,2-trifluoroacetate. 1H NMR (400 MHz, DMSO) 510.36 (s, 1H), 7.987.90 (m, 1H), 7.78-7.70 (m, 1H), 7.46-7.22 (m, 4H), 7.09-6.97 (m, 2H), 6.52 (s, 1H), 5.41 (s, 2H), 5.21-5.11 (m, 3H), 4.87-4.67 (m, 4H), 4.30-3.96 (m, 6H), 3.21-2.99 (m, 7H), 2.77-2.67 (m, 2H), 2.37 (s, 3H), 2.29-2.07 (m, 4H), 1.92-1.81 (m, 2H), 1.12 (d, J = 6.8 Hz, 6H), 0.87 (t, J = 7.2 Hz, 3H). LCMS (ESI): Rt = 0.815 min, m / z found 964.4 [M+H]+. Compound 099 2-((2-(5-isopropyl-2,4-bis(phosphonooxy)benzoyl)isoindolin-5-yl)methyl)-2-azaspiro[3.3]heptan-6-yl-((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 2,2,2-trifluoroacetate. ’H NMR (400 MHz, DMSO) 510.97-9.72 (m, 1H), 7.99-7.93 (m, 1H), 7.79-7.74 (m, 1H), 7.52-7.20 (m, 6H), 7.10-6.97 (m, 1H), 6.52 (s, 1H), 5.41 (s, 2H), 5.28-5.09 (m, 3H), 4.92-4.58 (m, 6H), 4.36-4.07 (m, 6H), 3.33-3.05 (m, 5H), 2.75-2.62 (m, 2H), 2.37-2.05 (m, 7H), 1.95-1.79 (m, 2H), 1.16 (d, J = 6.8 Hz, 6H), 0.87 (d, J = 7.2 Hz, 3H). LCMS (ESI): Rt = 1.659 min, m / z found 1044.4 [M+H]+. Compound 100 o 2-((2-(2-hydroxy-5-isopropyl-4-(phosphonooxy)benzoyl)isoindolin-5-yl)methyl)-2-azaspiro[3.5]nonan-7-yl((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 2,2,2-trifluoroacetate. 1H NMR (400 MHz, DMSO) 510.36 (s, 1H), 7.997.91 (m, 1H), 7.78 (d, J= 10.8 Hz, 1H), 7.53-7.24 (m, 4H), 7.11-6.99 (m, 2H), 6.54 (s, 1H), 5.43 (s, 2H), 5.28-5.13 (m, 3H), 4.82-4.69 (m, 4H), 4.47-4.33 (m, 2H), 3.88-3.78 (m, 5H), 3.25-3.03 (m, 6H), 2.39 (s, 3H), 2.24-1.49 (m, 12H), 1.14 (d, J= 6.8 Hz, 6H), 0.89 (t, J = 7.2 Hz, 3H). LCMS (ESI): Rt = 0.900 min, m / z found 992.4 [M+H]+. Compound 101 4-((((2-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-2-azaspiro[3.3]heptan-6-yl)oxy)carbonyl)oxy)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 2,2,2-trifluoroacetate. H NMR (400 MHz, DMSO) 510.16-9.95 (m, 2H), 9.64 (s, 1H), 8.12 (d, J = 9.2 Hz, 1H), 7.78 (d, J = 10.8 Hz, 1H), 7.48 (d, J = 8.4 Hz, 2H), 7.42-7.30 (m, 3H), 7.22 (d, J = 7.6 Hz, 2H), 7.04 (s, 1H), 6.53 (s, 1H), 6.40 (s, 1H), 5.47-5.41 (m, 2H), 5.2-5.24 (m, 2H), 5.20-5.10 (m, 2H), 4.964.87 (m, 1H), 4.86-4.70 (m, 4H), 4.36-4.27 (m, 2H), 4.22-4.12 (m, 2H), 4.09-3.95 (m, 2H), 3.92-3.78 (m, 1H),3.68-3.64 (m, 1H), 3.38-3.18 (m, 2H), 3.15-3.05 (m, 2H), 2.78-2.63 (m, 2H), 2.46-2.41 (m, 1H), 2.38 (s, 3H), 2.29-2.08 (m, 2H), 1.95-1.79 (m, 2H), 1.13 (d, J = 6.8 Hz, 6H), 0.88 (t, J = 7.2 Hz, 3H). LCMS (ESI): Rt = 1.044 min, m / z found 517.8 [1 / 2M+H]+. Compound 102 (S)-2-(2-(2-(((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)amino) acetamido)acetamido)-N-(2-(((2-(((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)amino)-2-oxoethoxy)methyl)amino)-2-oxoethyl)-3-phenylpropanamide 2,2,2-trifluoroacetate. ’H NMR (400 MHz, DMSO) 510.06 (s, 1H), 9.65 (s, 1H), 9.20 (s, 2H), 8.71-8.65 (m, 1H), 8.56-8.54 (m, 2H), 8.41-8.35 (m, 1H), 8.34-8.33 (m, 1H), 7.82-7.79 (m, 1H), 7.34-7.28 (m, 2H), 7.27-7.26 (m, 1H), 7.25-7.22   (m,   4H),   7.19 7.18 (m, 1H), 7.06-7.03 (m, 1H), 6.56-6.54 (m, 1H), 6.42 (s, 1H), 5.61-5.59 (m, 1H), 5.445.52 (m, 2H), 5.22-5.20 (m, 2H), 4.80-4.72 (m, 4H), 4.67-4.65 (m, 2H), 4.61-4.56 (m, 1H), 4.16-4.12 (m, 2H), 4.04-2.98 (m, 2H), 3.87-3.83 (m, 1H), 3.75-3.69 (m, 6H), 3.18-3.02 (m, 4H),2.80-2.66 (m, 1H), 2.41-2.33 (m, 3H), 2.20-2.16 (m, 2H), 1.94-1.80 (m, 2H), 1.15 (d, J = 6.8 Hz, 6H), 0.89 (t, J = 7.2 Hz, 3H). LCMS (ESI): Rt = 0.966 min, m / z found 1150.4 [M+H]+. Compound 103 HO 2-((2-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-2-azaspiro [3.3]heptan-6-yl)disulfaneyl)-2-methylpropyl-((lS,9S)-9-ethyl-5-fhioro-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 2,2,2-trifluoroacetate. H NMR (400 MHz, DMSO) 510.22-9.96 (m, 2H), 9.67 (s, 1H), 8.08 (d, J = 8.8 Hz, 1H), 7.81 (d, J = 10.8 Hz, 1H), 7.53-7.30 (m, 4H), 7.05 (s, 1H), 6.64-6.41 (m, 2H), 5.43 (s, 2H), 5.32-5.21 (m, 3H), 4.87-4.73 (m, 4H), 4.35-4.28 (m, 2H), 4.14-4.08 (m, 4H), 3.99-3.92 (m , 3H), 3.52-3.44 (m, 1H), 3.31-3.20 (m, 1H), 3.17-3.05 (m, 2H), 2.72-2.58 (m, 2H), 2.40 (s, 3H), 2.28-2.12 (m, 4H), 1.96-1.80 (m, 2H), 1.29 (s, 6H), 1.15 (d, J = 6.8 Hz, 6H), 0.89 (t, J = 7.2 Hz, 3H). LCMS (ESI): Rt = 1.468 min, m / z found 1004.3 [M+H]+. Compound 104 4-((2-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-2-azaspiro [3.3]heptan-6-yl) disulfaneyl)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 2,2,2-trifluoroacetate. H NMR (400 MHz, DMSO) 510.12-9.91 (m, 2H), 9.63 (s, 1H), 8.12 (d, J = 8.8 Hz, 1H), 7.78 (d, J = 10.8 Hz, 1H), 7.547.26 (m, 6H), 7.03 (s, 1H), 6.52-6.39 (m, 2H), 5.44 (s, 2H), 5.32-5.22 (m, 3H), 5.18-5.10 (m, 2H), 4.78 (s, 4H), 4.31-4.22 (m, 2H), 4.14-4.02 (m, 3H), 3.96-3.90 (m, 1H), 3.67-3.61 (m, 2H), 3.27-3.22 (m, 1H), 3.16-3.06 (m, 2H), 2.59-2.51 (m, 1H), 2.38 (s, 3H), 2.31-2.13 (m, 4H), 1.96-1.80 (m, 2H), 1.13 (d, J = 6.8 Hz, 6H), 0.88 (t, J = 7.2 Hz, 3H). LCMS (ESI): Rt = 1.103 min, m / z found 1038.4 [M+H]+. Compound 105 2-((2-(2-hydroxy-5-isopropyl-4-(phosphonooxy)benzoyl)isoindolin-5-yl)methyl)-2-azaspiro[3.3]heptan-6-yl((lR,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 2,2,2-trifluoroacetate. 1H NMR (400 MHz, DMSO) 57.99-7.91 (m, 1H), 7.77-7.68 (m, 1H), 7.30-7.02 (m, 7H), 6.52 (s, 1H), 5.41 (s, 2H), 5.21-5.12 (m, 3H), 4.874.66 (m, 4H), 4.26-3.89 (m, 6H), 3.22-2.99 (m, 8H), 2.76-2.67 m, 2H), 2.37 (s, 3H), 2.282.07 (m, 3H), 1.92-1.81 (m, 2H), 1.19-1.03 (m, 6H), 0.87 (t, J = 6.8 Hz, 3H). LCMS (ESI): Rt = 1.264 min, m / z found 965.0 [M+H]+. Compound 106 2-((2-(5-isopropyl-2,4-bis(phosphonooxy)benzoyl)isoindolin-5-yl)methyl)-2-azaspiro[3.3]heptan-6-yl-((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 2,2,2-trifluoroacetate. ’H NMR (400 MHz, DMSO) 511.23-9.80 (m, 1H), 7.99-7.96 (m, 1H), 7.79-7.74 (m, 1H), 7.47-7.19 (m, 6H), 7.10-6.97 (m, 1H), 6.52 (s, 1H), 5.42 (s, 2H), 5.25-5.12 (m, 3H), 4.95-4.56 (m, 6H), 4.34-4.09 (m, 6H), 3.32-3.07 (m, 5H), 2.73-2.62 (m, 2H), 2.40-2.06 (m, 7H), 1.95-1.80 (m, 2H), 1.17-1.14 (m, 6H), 0.88 (t, 7 = 7.2 Hz, 3H). LCMS (ESI): Rt = 1.088 min, m / z found 1043.6 [M+H]+. Compound 107 2-((2-(4-hydroxy-5-isopropyl-2-(phosphonooxy)benzoyl)isoindolin-5-yl)methyl)-2-azaspiro[3.3]heptan-6-yl((lR,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 2,2,2-trifluoroacetate. 1H NMR (400 MHz, DMSO) 510.22 (s, 1H), 9.92 (s, 1H), 7.99-7.97 (m, 1H), 7.79-7.77 (m, 1H), 7.33-7.31 (m, 1H), 7.31-7.27 (m, 3H), 7.097.03 (m, 3H), 6.53 (s, 1H), 5.42-5.40 (m, 2H), 5.29-5.09 (m, 3H), 4.92-4.73 (m, 3H), 4.664.64 (m, 2H), 4.38-4.21 (m, 2H), 4.23-3.96 (m, 4H), 3.22-3.02 (m, 6H), 2.69-2.67 (m, 2H), 2.39-2.35 (m, 3H), 2.17-2.13 (m, 2H), 1.89-1.85 (m, 2H), 1.15-1.13 (m, 6H), 0.87 (t, J = 7.2 Hz, 3H). LCMS (ESI): Rt = 1.015 min, m / z found 964.4 [M+H]+. Compound 108 HO 2-((2-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-2-azaspiro [3.3]heptan -6-yl)disulfaneyl)-2-methylpropyl ((lR,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 2,2,2-trifluoroacetate. H NMR (400 MHz, DMSO) 510.15-9.93 (m, 2H), 9.64 (s, 1H), 8.05 (d, J= 8.8 Hz, 1H), 7.79 (d, J = 10.8 Hz, 1H), 7.48-7.28 (m, 4H), 7.04 (s, 1H), 6.63-6.34 (m, 2H), 5.42 (s, 2H), 5.29-5.18 (m, 3H), 4.85-4.72 (m, 4H), 4.31-4.29 (m, 2H), 4.17- 3.92 (m, 6H), 3.27-3.03 (m, 4H), 2.65-2.52 (m, 2H), 2.38 (s, 3H), 2.25-2.13 (m, 4H), 1.94-1.80 (m, 2H), 1.27 (s, 6H), 1.13 (d, J= 6.8 Hz, 6H), 0.87 (t, J= 7.2 Hz, 3H). LCMS (ESI): Rt = 1.407 min, m / z found 1004.4 [M+H]+. Compound 109 cf3cooh (lS,2S)-2-((2-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl) piperazin-l-yl)ethyl)disulfaneyl)cyclopentyl((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 2,2,2-trifluoroacetate. H NMR (400 MHz, DMSO) 510.23-9.93 (m, 1H), 9.63 (s, 1H), 8.05 (d, J = 9.2 Hz, 1H), 7.77 (d, J = 10.8 Hz, 1H), 7.61-7.18 (m, 4H), 7.03 (s, 1H), 6.45-6.32 (m, 2H), 5.42 (s, 2H), 5.29-5.12 (m, 4H), 4.84-4.71 (m, 4H), 3.81-3.67 (m, 2H), 3.58- 2.73 (m, 15H), 2.37 (s, 3H), 2.29-2.04 (m, 5H), 1.96-1.52 (m, 7H), 1.13 (d, J = 6.8 Hz, 6H), 0.88 (t, J = 7.2 Hz, 3H). LCMS (ESI): Rt = 1.361 min, m / z found 1033.2 [M+H]+. Compound 110 CF3C00H (lR,2R)-2-((2-(4-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)piper azin-l-yl)ethyl)disulfaneyl)cyclopentyl((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 2,2,2-trifluoroacetate. H NMR (400 MHz, DMSO) 510.21-9.93 (m, 1H), 9.63 (s, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.78 (d, J = 10.8 Hz, 1H), 7.517.22 (m, 4H), 7.04 (s, 1H), 6.68-6.39 (m, 2H), 5.42 (s, 2H), 5.31-5.14 (m, 4H), 4.85-4.68 (m, 4H), 3.71-3.48 (m, 4H), 3.39-2.73 (m, 13H), 2.38 (s, 3H), 2.29 -2.01 (m, 5H), 1.96-1.52 (m, 7H), 1.13 (d, J = 6.8 Hz, 6H), 0.88 (t, J = 7.2 Hz, 3H). LCMS (ESI): Rt = 1.410 min, m / z found 1033.2 [M+H]+. Compound 111 2-((2-(6-hydroxy-3-isopropyl-lH-indazole-5-carbonyl)isoindolin-5-yl)methyl)-2-azaspiro[3.3]heptan-6-yl((lR,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 2,2,2-trifluoroacetate. ’H NMR (400 MHz, DMSO) 512.27 (s, 1H), 10.06 (s, 2H), 8.00 -7.96 (m, 1H), 7.79 (d, J= 11.2 Hz, 1H), 7.66 (d, J= 7.6 Hz, 1H), 7.50 -7.46 (m, 1H), 7.39 -7.31 (m, 3H), 6.86 (s, 1H), 6.53 (s, 1H), 5.92-5.86 (m, 1H), 5.45-5.41 (m, 2H), 5.26-5.18 (m, 3H), 4.89-4.82 (m, 3H), 4.65 (s, 2H), 4.34-4.01 (m, 6H), 2.38 (s, 4H), 2.22-2.08(m, 4H), 1.89-1.85(m, 2H), 1.33 (d, J = 6.8 Hz, 6H), 1.24 (s, 1H), 1.15 (s, 1H), 0.87 (t, J= 7.6 Hz, 3H). LCMS (ESI): Rt = 1.049 min, m / z found 908.2 [M+H]+. Compound 112 2-((2-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-((2,2,2-trifhioroethyl)carbamoyl)-4H-l,2,4-triazol-4-yl)benzyl)-2-azaspiro[3.3]heptan-6-yl)disulfaneyl)-2-methylpropyl ((lR,9S)-9-ethyl-5-fhioro-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 2,2,2-trifluoroacetate. *H NMR (400 MHz, DMSO) 510.21-10.09 (m, 1H), 9.80-9.61 (m, 2H), 8.04 (d, J = 8.8 Hz, 1H), 7.79 (d, J = 10.8 Hz, 1H), 7.48-7.41 (m, 4H), 7.32 (s, 1H), 6.71 (s, 1H), 6.51-6.30 (m, 2H), 5.43 (s, 2H), 5.28-5.24 (m, 3H), 4.36 (d, J= 5.6 Hz, 2H), 4.25-3.86 (m, 9H), 3.25-3.14 (m, 3H), 2.97-2.90 (m, 1H), 2.69-2.57 (m, 2H), 2.39 (s, 3H), 2.27-2.14 (m, 4H), 1.92-1.81 (m, 2H), 1.27 (s, 6H), 0.91-0.85 (m, 9H). LCMS (ESI): Rt = 1.256 min, m / z found 1127.2 [M+H]+. Compound 113 cf3cooh 2-((2-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-((2,2,2-trifhioroethyl)carbamoyl)-4H-l,2,4-triazol-4-yl)benzyl)-2-azaspiro[3.3]heptan-6-yl)disulfaneyl)-2-methylpropyl ((lS,9S)-9-ethyl-5-fhioro-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 2,2,2-trifluoroacetate. ’H NMR (400 MHz, DMSO) 510.17-10.01 (m, 2H), 9.72-9.61 (m, 2H), 8.04 (d, J = 8.8 Hz, 1H), 7.79 (d, J = 10.8 Hz, 1H), 7.48-7.41 (m, 4H), 7.32 (s, 1H), 6.71 (s, 1H), 6.52 (s, 1H), 6.30 (s, 1H), 5.42 (s, 2H), 5.30-5.23 (m, 3H), 4.36 (d, J = 5.6 Hz, 2H), 4.21-3.90 (m, 8H), 3.30-3.07 (m, 3H), 2.97-2.90 (m, 1H), 2.67-2.58 (m, 2H), 2.39 (s, 3H), 2.32-2.08 (m, 4H), 1.91-1.81 (m, 2H), 1.28 (s, 6H), 0.91-0.85 (m, 9H). LCMS (ESI): Rt = 1.236 min, m / z found 1127.2 [M+H]+. Compound 114 2-(2-((2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl)methyl)-2-azaspiro[3.3] heptan-6-yl)-N-((lR,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)acetamide 2,2,2-trifluoroacetate. 1H NMR (400 MHz, DMSO) 510.03 (s, 2H), 9.64 (s, 1H), 8.44 (d, J = 11.6 Hz, 1H), 7.80 (d, J= 11.2 Hz, 1H), 7.43-7.32 (m, 4H), 7.04 (s, 1H), 6.53 (s, 1H), 6.40 (s, 1H), 5.92-5.87 (m, 1H), 5.54-5.42(m, 3H), 5.24-5.10 (m, 2H), 4.79 (s, 4H), 4.29 (s, 2H), 4.16 - 4.01 (m, 3H), 3.89 (s, 1H), 3.16-3.08(m, 3H), 2.40 (s, 4H), 2.25 (d, J= 7.2 Hz, 2H), 2.09 (s, 2H), 1.97-1.85(m, 4H), 1.13 (d, J= 6.9 Hz, 6H), 0.87 (t, J= 7.2 Hz, 3H). LCMS (ESI): Rt = 1.084 min, m / z found 882.2 [M+H]+. Compound 115 (lS,2S)-2-((2-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-((2,2,2-trifluoroethyl) carbamoyl)-4H-l,2,4-triazol-4-yl)benzyl)-2-azaspiro[3.3]heptan-6-yl)disulfaneyl) cydopentyl((lS,9S)-9-ethyl-5-fhioro-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 2,2,2-trifluoroacetate. *H NMR (400 MHz, DMSO) 510.20-10.02 (m, 2H), 9.72 (s, 1H), 9.65-9.62 (m, 1H), 8.03 (d, J= 8.8 Hz, 1H), 7.78 (d, J = 10.8 Hz, 1H), 7.497.41 (m, 4H), 7.31 (s, 1H), 6.71 (s, 1H), 6.52 (s, 1H), 6.30 (s, 1H), 5.42 (s, 2H), 5.32-5.17 (m, 3H), 5.05-5.04 (m, 1H), 4.37-4.36 (m, 2H), 4.27-3.84 (m, 7H), 3.60-3.56 (m, 1H), 3.313.24 (m, 2H), 3.15-3.07 (m, 1H), 2.97-2.91 (m, 1H), 2.37 (s, 3H), 2.29-1.44 (m, 13H), 0.910.85 (m, 9H). LCMS (ESI): Rt = 1.665 min, m / z found 1139.4 [M+H]+. Compound 116 (lR,2R)-2-((2-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-((2,2,2-trifluoroethyl) carbamoyl)-4H-l,2,4-triazol-4-yl)benzyl)-2-azaspiro[3.3]heptan-6-yl)disulfaneyl) cyclopentyl((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 2,2,2-trifluoroacetate. ‘H NMR (400 MHz, DMSO) 510.23-9.91 (m, 2H), 9.71 (s, 1H), 9.65-9.61 (m, 1H), 8.01 (d, J= 8.8 Hz, 1H), 7.79 (d, J= 10.8 Hz, 1H), 7.47-7.40 (m, 4H), 7.33 (s, 1H), 6.70 (s, 1H), 6.53 (s, 1H), 6.29 (s, 1H), 5.43 (s, 2H), 5.32-5.19 (m, 3H), 5.11-5.03 (m, 1H), 4.41-4.30 (m, 2H), 4.26-3.87 (m, 7H), 3.61-3.59 (m, 1H), 3.25-3.23 (m, 2H), 3.13-3.07 (m, 1H), 2.96-2.91 (m, 1H), 2.68-2.62 (m, 1H), 2.38 (s, 3H), 2.31-1.41 (m, 12H), 0.95-0.82 (m, 9H). LCMS (ESI): Rt = 1.701 min, m / z found 1139.4 [M+H]+. Compound 117 2-((2-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-((2,2,2-trifhioroethyl)carbamoyl)-4H-l,2,4-triazol-4-yl)benzyl)-2-azaspiro[3.5]nonan-7-yl)disulfaneyl)-2-methylpropyl ((lR,9S)-9-ethyl-5-fhioro-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 2,2,2-trifluoroacetate. *H NMR (400 MHz, DMSO) 510.15-10.01 (m, 2H), 9.72 (s, 1H), 9.669.62 (m, 1H), 8.04 (d, J = 7.6 Hz, 1H), 7.79 (d, J= 10.8 Hz, 1H), 7.53-7.42 (m, 4H), 7.32 (s, 1H), 6.72 (s, 1H), 6.53 (s, 1H), 6.30 (s, 1H), 5.43 (s, 2H), 5.31-5.18 (m, 3H), 4.43-4.41 (m, 2H), 4.16-3.67 (m, 9H), 3.22-3.14 (m, 1H), 2.99-2.92 (m, 1H), 2.79-2.70 (m, 1H), 2.39 (s, 3H), 2.25-1.75 (m, 8H), 1.59-1.45 (m, 2H), 1.36-1.14 (m, 8H), 0.92-0.82 (m, 9H). LCMS (ESI): Rt = 1.376 min, m / z found 1155.3 [M+H]+. Compound 118 (lS,2S)-2-((2-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-((2,2,2-trifluoroethyl) carbamoyl)-4H-l,2,4-triazol-4-yl)benzyl)-2-azaspiro[3.3]heptan-6-yl)disulfaneyl) cydohexyl((lR,9S)-9-ethyl-5-fhioro-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 2,2,2-trifluoroacetate. ’H NMR (400 MHz, DMSO) 510.30 (s, 1H), 10.10 (s, 1H), 9.81 (s, 1H), 9.70 (t, J= 6.4 Hz, 1H), 8.11 (d, J= 8.8 Hz, 1H), 7.85 (d, J = 10.8 Hz, 1H), 7.56-7.49 k(m, 4H), 7.39 (s, 1H), 7.32 (s, 1H), 7.19 (s, 1H), 7.06 (s, 1H), 6.78 (s, 1H), 6.60 (s, 1H), 6.37 (s, 1H), 5.50 (s, 2H), 5.40-5.23 (m, 3H), 4.71-4.65 (m, 1H), 4.44 (d, J = 4.0 Hz, 2H), 4.24-4.01(m, 6H), 2.44 (s, 3H), 2.33-2.22(m, 5H), 2.14-2.04(m, 2H), 1.79-1.54(m, 5H), 1.46-1.31 (m, 6H), 0.98-0.93 (m, 9H). LCMS (ESI): Rt = 1.659 min, m / z found 577.3 [1 / 2M+H]+. Compound 119 (lR,2S)-2-((2-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-((2,2,2-trifluoroethyl) carbamoyl)-4H-l,2,4-triazol-4-yl)benzyl)-2-azaspiro[3.3]heptan-6-yl)disulfaneyl) cyclohexyl((lR,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 2,2,2-trifluoroacetate. ‘H NMR (400 MHz, DMSO) 510.32-10.21(m, 2H), 9.81 (s, 1H), 9.71 (t, J= 6.4 Hz, 1H), 8.02 (d, J= 8.8 Hz, 1H), 7.86 (d, J= 10.8 Hz, 1H), 7.55-7.48(m, 4H), 7.41 (s, 1H), 7.32 (s, 1H), 7.20 (s, 1H), 7.07 (s, 1H), 6.78 (s, 1H), 6.62 (s, 1H), 6.38 (s, 1H), 5.51-5.33(m, 5H), 4.68 (s, 1H), 4.42 (d, J = 4.8Hz, 2H), 4.26-4.00(m, 6H), 3.28 -3.15(m, 3H), 2.87 (s, 1H), 2.46 (s, 3H), 2.29-2.19(m, 5H), 2.06 (s, 2H), 1.76-1.61(m, 3H), 1.49-1.31(m, 4H), 0.98-0.93(m, 9H). LCMS (ESI): Rt = 1.359 min, m / z found 577.3 [1 / 2M+H]+. Compound 120 (lS,2S)-2-((2-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-((2,2,2-trifluoroethyl) carbamoyl)-4H-l,2,4-triazol-4-yl)benzyl)-2-azaspiro[3.3]heptan-6-yl)disulfaneyl) cyclohexyl((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 2,2,2-trifluoroacetate. ’H NMR (400 MHz, DMSO) 510.23 (s, 1H), 10.10 (s, 1H), 9.79 (s, 1H), 9.71 (t, J = 6.4 Hz, 1H), 8.10 (d, J = 8.8 Hz, 1H), 7.86 (d, J = 10.8 Hz, 1H), 7.57-7.49 (m, 4H), 7.39 (s, 1H), 7.30 (s, 1H), 7.17 (s, 1H), 7.04 (s, 1H), 6.79 (s, 1H), 6.60 (s, 1H), 6.38 (s, 1H), 5.50 (s, 2H), 5.40-5.20 (m, 3H), 4.73-4.67 (m, 1H), 4.43 (s, 2H), 4.28-3.40 (m, 6H), 2.45(s, 2H), 2.31-2.07(m, 8H), 1.79-1.31(m, 10H), 0.99-0.93 (m, 9H). LCMS (ESI): Rt = 1.355 min, m / z found 577.3 [1 / 2M+H]+. Compound 121 (lR,2S)-2-((2-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-((2,2,2-trifluoroethyl) carbamoyl)-4H-l,2,4-triazol-4-yl)benzyl)-2-azaspiro[3.3]heptan-6-yl)disulfaneyl) cyclohexyl((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 2,2,2-trifluoroacetate. ’H NMR (400 MHz, DMSO) 510.30-10.09(m, 2H), 9.80(s, 1H), 9.70 (t, J = 6.4 Hz, 1H), 8.05(d, J = 7.2 Hz, 1H), 7.86(d, J = 10.80 Hz, 1H), 7.55-7.48 (m, 4H), 7.41 (s, 1H), 7.31 (s, 1H), 7.18 (s, 1H), 7.05 (s, 1H), 6.78 (s, 1H), 6.62 (s, 1H), 6.37 (s, 1H), 5.50-5.31(m, 5H), 4.67 (s, 1H), 4.43 (d, J = 5.8 Hz, 2H), 4.25-4.00 (m, 6H), 2.46 (s, 3H), 2.31-2.22 (m, 5H), 2.07 (s, 2H), 1.98-1.91(m, 2H), 1.74-1.22 (m, 9H), 0.98-0.93 (m, 9H). LCMS (ESI): Rt = 1.392 min, m / z found 577.3 [1 / 2M+H]+. Compound 122 2-((1-(5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-(morpholinomethyl)phenyl)isoxazole-3-carboxamido)propan-2-yl)disulfaneyl)-2-methylpropyl((lR,9S)-9-ethyl-5-fhioro-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 2,2,2-trifluoroacetate. H NMR (400 MHz, DMSO) 510.01-9.75 (m, 2H), 9.70-9.61 (m, 1H), 9.08-9.03 (m, 1H), 8.02 (t, J = 7.6 Hz, 1H), 7.79-7.74 (m, 1H), 7.50-7.18 (m, 5H), 6.80-6.76 (m, 1H), 6.53-6.41 (m, 2H), 5.42 (s, 2H), 5.31-5.19 (m, 3H), 4.32 (s, 2H), 4.19-3.88 (m, 4H), 3.72-3.49 (m, 5H), 3.28-2.94 (m, 9H), 2.42-2.33 (m, 3H), 2.21-1.82 (m, 3H), 1.34-1.15 (m, 9H), 0.96-0.84 (m, 8H). LCMS (ESI): Rt = 1.186 min, m / z found 1077.3 [M+H]+. Compound 123 2-((1-(5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-(morpholinomethyl)phenyl)isoxazole-3-carboxamido)propan-2-yl)disulfaneyl)-2-methylpropyl((lS,9S)-9-ethyl-5-fhioro-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 2,2,2-trifluoroacetate. H NMR (400 MHz, DMSO) 510.03-9.76 (m, 2H), 9.70-9.59 (m, 1H), 9.17-8.94 (m, 1H), 8.08-7.92 (m, 1H), 7.76 (t, J = 11.2 Hz, 1H), 7.51-7.15 (m, 5H), 6.82-6.77 (m, 1H), 6.51-6.41 (m, 2H), 5.41 (s, 2H), 5.32-5.12 (m, 3H), 4.32 (s, 2H), 4.20-3.89 (m, 4H), 3.71-3.44 (m, 5H), 3.292.92 (m, 9H), 2.43-2.33 (m, 3H), 2.21-1.81 (m, 3H), 1.41-1.10 (m, 9H), 1.00-0.83 (m, 8H). LCMS (ESI): Rt = 1.158 min, m / z found 1077.3 [M+H]+. Compound 124 cf3cooh 2-(2,4-dihydroxy-5-isopropylbenzoyl)isoindolin-5-yl-((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 2,2,2-trifluoroacetate 'H NMR (400 MHz, DMSO) 5 9.99 (s, 1H), 9.71 (s, 1H), 9.64 (t, J = 6.4 Hz, 1H), 9.22 (t, J = 5.6 Hz, 1H), 8.45 (s, 3H), 7.90 (d, J = 8.8 Hz, 2H), 7.85 (d, J = 10.8 Hz, 1H), 7.42 (d, J = 8.8 Hz, 2H), 7.26 (s, 1H), 6.74 (s, 1H), 6.27 (s, 1H), 5.71 (d, J = 19.6 Hz, 1H), 5.53 (s, 2H), 5.43 (d, J = 19.6 Hz, 1H), 5.11 (s, 1H), 4.36-4.18 (m, 1H), 4.17-4.14 (m, 1H), 3.96-3.92 (m, 2H), 3.30 (s, 2H), 3.16-3.11 (m, 1H), 2.94-2.91(m, 1H), 2.43 (s, 3H), 2.19-2.14(m, 3H), 0.92-0.88 (m, 9H). LCMS (ESI): RT=1.380 min, m / z found 939.2[M+H]+. Biological Assays Cell lines The following cancer cell lines were employed: MIA PaCa-2 human pancreatic carcinoma (ATCC, #CRL-1420); MV4-11 human biphenotypic B myelomonocytic leukemia (ATCC, #CRL-9591); HCT-116 human colon carcinoma (ATCC, #CRL-247). Cell lines were cultured essentially according to ATCC recommendations. HSP90a-binding fluorescent polarization (FP) assay Binding of test compounds to HSP90a (HSP90AA1) protein was measured by 5 fluorescent polarization (FP) using the HSP90a (N-terminal) Assay Kit (BPS Bioscience, #50298), following the manufacturer’s instructions, except as noted. Fluorescently labeled HSP90-binding compound FITC-geldanamycin (5 nM final concentration) was provided and employed. A 2.5-fold serial dilution of each test compound ranging from 20 pM to 5.2 nM was assayed for binding to HSP90a. After the final step of adding HSP90a protein to 10 each assay well, plates were mixed by brief shaking, incubated at 25°C for 120 min, and fluorescence was measured using a PerkinElmer EnVision Plate Reader. Background-subtracted mP values were calculated from raw data and a four-parameter “log[inhibitor] vs. response” curve was fitted and IC50 values (the concentration at which 50% of the maximal inhibition occurs) calculated using GraphPad Prism 7 software. Results are shown in Table 15    1. Cmp P Value 001 17 002 101 003 16 004 3 005 22 006 8 007 3 008 5 009 16 010 9 011 100 Table 1 Cmp P Value 019 3 020 3 021 6 022 2 023 2 024 9 025 4 026 4 027 2 028 2 029 3 Cmp P Value 037 2 038 6 039 40 040 4 041 4 042 6 043 9 044 8 045 9 046 2 047 11 012 13 030 7 048 2 013 5 031 6 049 4 014 3 032 3 050 2 015 3 033 4 051 5 016 4 034 5 052 8 017 16 035 6 053 4 018 3 036 4 054 2 Cmp P Value Cmp P Value Cmp P Value 108 10 114 1 120 5 109 7 115 6 121 5 110 5 116 5 122 N / A 111 N / A 117 23 123 N / A 112 6 118 15 113 1 119 8 CellTiter-Glo® Reagent cancer cell line proliferation assays Cells were plated in 96-well tissue culture plates at 4,000 cells / well and incubated at 5   37°C / 5% CO2 for 72 hr in 100 pl of media. 3-fold serial dilutions of each test compound were prepared ranging from 20 pM to 1.02 nM. MIA Paca-2 cells (human pancreatic cancer cell line), MV4-11 cells (biphenotypic B-myelomonocytic leukemia), and HCT116 (human colorectal carcinoma cell line) were then treated with test compounds at various concentrations with a final concentration of 0.5% DMSO / well, and then incubated at 10   37°C / 5% CO2 for 24 hr. 100 pl of CellTiter-Glo® Reagent (Promega Corporation, Madison, WI) was added to each well and processed according manufacturer’s protocol. Results were analyzed and IC50-values were calculated in GraphPad 7 software. Results are shown in Table 2. A. IC50<100 nM; B. IC50=100-1000 nM; C. IC50>1000 nM. Table 2 Cmp. MIA Paca-2 cells (IC50 nm) MV4-11 cells (IC50 nm) HCT116 cells (IC50 nm) Cmp. MIA Paca-2 (IC50 nm) MV4-11 cells (IC50 nm) HCT116 cells (IC50 nm) 1 C B 63 B B 2 C B 64 B B 3 c A 65 B B 4 c A 66 B C 5 c A 67 B C 6 B A 68 B B 7 C A 69 B B 8 C A 70 B B 9 B A 71 B C 10 B A 72 C C 11 C A 73 C C 12 C A 74 B B 13 C A 75 C C 14 C A 76 A A 15 C B 77 B B 16 C A 78 B B 17 C A 79 B C 18 B A 80 B B 19 C B 81 A A 20 C B 82 B B 21 C B B 83 A A 22 C B C 84 C C 23 C B C 85 C C 24 C B B 86 B B 25 B A A 87 B B 26 B B B 88 B B 27 C B B 89 A A 28 B B A 90 A A 29 C B B 91 A A 30 C B B 92 A A 31 C B B 93 A A 32 B B B 94 B B 33 C B B 95 B B 34 B A B 96 B B 35 B A A 97 A A 36 C B C 98 A B 37 C B B 99 B B 38 B B B 100 A B 39 B B B 101 A A 40 C B B 102 A B 41 B A A 103 A A 42 C B B 104 A A 43 C B B 105 44 c B B 106 45 c B B 107 B C 46 c B B 108 B A 47 c B B 109 A A 48 c C B 110 A A 49 C B 111 B B 50 B B 112 A A 51 B C 113 A A 52 C C 114 B C 53 B C 115 A A 54 B B 116 A A 55 B C 117 A B 56 B C 118 A B 57 A C 119 A B 58 B C 120 A A 59 B 121 A B 60 A B 122 A 61 C C 123 A 62 B B 124 A Plasma Stability Test compounds were prepared in DMSO at 1 mM and 1 mM propantheline or mevinolin working solutions were prepared in acetonitrile. Propantheline served as a 5 positive control for human, dog, rat, and mouse plasma, while mevinolin was used a positive control for rat plasma. Assay plates were prewarmed at 37°C for 15 minutes before adding 398 pL of plasma. Then 2 pL of ImM test compound and 2 pL of ImM control compound were added to 398 pL of plasma to reach a final concentration of 5 pM for the test compound and 5 pM for the control compound. The final concentration of organic 10 solvents was 0.5 %. Each assay was performed in duplicate. Plasma samples were incubated at 37°C. Aliquots of 50 pL of each plasma sample were then taken at 0, 1, 2, 4, 8 and 24 hours. The reaction was halted by the addition of 450 pL cold methanol with 5% formic acid containing internal standards. All samples were vortexed for 10 minutes, followed by centrifugation at 3,220 g for 30 minutes to precipitate 15 proteins. From each sample 100 pL of supernatant was transferred to a new plate. Sample supernatants were diluted with ultrapure water and loaded on to a liquid chromatography mass spectrometer. Samples were analyzed by LC-MS / MS. All calculations were carried out using Microsoft Excel. Peak area ratios were determined from extracted ion chromatograms. Percent compounds remaining at each time point were calculated by the following equation: Remaining Percentage t min (%) = (Peak Area Ratio t min / Peak Area Ratio 0 min) 5   *100. Where Peak Area Ratio t min is peak area ratio of control and test compounds at t min; Peak Area Ratio 0 min is peak area ratio of control and test compounds at zero time point. The slope value, k, was determined by linear regression of the natural logarithm of the remaining percentage of the parent drug vs. incubation time curve. Results are shown in Table 3. 10                                        Table 3 Cmp Plasma stability_Remaining Percentages (%) (h |d|r | m) 001 29 | 31 | 23 | 24 002 29 | 59 | 48 | 33 003 BD | BD | 23 | 29 004 20 | 40 | 26 | 41 005 BD | BD | 13 | 54 006 2 | 8 | 22 | 32 007 38 | 42 | 39 | 47 008 63 | 68 | 65 | 69 009 14 | 33 | 52 | 66 010 BD|BD|BD|BD 011 1 | 30 | 22 | 34 012 38 | 45 | 37 | 40 013 54 | 67 | 60 | 61 014 30 | 43 | 33 | 35 015 18 | 31 | 17 | 25 016 27 | 42 | 57 | 42 017 88 | 92 | 83 | 97 018 104 | 94 | 84 | 97 019 68 | 61 | 94 | 99 020 83 | 87 | 110 | 86 021 104 | 94 | 88 | 105 022 94 | 96 | 93 | 93 023 95 | 98 | 117 | 83 024 89 | 94 | 108 | 94 025 91 | 87 | 93 | 96 026 101 | 99 | 116 | 98 027 93 | 104 | 91 | 99 028 103 | 88 | 90 | 50 Cmp Plasma stability_Remaining Percentages (%) (h |d|r| m) 043 94 | 99 | 90 | 27 044 91 | 99 | 84 | 32 045 NC 046 86 | 89 | 87 | 92 047 101 | 74 | 99 | 98 048 81 | 71 | 94 | 65 049 98 | 94 | 95 | 97 050 88 | 67 | 108 | 70 051 105 | 91 | 88 | 98 052 111 | 95 | 92 | 26 053 109 | 62 | 97 | 99 054 109 | 112 | 94 | 86 055 100 | 106 | 103 | 47 056 98 | 98 | 91 | 88 057 88 | 56 | 112 | 96 058 92 | 104 | 108 | 116 059 97 | 94 | 97 | 24 060 86 | 102 | 93 | 93 061 115 | 101 | 103 | 49 062 98 | 82 | 99 | 40 063 91 | 108 | 90 | 27 064 96 | 60 | 106 | 42 065 109 | 85 | 85 | 58 066 94 | 91 | 101 |2 067 99 | 101 | 104 | 22 068 107 | 97 | 112 | 51 069 103 | 96 | 101 | 94 070 101 | 106 | 97 | 21 Cmp Plasma stability_Remaining Percentages (%) (h |d|r| m) 085 68 | 55 | 88 | 102 086 40 | 91 | 41 | 7 087 91 | 95 | 96 | 103 088 85 | 95 | 91 | 100 089 48 | 106 | 86 | 88 090 12 | 82 | 18 | 18 091 63 | 90 | 96 | 90 092 44 | 89 | 91 | 110 093 0.98 | 82 | 22 | 16 094 44 | 74 | 86 | 103 095 99 | 95 | 84 | 24 096 115 | 83 | 57 | 10 097 91 | 89 | 96 | 68 098 94 | 85 | 101 | 35 099 88 | 92 | 89 | 83 100 105 | 100 | 108 | 54 101 1.2 | 2.3 | 3.7 | 1.1 102 96 | 63 | 108 | 90 103 88 | 96 | 101 | 90 104 3.1 | 29 | 8.5 | 30 105 110 | 111 | 117 | 54 106 NC 107 91 | 89 | 94 | 6 108 63 | 71 | 86 | 85 109 23 | 58 | 91 | 84 110 31 | 62 | 76 | 86 111 58 | 96 | 97 | 0.41 112 109 | 104 | 112 | 110 029 108 | 89 | 95 | 19 030 110 | 91 | 93 | 60 031 103 | 99 | 84 | 26 032 102 | 84 | 87 | 54 033 106 | 94 | 89 | 41 034 109 | 105 | 84 | 49 035 105 | 102 | 84 | 45 036 97 | 86 | 98 | 47 037 105 | 81 | 103 | 40 038 100 | 105 | 87 | 16 039 98 | 115 | 85 | 2 040 104 | 92 | 108 | 90 041 94 | 100 | 111 | 24 042 87 | 89 | 101 | 86 071 96 | 108 | 109 | 82 072 102 | 105 | 108 | 93 073 96 | 103 | 114 | 110 074 102 | 98 | 100 | 114 075 92 | 99 | 104 | 90 076 104 | 91 | 115 | 106 077 51 | 29 | 36 | 42 078 59 | 53 | 94 | 15 079 64 | 51 | 103 | 90 080 57 | 64 | 88 | 68 081 72 | 85 | 104 | 88 082 86 | 49 | 99 | 104 083 78 | 84 | 92 | 90 084 69 | 31 | 60 | 28 113 108 | 110 | 100 | 98 114 103 | 110 | 113 | 114 115 65 | 103 | 93 | 66 116 74 | 99 | 101 | 113 117 110 | 89 | 101 | 103 118 105 | 109 | 109 | 110 119 89 | 85 | 99 | 111 120 86 | 110 | 115 | 85 121 96 | 101 | 116 | 114 122 105 | 84 | 114 | 86 123 90 | 84 | 93 | 49 124 6.6 | 39 | 29 | 13 h, human; d, dog; r, rat; m, mouse. BD = below limit of detection. NC = not conducted. Data for compounds 001 to 027 and 124 was obtained after 2 hrs. Data for compounds 028 to 123 was obtained after 24 hrs and compounds. 5          Modifications and variations of the described methods and compositions of the present disclosure will be apparent to those skilled in the art without departing from the scope and spirit of the disclosure. Although the disclosure has been described in connection with specific embodiments, it should be understood that the disclosure as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the 10 described modes for carrying out the disclosure are intended and understood by those skilled in the relevant field in which this disclosure resides to be within the scope of the disclosure as represented by the following claims. INCORPORATION BY REFERENCE 15           All patents and publications mentioned in this specification are herein incorporated by reference to the same extent as if each independent patent and publication was specifically and individually indicated to be incorporated by reference.

Claims

Listing of Claims:

1. A compound of the Formula I:or a pharmaceutically acceptable salt thereof, wherein L is a linker and A is a chemicalmoiety that binds HSP90 protein.

2. The compound of Claim 1, wherein the compound is of the Formula II or III:or a pharmaceutically acceptable salt thereof.

3. The compound of Claim 1 or 2, wherein the compound is of the Formula II:15 or a pharmaceutically acceptable salt thereof4. The compound of any one of Claims 1 to 3, wherein A is selected from5 W is 5- or 6-membered heteroaryl optionally substituted with 1 to 3 groups selected from R2;R1 is halo, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, or halo(Ci-C4)alkoxy;R2 is (Ci-C4)alkyl, halo(Ci-C4)alkyl, (C2-C6)alkenyl, halo(C2-C6)alkenyl, (C2-C6)alkynyl, halo(C2-C6)alkynyl, CN, -Ci-4alkylORa, -ORa, -C(O)Ra, -C(O)ORa, -10 C(O)NRaRb, -C(O)NRa(Ci-4alkylene)ORa, -C(O)NRa(Ci-4alkylene)NRaRb, -C(O)NRa(Ci-4alkylene)OR, -NRaRb, -O(Ci-4alkylene)NRaRb, -SH, -S(Ci-4alkyl), -Ci-4alkylNRaRb, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -SO2NRaRb, -NRa(Ci-4alkyl)ORa, -NRa(Ci-4alkyl)NRaRb, -Ci-6alkylC(O)NRaRb, phenyl or monocyclic heteroaryl, wherein said phenyl and monocyclic heteroaryl are each optionally and independently substituted with 1 to 3 groups selected 15 fromR4;Ra and Rb are each independently selected from hydrogen and (Ci-C4)alkyl, wherein said (Ci-C4)alkyl is optionally substituted with one or more halo or a monocyclic heterocyclyl, or both;R3 and R4 are each independently hydrogen, halo, -NRaRb, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, or halo(Ci-C4)alkoxy;Q and U are each independently selected from phenyl, mono or bicyclic heteroaryl, mono or bicyclic heterocyclyl, and cycloalkyl, each of which being optionally substituted with 1 to 3 groups selected from R2;V is phenyl or mono or bicyclic heteroaryl optionally substituted with 1 to 3 groups selected from R3;R10, R11, R13, and R14 are each independently selected from hydrogen, halo, -CN, (Ci-C4)alkyl, halo(Ci-C4)alkyl, and -C(O)NRaRb; andR15 is hydrogen, (Ci-C4)alkyl, or halo(Ci-C4)alkyl.

5. The compound of any one of Claims 1 to 4, or a pharmaceutically acceptable saltthereof, wherein A is selected fromHO, whereinR14 is (Ci-C4)alkyl.The compound of any one of Claims 1to 5, or a pharmaceutically acceptable saltthereof, wherein A isHOrv7.     The compound of any one of Claims 1 to 6, or a pharmaceutically acceptable saltHOZ is N or CH.

8. The compound of Claim 7, or a pharmaceutically acceptable salt thereof,wherein Z is CH.

9. The compound of any one of Claims 4 to 8, wherein each R3 is independently selected from hydrogen, halo, and halo(Ci-C4)alkyl.

10. The compound of any one of Claims 4 to 9, or a pharmaceutically acceptable salt11. The compound of any one of Claims 4 to 10, or a pharmaceutically acceptable salt1012. The compound of any one of Claims 4 to 11, or a pharmaceutically acceptable saltthereof, wherein A isHO             HO                HO13. The compound of any one of Claims 4 to 12, or a pharmaceutically acceptable salt thereof, wherein A isHO14. The compound of any one of Claims 4 to 13, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from halo and (Ci-C4)alkyl.

15. The compound of any one of Claims 4 to 14, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from chloro, isopropyl, methyl, propyl, and ethyl.

16. The compound of any one of Claims 4 to 15, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from isopropyl and ethyl.

17. The compound of any one of Claims 4 to 16, or a pharmaceutically acceptable salt thereof, wherein R2 is selected from -ORa, -SRa, -C(O)NRaRb, and -C(O)NRa(Ci-4alkylene)NRaRb.

18. The compound of any one of Claims 4 to 17, or a pharmaceutically acceptable salt thereof, wherein Ra and Rb are each independently selected from hydrogen and (Ci-C4)alkyl, wherein said (Ci-C4)alkyl is optionally substituted with 1 to 3 halo or a 6-membered heterocyclyl.

19. The compound of any one of Claims 4 to 18, or a pharmaceutically acceptable salt thereof, wherein R2 is selected from OH, -C(O)NHCH2CF3, -C(O)NHCH2CH3, -C(O)NHCH(CH3)2, -C(O)NH(CH2CH3)2, -C(O)NHCH(CH3)CF3, -C(O)NHcyclopropyl, -C(O)NHmethylcyclopropyl, C(O)NH2, and -C(O)NH(CH2)2piperidinyl.

20. The compound of any one of Claims 4 to 19, or a pharmaceutically acceptable salt thereof, wherein R2 is selected from -C(O)NHCH2CF3 and OH.

21. The compound of any one of Claims 4 to 20, or a pharmaceutically acceptable salt thereof, wherein R2 is OH.

22. The compound of any one of Claims 1 to 21, or a pharmaceutically acceptable salt thereof, whereinL is selected from -(CH2)r-HET1-X1-HET2-(CH2)s-OC(O)-, -(CH2)r-HET1-X1-(CH2)q-HET2-(CH2)s-OC(O)-, -(CH2)r-HET1-X1-HET2-(CH2)s-C(O)O-(CH2)m-X2-, -(CH2)r-HET1-HET2-(CH2)s-C(O)-(CH2)m-X2-, -(CH2)yOC(O)-, -(CH2)r-HET1-(CH2)w-S-S-HET2-(CH2)s-OC(O)-,    -(CH2)r-HET1-X1-(CH2)s-OC(O)-,    -(CH2)r-HET1-X1-HET2-(CH2)s-NHC(O)O-(CH2)m-X2-, -(CH2)r-HET1-C(O)O-(CH2)m-X2-, -(CH2)rNRf(CH2)v-HET2-X1-HET1-(CH2)s-OC(O)-,  -(CH2)rNRf(CH2)v-HET2-X1-HET1-(CH2)s-C(O)O-(CH2)m-X2-,  -(CH2)rNRf(CH2)v-HET2-(CH2)s-NHC(O)O-(CH2)m-X2-, -(CH2)r-HET3-OC(O)-, -(CH2)r HET^X^HET^OQO)-, -(CH2)r-HET3-X1-(CH2)s-OC(O)-,   -(CH2)r-HET3-X1-HET2-OC(O)-, -X^HET^OQO)-, -X1-HET3-X2-(CH2)S-OC(O)-, -(CH2)r-HET1-HET2-(CH2)s-OC(O)-, -(CH2)r-HET1-(CH2)q-HET2-(CH2)s-OC(O)-, -(CH2)r-HET1-X1-(CH2)w-S-S-HET2-(CH2)s-OC(O)-,    -(CH2)r-HET1-HET2-(CH2)s-NHC(O)O-(CH2)m-X2-,    -(CH2)r-HET1-NHC(O)O-(CH2)m-X2-,    -(CH2)rNRf(CH2)v-HET2-X1-(CH2)q-HET1-(CH2)s-OC(O)-,    -(CH2)rNRf(CH2)v-HET2-HET1-(CH2)s-C(O)O-(CH2)m-X2-, -(CH2)rNRf(CH2)v-OC(O)-, -(CH2)rNRf(CH2)v-HET2-(CH2)w-S-S-HET1-(CH2)s-OC(O)-, -(CH2)rNRf(CH2)v-HET2-X1-(CH2)s-OC(O)-, -(CH2)rNRf(CH2)v-HET2-X1-HET1-(CH2)s-NHC(O)O-(CH2)m-X2-, -(CH2)rNRf(CH2)v-HET2-C(O)O-(CH2)m-X2-, -(CH2)rNRf(CH2)v-HET2-X1-(CH2)s-OC(O)-, -(CH2)rNRf(CH2)v-HET2-X1-(CH2)s-C(O)-(CH2)m-X2-, -(CH2)rNRf(CH2)v-HET2-X1-(CH2)q-HET1-(CH2)s-NHC(O)O-(CH2)m-X2-, -(CH2)rNRf(CH2)v-HET2-X1-(CH2)s-NHC(O)O-(CH2)m-X2-, -(CH2)rNRf(CH2)v-HET2-X1-HET1-(CH2)s-NHC(O)O-(CH2)m-X2-(CH2)m-X2-, -(CH2)rNRf(CH2)v-HET2-X1-(CH2)s-NHC(O)O-(CH2)m-X2-, -(CH2)r-HET1-X1-(CH2)q-HET3-(CH2)s-OC(O)-, -(CH2)r-HET1-X1-HET3-(CH2)s-C(O)O-(CH2)m-X2-, -(CH2)r-HET1-HET3-(CH2)s-C(O)-(CH2)m-X2-, -(CH2)r-HET1-(CH2)w-S-S-HET3-(CH2)s-OC(O)-, -(CH2)r-HET1-X1-HET3-(CH2)s-NHC(O)O-(CH2)m-X2-,       -(CH2)r-HET3-C(O)O-(CH2)m-X2-,       -(CH2)rNRf(CH2)v-HET2-X1-HET3-(CH2)s-OC(O)-, -(CH2)rNRf(CH2)v-HET3-X1-HET1-(CH2)s-C(O)O-(CH2)m-X2-, -(CH2)rNRf(CH2)v-HET3<CH2)s-NHC(O)O-(CH2)m-X2-, -C(O)NH-CRR’-C(O)NH-CRR’-C(O)NHCRR’C(O)NH(CH2)m-X2-, and -C(O)NH-CRR’-C(O)NH-CRR’-C(O)NH-HET2-(CH2)s-OC(O)-.m, q, r, s, v, w, and y are each independently 0 to 4;Rf is selected from hydrogen and (Ci-C4)alkyl;X1 and X2 are each independently selected from CO and -CH2-;HET1, HET2, and HET3 are each independently selected from monocyclic heterocyclyl, bicyclic heterocyclyl, monocyclic cycloalkyl, and phenyl; andR’ and R” are each independently selected from hydrogen and (Ci-C4)alkyl, wherein said (Ci-C4)alkyl is optionally substituted with phenyl or NHC(O)NH2.

23. The compound of any one of Claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein L is selected from -(CH2)r-HET1-X1-HET2-(CH2)s-OC(O)-, -(CH2)r-HET1-X1-(CH2)q-HET2-(CH2)s-OC(O)-, -(CH2)r-HET1-X1-HET2-(CH2)s-C(O)O-(CH2)m-X2-, -(CH2)r-HET1-HET2-(CH2)s-C(O)-(CH2)m-X2-, -(CH2)yOC(O)-, -(CH2)r-HET1-(CH2)w-S-S-HET2-(CH2)s-OC(O)-, -(CH2)r-HET1-X1-(CH2)s-OC(O)-, -(CH2)r-HET1-X1-HET2-(CH2)s-NHC(O)O-(CH2)m-X2-, -(CH2)r-HET1-C(O)O-(CH2)m-X2-, -(CH2)rNRf(CH2)v-HET2-X1-HET1-(CH2)s-OC(O)-, -(CH2)rNRf(CH2)v-HET2-X1-HET1-(CH2)s-C(O)O-(CH2)m-X2-, -(CH2)rNRf(CH2)v-HET2-(CH2)s-NHC(O)O-(CH2)m-X2-, -(CH2)r-HET3-OC(O)-, -(CH2)r-HE^-X^HE^-OCCO)-, -(CH2)r-HET3-X1-(CH2)s-OC(O)-,   -(CH2)r-HET3-X1-HET2-OC(O)-, -X^HETXOCCO)-, -X1-HET3-X2-(CH2)s-OC(O)-, -C(O)NH-CRR’-C(O)NH-CRR’ -C(O)NHCRR’C(O)NH(CH2)m-X2-, and -C(O)NH-CRR’ -C(O)NH-CRR’ -C(O)NH-HET2-(CH2)s-OC(O)-.

24. The compound of Claim 22 or 23, or a pharmaceutically acceptable salt thereof, wherein HET1 is monocyclic heterocyclyl.

25. The compound of any one of Claims 22 to 24, or a pharmaceutically acceptable salt thereof, wherein HET1 is selected from piperazinyl, azetindinyl, and piperidinyl.

26. The compound of any one of Claims 22 to 25, or a pharmaceutically acceptable salt thereof, wherein HET2 is selected from monocyclic heterocyclyl, monocyclic cycloalkyl, and phenyl.

27. The compound of any one of Claims 22 to 26, or a pharmaceutically acceptable salt thereof, wherein HET2 is selected from cyclohexyl, piperidinyl, cyclopropyl, and phenyl.

28. The compound of any one of Claims 22 to 27, or a pharmaceutically acceptable salt thereof, wherein HET3 is bicyclic heterocyclyl.

29. The compound of any one of Claims 22 to 28, or a pharmaceutically acceptable salt thereof, wherein HET3 is selected from 2-azaspiro[3.3]heptanyl, 2,7-diazaspiro[3.5]nonanyl, 2-azaspiro[3.5]nonanyl, 3-azabicyclo[3.1.0]hexanyl, 8-azabicyclo[3.2.1]octanyl, 3,8-diazabicyclo[3.2.1]octanyl, 3,6-diazabicyclo[3.1.1]heptanyl, and octahydro-lH-pyrrolo[2,3-c]pyridinyl.

30. The compound of any one of Claims 22 to 29, or a pharmaceutically acceptable salt thereof, wherein risk31. The compound of any one of Claims 22 to 30, or a pharmaceutically acceptable salt thereof, wherein s is 0, 1, 2, or 3.

32. The compound of any one of Claims 22 to 31, or a pharmaceutically acceptable salt thereof, wherein q is 1.

33. The compound of any one of Claims 22 to 32, or a pharmaceutically acceptable salt thereof, wherein m is 1.

34. The compound of any one of Claims 22 to 33, or a pharmaceutically acceptable salt thereof, wherein y is 1 to 4.

35. The compound of any one of Claims 22 to 34, or a pharmaceutically acceptable salt thereof, wherein w is 1 to 4.

36. The compound of any one of Claims 22 to 35, or a pharmaceutically acceptable salt thereof, wherein v is 1.

37. The compound of any one of Claims 1 to 36, or a pharmaceutically acceptable salt5 thereof, wherein L is selected fromwherein * indicates the point of attachment to A.5   38. The compound of Claim 1, wherein the compound is selected from10HOHOHOHOo03C00 / v10HOHO10or a pharmaceutically acceptable salt of any of the foregoing.

39. A pharmaceutical composition comprising a compound of any one of Claims 1 to 38, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

40. A method of treating cancer comprising administering to a subject a therapeutically effective amount of a compound of any one of Claims 1 to 38, or a pharmaceutically acceptable salt thereof, or the composition of Claim 39.15