Compounds and methods for inhibiting autophagy

Abstract

The present disclosure provides compounds of formula I: A-B-E3L I or a pharmaceutically acceptable salt thereof, and uses thereof, for example in the inhibition of autophagy, and the treatment of diseases, disorders, and conditions by the inhibition of autophagy.

Description

COMPOUNDS AND METHODS FOR INHIBITING AUTOPHAGYCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to United States Provisional Application No. 63 / 605,371, filed December 1, 2023, the entirety of which is incorporated herein by reference.BACKGROUND

[0002] Autophagy is a cellular mechanism for the removal of aggregated proteins and cellular waste from the cell. See Turco, et cd., Molecular Cell, 74:330-346 (2019). The process is initiated by the formation of a double membraned structure termed the “phagophore” which forms around the cargo to be degraded and then upon closing matures into an “autophagosome”, completely encapsulating the cargo. The autophagosome along with its enclosed contents then fuse with the degradative lysosome wherein the autophagosome plus cargo are degraded. See Nakatogawa, H., Nat Rev Mol Cell Biol 21, 439-458 (2020).

[0003] Autophagy is understood to play a role in both tumor growth and cancer-cell development and proliferation. See Yun and Lee, Int. J. Mol. Sci., 2018 Nov; 19(11):3466. Restricting autophagy has recently been shown to be useful for the treatment of certain diseases, disorders, and conditions, including cancer. See Yang, et al., Cancer Discov., 2014 Aug; 4(8):905-913.SUMMARY

[0004] The present disclosure provides, among other things, compounds and compositions useful for the inhibition of autophagy. In particular, the present disclosure leverages the insights that particular heterobifunctional small molecule compounds can be used to disrupt the autophagy process by degrading precursors of autophagosome formation.

[0005] In some embodiments, the present disclosure provides a compound represented by Formula I:A-B-E3Lor a pharmaceutically acceptable salt thereof, wherein:A is a moiety that binds to or associates with FIP200;B is a linker moiety; andE3L is a ubiquitin E3 ligase binding moiety.

[0006] In some embodiments, a compound described herein is a compound of formula I, wherein A is selected from formula II- 1 , II-2, II-3, or II-4 :or a pharmaceutically acceptable salt thereof, wherein:G1is an optionally substituted Ce-Cn aryl or an optionally substituted 5- to 6- membered heteroaryl;X1is -S-, -N(R3)-, -O-, optionally substituted C1-C6aliphatic, or optionally substituted C3-C6 cycloaliphatic;X2is independently C(R3) or N, provided that, when X2is N, then X1is optionally substituted C1-C6aliphatic, or optionally substituted C3-C6 cycloaliphatic; when a bond between X3and X4is a single bond, then X3is N(R2a), and X4is C(O) when a bond between X3and X4is a double bond, then X3is C(R2b) and X4is C(R3), or N;each R1is independently selected from halogen, optionally substituted C1-C6aliphatic, and optionally substituted -O-C1-C6aliphatic; or two instances of R1come together with the atoms to which they are attached to form a n optionally substituted Ce-Cn aryl ring, an optionally substituted C4-C6 cycloaliphatic ring, a 5- to 6- membered heteroaryl ring comprising 1 to 3 heteroatoms selected from N, O, and S, or an optionally substituted 5- to 6- membered heterocyclic ring comprising 1 to 3 heteroatoms selected from N, O, and S;R2ais optionally substituted C1-C6aliphatic;R2bis hydrogen, optionally substituted C1-C6aliphatic, optionally substituted -N(R3)- C1-C6aliphatic, or optionally substituted -O-C1-C6aliphatic; each R3is independently selected from hydrogen, halogen, and optionally substituted C1-C6aliphatic;R4is selected from optionally substituted C6-C12 aryl, optionally substituted 5- to 12- membered heteroaryl ring comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted 4- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, and optionally substituted C1-C6aliphatic;R5is an optionally substituted 4- to 6-membered heterocyclic ring, an optionally substituted 5- to 6-membered heteroaryl ring, an optionally C3-C6 cycloaliphatic ring, an optionally substituted C6-C12 aryl, or an optionally substituted C1-C6aliphatic;L1is a bond, -C(O)-, -S(O)-, -S(O)2-, or -NR3-; n is independently 0, 1, 2, 3, 4, 5, or 6; each of X5, X6, and X7is independently selected from the group consisting of N and CH;R7is hydrogen, an optionally substituted -O-C1-C6aliphatic, -S(O)2R3, optionally substituted C1-C6aliphatic, an optionally substituted 4- to 12-membered heterocycle ring comprising 1 to 4 heteroatoms selected from N, O, and S, anoptionally substituted Ce-Cn aryl, or an optionally substituted 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and SG2is optionally substituted Ce-Cn aryl, optionally substituted 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, optionally substituted 5- to 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, or optionally substituted C3-C6 cycloaliphatic;G3is optionally substituted 4- to 12-membered heterocycle ring comprising 1 to 4 heteroatoms selected from N, O, and S, optionally substituted 5- to 6-membered heteroaryl ring comprising 1 to 4 heteroatoms selected from N, O, and S, an optionally substituted C3-C6 cycloaliphatic ring or optionally substituted Ce-Ci2aryl;L2is a bond, -NR3-C(O)-, -C(O)-NR3-, optionally substituted C1-C6aliphatic, optionally substituted 4- to 6-membered heterocyclic, or optionally substituted C3- Ce cycloaliphatic;L3is -NR3-, -O-, -C(O)-, -NR3-C(O)-, -NR3-S(O)2-, -C(O)-NR3-, -S(O)2NR3-, -NR3- C(O)-NR3-, optionally substituted C1-C6aliphatic, or optionally substituted C3-C6 cycloaliphatic ring;* represents a point of attachment to moiety B; and wherein: when A is a moiety of formula II- 3 then R6is a bond, optionally substituted C1-C6aliphatic, optionally substituted 2- to 6-membered heteroaliphatic, optionally substituted 4- to 6-membered heterocycle comprising one 1 to 3 heteroatoms selected from N, O, and S, optionally substituted Ce-Ci2aryl, or optionally substituted C3-C6 cycloaliphatic; and R8is halogen, -OR3, -C(O)N(R3)2, - C(O)OR3, optionally substituted C1-C6aliphatic, optionally substituted C3-C6 cycloaliphatic, optionally substituted Ce-Ci2aryl; and when A is of formula II-4, then R6is H, halogen, optionally substituted C1-C6aliphatic, optionally substituted 2- to 6-membered heteroaliphatic, optionallysubstituted 4- to 6-membered heterocycle comprising one 1 to 3 heteroatoms selected from N, O, and S, optionally substituted Ce-Cn aryl, or optionally substituted C3-C6 cycloaliphatic; and R8is a bond, -O-, -C(O)NR3-, -C(O)OR3, optionally substituted C1-C6aliphatic, optionally substituted C3-C6 cycloaliphatic, or optionally substituted C6-C12 aryl.

[0007] In some embodiments, the present disclosure provides a method of treating a disease, disorder, or condition in a subject comprising administering to the subject a compound or composition described herein.

[0008] In some embodiments, the present disclosure provides a method of inhibiting autophagy in a subject comprising administering to the subject a compound or composition described herein.BRIEF DESCRIPTION OF THE DRAWING

[0009] Figure 1 presents certain data illustrating remaining levels of FIP-200 (Rblccl) in different groups after treatment with 1-26.DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0010] Autophagy inhibition has emerged as a promising mode of treatment of particular diseases, disorders, and conditions, including, for example, cancer. The present disclosure provides, among other things, certain compounds and compositions, and uses thereof, that inhibit autophagy, and can therefore be used for the treatment of said diseases, disorders, and conditions.

[0011] Accordingly, in some embodiments, the present disclosure provides a compound represented by formula I:A-B-E3LIor a pharmaceutically acceptable salt thereof, wherein A is a moiety that binds to or associates with FIP200, B is a linker moiety, and E3L is a ubiquitin E3 ligase binding moiety. Classes and subclasses of A B, and E3L are described herein.Compounds and Definitions

[0012] Compounds of this disclosure include those described generally above and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of Elements, CAS version, Handbook of Chemistry and Physics, 75thEd. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry”, 5thEd., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0013] Unless otherwise stated, structures depicted herein are meant to include all stereoisomeric (e.g., enantiomeric or diastereomeric) forms of the structure, as well as all geometric or conformational isomeric forms of the structure. For example, the R and S configurations of each stereocenter are contemplated as part of the disclosure. Therefore, single stereochemical isomers, as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of provided compounds are within the scope of the disclosure. For example, in some cases, Table 1 shows one or more stereoisomers of a compound, and unless otherwise indicated, represents each stereoisomer alone and / or as a mixture. Unless otherwise stated, all tautomeric forms of provided compounds are within the scope of the disclosure.

[0014] Unless otherwise indicated, structures depicted herein are meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including replacement of hydrogen by deuterium or tritium, or replacement of a carbon by13C- or14C-enriched carbon are within the scope of this disclosure.

[0015] About or approximately: As used herein, the term "approximately" or "about," as applied to one or more values of interest, refers to a value that is similar to a stated reference value. In general, those skilled in the art, familiar within the context, will appreciate the relevant degree of variance encompassed by "about" or "approximately" in that context. For example, in some embodiments, the term "approximately" or "about" may encompass a range of values that are within (i.e., ±) 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less of the referred value.

[0016] Administering: As used herein, the term "administering" or "administration" typically refers to the administration of a composition to a subject to achieve delivery of an agent that is, or is included in, a composition to a target site or a site to be treated. Those of ordinary skill in the art will be aware of a variety of routes that may, in appropriate circumstances, be utilized for administration to a subject, for example a human. For example, in some embodiments, administration may be ocular, oral, parenteral, topical, etc. In some particular embodiments, administration may be bronchial (e.g., by bronchial instillation), buccal, dermal (which may be or comprise, for example, one or more of topical to the dermis, intradermal, interdermal, transdermal, etc. , enteral, intra-arterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intraventricular, within a specific organ (e.g., intrahepatic), mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (e.g., by intratracheal instillation), vaginal, vitreal, etc. In some embodiments, administration may be parenteral. In some embodiments, administration may be oral. In some particular embodiments, administration may be intravenous. In some particular embodiments, administration may be subcutaneous. In some embodiments, administration may involve only a single dose. In some embodiments, administration may involve application of a fixed number of doses. In some embodiments, administration may involve dosing that is intermittent (e.g., a plurality of doses separated in time) and / or periodic (e.g., individual doses separated by a common period of time) dosing. In some embodiments, administration may involve continuous dosing (e.g., perfusion) for at least a selected period of time. In some embodiments, administration may comprise a prime-and-boost protocol. A prime-and-boost protocol can include administration of a first dose of a pharmaceutical composition (e.g., an immunogenic composition, e.g., a vaccine) followed by, after an interval of time, administration of a second or subsequent dose of a pharmaceutical composition (e.g., an immunogenic composition, e.g., a vaccine). In the case of an immunogenic composition, a prime-and-boost protocol can result in an increased immune response in a patient.

[0017] Agent: As used herein, the term “agent”, may refer to a compound, molecule, or entity of any chemical class including, for example, a small molecule, polypeptide, nucleic acid, saccharide, lipid, metal, or a combination or complex thereof. In some embodiments, the term “agent” may refer to a compound, molecule, or entity that comprises a polymer. In some embodiments, the term may refer to a compound or entity that comprises one or more polymeric moi eties. In some embodiments, the term “agent” may refer to a compound, molecule, or entity that is substantially free of a particular polymer or polymeric moiety. In some embodiments, the term may refer to a compound, molecule, or entity that lacks or is substantially free of any polymer or polymeric moiety.

[0018] Aliphatic: The term “aliphatic” refers to a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “cycloaliphatic”), that has a single point or more than one points of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-12 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms (e.g., Cue). In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms (e.g., C1-5). In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms (e.g., C1-4). In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms (e.g., C1-3), and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms (e.g., C1-2). Suitable aliphatic groups include, but are not limited to,linear or branched, substituted or unsubstituted alkyl, alkenyl, or alkynyl groups and hybrids thereof. A preferred aliphatic group is Ci-6 alkyl.

[0019] Alkyl: The term “alkyl”, used alone or as part of a larger moiety, refers to a saturated, optionally substituted straight or branched chain hydrocarbon group having (unless otherwise specified) 1-12, 1-10, 1-8, 1-6, 1-4, 1-3, or 1-2 carbon atoms (e.g., C1-12, C1-10, C1-8, C1-6, C1-4, C1-3, or C1-2). Exemplary alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, and heptyl.

[0020] Alkylene: The term “alkylene” is refers to a bivalent alkyl group. In some embodiments, “alkylene” is a bivalent straight or branched alkyl group. In some embodiments, an "alkylene chain" is a polymethylene group, i.e., -(CH2)n-, wherein n is a positive integer, e.g., from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. An optionally substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms is optionally replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group and also include those described in the specification herein. It will be appreciated that two substituents of the alkylene group may be taken together to form a ring system. In certain embodiments, two substituents can be taken together to form a 3- to 7-membered ring. The substituents can be on the same or different atoms. The suffix “-ene” or “-enyl” when appended to certain groups herein are intended to refer to a bifunctional moiety of said group. For example, “-ene” or “-enyl”, when appended to “cyclopropyl” becomes “cyclopropylene” or “cyclopropylenyl” and is intended to refer to a bifunctional cyclopropyl group, e.g.,

[0021] Alkenyl: The term “alkenyl”, used alone or as part of a larger moiety, refers to an optionally substituted straight or branched chain or cyclic hydrocarbon group having at least one double bond and having (unless otherwise specified) 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms(e.g., C2-12, C2-10, C2-8, C2-6, C2-4, or C2-3). Exemplary alkenyl groups include ethenyl, propenyl, butenyl, pentenyl, hex enyl, and heptenyl. The term “cycloalkenyl” refers to an optionally substituted non-aromatic monocyclic or multicyclic ring system containing atleast one carbon-carbon double bond and having about 3 to about 10 carbon atoms. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, and cycloheptenyl.

[0022] Alkynyl: The term “alkynyl”, used alone or as part of a larger moiety, refers to an optionally substituted straight or branched chain hydrocarbon group having at least one triple bond and having (unless otherwise specified) 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms (e g-, C2-12, C2-10, C2-8, C2-6, C2-4, or C2-3). Exemplary alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and heptynyl.

[0023] Aryl: The term “aryl” refers to monocyclic and bicyclic ring systems having a total of six to fourteen ring members (e.g., Ce-Cu), wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to seven ring members. In some embodiments, an “aryl” group contains between six and twelve total ring members (e.g., G,- C12). The term “aryl” may be used interchangeably with the term “aryl ring”. In certain embodiments, “aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Unless otherwise specified, “aryl” groups are hydrocarbons. In some embodiments, an “aryl” ring system is an aromatic ring (e.g., phenyl) that is fused to a non-aromatic ring (e.g., cycloalkyl). Examples of aryl rings include that are fused include

[0024] Biological sample: As used herein, the term “biological sample” typically refers to a sample obtained or derived from a biological source (e.g., a tissue or organism or cell culture) of interest, as described herein. In some embodiments, a source of interest comprises an organism, such as an animal or human. In some embodiments, a biological sample is or comprises biological tissue or fluid. In some embodiments, a biological sample may be or comprise bone marrow; blood; blood cells; ascites; tissue or fine needle biopsy samples; cellcontaining body fluids; free floating nucleic acids; sputum; saliva; urine; cerebrospinal fluid, peritoneal fluid; pleural fluid; feces; lymph; gynecological fluids; skin swabs; vaginal swabs;oral swabs; nasal swabs; washings or lavages such as a ductal lavages or broncheoalveolar lavages; aspirates; scrapings; bone marrow specimens; tissue biopsy specimens; surgical specimens; feces, other body fluids, secretions, and / or excretions; and / or cells therefrom, etc. In some embodiments, a biological sample is or comprises cells obtained from an individual. In some embodiments, obtained cells are or include cells from an individual from whom the sample is obtained. In some embodiments, a sample is a “primary sample” obtained directly from a source of interest by any appropriate means. For example, in some embodiments, a primary biological sample is obtained by methods selected from the group consisting of biopsy (e.g., fine needle aspiration or tissue biopsy), surgery, collection of body fluid (e.g., blood, lymph, feces etc.), etc. In some embodiments, as will be clear from context, the term “sample” refers to a preparation that is obtained by processing (e.g., by removing one or more components of and / or by adding one or more agents to) a primary sample. For example, filtering using a semi-permeable membrane. Such a “processed sample” may comprise, for example, nucleic acids or proteins extracted from a sample or obtained by subjecting a primary sample to techniques such as amplification or reverse transcription of mRNA, isolation and / or purification of certain components, etc.

[0025] Bridged bicyclic: As used herein, the term “bridged bicyclic” refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge. As defined by IUPAC, a “bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bridged bicyclics include:

[0026] Carrier: As used herein, the term “carrier” refers to a diluent, adjuvant, excipient, or vehicle with which a composition is administered. In some exemplary embodiments, carriers can include sterile liquids, such as, for example, water and oils, including oils of petroleum, animal, vegetable or synthetic origin, such as, for example, peanut oil, soybean oil, mineral oil, sesame oil and the like. In some embodiments, carriers are or include one or more solid components.

[0027] Combination therapy: As used herein, the term “combination therapy” refers to those situations in which a subject is simultaneously exposed to two or more therapeutic regimens (e.g., two or more therapeutic agents or modality(ies)). In some embodiments, the two or more regimens may be administered simultaneously; in some embodiments, such regimens may be administered sequentially (e.g., all “doses” of a first regimen are administered prior to administration of any doses of a second regimen); in some embodiments, such agents are administered in overlapping dosing regimens. In some embodiments, “administration” of combination therapy may involve administration of one or more agent(s) or modality(ies) to asubject receiving the other agent(s) or modality(ies) in the combination. For clarity, combination therapy does not require that individual agents be administered together in a single composition (or even necessarily at the same time), although in some embodiments, two or more agents, or active moieties thereof, may be administered together in a combination composition, or even in a combination compound (e.g., as part of a single chemical complex or covalent entity).

[0028] Composition: Those skilled in the art will appreciate that the term “composition” may be used to refer to a discrete physical entity that comprises one or more specified components. In general, unless otherwise specified, a composition may be of any form - e.g., gas, gel, liquid, solid, etc.

[0029] Cycloaliphatic. As used herein, the term “cycloaliphatic” refers to a monocyclic C3-8 hydrocarbon or a bicyclic Ce-io hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point or more than one points of attachment to the rest of the molecule.

[0030] Cycloalkyl. As used herein, the term “cycloalkyl” refers to an optionally substituted saturated ring monocyclic or polycyclic system of about 3 to about 10 ring carbon atoms. Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0031] Dosage form or unit dosage form: Those skilled in the art will appreciate that the term “dosage form” may be used to refer to a physically discrete unit of an active agent (e.g., a therapeutic or diagnostic agent) for administration to a subject. Typically, each such unit contains a predetermined quantity of active agent. In some embodiments, such quantity is a unit dosage amount (or a whole fraction thereof) appropriate for administration in accordance with a dosing regimen that has been determined to correlate with a desired or beneficial outcome when administered to a relevant population (i.e., with a therapeutic dosing regimen).

[0032] Dosing regimen or therapeutic regimen: Those skilled in the art will appreciate that the terms “dosing regimen” and “therapeutic regimen” may be used to refer to a set of unit doses (typically more than one) that are administered individually to a subject, typicallyseparated by periods of time. In some embodiments, a given therapeutic agent has a recommended dosing regimen, which may involve one or more doses. In some embodiments, a dosing regimen comprises a plurality of doses each of which is separated in time from other doses. In some embodiments, individual doses are separated from one another by a time period of the same length; in some embodiments, a dosing regimen comprises a plurality of doses and at least two different time periods separating individual doses. In some embodiments, all doses within a dosing regimen are of the same unit dose amount. In some embodiments, different doses within a dosing regimen are of different amounts. In some embodiments, a dosing regimen comprises a first dose in a first dose amount, followed by one or more additional doses in a second dose amount different from the first dose amount. In some embodiments, a dosing regimen comprises a first dose in a first dose amount, followed by one or more additional doses in a second dose amount same as the first dose amount. In some embodiments, a dosing regimen is correlated with a desired or beneficial outcome when administered across a relevant population (i.e., is a therapeutic dosing regimen).

[0033] Excipient: As used herein, the term “excipient” refers to a non-therapeutic agent that may be included in a pharmaceutical composition, for example, to provide or contribute to a desired consistency or stabilizing effect. Suitable pharmaceutical excipients include, for example, starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.

[0034] Halogen: The term “halogen” means F, Cl, Br, or I.

[0035] Heteroaliphatic. The term “heteroaliphatic” or “heteroaliphatic group”, as used herein, denotes an optionally substituted hydrocarbon moiety having, in addition to carbon atoms, from one to five heteroatoms, that may be straight-chain (i.e., unbranched), branched, or cyclic (“heterocyclic”) and may be completely saturated or may contain one or more units of unsaturation, but which is not aromatic. The term “heteroatom” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. The term “nitrogen” also includes a substituted nitrogen. Unless otherwisespecified, heteroaliphatic groups contain 1-10 carbon atoms wherein 1-3 carbon atoms are optionally and independently replaced with heteroatoms selected from oxygen, nitrogen, and sulfur. In some embodiments, heteroaliphatic groups contain 1-4 carbon atoms, wherein 1-2 carbon atoms are optionally and independently replaced with heteroatoms selected from oxygen, nitrogen, and sulfur. In yet other embodiments, heteroaliphatic groups contain 1-3 carbon atoms, wherein 1 carbon atom is optionally and independently replaced with a heteroatom selected from oxygen, nitrogen, and sulfur. Suitable heteroaliphatic groups include, but are not limited to, linear or branched, heteroalkyl, heteroalkenyl, and heteroalkynyl groups. For example, a 1- to 10 atom heteroaliphatic group includes the following exemplary groups: -O-CH3, -CH2-O-CH3, -O-CH2-CH2-O-CH2-CH2-O-CH3, and the like.

[0036] Heteroaryl: The terms “heteroaryl” and “heteroar-”, used alone or as part of a larger moiety, e.g., “heteroaralkyl”, or “heteroaralkoxy”, refer to monocyclic or bicyclic ring groups having 5 to 10 ring atoms (e.g., 5- to 6-membered monocyclic heteroaryl or 9- to 10- membered bicyclic heteroaryl); having 6, 10, or 14 7t-electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, imidazo[l,2- a]pyrimidinyl, imidazo[l,2-a]pyridyl, imidazo[4,5-b]pyridyl, imidazo[4,5-c]pyridyl, pyrrol opyridyl, pyrrolopyrazinyl, thienopyrimidinyl, tri azol opyridyl, andbenzoisoxazolyl. The terms “heteroaryl” and “heteroar-”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring (i.e., a bicyclic heteroaryl ring having 1 to 3 heteroatoms). Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzotri azolyl, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4 / / quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, pyrido[2,3-b]-l,4-oxazin-3(4H)-one, 4H-thieno[3,2-b]pyrrole, and benzoisoxazolyl. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring”, “heteroaryl group”, or “heteroaromatic”, any of which terms include rings that are optionally substituted.

[0037] Heteroatom: The term “heteroatom” as used herein refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen.

[0038] Heterocycle: As used herein, the terms “heterocycle”, “heterocyclyl”, “heterocyclic radical”, and “heterocyclic ring” are used interchangeably and refer to a stable 3- to 8-membered monocyclic, a 6- to 10-membered bicyclic, or a 10- to 16-membered polycyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, such as one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR+(as in N-substituted pyrrolidinyl). A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and thiamorpholinyl. A heterocyclyl group may be mono-, bi-, tri-, or polycyclic, preferably mono-, bi-, or tricyclic, more preferably mono- or bicyclic. A bicyclic heterocyclic ring also includes groups in which the heterocyclic ring is fused to one or more aryl rings. Exemplary bicyclic heterocyclic groups include indolinyl, isoindolinyl, benzodi oxolyl, 1,3- dihydroisobenzofuranyl, 2,3-dihydrobenzofuranyl, and tetrahydroquinolinyl. A bicyclic heterocyclic ring can also be a spirocyclic ring system (e.g., 7- to 11-membered spirocyclic fused heterocyclic ring having, in addition to carbon atoms, one or more heteroatoms as defined above (e.g., one, two, three or four heteroatoms)). A bicyclic heterocyclic ring can also be abridged ring system (e.g., 7- to 11-membered bridged heterocyclic ring having one, two, or three bridging atoms.

[0039] Oral: The phrases “oral administration” and “administered orally” as used herein have their art-understood meaning referring to administration by mouth of a compound or composition.

[0040] Parenteral: The phrases “parenteral administration” and “administered parenterally” as used herein have their art-understood meaning referring to modes of administration other than enteral and topical administration, usually by injection, and include, without limitation, intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticulare, subcapsular, subarachnoid, intraspinal, and intrastemal injection and infusion.

[0041] Partially unsaturated: As used herein, the term “partially unsaturated” refers to a ring moiety that includes at least one double or triple bond between ring atoms. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic (e.g., aryl or heteroaryl) moi eties, as herein defined.

[0042] Patient or subject: As used herein, the term “patient” or “subject” refers to any organism to which a provided composition is or may be administered, e.g., for experimental, diagnostic, prophylactic, cosmetic, and / or therapeutic purposes. Typical patients or subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and / or humans). In some embodiments, a patient is a human. In some embodiments, a patient or a subject is suffering from or susceptible to one or more disorders or conditions. In some embodiments, a patient or subject displays one or more symptoms of a disorder or condition. In some embodiments, a patient or subject has been diagnosed with one or more disorders or conditions. In some embodiments, a patient or a subject is receiving or has received certain therapy to diagnose and / or to treat a disease, disorder, or condition.

[0043] Pharmaceutical composition: As used herein, the term “pharmaceutical composition” refers to an active agent, formulated together with one or more pharmaceuticallyacceptable carriers. In some embodiments, the active agent is present in unit dose amount appropriate for administration in a therapeutic or dosing regimen that shows a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population. In some embodiments, pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin, lungs, or oral cavity; intravaginally or intrarectally, for example, as a pessary, cream, or foam; sublingually; ocularly; transdermally; or nasally, pulmonary, and to other mucosal surfaces.

[0044] Pharmaceutically acceptable: As used herein, the phrase “pharmaceutically acceptable” refers to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0045] Pharmaceutically acceptable salt: The term “pharmaceutically acceptable salt”, as used herein, refers to salts of such compounds that are appropriate for use in pharmaceutical contexts, i.e., salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977).

[0046] Substituted or optionally substituted: As described herein, compounds of the invention may contain “optionally substituted” moieties. In general, the term “substituted,”whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. “Substituted” applies to one or more r hydrogens that are either explicit or implicit from the structure (e.g., refers to at). Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes provided herein. Groups described as being “substituted” preferably have between 1 and 4 substituents, more preferably 1 or 2 substituents. Groups described as being “optionally substituted” may be unsubstituted or be “substituted” as described above.

[0047] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; -(CH2)o 4R0; -(CH2)o 4OR0; -0(CH2)o-4R°, -O- (CH2)O-4C(0)OR°; -(CH2)O-4CH(OR°)2; -(CH2)O-4SR°; -(CH2)o-4Ph, which may be substituted with R°; -(CH2)o-40(CH2)o-iPh which may be substituted with R°; -CH=CHPh, which may be substituted with R°; -(CH2)o-40(CH2)o-i -pyridyl which may be substituted with R°; -NO2; - CN; -N3; -(CH2)O- 4N(RO)2; -(CH2)O4N(RO)C(O)R°; -N(R°)C(S)R°; -(CH2)O-4N(RO)C(O)NR°2; -N(RO)C(S)NR°2; -(CH2)O ^N(R°)C(O)OR°;N(R°)N(R°)C(O)R°; -N(R°)N(RO)C(O)NRO2; -N(R°)N(R°)C(O)OR°; -(CH2)o4C(O)R°; C(S)R°; -(CH2)O 4C(O)ORO; -(CH2)O4C(O)SRO; -(CH2)O4C(O)OSiR°3; -(CH2)o4OC(O)R°; - OC(0)(CH2)O4SRO; -(CH2)O 4SC(O)RO; -(CH2)O4C(O)NRO2; -C(S)NRO2; -C(S)SR°; - SC(S)SR°, -(CH2)O 4OC(O)NRO2; -C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH2C(O)RO; - C(NOR°)R°; -(CH2)O 4SSRO; -(CH2)O4S(O)2RO; -(CH2)O4S(O)2ORO; -(CH2)O4OS(O)2RO; - S(O)2NR°2; -(CH2)O 4S(O)RO; -N(RO)S(O)2NR°2; -N(RO)S(O)2R°; -N(OR°)R°; -C(NH)NRO2; -P(O)2RO; -P(O)RO2; -OP(O)RO2; -OP(O)(ORO)2; SiR°3; -(Ci4straight or branched alkylene)O-N(R°)2; or -(Ci-4straight or branched alkylene)C(O)O-N(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, Ci-6 aliphatic, -CH2Ph, - 0(CH2)o-iPh, -CH2-(5- to 6-membered heteroaryl ring), or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3 - to 12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0048] Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms), are independently halogen, -(CH2)0 2R*, -(haloR*), -(CH2)0 2OH, -(CH2)0 2OR*, -(CH2)02CH(OR*)2, -O(haloR’), -CN, -N3, -(CH2)0 2C(O)R*, -(CH2)0 2C(O)OH, -(CH2)02C(O)OR*, -(CH2)O 2SR*, -(CH2)O2SH, -(CH2)O 2NH2, -(CH2)O 2NHR*, -(CH2)O 2NR*2, - NO2, -SiR*3, -OSiR*3, -C(O)SR* -(Ci-4straight or branched alkylene)C(O)OR*, or -SSR* wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from Ci-4aliphatic, -CH2Ph, -0(CH2)o-iPh, or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =0 and =S.

[0049] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =0 (“oxo”), =S, =NNR*2, =NNHC(O)R*,wherein each independent occurrence of R* is selected from hydrogen, C1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: -O(CR*2)2-3O-, wherein each independent occurrence of R* is selected from hydrogen, C1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0050] Suitable substituents on the aliphatic group of R* include halogen, - R*, -(haloR*), -OH, -OR*, -O(haloR*), -CN, -C(O)OH, -C(O)OR*, -NH2, -NHR*, -NR*2, or -NO2, wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1-4 aliphatic, -CH2Ph, -0(CH2)o-iPh, or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0051] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include-C(O)Rf, -C(O)ORf, -C(O)C(O)Rt, C(O)CH2C(O)Rt, -S(O)2R^ -SCO^NR^, -C(S)NRf2, -C(NH)NR\ or -N(Rt)S(O)2Rt; wherein each R1' is independently hydrogen, C1-6 aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R1', taken together with their intervening atom(s) form an unsubstituted 3- to 12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0052] Suitable substituents on the aliphatic group of R1' are independently halogen, - R*, -(haloR*), -OH, -OR*, -O(haloR*), -CN, -C(O)OH, -C(O)OR*, -NH2, -NHR*, -NR*2, or -NO2, wherein each R* is unsubstituted or where preceded by “halo” is substituted only withone or more halogens, and is independently C1-4 aliphatic, -CH2PI1, -0(CH2)o iPh, or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0053] Small molecule: As used herein, the term “small molecule” means a low molecular weight organic and / or inorganic compound. In general, a “small molecule” is a molecule that is less than about 5 kilodaltons (kD) in size. In some embodiments, a small molecule is less than about 4 kD, 3 kD, about 2 kD, or about 1 kD. In some embodiments, the small molecule is less than about 800 daltons (D), about 600 D, about 500 D, about 400 D, about 300 D, about 200 D, or about 100 D. In some embodiments, a small molecule is less than about 2000 g / mol, less than about 1500 g / mol, less than about 1000 g / mol, less than about 800 g / mol, or less than about 500 g / mol. In some embodiments, a small molecule is not a polymer.

[0054] In some embodiments, a small molecule does not include a polymeric moiety. In some embodiments, a small molecule is not and / or does not comprise a protein or polypeptide (e.g., is not an oligopeptide or peptide). In some embodiments, a small molecule is not and / or does not comprise a polynucleotide (e.g., is not an oligonucleotide). In some embodiments, a small molecule is not and / or does not comprise a polysaccharide; for example, in some embodiments, a small molecule is not a glycoprotein, proteoglycan, glycolipid, etc.). In some embodiments, a small molecule is not a lipid.

[0055] In some embodiments, a small molecule is a modulating agent (e.g., is an inhibiting agent or an activating agent). In some embodiments, a small molecule is biologically active. In some embodiments, a small molecule is detectable (e.g., comprises at least one detectable moiety). In some embodiments, a small molecule is a therapeutic agent.

[0056] Those of ordinary skill in the art, reading the present disclosure, will appreciate that certain small molecule compounds described herein may be provided and / or utilized in any of a variety of forms such as, for example, crystal forms (e.g., polymorphs, solvates, etc), salt forms, protected forms, pro-drug forms, ester forms, isomeric forms (e.g., optical and / or structural isomers), isotopic forms, etc.

[0057] Those of ordinary skill in the art will appreciate that certain small molecule compounds have structures that can exist in one or more steroisomeric forms. In some embodiments, such a small molecule may be utilized in accordance with the present disclosure in the form of an individual enantiomer, diastereomer or geometric isomer, or may be in the form of a mixture of stereoisomers; in some embodiments, such a small molecule may be utilized in accordance with the present disclosure in a racemic mixture form.

[0058] Those of skill in the art will appreciate that certain small molecule compounds have structures that can exist in one or more tautomeric forms. In some embodiments, such a small molecule may be utilized in accordance with the present disclosure in the form of an individual tautomer, or in a form that interconverts between tautomeric forms.

[0059] Those of skill in the art will appreciate that certain small molecule compounds have structures that permit isotopic substitution (e.g.,2H or3H for H;nC,13C or14C for12C;13N or15N for14N;17O or18O for16O;36C1 for35C1 or37C1;18F for19F;131I for127I; etc.). In some embodiments, such a small molecule may be utilized in accordance with the present disclosure in one or more isotopically modified forms, or mixtures thereof.

[0060] In some embodiments, reference to a particular small molecule compound may relate to a specific form of that compound. In some embodiments, a particular small molecule compound may be provided and / or utilized in a salt form (e.g., in an acid-addition or baseaddition salt form, depending on the compound); in some such embodiments, the salt form may be a pharmaceutically acceptable salt form.

[0061] In some embodiments, where a small molecule compound is one that exists or is found in nature, that compound may be provided and / or utilized in accordance in the present disclosure in a form different from that in which it exists or is found in nature. Those of ordinary skill in the art will appreciate that, in some embodiments, a preparation of a particular small molecule compound that contains an absolute or relative amount of the compound, or of a particular form thereof, that is different from the absolute or relative (with respect to another component of the preparation including, for example, another form of the compound) amount of the compound or form that is present in a reference preparation of interest (e.g., in a primarysample from a source of interest such as a biological or environmental source) is distinct from the compound as it exists in the reference preparation or source. Thus, in some embodiments, for example, a preparation of a single stereoisomer of a small molecule compound may be considered to be a different form of the compound than a racemic mixture of the compound; a particular salt of a small molecule compound may be considered to be a different form from another salt form of the compound; a preparation that contains only a form of the compound that contains one conformational isomer ((Z) or (E)) of a double bond may be considered to be a different form of the compound from one that contains the other conformational isomer ((E) or (Z)) of the double bond; a preparation in which one or more atoms is a different isotope than is present in a reference preparation may be considered to be a different form; etc.

[0062] Those skilled in the art will further appreciate that, in small molecule structures, the symbol , as used herein, refers to a point of attachment between two atoms. Additionally or alternatively, the symbol refers to a point of attachment ring in a spirocyclic manner.

[0063] Those skilled in the art will appreciate that, in small molecule structures, the symbol — , as used herein, refers to a bond that is either a single bond, e.g., — , or a double bond, e.g., =. For example, when used in a cyclic structure, such as: b J Ik A or , it is understood to encompass any of the following chemically feasible structures:000...0

[0064] Treat: As used herein, the terms “treat,” “treatment,” or “treating” refer to any method used to partially or completely alleviate, ameliorate, relieve, inhibit, prevent, delay onset of, reduce severity of, and / or reduce incidence of one or more symptoms or features of a disease, disorder, and / or condition. Treatment may be administered to a subject who does not exhibit signs of a disease, disorder, and / or condition. In some embodiments, treatment may be administered to a subject who exhibits only early signs of the disease, disorder, and / orcondition, for example, for the purpose of decreasing the risk of developing pathology associated with the disease, disorder, and / or condition.

[0065] Therapeutic agent: As used herein, the term “therapeutic agent” in general refers to any agent that elicits a desired effect (e.g., a desired biological, clinical, or pharmacological effect) when administered to a subject. In some embodiments, an agent is considered to be a therapeutic agent if it demonstrates a statistically significant effect across an appropriate population. In some embodiments, an appropriate population is a population of subjects suffering from and / or susceptible to a disease, disorder or condition. In some embodiments, an appropriate population is a population of model organisms. In some embodiments, an appropriate population may be defined by one or more criterion such as age group, gender, genetic background, preexisting clinical conditions, prior exposure to therapy. In some embodiments, a therapeutic agent is a substance that alleviates, ameliorates, relieves, inhibits, prevents, delays onset of, reduces severity of, and / or reduces incidence of one or more symptoms or features of a disease, disorder, and / or condition in a subject when administered to the subject in an effective amount. In some embodiments, a “therapeutic agent” is an agent that has been or is required to be approved by a government agency before it can be marketed for administration to humans. In some embodiments, a “therapeutic agent” is an agent for which a medical prescription is required for administration to humans. In some embodiments, therapeutic agents may be KAT inhibitors, for example, KAT-5 inhibitors, as described herein.

[0066] Therapeutically effective amount: As used herein, the term “therapeutically effective amount” refers to an amount that produces a desired effect (e.g., a desired biological, clinical, or pharmacological effect) in a subject or population to which it is administered. In some embodiments, the term refers to an amount statistically likely to achieve the desired effect when administered to a subject in accordance with a particular dosing regimen (e.g., a therapeutic dosing regimen). In some embodiments, the term refers to an amount sufficient to produce the effect in at least a significant percentage (e.g., at least about 25%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, or more) of a population that is suffering from and / or susceptible to a disease, disorder, and / or condition. Insome embodiments, a therapeutically effective amount is one that reduces the incidence and / or severity of, and / or delays onset of, one or more symptoms of the disease, disorder, and / or condition. Those of ordinary skill in the art will appreciate that the term “therapeutically effective amount” does not in fact require successful treatment be achieved in a particular individual. Rather, a therapeutically effective amount may be an amount that provides a particular desired response in a significant number of subjects when administered to patients in need of such treatment, e.g., in at least about 25%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, or more patients within a treated patient population. In some embodiments, reference to a therapeutically effective amount may be a reference to an amount sufficient to induce a desired effect as measured in one or more specific tissues (e.g., a tissue affected by the disease, disorder or condition) or fluids (e.g., blood, saliva, serum, sweat, tears, urine). Those of ordinary skill in the art will appreciate that, in some embodiments, a therapeutically effective amount of a particular agent or therapy may be formulated and / or administered in a single dose. In some embodiments, a therapeutically effective agent may be formulated and / or administered in a plurality of doses, for example, as part of a dosing regimen.Heterobifunctional FIP200 Degraders

[0067] The present disclosure provides, among other things, compounds useful for inhibiting autophagy, whereby inhibiting autophagy in a subject is useful for the treatment of particular diseases, disorders, and condition, as recited herein. In some embodiments, compounds of the present disclosure are degraders of FIP200. In some embodiments, compounds of the present disclosure are heterobifunctional compounds comprising on one end, a moiety that binds to or associates with FIP200, and on the other end an E3 ligase binder, wherein the moiety that binds to or associates with FIP200 and the moiety that is an E3 ligase binder are connected by a linker.

[0068] In some embodiments, a compound of the present disclosure is represented by formula I:A-B-E3LI or a pharmaceutically acceptable salt thereof, wherein:A is a moiety that binds to or associates with FIP200;B is a linker moiety; andE3L is a ubiquitin E3 ligase binding moiety.

[0069] In some embodiments, a moiety that binds or associates with FIP200 is one that covalently binds directly to FIP200 or one that undergoes one or more of hydrogen bonding, electrostatic interactions, pi stacking, van der Waals interactions, or dipole-dipole interactions with FIP200.

[0070] In some embodiments of formula I, A is selected from a moiety of formula II- 1 , II-G1is an optionally substituted C6-C12 aryl or an optionally substituted 5- to 6- membered heteroaryl;X1is -S-, -N(R3)-, -O-, optionally substituted C1-C6aliphatic, or optionally substituted C3-C6 cycloaliphatic;X2is C(R3) or N, provided that, when X2is N, then X1is optionally substituted C1-C6aliphatic, or optionally substituted C3-C6 cycloaliphatic; when a bond between X3and X4is a single bond, then X3is N(R2a), and X4is C(O) when a bond between X3and X4is a double bond, then X3is C(R2b) and X4is C(R3), or N; each R1is independently selected from halogen, optionally substituted C1-C6aliphatic, and optionally substituted -O-C1-C6aliphatic; or two instances of R1come together with the atoms to which they are attached to form an optionally substituted C6-C12 aryl ring, an optionally substituted C4-C6 cycloaliphatic ring, a 5- to 6- membered heteroaryl ring comprising 1 to 3 heteroatoms selected from N, O, and S, or an optionally substituted 5- to 6- membered heterocyclic ring comprising 1 to 3 heteroatoms selected from N, O, and S;R2ais optionally substituted C1-C6aliphatic;R2bis hydrogen, optionally substituted C1-C6aliphatic, optionally substituted -N(R3)- C1-C6aliphatic, or optionally substituted -O-C1-C6aliphatic; each R3is independently selected from hydrogen, halogen, and optionally substituted C1-C6aliphatic;R4is selected from optionally substituted C6-C12 aryl, optionally substituted 5- to 12- membered heteroaryl ring comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted 4- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, and optionally substituted C1-C6aliphatic;R5is an optionally substituted 4- to 6-membered heterocyclic ring, an optionally substituted 5- to 6-membered heteroaryl ring, an optionally C3-C6 cycloaliphatic ring, an optionally substituted C6-C12 aryl, or an optionally substituted C1-C6aliphatic;L1is independently a bond, -C(O)-, -S(O)-, -S(O)2-, or -NR3-; n is 0, 1, 2, 3, 4, 5, or 6;each of X5, X6, and X7are independently selected from the group consisting of N andCH;R7is hydrogen, an optionally substituted -O-C1-C6aliphatic, -S(O)2R3, optionally substituted C1-C6aliphatic, an optionally substituted 4- to 12-membered heterocycle ring comprising 1 to 4 heteroatoms selected from N, O, and S, an optionally substituted Ce-Cn aryl, or an optionally substituted 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and SG2is an optionally substituted Ce-Cn aryl, optionally substituted 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, optionally substituted 5- to 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, or optionally substituted C3-C6 cycloaliphatic;G3is an optionally substituted 4- to 12-membered heterocycle ring comprising 1 to 4 heteroatoms selected from N, O, and S, an optionally substituted 5- to 6- membered heteroaryl ring comprising 1 to 4 heteroatoms selected from N, O, and S, an optionally substituted C3-C6 cycloaliphatic ring or optionally substituted Ce- C12 aryl;L2is a bond, -NR3-C(O)-, -C(O)-NR3-, optionally substituted C1-C6aliphatic, optionally substituted 4- to 6-membered heterocyclic, or optionally substituted C3- Ce cycloaliphatic;L3is-NR3-, -O-, -C(O)-, -NR3-C(O)-, -NR3-S(O)2-, -C(O)-NR3-, -S(O)2NR3-, -NR3- C(O)-NR3-, optionally substituted C1-C6aliphatic, or an optionally substituted C3- Ce cycloaliphatic ring;* represents a point of attachment to moiety B; and wherein: when A is a moiety of formula II-3 then R6is a bond, optionally substituted C1-C6aliphatic, optionally substituted 2- to 6-membered heteroaliphatic, optionally substituted 4- to 6-membered heterocycle comprising one 1 to 3 heteroatoms selected from N, O, and S, optionally substituted C6-C12 aryl, or optionallysubstituted C3-C6 cycloaliphatic; and R8is independently halogen, -OR3, - C(O)N(R3)2, -C(O)OR3, optionally substituted C1-C6aliphatic, optionally substituted C3-C6 cycloaliphatic, optionally substituted C6-C12 aryl; and when A is of formula II-4, then R6is H, halogen, optionally substituted C1-C6aliphatic, optionally substituted 2- to 6-membered heteroaliphatic, optionally substituted 4- to 6-membered heterocycle comprising one 1 to 3 heteroatoms selected from N, O, and S, optionally substituted C6-C12 aryl, or optionally substituted C3-C6 cycloaliphatic; and R8is a bond, -O-, -C(O)NR3-, -C(O)OR3, optionally substituted C1-C6aliphatic, optionally substituted C3-C6 cycloaliphatic, or optionally substituted C6-C12 aryl.

[0071] In some embodiments of formula I, A is selected from a moiety of formula II- 1 orII-2:or a pharmaceutically acceptable salt thereof, wherein:G1is an optionally substituted C6-C12 aryl or an optionally substituted 5- to 6- membered heteroaryl;X1is -S-, -N(R3)-, -O-, optionally substituted C1-C6aliphatic, or optionally substituted C3-C6 cycloaliphatic;X2is C(R3) or N, provided that, when X2is N, then X1is optionally substituted C1-C6aliphatic, or optionally substituted C3-C6 cycloaliphatic; when a bond between X3and X4is a single bond, then X3is N(R2a), and X4is C(O) when a bond between X3and X4is a double bond, then X3is C(R2b) and X4is C(R3), or N;each R1is independently selected from halogen, optionally substituted C1-C6aliphatic, and optionally substituted -O-C1-C6aliphatic; or two instances of R1come together with the atoms to which they are attached to form a n optionally substituted Ce-Cn aryl ring, an optionally substituted C4-C6 cycloaliphatic ring, a 5- to 6- membered heteroaryl ring comprising 1 to 3 heteroatoms selected from N, O, and S, or an optionally substituted 5- to 6- membered heterocyclic ring comprising 1 to 3 heteroatoms selected from N, O, and S;R2ais optionally substituted C1-C6aliphatic,;R2bis hydrogen, optionally substituted C1-C6aliphatic, optionally substituted -N(R3)- C1-C6aliphatic, or optionally substituted -O-C1-C6aliphatic; each R3is independently selected from hydrogen, halogen, and optionally substituted C1-C6aliphatic;R4is selected from optionally substituted C6-C12 aryl; optionally substituted 5- to 12- membered heteroaryl ring comprising 1 to 3 heteroatoms selected from N, O, and S; and optionally substituted C1-C6aliphatic;R5is an optionally substituted 4- to 6-membered heterocyclic ring, an optionally substituted 5- to 6-membered heteroaryl ring, an optionally C3-C6 cycloaliphatic ring, an optionally substituted C6-C12 aryl, or an optionally substituted C1-C6aliphatic;L1is a bond, -C(O)-, -S(O)-, -S(O)2-, or -NR3-; n is 0, 1, 2, 3, 4, 5, or 6; and* represents a point of attachment to moiety B.

[0072] In some embodiments of formula I, A is a moiety of formula II- 1 :or a pharmaceutically acceptable salt thereof, wherein:G1is an optionally substituted Ce-Cn aryl or an optionally substituted 5- to 6- membered heteroaryl;X1is -S-, -N(R3)-, -O-, optionally substituted C1-C6aliphatic, or optionally substituted C3-C6 cycloaliphatic;X2is C(R3) or N, provided that, when X2is N, then X1is optionally substituted C1-C6aliphatic, or optionally substituted C3-C6 cycloaliphatic; when a bond between X3and X4is a single bond, then X3is N(R2a), and X4is C(O) when a bond between X3and X4is a double bond, then X3is C(R2b) and X4is C(R3), or N; each R1is independently selected from halogen, optionally substituted C1-C6aliphatic, and optionally substituted -O-C1-C6aliphatic; or two instances of R1come together with the atoms to which they are attached to form a n optionally substituted C6-C12 aryl ring, an optionally substituted C4-C6 cycloaliphatic ring, a 5- to 6- membered heteroaryl ring comprising 1 to 3 heteroatoms selected from N, O, and S, or an optionally substituted 5- to 6- membered heterocyclic ring comprising 1 to 3 heteroatoms selected from N, O, and S;R2ais optionally substituted C1-C6aliphatic;R2bis hydrogen, optionally substituted C1-C6aliphatic, optionally substituted -N(R3)- C1-C6aliphatic, or optionally substituted -O-C1-C6aliphatic; each R3is independently selected from hydrogen, halogen, and optionally substituted C1-C6aliphatic;R4is selected from optionally substituted Ce-Cn aryl; optionally substituted 5- to 12- membered heteroaryl ring comprising 1 to 3 heteroatoms selected from N, O, and S; and optionally substituted C1-C6aliphatic;R5is an optionally substituted 4- to 6-membered heterocyclic ring, an optionally substituted 5- to 6-membered heteroaryl ring, an optionally C3-C6 cycloaliphatic ring, an optionally substituted C6-C12 aryl, or an optionally substituted C1-C6aliphatic;L1is a bond, -C(O)-, -S(O)-, -S(O)2-, or -NR3-; n is 0, 1, 2, 3, 4, 5, or 6; and* represents a point of attachment to moiety B.

[0073] In some embodiments of formula I, A is a moiety of formula II-2 :II-2 or a pharmaceutically acceptable salt thereof, wherein:G1is an optionally substituted C6-C12 aryl or an optionally substituted 5- to 6- membered heteroaryl;X1is -S-, -N(R3)-, -O-, optionally substituted C1-C6aliphatic, or optionally substituted C3-C6 cycloaliphatic;X2is C(R3) or N, provided that, when X2is N, then X1is optionally substituted C1-C6aliphatic, or optionally substituted C3-C6 cycloaliphatic; when a bond between X3and X4is a single bond, then X3is N(R2a), and X4is C(O) when a bond between X3and X4is a double bond, then X3is C(R2b) and X4is C(R3), or N; each R1is independently selected from halogen, optionally substituted C1-C6aliphatic, and optionally substituted -O-C1-C6aliphatic; ortwo instances of R1come together with the atoms to which they are attached to form a n optionally substituted Ce-Cn aryl ring, an optionally substituted C4-C6 cycloaliphatic ring, a 5- to 6- membered heteroaryl ring comprising 1 to 3 heteroatoms selected from N, O, and S, or an optionally substituted 5- to 6- membered heterocyclic ring comprising 1 to 3 heteroatoms selected from N, O, and S;R2ais optionally substituted C1-C6aliphatic,;R2bis hydrogen, optionally substituted C1-C6aliphatic, optionally substituted -N(R3)- C1-C6aliphatic, or optionally substituted -O-C1-C6aliphatic; each R3is independently selected from hydrogen, halogen, and optionally substituted C1-C6aliphatic;R4is selected from optionally substituted C6-C12 aryl; optionally substituted 5- to 12- membered heteroaryl ring comprising 1 to 3 heteroatoms selected from N, O, and S; and optionally substituted C1-C6aliphatic;R5is an optionally substituted 4- to 6-membered heterocyclic ring, an optionally substituted 5- to 6-membered heteroaryl ring, an optionally C3-C6 cycloaliphatic ring, an optionally substituted C6-C12 aryl, or an optionally substituted C1-C6aliphatic;L1is a bond, -C(O)-, -S(O)-, -S(O)2-, or -NR3-; n is 0, 1, 2, 3, 4, 5, or 6; and* represents a point of attachment to moiety B.

[0074] As described herein, with respect to formula II- 1 and II-2 , X1is S, N(R3), O, optionally substituted C1-C6aliphatic, or optionally substituted C3-C6 cycloaliphatic. In some embodiments, X1is S, optionally substituted C1-C6aliphatic or optionally substituted C3-C6 cycloaliphatic. In some embodiments, X1is S or optionally substituted C1-C6aliphatic. In some embodiments, X1is S. In some embodiments, X1is N(R3). In some embodiments, X1is N(H). In some embodiments, X1is O. In some embodiments, X1is optionally substituted Ci- Ce aliphatic. In some embodiments, X1is C1-C6alkylene. In some embodiments, X1is -CH2-In some embodiments, X1is optionally substituted C3-C6 cycloaliphatic. In some embodiments X1is cyclopropyl.

[0075] As described herein, X2is, C(R3) or N, provided that, when X2is N, then X1is optionally substituted C1-C6aliphatic, or optionally substituted C3-C6 cycloaliphatic. In some embodiments, X2is C(R3). In some embodiments, X2is C(H). In some embodiments, X2is N.

[0076] In some embodiments, X1is S, N(R3), or O and X2is C(R3). In some embodiments, X1is optionally substituted C1-C6aliphatic, or optionally substituted C3-C6 cycloaliphatic, and X2is N. In some embodiments, X1is S, and X2is C(R3). In some embodiments, X1is S, and X2is C(H).

[0077] In some embodiments, a moiety:is:

[0078] As described herein, when a bond between X3and X4is a single bond, then X3is N(R2a), and X4is C(O). In some embodiments, a bond between X3and X4is a single bond.

[0079] As described herein, when a bond between X3and X4is a double bond, then X3is C(R2b) and X4is C(R3) or N. In some embodiments, a bond between X3and X4is a double bond. In some embodiments, when a bond between X3and X4is a double bond, then X3is C(R2b) and X4is N.

[0080] As described herein, with respect to formula II- 1 and II-2, G1is an optionally substituted Ce-Cn aryl or an optionally substituted 5- to 6-membered heteroaryl. In some embodiments, G1is optionally substituted monocyclic or bicyclic Ce-Cn aryl. In some embodiments, G1is optionally substituted phenyl.

[0081] In some embodiments, G1is optionally substituted naphthyl. In some embodiments, G1is unsubstituted naphthyl.

[0082] In some embodiments, G1is phenyl or naphthyl.

[0083] As described herein, each R1is independently selected from halogen, optionally substituted C1-C6aliphatic, and optionally substituted -O-C1-C6aliphatic. In some embodiments, R1is halogen. In some embodiments, R1is chloride. In some embodiments, n is 2 and each R1is halogen. In some embodiments, n is 2 and each R1is chloride. In some embodiments, n is 2, and one instance of R1is halogen, and another instance of R1is C1-C6aliphatic or -O-C1-C6aliphatic. In some embodiments, R1is optionally substituted C1-C6aliphatic. In some embodiments, R1is C1-C6alkyl. In some embodiments, R1is methyl. In some embodiments, R1is optionally substituted O-C1-C6aliphatic. In some embodiments, R1is optionally substituted -O-C1-C6alkyl. In some embodiments, R1is -O-CH3.

[0084] In some embodiments, two instances of R1come together with the atoms to which they are attached to form an optionally substituted C6-C12 aryl ring, an optionally substituted C4-C6 cycloaliphatic ring, a 5- to 6- membered heteroaryl ring comprising 1 to 3 heteroatoms selected from N, O, and S, or an optionally substituted 5- to 6-membered heterocyclic ring comprising 1 to 3 heteroatoms selected from N, O, and S.

[0085] In some embodiments, two instances of R1come together, with the atoms to which they are attached to form an optionally substituted C6-C12 aryl ring or a 5- to 6- membered heteroaryl ring comprising 1 to 3 heteroatoms selected from N, O, and S.

[0086] In some embodiments, two instances of R1come together with the atoms to which they are attached to form an optionally substituted C6-C12 aryl ring.

[0087] In some embodiments, two instances of R1come together with the atoms to which they are attached to form an optionally substituted C4-C6 cycloaliphatic ring. In some embodiments, two instances of R1come together to form a cyclopentyl or cyclohexyl ring.

[0088] In some embodiments, two instances of R1come together with the atoms to which they are attached to form a 5- to 6- membered heteroaryl ring comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, two instances of R1come together with theatoms to which they are attached to form an optionally substituted 5- to 6-membered heterocyclic ring comprising 1 to 3 heteroatoms selected from N, O, and S.

[0089] In some embodiments, a moiety:

[0090] In some embodiments, a moiety:

[0091] As described herein, R2ais optionally substituted C1-C6aliphatic, optionally substituted -N(R3)-C1-C6aliphatic, or optionally substituted -O-C1-C6aliphatic. In some embodiments, R2ais optionally substituted C1-C6aliphatic. In some embodiments, R2ais Ci- Ce alkyl. In some embodiments is R2ais methyl, ethyl, propyl, butyl, pentyl, or hexyl. In some embodiments, R2ais methyl or ethyl. In some embodiments, R2ais ethyl. In some embodiments, R2ais C1-C6optionally substituted with halogen. In some embodiments, R2ais -CH2-CHF2.

[0092] As described herein, R2bis hydrogen, optionally substituted C1-C6aliphatic, optionally substituted -N(R3)-C1-C6aliphatic, or optionally substituted -O-C1-C6aliphatic. In some embodiments, R2bis hydrogen. In some embodiments, R2bis optionally substituted Ci- Ce aliphatic. In some embodiments, R2bis In some embodiments, R2bis optionally substituted C1-C6aliphatic. In some embodiments, R2bis C1-C6alkyl. In some embodiments is R2bismethyl, ethyl, propyl, butyl, pentyl, or hexyl. In some embodiments, R2ais methyl or ethyl. In some embodiments, R2ais ethyl.

[0093] In some embodiments, R2bis optionally substituted -N(R3)-C1-C6aliphatic. In some embodiments, R2bis -N(H)-C1-C6aliphatic. In some embodiments, R2bis -N(H)-CH2-CH3.

[0094] In some embodiments, R2bis optionally substituted -O-C1-C6aliphatic. In some embodiments, R2bis -O-C1-C6alkyl. In some embodiments, R2bis -O-CH2-CH3.

[0095] In some embodiments of formula II- 1 or II-2, a moiety:

[0096] In some embodiments of formula II- 1 or II-2, a moiety:

[0097] As described herein, each R3is independently selected from hydrogen, halogen, and optionally substituted C1-C6aliphatic. In some embodiments, R3is hydrogen. In some embodiments, R3is halogen. In some embodiments, R3is optionally substituted C1-C6aliphatic. In some embodiments, R3is optionally substituted C1-C6alkyl. In some embodiments, R3is methyl.

[0098] As described herein, R4is selected from optionally substituted C6-C12 aryl, optionally substituted 5- to 12- membered heteroaryl ring comprising 1 to 3 heteroatoms selected from N, O, and S; and optionally substituted C1-C6aliphatic.

[0099] In some embodiments, R4is optionally substituted phenyl or optionally substituted 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S.

[0100] In some embodiments, R4is optionally substituted Ce-Cn aryl. In some embodiments, R4is optionally substituted phenyl. In some embodiments, R4is phenyl optionally substituted with halogen, -(CH2)o 4R0, -(CH2)o 4OR0, or -(CH2)o-4N(R°)2. In some embodiments, R4is phenyl optionally substituted with halogen. In some embodiments, R4is phenyl substituted with bromide or chloride. In some embodiments, R4is phenyl substituted with bromide. In some embodiments, R4is unsubstituted phenyl. In some embodiments, R4is optionally substituted napthyl.

[0101] In some embodiments of formula II- 1, R4is:

[0102] In some embodiments of formula II-2, R4is:where * represents a point of attachment to moiety B of formula I.

[0103] In some embodiments, R4is optionally substituted 5- to 12- membered heteroaryl ring comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R4isoptionally substituted monocyclic 5- to 6- membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R4is pyrrolidine, pyrazole, imidazole, pyridine, pyrimidine, or pyrazine. In some embodiments of formula II-l, R4is:

[0104] In some embodiments, R4is optionally substituted 4- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R4is optionally substituted monocyclic 4- to 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R4is optionally substituted tetrahydropyran. In some embodiments of formula II- 1, R4is:

[0105] In some embodiments, R4is optionally substituted C1-C6aliphatic. In some embodiments, R4is optionally substituted C1-C6alkyl. In some embodiments, R4is methyl, ethyl, propyl, butyl, pentyl, or hexyl. In some embodiments, R4is methyl.

[0106] As described herein, R5is an optionally substituted 4- to 6-membered heterocyclic ring, an optionally substituted 5- to 6-membered heteroaryl ring, an optionally C3-C6 cycloaliphatic ring, an optionally substituted C6-C12 aryl, or an optionally substituted C1-C6aliphatic.

[0107] In some embodiments, R5is optionally substituted 4- to 6-membered heterocyclic ring comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R5is optionally substituted 5- to 6-membered heterocyclic ring comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R5is optionally substituted 5-membered heterocyclyl. In some embodiments, R5is optionally substituted 6-membered heterocyclyl. Insome embodiments, R5is azetidine, pyrrolidine, piperidine, or piperazine. In some embodiments of formula II- 1, R5is:where * represents a point of attachment to moiety B of formula I.

[0108] In some embodiments of formula II- 1, R5is:

[0109] As described herein, L1is a bond, -C(O)-, -S(O)-, -S(O)2-, or -NR3-. In some embodiments, L1is a bond. In some embodiments, L1is -C(O)-. In some embodiments, L1is -S(O)-. In some embodiments, L1is -S(O)2-. In some embodiments, L1is -NR3-. In some embodiments L1is -NH-.

[0110] As described herein, n is 0, 1, 2, 3, 4, 5, or 6. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6.[OHl] In some embodiments of formula I, A is selected from a moiety of formula II-3 orII-4:or a pharmaceutically acceptable salt thereof, wherein: each of X5, X6, and X7are independently selected from the group consisting of N andCH;R7is hydrogen, an optionally substituted -O-C1-C6aliphatic, -S(O)2R3, optionally substituted C1-C6aliphatic, an optionally substituted 4- to 12-membered heterocycle ring comprising 1 to 4 heteroatoms selected from N, O, and S, an optionally substituted Ce-Cn aryl, or an optionally substituted 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and SG2is an optionally substituted Ce-Cn aryl, optionally substituted 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, optionally substituted 5- to 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, or optionally substituted C3-C6 cycloaliphatic;G3is an optionally substituted 4- to 12-membered heterocycle ring comprising 1 to 4 heteroatoms selected from N, O, and S, an optionally substituted 5- to 6- membered heteroaryl ring comprising 1 to 4 heteroatoms selected from N, O, and S, an optionally substituted C3-C6 cycloaliphatic ring or optionally substituted Ce- C12 aryl;L2is a bond, -NR3-C(O)-, -C(O)-NR3-, optionally substituted C1-C6aliphatic, optionally substituted 4- to 6-membered heterocyclic, or optionally substituted C3- Ce cycloaliphatic;L3is-NR3-, -O-, -C(O)-, -NR3-C(O)-, -NR3-S(O)2-, -C(O)-NR3-, -S(O)2NR3-, -NR3- C(O)-NR3-, optionally substituted C1-C6aliphatic, or an optionally substituted C3- Ce cycloaliphatic ring;* represents a point of attachment to moiety B; and wherein: when A is a moiety of formula II- 3 then R6is a bond, optionally substituted C1-C6aliphatic, optionally substituted 2- to 6-membered heteroaliphatic, optionally substituted 4- to 6-membered heterocycle comprising one 1 to 3 heteroatoms selected from N, O, and S, optionally substituted C6-C12 aryl, or optionally substituted C3-C6 cycloaliphatic; and R8is independently halogen, -OR3, -C(O)N(R3)2, -C(O)OR3, optionally substituted C1-C6aliphatic, optionally substituted C3-C6 cycloaliphatic, optionally substituted C6-C12 aryl; and when A is of formula II-4, then R6is H, halogen, optionally substituted C1-C6aliphatic, optionally substituted 2- to 6-membered heteroaliphatic, optionally substituted 4- to 6-membered heterocycle comprising one 1 to 3 heteroatoms selected from N, O, and S, optionally substituted C6-C12 aryl, or optionally substituted C3-C6 cycloaliphatic; and R8is a bond, -O-, -C(O)NR3-, -C(O)OR3, optionally substituted C1-C6aliphatic, optionally substituted C3-C6 cycloaliphatic, or optionally substituted C6-C12 aryl.

[0112] In some embodiments of formula I, A is a moiety of formula II-3 :II-3 or a pharmaceutically acceptable salt thereof, wherein: each of X5, X6, and X7are independently selected from the group consisting of N and CH;R7is hydrogen, an optionally substituted -O-C1-C6aliphatic, -S(O)2R3, optionally substituted C1-C6aliphatic, an optionally substituted 4- to 12-membered heterocycle ring comprising 1 to 4 heteroatoms selected from N, O, and S, an optionally substituted C6-C12 aryl, or an optionally substituted 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and SG2is an optionally substituted C6-C12 aryl, optionally substituted 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, optionally substituted 5- to 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, or optionally substituted C3-C6 cycloaliphatic;G3is an optionally substituted 4- to 12-membered heterocycle ring comprising 1 to 4 heteroatoms selected from N, O, and S, an optionally substituted 5- to 6- membered heteroaryl ring comprising 1 to 4 heteroatoms selected from N, O, and S, an optionally substituted C3-C6 cycloaliphatic ring or optionally substituted Ce- C12 aryl;L2is a bond, -NR3-C(O)-, -C(O)-NR3-, optionally substituted C1-C6aliphatic, optionally substituted 4- to 6-membered heterocyclic, or optionally substituted C3- Ce cycloaliphatic;L3is-NR3-, -O-, -C(O)-, -NR3-C(O)-, -NR3-S(O)2-, -C(O)-NR3-, -S(O)2NR3-, -NR3- C(O)-NR3-, optionally substituted C1-C6aliphatic, or an optionally substituted C3- Ce cycloaliphatic ring;* represents a point of attachment to moiety B; andR6is a bond, optionally substituted C1-C6aliphatic, optionally substituted 2- to 6- membered heteroaliphatic, optionally substituted 4- to 6-membered heterocycle comprising one 1 to 3 heteroatoms selected from N, O, and S, optionally substituted Ce-Ci2aryl, or optionally substituted C3-C6 cycloaliphatic; and each R8is independently halogen, -OR3, -C(O)N(R3)2, -C(O)OR3, optionally substituted C1-C6aliphatic, optionally substituted C3-C6 cycloaliphatic, optionally substituted Ce-Ci2aryl.

[0113] In some embodiments of formula I, A is a moiety of formula II-4 :II-4 or a pharmaceutically acceptable salt thereof, wherein:each of X5, X6, and X7are independently selected from the group consisting of N andCH;R7is hydrogen, an optionally substituted -O-C1-C6aliphatic, -S(O)2R3, optionally substituted C1-C6aliphatic, an optionally substituted 4- to 12-membered heterocycle ring comprising 1 to 4 heteroatoms selected from N, O, and S, an optionally substituted Ce-Cn aryl, or an optionally substituted 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and SG2is an optionally substituted Ce-Cn aryl, optionally substituted 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, optionally substituted 5- to 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, or optionally substituted C3-C6 cycloaliphatic;G3is an optionally substituted 4- to 12-membered heterocycle ring comprising 1 to 4 heteroatoms selected from N, O, and S, an optionally substituted 5- to 6- membered heteroaryl ring comprising 1 to 4 heteroatoms selected from N, O, and S, an optionally substituted C3-C6 cycloaliphatic ring or optionally substituted Ce- C12 aryl;L2is a bond, -NR3-C(O)-, -C(O)-NR3-, optionally substituted C1-C6aliphatic, optionally substituted 4- to 6-membered heterocyclic, or optionally substituted C3- Ce cycloaliphatic;L3is-NR3-, -O-, -C(O)-, -NR3-C(O)-, -NR3-S(O)2-, -C(O)-NR3-, -S(O)2NR3-, -NR3- C(O)-NR3-, optionally substituted C1-C6aliphatic, or an optionally substituted C3- Ce cycloaliphatic ring;* represents a point of attachment to moiety B;R6is H, halogen, optionally substituted C1-C6aliphatic, optionally substituted 2- to 6- membered heteroaliphatic, optionally substituted 4- to 6-membered heterocycle comprising one 1 to 3 heteroatoms selected from N, O, and S, optionally substituted C6-C12 aryl, or optionally substituted C3-C6 cycloaliphatic; andR8is a bond, -O-, -C(O)NR3-, -C(O)OR3, optionally substituted C1-C6aliphatic, optionally substituted C3-C6 cycloaliphatic, or optionally substituted C6-C12 aryl.

[0114] As described herein, each of X5, X6, and X7are independently selected from the group consisting of N and CH. In some embodiments, each of X5, X6, and X7are N. In some embodiments, each of X5, X6, and X7are CH. In some embodiments, X5is N and X6and X7are CH. In some embodiments, X6is N and X5and X7are CH. In some embodiments, X7is N, and X5and X6are CH. In some embodiments, X5and X6are N and X7is CH. In some embodiments, X5and X7are N and X6is CH. In some embodiments, X6and X7are N and X5is CH.

[0115] As described herein, R7is hydrogen, an optionally substituted -O-C1-C6aliphatic, - S(O)2R3, optionally substituted C1-C6aliphatic, an optionally substituted 4- to 12-membered heterocycle ring comprising 1 to 4 heteroatoms selected from N, O, and S, an optionally substituted C6-C12 aryl, or an optionally substituted 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S.

[0116] In some embodiments, R7is hydrogen.

[0117] In some embodiments, each R7is independently an optionally substituted -O-C1-C6aliphatic, -S(O)2R3, optionally substituted C1-C6aliphatic, an optionally substituted 4- to 12- membered heterocycle ring comprising 1 to 4 heteroatoms selected from N, O, and S, an optionally substituted C6-C12 aryl, or an optionally substituted 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S.

[0118] In some embodiments, R7is optionally substituted -O-C1-C6aliphatic. In some embodiments, R7is optionally substituted -O-C1-C6alkyl. In some embodiments, R7is -O- CH3.

[0119] In some embodiments, R7is -S(O)2R3. In some embodiments, R7is optionally substituted -S(O)2-C1-C6aliphatic.

[0120] In some embodiments, R7is optionally substituted C1-C6aliphatic.

[0121] In some embodiments, R7is an optionally substituted 4- to 12-membered heterocycle ring comprising 1 to 4 heteroatoms selected from N, O, and S. In someembodiments, R7is an optionally substituted monocyclic 4- to 6-membered heterocycle ring comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R7is optionally substituted tetrahydropyran or morpholine. In some embodiments, R7is a bicyclic or spirocyclic 6- to 12-membered heterocycle ring comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, R7is:

[0122] In some embodiments, R7is optionally substituted Ce-Cn aryl. In some embodiments, R7is optionally substituted phenyl. In some embodiments, R7is phenyl optionally substituted with -(CH2)o-4R° or -(CH2)o-4N(R°)2. In some embodiments, R7is phenyl optionally substituted with -NH2. In some embodiments, R7is optionally substituted naphthyl. In some embodiments, R7is:

[0123] In some embodiments, R7is optionally substituted 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, R7is optionally substituted monocyclic 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, R7is monocyclic 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S optionally substituted with - (CH2)O 4R0or -(CH2)O 4N(R°)2. In some embodiments, R7is monocyclic 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S optionally substituted with -CH3 or -NH2. In some embodiments, R7is optionally substituted pyridine, pyrazine, pyrimidine, pyrazole, pyrrole, or imidazole. In some embodiments, R7is:,

[0126] As described herein, G2is an optionally substituted C6-C12 aryl, optionally substituted 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, optionally substituted 5- to 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, or optionally substituted C3-C6 cycloaliphatic.

[0127] In some embodiments, G2is optionally substituted C6-C12 aryl or optionally substituted 5- to 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S.

[0128] In some embodiments, G2is optionally substituted C6-C12 aryl. In some embodiments, G2is optionally substituted phenyl. In some embodiments, G2is unsubstituted phenyl. In some embodiments, G2is naphthyl.

[0129] In some embodiments, G2is optionally substituted 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, G2is optionally substituted monocyclic 4- to 6- membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, G2is optionally substituted bicyclic 7- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S.

[0130] In some embodiments, G2is optionally substituted 5- to 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S.

[0131] In some embodiments, G2is optionally substituted C3-C6 cycloaliphatic. In some embodiments, G2is optionally substituted partially unsaturated Ce cycloaliphatic.

[0132] In some embodiments of formula II- 3 or II-4, a moiety:

[0133] As described herein, G3is an optionally substituted 4- to 12-membered heterocycle ring comprising 1 to 4 heteroatoms selected from N, O, and S, an optionally substituted 5- to 6-membered heteroaryl ring comprising 1 to 4 heteroatoms selected from N, O, and S, an optionally substituted C3-C6 cycloaliphatic ring, or optionally substituted C6-C12 aryl.

[0134] In some embodiments, G3is optionally substituted 4- to 12-membered heterocycle ring comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, G3is optionally substituted monocyclic 4- to 6-membered heterocycle ring comprising 1 to 3 heteroatoms selected from N, O, and S. In some embodiments, G3is optionally substituted pyrrolidine or piperidine. In some embodiments, G3is pyrrolidine or piperidine optionally substituted with -(CH2)o 4R0or -(CH2)o 4Ph, which may be substituted with R°. In some embodiments, G3is pyrrolidine or piperidine optionally substituted with -C(O)N(R3)2

[0135] In some embodiments, G3is optionally substituted bicyclic or spirocyclic 6- to 12- membered heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S. In some embodiments, G3is bicyclic or spirocyclic 6- to 12-membered heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, optionally substituted with -(CH2)o 4R0or -C(O)N(R3)2. In some embodiments, G3is bicyclic or spirocyclic 6- to 12-membered heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, optionally substituted with -C(O)N(R3)2. In some embodiments, G3is bicyclic or spirocyclic 6- to 10-membered heterocyclyl comprising 1 to 4 heteroatoms selected from N, O, and S, optionally substituted with -C(O)N(R3)2. In some embodiments, G3is bicyclic or spirocyclic 6- to 10-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted with -C(O)N(R3)2. . In some embodiments, G3is bicyclic or spirocyclic 6- to 10-membered heterocyclyl comprising 1 to 2 heteroatoms selected from N, O, and S, optionally substituted with -C(O)N(R3)2. In some embodiments, G3is octahydro- IH-indole, optionally substituted with -C(O)N(R3)2. In some embodiments, G3is octahydro- IH-indole, optionally substituted with -C(O)NH(R3), where R3is C1-C6aliphatic. In some embodiments, G3is octahydro-lH- indole, optionally substituted with -C(0)NH(CH3).

[0136] In some embodiments, G3is an optionally substituted 5- to 6-membered heteroaryl ring comprising 1 to 4 heteroatoms selected from N, O, and S.

[0137] In some embodiments, G3is an optionally substituted C3-C6 cycloaliphatic ring.

[0138] In some embodiments, G3is optionally substituted C6-C12 aryl.

[0139] As described herein, L2is a bond, -NR3-C(O)-, -C(O)-NR3-, optionally substituted C1-C6aliphatic, optionally substituted 4- to 6-membered heterocyclic, or optionally substituted C3-C6 cycloaliphatic.

[0140] In some embodiments, L2is a bond.

[0141] In some embodiments, L2is optionally substituted C1-C6aliphatic. In some embodiments, L2is C1-C6alkylene. In some embodiments, L2is -C(H)(CH3)-, -C(CH3)2-, or - CH2-. In some embodiments, L2is a bond or selected from:

[0142] In some embodiments, L2is:In some embodiments, L2is:In some embodiments, L2is:

[0143] In some embodiments, L2is -NR3-C(O)-. In some embodiments, L2is -NH-C(O)-.

[0144] In some embodiments, L2is -C(O)-NR3-. In some embodiments, L2is -C(O)-NH-.

[0145] In some embodiments, L2is optionally substituted 4- to 6-membered heterocyclic.In some embodiments, L2is optionally substituted azetidine or oxetane. In some embodiments, L2is:

[0146] In some embodiments, L2is optionally substituted C3-C6 cycloaliphatic. In some embodiments, L2is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, L2is:

[0147] As described herein, L3is-NR3-, -O-, -C(O)-, -NR3-C(O)-, -NR3-S(O)2-, -C(O)- NR3-, -S(O)2NR3-, -NR3-C(O)-NR3-, optionally substituted C1-C6aliphatic, or an optionally substituted C3-C6 cycloaliphatic ring. In some embodiments, L3is -NR3-. In some embodiments, L3is -NH-. In some embodiments, L3is -O-. In some embodiments, L3is - C(O)-. In some embodiments, L3is -NR3-C(O)-. In some embodiments, L3is -NH-C(O)-. In some embodiments, L3is -NR3-S(O)2-. In some embodiments, L3is -NH-S(O)2-. In some embodiments, L3is -C(O)-NR3-. In some embodiments, L3is -C(O)-NH-. In someembodiments, L3is -S(O)2 NR3-. In some embodiments, L3is-S(O)2-NH-. In some embodiments, L3is -NR3-C(O)-NR3-. In some embodiments, L3is -NH-C(O)-NH-.

[0148] In some embodiments, L3is optionally substituted C1-C6aliphatic. In some embodiments, L3is optionally substituted C1-C6alkylene. In some embodiments, L3is - (CH2)I-6-. In some embodiments, L3is -CH2-.

[0149] In some embodiments, L3is an optionally substituted C3-C6 cycloaliphatic ring. In some embodiments, L3is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In some embodiments, L3is cyclopropyl.

[0150] As described herein with respect to formula II-3, R6is a bond, optionally substituted C1-C6aliphatic, optionally substituted 2- to 6-membered heteroaliphatic, optionally substituted 4- to 6-membered heterocycle comprising one 1 to 3 heteroatoms selected from N, O, and S, optionally substituted C6-C12 aryl, or optionally substituted C3-C6 cycloaliphatic. In some embodiments of formula II-3, R6is a bond or optionally substituted C1-C6aliphatic.

[0151] In some embodiments of formula II-3, R6is a bond.

[0152] In some embodiments of formula II-3, R6is optionally substituted C1-C6aliphatic.In some embodiments, R6is C1-C6alkylene. In some embodiments, R6is -CH2-. In some embodiments, R6is C2-C6 alkynlene.

[0153] In some embodiments of formula II-3, R6is optionally substituted 2- to 6-membered heteroaliphatic.

[0154] In some embodiments of formula II-3, R6is optionally substituted 4- to 6-membered heterocycle comprising one 1 to 3 heteroatoms selected from N, O, and S.

[0155] In some embodiments of formula II-3, R6is optionally substituted C6-C12 aryl.

[0156] In some embodiments of formula II-3, R6is optionally substituted C3-C6 cycloaliphatic.

[0157] As described herein with respect to formula II-3, each R8is independently halogen, -OR3, -C(O)N(R3)2, -C(O)OR3, optionally substituted C1-C6aliphatic, optionally substituted C3-C6 cycloaliphatic, optionally substituted C6-C12 aryl.

[0158] In some embodiments of formula II-3, R8is halogen.

[0159] In some embodiments of formula II-3, R8is -OR3. In some embodiments of formulaII-3, R8is -OH. In some embodiments of formula II-3, R8is -O-CH3.

[0160] In some embodiments of formula II-3, R8is -C(O)N(R3)2. In some embodiments of formula II-3, R8is -C(O)NH2. In some embodiments of formula II-3, R8is -C(O)N(H)(Ci- Ce aliphatic). In some embodiments of formula II-3, R8is -C(O)N(H)(CH3). In some embodiments of formula II-3, R8is -C(O)N(H)-CH2-CH2-O-CH3.

[0161] In some embodiments of formula II-3, R8is -C(O)OR3. In some embodiments, R8is -C(O)OH. In some embodiments, R8is -C(O)OCH3.

[0162] In some embodiments of formula II-3, R8is optionally substituted C1-C6aliphatic. In some embodiments, R8is methyl, ethyl, or propyl. In some embodiments, R8is -CH3 or - C(H)(CH3)2.

[0163] In some embodiments of formula II-3, R8is optionally substituted C3-C6 cycloaliphatic. In some embodiments, R8is optionally substituted cyclopropyl.

[0164] In some embodiments of formula II-3, R8is optionally substituted C6-C12 aryl. In some embodiments, R8is optionally substituted phenyl.

[0165] In some embodiments, with respect to formula II-3, a moiety:

[0166] As described herein with respect to formula II-4, R6is H, halogen, optionally substituted C1-C6aliphatic, optionally substituted 2- to 6-membered heteroaliphatic, optionallysubstituted 4- to 6-membered heterocycle comprising one 1 to 3 heteroatoms selected from N, O, and S, optionally substituted C6-C12 aryl, or optionally substituted C3-C6 cycloaliphatic.

[0167] In some embodiments of formula II-4, R6is H.

[0168] In some embodiments of formula II-4, R6is halogen.

[0169] In some embodiments of formula II-4, R6is optionally substituted C1-C6aliphatic.

[0170] In some embodiments of formula II-4, R6is optionally substituted 2- to 6-membered heteroaliphatic.

[0171] In some embodiments of formula II-4, R6is optionally substituted 4- to 6-membered heterocycle comprising one 1 to 3 heteroatoms selected from N, O, and S.

[0172] In some embodiments of formula II-4, R6is optionally substituted Ce-Cn aryl.

[0173] In some embodiments of formula II-4, R6is optionally substituted C3-C6 cycloaliphatic.

[0174] As described herein with respect to formula II-4, R8is a bond, -O-, -C(O)NR3-, - C(O)OR3, optionally substituted C1-C6aliphatic, optionally substituted C3-C6 cycloaliphatic, or optionally substituted C6-C12 aryl.

[0175] In some embodiments of formula II-4, R8is a bond.

[0176] In some embodiments of formula II-4, R8is -O-.

[0177] In some embodiments of formula II-4, R8is -C(O)NR3-. In some embodiments, R8is -C(O)NH-. In some embodiments, R8is -C(O)N(C1-C6aliphatic)-.

[0178] In some embodiments of formula II-3, R8is -C(O)OR3-. In some embodiments, R8is -C(O)OCH2-.

[0179] In some embodiments of formula II-4, R8is optionally substituted C1-C6aliphatic. In some embodiments, R8is methyl, ethyl, or propyl. In some embodiments, R8is -CH3 or - C(H)(CH3)2.

[0180] In some embodiments of formula II-4, R8is optionally substituted C3-C6 cycloaliphatic. In some embodiments, R8is optionally substituted cyclopropyl.

[0181] In some embodiments of formula II-4, R8is optionally substituted C6-C12 aryl.

[0182] In some embodiments, with respect to formula II-4, a moiety:indicates a point of attachment to moiety B.

[0183] In some embodiments, A is selected from:wherein R1, R2a, R2b, R4, R5, L1, G1, n, G2, G3, L3, R6, R7, and R8are as described in classes and subclasses herein, and * represents a point of attachment to moiety B.

[0184] In some embodiments of formula I, A is selected from:

[0185] In some embodiments, the present disclosure provides a compound of formula I:A-B-E3LI or a pharmaceutically acceptable salt thereof, wherein:A is a moiety of formula II- 1 :11-1 wherein: each G1is independently an optionally substituted Ce-Cn aryl;X1is -S-;X2is -C(R3)-; a bond between X3and X4is a single bond each X3is independently -C(H)(R2b)- or -N(R2a)-;X4is -C(O)-; each R1is independently selected from halogen, optionally substituted C1-C6aliphatic, and optionally substituted -O-C1-C6aliphatic; or two instances of R1come together with the atoms to which they are attached to form a n optionally substituted C6-C1 2ryl ring, an optionally substituted C4-C6 cycloaliphatic ring, a 5- to 6- membered heteroaryl ring comprising 1 to 3 heteroatoms selected from N, O, and S, or an optionally substituted 5- to 6- membered heterocyclic ring comprising 1 to 3 heteroatoms selected from N, O, and S; each R2ais independently optionally substituted C1-C6aliphatic; each R2bis independently hydrogen, optionally substituted C1-C6aliphatic, optionally substituted -N(R3)-C1-C6aliphatic, or optionally substituted -O-C1-C6aliphatic; each R3is independently selected from hydrogen, halogen, and optionally substituted C1-C6aliphatic;each R4is independently selected from optionally substituted C6-C12 aryl, optionally substituted 5- to 12- membered heteroaryl ring comprising 1 to 3 heteroatoms selected from N, O, and S; each R5is independently an optionally substituted 4- to 6-membered heterocyclic ring, an optionally substituted 5- to 6-membered heteroaryl ring, or an optionally C3-C6 cycloaliphatic ring; each L1is independently a bond, -C(O)-; each n is independently 0, 1, 2, 3, 4, 5, or 6;* represents a point of attachment to moiety B; andB is a linker moiety that is an optionally substituted C2-30 aliphatic group wherein one or more carbons are optionally and independently replaced by -Cy-, -NRZ-, - N(RZ)C(O)-, -C(O)N(RZ)-, -N(RZ)C(O)O-, -OC(O)N(RZ)-, -N(RZ)C(O)N(RZ) -, - OC(O)O-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -SO-, -SO2-, wherein each -Cy- is independently an optionally substituted 3-12 membered heterocyclyl ring having 1- 3 heteroatoms selected from N, O, and S, an optionally substituted 3-8 membered heteroaryl ring having 1-4 heteroatoms selected from N, O, and S, an optionally substituted C3-C6 cycloalkyl, or an optionally substituted C6-C12 aryl, and each Rzis independently H or an optionally substituted group selected from C1-C20 aliphatic, or C3-C12 cycloaliphatic.

[0186] In some embodiments, the present disclosure provides a compound of formula I: A-B-E3Lor a pharmaceutically acceptable salt thereof, wherein:A is a moiety of formula II-2 :II-2 wherein:G1is an optionally substituted Ce-Cn aryl;X1is -S-;X2is -C(R3)-; a bond between X3and X4is a single bond each X3is independently -C(H)(R2b)- or -N(R2a)-;X4is -C(O)-; each R1is independently selected from halogen, optionally substituted C1-C6aliphatic, and optionally substituted -O-C1-C6aliphatic; or two instances of R1come together with the atoms to which they are attached to form a n optionally substituted Ce-Cn aryl ring, an optionally substituted C4-C6 cycloaliphatic ring, a 5- to 6- membered heteroaryl ring comprising 1 to 3 heteroatoms selected from N, O, and S, or an optionally substituted 5- to 6- membered heterocyclic ring comprising 1 to 3 heteroatoms selected from N, O, and S;R2ais optionally substituted C1-C6aliphatic;R2bis hydrogen, optionally substituted C1-C6aliphatic, optionally substituted -N(R3)- C1-C6aliphatic, or optionally substituted -O-C1-C6aliphatic; each R3is independently selected from hydrogen, halogen, and optionally substituted C1-C6aliphatic;R4is selected from optionally substituted C6-C12 aryl, optionally substituted 5- to 12- membered heteroaryl ring comprising 1 to 3 heteroatoms selected from N, O, and S;R5is an optionally substituted 4- to 6-membered heterocyclic ring, an optionally substituted 5- to 6-membered heteroaryl ring, or an optionally C3-C6 cycloaliphatic ring;L1is a bond, -C(O)-;n is 0, 1, 2, 3, 4, 5, or 6;* represents a point of attachment to moiety B; andB is a linker moiety that is an optionally substituted C2-30 aliphatic group wherein one or more carbons are optionally and independently replaced by -Cy-, -NRZ-, - N(RZ)C(O)-, -C(O)N(RZ)-, -N(RZ)C(O)O-, -OC(O)N(RZ)-, -N(RZ)C(O)N(RZ) -, - OC(O)O-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -SO-, -SO2-, wherein each -Cy- is independently an optionally substituted 3-12 membered heterocyclyl ring having 1- 3 heteroatoms selected from N, O, and S, an optionally substituted 3-8 membered heteroaryl ring having 1-4 heteroatoms selected from N, O, and S, an optionally substituted C3-C6 cycloalkyl, or an optionally substituted C6-C12 aryl, and each Rzis independently H or an optionally substituted group selected from C1-C20 aliphatic, or C3-C12 cycloaliphatic.

[0187] In some embodiments, when A is a moiety of formula II-l or II-2, X4is C(O), a bond between X4and X3is a single bond, G1is napthyl, X1is S, X2is C(R3), R4is optionally substituted phenyl, and R5is optionally substituted 5- to 6-membered heterocycle.

[0188] In some embodiments, when A is a moiety of formula II-l, X4is C(O), a bond between X4and X3is a single bond, G1is napthyl, X1is S, X2is C(R3), R4is optionally substituted phenyl, and R5is optionally substituted 5- to 6-membered heterocycle.

[0189] In some embodiments, when A is a moiety of formula II-2, X4is C(O), a bond between X4and X3is a single bond, G1is napthyl, X1is S, X2is C(R3), R4is optionally substituted phenyl, and R5is optionally substituted 5- to 6-membered heterocycle.

[0190] In some embodiments, the present disclosure provides a compound of formula I: A-B-E3LI or a pharmaceutically acceptable salt thereof, wherein:A is a moiety of formula II-3 :II-3Each of X5, X6, and X7are independently selected from the group consisting of N and CH;R7is an optionally substituted 4- to 12-membered heterocycle ring comprising 1 to 4 heteroatoms selected from N, O, and S, an optionally substituted Ce-Cn aryl, or an optionally substituted 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and SG2is an optionally substituted Ce-Cn aryl, or optionally substituted 5- to 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S;G3is an optionally substituted 4- to 12-membered heterocycle ring comprising 1 to 4 heteroatoms selected from N, O, and S;L2is optionally substituted C1-C6aliphatic, or optionally substituted C3-C6 cycloaliphatic;L3is-NR3-, -O-, -C(O)-, -NR3-C(O)-, -NR3-S(O)2-, -C(O)-NR3-, -S(O)2NR3-, or - NR3-C(O)-NR3-;* represents a point of attachment to moiety B;R6is a bond; and each R8is independently halogen, -OR3, -C(O)N(R3)2, -C(O)OR3, optionally substituted C1-C6aliphatic, optionally substituted C3-C6 cycloaliphatic, optionally substituted Ce-Ci2aryl.

[0191] In some embodiments, the present disclosure provides a compound of formula I:A-B-E3LIor a pharmaceutically acceptable salt thereof, wherein:A is a moiety of formula II-4 :each of X5, X6, and X7are independently selected from the group consisting of N and CH;R7is an optionally substituted 4- to 12-membered heterocycle ring comprising 1 to 4 heteroatoms selected from N, O, and S, an optionally substituted Ce-Cn aryl, or an optionally substituted 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and SG2is an optionally substituted Ce-Cn aryl, or optionally substituted 5- to 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S;G3is an optionally substituted 4- to 12-membered heterocycle ring comprising 1 to 4 heteroatoms selected from N, O, and S;L2is optionally substituted C1-C6aliphatic, or optionally substituted C3-C6 cycloaliphatic;L3is-NR3-, -O-, -C(O)-, -NR3-C(O)-, -NR3-S(O)2-, -C(O)-NR3-, -S(O)2NR3-, or - NR3-C(O)-NR3-;* represents a point of attachment to moiety B;R6is H, halogen, optionally substituted C1-C6aliphatic, optionally substituted 2- to 6- membered heteroaliphatic, optionally substituted 4- to 6-membered heterocycle comprising one 1 to 3 heteroatoms selected from N, O, and S, optionally substituted Ce-Ci2aryl, or optionally substituted C3-C6 cycloaliphatic; andR8is a bond.

[0192] In some embodiments, when A is a moiety of formula II-3 or II-4, X5and X7are each N, X6is CH, G3is optionally substituted 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, L2is optionally substituted C1-C6aliphatic, L3is - NR3-C(O)- or -C(O)-NR3-, G2is optionally substituted phenyl, and R7is optionally substituted 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S.

[0193] In some embodiments, when A is a moiety of formula II-3, X5and X7are each N, X6is CH, G3is optionally substituted 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, L2is optionally substituted C1-C6aliphatic, L3is -NR3- C(O)- or -C(O)-NR3-, G2is optionally substituted phenyl, and R7is optionally substituted 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S.

[0194] In some embodiments, when A is a moiety of formula II-4, X5and X7are each N, X6is CH, G3is optionally substituted 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, L2is optionally substituted C1-C6aliphatic, L3is -NR3- C(O)- or -C(O)-NR3-, G2is optionally substituted phenyl, and R7is optionally substituted 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S.

[0195] In some embodiments, A is represented by:wherein R1, n, G1, R2a, R4, R5, and L1are as described in classes and subclasses herein, and * represents a point of attachment to moiety B.

[0196] In some embodiments, A is represented by:wherein R1, n, G1, R2a, R4, R5, and L1are as described in classes and subclasses herein, and * represents a point of attachment to moiety B.

[0197] In some embodiments, A is represented by:wherein R1, n, G1, R2b, R4, R5, and L1are as described in classes and subclasses herein, and * represents a point of attachment to moiety B.

[0198] In some embodiments, A is represented by:wherein R1, n, G1, R2b, R4, R5, and L1are as described in classes and subclasses herein, and * represents a point of attachment to moiety B.

[0199] In some embodiments, A is represented by:wherein R6, G2, G3, L2, R7, and L3are as described in classes and subclasses herein, and * represents a point of attachment to moiety B.

[0200] In some embodiments, A is represented by:wherein R6, G2, G3, L2, R7, and L3are as described in classes and subclasses herein, and * represents a point of attachment to moiety B.

[0201] In some embodiments, A is represented by:wherein R6, G3, L2, R7, and L3are as described in classes and subclasses herein, and * represents a point of attachment to moiety B.

[0202] In some embodiments, A is represented by:wherein R6, G3, L2, R7, and L3are as described in classes and subclasses herein, and * represents a point of attachment to moiety B.

[0203] In some embodiments, A is represented by:wherein R6, G2, L2, R7, and L3are as described in classes and subclasses herein, and * represents a point of attachment to moiety B.

[0204] In some embodiments, A is represented by:wherein R6, G2, G3, L2, R7, and L3are as described in classes and subclasses herein, and * represents a point of attachment to moiety B.

[0205] In some embodiments, E3L is a moiety that binds a Von Hippel-Lindau tumor suppressor, an inhibitor of apoptosis protein, or cereblon. In some embodiments, E3L is a moiety that binds a Von-Hippel Lindau tumor suppressor. In some embodiments, a moiety that binds a Von-Hippel Lindau tumor suppressor is selected from:

[0206] In some embodiments, a moiety that binds a Von-Hippel Lindau tumor suppressor is:

[0207] In some embodiments, a moiety that binds a Von-Hippel Lindau tumor suppressor is:

[0208] In some embodiments, a moiety that binds a Von-Hippel Lindau tumor suppressor is:

[0209] In some embodiments, a moiety that binds a Von-Hippel Lindau tumor suppressor is:

[0210] In some embodiments, a moiety that binds a Von-Hippel Lindau tumor suppressor is:

[0211] In some embodiments, a moiety that binds a Von-Hippel Lindau tumor suppressor is:

[0212] In some embodiments, a moiety that binds a Von-Hippel Lindau tumor suppressor is:

[0213] In some embodiments, a moiety that binds a Von-Hippel Lindau tumor suppressor is:

[0214] In some embodiments, a moiety that binds a Von-Hippel Lindau tumor suppressor is:

[0215] In some embodiments, E3L is a moiety that is an inhibitor of apoptosis protein. In some embodiments, a moiety that is an inhibitor of apoptosis protein is selected from:

[0216] In some embodiments, a moiety that is an inhibitor of apoptosis protein is:

[0217] In some embodiments, a moiety that is an inhibitor of apoptosis protein is:

[0218] In some embodiments, a moiety that is an inhibitor of apoptosis protein is:

[0219] In some embodiments of formula I, E3L is a moiety that binds cereblon. In some embodiments a moiety that binds cereblon is selected from:

[0223] In some embodiments, a moiety that binds cereblon is:

[0224] In some embodiments, a moiety that binds cereblon is:

[0225] In some embodiments, a moiety that binds cereblon is:

[0226] In some embodiments, a moiety that binds cereblon is:

[0227] In some embodiments, a moiety that binds cereblon is:

[0228] In some embodiments, a moiety that binds cereblon is:

[0229] In some embodiments, a moiety that binds cereblon is:

[0230] In some embodiments, a moiety that binds cereblon is:

[0231] In some embodiments, a moiety that binds cereblon is:

[0232] In some embodiments, A is a moiety of formula II- 1 and E3L is a moiety that binds a Von Hippel-Lindau tumor suppressor, an inhibitor of apoptosis protein, or cereblon. In some embodiments I, A is a moiety of formula II- 1 and E3L is a moiety that binds a Von Hippel- Lindau tumor suppressor. In some embodiments, A is a moiety of formula 11-1 and E3L is a moiety that binds an inhibitor of apoptosis protein. In some embodiments, A is a moiety of formula 11-1 and E3L is a moiety that binds cereblon. In some embodiments, A is a moiety of formula 11-2 and E3L is a moiety that binds a Von Hippel-Lindau tumor suppressor, an inhibitor of apoptosis protein, or cereblon. In some embodiments, A is a moiety of formula II-2 and E3L is a moiety that binds a Von Hippel-Lindau tumor suppressor. In some embodiments, A is a moiety of formula 11-2 and E3L is a moiety that binds an inhibitor of apoptosis protein. In some embodiments, A is a moiety of formula 11-2 and E3L is a moiety that binds cereblon. In some embodiments, A is a moiety of formula II- 3 and E3L is a moiety that binds a Von Hippel- Lindau tumor suppressor, an inhibitor of apoptosis protein, or cereblon. In some embodiments, A is a moiety of formula 11-3 and E3L is a moiety that binds a Von Hippel-Lindau tumor suppressor. In some embodiments, A is a moiety of formula 11-3 and E3L is a moiety that bindsan inhibitor of apoptosis protein. In some embodiments, A is a moiety of formula II-3 and E3L is a moiety that binds cereblon. In some embodiments, A is a moiety of formula II-4 and E3L is a moiety that binds a Von Hippel-Lindau tumor suppressor, an inhibitor of apoptosis protein, or cereblon. In some embodiments, A is a moiety of formula II-4 and E3L is a moiety that binds a Von Hippel-Lindau tumor suppressor. In some embodiments, A is a moiety of formula II-4 and E3L is a moiety that binds an inhibitor of apoptosis protein. In some embodiments, A is a moiety of formula II-4 and E3L is a moiety that binds cereblon.

[0233] In some embodiments, a compound of formula l is a compound of formula III- 1 :III-l or a pharmaceutically acceptable salt thereof, wherein R1, R2a, R4, R5, L1, G1, n and B are as described in classes and subclasses herein.

[0234] In some embodiments, a compound of formula I is a compound of formula III-2 :III-2 or a pharmaceutically acceptable salt thereof, wherein R1, R2a, R4, R5, L1, G1, n and B are as described in classes and subclasses herein.

[0235] In some embodiments, a compound of formula l is a compound of formula III-3 :III-3 or a pharmaceutically acceptable salt thereof, wherein R6, R7, R8, L3, G2, G3, and B are as described in classes and subclasses herein.

[0236] In some embodiments, a compound of formula I is a compound of formula III-4 :III-4 or a pharmaceutically acceptable salt thereof, wherein R7, R8, L3, G2, G3, and B are as described in classes and subclasses herein.

[0237] In some embodiments, a compound of formula I is a compound of formula III-5 :III-5or a pharmaceutically acceptable salt thereof, wherein R1, R2a, R4, R5, L1, G1, n and B are as described in classes and subclasses herein.

[0238] In some embodiments, a compound of formula I is a compound of formula III-6 :III-6 or a pharmaceutically acceptable salt thereof, wherein R1, R2a, R4, R5, L1, G1, n and B are as described in classes and subclasses herein.

[0239] In some embodiments, a compound of formula I is a compound of formula III-7:III-7 or a pharmaceutically acceptable salt thereof, wherein R6, R7, R8, L3, G2, G3, and B are as described in classes and subclasses herein.

[0240] In some embodiments, a compound of formula I is a compound of formula III-8 :or a pharmaceutically acceptable salt thereof, wherein R7, R8, L3, G2, G3, and B are as described in classes and subclasses herein.

[0241] In some embodiments, a compound of formula I is a compound of formula III-9 :III-9 or a pharmaceutically acceptable salt thereof, wherein R7, R8, L3, G2, G3, and B are as described in classes and subclasses herein.

[0242] In some embodiments, a compound of formula I is a compound of formula III- 10:III- 10 or a pharmaceutically acceptable salt thereof, wherein R7, R8, L3, G2, G3, and B are as described in classes and subclasses herein.

[0243] In some embodiments, a compound of formula l is a compound of formula III- 11 :Ill- 11 or a pharmaceutically acceptable salt thereof, wherein R1, R2a, R4, R5, L1, G1, n and B are as described in classes and subclasses herein.

[0244] In some embodiments, a compound of formula I is a compound of formula III- 12:or a pharmaceutically acceptable salt thereof, wherein R7, R8, L3, G2, G3, and B are as described in classes and subclasses herein.

[0245] In some embodiments, a compound of formula I is a compound of formula III-l 3 :III- 13 or a pharmaceutically acceptable salt thereof, wherein R7, R8, L3, G2, G3, and B are as described in classes and subclasses herein.

[0246] In some embodiments, a compound of formula I is a compound of formula III- 14:III- 14 or a pharmaceutically acceptable salt thereof, wherein R6, R7, R8, L3, G2, G3, and B are as described in classes and subclasses herein.

[0247] As described herein, B is a linker moiety.

[0248] In some embodiments, B is a linker moiety that is an optionally substituted C2-30 aliphatic group wherein one or more carbons are optionally and independently replaced by - Cy-, -NRZ-, -N(RZ)C(O)-, -C(O)N(RZ)-, -N(RZ)C(O)O-, -OC(O)N(RZ)-, -N(RZ)C(O)N(RZ) -,-0C(0)0-, -0-, -C(0)-, -0C(0)-, -C(0)0-, -SO-, -SO2-, wherein each -Cy- is independently an optionally substituted 3-12 membered heterocyclyl ring having 1-3 heteroatoms selected from N, O, and S, an optionally substituted 3-8 membered heteroaryl ring having 1-4 heteroatoms selected from N, O, and S, an optionally substituted C3-C6 cycloalkyl, or an optionally substituted C6-C12 aryl, and each Rzis independently H or an optionally substituted group selected from C1-C20 aliphatic, or C3-C12 cycloaliphatic.

[0249] In some embodiments, B is a linker moiety represented by formula IV:* - G4- G5- G6- # wherein:* represents a point of attachment to A and # represents a point of attachment to E3L;G4is an optionally substituted C1-4 aliphatic group wherein one or more carbon atoms are optionally and independently replaced by -C(O)N(RZ)- or -O-, and each Rzis independently H or an optionally substituted C1-C4 aliphatic group;G5is an optionally substituted C1-5 aliphatic group wherein one or more carbon atoms are optionally and independently replaced by -Cy-, -NRZ-, or -O-, wherein each -Cy- is independently an optionally substituted 3-6 membered heterocyclyl ring having 1-3 heteroatoms selected from N, O, and S or optionally substituted C3-C6 cycloalkyl, and each Rzis independently H or an optionally substituted C1-C4 aliphatic group; andG6is a bond or an optionally substituted C1-4 aliphatic group wherein one or more carbon atoms are optionally and independently replaced by -Cy-, -NRZ-, -O-, or -C(O)-, wherein each - Cy- is independently an optionally substituted 3-6 membered heterocyclyl ring having 1-3 heteroatoms selected from N, O, and S, and each Rzis independently H or an optionally substituted C1-C4 aliphatic group.

[0250] As described herein, G4is an optionally substituted C1-4 aliphatic group wherein one or more carbons are optionally and independently replaced by -C(O)N(RZ)- or -O-, and each Rzis independently H or an optionally substituted C1-C4 aliphatic group.

[0251] In some embodiments, G4is an optionally substituted C1-4 aliphatic group wherein one or more carbon atoms are optionally and independently replaced by -O-. In someembodiments, G4is a C1-4 aliphatic group wherein one carbon atom is replaced by -O-. In some embodiments, G4is an optionally substituted C1-4 aliphatic group wherein one or more carbon atoms are optionally and independently replaced by -O- and further wherein the C1-4 aliphatic group contains one or more units of unsaturation. In some embodiments, G4is a C1-4 aliphatic group wherein one carbon atom is replaced by -O- and further wherein the C1-4 aliphatic group contains one or more units of unsaturation.

[0252] In some embodiments, G4is an optionally substituted C1-4 aliphatic group. In some embodiments, G4is an optionally substituted C1-3 aliphatic group. In some embodiments, G4is an optionally substituted C1-2 aliphatic group. In some embodiments, G4is an unsaturated C1-2 aliphatic group. In some embodiments, G4is C2 alkynyl. In some embodiments, G4is an optionally substituted C1-4 aliphatic group wherein one or more carbon atoms are optionally and independently replaced by -O- or -C(O)N(RZ)-. In some embodiments, G4is an optionally substituted C1-4 aliphatic group wherein one or more carbon atoms are optionally and independently replaced by -O- or -C(O)NH-. In some embodiments, G4is a C1-4 aliphatic group wherein one or more carbon atoms are optionally and independently replaced by -O- or - C(O)NH-.

[0253] As described herein, G5is an optionally substituted C1-5 aliphatic group wherein one or more carbon atoms are optionally and independently replaced by -Cy-, -NRZ-, or -O-, wherein each -Cy- is independently an optionally substituted 3-6 membered heterocyclyl ring having 1-3 heteroatoms selected from N, O, and S or optionally substituted C3-C6 cycloalkyl, and each Rzis independently H or an optionally substituted C1-C4 aliphatic group.

[0254] In some embodiments, G5is an optionally substituted C1-5 aliphatic group wherein one or more carbon atoms are optionally and independently replaced by -O-. In some embodiments, G5is a C1-5 aliphatic group wherein one carbon is replaced by -O-. In some embodiments, G5is an optionally substituted C1-5 aliphatic group wherein one or more carbon atoms are optionally and independently replaced by -Cy-, wherein each -Cy- is independently an optionally substituted 3-6 membered heterocyclyl ring having 1-3 heteroatoms selected from N, O, and S or optionally substituted C3-C6 cycloalkyl. In some embodiments, G5is anoptionally substituted C1-5 aliphatic group wherein one carbon atom is replaced by -Cy-, wherein -Cy- is an optionally substituted 3-6 membered heterocyclyl ring having 1-3 heteroatoms selected from N, O, and S. In some embodiments, G5is an optionally substituted C1-5 aliphatic group wherein one carbon atom is replaced by piperidinyl. In some embodiments, G5is an optionally substituted C1-5 aliphatic group wherein one or more carbon atoms are optionally and independently replaced by -Cy- or -NRZ-, wherein each -Cy- is independently an optionally substituted 3-6 membered heterocyclyl ring having 1-3 heteroatoms selected from N, O, and S. In some embodiments, G5is an optionally substituted C1-5 aliphatic group wherein one or more carbon atoms are optionally and independently replaced by piperidinyl or -NH-. In some embodiments, G5is an optionally substituted C1-5 aliphatic group wherein one or more carbon atoms are optionally and independently replaced by -Cy- or -NRZ-, wherein each -Cy- is independently an optionally substituted 3-6 membered heterocyclyl ring having 1-3 heteroatoms selected from N, O, and S or optionally substituted C3-C6 cycloalkyl. In some embodiments, G5is an optionally substituted C1-5 aliphatic group wherein one or more carbon atoms are optionally and independently replaced by piperidinyl, cyclobutyl, or -NH-.

[0255] As described herein, G6is a bond or an optionally substituted C1-4 aliphatic group wherein one or more carbon atoms are optionally and independently replaced by -Cy-, -NRZ-, -O-, or -C(O)-, wherein each -Cy- is independently an optionally substituted 3-6 membered heterocyclyl ring having 1-3 heteroatoms selected from N, O, and S, and each Rzis independently H or an optionally substituted C1-C4 aliphatic group.

[0256] In some embodiments, G6is a bond.

[0257] In some embodiments, G6is an optionally substituted C1-4 aliphatic group wherein one or more carbon atoms are optionally and independently replaced by -O-. In some embodiments, G6is a C1-4 aliphatic group wherein one carbon atom is replaced by -O-. In some embodiments, G6is an optionally substituted C1-4 aliphatic group wherein one or more carbon atoms are optionally and independently replaced by -Cy- or -NRZ-, wherein each -Cy- is independently an optionally substituted 3-6 membered heterocyclyl ring having 1-3 heteroatoms selected from N, O, and S. In some embodiments, G6is an optionally substitutedCi-5 aliphatic group wherein one or more carbon atoms are optionally and independently replaced by piperidinyl or -NH-. In some embodiments, G6is an optionally substituted C1-4 aliphatic group wherein one or more carbon atoms are optionally and independently replaced by -Cy-, wherein each -Cy- is independently an optionally substituted 3-6 membered heterocyclyl ring having 1-3 heteroatoms selected from N, O, and S. In some embodiments, G6is an optionally substituted C1-4 aliphatic group wherein one carbon atom is replaced by -Cy-, wherein -Cy- is an optionally substituted 3-6 membered heterocyclyl ring having 1-3 heteroatoms selected from N, O, and S. In some embodiments, G6is an optionally substituted Ci-4 aliphatic group wherein one carbon atom is replaced by piperizinyl. In some embodiments, G6is an optionally substituted Ci-4 aliphatic group wherein one or more carbon atoms are optionally and independently replaced by -Cy- or -O-, wherein each -Cy- is independently an optionally substituted 3-6 membered heterocyclyl ring having 1-3 heteroatoms selected from N, O, and S. In some embodiments, G6is an optionally substituted Ci-4 aliphatic group wherein one or more carbon atoms are optionally and independently replaced by piperidinyl or -O-. In some embodiments, G6is an optionally substituted Ci-4 aliphatic group wherein one or more carbon atoms are optionally and independently replaced by -Cy-, -NRZ-, or -C(O)-, wherein each -Cy- is independently an optionally substituted 3-6 membered heterocyclyl ring having 1- 3 heteroatoms selected from N, O, and S. In some embodiments, G6is an optionally substituted Ci-4 aliphatic group wherein one or more carbon atoms are optionally and independently replaced by piperidinyl, -NH-, or -C(O)-.

[0258] In some embodiments, B is selected from Table B 1 :Table Blwherein * represents a point of attachment to A and # represents a point of attachment to E3L.

[0259] In some embodiments, B is selected from Table B2:Table B2wherein * represents a point of attachment to A and # represents a point of attachment to E3L.

[0260] In some embodiments, B is selected from Table B3:Table B3Attorney Docket No. 2013075-0110wherein * represents a point of attachment to A and # represents a point of attachment to E3L.

[0261] In some embodiments, a compound of formula I is selected from Table 1 :Table 1Attorney Docket No. 2013075-0110

[0262] In some embodiments, a compound of formula I is selected from Table 2:Table 2

[0263] In some embodiments, provided compounds are provided and / or utilized in a salt form (e.g., a pharmaceutically acceptable salt form). Reference to a compound provided herein is understood to include reference to salts thereof, unless otherwise indicated.FIP200 and the Role of Autophagy

[0264] The present disclosure encompasses an insight that particular proteins associated with the autophagy process are critical for normal autophagy function, and that by degrading said proteins, autophagy can therefore be inhibited or otherwise reduced relative to a normal cell system. In particular, the present disclosure encompasses an insight that degradation of FIP200 disrupts autophagy, which can be leveraged into the treatment of particular diseases, disorders, or conditions.

[0265] Autophagy is the cellular process of degradation of cellular materials, including protein aggregates, whole organelles, and pathogens. In cells, autophagy is initiated by the formation of a double membraned structure termed the “phagophore ” which forms around the cargo to be degraded. The phagophore then matures into an “autophagosome”, which has completely encapsulated the cargo. The complete autophagosome, along with its enclosed contents, then fuse with the lysosome, which causes the degradation of the autophagosome and its cargo.

[0266] The formation of the phagophore is initiated by the dual action of two distinct molecular cascades (the ATG5-ATG12 lipidation pathway) and the ULK1-FIP200-ATG13- ATG101 complex (referred to herein as the “ULK1 complex”). Both pathways act synergistically to promote the formation of phagophores and completion into the final autophagosome. FIP200 is a central component of the ULK1 complex and was originally identified as an interacting partner of ULK1. The ULK1 complex comprises of the Unc51-like kinase (ULK1), the scaffold protein FAK family kinase-interacting protein of 200 kDa (FIP200, also known as RB1CC1), ATG13 and ATG101. It has been found that cells lacking FIP200 have a significant defect at the most upstream event of autophagy - the formation of the phagophore. Without wishing to be bound by theory, it is hypothesized that FIP200 is an essential component of the autophagy pathway.

[0267] Inhibition of autophagy is being investigated as an oncology treatment paradigm since some cancers become hyper-reliant on autophagy for growth. Previous work by others have identified inhibitors of autophagy pathway generally, including certain small molecule inhibitors of the ULK1 kinase or ATG7 (a key component of the ATG5-12 lipidation cascade), but other more specific inhibitors of key autophagy regulatory proteins remain lacking. Certain inhibitors have been determined to be incomplete or generate off-target toxicity.

[0268] The present disclosure overcomes the problems associated with previous autophagy inhibitors and provides a new and surprisingly useful class of compounds that are PROTACs (PRoteOlysis TArgeting Chimaeras) against FIP200. Generally, PROTACs are heterobifunctional molecules which link a cargo binder to an E3 ubiquitin ligase via a binder,thereby promoting ubiquitination and destruction of the target via the proteasome. As described herein, binders of E3 ubiquitin ligase are known and described in various publications, including WO 2023 / 283606, and Bricelj, et al., Frontiers in Chemistry, 9:70317 (July 2021), each of which is incorporated by reference in its entirety. The present disclosure leverages the insight that compounds comprising a E3 ubiquitin ligase binder and a moiety that binds to or associates with FIP200 causes degradation of FIP200, and thereby inhibits the autophagy pathway in a cell.Uses, Formulation, and AdministrationPharmaceutically Acceptable Compositions

[0269] According to another embodiment, the present disclosure provides a composition comprising a compound described herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle. In some embodiments, a composition described herein comprises a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient. In certain embodiments, a composition described herein is formulated for administration to a patient in need of such composition. In some embodiments, a composition described herein is formulated for oral administration to a patient.

[0270] In some embodiments, a compound or composition as described herein can be used for the treatment of a disease, disorder, or condition. In some embodiments, a compound as described herein can be used for the treatment of a disease, disorder, or condition. In some embodiments, a composition as described herein can be used for the treatment of a disease, disorder or condition.

[0271] In some embodiments, a compound or composition as described herein can be used to inhibit autophagy in a subject. In some embodiments, a compound as described herein can be used to inhibit autophagy in a subject. In some embodiments, a composition as described herein can be used to inhibit autophagy in a subject.

[0272] Compounds and compositions, according to method of the present disclosure, are administered using any amount and any route of administration effective for treating or lessening the severity of a disorder provided herein. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like. Compounds described herein are preferably formulated in unit dosage form for ease of administration and uniformity of dosage.

[0273] Compositions of the present disclosure may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, intraperitoneally, intraci stemally or via an implanted reservoir. In some embodiments, the compositions are administered orally, intraperitoneally or intravenously.

[0274] Sterile injectable forms of the compositions described herein may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3 -butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

[0275] For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancerswhich are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.

[0276] Injectable formulations can be sterilized, for example, by filtration through a bacterial- retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0277] In order to prolong the effect of a compound of the present disclosure, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0278] In some embodiments, provided pharmaceutically acceptable compositions are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, pharmaceutically acceptable compositions described herein are administered without food. In other embodiments, pharmaceutically acceptable compositions described herein are administered with food. Pharmaceutically acceptable compositions described herein may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and com starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, usefuldiluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.

[0279] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and / or i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0280] Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.Ill

[0281] The active compounds can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0282] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0283] Alternatively, pharmaceutically acceptable compositions described herein may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature butliquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

[0284] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds described herein with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

[0285] Pharmaceutically acceptable compositions described herein may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0286] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.

[0287] For topical applications, provided pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of compounds described herein include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, provided pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0288] For ophthalmic use, provided pharmaceutically acceptable compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such asbenzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.

[0289] Pharmaceutically acceptable compositions described herein may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well- known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0290] Dosage forms for topical or transdermal administration of a compound disclosed herein include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this disclosure. Additionally, the present disclosure contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.Methods of Treatment

[0291] In some embodiments, the present disclosure provides a method of treating a disease, disorder, or condition in a subject comprising administering to the subject a compound described herein (e.g., a compound of formula I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising said compound, as described in classes and subclasses herein. In some embodiments, said disease, disorder, or condition is a form of cancer, Ischemia-Reperfusion injury following a stroke or myocardial infarction, a neurodegenerative disease, a bacterial infection, a viral infection or an inflammatory disease.

[0292] In some embodiments, a form of cancer includes pancreatic ductal adenocarcinoma, colorectal adenocarcinoma, multiple myeloma, lung adenocarcinoma, skin cutaneous melanoma, uterine corpus endometrioid carcinoma, uterine carcinosarcoma, thyroid carcinoma, acute myeloid leukemia, bladder urothelial carcinoma, gastric adenocarcinoma, cervical adenocarcinoma, head and neck squamous cell carcinoma, or other Ras family- associated cancer. In some embodiments, the method further comprises administering a compound described herein and a RTK, RAS, RAF, MEK, ERK, or MAPK inhibitor for treatment of a RAS family-associated cancer. In some embodiments, the method further comprises administering a compound described herein and a RTK, RAS, RAF, MEK, or ERK inhibitor for treatment of a RAS family-associated cancer. In some embodiments, the method further comprises administering a compound described herein and an immune checkpoint inhibitor. In some embodiments, an immune checkpoint inhibitor is selected from a PD-1 inhibitor, a PD-L1 inhibitor, a CTLA4 inhibitor, a LAG-3 inhibitor, and a TIGIT inhibitor. In some embodiments, the method further comprises administering a compound described herein and a T-cell engager or immunotherapy that binds to both a cancer cell and an immune cell. In some embodiments, a T-cell engager or immunotherapy is a bispecific antibody. In some embodiments, a bispecific antibody binds to CD3 on a T-cell and a target on a cancer cell.

[0293] In some embodiments, a neurodegenerative disease is Alzheimer’s disease (AD), Parkinson’s disease (PD), or Huntington’s disease (HD).

[0294] In some embodiments, a bacterial infection is Porphyromonas gingivalis and Brucella abortus.

[0295] In some embodiments, a viral infection is a coronavirus. In some embodiments a viral infection is a coronavirus, e.g., SARS-CoV-2, SARS-CoV, MERS-CoV, HCoV-NL63, HCoV-229E, HCoV-OC43, or HKUl.

[0296] In some embodiments, an inflammatory disease is Crohn’s disease or inflammatory bowel disease.

[0297] In some embodiments, the present disclosure provides a method of inhibiting autophagy in a subject comprising administering to the subject a compound of formula I or a pharmaceutical composition as described in classes and subclasses herein.EXEMPLARY EMBODIMENTS

[0298] The present disclosure provides the following non-limiting numbered embodiments.Embodiment 1. A compound of formula I:A-B-E3L or a pharmaceutically acceptable salt thereof, wherein:A is a moiety that binds to or associates with FIP200;B is a linker moiety; andE3L is a ubiquitin E3 ligase binding moiety.Embodiment 2. The compound of Embodiment 1, wherein A is selected from formulaG1is an optionally substituted Ce-Cn aryl or an optionally substituted 5- to 6- membered heteroaryl;X1is -S-, -N(R3)-, -O-, optionally substituted C1-C6aliphatic, or optionally substituted C3-C6 cycloaliphatic;X2is independently C(R3) or N, provided that, when X2is N, then X1is optionally substituted C1-C6aliphatic, or optionally substituted C3-C6 cycloaliphatic; when a bond between X3and X4is a single bond, then X3is N(R2a), and X4is C(O) when a bond between X3and X4is a double bond, then X3is C(R2b) and X4is C(R3), or N; each R1is independently selected from halogen, optionally substituted C1-C6aliphatic, and optionally substituted -O-C1-C6aliphatic; or two instances of R1come together with the atoms to which they are attached to form a n optionally substituted C6-C12 aryl ring, an optionally substituted C4-C6 cycloaliphatic ring, a 5- to 6- membered heteroaryl ring comprising 1 to 3 heteroatoms selected from N, O, and S, or an optionally substituted 5- to 6- membered heterocyclic ring comprising 1 to 3 heteroatoms selected from N, O, and S;R2ais optionally substituted C1-C6aliphatic;R2bis hydrogen, optionally substituted C1-C6aliphatic, optionally substituted -N(R3)- C1-C6aliphatic, or optionally substituted -O-C1-C6aliphatic; each R3is independently selected from hydrogen, halogen, and optionally substituted C1-C6aliphatic;R4is selected from optionally substituted C6-C12 aryl, optionally substituted 5- to 12- membered heteroaryl ring comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted 4- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, and optionally substituted C1-C6aliphatic;R5is an optionally substituted 4- to 6-membered heterocyclic ring, an optionally substituted 5- to 6-membered heteroaryl ring, an optionally C3-C6 cycloaliphaticring, an optionally substituted Ce-Cn aryl, or an optionally substituted C1-C6aliphatic;L1is a bond, -C(O)-, -S(O)-, -S(O)2-, or -NR3-; n is independently 0, 1, 2, 3, 4, 5, or 6; each of X5, X6, and X7is independently selected from the group consisting of N and CH;R7is hydrogen, an optionally substituted -O-C1-C6aliphatic, -S(O)2R3, optionally substituted C1-C6aliphatic, an optionally substituted 4- to 12-membered heterocycle ring comprising 1 to 4 heteroatoms selected from N, O, and S, an optionally substituted Ce-Cn aryl, or an optionally substituted 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and SG2is optionally substituted Ce-Cn aryl, optionally substituted 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, optionally substituted 5- to 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, or optionally substituted C3-C6 cycloaliphatic;G3is optionally substituted 4- to 12-membered heterocycle ring comprising 1 to 4 heteroatoms selected from N, O, and S, optionally substituted 5- to 6-membered heteroaryl ring comprising 1 to 4 heteroatoms selected from N, O, and S, an optionally substituted C3-C6 cycloaliphatic ring or optionally substituted C6-C12 aryl;L2is a bond, -NR3-C(O)-, -C(O)-NR3-, optionally substituted C1-C6aliphatic, optionally substituted 4- to 6-membered heterocyclic, or optionally substituted C3- Ce cycloaliphatic;L3is -NR3-, -O-, -C(O)-, -NR3-C(O)-, -NR3-S(O)2-, -C(O)-NR3-, -S(O)2NR3-, -NR3- C(O)-NR3-, optionally substituted C1-C6aliphatic, or optionally substituted C3-C6 cycloaliphatic ring;* represents a point of attachment to moiety B; and wherein:when A is a moiety of formula II- 3 then R6is a bond, optionally substituted C1-C6aliphatic, optionally substituted 2- to 6-membered heteroaliphatic, optionally substituted 4- to 6-membered heterocycle comprising one 1 to 3 heteroatoms selected from N, O, and S, optionally substituted Ce-Cn aryl, or optionally substituted C3-C6 cycloaliphatic; and R8is halogen, -OR3, -C(O)N(R3)2, - C(O)OR3, optionally substituted C1-C6aliphatic, optionally substituted C3-C6 cycloaliphatic, optionally substituted C6-C12 aryl; and when A is of formula II-4, then R6is H, halogen, optionally substituted C1-C6aliphatic, optionally substituted 2- to 6-membered heteroaliphatic, optionally substituted 4- to 6-membered heterocycle comprising one 1 to 3 heteroatoms selected from N, O, and S, optionally substituted C6-C12 aryl, or optionally substituted C3-C6 cycloaliphatic; and R8is a bond, -O-, -C(O)NR3-, -C(O)OR3, optionally substituted C1-C6aliphatic, optionally substituted C3-C6 cycloaliphatic, or optionally substituted C6-C12 aryl.Embodiment 3. The compound of Embodiment 2, wherein two R1come together, with the atoms to which they are attached, to form an optionally substituted C6-C12 aryl ring or a 5- to 6- membered heteroaryl ring comprising 1 to 3 heteroatoms selected from N, O, and S.Embodiment 4. The compound of Embodiment 2, wherein n is 2 and each R1is halogen.Embodiment 5. The compound of Embodiment 4, wherein each R1is chloride.Embodiment 6. The compound of any one of Embodiments 2-5, wherein a bond between X4and X3is a single bond.Embodiment 7. The compound of any one of Embodiments 2-5, wherein a bond between X4and X3is a double bond, X3is C(R2b), and X4is N.Embodiment 8. The compound of any one of Embodiments 2-7, wherein X1is S.Embodiment 9. The compound of any one of Embodiments 2-8, wherein R4is optionally substituted phenyl or optionally substituted 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S.Embodiment 10. The compound of any one of Embodiments 2-9, wherein a moiety:Embodiment 11. The compound of any one of Embodiments 2-10, wherein G1is phenyl or naphthyl.Embodiment 12. The compound of any one of Embodiments 2-11, wherein R5is optionally substituted 5- to 6-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S.Embodiment 13. The compound of any one of Embodiments 2-12, wherein L1is C(O).Embodiment 14. The compound of Embodiment 2, wherein A is of formula II- 1 or II-2,X4is C(O), a bond between X4and X3is a single bond, G1is napthyl, X1is S, X2isC(R3), R4is optionally substituted phenyl, and R5is optionally substituted 5- to 6- membered heterocycle.Embodiment 16. The compound of Embodiment 2, wherein X5and X7are each N and X6is CH.Embodiment 17. The compound of Embodiment 2, wherein G3is an optionally substituted 4- to 12-membered heterocycle ring comprising 1 to 4 heteroatoms selected from N, O, and S.Embodiment 18. The compound of Embodiment 17, wherein G3is optionally substituted 4- to 6-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S.Embodiment 19. The compound of Embodiment 17, wherein G3is optionally substituted 6- to 12-membered bicyclic heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S.Embodiment 20. The compound of any one of Embodiments 2 or 16-19, wherein L2is optionally substituted C1-C6aliphatic.Embodiment 21. The compound of any one of Embodiments 2 or 16-19, wherein L2is a bond or selected from:Embodiment 22. The compound of Embodiment 21, wherein L2is:Embodiment 23. The compound of any one of Embodiments 2 or 16-22, wherein G2is optionally substituted Ce-Cn aryl or optionally substituted 5- to 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S.Embodiment 24. The compound of any one of Embodiments 2 or 16-23, wherein R7is optionally substituted 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S.Embodiment 25. The compound of Embodiment 2, wherein A is of formula II-3 or II-4,X5and X7are each N, X6is CH, G3is optionally substituted 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, L2is optionally substituted C1-C6aliphatic, L3is -NR3-C(O)- or -C(O)-NR3-, G2is optionally substituted phenyl, and R7is optionally substituted 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S.Embodiment 26. The compound of Embodiment 2, wherein a moiety:Embodiment 27. The compound of Embodiment 2, wherein a moiety:Embodiment 28. The compound of Embodiment 2, wherein A is selected from:Embodiment 30. The compound of any one of Embodiments 2-29, wherein E3L is a moiety that binds a Von Hippel-Lindau tumor suppressor, an inhibitor of apoptosis protein, or cereblon.Embodiment 31. The compound of Embodiment 30, wherein E3L is a moiety that binds a Von-Hippel Lindau tumor suppressor.Embodiment 32. The compound of Embodiment 31, wherein E3L is a moiety that binds a Von-Hippel Lindau tumor suppressor and is represented by any one of the following structures:Embodiment 33. The compound of Embodiment 30, wherein E3L is a moiety that binds an inhibitor of apoptosis protein.Embodiment 34. The compound of Embodiment 33, wherein E3L is a moiety that binds an inhibitor of apoptosis protein and is represented by any one of the following structures:Embodiment 35. The compound of Embodiment 30, wherein E3L is a moiety that binds cereblon.Embodiment 36. The compound of Embodiment 35, wherein E3L is a moiety that binds cereblon and is represented by any one of the following structures:Embodiment 37. The compound of Embodiment 2, wherein the compound is represented by formula III-l :III-lEmbodiment 38. The compound of Embodiment 2, wherein the compound is represented by formula III-2:III-2Embodiment 39. The compound of Embodiment 2, wherein the compound is represented by formula III-3III-3Embodiment 40. The compound of Embodiment 2, wherein the compound is represented by formula III-4:III-4Embodiment 4E The compound of Embodiment 2, wherein the compound is represented by formula III-5 :III-5Embodiment 42. The compound of Embodiment 2, wherein the compound is represented by formula III-6:III-6Embodiment 43. The compound of Embodiment 2, wherein the compound is represented by formula III-7III-7Embodiment 44. The compound of Embodiment 2, wherein the compound is represented by formula III-8 :Embodiment 45. The compound of Embodiment 2, wherein the compound is represented by formula HI-9:III-9Embodiment 46. The compound of Embodiment 2, wherein the compound is represented by formula III- 10:III- 10Embodiment 47. The compound of Embodiment 2, wherein the compound is represented by formula III- 11 :III- 11Embodiment 48. The compound of Embodiment 2, wherein the compound is represented by formula III- 12:III- 12Embodiment 49. The compound of Embodiment 2, wherein the compound is represented by formula III- 13 :Ill- 13Embodiment 50. The compound of Embodiment 2, wherein the compound is represented by formula III- 14:Embodiment 51. The compound of any one of Embodiments 1-50, wherein B is a linker moiety that is an optionally substituted C2-30 aliphatic group wherein one or more carbons are optionally and independently replaced by -Cy-, -NRZ-, -N(RZ)C(O)-, - C(O)N(RZ)-, -N(RZ)C(O)O-, -OC(O)N(RZ)-, -N(RZ)C(O)N(RZ) -, -OC(O)O-, -O-, - C(O)-, -OC(O)-, -C(O)O-, -SO-, -SO2-, wherein each -Cy- is independently an optionally substituted 3-12 membered heterocycle ring having 1-3 heteroatoms selected from N, O, and S, an optionally substituted 3-8 membered heteroaryl ring having 1-4heteroatoms selected from N, O, and S, an optionally substituted C3-C6 cycloalkyl, or an optionally substituted C6-C12 aryl, and each Rzis independently H or an optionally substituted group selected from C1-C20 aliphatic, or C3-C12 cycloaliphatic.Embodiment 52. The compound of any one of Embodiments 1-50, wherein B is selected from Table Bl.Embodiment 53. The compound of Embodiments 1 or 2, wherein the compound is selected from Table 1.Embodiment 54. A pharmaceutical composition comprising a compound of any one of Embodiments 1-53, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.Embodiment 55. A method of treating a disease, disorder, or condition in a subject comprising administering to the subject a compound of any one of Embodiments 1-53 or a pharmaceutical composition of Embodiment 54.Embodiment 56. The method of Embodiment 55, wherein the disease, disorder, or condition is selected from forms of cancer, Ischemia-Reperfusion injury following a stroke or myocardial infarction, a neurodegenerative disease, a bacterial infection, a viral infection and an inflammatory disease.Embodiment 57. The method of Embodiment 56, wherein the form of cancer is selected from pancreatic ductal adenocarcinoma, colorectal adenocarcinoma, multiple myeloma, lung adenocarcinoma, skin cutaneous melanoma, uterine corpus endometrioidcarcinoma, uterine carcinosarcoma, thyroid carcinoma, acute myeloid leukemia, bladder urothelial carcinoma, gastric adenocarcinoma, cervicaladenocarcinoma, head and neck squamous cell carcinoma, or other Ras family- associated cancer.Embodiment 58. The method of Embodiment 57, wherein the method further comprises administering a RTK, RAS, RAF, MEK, ERK, or MAPK inhibitor.Embodiment 59. The method of Embodiment 57, wherein the method further comprises administering an immune checkpoint inhibitor.Embodiment 60. The method of Embodiment 59, wherein the immune checkpoint inhibitor is selected from a PD-1 inhibitor, a PD-L1 inhibitor, a CTLA4 inhibitor, a LAG-3 inhibitor, and a TIGIT inhibitor.Embodiment 61. The method of Embodiment 57, wherein the method further comprises administering a T-cell engager or immunotherapy that binds to both a cancer cell and an immune cell.Embodiment 62. The method of Embodiment 61, wherein a T-cell engager or immunotherapy is a bispecific antibody.Embodiment 63. The method of Embodiment 62, wherein the bispecific antibody binds to CD3 on a T-cell and a target on a cancer cell.Embodiment 64. The method of Embodiment 56, wherein the neurodegenerative disease is selected from Alzheimer disease (AD), Parkinson disease (PD), and Huntington disease (HD).Embodiment 65. The method of Embodiment 56, wherein the bacterial infection is selected from Porphyromonas gingivalis and Brucella abortus.Embodiment 66. The method of Embodiment 56, wherein the viral infection is a coronavirus.Embodiment 67. The method of Embodiment 56, wherein the inflammatory disease is selected from Crohn’s disease and inflammatory bowel disease.Embodiment 68. A method of inhibiting autophagy in a subject comprising administering to the subject a compound of any one of Embodiments 1-53, or a pharmaceutical composition of Embodiment 54.Embodiment 69. Use of a compound of any one of Embodiments 1-53 or a pharmaceutical composition of Embodiment 54 for the treatment of a disease, disorder, or condition.Embodiment 70. Use of a compound of any one of Embodiments 1-53 or a pharmaceutical composition of Embodiment 54 for inhibiting autophagy in a subject.EXAMPLES

[0299] As described in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. It will be appreciated that, although the general methods depict the synthesis of certain compounds of the present disclosure, the following general methods and other methods known to one of ordinary skill in the art can be applied to all compounds and subclasses and species of each of these compounds, as described herein.Table of AbbreviationsACN: acetonitrileCDI: l,l'-carbonyldiimidazoleDBU: l,8-diazabicyclo(5.4.0)undec-7-eneDCM: dichloromethaneDDQ: 2,3-dichloro-5,6-dicyano-l,4-benzoquinoneDEA: diethanolamineDIAD: diisopropyl azodi carb oxy lateDIEA, DIPEA: N,N-diisopropylethylamineDMF: dimethylformamideDMSO: dimethyl sulfoxide dppf: 1,1 ' -bis(diphenylphosphino)ferroceneEDC: l-ethyl-3-(3-dimethylaminopropyl)carbodiimide eq. or equiv.: equivalent or equivalents h or hr: hour or hoursHATU: l-[Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphateHEP: heptaneHOBt: hydroxy benzotriazoleHPLC: high performance liquid chromatographyIPA: isopropyl alcoholLDA: lithium diisopropylamideLCMS: liquid chromatography mass spectrometryLiHDMS: lithium bis(trimethylsilyl)amide m-CPBA: meta-chloroperbenzoic acidMTBE: methyl tert-butyl etherNMP: N-methyl-2-pyrrolidoneNMR: nuclear magnetic resonancePE: petroleum etherRT or rt: room temperatureTBAB: tetrabutyl azanium bromideTBAF: tetrabutylammonium fluorideSynthesis of Certain IntermediatesINT-1. Synthesis of 2-((3-ethyl-4-oxo-3,4-dihydrobenzo[g]quinazolin-2-yl)thio)-2- phenylacetic acid, INT-1.Step-1. Synthesis of bromo(phenyl)acetic acid

[0300] To a solution of NaNCh (219.1 g, 3175 mmol, 1.60 equiv) in water (600 mL) was slowly added (+ / -)-a-phenylglycine (300.0 g, 1984 mmol, 1.00 equiv) in HBr in water (5L, 30%) at -15 °C under nitrogen atmosphere. The reaction was allowed to proceed for 3 h and warmed from -15 °C to room temperature. The reaction mixture was extracted by diethyl ether (3x2L). The combined organic layers were washed with brine (1x800 mL), dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure to afford product bromo(phenyl)acetic acid (310 g, 69%) as a brown oil, which was used for next step without purification.Step-2. 3-ethyl-2-sulfanylbenzo[g]quinazolin-4-one

[0301] To a mixture of 3-amino-2-naphthoic acid (250 g, 1335 mmol, 1.00 equiv) and TEA(297.3 g, 2.94 mol, 2.20 equiv) in anhydrous EtOH (8 L) was added isothiocyanatoethane(128.0 g, 1.47 mol, 1.10 equiv). The mixture was refluxed until the starting material was consumed (16 h; TLC, ethyl acetate / methanol, 99.9:0.1) and cooled to room temperature. The formed precipitate was filtered and washed with cold ethanol (2x500 mL) to give 3-ethyl-2- sulfanylbenzo[g]quinazolin-4-one (260 g, 71%) as a light-yellow solid.Step-3. Synthesis of ({3-ethyl-4-oxobenzo[g]quinazolin-2-yl}sulfanyl)(phenyl)acetic acid

[0302] To a suspension of 3-ethyl-2-sulfanylbenzo[g]quinazolin-4-one (250 g, 975 mmol, 1.00 equiv) in MeCN (5000 mL) was added NaH (58.5 g, 1463 mmol, 1.50 equiv, 60%) in portions at room temperature under nitrogen atmosphere. The reaction was stirred for 3.0 h at room temperature, bromo(phenyl)acetic acid (293.6 g, 1365 mmol, 1.40 equiv.) in MeCN (800 mL) was added dropwise. The mixture was stirred for 5 h. The reaction was quenched by the addition of HC1 (6 M in water, 300 mL) and diluted with water (5 L). The precipitated solids were collected by filtration and washed with water (3x100 mL). The resulting solid was dried under infrared light. This resulted in ({3-ethyl-4-oxobenzo[g]quinazolin-2- yl}sulfanyl)(phenyl)acetic acid (211 g, 50%) as a yellow solid, INT-1. Yield: 211 g, 50.0%; Appearance: Yellow solid; ’H NMR (300 MHz, DMSO-A) 5 13.24 (s, 1H), 8.81 (s, 1H), 8.20 (d, .7= 8.3 Hz, 1H), 8.11 (d, J = 8.4 Hz, 1H), 8.08 (s, 1H), 7.67 (ddd, J= 8.3, 6.7, 1.3 Hz, 1H), 7.63-7.54 (m, 3H), 7.48-7.37 (m, 3H), 5.70 (s, 1H), 4.10 (q, J= 7.3 Hz, 2H), 1.30 (t, J = 7.0 Hz, 3H) HPLC purity: 99 5%; LCMS Calculated for C22H18N2O3S: 390 10; Observed: 391.1 [M+H]+.INT-2 & INT-3. Synthesis of ((R)-2-((3-ethyl-4-oxo-3,4-dihydrobenzo[g]quinazolin-2- yl)thio)-2-phenylacetyl)-D-proline, INT-2, & ((S)-2-((3-ethyl-4-oxo-3,4- dihydrobenzo[g]quinazolin-2-yl)thio)-2-phenylacetyl)-D-proline, INT-3.Step-1. Synthesis of tert-butyl (2-((3-ethyl-4-oxo-3,4-dihydrobenzo[g]quinazolin-2-yl)thio)-2- phenylacetyl)-D-prolinate

[0303] To a solution of ({3-ethyl-4-oxobenzo[g]quinazolin-2-yl}sulfanyl)(phenyl)acetic acid (40 g, 102.443 mmol, 1 equiv), HATU (46.74 g, 122.93 mmol, 1.2 equiv) in DCM (1 L), was added DIEA (39.72 g, 307.33 mmol, 3 equiv). After stirring for 30 mins, added tert-butyl (2R)- pyrrolidine-2-carboxylate (19.30 g, 112.69 mmol, 1.1 equiv) in the mixture. The reaction was stirred at 50 °C for 16 h under N2 atmosphere. The reaction mixture was concentrated to dryness and purified by silica gel column chromatography (Ethyl acetate: Petroleum ether =30% - 90%) to give product tert-butyl (2R)-l-[2-({3-ethyl-4-oxobenzo[g]quinazolin-2- yl}sulfanyl)-2-phenylacetyl]pyrrolidi ne-2-carboxylate (45 g, 80.80%) as a red solid.Step-2. Synthesis of (2-((3-ethyl-4-oxo-3,4-dihydrobenzo[g]quinazolin-2-yl)thio)-2- phenylacetyl)-D-proline

[0304] To a solution of tert-butyl (2R)-l-[(2R)-2-({3-ethyl-4-oxobenzo[g]quinazolin-2- yl}sulfanyl)-2-phenylacetyl]pyrrolidine-2-carboxylate (45 g, 82.769 mmol, 1 equiv) in TFA (140 mL) at room temperature under nitrogen atmosphere. The reaction was stirred for 2.0 h at room temperature. The resulting mixture was concentrated in vacuum. The residue was diluted with H2O (300 mL), extracted with EtOAc(100 mLx3), washed with brine(100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuum. The residue was purified by trituration with EtOAc( 100 mL) and filtered. The collected solids were dried in vacuum to afford (2R)-l-[(2R)-2-({3-ethyl-4-oxobenzo[g]quinazolin-2-yl}sulfanyl)-2- phenylacetyl]pyrrolidine-2-carboxylic acid (24 g, 59.47%) as a yellow solid.Step-3. Synthesis of ((R)-2-((3-ethyl-4-oxo-3,4-dihydrobenzo[g]quinazolin-2-yl)thio)-2- phenylacetyl)-D-proline, INT-2 & ((S)-2-((3-ethyl-4-oxo-3,4-dihydrobenzo[g]quinazolin-2- yl) thio) -2-phenylace tyl ) -D -proline, INT-3

[0305] The (2R)-l-[2-({3 -ethyl -4-oxobenzo[g]quinazolin-2-yl}sulfanyl)-2-phenylacetyl]pyrr olidine-2-carboxylic acid (24 g, 49.224 mmol, 1 equiv) was purified by Chiral-SFC with the following conditions: Column: CHIRAL ART Cellulose-SJ, 3*25 cm, 5 pm; Mobile Phase A: CO2, Mobile Phase B: MeOH-Preparative; Flow rate: 80 mL / min; Gradient: isocratic 45% B; Column Temperature(°C): 25; Back Pressure(bar): 100; Wave Length: 220 nm; RTl(min): 2.85; RT2 (min): 5.00; Sample Solvent: MeOH: DCM=2: 1; Injection Volume: 9 mL; Number Of Runs: 80. This resulted in (2R)-l-[(2R)-2-({3-ethyl-4-oxobenzo[g]quinazolin-2- yl}sulfanyl)-2-phenylacetyl]pyrrolidine -2-carboxylic acid, INT-2 (11.2 g, 46.67%) as a yellow solid, Yield: 10.8 g, 46.7%; Appearance: White solid; ’H NMR (300 MHz, DMSO- <Z6) 5 12.43 (s, 1H), 8.79 (d, J= 8.1 Hz, 1H), 8.27 - 8.14 (m, 2H), 8.13 - 7.94 (m, 1H), 7.75 - 7.51 (m, 4H), 7.46 - 7.28 (m, 3H), 6.12 (d, J= 42.0 Hz, 1H), 4.35 - 4.15 (m, 2H), 4.13 - 4.01 (m, 2H), 3.50 - 3.41 (m, 1H), 3.18 (d, J= 4.1 Hz, 1H), 2.14 - 2.04 (m, 1H), 1.99 - 1.86 (m, 2H), 1 27 (t, J = 7.0 Hz, 3H) HPLC purity: 99 5%; LCMS Calculated for C27H25N3O4S: 487.16; Observed: 488.2 [M+H]+. This resulted in (S)-2-((3-ethyl-4-oxo-3,4-dihydrobenzo [g]quinazolin-2-yl)thio)-2-phenylacetyl)-D-proline, INT-3. Yield: 10.8 g, 46.7%;Appearance: White solid; ’H NMR (300 MHz, DMSO-A) 5 12.43 (s, 1H), 8.80 (d, J= 8.1 Hz, 1H), 8.21 - 8.18 (m, 2H), 8.12 - 7.96 (m, 1H), 7.70 - 7.53 (m, 4H), 7.44 - 7.31 (m, 3H), 6.12 - 6.08 (m, 1H), 4.35 - 4.15 (m, 2H), 4.14 - 4.04 (m, 2H), 3.48 - 3.41 (m, 1H), 3.17 (d, J = 4.1 Hz, 1H), 2.15 - 2.04 (m, 1H), 1.99 - 1.86 (m, 2H), 1.30 (t, J= 7.0 Hz, 3H). HPLC purity: 99.5%; LCMS Calculated for C27H25N3O4S: 487.16; Observed: 488.2 [M+H]+.INT-4 & INT-5. Synthesis of tert-butyl N-(4'-{[(lS)-l-[2-methyl-6- (trifluoromethanesulfonyloxy)pyrimidin-4-yl]ethyl]carbamoyl}-[l,l'-biphenyl]-4- yl)carbamate, INT-4, and (2S,3aS,7aS)-l-(6-((S)-l-(4'-((tert-butoxycarbonyl) amino)- [l,l'-biphenyl]-4-carboxamido)ethyl)-2-methylpyrimidin-4-yl) octahydro-lH-indole-2- carboxylic acid, INT-5.Step-1. Synthesis of ethyl (4S)-4-{[(tert-butoxy)carbonyl]amino}-3-oxopentanoate

[0306] To a stirred solution of (2S)-2-{[(tert-butoxy)carbonyl]amino} propanoic acid (30.0 g, 158 mmol) in tetrahydrofuran (300 mL) were added l-(lH-imidazole-l-carbonyl)-lH- imidazole (38.2 g, 236 mmol) at room temperature. The reaction was stirred for 16.0 hours at room temperature. To the above mixture was then added 1-ethyl 3-potassium propanedioate (40.1 g, 236 mmol) and dichloromagnesium (15.0 g, 158 mmol). The reaction mixture was quenched with saturated ammonium chloride aqueous solution (50.0 mL). The resulting mixture was extracted with ethyl acetate (150 mL x 2). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford ethyl (4S)-4-{[(tert-butoxy)carbonyl]amino}-3- oxopentanoate (40.0 g, 154 mmol, 95% purity, 97% yield)) as a red oil.Step-2. Synthesis of tert-butyl (S)-(l-(6-hydroxy-2-methylpyrimidin-4-yl)ethyl)carbamate

[0307] To a stirred solution of ethanimidamide hydrochloride (5.45 g, 57.7 mmol) in methanol (100 mL) were added sodium methanolate (30% in MeOH) (10.3 g, 57.7 mmol) at room temperature. The reaction was stirred for 20 min at room temperature. To the above mixture was then added ethyl (4S)-4-{[(tert-butoxy)carbonyl]amino}-3-oxopentanoate (10 g, 38.5 mmol) and the reaction mixture was stirred 3.0 hours at room temperature. The resulting mixture was filtered, the filter cake was washed with MeOH (20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with ethyl acetate (100%) to afford tert-butyl N-[(lS)-l-(6-hydroxy- 2-methylpyrimidin-4-yl)ethyl]carbamate (6.50 g, crude). The crude product (6.5 g) was separated by the following condition: Column: CHIRAL ART Cellulose-SC, 3*25 cm, 5 pm; Mobile Phase A: CO2, Mobile Phase B: IPA: HEX=1 : 1(0.1% 2M NH3-MeOH); Flow rate: 80 mL / min; Gradient: isocratic 40% B; Column Temperature(°C): 35; Back Pressure(bar): 100; Wave Length: 220 nm; RT2(min): 4.8; Sample Solvent: MeOH— HPLC; Injection Volume: 1.5 mL; Number Of Runs: 40. This resulted in tert-butyl N-[(lS)-l-(6-hydroxy-2- methylpyrimidin-4-yl)ethyl]carbamate (4.50 g, 17.7 mmol, 95% purity, ee>95%, Rt = 2.648 min, 45% yield) as a white solid. Chiral-SFC: Column Name: LSC 100x4.6mm 3.0um; CoSolvent : B:IPA (50%Hex); Start Cone, of Pump B : 10.0%; Total Flow : 3.0000 mL / min; BPRPressure : 15.00 MPa; Oven Temperature : 35 C. Rt = 2.648 min.Step-3. Synthesis of 6-[(lS)-l -aminoethyl] -2-methylpyrimidin-4-ol

[0308] A solution of tert-butyl N-[(lS)-l-(6-hydroxy-2-methylpyrimidin-4- yl)ethyl]carbamate (4.0 g, 15.7 mmol) in trifluoroacetic acid (10.0 mL) and methylene chloride (40.0 mL) was stirred for 2 hours at room temperature. The resulting mixture was concentrated under reduced pressure. The crude residue was used to next reaction directly.Step-4. Synthesis of tert-butyl N-(4'-{[(lS)-l-(6-hydroxy-2-methylpyrimidin-4- yl)ethyl carbamoyl}- [ 1, 1 '-biphenyl / -4 -y I) carbamate

[0309] To a stirred solution of 6-[(lS)-l-aminoethyl]-2-methylpyrimidin-4-ol (3.90 g, crude,15.5 mmol) and 4'-{[(tert-butoxy)carbonyl]amino}-[l,l'-biphenyl]-4-carboxylic acid (4.85 g,15.5 mmol) in methylene chloride (40.0 mL) were added ethylbi s(propan-2-yl)amine (10.0 g,77.5 mmol) and l-[(dimethylamino)(dimethyliminiumyl)methyl]-3-oxo-lH,2H,3H-3X5- [l,2,3]triazolo[5,4-b]pyridin-3-ylium-2-ide; hexafluoro-k5-phosphamide (7.03 g, 18.5 mmol) at room temperature. The resulting mixture was stirred for 2 hours at room temperature. The solids were collected by filtration and the filter cake was washed with water (10 mL x 3) and DCM (10 mL x 3). The resulted solid was dried with an infrared lamp to afford tert-butyl N- (4'-{[(lS)-l-(6-hydroxy-2-methylpyrimidin-4-yl)ethyl]carbamoyl}-[l,r-biphenyl]-4- yl)carbamate (5.10 g, 11.3 mmol, 95% purity) as a grey solid.Step-5. Synthesis of tert-butyl N-(4'-{[(lS)-l-[2-methyl-6-(trifluoromethanesulfo nyloxy)pyrimidin-4-yl] ethyl] carbamoyl}-[l, 1 '-biphenyl] -4-yl)carbamate, INT-4

[0310] To a stirred solution of tert-butyl N-(4'-{[(lS)-l-(6-hydroxy-2-methylpyrimidin-4- yl)ethyl]carbamoyl}-[l,l'-biphenyl]-4-yl)carbamate (6.0 g, 13.3 mmol) in pyridine (60 mL) was added trifluoromethanesulfonyl trifluoromethanesulfonate (11.2 g, 39.9 mmol) dropwise at 0 °C and the reaction mixture was stirred for 3 hours at the same temperature. The reactionwas diluted with 50 mL of water and acidified with hydrochloric acid (1 M) to pH = 5-6. The resulting mixture was extracted with ethyl acetate (20 mL x 2) and the combined organic phase was washed with brine (2 mL). The organic phase was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate) to afford tertbutyl N-(4'-{[(lS)-l-[2-methyl-6-(trifluoromethanesulfonyloxy)pyrimidin-4- yl]ethyl]carbamoyl}-[l,l'-biphenyl]-4-yl)carbamate, INT-4 (3.60 g, 6.20 mmol, 95% purity, 46.4% yield) as an off-white solid.Step-6. Synthesis of (2S,3aS, 7aS)-l-{6-[(lS)-l-[(4'-{[(tert-butoxy)carbonyl]amino}-[l,l'- biphenyl ]-4-yl) formamido ] ethyl ]-2-methylpyrimidin-4-yl}-octahydro-lH-indole-2-carboxylic acid, INT-5

[0311] To a stirred solution of tert-butyl N-(4'-{[(lS)-l-[2-methyl-6- (trifluoromethanesulfonyloxy)pyrimidin-4-yl]ethyl]carbamoyl } -[ 1 , 1 '-biphenyl]-4- yl)carbamate (2.00 g, 3.44 mmol) and ethylbi s(propan-2-yl)amine (1.77 g, 13.7 mmol) in isopropyl alcohol (20 mL) was added (2S,3aS,7aS)-octahydro-lH-indole-2-carboxylic acid (871 mg, 5.15 mmol). The reaction mixture was stirred for 0.5 hour at 80 °C. The reaction was diluted with 5 mL of water and acidified with hydrochloric acid (1 M) to pH = 5-6. The resulting mixture was extracted with ethyl acetate (2 mL x 2) and the combined organic phase was washed with brine (2 mL). The organic phase was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate) to afford (2S,3aS,7aS)-l-{6-[(lS)-l-[(4'-{[(tert-butoxy)carbonyl]amino}-[l,l'-biphenyl]-4- yl)formamido]ethyl]-2-methylpyri midin-4-yl}-octahydro-lH-indole-2-carboxylic acid, INT-5. Yield: 1.7 g, 82.5%; Appearance: White solid; 'll NMR (400 MHz, DMSO-6) 5 9.50 (s, 1H), 8.85 (d, J = 6.9 Hz, 1H), 7.96 (d, J = 8.3 Hz, 2H), 7.77 (d, J = 8.2 Hz, 2H), 7.67 (d, J = 8.8 Hz, 2H), 7.58 (d, J= 8.8 Hz, 2H), 6.78 (s, 1H), 5.01 (s, 1H), 4.49 (t, J= 8.9 Hz, 1H), 4.03 (d, J= 6.3 Hz, 1H), 2.45 (s, 3H), 2.28 (s, 1H), 2.11 - 1.96 (m, 1H), 1.89 - 1.58 (m, 4H), 1.54 (d, J = 6.9 Hz, 3H), 1.50 (s, 9H), 1.46 - 1.10 (m, 5H). HPLC purity: 97.93%; LCMS Calculated for C34H41N5O5: 599 31; Observed: 600 4[M+H]+INT-6. Synthesis of tert-butyl (4'-(((S)-l-(2-bromo-6-((2S,3aS,7aS)-2-(methylcarbamoyl)octahydro-lH-indol-l-yl)pyrimidin-4-yl)ethyl)carbamoyl)-[l,l'- biphenyl]-4-yl)carbamate, INT-6.Step-1. Synthesis of tert-butyl (2S,3aS, 7aS)-2-(methylcarbamoyl)-octahydro-lH-indole-l- carboxylate

[0312] To a solution of (2,S',3aA',7aA')- l -[(tert-butoxy)carbonyl]-octahydro- l / / -indole-2- carboxylic acid (1.3 g, 4.82 mmol), Methylamine hydrochloride (972 mg, 14.4 mmol), DIPEA (1.86 g, 14.4 mmol) in DMF (15 mL ) was added HATU (2.19 g, 5.78 mmol) at rt under N2. The reaction mixture was stirred for 0.5 h at rt. The reaction mixture was added water (20 mL)and extracted with EA (30 mL X 3). The organic layer was washed with water (20 mL X 2), dried over anhydrous sodium sulfate, filtered, concentrated to give residue, which was purified by flash silica gel chromatography (DCM / MeOH = 20 / 1) to give tert-butyl (2S,3aS,7a.S)-2- (methylcarbamoyl)-octahydro- lrt-indole- l -carboxylate (1.06 g, 3.75 mmol, 100% purity, 78% yield) as a white solid.Step-2. Synthesis of (2S',3aS',7aS)-N-methyl-octahydro-17 / -indole-2-carboxamide

[0313] To a mixture of tert-butyl (2S',3aS',7aS)-2-(methylcarbamoyl)-octahydro-17 / -indole-l- carboxylate (1.1 g, 3.89 mmol) in DCM (5 mL) was added TFA (2 mL, 3.89 mmol) at rt. The reaction mixture was stirred at rt for 2 h. The reaction mixture was concentrated to give (2S',3aS',7aS)-N-methyl-octahydro-17 / -indole-2-carboxamide (709 mg, 3.88 mmol, 100% purity, 100% yield) as a light-yellow oil.Step-3. Synthesis of benzyl N-[(lS)-l-{6-[(2S,3aS, 7aS)-2-(methylcarbamoyl)-octahydro-lH- indol-l-yl ]-2-chloropyrimidin-4-yl}ethyl ] carbamate

[0314] To a mixture of (2S',3aS',7aS)-N-methyl-octahydro-17 / -indole-2-carboxamide (709 mg, 3.88 mmol), benzyl A-[(15)-l-(2,6-dichloropyrimidin-4-yl)ethyl]carbamate (1.26 g, 3.88 mmol) in MeCN (5 mL ) was added DIPEA (1.49 g, 11.6 mmol) at rt. The reaction mixture was stirred at rt for 12 h. The reaction mixture was concentrated to give crude product, which was further purified by flash silica gel chromatography (DCM / MeOH = 20 / 1) to give benzyl A-[(15)-l-{6-[(2S',3aS',7aS)-)-(methylcarbamoyl)-octahydro-U / -indol-l-yl]-2- chloropyrimidin-4-yl} ethyl] carbamate (1.30 g, 2.75 mmol, 100% purity, 71% yield) as a white solid.Step-4. Synthesis of tert-butyl N-[(lS)-l-{6-[(2S,3aS, 7aS)-2-(methylcarbamoyl)-octahydro- IH-indol-l-yl ]-2-bromopyrimidin-4-yl}ethyl ] carbamate

[0315] To a mixture of benzyl A-[(15)-l-{6-[(2S',3aS,7aS)-2-(methylcarbamoyl)-octahydro-17 / -indol-l-yl]-2-chloropyrimidin-4-yl}ethyl]carbamate (1.3 g, 2.75 mmol) in HBr in AcOH(25 mL ) was stirred for 12 h at 80 °C. The reaction mixture was adjusted pH to 8-9 with Sat. NaHCCh (aq). The solution was added BOC2O (1.20 g, 5.50 mmol) at rt. The reaction mixture was stirred for 3 h at rt. The reaction mixture was added water (100 mL) and extracted with EA (100 mL X 3). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated to give residue, which was purified by flash silica gel chromatography (DCM / MeOH = 20 / 1) to give tert-butyl A-[(15)-l-{6-[(2S',3aS,7aS)-2-(methylcarbamoyl)- octahydro-1H-indol-l-yl]-2-bromopyrimidin-4-yl} ethyl]carbamate (1.20 g, 2.48 mmol, 96% purity, 91% yield) as a white solid.Step-5. Synthesis of (2S,3aS,7aS)-l-{6-[(l S)-l-aminoethyl]-2-bromopyrimidin-4-yl}-N- methyl-octahydro-lH-indole-2-carboxamide

[0316] To a solution of tert-butyl A-[(15)-l-{6-[(2S',3aS,7aS)-2-(methylcarbamoyl)- octahydro-lH / -indol-l-yl]-2-bromopyrimidin-4-yl}ethyl]carbamate (1.2 g, 2.48 mmol) in DCM (5 mL ) was added TFA (2 mL, 2.48 mmol) at rt. The reaction mixture was stirred for 2 h at rt. The reaction mixture was concentrated to give (2S',3aS,7aS)-l-{6-[(15)-l-aminoethyl]- 2-bromopyrimidin-4-yl}-N -methyl-octahydro-lH / -indole-2-carboxamide (930 mg, 2.43 mmol, 100% purity, 98% yield) as a light-yellow oil.Step-6. Synthesis of tert-butyl (4'-(((S)-l-(2-bromo-6-((2S,3aS, 7aS)-2-(methylcarbamoyl) octahydro- lH-indol-l-yl)pyrimidin-4-yl) ethyl) carbamoyl) -[ 1, 1 '-biphenyl / -4-yl) carbamate

[0317] To a solution of (2S',3aS,7aS)-l-{6-[(15)-l-aminoethyl]-2-bromopyrimidin-4-yl}-7V- methyl-octahydro-1H-indole-2-carboxamide (930 mg, 2.43 mmol), 4'-{[(tert- butoxy)carbonyl]amino}-[l,l'-biphenyl]-4-carboxylic acid (761 mg, 2.43 mmol), HATU (1.10 g, 2.91 mmol) in DMF (15 mL ) was added DIPEA (942 mg, 7.29 mmol) at rt. The reaction mixture was stirred for 2 h at rt. The reaction mixture was added water (20 mL) and extracted with EA (30 mL X 3). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated to give residue, which was purified by flash silica gel chromatography (DCM / MeOH = 20 / 1) to give tert-butyl (4'-((l-(2-bromo-6-((2S,3aS, 7aS)-2-(methylcarbamoyl)octahydro-lH-indol-l-yl)pyrimidin-4-yl)ethyl)carbamoyl)-[ 1, 1 '-biphenyl ]- 4-yl) carbamate (905 mg, 1.33 mmol, 100% purity, 55% yield) as a light yellow solid. The product was sent for SFC for further purification (Mobile phase: CO2 / MeOH[0.2%NH3(7M in MeOH)]=50 / 50, Column: Regis (R,R)Whelk-Ol (4.6*100mm,3.5um)) to get Isomer I (Peak- 1, INT-6): 405 mg and Isomer II (Peak-2): 386 mg.INT-7. Synthesis A: (2S,3aS,7aS)-l-{2-bromo-6-[(lS)-l-{[4-(morpholin-4-yl)phenyl] formamido}ethyl]pyrimidin-4-yl}-N-methyl-octahydro-lH-indole-2-carboxamide, INT-7.Step-1. Synthesis of (2S,3aS, 7aS)-l-{6-[(lS)-l-aminoethyl]-2-bromopyrimidin-4-yl}-N- methyl-octahydro-lH-indole-2-carboxamide

[0318] To a solution of tert-butyl N-[(lS)-l-{6-[(2S,3aS,7aS)-2-(methylcarbamoyl)- octahydro-lH-indol-l-yl]-2-bromopyrimidin-4-yl}ethyl]carbamate (10 g, 20.7 mmol) in DCM (100 mL) was added TFA (50 mL), the reaction mixture was stirred at r.t. for 2 h. The mixturewas concentrated under reduced pressure to give the crude product as TFA salt, which was directly used in the next steps.Step-2. Synthesis of (2S,3aS, 7aS)-l-{2-bromo-6-[(lS*)-l-{[4-(morpholin-4- yl)phenyl]formamido}ethyl]pyrimidin-4-yl}-N-methyl-octahydro-lH-indole-2-carboxamide

[0319] To a solution of 4-(morpholin-4-yl)benzoic acid (5.11 g, 24.7 mmol) and DIPEA (26.6 g, 206 mmol) in DMF (150 mL) was added HATU (8.97 g, 23.6 mmol), the mixture was stirred at r.t. for 1 h. Then the mixture was cooled to -40 °C, (2S,3aS,7aS)-l-[6-(l-aminoethyl)-2- bromopyrimidin-4-yl]-N-methyl-octahydro-lH-indole-2-carboxamide (7.9 g, 20.6 mmol) was added dropwise at -40 °C, the mixture was stirred for Ih. The mixture was concentrated under reduced pressure to give the crude residue, which was purified by column chromatography on silica gel eluting with EtOAc / PE (0- 66%) to give (2S,3aS,7aS)-l-(2-bromo-6-(l-(4- morpholinobenzamido)ethyl)pyrimidin-4-yl)-N-methyloctahydro-lH-indole-2-carboxamide (11.9 g). Then the product was separated with SFC to give the product (2S,3aS,7aS)-l-{2- bromo-6-[(lS)-l-{[4-(morpholin-4-yl)phenyl]formamido}ethyl]pyrimidin-4-yl}-N-methyl- octahydro-lH-indole-2-carboxamide (Peak-1, INT-7 ) . Yield: 4.4 g, 34 %; Appearance: White solid; 'H NMR (400 MHz, DMSO-cf.) 8 8.46 (d, J = 6.8 Hz, IH), 8.14 - 7.89 (m, IH), 7.79 (d, J= 8.8 Hz, 2H), 6.97 (d, J= 9.0 Hz, 2H), 6.64 - 5.87 (m, IH), 4.84 (t, J= 7.2 Hz, IH), 4.36 - 4.16 (m, IH), 3.83 - 3.68 (m, 4H), 3.32 (s, IH), 3.25 - 3.19 (m, 4H), 2.65 - 2.53 (m, 3H), 2.39 - 1.80 (m, 4H), 1.72 - 1.53 (m, 3H), 1.48 - 1.36 (m, 5H), 1.30 - 1.01 (m, 2H); HPLC purity: 91.07%; LCMS Calculated for C27H35BrN6O3: 571.52; Observed: 571.4 [M+H]+.INT-7. Synthesis B: (2S,3aS,7aS)-l-{2-bromo-6-[(lS)-l-{[4-(morpholin-4-yl)phenyl] formamido}ethyl]pyrimidin-4-yl}-N-methyl-octahydro-lH-indole-2-carboxamide, INT-7.Step-1. Synthesis of l-(2,6-dichloropyrimidin-4-yl)ethan-l-one

[0320] A solution of methyl 2,6-dichloropyrimidine-4-carboxylate (100 g, 483 mmol) in THF (1200 mL) was added MeMgBr (136 mL, 579 mmol, 3 mol / L in THF) at -78 °C under nitrogen atmosphere. The reaction mixture was stirred for 2.0 hours at -78 degrees. The reaction was quenched by the addition of sat. NH4CI (aq, 1000 mL) at -78 degrees to room temperature, and then extracted with ethyl acetate (3x500 mL). The combined organic phase was washed with brine (300 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (20: 1) to afford l-(2,6-dichloropyrimidin-4-yl)ethan-l-one (47.7 g, 249 mmol, 99.3% purity, 51.4% yield) as brown oil.Step-2. Synthesis of (R)-N-[(lZ)-l-(2,6-dichloropyrimidin-4-yl)ethylidene]-2-methylpropane- 2-sulfmamide

[0321] A solution of l-(2,6-dichloropyrimidin-4-yl)ethan-l-one (50.0 g, 261 mmol), (R)- 2-methylpropane-2-sulfinamide (31.6 g, 261 mmol) and Ti(EtO)4 (178 g, 783 mmol) in THF(500 mL) at 0°C. The reaction mixture was stirred for 2.0 hours at 80°C. The mixture was allowed to cool down to room temperature, diluted with water (500 mL) and extracted with ethyl acetate (3x300mL). The combined organic phase was washed with brine (500 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by silica gel column chromatography, eluted with ethyl acetate / petroleum ether (30% to 100%) to afford (R)-N-[(lZ)-l-(2,6-dichloropyrimidin-4-yl)ethylidene]-2-methylpropane-2- sulfinamide (55.0 g, 287 mmol, 89.4% purity, 72.6% yield) as a yellow solid.Step-3. Synthesis of f(R)-N-[(lS)-l-(2,6-dichloropyrimidin-4-yl)ethyl]-2-methylpropane-2- sulfinamide and f(R)-N-[(lR)-l-(2,6-dichloropyrimidin-4-yl)ethyl]-2-methylpropane-2- sulfinamide

[0322] A mixture of (R)-N-[(lZ)-l-(2,6-dichloropyrimidin-4-yl)ethylidene]-2- methylpropane-2-sulfmamide (55.0 g, 186 mmol) in THF (500 mL) was added LiBJLj (4.46 g, 186 mmol) at -78 degree C, and the reaction mixture was stirred for 1.0 hour at -78 degree C. The resulting mixture was quenched with water (500 mL) and extracted with ethyl acetate (3x300 mL). The combined organic phase was washed with brine (500 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by silica gel column chromatography, eluted with ethyl acetate / petroleum ether (70% to 100%) to afford (R)-N-[(lS)-l-(2,6-dichloropyrimidin-4-yl)ethyl]-2-methylpropane-2-sulfinamide (25.2 g, 94.5% purity, 54.2% yield) as yellow solid and (R)-N-[(lR)-l-(2,6-dichloropyrimidin- 4-yl)ethyl]-2-methylpropane-2-sulfinamide (15.1 g, 91.5% purity, 27.4% yield) as yellow solid.Step-4. Synthesis of (2S,3aS, 7aS)-l-{2-chloro-6-[(lS)-l-{[(R)-2-methylpropane-2- sulfmyl]amino}ethyl]pyrimidin-4-yl}-octahydro-lH-indole-2-carboxylic acid

[0323] A mixture of (R)-N-[(lS)-l-(2,6-dichloropyrimidin-4-yl)ethyl]-2-methylpropane- 2-sulfinamide(18.0 g, 60.7 mmol), (2S,3aS,7aS)- octahydro-lH-indole-2-carboxylic acid (10.2 g, 60.7 mmol) and DIEA (23.4 g, 182 mmol) in DMF (200 mL) at room temperature, and the reaction mixture was stirred for 4.0 hours at 60°C. The mixture was allowed to cool down toroom temperature, diluted with water (200 mL) and extracted with ethyl acetate (3x300 mL). The combined organic phase was washed with brine (500 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by silica gel column chromatography, eluted with ethyl acetate / petroleum ether (60% to 100%) to afford (2S,3aS,7aS)-l-{2-chloro-6-[(lS)-l-{[(R)-2-methylpropane-2- sulfinyl]amino}ethyl]pyrimidin-4-yl}-octahydro-lH-indole-2-carboxylic acid (14.1 g, 33.0 mmol, 84.7% purity, 27.1% yield) as yellow solid.Step-5. Synthesis of (2S,3aS, 7aS)-l-{2-chloro-6-[(lS)-l-{[(R)-2-methylpropane-2- sulfmyl]amino}ethyl]pyrimidin-4-yl}-octahydro-lH-indole-2-carboxylic acid

[0324] A mixture of (2S,3aS,7aS)-l-{2-chloro-6-[(lS)-l-{[(R)-2-methylpropane-2- sulfinyl]amino}ethyl]pyrimidin-4-yl}-N-methyl-octahydrolH-indole-2-carboxamide (15.0 g, 33.9 mmol), methanamine hydrochloride (2.28 g, 33.9 mmol) and DIEA (13.0 g, 101 mmol) in DMF (120 mL) was stirred at room temperature for 10 min. HATU (15.4 g, 40.6 mmol) was then added, and the reaction mixture was stirred for 2.0 hours at room temperature. The residue was purified by prep-HPLC (NH3.H2O buffer) to give (2S,3aS,7aS)-l-{2-chloro-6-[(lS)-l- {[(R)-2-methylpropane-2- sulfinyl]amino}ethyl]pyrimidin-4-yl}-octahydro-lH-indole-2- carboxylic acid (11.1 g, 25.9 mmol, 86.5% purity, 76.5% yield) as yellow solid.Step-6. Synthesis of (2S,3aS, 7aS)-l-{6-[(lS)-l-aminoethyl]-2- bromopyrimidin-4-yl}-N- methyl-octahydro-lH-indole-2-carboxamide

[0325] A mixture of (2S,3aS,7aS)-l-{2-chloro-6-[(lS)-l-{[(R)-2-methylpropane-2- sulfinyl]amino}ethyl]pyrimidin-4-yl}-N-methyl-octahydrolH-indole-2-carboxamide (13.0 g, 29.4 mmol) in HBr / AcOH (40% in AcOH, 50 mL), and the reaction mixture was stirred for 2.0 hours at 50 degree C. The resulting mixture was concentrated in vacuum, the residue was purified by prep-HPLC (NH3.H2O buffer) to give (2S,3aS,7aS)-l-{6-[(lS)-l-aminoethyl]-2- bromopyrimidin-4-yl}-N-methyl-octahydro-lH-indole-2-carboxamide (5.17 g, 13.5 mmol, 94.1% purity, 46.1% yield) as yellow solid.Step-7. Synthesis of (2S,3aS, 7aS)-l-{2-bromo-6-[(lS)-l-{[4- (morpholin-4- yl)phenyl]formamido}ethyl]pyrimidin-4-yl}-N-methyl-octahydro-lH-indole-2-carboxamide,INT-7

[0326] A mixture of (2S,3aS,7aS)-l-{6-[(lS)-l-aminoethyl]-2-bromopyrimidin-4-yl}-N- methyl-octahydro-lHindole-2-carboxamide (5.50 g, 14.3 mmol), DIEA (3.69 g, 28.6 mmol) and 4-(morpholin-4-yl)benzoic acid (2.96 g, 14.3 mmol) in DMF (50.0 mL), and the mixture was stirred at room temperature for 10 min. HATU (6.49 g, 17.1 mmol) was then added, and the reaction mixture was stirred for 1.0 hour at 0 degree C. The resulting mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mLx3). The combined organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (NH3.H2O buffer) to give (2S,3aS,7aS)-l- {2-bromo-6-[(lS)-l-{[4-(morpholin-4-yl)phenyl]formamido}ethyl]pyrimidin-4-yl}-N- methyl-octahydro-lH-indole-2-carboxamide, INT-7. Yield: 5.11g, 59.7%; Appearance: white solid; ’H NMR (300 MHz, DMSO-A) 5 8.46 (d, J= 7.6 Hz, 1H), 7.80 (d, J= 8.6 Hz, 2H),6.98 (d, J= 8.7 Hz, 2H), 6.59 (s, 1H), 4.84 (t, J= 7.2 Hz, 1H), 4.03 - 3.98 (m, 1H), 3.85 - 3.64 (m, 4H), 3.22 - 3.09 (m 4H), 2.60 (d, J= 4.7 Hz, 3H), 1.99 (m, 3H), 1.62 -1.55 (m, 2H), 1.41 - 1.31 (m, 4H), 1.18 - 1.12 (m, 4H).INT-8. Synthesis of (2S,3aS,7aS)-l-{2-bromo-6-[(lS)-l-{[4- (morpholin-4- yl)phenyl]formamido}ethyl]pyrimidin-4-yl}-N-methyl-octahydro-lH-indole-2- carboxamide, INT-8.Step-1. Synthesis of (2S,3aS, 7aS)-l-(6-((R)-l-(((R)-tert-butylsulfinyl)amino)ethyl)-2- chloropyrimidin-4-yl)octahydro-lH-indole-2-carboxylic acid

[0327] To a stirred solution of (S)-N-[(lS)-l-(2,6-dichloropyrimidin-4-yl)ethyl]-2- methylpropane-2-sulfmamide (1.0 g, 3.37 mmol), DIEA (1.30 g, 10.1 mmol) and (2S,3aS,7aS)- octahydro-lH-indole-2-carboxylic acid (683 mg, 4.04 mmol) in DMF (10 mL) at room temperature. The resulting mixture was stirred for 4 hours at 60 °C. The mixture was allowed to cool down to room temperature. The resulting mixture was used in the next step directly without further purification.Step-2. Synthesis of (2S,3aS, 7aS)-l-{2-chloro-6-[(lR)-l-{[(R)-2-methylpropane-2- sulfmyl]amino}ethyl]pyrimidin-4-yl}-N-methyl-octahydro-lH-indole-2-carboxamide

[0328] To the above mixture was added methanamine hydrochloride (380 mg, 5.62 mmol) and HATU (4.25 g, 11.2 mmol) in portions over 2 min at 0°C. The resulting mixture was stirred at 0°C for additional 2 hours. The resulting mixture was diluted with water (200 mL) and extracted with ethyl acetate (lOOmL x 3). The combined organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluted with ethyl acetate / petroleumether (0% to 90%) to afford (2S,3aS, 7aS)-l-{2-chloro-6-[(lR)-l-{[(R)-2-methylpropane-2- sulfinyl]amino}ethyl]pyrimidin-4-yl}-N-methyl-octahydro-lH-indole-2-carboxamide (1.20 g, 80% purity, 72% yield) as a yellow solid.Step-3. Synthesis of (2S,3aS, 7aS)-l-{6-[(lR)-l-aminoethyl]-2-bromopyrimidin-4-yl}-N- methyl-octahydro-lH-indole-2-carboxamide

[0329] A solution of (2S,3aS,7aS)-l-{2-chloro-6-[(lR)-l-{[(R)-2-methylpropane-2- sulfinyl]amino}ethyl]pyrimidin-4-yl}-N-methyl-octahydro-lH-indole-2-carboxamide (1.1g, 2.48 mmol) in HBr / AcOH (40% in AcOH, 15 mL) was stirred for 4 hours at 60°C. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was triturated with the addition of n-hexane: ethyl acetate= 5: 1( 200 mL) for 3 hours at room temperature. The precipitated solids were collected by filtration and the filter cake was washed with n-hexane (3x50 mL). The resulting solid was dried under infrared light. This resulted in (2S,3aS,7aS)-l-{6-[(lR)-l-aminoethyl]-2-bromopyrimidin-4-yl}-N-methyl- octahydro-lH-indole-2-carboxamide (1.20 g, crude) as a brown solid.Step-4. Synthesis of (2S,3aS, 7aS)-l-{2-bromo-6-[(lR)-l-{[4-(morpholin-4- yl)phenyl]formamido}ethyl]pyrimidin-4-yl}-N-methyl-octahydro-lH-indole-2-carboxamide, INT-8

[0330] Into a 40 mL vial were added (2S,3aS,7aS)-l-{6-[(lR)-l-aminoethyl]-2- bromopyrimidin-4-yl}-N-methyl-octahydro-lH-indole-2-carboxamide (1.1 g, 2.87 mmol), 4- (morpholin-4-yl)benzoic acid (652 mg, 3.15 mmol), DIEA (1.11 g, 8.61 mmol) and HATU (1.63 g, 4.30 mmol) in DMF (15 mL ) at room temperature and react at 0°C for 2 hours. The resulting mixture was diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluted with ethyl acetate / petroleum ether (0% to 90%) to afford (2S,3aS,7aS)- l-{2-bromo-6-[(lR)-l-{[4-(morpholin-4-yl)phenyl]formamido}ethyl]pyrimidin-4-yl}-N-methyl-octahydro-lH-indole-2-carboxamide (850 mg, 1.48 mmol, 80% purity, 51% yield ) as a yellow solid. ’H NMR (300 MHz, DMSO-A) 5 8.58 - 8.47 (m, 1H), 8.05 - 7.92 (m, 1H), 7.82 (d, J= 8.4 Hz, 2H), 6.98 (d, J= 8.4 Hz, 2H), 6.55 - 6.05 (m, 1H), 4.89 - 4.75 (m, 1H), 4.28 - 4.19 (m, 1H), 3.75 - 3.69 (m, 4H), 3.22 (t, J= 4.8 Hz, 4H), 3.18 (d, J = 4.7 Hz, 3H), 2.62 (d, J= 4.4 Hz, 2H), 2.42 - 1.82 (m, 6H), 1.75 - 1.55 (m, 4H), 1.45 - 1.38 (m, 4H), 1.29- 1.10 (m, 2H).INT-9. Synthesis of (2S,3aS,7aS)-l-(2-iodo-6-((S)-l-(4- morpholinobenzamido)ethyl)pyrimidin-4-yl)-N-methyloctahydro-lH-indole-2- carboxamide, INT-9.Step-1. Synthesis of (2S,3aS, 7aS)-l-(2-iodo-6-((S)-l-(4- morpholinobenzamido)ethyl)pyrimidin-4-yl)-N-methyloctahydro-lH-indole-2-carboxamide,INT-B

[0331] To a stirred mixture of (2S,3aS,7aS)-l-(2-bromo-6-((S)-l-(4- morpholinobenzamido)ethyl)pyrimidin-4-yl)-N-methyloctahydro-lH-indole-2-carboxamide(300 mg, 52.5 mmol), Pd(PPh3)4 (60 mg, 52.8 pmol) and 1,1,1,2,2,2-hexamethyldistannane (206 mg, 63.2 mmol) in dioxane (5 mL ) at room temperature. The resulting mixture was stirred at 100 °C for 5.0 hours under nitrogen atmosphere. The reaction mixture was cooled to room temperature. I2 (160 mg, 63.2 mmol) was then added, and the reaction mixture was stirred for 2.0 hours at room temperature. The mixture was diluted with water (30.0 mL) and extractedwith ethyl acetate (30 mLx2). The combined organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by reverse phase flash with the following conditions (column, C18 silica gel; mobile phase, H2O / 0.1% NH4OH in MeOH, 50% to 80% gradient in 10 min; detector, UV 254 nm.) to afford (2S,3aS,7aS)-l-(2-iodo-6-((S)-l-(4-morpholinobenzamido)ethyl)pyrimidin-4-yl)-N- methyloctahydro-lH-indole-2-carboxamide. Yield: 250 mg, 76.0%; Appearance: White solid; *HNMR (300 MHz, DMSO-A) 5 8.46 (d, J= 7.6 Hz, 1H), 7.80 (d, J= 8.6 Hz, 2H), 6.98 (d, J= 8.7 Hz, 2H), 6.59 (s, 1H), 4.84 (t, J= 7.2 Hz, 1H), 4.03 - 3.98 (m, 1H), 3.85 - 3.64 (m, 4H), 3.22 - 3.09 (m 4H), 2.60 (d, J= 4.7 Hz, 3H), 1.99 (m, 4H), 1.62 -1.55 (m, 2H), 1.41 - 1.31 (m, 4H), 1.18 - 1.12 (m, 4H); HPLC purity: 91.6%; LCMS Calculated for C27H35IN6O3: 618.18; Observed: 619.3 [M+H]+INT-10. Synthesis of l-{[2-(prop-2-yn-l-yloxy)ethoxy]methyl}piperidin-4-amine, INT-10.Step-1. Synthesis of [2-(prop-2-yn-l-yloxy) ethoxy] methyl me thane sulfonate.

[0332] A solution of [2-(prop-2-yn-l-yloxy) ethoxy] methanol (1.00 g, 7.68 mmol) and TEA (2.32 g, 23.0 mmol) in THF (10 mL) was added MsCl (1.13 g, 9.98 mmol) at 0°C. The resulting mixture was stirred for 2.0 hours at 0°C under nitrogen atmosphere. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mLx3). The combined organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuum to afford [2-(prop-2-yn-l-yloxy)ethoxy] methyl methanesulfonate (1.30 g, crude) as yellow oil.Step-2. Synthesis of tert-butyl N-(l -{[2 -(prop-2 -yn-l-yloxy) ethoxy] methyl] piperidin-4-yl) carbamate.

[0333] To a solution of [2-(prop-2-yn-l-yloxy) ethoxy] methyl methanesulfonate (1.30 g, 6.24 mmol), tert-butyl N-(piperidin-4-yl) carbamate (1.24 g, 6.24 mmol) in MeCN (20 mL) was added DIEA (2.41 g, 18.7 mmol) for 2.0 hours at 80°C under nitrogen atmosphere. The reaction mixture was cooled to room temperature and quenched by the addition of water (50.0 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (3x50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous ISfeSC After filtration, the filtrate was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate / ethyl acetate (10% to 70%) to afford tert-butyl N-(l-{[2-(prop-2-yn-l-yloxy)ethoxy] methyl} piperidin-4-yl) carbamate (1.00 g, 3.20 mmol, 84.2% purity, 51.5% yield) as a yellow solid.Step-3. Synthesis of l-{[2-(prop-2-yn-l-yloxy) ethoxy] methyl} piper idin-4-amine.

[0334] A solution of tert-butyl N-(l-{[2-(prop-2-yn-l-yloxy)ethoxy]methyl}piperidin-4- yl)carbamate (1.00 g, 3.20 mmol) in DCM / TFA(1 : 1, 10 mL) was stirred for 2.0 hours at room temperature. The resulting mixture was concentrated in vacuum to afford l-{[2-(prop-2-yn-l- yloxy)ethoxy]methyl}piperidin-4-amine as TFA salt (900 mg, 4.23 mmol, crude), INT-10. Yield: 900 mg, crude; Appearance: yellow oil;1H NMR (300 MHz, DMSO-r / c.) 54.55 - 4.40 (m, 2H), 3.79 - 3.60 (m, 6H), 3.51 - 3.48 (m, 1H), 2.85 - 2.71 (m, 1H), 2.50 - 2.21 (m, 6H), 1.87 - 1.54 (m, 4H), 1.50 - 1.48 (m, 2H). HPLC purity: 85.8%; LCMS Calculated for C12H22N2O2: 226.21; Observed: 227.4[M+H]+.INT-11. Synthesis of 2-(2,6-dioxopiperidin-3-yl)-4-[(piperidin-4-yl)amino]-2,3-dihydro-IH-isoindole-l, 3-dione, INT-11.Step-1. Synthesis of tert-butyl 4-{[2-(2,6-dioxopiperidin-3-yl)-l,3-dioxo-2,3-dih ydro-lH- isoindol-4-yl]amino}piperidine-l-carboxylate.

[0335] A mixture of 2-(2,6-dioxopiperidin-3-yl)-4-fluoro-2,3-dihydro-lH-isoindole-l,3- dio ne (200 mg, 724 pmol), tert-butyl 4-aminopiperidine-l-carboxylate (173 mg, 868 pmol) and DIEA (279 mg, 2.17 mmol) in DMF (2 mL) at room temperature. The reaction mixture was stirred for 3.0 hours at 170°C in microwave reactivity meter. The mixture was allowed to cool down to room temperature, quenched with water (5 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (NH3.H2O buffer) to give tert-butyl 4-{[2-(2,6-dioxopiperidin-3-yl)-l,3-dioxo- 2,3-dihydro-lH-isoindol-4-yl]amino}piperidine-l-carboxylate (170 mg, 372 pmol, 88.0% purity, 51.5% yield) as yellow solid.Step-2. Synthesis of 2-(2,6-dioxopiperidin-3-yl)-4-[(piperidin-4-yl)amino]-2,3-dihydr o-lH- isoindole-1 , 3-dione, INT-11

[0336] A solution of tert-butyl 4-{[2-(2,6-dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihydro-lH- isoindol-4-yl]amino}piperidine-l-carboxylate (170 mg, 372 pmol) in DCM / TFA (2 : 1, 2 mL) was stirred for 2.0 hours at room temperature. The resulting mixture was concentrated in vacuum to afford 2-(2,6-dioxopiperidin-3-yl)-4-[(piperidin-4-yl)amin o] -2, 3 -dihydro- 1H- isoindole-1, 3-dione as TFA salt, INT-11. Yield: 150.0 mg, crude; Appearance: yellow oil; ’H NMR (300 MHz, DMSO-A) 5 11.31 (s, 1H), 7.81 - 7.73 (m, 1H), 7.69 - 7.52 (m, 1H), 7.29 - 7.11 (m, 1H), 4.41 - 4.32 (m, 2H), 2.95 - 2.81 (m, 5H), 2.38 - 2.21 (m, 4H), 1.88 - 1.76 (m, 4H) HPLC purity: 84 8%; LCMS Calculated for C18H20N4O4: 356 10; Observed: 357.0[M+H]+.INT-12. Synthesis of 2-[(3-{4-[(2S,3aS,7aS)-2-(methylcarbamoyl)-octahydro-lH-indol-l- yl]-6-[(lS)-l-{[4-(morpholin-4-yl)phenyl]formamido}ethyl]pyrimidin-2-yl}prop-2-yn-l- yl)oxy]ethylmethanesulfonate, INT-12.Step-1. Synthesis of (2S,3 aS, 7aS)-l-{2-[3-(2-hydroxyethoxy)prop-l-yn-l-yl]-6-[(lS)-l-{[4- (morpholin-4-yl)phenyl]formamido}ethyl]pyrimidin-4-yl}-N-methyl-octahydro -lH-indole-2- carboxamide.

[0337] A mixture of (2S,3aS,7aS)-l-{2-bromo-6-[(lS)-l-{[4-(morpholin-4- yl)phenyl]forma mido}ethyl]pyrimidin-4-yl}-N-methyl-octahydro-lH-indole-2-carboxamide (400 mg, 699 pmol), 2-(prop-2-yn-l-yloxy)ethan-l-ol (139.0 mg, 1.39 mmol), Pd(PPh3)C12 (48.9 mg, 69.9 pmol), Cui (26.4 mg, 139 pmol) and DIEA (269 mg, 2.09 mmol) in MeCN (5.0 mL) at room temperature. After stirring for 3.0 hours at 60°C under nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with ethyl acetate / petroleum ether (30-100%, 15 min) to afford (2S,3aS,7aS)-l-{2-[3-(2-hydroxyethoxy)prop-l-yn-l-yl]-6-[(lS)-l-{[4-(morpholin-4- yl)phenyl]formamido}ethyl]pyrimidin-4-yl}-N-methyl-octahydro-lH-indole-2-carboxamid e (280 mg, 473 pmol, 81.7% purity, 67.9 yield) as a yellow solid.Step-2. Synthesis of 2-[(3-{4-[(2S,3aS, 7aS)-2-(methylcarbamoyl)-octahydro-lH-indol-l-yl]~ 6-[ ( 1S)-1~{[ 4-(morpholin-4-yl)phenyl ]formamido}ethyl ]pyrimidin-2-yl}prop-2-yn-l- yl)oxy ] ethylmethane sulf onate, INT-12

[0338] A solution of (2S,3aS,7aS)-l-{2-[3-(2-hydroxyethoxy)prop-l-yn-l-yl]-6-[(lS)-l- {[4-(morpholin-4-yl)phenyl]formamido}ethyl]pyrimidin-4-yl}-N-methyl-octahydro-lH-I ndole-2-carboxamide (280 mg, 473 pmol) and TEA (142 mg, 1.41 mmol) in DCM (60 mL) was added MsCl (64.6 mg, 567 pmol) at 0°C. The resulting mixture was stirred for 2.0 hours at 0°C under nitrogen atmosphere. The mixture was diluted with water (10 mL) and extracted with DCM (10 mLx3). The combined organic phase was washed with brine (100 mL), driedover anhydrous sodium sulfate, filtered and concentrated in vacuum to afford 2-[(3-{4- [(2S,3aS,7aS)-2-(methylcarbamoyl)-octahydro-lH-indol-l-yl]-6-[(lS)-l-{[4-(morpholin-4- yl)phenyl]formamido}ethyl]pyrimidin-2-yl}prop-2-yn-l-yl)oxy]ethylmethanesulfonate (320 mg, crude) as a yellow oil.INT-13. Synthesis of 2-(2,6-dioxopiperidin-3-yl)-4-({l-[(piperidin-4-yl)methyl]piperidin-4-yl}amino)-2,3-dihydro-lH-isoindole-l, 3-dione, INT-13Step-1. Synthesis of benzyl 4-(4-{[(tert-butoxy)carbonyl]amino}piperidine-l-carbon yl)piperidine-l -carboxylate.

[0339] To a 100 mL three-necked flask was added l-[(benzyloxy)carbonyl]piperidine-4- carboxylic acid (3.00 g, 11.3 mmol) and DCM (30 mL), followed by the addition of DMF (164 mg, 2.26 mmol) and oxalyl chloride (7.17 g, 56.5 mmol) was stirred at 0°C for 1.0 hour. The mixture was concentrated in vacuum, the residue was dissolved in DCM(50 ml) and dropwise to a solution of / c / 7-butyl N-(piperidin-4-yl)carbamate (6.78 g, 33.9 mmol) and TEA (1.57 g, 12.4 mmol) in DCM (15 ml) at 0°C. The resulting mixture was stirred for 3.0 hours at 0°C, diluted with water (50 mL) and extracted with DCM (50 mLx3). The combined organic phase was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography, eluted with ethyl acetate / petroleum ether (0% to 50%) to afford benzyl4-(4-{[(tert-butoxy)carbonyl]amino}piperidine-l- carbonyl)piperidine-l -carboxylate (2.00 g, 4.48 mmol, 92% purity, 39.7% yield) as white solid.Step-2. Synthesis of benzyl 4-[(4-{[(tert-butoxy)carbonyl]amino}piperidin-l-yl)meth yl ]piperidine-l -carboxylate.

[0340] To a solution of benzyl 4-(4-{[(tert-butoxy)carbonyl]amino}piperidine-l- carbonyl)pip eridine-1 -carboxylate (2.00 g, 4.48 mmol) in BH3 / THF (2 mol / L, 20 mL) and stirred for 12.0 hours at room temperature. The resulting mixture was quenched with MeOH (4 mL), and then the reaction mixture was stirred for 12.0 hours at 80°C. The resulting mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mLx3). The combined organic phase was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography, eluted with ethyl acetate / petroleum ether (0% to 50%) to afford benzyl 4-[(4- [ [( / c / 7-butoxy)carbonyl]amino [piperidin- l-yl)methyl]piperidine-l -carboxylate (900 mg, 2.08 mmol, 92% purity, 46% yield) as white solid.Step-3. Synthesis of benzyl 4-[(4-aminopiperidin-l-yl)methyl]piperidine-l-carboxylate.

[0341] A solution of benzyl 4-[(4-{[(terLbutoxy)carbonyl]amino}piperidin-l-yl)methy l]piperidine-l -carboxylate (2.00 g, 4.63 mmol) in TFA / DCM (2: 1, 20 mL) was stirred for 2.0 hours at room temperature. The resulting mixture was concentrated in vacuum to afford benzyl 4-[(4-aminopiperi din- l-yl)methyl]piperi dine- 1 -carboxylate as TFA salt (1.70 g, crude) as a brown oil.Step-4. Synthesis of benzyl 4-[(4-{[2-(2,6-dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihydro-lH- isoindol-4-yl]amino}piperidin-l-yl)methyl]piperidine-l-carboxylate.

[0342] To a solution of benzyl 4- [(4-aminopiperi din- l-yl)methyl]piperi dine- 1 -carboxylate (1.70 g, 5.12 mmol) and 2-(2,6-dioxopiperidin-3-yl)-4-fluoro-2,3-dihydro-lH-isoindole-l,3- dione (1.69 g, 6.14 mmol) in DMF (20 mL) was added DIEA (1.97 g, 15.3 mmol) at room temperature. The reaction mixture was stirred for 3.0 hours at 170°C in microwave reactivity meter. The mixture was allowed to cool down to room temperature, quenched with water (50mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (TFA buffer) to give benzyl 4-[(4-{[2-(2,6- dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihydro-lH-isoindol-4-yl]amino}piperidin-l- yl)methyl]piperidine-l -carboxylate (1.30 g, 2.21 mmol, 78.5% purity, 43.3% yield) as yellow solid.Step-5. Synthesis of 2-(2,6-dioxopiperidin-3-yl)-4-({l-[(piperidin-4-yl)methyl]piperid in-4- yl}amino)-2, 3-dihydro-lH-isoindole-l , 3-dione, INT-13

[0343] Into a 50 mL round-bottom flask, was placed benzyl 4-[(4-{[2-(2,6-dioxopiperidin- 3-yl)-l,3-dioxo-2,3-dihydro-lH-isoindol-4-yl]amino}piperidin-l-yl)methyl]piperidine-l- carboxylate (1.30 g, 2.21 mmol) in MeOH (20 mL) was added Pd / C (64 mg, 10%), Pd(OH)2 (31.4 mg, 20%) and HCl / MeOH (2 mL, 4 moL / L in MeOH) at room temperature under nitrogen atmosphere, and then the reaction mixture was degassed and purged with hydrogen for three times. The reaction mixture was stirred in a hydrogen atmosphere at 50°C for 2.0 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuum to give 2- (2,6-dioxopiperidin-3-yl)-4-({l-[(piperidin-4-yl)methyl]piperidin-4-yl}amino)-2,3-dihydro- lH-isoindole-l,3-dione as HC1 salt. Yield: 1.00 g, crude; Appearance: yellow solid.;1H NMR (300 MHz, DMSO-A) 5 11.11 (s, 1H), 7.63 - 7.58 (m, 1H), 7.30 - 7.18 (m, 1H), 7.11 - 7.09 (m, 1H), 5.07 - 5.01 (m, 1H), 4.96 - 4.85 (m, 1H), 3.29 - 3.10 (m, 3H), 3.17 - 2.65 (m, 4H), 2.59 - 2.30 (m, 5H), 2.20 - 2.01 (m, 3H), 1.95 - 1.93 (m, 4H), 1.90 - 1.45 (m, 4H), 1.41 - 1.35 (m, 2H) HPLC purity: 89 5%; LCMS Calculated for C24H31N5O4: 453 20; Observed: 454.4[M+H]+.INT-14. Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-{4-[(piperidin-4-yl)methyl]piperaz in- l-yl}-2,3-dihydro-lH-isoindole-l, 3-dione, INT-14.Step-1. Synthesis of tert-butyl 4-({4-[2-(2,6-dioxopipe ridin-3-yl)-l,3-dioxo-2,3-dihy dro-lH- isoindol-5-yl]piperazin-l-yl}methyl)piperidine-l-carboxylate.

[0344] A mixture of 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydro-lH-isoindole-l,3- dione (500 mg, 1.81 mmol), tert-butyl 4-[(piperazin-l-yl)methyl]piperidine-l-carboxylate (666 mg, 2.35 mmol) and DIE A (700 mg, 5.43 mmol) in DMF (5.0 mL) at room temperature. The reaction mixture was stirred for 3.0 hours at 170°C in microwave reactivity meter. The mixture was allowed to cool down to room temperature, quenched with water (5 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (TFA buffer) to give tert-butyl 4-({4-[2-(2,6-dioxopipe ridin-3-yl)- 1, 3-di oxo-2, 3-dihy dro-lH-isoindol-5-yl]piperazin-l-yl}methyl)piperi dine- 1- carboxylate (270 mg, 500 pmol, 88.2% purity, 27.6 yield) as yellow solid.Step-2. Synthesis of 2-(2, 6-dioxopiperidin-3-yl)-5-{4-[(piperidin-4-yl)methyl]piperaz in-l-yl}- 2, 3-dihydro-lH-isoindole-l , 3-dione

[0345] A solution of tert-butyl 4-({4-[2-(2,6-dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihydro- lH-isoindol-5-yl]piperazin-l-yl}methyl)piperidine-l -carboxylate (280 mg, 518 pmol) in TFA / DCM(1:1, 3 mL) was stirred for 2.0 hours at room temperature. The resulting mixture was concentrated in vacuum to afford 2-(2,6-dioxopiperidin-3-yl)-5-{4-[(piperidin-4- yl)methyl]piperazin-l-yl}-2,3-dihydro-lH-isoindole-l, 3-dione (210 mg, 477 pmol, crude) as a brown oil, which was used for next step directly.INT-15. Synthesis of 3-{4-[(2S,3aS,7aS)-2-(methylcarbamoyl)-octahydro-lH-indol-l-yl]- 6-[(lS)-l-{[4-(morpholin-4- yl)phenyl]formamido}ethyl]pyrimidin-2-yl}prop-2-yn-l- ylmethanesulfonate, INT-15.Step-1. Synthesis of (2S,3aS, 7aS)-N-methyl-l-{6-[(lS)-l-{[4-(morpholin-4- yl)phenyl]forma mido}ethyl]-2-{3-[(trimethylsilyl)oxy]prop-l-yn-l-yl}pyrimidin-4-yl}-octahydro-lH-indole-2 -carboxamide

[0346] A solution of (2S,3aS,7aS)-l-{2-bromo-6-[(lS)-l-{[4-(morpholin-4- yl)phenyl]formamido}ethyl]pyrimidin-4-yl}-N-methyl-octahydrolH-indole-2-carboxamide (500 mg, 874 pmol), trimethyl(prop-2-yn-l-yloxy)silane (112 mg, 874 pmol), Pd(PPh3)2Ch (121 mg, 174 pmol), TEA (264 mg, 2.62 mmol) and Cui (16.6 mg, 87.4 pmol) in DMF(10 mL). The mixture was replaced with N2, then sealed and stirred for 6 hours at 50°C. After cooling to ambient temperature, the reaction mixture was diluted with water (50 mL), and then extracted with ethyl acetate (25 mLx3). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by prep-HPLC (NH3.H2O buffer) to afford (2S,3aS,7aS)-N-methyl-l-{6-[(lS)-l-{[4-(morpholin-4- yl)phenyl]formamido}ethyl]-2-{3-[(trimethylsilyl)oxy]prop-l-yn-l-yl}pyrimidin-4-yl}- octahydro-lH-indole-2-carboxamide (359 mg, 580 pmol, 96.2% purity, 68.1% yield) as a yellow solid.Step-2. Synthesis of (2S,3aS, 7aS)-l-[2-(3-hydroxyprop-l-yn-l-yl)-6-[(lS)-l-{[4-(morpholin- 4- yl)phenyl ]formamido}ethyl ]pyrimidin-4-yl ]-N-methyl-octahydro-lH-indole-2-carboxamid e

[0347] A solution of (2S,3aS,7aS)-N-methyl-l-{6-[(lS)-l-{[4-(morpholin-4- yl)phenyl]formamido}ethyl]-2-{3-[(trimethylsilyl)oxy]prop-l-yn-l- yl}pyrimidin-4-yl}- octahydro-lH-indole-2-carboxamide (420 mg, 678 pmol) in HCl / MeOH (5.0 mL, 4 mol / L) was stirred for 1.0 hour at room temperature. The resulting mixture was concentrated in vacuum to afford (2S,3aS,7aS)-l-[2-(3-hydroxyprop-l-yn-l-yl)-6-[(lS)-l-{[4-(morpholin-4- yl)phenyl]formamido}ethyl]pyrimidin-4-yl]-N-m ethyl -octahydro- lH-indole-2-carboxamide (315 mg, crude) as a brown oil, which was used for next step directly.Step-3. Synthesis of 3-{4-[(2S,3aS, 7aS)-2-(methylcarbamoyl)-octahydro-lH-indol-l-yl]-6-[(l S)-l-{[4-(morpholin-4-yl)phenyl]formamido}ethyl]pyrimidin-2-yl}prop-2-yn-l-ylmethanesul fonate, INT-15

[0348] Into a 100 mL 3-necked round-bottom was placed (2S,3aS,7aS)-l-[2-(3- hydroxyprop- 1 -yn- 1 -y l)-6- [( 1 S)- 1 -{ [4-(morpholin-4- yl)phenyl]formamido} ethyl]pyrimidin- 4-yl]-N-methyl-octahydro-lH-indole-2-carboxamide (350 mg, 640 pmol), TEA (64.6 mg, 640 pmol) in DCM (10 mL) was added MsCl (94.8 mg, 832 pmol) at 0°C . The resulting mixture was stirred for 1.0 hours at 0 °C under nitrogen atmosphere. The mixture was diluted with water (20.0 mL) and extracted with DCM (30 mLx3). The combined organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to afford 3-{4-[(2S,3aS,7aS)-2-(methylcarbamoyl)-octahydro-lH-indol-l-yl]-6-[(lS)-l-{[4- (morpholin-4-yl)phenyl]formamido}ethyl]pyrimidin-2-yl}prop-2-yn-l-yl methanesulfonate (296 mg, crude) as a yellow solid.INT-16. Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-{4-[(piperidin-4-yl)methyl]piperazin- l-yl}-2,3-dihydro-lH-isoindole-l, 3-dione, INT-16.Step-1. Synthesis of tert-butyl 4-({4-[2-(2,6-dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihydr o-lH- isoindol-5-yl]piperazin-l-yl}methyl)piperidine-l-carboxylate.

[0349] Into a 50 mL 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydro-lH-isoindole-l,3- dione (3.00 g, 10.8 mmol), tert-butyl 4-[(piperazin-l-yl)methyl]piperidine-l -carboxylate (3.65 g, 12.9 mmol) and DIEA (4.17 g, 32.4 mmol) in DMF (30 mL) at room temperature. The reaction mixture was stirred for 3.0 hours at 170°C in microwave reactivity meter. The mixture was allowed to cool down to room temperature, quenched with water (20 mL) and extracted with ethyl acetate (30 mLx3). The combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (formic acid buffer) to give tert-butyl 4-({4-[2-(2,6-dioxopiperidin-3- yl)- 1 ,3 -di oxo-2, 3 -dihydro- lH-isoindol-5-yl]piperazin- 1 -yl }methyl)piperidine- 1 -carboxylate (2.20 g, 4.0 7 mmol, 84.5% purity, 37.8% yield) as yellow solid.Step-2. Synthesis of 2-(2, 6-dioxopiperidin-3-yl)-5-{4-[(piperidin-4-yl)methyl]piperaz in-l-yl}- 2, 3-dihydro-lH-isoindole-l , 3-dione, INT-16

[0350] A solution of tert-butyl 4-({4-[2-(2,6-dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihydro- lH-isoindol-5-yl]piperazin-l-yl}methyl)piperidine-l -carboxylate (2.20 g, 4.07 mmol) in TFA / DCM (1 : 1, 20 mL) was stirred for 1.0 hour at room temperature. The resulting mixture was concentrated in vacuum to afford 2-(2,6-dioxopiperidin-3-yl)-5-{4-[(piper idin-4- yl)methyl]piperazin-l-yl}-2,3-dihydro-lH-isoindole-l, 3-dione as TFA salt, INT-16. Yield: 2.00 g, crude; Appearance: yellow solid; 'HNMR (300 MHz, DMSO- e) 5 11.21 (s, 1H), 8.05 - 7.98 (m, 1H), 7.69 - 7.51 (m, 1H), 7.29 - 7.27 (m, 1H), 4.41 - 4.32 (m, 1H), 3.81 - 3.76 (m, 8H), 2.34 - 2.21 (m, 4H), 1.89 - 1.81 (m, 7H), 1.55 - 1.52 (m, 5H). HPLC purity: 89.8%; LCMS Calculated for C23H29N5O4: 439 20; Observed: 440 10[M+H]+INT-17. Synthesis of 2-{2-[(3-{4-[(2S,3aS,7aS)-2-(methylcarbamoyl)- octahydro-lH- indol-l-yl]-6-[(lS)-l-{[4-(morpholin-4-yl)phenyl]formamido}ethyl]pyrimidin-2-yl}prop- 2-yn-l-yl)oxy]ethoxy}ethyl methanesulfonate, INT-17.Step-1. Synthesis of (2S,3aS, 7aS)-l-(2-{3-[2-(2- hydroxyethoxy)ethoxy]prop-l-yn-l-yl}-6-[(lS)-l-{[ 4-(morpholin-4-yl)phenyl ]formamido}ethyl ]pyrimidin-4-yl)-N-methyl-octahydro-lH-i ndole-2-carboxamide

[0351] A solution of (2S,3aS,7aS)-l-{2-bromo-6-[(lS)-l-{[4-(morpholin-4- yl)phenyl]formamido}ethyl]pyrimidin-4-yl}-N-methyl-octahydrolH-indole-2-carboxamide (200 mg, 349 pmol), 2-[2-(prop-2-yn-l-yloxy)ethoxy]ethan-l-ol (50.3 mg, 349 pmol), Pd(PPh3)2Cl2(48.9 mg, 69.8 pmol), TEA (105 mg, 1.04 mmol) and Cui (66.3 mg, 349 pmol) in DMF(5 mL) at room temperature. The mixture was replace with N2, then sealed and stirred for 2.0 hours at 50 °C. After cooling to ambient temperature, the resulting mixture diluted with water (10 mL) and extracted with ethyl acetate (10 mLx3). The combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (NH3.EEO buffer) to give (2S,3aS,7aS)-l-(2- { 3 - [2-(2- hydroxy ethoxy)ethoxy]prop- 1 -yn- 1 -yl }-6-[(l S)- 1 - { [4-(morpholin-4- yl)phenyl]formamido}ethyl]pyrimidin-4-yl)-N-m ethyl -octahydro- lH-indole-2-carboxamide (128 mg, 203 pmol, 98.4% purity, 54.1% yield) as a yellow solid.Step-2. Synthesis of 2-{2-[(3-{4-[(2S,3aS, 7 aS) -2 -(methylcarbamoyl)- octahydro- IH-indol-l-y I ]-6-[ ( lS)-l-{[ 4-(morpholin-4-yl)phenyl ]formamido}ethyl ]pyrimidin-2-yl}prop-2-yn-l-yl)oxy ]ethoxy}ethyl me thane sulfonate- INT-17

[0352] A mixture of (2S,3aS,7aS)-l-(2-{3-[2-(2-hydroxyethoxy)ethoxy]prop-l-yn-l-yl}- 6-[(lS)-l-{[4-(morpholin-4- yl)phenyl]formamido}ethyl]pyrimidin-4-yl)-N-methyl- octahydro-lH-indole-2-carboxamide (130 mg, 204 pmol) and TEA (61.8 mg, 612 pmol) in DCM (10.0 mL) was stirred at room temperature for 10 min. MsCl (27.8 mg, 244 pmol) wasthen added at 0 degrees, and then the reaction mixture was stirred for 2.0 hours at 0 degrees. The resulting mixture was diluted with water (20 mL) and extracted with DCM (20 mL x 3). The combined organic phase was washed with brine (30 mL), dried over ISfeSCU, filtered and concentrated in vacuum to give 2-{2-[(3-{4-[(2S,3aS,7aS)-2-(methylcarbamoyl)- octahydro- lH-indol-l-yl]-6-[(lS)-l-{[4-(morpholin-4-yl)phenyl]formamido}ethyl]pyrimidin-2-yl}prop- 2 -yn-l-yl)oxy] ethoxy (ethyl methanesulfonate (95.2 mg, crude) as brown solid.Example 1. Synthesis of (2R)-N-(2-{2-[2-(4-{[2-(2,6-dioxopiperidin-3-yl)-l,3-dioxo-2,3- dihydro-lH-isoindol-4-yl]amino}piperidin-l-yl)ethoxy]ethoxy}ethyl)-l-[(2R)-2-({3- ethyl-4-oxo-3H,4H-benzo [g] quinazolin-2-yl} sulfanyl)-2-phenylacetyl] pyrolidine-2- carboxamide, 1-1.Step-1. Synthesis of 4-[(l-{2-[2-(2-aminoethoxy) ethoxy] ethyl} piperidin-4-yl) amino] -2-(2,6-dioxopiperidin-3-yl)-2, 3-dihydro-lH-isoindole-l , 3-dione

[0353] The mixture of tert-butyl N-(2-{2-[2-(4-{[2-(2,6-dioxopiperidin-3-yl)-l,3-dioxo-2,3- dihydro-lH-isoindol-4-yl]amino}piperidin-l-yl)ethoxy]ethoxy}ethyl)carbamate (300 mg, 0.510 mmol) and HC1 -di oxane (2 mL) was stirred at RT for 2 h. The reaction mixture solution was concentrated to give the crude product 4-[(l-{2-[2-(2- aminoethoxy)ethoxy]ethyl}piperidin-4-yl)amino]-2-(2,6-dioxopiperidin-3-yl)-2,3-di hydro- IH-isoindole-l, 3-dione (248 mg, 0.510 mmol, 100% purity, 100% yield) as colorless oil.Step-2. Synthesis of (2R)-N-(2-{2-[2-(4-{[2-(2, 6-dioxopiperidin-3-yl)~ 1 , 3-dioxo-2, 3-dihydro- lH-isoindol-4-yl]amino]piperidin-l-yl)ethoxy]ethoxy}ethyl)-l-[(2R)-2-({3-ethyl-4-oxo- 3H,4H-benzo[g]quinazolin-2-yl}sulfanyl)-2-phenylacetyl]pyrrolidine-2-carboxamide

[0354] To a solution of 4-[(l-{2-[2-(2-aminoethoxy)ethoxy]ethyl}piperidin-4-yl)amino]-2- (2, 6-dioxopiperidin-3-yl)-2,3-dihydro-lH-isoindole-l, 3-dione (45 mg, 0.092 mmol) in DMF (2 mL) and DIEA (0.1 mL, 0.779 mmol) was added HATU (38.5 mg, 0.102 mmol) and (2R)- l-[(2R)-2-({3 -ethyl -4-oxo-3H,4H-benzo[g]quinazolin-2-yl}sulfanyl)-2- phenylacetyl]pyrrolidine-2-carboxylic acid (44.9 mg, 0.092 mmol). The mixture solution was stirred at RT for 2 h. The reaction mixture was poured into water (10 mL), extracted with EtOAc (10 mL x 3). The combined organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give the crude product, which was purified by prep-HPLC (column : Gemini - Cl 8, 150 x 21.2 mm, 5um; mobile phase : ACN - H2O (0.1%FA); gradient : 25 - 35% ACN, flow rate: 20 mL / min) to give (2R)-N-(2- {2-[2-(4-{[2-(2,6-dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihydro-lH-isoindol-4- yl]amino}piperi din- l-yl)ethoxy]ethoxy (ethyl)- l-[(2R)-2-({3 -ethyl -4-oxo-3H,4H- benzo[g]quinazolin-2-yl}sulfanyl)-2-phenylacetyl]pyrrolidine -2-carboxamide, 1-1. Yield: 25.0 mg, 28.3%; Appearance: yellow solid; 1H NMR (400 MHz, DMSO-tL) 8 11.08 (s, 1H), 8.79 (d, J= 16.8 Hz, 1H), 8.21 - 7.98 (m, 3H), 7.77 - 7.54 (m, 6H), 7.43 - 7.29 (m, 3H), 7.13(d, J= 8.6 Hz, 1H), 7.04 (t, J= 6.4 Hz, 1H), 6.23 - 5.93 (m, 2H), 5.08 - 5.02 (m, 1H), 4.41 - 4.31 (m, 1H), 4.18 - 4.01 (m, 3H), 3.51 - 3.44 (m, 6H), 3.37 (t, J = 6.0 Hz, 2H), 3.28 - 3.06 (m, 4H), 2.94 - 2.72 (m, 3H), 2.64 - 2.53 (m, 2H), 2.47 - 2.44 (m, 2H), 2.22 - 1.81 (m, 10H), 1.51 - 1.40 (m, 2H), 1.29 - 1.22 (m, 3H). HPLC purity: 100%; LCMS Calculated for C5IH56N8O9S: 957.12; Observed: 957.6, [M+H]+.Example 2. Synthesis of (2R)-N-(2-{2-[2-(4-{[2-(2,6-dioxopiperidin-3-yl)-l,3-dioxo-2,3- dihydro-lH-isoindol-4-yl]amino}piperidin-l-yl)ethoxy]ethoxy}ethyl)-l-[(2S)-2-({3-ethyl-4-oxo-3H,4H-benzo[g]quinazolin-2-yl}sulfanyl)-2-phenylacetyl]pyrrolidine-2- carboxamide, 1-2.Step-1. Synthesis of (2R)-N-(2-{2-[2-(4-{[2-(2, 6-dioxopiperidin-3-yl)-l , 3-dioxo-2, 3-dihydro- lH-isoindol-4-yl]amino}piperidin-l-yl)ethoxy]ethoxy}ethyl)-l-[(2S)-2-({3-ethyl-4-oxo-3H,4H-benzo[g]quinazolin-2-yl}sulfanyl)-2-phenylacetyl]pyrrolidine-2-carboxamide

[0355] To a solution of 4-[(l-{2-[2-(2-aminoethoxy)ethoxy]ethyl}piperidin-4-yl)amino]-2- (2, 6-dioxopiperidin-3-yl)-2,3-dihydro-lH-isoindole-l, 3-dione (60 mg, 0.123 mmol) in DMF (2 mL ) and DIEA (0.1 mL, 0.779 mmol) was added (2R)-l-[(2S)-2-({3-ethyl-4-oxo-3H,4H- benzo[g]quinazolin-2-yl}sulfanyl)-2-phenylacetyl]pyrrolidine-2-carboxylic acid (59.9 mg,0.123 mmol) and HATU (51.4 mg, 0.135 mmol). The mixture solution was stirred at rt for 2 h. The reaction mixture was poured into water (10 mL), extracted with EtOAc (10 mL x 3). The combined organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give the crude product, which was purified by prep-HPLC (column : Gemini - Cl 8, 150 x 21.2 mm, 5um; mobile phase : ACN - H2O (0.1%FA); gradient : 25 - 35% ACN, flow rate: 20 mL / min) to give (2R)-N-(2-{2-[2-(4-{[2- (2,6-dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihydro-lH-isoindol-4-yl]amino}piperidin-l-yl)e thoxy]ethoxy}ethyl)-l-[(2S)-2-({3-ethyl-4-oxo-3H,4H-benzo[g]quinazolin-2-yl} sulfanyl)-2- phenylacetyl]pyrrolidine-2-carboxamide (39.5 mg, 0.04131 mmol) as a yellow solid, 1-2. Yield: 40 mg, 33.7%; Appearance: yellow solid; 'H NMR (400 MHz, DMSO-tL) 5 11.10 (s, 1H), 8.81 (d, J= 7.2 Hz, 1H), 8.21 - 7.98 (m, 3H), 7.73 - 7.28 (m, 9H), 7.18 - 7.10 (m, 1H), 7.03 (d, J= 7.0 Hz, 1H), 6.25 - 5.85 (m, 2H), 5.23 - 5.00 (m, 1H), 4.33 - 4.05 (m, 3H), 3.53 - 3.42 (m, 4H), 3.40 - 3.35 (m, 2H), 3.31 - 3.29 (m, 2H), 3.18 - 2.72 (m, 7H), 2.62 - 2.54 (m, 1H), 2.48 - 2.41 (m, 4H), 2.25 - 1.78 (m, 10H), 1.52 - 1.40 (m, 2H), 1.29 - 1.22 (m, 3H). HPLC purity: 98.85%; LCMS Calculated for CsiHseNsCbS: 957.12; Observed: 957.6, [M+H]+.Example 3. Synthesis of (2S,4R)-l-[(2S)-2-(3-{2-[2-(2-{[(2R)-l-[(2R)-2-({3-ethyl-4-oxo- 3H,4H-benzo [g] quinazolin-2-yl}sulfanyl)-2-phenylacetyl] pyrrolidin-2-yl]for mamido}ethoxy)ethoxy]ethoxy}propanamido)-3,3-dimethylbutanoyl]-4-hydroxy-N-{[4- (4-methyl-l,3-thiazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide, 1-3.Step-1. Synthesis of (2S,4R)-l-[(2S)-2-(3-{2-[2-(2-{[(2R)-l-[(2R)-2-({3-ethyl-4-oxo-3H,4H- benzo[g]quinazolin-2-yl}sulfanyl)-2-phenylacetyl]pyrrolidin-2-yl]formamido} ethoxy)ethoxy]ethoxy}propanamido)-3, 3-dimethylbutanoyl]-4-hydroxy-N-{[4-(4-me thyl-1, 3- thiazol-5-yl)phenyl methyl }pyrrolidine-2-carboxamide

[0356] To a solution of (2S,4R)-l-[(2S)-2-(3-{2-[2-(2-aminoethoxy)ethoxy]ethoxy}propane mido)-3,3-dimethylbutanoyl]-4-hydroxy-N-{[4-(4-methyl-l,3-thiazol-5-yl)phenyl] methyl]pyrrolidine-2-carboxamide (50 mg, 0.079 mmol) in DMF (2 mL) and DIEA (0.1 mL, 0.779 mmol) was added (2R)-l-[(2R)-2-({3-ethyl-4-oxo-3H,4H-benzo[g] quinazolin-2- yl}sulfanyl)-2-phenylacetyl]pyrrolidine-2-carboxylic acid (38.4 mg, 0.079 mmol) and DEPBT (28.3 mg, 0.095 mmol). The mixture solution was stirred at rt for 2 h. The reaction mixture was poured into water (10 mL), extracted with EtOAc (10 mL x 3). The combined organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give the crude product, which was purified by prep-HPLC (column : Gemini - C18, 150 x 21.2 mm, 5um; mobile phase : ACN - H2O (0.1%FA); gradient : 25 - 35% ACN, flow rate: 20 mL / min) to give (2S,4R)-l-[(2S)-2-(3-{2-[2-(2-{[(2R)-l-[(2R)-2-({3-ethyl-4-oxo-3H,4H-benzo[g]quinazolin-2-yl}sulfanyl)-2-phenylacetyl]pyrrolidin-2- yl]formamid o}ethoxy)ethoxy]ethoxy}propanamido)-3,3-dimethylbutanoyl]-4-hydroxy-N- {[4-(4-methyl-l,3-thiazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide, 1-3. Yield: 15 mg, 16.7%; Appearance: white solid; 'HNMR (400 MHz, DMSO ) 8 8.97 (s, 1H), 8.79 (d, J = 17.8 Hz, 1H), 8.57 - 8.51 (m, 1H), 8.22 - 8.17 (m, 1H), 8.11 (d, J = 8.4 Hz, 1H), 8.06 - 7.98 (m, 1H), 7.93 - 7.87 (m, 1H), 7.80 - 7.61 (m, 4H), 7.59 - 7.54 (m, 1H), 7.42 - 7.28 (m, 7H), 6.03 (d, J= 69.8 Hz, 1H), 5.12 (d, J= 3.6 Hz, 1H), 4.54 (d, J= 9.4 Hz, 1H), 4.47 - 4.39 (m, 2H), 4.38 - 4.31 (m, 2H), 4.25 - 4.02 (m, 4H), 3.70 - 3.54 (m, 4H), 3.50 - 3.44 (m, 7H), 3.37 - 3.33 (m, 2H), 3.28 - 3.05 (m, 4H), 2.57 - 2.52 (m, 1H), 2.44 (s, 3H), 2.38 - 2.32 (m, 1H), 2.17 - 2.06 (m, 2H), 2.05 - 1.93 (m, 2H), 1.93 - 1.80 (m, 2H), 1.30 - 1.22 (m, 3H), 0.91 (d, J = 8.6 Hz, 9H).HPLC purity: 97.82%; LCMS Calculated for C58H70N8O10S2: 1103.36; Observed: 1103.8, [M+H]+.Example 4. Synthesis of l-{6-[(lS)-l-({4'-amino-[l,l'-biphenyl]-4-yl}formamido) ethyl]- 2-methylpyrimidin-4-yl}-N-(2-{2-[2-(4-{[2-(2,6-dioxopiperidin-3-yl)-l,3-dioxo-2,3- dihydro-lH-isoindol-4-yl]amino}piperidin-l-yl)ethoxy]ethoxy}ethyl)-octa hydro-lH- indole-2-carboxamide, 1-4.Step-1. Synthesis of tert-butyl (3aS, 7aS)-2-[(2-{2-[2-(4-{[2-(2,6-dioxopiperidin-3-yl)-l,3- dioxo-2,3-dihydro-lH-isoindol-4-yl]amino}piperidin-l-yl)ethoxy]ethoxy}ethyl) carbamoyl] - octahydro-lH-indole-l-carboxylate

[0357] To a solution of 4-[(l-{2-[2-(2-aminoethoxy)ethoxy]ethyl}piperidin-4-yl)amino]-2- (2, 6-dioxopiperidin-3-yl)-2,3-dihydro-lH-isoindole-l, 3-dione (95 mg, 0.195 mmol) in DMF (2 mL) and DIPEA(0.1 mL, 0.779 mmol) was added l-[(tert-butoxy)carbonyl]-octahydro-lH- indole-2-carboxylic acid (52.4 mg, 0.1945 mmol) and HATU (81.3 mg, 0.214 mmol). The mixture solution was stirred at RT for 4 h. The reaction mixture was poured into water (5 mL), extracted with EtOAc (10 mL x 3). The combined organic layer was washed with brine (5 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by flash silica gel chromatography (MeOH / DCM = 0-5%) to give tert-butyl (3aS,7aS)-2-[(2- {2-[2-(4-{[2-(2,6-dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihydro-lH-isoindol-4- yl]amino}piperidin- 1 -yl) ethoxy]ethoxy }ethyl)carbamoyl]-octahydro- IH-indole- 1 - carboxylate (100 mg, 0.135 mmol, 100% purity, 69.9% yield ) as yellow oil.Step-2. Synthesis of (3aS, 7aS)-N-(2-{2-[2-(4-{[2-(2,6-dioxopiperidin-3-yl)-l,3-dioxo-2,3- dihydro-lH-isoindol-4-yl]amino}piperidin-l-yl) ethoxy] ethoxy}ethyl) -octa hydro-lH-indole- 2-carboxamide

[0358] To a solution of tert-butyl (3aS,7aS)-2-[(2-{2-[2-(4-{[2-(2,6-dioxopiperidin-3-yl)-l,3- dioxo-2,3-dihydro-lH-isoindol-4-yl]amino}piperidin-l-yl)ethoxy]ethoxy}ethyl) carbamoyl]- octahydro-lH-indole-1 -carboxylate (100 mg, 0.135 mmol) in DCM (1 mL) was added TFA (2 mL). The mixture solution was stirred at RT for 2 h. The reaction mixture solution was concentrated to give the crude product (3aS,7aS)-N-(2-{2-[2-(4-{[2-(2,6-dioxopiperidin-3-yl)-1.3-dioxo-2,3-dihydro-lH-isoindol-4-yl]amino}piperidin-l-yl) ethoxy]ethoxy}ethyl)- octahydro-lH-indole-2-carboxamide (86.4 mg, 0.135 mmol, 100% purity, 100% yield) as yellow oil.Step-3. Synthesis of tert-butyl N-(4'-{[ (1S)-1~( 6-{2-[ (2-{2-[2-( 4-{[2-(2, 6-dioxo piperidin-3-yl)-1.3-dioxo-2,3-dihydro-lH-isoindol-4-yl]amino}piperidin-l-yl)ethoxy] ethoxy}ethyl)carbamoyl / -octahydro- lH-indol-l-yl}-2-methylpyrimidin-4-yl)ethyl / carbamoyl}- [1, 1 '-biphenyl] -4-yl) carbamate

[0359] To a solution of (2S,3aS,7aS)-N-(2-{2-[2-(4-{[2-(2,6-dioxopiperidin-3-yl)-l,3-dioxo- 2,3-dihydro-lH-isoindol-4-yl]amino}piperidin-l-yl)ethoxy]ethoxy}ethyl)-octahydro-lH- indole-2-carboxamide (80 mg, 0.125 mmol) in i-PrOH (3 mL) and DIEA (0.1 mL, 0.779 mmol) was added tert-butyl N-(4'-{[(lS)-l-{2-methyl-6-[(4-methylbenzene sulfonyl)oxy]pyrimidin- 4-yl}ethyl]carbamoyl}-[l,l'-biphenyl]-4-yl)carbamate (75.4 mg, 0.125 mmol). The mixture solution was stirred at 80 °C for 4 h. The reaction mixture was concentrated to give the crude product, which was purified by flash silica gel chromatography (MeOH / DCM = 0-10%) to give tert-butyl N-(4'-{[(lS)-l-(6-{2-[(2-{2-[2-(4-{[2-(2,6-dioxopiperidin-3-yl)-l,3-dioxo-2,3- dihydro-lH-isoindol-4-yl]a mino}piperidin-l-yl)ethoxy]ethoxy}ethyl)carbamoyl]-octahydro- lH-indol-l-yl}-2-methylpyrimidin-4-yl)ethyl]carbamoyl}-[l,T-biphenyl]-4-yl)carbamate (100 mg, 0.0935 mmol, 100% purity, 75.1% yield) as yellow oil.Step-4. Synthesis of l-{6-[(lS)-l-({4'-amino-[lf '-biphenyl]-4-yl}formamido) ethyl]-2- methylpyrimidin-4-yl}-N-(2-{2-[2-(4-{[2-(2, 6-dioxopiperidin-3-yl)-l , 3-di oxo-2, 3-dihydro- lH-isoindol-4-yl]amino}piperidin-l-yl)ethoxy]ethoxy}ethyl)-octa hydro-lH-indole-2- carboxamide

[0360] To a solution of tert-butyl N-(4'-{[(lS)-l-(6-{2-[(2-{2-[2-(4-{[2-(2,6-dioxopiperidin- 3-yl)-l,3-dioxo-2,3-dihydro-lH-isoindol-4-yl]amino}piperidin-l-yl)ethoxy]ethoxy} ethyl)carbamoyl]-octahydro- IH-indol- 1 -yl } -2-methylpyrimidin-4-yl)ethyl]carbamoyl } -[ 1 , T- biphenyl]-4-yl)carbamate (100 mg, 0.0935 mmol) in DCM (1 mL) was added TFA (2 mL). The mixture solution was stirred at RT for 2 h. The reaction mixture was concentrated to give the crude product, which was purified by prep-HPLC (column : Gemini - C18, 150 x 21.2 mm, 5um; mobile phase : ACN - H2O (0.1%FA); gradient : 25 - 35% ACN, flow rate: 20 mL / min) to give l-{6-[(lS)-l-({4'-amino-[l,r-biphenyl]-4-yl}formamido)ethyl]-2-methylpyrimidin-4- yl}-N-(2-{2-[2-(4-{[2-(2,6-dioxopiperi din-3-yl)-l,3-dioxo-2,3-dihydro-lH-isoindol-4- yl]amino}piperidin-l-yl)ethoxy]ethox y}ethyl)-octahydro-lH-indole-2-carboxamide, 1-4: 27 mg, 27.3%; Appearance: yellow solid; *HNMR (400 MHz, DMSO-tL) 5 11.09 (s, 1H), 8.60 (d, J= 7.0 Hz, 1H), 8.14 (s, 1H), 7.98 (s, 1H), 7.88 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 8.4 Hz,2H), 7.60 - 7.54 (m, 1H), 7.44 (d, J = 8.6 Hz, 2H), 7.15 (d, J = 8.6 Hz, 1H), 7.04 (d, J = 7.0 Hz, 1H), 6.65 (d, J= 8.6 Hz, 2H), 6.24 (d, J= 8.2 Hz, 2H), 5.33 (s, 2H), 5.05 (dd, J= 12.8, 5.4 Hz, 1H), 4.91 - 4.83 (m, 1H), 4.30 (s, 1H), 3.78 - 3.46 (m, 9H), 3.42 (t, J= 6.0 Hz, 2H), 3.17 (s, 1H), 2.94 - 2.81 (m, 3H), 2.62 - 2.57 (m, 2H), 2.57 - 2.53 (m, 2H), 2.39 - 2.25 (m, 6H), 2.09 - 1.84 (m, 6H), 1.72 - 1.50 (m, 5H), 1.48 - 1.38 (m, 5H), 1.30 - 1.08 (m, 2H). HPLC purity: 92.08%; LCMS Calculated for C53H64NIO08: 969.15; Observed: 969.7 [M+H]+.Example 5. Synthesis of (2S,3aS,7aS)-l-{6-[(lS)-l-({4'-amino-[l,l'-biphenyl]-4- yl}formam ido)ethyl]-2-(3-{2-[2-(4-{[2-(2,6-dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihydro- lH-isoindol-4-yl]amino}piperidin-l-yl)-2-oxoethoxy]ethoxy}propyl) pyrimidin-4-yl}-N- methyl-octahydro-lH-indole-2-carboxamide, 1-5.Step-1. Synthesis of tert-butyl 2-[2-(prop-2-yn-l-yloxy)ethoxy]acetate

[0361] To a solution of 2-(prop-2-yn-l-yloxy)ethan-l-ol (200 mg, 1.99 mmol) in THF (15 mL ) was added NaH (95.1 mg, 2.38 mmol) at rt. under N2. The reaction mixture was stirred for 0.5 h at rt. The reaction mixture was added tert-butyl 2-bromoacetate (425 mg, 2.18 mmol) at rt under N2. The reaction mixture was concentrated to give residue, which was purified by flash silica gel chromatography (DCM / MeOH = 20 / 1) to give tert-butyl 2-[2-(prop-2-yn-l- yloxy)ethoxy] acetate (80.0 mg, 373 pmol, 100% purity, 19% yield) as a colorless oil.Step-2. Synthesis of 2-[2-(prop-2-yn-l-yloxy)ethoxy]acetic acid

[0362] To a solution of tert-butyl 2-[2-(prop-2-yn-l-yloxy)ethoxy]acetate (80 mg, 373 pmol) in DCM (5 mL ) was added TFA (1 mL, 373 pmol) at rt. The reaction mixture was stirred for 1 h at rt. The reaction mixture was concentrated to give crude 2-[2-(prop-2-yn-l- yloxy)ethoxy]acetic acid (58.9 mg, 372 pmol, 100% purity, 100% yield) as a colorless oil.Step-3. Synthesis of tert-butyl N-(l-{2-[2-(prop-2-yn-l-yloxy)ethoxy]acetyl} piperidin-4- yl)carbamate

[0363] To a solution of 2-[2-(prop-2-yn-l-yloxy)ethoxy]acetic acid (58 mg, 366 pmol), DIPEA (236 mg, 1.83 mmol), tert-butyl A-(piperidin-4-yl)carbamate (80.5 mg, 402 pmol) in DMF (5 mL ) was added HATU (166 mg, 439 pmol) at rt. The reaction mixture was stirred for 2 h at rt. The reaction mixture was added water (20 mL) and extracted with EA (30 mL X 3). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated to give residue, which was purified by flash silica gel chromatography (DCM / MeOH = 20 / 1) to give tert-butyl A-(l-{2-[2-(prop-2-yn-l-yloxy)ethoxy]acetyl}piperidin-4-yl)carbamate (120 mg, 352 pmol, 100% purity, 96% yield) as a colorless oil.Step-4. Synthesis of tert-butyl N-(4'-{[(lS)-l-{6-[(2S,3aS, 7aS)-2-(methylcarbamoyl)- octahydro-lH-indol-l-yl -2-( 3-{2-[2-( 4-{[ ( tert-butoxy)carbonyl ]amino}piperidin-l-yl)-2-oxoethoxy ] ethoxy }pr op- l-yn-l-yl)pyrimidin-4-yl}ethyl ] carbamoyl}- [ 1, 1 '-biphenyl ]-4- yl)carbamate

[0364] To a solution of tert-butyl N-(l-{2-[2-(prop-2-yn-l-yloxy)ethoxy]acetyl}piperidin-4- yl)carbamate (40.1 mg, 118 pmol), tert-butyl A-(4'-{[(15)-l-{6-[(2S',3aS,7aS)-2- (methylcarbamoyl)-octahydro-17 / -indol-l-yl]-2-bromopyrimidin-4-yl}ethyl] carbamoyl}- [l,l'-biphenyl]-4-yl)carbamate (80 mg, 118 pmol), Cui (2.24 mg, 11.8 pmol), [Ph3P]2PdCl2(16.5 mg, 23.6 pmol) in DMF (5 mL ) was added TEA (119 mg, 1.18 mmol) at rt under N2. The reaction mixture was stirred for 2 h at 80 °C under ISb.The reaction mixture was added water (20 mL) and extracted with EA (30 mL X 3). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated to give residue, which was purified by flash silica gel chromatography (DCM / MeOH = 20 / 1) to give tert-butyl A-(4'-{[(15)-l-{6- [(2S',3aS,7aS)-2-(methylcarbamoyl)-octahydro-l / / -indol-l-yl]-2-(3-{2-[2-(4-{[(tert- butoxy)carbonyl]amino}piperidin-l-yl)-2-oxoeth oxy]ethoxy}prop-l-yn-l-yl)pyrimidin-4- yl}ethyl]carbamoyl}-[l,l'-biphenyl]-4-yl)carbamate (102 mg, 108 pmol, 100% purity, 92% yield) as a light yellow solid.Step-5. Synthesis of tert-butyl N-(4'-{[(lS)-l-{6-[(2S,3aS, 7aS)-2-(methylcarbamoyl)- octahydro-lH-indol-l-yl ]-2-( 3-{2-[2-( 4-{[ ( tert-butoxy)carbonyl ]amino}piperidin-l-yl)-2- oxoethoxy ] ethoxy }pr op- l-yn-l-yl)pyrimidin-4-yl}ethyl ] carbamoyl}- [ 1, 1 '-biphenyl ]-4- yl)carbamate

[0365] To a solution of tert-butyl A-(4'-{[(15)-l-{6-[(2S',3aS,7aS)-2-(methylcarbamoyl)- octahydro-l / / -indol-l-yl]-2-(3-{2-[2-(4-{[(tert-butoxy)carbonyl]amino}piperidin-l-yl)-2- oxoethoxy]ethoxy (prop- 1 -yn- 1 -yl)pyrimidin-4-yl } ethyl]carbamoyl } -[ 1 , 1 '-biphenyl]-4- yl)carbamate (102 mg, 108 pmol) in MeOH (10 mL ) was added Pd / C (20 mg) at rt. The reaction mixture was stirred for 12 h at rt under H2. The reaction mixture was filtered, concentrated to give tert-butyl A-(4'-{[(lS)-l-{6-[(2S',3aS,7aS)-2-(methylcarbamoyl)- octahydro- 1 rt-indol- 1 -yl]-2-(3 -{2-[2-(4- { [(tert-butoxy) carbonyl]amino Jpiperidin- 1 -yl)-2-oxoethoxy]ethoxy (prop- 1 -yn- 1 -yl)pyrimidin-4-yl ( ethyl]carbamoyl (-[1,1 '-biphenyl]-4- yl)carbamate (102 mg, 108 pmol, 100% purity, 100% yield) as a light yellow oil, which was used for next step directly without furtherStep-6. Synthesis of (2S,3aS, 7aS)-l-{6-[(lS)-l-({4'-amino-[l,r~biphenyl]-4- yl}formamido)ethyl]-2-(3-{2-[2-(4-aminopiperidin-l-yl)-2-oxoethoxy] ethoxy} propyl)pyrimidin-4-yl}-N-methyl-octahydro-lH-indole-2-carboxamide

[0366] To a solution of tert-butyl A-(4'-{[(15)-l-{6-[(2S',3aS,7aS -2-(methylcarbamoyl)- octahydro-lrt-indol-l-yl]-2-(3-{2-[2-(4-{[(tert-butoxy)carbonyl]amino(piperidin-l-yl)-2- oxoethoxy]ethoxy( propyl)pyrimidin-4-yl(ethyl]carbamoyl(-[l,l'-biphenyl]-4- yl)carbamate (108 mg, 114 pmol) in DCM (5 mL ) was added TFA (1 mL, 114 pmol) at rt. The reaction mixture was stirred for 1 h at rt. The reaction mixture was concentrated to give (2S',3aS,7aS -l-{6-[(lS)-l-({4'-amino-[l,l'-biphenyl]-4-yl(formamido)ethyl]-2-(3-{2- [2-(4-aminopiperidin-l-yl)-2-oxoethoxy] ethoxy (propyl)pyrimidin-4-yl(-7V-methyl- octahydro-lrt-indole-2-carboxamide (84.0 mg, 113 pmol, 100% purity, 100% yield) as a light yellow oil, which was used for next step directly without further purification.Step-7. Synthesis of (2S,3aS, 7aS)-l-{6-[(lS)-l-({4'-amino-[lf'-biphenyl]-4-yl}formamido) ethyl] -2-(3-{2-[2-(4-{[2-(2,6-dioxopiperidin-3-yl)-l,3-dioxo-2, 3-dihydro-lH-isoindol-4- yl]amino}piperidin-l-yl)-2-oxoethoxy]ethoxy}propyl) pyrimidin-4-yl}-N-methyl-octahydro- lH-indole-2-carboxamide

[0367] To a solution of (2S',3aS,7aS)-l-{6-[(15)-l-({4'-amino-[l,l'-biphenyl]-4- yl(formamido)ethyl]-2-(3-{2-[2-(4-aminopiperidin-l-yl)-2-oxoethoxy]ethoxy (propyl) pyrimidin-4-yl(-A-methyl-octahydro-U / -indole-2-carboxamide (84 mg, 113 pmol), 2-(2,6- dioxopiperidin-3-yl)-4-fluoro-2,3-dihydro-lJ / -isoindole-l, 3-dione (31.2 mg, 113 pmol) in DMSO (5 mL ) was added DIPEA (73.0 mg, 565 pmol) at rt. The reaction mixture was stirred for 12 h at 80 °C. The reaction mixture was added water (20 mL) and extracted with EA (30 mL X 3). The organic layer was washed with water (20 mL X 2), dried over anhydroussodium sulfate, filtered, concentrated to give residue, which was purified by flash silica gel chromatography (DCM / MeOH = 20 / 1) to give crude product, which was further purified by Prep-HPLC (ACN / water / 0.1% NH4OH) to give (2S',3aS,7aS)-l-{6-[(15)-l-({4'-amino-[l,r- biphenyl]-4-yl}formamido)ethyl]-2-(3-{2-[2-(4-{[2-(2,6-dioxopiperidin-3-yl)-l,3-dioxo-2,3- dihydro-l / Z-isoindol-4-yl]amino}piperidin-l-yl)-2-oxoethoxy]ethoxy}propyl)pyrimidin-4- yl}-7V-methyl-octahydro-l / Z-indole-2-carboxamide, 1-5. Yield: 7.6 mg, 16%; Appearance: Yellow solid; *H NMR (400 MHz, DMSO-d6) 5 11.09 (s, 1H), 8.61 (d, J= 7.8 Hz, 1H), 7.88 (d, J= 8.4 Hz, 2H), 7.79 (s, 1H), 7.64 (d, J= 8.4 Hz, 2H), 7.61 - 7.55 (m, 1H), 7.44 (d, J = 8.6 Hz, 2H), 7.22 (d, J= 8.6 Hz, 1H), 7.05 (d, J= 7.0 Hz, 1H), 6.65 (d, J= 8.6 Hz, 2H), 6.25 (d, J= 8.4 Hz, 1H), 5.34 (s, 2H), 5.04 (dd, J= 12.8, 5.4 Hz, 1H), 4.92 - 4.83 (m, 1H), 4.24 (d, J= 12.2 Hz, 1H), 4.16 (s, 1H), 3.80 (d, J= 10.2 Hz, 2H), 3.58 - 3.39 (m, 5H), 3.18 - 3.10 (m, 1H), 2.92 - 2.78 (m, 2H), 2.63 - 2.54 (m, 5H) 2.30 - 2.21 (m, 1H), 2.11 - 1.75 (m, 10H), 1.74 - 1.52 (m, 4H), 1.51 - 0.98 (m, 12H); HPLC purity: 95 %; LCMS Calculated for C54H64N10O9: 997.17; Observed: 977.9 [M+H]+.Example 6. Synthesis of (2S,3aS,7aS)-l-{6-[(lS)-l-({4'-amino-[l,l'-biphenyl]-4-yl}form amido)ethyl]-2-(3-{2-[2-(4-{[2-(2,6-dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihydro-lH- isoindol-4-yl]amino}piperidin-l-yl)ethoxy]ethoxy}propyl)pyrimidin-4-yl}-N-methyl- octahydro-lH-indole-2-carboxamide, 1-6.Step-1. Synthesis of 2-[2-(prop-2-yn-l-yloxy)ethoxy]ethyl 4-methylbenzene-l -sulfonate

[0368] To a mixture of 2-[2-(prop-2-yn-l-yloxy)ethoxy]ethan-l-ol (500 mg, 3.46 mmol), TsCl (791 mg, 4.15 mmol) in DCM (20 mL ) was added TEA (1.04 g, 10.3 mmol) at rt. The reaction mixture was stirred at rt for 12 h. The reaction mixture was concentrated to give crude product, which was further purified by flash silica gel chromatography (DCM / MeOH = 20 / 1) to give 2- [2-(prop-2-yn-l-yloxy)ethoxy]ethyl 4-methylbenzene-l -sulfonate (550 mg, 1.84 mmol, 100% purity, 53% yield) as a colorless oil.Step-2. Synthesis of tert-butyl N-(l-{2-[2-(prop-2-yn-l-yloxy)ethoxy]ethyl}piperidin-4-yl) carbamate

[0369] To a solution of 2-[2-(prop-2-yn-l-yloxy)ethoxy]ethyl 4-methylbenzene-l -sulfonate (150 mg, 502 pmol), tert-butyl 7V-(piperidin-4-yl)carbamate (120 mg, 602 pmol) in DMF (15mL ) was added K2CO3 (207 mg, 1.50 mmol) at rt. The reaction mixture was stirred for 12 h at 80 °C. The reaction mixture was added water (20 mL) and extracted with EA (30 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated to give residue, which was purified by flash silica gel chromatography (DCM / MeOH = 20 / 1) to give / crt-butyl N -(l-{2-[2-(prop-2-yn-l-yloxy)ethoxy]ethyl }piperidin-4-yl)carbamate (130 mg, 398 pmol, 100% purity, 80% yield) as a colorless oil.Step-3. Synthesis of tert-butyl N-[l-(2-{2-[(3-{4-[(2S,3aS, 7aS)-2-(methylcarbamoyl)- octahydro-lH-indol-l-yl ]-6-[ (1S)-1~[ <4'-{[(tert-butoxy)carbonyl ] amino}- [ 1, 1 '-biphenyl ]-4- yl)formamido] ethyl]pyrimidin-2-yl}prop-2-yn-l-yl)oxy]ethoxy}ethyl) piperidineyl] carbamate

[0370] To a solution of tert-butyl A-(l-{2-[2-(prop-2-yn-l-yloxy)ethoxy]ethyl}piperidin-4- yl)carbamate (47.9 mg, 147 pmol), tert-butyl (4'-(((5)-l-(2-bromo-6-((2S',3aS,7aS)-2- (methylcarbamoyl)octahydro-U / -indol-l-yl)pyrimidin-4-yl)ethyl)carbamoyl)-[l,l'-biphenyl]- 4-yl)carbamate (100.0 mg, 147 pmol), Cui (2.79 mg, 14.7 pmol), [PhsP^PdCL (20.6 mg, 29.4 pmol) in DMF (5 mL ) was added TEA (148 mg, 1.47 mmol) at rt under N2. The reaction mixture was stirred for 2 h at 80 °C under N2. The reaction mixture was added water (20 mL) and extracted with EA (30 mL X 3). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated to give residue, which was purified by flash silica gel chromatography (DCM / MeOH = 20 / 1) to give tert-butyl A-[l-(2-{2-[(3-{4-[(2S',3aS,7aS)-2- (methylcarbamoyl)-octahydro-U / -indol-l-yl]-6-[(15)-l-[(4'-{[(tert-butoxy)carbonyl]amino}- [l,l'-biphenyl]-4-yl)formamido]ethyl]pyrimidin-2-yl}prop-2-yn-l- yl)oxy]ethoxy}ethyl)piperidin-4-yl]carbamate (125 mg, 135 pmol, 100% purity, 93% yield) as a light yellow solid.Step-4. Synthesis of tert-butyl N-(l-{2-[2-(3-{4-[(2S,3aS, 7aS)-2-(methylcarbamoyl)~ octahydro-lH-indol-l-yl ]-6-[ (1S)-1~[ e'-{[(tert-butoxy)carbonyl ] amino}- [ 1, 1 '-biphenyl ]-4- yl)formamido]ethyl]pyrimidin-2-yl}propoxy)ethoxy]ethyl}piperidin-4-yl)carbamate

[0371] To a solution of tert-butyl A-[l-(2-{2-[(3-{4-[(2S',3aS,7aS)-2-(methylcarbamoyl)- octahydro-lJ / -indol-l-yl]-6-[(15)-l-[(4'-{[(tert-butoxy)carbonyl]amino}-[l,T-biphenyl]-4- yl)formamido]ethyl]pyrimidin-2-yl(prop-2-yn-l-yl)oxy]ethoxy (ethyl) piperidin-4- yl]carbamate (125 mg, 135 pmol) in MeOH (15 mL ) was added Pd / C (30 mg ) at rt. The mixture solution was stirred at rt for 12 h under H2. The mixture solution was filtered and concentrated to afford tert-butyl A-(l-{2-[2-(3-{4-[(2S',3aS,7aS)-2-(methylcarbamoyl)- octahydro-17 / -indol-l-yl]-6-[(15)-l-[(4'-{[(tert-butoxy)ca rbonyl]amino(-[l,l'-biphenyl]-4- yl)formamido]ethyl]pyrimidin-2-yl(propoxy)ethoxy] ethyljpip eridin-4-yl)carbamate (120 mg, 129 pmol, 100% purity, 96% yield) as a light yellow solid.Step-5. Synthesis of (2S,3aS, 7aS)-l-{6-[(lS)-l-({4'-amino-[l,r-biphenyl]-4- yl}formamido)ethyl]-2-(3-{2-[2-(4-aminopiperidin-l-yl)ethoxy]ethoxy}propyl) pyrimidin-4- yl}-N-methyl-octa hydro- lH-indole-2-carboxamide

[0372] To a solution of tert-butyl 7V-(l-{2-[2-(3-{4-[(2S',3aS,7aS)-2-(methylcarbamoyl)- octahydro-l1H-indol-l-yl]-6-[(15)-l-[(4'-{[(tert-butoxy)carbonyl]amino}-[l,T-biphenyl]-4- yl)formamido]ethyl] pyrimidin-2-yl(propoxy)ethoxy]ethyl(piperidin-4-yl)carbamate (120 mg, 129 pmol) in DCM (5 mL ) was added TFA (1 mL, 129 pmol) at rt. The reaction mixture was stirred for 2 h at rt. The reaction mixture was concentrated to give (25',3a5',7a5)-l-{6-[(l,S)-l- ({4'-amino-[l,l'-biphenyl]-4-yl( formamido)ethyl]-2-(3-{2-[2-(4-aminopiperidin-l- yl)ethoxy] ethoxy (propyl) pyrimidin-4-yl(- N-methyl-octahydro-17 / -indole-2-carboxamide (92.0 mg, 126 pmol, 100% purity, 98% yield) as a light yellow oil.Step-6. Synthesis of (2S,3aS, 7aS)-l-{6-[(lS)-l-({4’-amino-[l,r-biphenyl]-4-yl} formamido)ethyl]-2-(3-{2-[2-(4-{[2-(2,6-dioxopiperidin-3-yl)-l, 3-dioxo-2,3-dihydro-lH- isoindol-4-yl]amino}piperidin-l-yl)ethoxy]ethoxy}propyl)pyrimidin-4-yl}-N-methyl- octahydro-lH-indole-2-carboxamide

[0373] To a solution of (2S',3aS,7aS)-l-{6-[(15)-l-({4'-amino-[l,r-biphenyl]-4- yl(formamido)ethyl]-2-(3-{2-[2-(4-aminopiperidin-l-yl)ethoxy]ethoxy (propyl) pyrimidin-4-yl J-A-methyl -octahydro- \H -indole-2-carboxamide (30 mg, 41.2 pmol), 2-(2,6- dioxopiperidin-3-yl)-4-fluoro-2,3-dihydro-U / -isoindole-l, 3-dione (13.6 mg, 49.4 pmol) in DMSO (5 mL ) was added DIPEA (15.8 mg, 123 pmol) at rt. The reaction mixture was stirred for 12 h at 80 °C. The reaction mixture was added water (20 mL) and extracted with EA (30 mL X 3). The organic layer was washed with water (20 mL X 2), dried over anhydrous sodium sulfate, filtered, concentrated to give residue, which was purified by flash silica gel chromatography (DCM / MeOH = 20 / 1) to give crude product, which was further purified by Prep-HPLC (ACN / water / 0.1% NH4OH) to give (2S',3aS,7aS)-l-{6-[(15)-l-({4'-amino-[l,l'- biphenyl]-4-yl}formamido)ethyl]-2-(3-{2-[2-(4-{[2-(2,6-dioxopiperidin-3-yl)-l,3-dioxo-2,3- dihydro-lJ / -isoindol-4-yl]amino}piperidin-l-yl)ethoxy] ethoxy }propyl)pyrimidin-4-yl}-A- methyl-octahydro-UT-indole-2-carboxamide, 1-6. Yield: 6.9 mg, 16%; Appearance: Yellow solid; 'H NMR (400 MHz, DMSO-d6) 8 11.09 (s, 1H), 8.60 (d, J= 7.8 Hz, 1H), 7.88 (d, J = 8.2 Hz, 2H), 7.90 (s, 1H), 7.84 (d, J= 8.4 Hz, 2H), 7.60 - 7.53 (m, 1H), 7.44 (d, J= 8.4 Hz, 2H), 7.14 (d, J = 8.8 Hz, 1H), 7.03 (d, J = 7.0 Hz, 1H), 6.65 (d, J = 8.4 Hz, 2H), 6.23 (d, J = 8.2 Hz, 1H), 5.33 (s, 2H), 5.05 (dd, J= 13.0, 5.4 Hz, 1H), 4.93 - 4.84 (m, 1H), 4.27 (s, 1H), 3.82 - 3.35 (m, 9H), 2.94 - 2.71 (m, 3H), 2.64 - 2.52 (m, 6H), 2.31 - 2.12 (m, 4H) 2.08 - 1.96 (m, 3H), 1.92 - 1.81 (m, 6H), 1.71 - 1.50 (m, 4H), 1.47 - 1.32 (m, 7H), 1.30 - 1.05 (m, 4H); HPLC purity: 95%; LCMS Calculated for Cs^eNioOs: 982.52; Observed: 983.9 [M+H]+.Example 8. Synthesis of (2S,4R)-l-[(2S)-2-{3-[2-(2-{2-[(l-{6-[(lS)-l-({4'-amino-[l,l'- biphenyl]-4-yl}formamido)ethyl]-2-methylpyrimidin-4-yl}-octahydro-lH-indol-2- yl)formamido]ethoxy}ethoxy)ethoxy]propanamido}-3,3-dimethylbutano yl]-4-hydroxy- N-{[4-(4-methyl-l,3-thiazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide, 1-8.Step-7. Synthesis of tert-butyl N-(2-{2-[2-(2-{[(2S)-l-[(2S,4R)-4-hydroxy-2-({[4-(4-methyl-1, 3-thiazol-5-yl)phenyl]methyl}carbamoyl)pyrrolidin-l-yl]-3, 3 -dimethyl- l-oxobutan-2- yl]carbamoyl}ethoxy) ethoxy] ethoxy}ethyl) carbamate

[0374] To a solution of 3-{2-[2-(2-{[(tert-butoxy)carbonyl]amino}ethoxy)ethoxy] ethoxyjpropanoic acid (186 mg, 0.581 mmol) in DIEA (0.3 mL, 2.337 mmol) and DMF (3 mL ) was added HATU (242 mg, 0.639 mmol) and (2S,4R)-l-[(2S)-2-amino-3,3- dimethylbutanoyl]-4-hydroxy-N-{[4-(4-methyl-l,3-thiazol-5-yl)phenyl]methyl}pyro lidine-2- carboxamide (250 mg, 0.581 mmol). The mixture solution was stirred at RT for 2 h. The reaction mixture was poured into water (10 mL), extracted with EtOAc (10 mL x 3), the aqueous solution was dried by lyophilization to give the crude product, which was purified by flash silica gel chromatography (MeOH / DCM = 0-20%) to give tert-butyl N-(2-{2-[2-(2- {[(2S)-l-[(2S,4R)-4-hydroxy-2-({[4-(4-methyl-l,3-thiazol-5- yl)phenyl]methyl}carbamoyl)pyrrolidin-l-yl]-3,3-dimethyl-l-oxobutan-2- yl]carbamoyl}ethoxy)ethoxy]ethoxy}ethyl)carbamate (380 mg, 0.518 mmol, 100% purity, 89.2% yield) as colorless oil.Step-2. Synthesis of (2S,4R)-l-[(2S)-2-(3-{2-[2-(2-aminoethoxy)ethoxy]ethoxy}pro panamido)-3, 3 -dimethylbutanoyl ]-4-hydroxy-N-{[ 4-( 4-methyl-l, 3-thiazol-5- yl)phenyl methyl }pyrrolidine-2-carboxamide

[0375] To a solution of tert-butyl N-(2-{2-[2-(2-{[(2S)-l-[(2S,4R)-4-hydroxy-2-({[4-(4- methyl- 1 ,3 -thiazol-5-yl)phenyl]methyl } carbamoyl)pyrrolidin- 1 -y 1] -3 ,3 -dimethyl- 1 -ox obutan-2-yl]carbamoyl}ethoxy)ethoxy]ethoxy}ethyl)carbamate (200 mg, 0.273 mmol) in DCM (1 mL) was added TFA (2 mL). The reaction was stirred at RT for 2 h. The reaction mixture solution was concentrated to give the crude product (2S,4R)-l-[(2S)-2-(3-{2-[2-(2- aminoethoxy)ethoxy]ethoxy}propanamido)-3,3-dimethylbutanoyl]-4-hydroxy-N-{[4-(4- methyl-l,3-thiazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide (172 mg, 0.273 mmol, 100% purity, 100% yield) as colorless oil.Step-3. Synthesis of tert-butyl 2-[(2-{2-[2-(2-{[(2S)-l-[(2S,4R)-4-hydroxy-2-({[4-(4-methyl-1, 3-thiazol-5-yl)phenyl]methyl}carbamoyl)pyrrolidin-l-yl]-3, 3 -dimethyl- 1 -ox obutan-2- yl]carbamoyl}ethoxy)ethoxy]ethoxy}ethyl)carbamoyl]-octahydro-lH-indol e-1 -carboxylate

[0376] To a solution of (2S,4R)-l-[(2S)-2-(3-{2-[2-(2-aminoethoxy)ethoxy]eth oxy}propanamido)-3,3-dimethylbutanoyl]-4-hydroxy-N-{[4-(4-methyl-l,3-thiazol-5- yl)phenyl]methyl]pyrrolidine-2-carboxamide (100 mg, 0.158 mmol) in DMF (2 mL) and DIEA (0.1 mL, 0.779 mmol) was added l-[(tert-butoxy)carbonyl]-octahydro-lH-indole-2- carboxylic acid (42.4 mg, 0.158 mmol) and HATU (65.8 mg, 0.173 mmol). The mixture solution was stirred at RT for 2 h. The reaction mixture was poured into water (5 mL), extracted with EtOAc (10 mL x 3). The combined organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by flash silica gel chromatography (MeOH / DCM = 0-5%) to give tert-butyl 2-[(2-{2-[2-(2-{[(2S)-l- [(2S,4R)-4-hydroxy-2-({[4-(4-methyl-l,3-thiazol-5-yl)phenyl]methyl}carbamoyl)pyrrolidin- l-yl]-3,3-dimethyl-l-oxobutan-2-yl]carbamoyl}ethoxy)ethoxy]ethoxy}ethyl)carbamoyl]- octahydro- IH-indole-l -carboxylate (100 mg, 0.113 mmol, 100% purity, 71.9% yield) as colorless oil.Step-4. Synthesis of (2S,4R)-l-[(2S)-3,3-dimethyl-2-{3-[2-(2-{2-[(octahydro-lH-indol-2- yl)formamido ]ethoxy}ethoxy)ethoxy]propanamido}butanoyl ]-4-hydroxy-N-{[ 4-( 4-methyl-l, 3- thiazol-5-yl)phenyl methyl }pyrrolidine-2-carboxamide

[0377] To a solution of tert-butyl 2-[(2-{2-[2-(2-{[(2S)-l-[(2S,4R)-4-hydroxy-2-({[4-(4- methyl-l,3-thiazol-5-yl)phenyl]methyl}carbamoyl)pyrrolidin-l-yl]-3,3-dimethyl-l-ox obutan-2-yl]carbamoyl}ethoxy)ethoxy]ethoxy}ethyl)carbamoyl]-octahydro-lH-indol e-1- carboxylate (100 mg, 0.113 mmol) in DCM (1 mL) was added TFA (2 mL). The mixture solution was stirred at RT for 2 h. The reaction mixture solution was concentrated to give the crude product (2S,4R)-l-[(2S)-3,3-dimethyl-2-{3-[2-(2-{2-[(octahydro-lH-indol- 2yl)formamido]ethoxy}ethoxy)ethoxy]propanamido}butanoyl]-4-hydroxy-N-{[4-(4-methyl-l,3-thiazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxami de (88 mg, 0.113 mmol, 100% purity, 100% yield) as colorless oil.Step-5. Synthesis of tert-butyl N-(4'-{[(lS)-l-(6-{2-[(2-{2-[2-(2-{[(2S)-l-[(2S,4R)-4-hydroxy- 2-( {[ 4-( 4-methyl-l, 3-thiazol-5-yl)phenyl ]methyl}carbamoyl)pyrrolidin-l-y I -3, 3-dimethyl-l- oxobutan-2-yl ]carbamoyl}ethoxy)ethoxy ]ethoxy}ethyl) carbamoyl / -octahydro- IH-indol-l-yl}- 2-methylpyrimidin-4-yl)ethyl carbamoyl}- [ 1, 1 '-biphenyl / -4-yl) carbamate

[0378] To a solution of (2S,4R)-l-[(2S)-3,3-dimethyl-2-{3-[2-(2-{2-[(octahydro-lH-indol-2- yl)formamido]ethoxy}ethoxy)ethoxy]propanamido}butanoyl]-4-hydroxy-N-{[4-(4-methyl- l,3-thiazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide (88 mg, 0.113 mmol) in i-PrOH (2 mL) and DIEA (0.1 mL, 0.779 mmol) was added tert-butyl N-(4'-{[(lS)-l-{2-methyl-6-[(4- methylbenzenesulfonyl)oxy]pyrimidin-4-yl}ethyl]carbamoyl}-[l,T-biphenyl]-4-yl)carbamate (68 mg, 0.113 mmol). The mixture solution was stirred at RT for 16 h. The reaction mixture was concentrated to give the crude product, which was purified by flash silica gel chromatography (MeOH / DCM = 0-10%) to give tert-butyl N-(4'-{[(lS)-l-(6-{2-[(2-{2-[2-(2- {[(2S)-l-[(2S,4R)-4-hydroxy-2-({[4-(4-methyl-l,3-thiazol-5- yl)phenyl]methyl}carbamoyl)pyrrolidin-l-yl]-3,3-dimethyl-l-oxobutan-2- yl]carbamoyl } ethoxy)ethoxy] ethoxy } ethyl)carbamoyl]-octahydro- IH-indol- 1 -yl } -2- methylpyrimidin-4-yl)ethyl]carbamoyl}-[l,T-biphenyl]-4-yl)carbamate (100 mg, 0.082 mmol, 100% purity, 73.6% yield) as colorless oil.Step-6. Synthesis of (2S,4R)-l-[(2S)-2-{3-[2-(2-{2-[(l-{6-[(lS)-l-({4'-amino-[l, -biphenyl]- 4-yl}formamido)ethyl]-2-methylpyrimidin-4-yl}-octahydro-lH-indol-2-yl) formamido]ethoxy}ethoxy)ethoxy]propanamido}-3, 3 -dimethylbutanoyl] -4-hydroxy-N-{ [4-(4- methyl-1, 3-thiazol-5-yl)phenyl methyl }pyrrolidine-2-carboxamide

[0379] To a solution of tert-butyl N-(4'-{[(lS)-l-(6-{2-[(2-{2-[2-(2-{[(2S)-l-[(2S,4R)-4- hydroxy-2-({[4-(4-methyl-l,3-thiazol-5-yl)phenyl]methyl}carbamoyl)pyrrolidin-l-yl] -3,3- dimethyl-l-oxobutan-2-yl]carbamoyl}ethoxy)ethoxy]ethoxy}ethyl)carbamoyl]-octahydro-lH-indol-l-yl}-2-methylpyrimidin-4-yl)ethyl]carbamoyl}-[l,T-biphenyl]-4-yl)carbamate (100 mg, 0.082 mmol) in DCM (1 mL) was added TFA (2 mL). The mixture solution was stirred at RT for 2 h. The reaction mixture was concentrated to give the crude product, which was purified by prep-HPLC (column : Gemini - Cl 8, 150 x 21.2 mm, 5um; mobile phase : ACN - H2O (0.1%NH4HCO3); gradient : 25 - 35% ACN, flow rate: 20 mL / min) to give (2S,4R)-l-[(2S)-2-{3-[2-(2-{2-[(l-{6-[(lS)-l-({4'-amino-[l,r-biphenyl]-4- yl}formamido)ethyl]-2-methylpyrimidin-4-yl}-octahydro-lH-indol-2- yl)formamido]ethoxy}ethoxy)ethoxy]propanamido}-3,3-dimethylbutan oyl]-4-hydroxy-N- {[4-(4-methyl-l,3-thiazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide , 1-8. Yield: 40 mg, 40.7%; Appearance: white solid; *HNMR (400 MHz, DMSO-tL) 8 8.98 (s, 1H), 8.73 (s, 1H), 8.56 (t, J= 6.0 Hz, 1H), 8.21 (s, 1H), 7.95 - 7.87 (m, 3H), 7.65 (d, J= 8.2 Hz, 2H), 7.51 - 7.28 (m, 7H), 6.96 - 5.85 (m, 3H), 5.37 (s, 2H), 5.12 (s, 1H), 5.02 - 4.86 (m, 1H), 4.55 (d, J = 9.4 Hz, 1H), 4.46 - 4.40 (m, 2H), 4.35 (s, 1H), 4.21 (dd, J= 16.0, 5.6 Hz, 1H), 3.70 - 3.65 (m, 1H), 3.64 - 3.55 (m, 3H), 3.54 - 3.46 (m, 8H), 3.46 - 3.39 (m, 3H), 3.14 (s, 1H), 2.59 - 2.52 (m, 1H), 2.45 - 2.33 (m, 8H), 2.13 - 1.86 (m, 5H), 1.84 - 1.66 (m, 2H), 1.65 - 1.56 (m, 2H), 1.53 - 1.39 (m, 5H), 1.31 - 1.22 (m, 1H), 1.18 - 1.08 (m, 1H), 0.92 (d, J = 8.2 Hz, 9H). HPLC purity: 93.72%; LCMS Calculated for C60H78N10O9S: 1115.41; Observed: 1115.8, [M+H]+.Example 9. Synthesis of (2S,3aS,7aS)-l-{6-[(lS)-l-({4'-amino-[l,l'-biphenyl]-4- yl}formami do)ethyl]-2-(3-{2-[2-(2-{[(2S)-l-[(2S,4R)-4-hydroxy-2-({[4-(4-methyl-l,3- thiazol-5-yl)phenyl]methyl}carbamoyl)pyrrolidin-l-yl]-3,3-dimethyl-l-oxobutan-2- yl]carbamoyl}ethoxy)ethoxy]ethoxy}propyl)pyrimidin-4-yl}-N-methyl-octahydro-lH- indole-2-carboxamide, 1-9.Attorney Docket No. 2013075-00110Step-1. Synthesis of tert-butyl 3-{2-[2-(prop-2-yn- 1 -yloxy)ethoxy] ethoxyfpropanoate

[0380] To a mixture of 2-[2-(prop-2-yn-l-yloxy)ethoxy]ethan-l-ol (500 mg, 3.46 mmol), tertbutyl prop-2-enoate (531 mg, 4.15 mmol) in MeCN (15 mL ) was added Triton B ( 40% in H2O) (287 mg, 692 pmol) at rt. The reaction mixture was stirred at rt for 12 h. The reaction mixture was concentrated to give crude product, which was further purified by flash silica gel chromatography (DCM / MeOH = 20 / 1) to give tert-butyl 3-{2-[2-(prop-2-yn-l-yloxy)ethoxy]ethoxy}propanoate (560 mg, 2.05 mmol, 100% purity, 59% yield) as a colorless oil.Step-2. Synthesis of tert-butyl 3-(2-(2-((3-(4-((S)-l-(4'-((tert-butoxycarbonyl)amino)-[l,r- biphenyl]-4-carboxamido)ethyl)-6-((2S,3aS, 7aS)-2-(methylcarbamoyl)octahydro -IH-indol-l-yl) pyrimidin-2-yl)prop-2-yn-l-yl)oxy)ethoxy)ethoxy)propanoate

[0381] To a solution of tert-butyl (4'-(((6T)-l-(2-bromo-6-((2S,3a5,7a5T)-2- (methylcarbamoyl)octahydro-l / / -indol-l-yl)pyrimidin-4-yl)ethyl)carbamoyl)-[l,T-biphenyl]-4- yl)carbamate (100 mg, 147 pmol), tert-butyl 3-{2-[2-(prop-2-yn-l- yloxy)ethoxy] ethoxy J propanoat e (40.0 mg, 147 pmol), Cui (2.79 mg, 14.7 pmol), [PhiP^PdCh (20.6 mg, 29.4 pmol) in DMF (5 mL ) was added TEA (148 mg, 1.47 mmol) at rt under N2. The reaction mixture was stirred for 2 h at 80 °C under N2. The reaction mixture was added water (20 mL) and extracted with EA (30 mL X 3). The organic layer was dried over anhydrous sodium sulfate, fdtered, concentrated to give residue, which was purified by flash silica gel chromatography (DCM / MeOH = 20 / 1) to give tert-butyl 3-(2-(2-((3-(4-((5)-l-(4'-((tert- butoxycarbonyl)amino)-[l,r-biphenyl]-4-carboxamido)ethyl)-6-((21S',3a5',7a5) -2-(methylcarbamoyl)octahy dro- 1 / 7-indol- 1 -yl)pyrimidin-2-yl)prop-2-yn- 1 -yl)oxy)ethoxy)ethox y)propanoate (120 mg, 138 pmol, 95% purity, 94% yield) as a light yellow solid.Step-3. Synthesis of tert-butyl 3-(2-(2-(3-(4-((S)-l-(4'-((tert-butoxycarbonyl)amino)-fl,r- biphenyl]-4-carboxamido)ethyl)-6-((2S,3aS, 7 aS) -2 -(methylcarbamoyl) octahydro- IH-indol-l-yl) pyrimidin-2-yl)propoxy)ethoxy)ethoxy)propanoate

[0382] To a solution of tert-butyl 3-(2-(2-((3-(4-((5')-l-(4'-((tert-butoxycarbonyl)amino)-[l,l'- biphenyl]-4-carboxamido)ethyl)-6-((25,3aS',7aS)-2-(methylcarbamoyl)octahydro-l / / -indol-l- yl)pyrimidin-2-yl)prop-2-yn-l-yl)oxy)ethoxy)ethoxy)propanoate (120 mg, 138 pmol) in MeOHAttorney Docket No. 2013075-00110(15 mL ) was added Pd / C (30 mg ) at rt. The mixture solution was stirred at rt for 12 h under H2. The mixture solution was fdtered and concentrated to afford te / T-butyl 3-(2-(2-(3-(4-((5)-l-(4'- ((7er / -butoxycarbonyl)amino)-[l,T-biphenyl]-4-carboxamido)ethyl)-6-((25,3a5,7aS)-2- (methylcarbam oyl)octahydro- 1 / 7-indol- 1 -yl)pyrimidin-2-yl)propoxy)ethoxy)ethoxy)propanoate (89.0 mg, 101 pmol, 100% purity, 74% yield) as a light yellow solid.Step-4. Synthesis of 3-(2-(2-(3-(4-((S)-l-(4'-amino-[l,r-biphenyl]-4-carboxamido) ethyl)-6- ((2S,3aS, 7aS)-2-(methylcarbamoyl)oclahydro-lH-indol-l-yl)pyrimidin-2-yl)propoxy)elhoxy)elh oxy)propanoic acid

[0383] To a solution of tert-butyl 3-(2-(2-(3-(4-((5)-l-(4'-((tert-butoxycarbonyl)amino)-[l,T- biphenyl]-4-carboxamido)ethyl)-6-((2S',3aS,7aS)-2-(methylcarbamoyl)octahydro-l / 7-indol-l- yl)pyrimidin-2-yl)propoxy)ethoxy)ethoxy)propanoate (89 mg, 101 pmol) in DCM (5 mL ) was added TFA (1 mL, 101 pmol) at rt. The reaction mixture was stirred for 2 h at rt. The reaction mixture was concentrated to give 3-(2-(2-(3-(4-((5)-l-(4'-amino-[l,l'-biphenyl]-4- carboxamido)ethyl)-6-((25,3a5,7aS)-2-(methylcarbamoyl) octahydro- 1 / 7-indol-l -yl)pyrimidin-2- yl)propoxy)ethoxy)eth oxy)propanoic acid (72.0 mg, 100 pmol, 100% purity, 99% yield) as a light yellow oil.Step-5. Synthesis of (2S,3aS, 7aS)-l-{6-[(lS)-l-((4'-amino-[l,l'-biphenyl]-4-yl}formamido) ethyl ]-2-(3-{2-[ 2-( 2-{[ ( 2S)-l-[ < 2S, 4R)-4-hydroxy-2-( {[ 4-(4-methyl-l, 3-thiazol-5-yl)phenyl Jme thyl}carbamoyl)pyrrolidin-l-yl]-3, 3-dimethyl-l-oxobutan-2-yl]carbamoyl}ethoxy)ethoxy]ethox y}propyl)pyrimidin-4-yl}-N-methyl-octahydro-lH-indole-2-carboxamide

[0384] To a solution of 3-(2-(2-(3-(4-((5)-l-(4'-amino-[l,r-biphenyl]-4-carboxamido)ethyl)-6- ((2S,3a5,7aS)-2-(methylcarbamoyl)octahydro-l / 7-indol-l-yl)pyrimidin-2-yl) propoxy)ethoxy)ethoxy) propanoic acid (70 mg, 97.6 pmol), (25,4 R)-l-[(25)-2-amino-3,3- dimethylbutanoyl]-4-hydroxy-A-{[4-(4-methyl-l,3-thiazol-5-yl)phenyl]methyl}pyrrolidine-2- carboxamide (42.0 mg, 97.6 pmol), HATU (44.4 mg, 117 pmol) in DMF (2 mL ) was added DIPEA (37.7 mg, 292 pmol) at rt. The reaction mixture was stirred for 2 h at rt. The reaction mixture was added water (20 mL) and extracted with EA (30 mL X 3). The organic layer was washed with water (20 mL X 2), dried over anhydrous sodium sulfate, filtered, concentrated to give residue, which was purified by flash silica gel chromatography (DCM / MeOH = 20 / 1) to giveAttorney Docket No. 2013075-00110 crude product, which was further purified by Prep-HPLC (ACN / water / 0.1 % NH40H) to give (25,3a5',7a5)-l-{6-[(15)-l-({4'-amino-[l,r-biphenyl]-4-yl}formamido)ethyl]-2-(3-{2-[2-(2- { [(25)- 1 -[(25,4A)-4-hydroxy-2-( { [4-(4-m ethyl- 1 ,3 -thiazol-5-yl)phenyl]methyl } carbarn oyl)pyrrolidin- 1 -y 1 ] -3 ,3 -dimethyl- 1 -oxobutan-2-yl] carbamoyl } ethoxy)ethoxy] ethoxy }propyl)pyrimidin-4-yl}-jV-methyl-octahydro-l / / -indole-2-carboxamide, 1-9. Yield: 55.2 mg, 50%; Appearance: White solid; 'H NMR (400 MHz, DMSO-rC) 6 8.98 (s, 1H), 8.62 - 8.55 (m, 2H), 7.93 - 7.87 (m, 4H), 7.64 (d, J = 8.4 Hz, 2H), 7.46 - 7.37 (m, 6H), 6.65 (d, J = 8.4 Hz, 2H), 6.36 (s, 1H), 5.34 (s, 2H), 5.12 (d, J= 3.6 Hz, 1H), 4.94 - 4.87 (m, 1H), 4.55 (d, J = 9.2 Hz, 2H), 4.46 - 4.41 (m, 2H), 4.35 (s, 1H), 4.22 (d, J = 15.8, 5.6 Hz, 1H), 3.69 - 3.56 (m, 4H), 3.51 - 3.41 (m, 11H), 2.64 - 2.54 (m, 6H), 2.44 (s, 3H), 2.38 - 2.32 (m, 2H), 2.06 - 2.00 (m, 2H), 1.96 - 1.80 (m, 5H), 1.72 - 1.57 (m, 3H), 1.52 - 1.35 (m, 6H), 1.30 - 1.20 (m, 1H), 1.17 - 1.05 (m, 1H), 0.93 (s, 9H); HPLC purity: 99%; LCMS Calculated for C6iH8oNio09S: 1128.58; Observed: 1130.0 [M+HT.Example 10. Synthesis of (2S,3aS,7aS)-l-(2-(3-(2-(2-(4-((2-(2,6-dioxopiperidin-3-yl)-l,3- dioxoisoindolin-4-yl)oxy)piperidin-l-yl)ethoxy)ethoxy)propyl)-6-((S)-l-(4- inorpholinobenzamido)ethyl)pyrimidin-4-yl)-N-methyloctahydro-lH-indole-2-carboxamide,1-10.Attorney Docket No. 2013075-00110Step-1. Synthesis of tert-butyl 4-{[2-(2, 6-di oxopiper idin- 3 -yl)-l , 3-dioxo-2, 3-dihydro-lH-isoindol- 4-yl]oxy}piperidine-l -carboxylate

[0385] A mixture of 2-(2,6-dioxopiperidin-3-yl)-4-hydroxy-2,3-dihydro-lH-isoindole-l,3- dione (2.00 g, 7.29 mmol), CS2CO3 (4.71 g, 14.5 mmol) and Zc'rt-butyl 4-bromopiperidine-l- carboxylate (3.83 g, 14.5 mmol) in DMF (20 mL) was allowed to stirred at 80°C for 16.0 hours. The reaction was quenched by the addition of water (50 mL) at room temperature, and then extracted with ethyl acetate (50 mLx3). The combined organic phase was washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (TFA buffer) to afford te / 7-butyl 4- {[2-(2, 6-di oxopiperi din-3 -yl)- 1,3- di oxo-2, 3-dihydro-lH-isoindol-4-yl]oxy [piperidine- 1 -carboxylate (90.0 mg, 196 pmol, 85% purity, 2.7% yield) as a yellow oil.Step-2. Synthesis of 2-(2, 6-dioxopiperidin-3-yl)-4-(piperidin-4-yloxy)-2, 3-dihydro-lH-isoindole- 1, 3-dione

[0386] A solution of tert-butyl 4-{[2-(2,6-dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihydro-lH- isoindol-4-yl]oxy}piperidine-l-carboxylate (85.0 mg, 185 pmol) in TFA : DCM (1 : 1, 2.0 mL) was stirred for 1.0 hour at room temperature. The resulting mixture was concentrated in vacuum to afford 2-(2,6-dioxopiperidin-3-yl)-4-(piperidin-4-yloxy)-2,3-dihydro-lH-isoindole-l, 3-dione (60.0 mg, crude) as a brown oil, which was used for next step directly.Step-3. Synthesis of (2S,3aS, 7aS)-l-(2-(3-(2-(2-(4-((2-(2,6-dioxopiperidin-3-yl)-l,3- dioxoisoindolin-4-yl)oxy)piperidin-l-yl)ethoxy)ethoxy)prop-l-yn-l-yl)-6-((S)-l-(4- morpholinobenzamido)ethyl)pyrimidin-4-yl)-N-methyloctahydro-lH-indole-2-carboxamide

[0387] A mixture of 2-(2,6-dioxopiperidin-3-yl)-4-(piperidin-4-yloxy)-2,3-dihydro-lH- isoindole-1, 3-dione (40.0 mg, 111 pmol), 2-(2-((3-(4-((2S,3aS,7aS)-2- (methylcarbamoyl)octahydro- IH-indoL 1 -yl)-6-((S)- 1 -(4-morpholinobenzamido)ethyl)pyrimidin- 2-yl)prop-2-yn-l-yl)oxy)ethoxy)ethyl methanesulfonate (118 mg, 166 pmol) and Nal (33.3 mg, 222 pmol), K2CO3 (30.6 mg, 222 pmol) in DMF (1 mL) at room temperature. The reaction mixture was stirred for 16.0 hours at 100°C. The mixture was allowed to cool down to room temperature, quenched with water (10 mL) and extracted with ethyl acetate (10 mLx3). The combined organicAttomey Docket No. 2013075-00110 phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (TFA buffer) to give (2S,3aS,7aS)-l-(2-(3-(2-(2-(4-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)oxy)piperidin- 1 -yl)ethoxy)ethoxy)prop- 1 -yn- 1 -yl)-6-((S)-l -(4- morpholinobenzamido)ethyl)pyrimidin-4-yl)-N-methyloctahydro-lH-indole-2-carboxamide (30.0 mg, 31.2 pmol, 85.0% purity, 28.3% yield) as a yellow solid.Step-4. Synthesis of 2S,3aS, 7aS)-l-(2-(3-(2-(2-(4-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindo lin-4-yl)oxy)piperidin-l-yl)ethoxy)ethoxy)propyl)-6-((S)-l-(4-morpholinobenzamido)ethyl)pyrimi din-4-yl)-N-methyloctahydro-lH-indole-2-carboxamide, 1-10

[0388] Into a 50 mL round-bottom flask, was placed (2S,3aS,7aS)-l-(2-(3-(2-(2-(4-((2-(2,6- dioxopiperidin-3-yl)- 1 ,3-dioxoisoindolin-4-yl)oxy)piperidin- 1 -yl)ethoxy)ethoxy)prop- 1 -yn- 1 - yl)-6-((S)-l-(4-morpholinobenzamido)ethyl)pyrimidin-4-yl)-N-methyloctahydro-lH-indole-2- carboxamide (25.0 mg, 25.6 pmol) in MeOH (1.0 mL) was added Raney-Ni (10.9 mg, 128 pmol) at room temperature under nitrogen atmosphere and then the reaction mixture was degassed and purged with hydrogen for three times. The resulting reaction mixture was stirred for 2.0 hours at room temperature under hydrogen atmosphere (1 atm). The reaction mixture was filtered and the filtrate was concentrated in vacuum. The residue was purified by prep-HPLC (FA buffer) to afford (2S,3aS,7aS)-l-(2-(3-(2-(2-(4-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)oxy)piperidin- 1 -yl)ethoxy)ethoxy)propyl)-6-((S)- 1 -(4-morpholinobenzamido)ethyl)pyrimidin- 4-yl)-N-methyloctahydro-lH-indole-2-carboxamide, 1-10. Yield: 5.00 mg, 19.9%; Appearance: White solid; 'HNMR (400 MHz, DMSO-< / 6) 8.42 - 8.35 (m, 4H), 7.80 - 7.72 (m, 4H), 7.51 (d, J = 8.6 Hz, 1H), 7.42 (d, J= 7.2 Hz, 1H), 6.95 (d, J= 8.6 Hz, 2H), 5.13 - 5.02 (m, 1H), 4.90 - 4.80 (m, 1H), 4.71 - 4.66 (m, 1H), 4.28 - 4.21 (m, 1H), 3.75 - 3.72 (m, 4H), 3.54 - 3.43 (m, 6H), 3.42 - 3.37 (m, 2H), 3.22 - 3.19 (m, 4H), 2.87 - 2.78 (m, 1H), 2.73 - 2.66 (m, 2H), 2.63 - 2.54 (m, 6H), 2.44 - 2.14 (m, 6H), 2.05 - 1.78 (m, 10H), 1.78 - 1.51 (m, 5H), 1.47 - 1.35 (m, 4H). HPLC purity: 73 7%; LCMS Calculated for C52H67N9O10: 977 50; Observed: 978 4 [M+H]+Example 11. Synthesis of (2S,3aS,7aS)-l-{2-[3-(2-{4-[(4-{[2-(2,6-dioxopiperidin-3-yl)-l,3- dioxo-2,3-dihydro-lH-isoindol-4-yl]amino}piperidin-l-yl)methyl]piperidin-l-Attomey Docket No. 2013075-00110 yl}ethoxy)propyl]-6-[(lS)-l-{[4-(morpholin-4-yl)phenyl]formamido}ethyl]pyrimidin-4-yl}- N-methyl-octahydro-lH-indole-2-carboxamide, 1-11.Step-1. Synthesis of (2S,3aS, 7aS)-l-{2-[3-(2-{4-[(4-{[2-(2,6-dioxopiperidin-3-yl)-l,3-dioxo-2,3- dihydro-lH-isoindol-4-yl]amino}piperidin-l-yl)methyl]piperidin-l-yl}etho xy)prop-l-yn-l-yl]-6- [(1 S)-l-{[4-(morpholin-4-yl)phenyl ]formamido}ethyl Jpyrimidi n-4-yl}-N-methyl-octahydro-lH- indole-2-carboxamide.

[0389] A mixture of 2-[(3-{4-[(2S,3aS,7aS)-2-(methylcarbamoyl)-octahydro-lH-indol-l-yl]- 6-[( 1 S)- 1 - { [4-(morpholin-4-yl)phenyl]formamido } ethyl]pyrimidin-2-yl } prop-2-yn- 1 - yl)oxy]ethyl methanesulfonate (100 mg, 149 pmol), 2-(2,6-dioxopiperidin-3-yl)-4-({ 1- [(piperidin-4-yl)methyl]piperidin-4-yl}amino)-2,3-dihydro-lH-isoindole-l, 3-dione (80.7 mg, 178 pmol) and K2CO3 (70.6 mg, 447 pmol) in DMF (1 mL) was stirred at 80°C for 6.0 hours. The resulting mixture was quenched with water (5 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (TFA buffer) to give (2S,3aS,7aS)-l-{2-[3-(2-{4-[(4-{ [2-(2,6-dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihydro-lH- isoindol-4-yl]amino}piperidin-l-yl)methyl]piperidin-l-yl}ethoxy)prop-l-yn-l-yl]-6-[(lS)-l-{[4- (morpholin-4-yl)phenyl]formamido}ethyl]pyrimidin-4-yl}-N-methyl -octahydro- lH-indole-2- carboxamide (40.0 mg, 38.9 pmol, 77.9% purity, 21 .2% yield) as yellow solid.Step-2. Synthesis of (2S,3aS, 7aS)-l-{2-[3-(2-{4-[(4-{[2-(2,6-dioxopiperidin-3-yl)-l,3-dioxo-2,3- dihydro-lH-isoindol-4-yl]amino}piperidin-l-yl)methyl]piperidin-l-yl}etho xy)propyl]-6-[ ( 1 S)-l-Attorney Docket No. 2013075-00110{[4-(morpholm-4-yl)phenyl]formamido}ethyl]pyrimidin-4-yl}-N-methyl-octahydro-lH-indole-2- carboxamide, 1-11

[0390] Into a 50 mL round-bottom flask, was placed (2S,3aS,7aS)-l-{2-[3-(2-{4-[(4-{[2-(2,6- dioxopiperidin-3-yl)-l,3-di oxo-2, 3-dihydro-lH-isoindol-4-yl]amino}piperidin-l-yl)m ethyl]piperidin- 1 -yl } ethoxy )prop- 1 -yn- 1 -yl]-6-[(l S)- 1 -{ [4-(morpholin-4-yl)phenyl]fo rmamido}ethyl]pyrimidin-4-yl}-N-methyl-octahydro-lH-indole-2-carboxamide (40.0 mg, 38.9 pmol) in MeOH (5 mL) was added Pd / C (10 mg, 10%) at room temperature under nitrogen atmosphere and then the reaction mixture was degassed and purged with hydrogen for three times. The resulting reaction mixture was stirred for 3 hours under hydrogen atmosphere. The reaction mixture was filtered and the filtrate was concentrated, and the residue was purified by prep-HPLC (NH4HCO3 buffer) to give (2S,3aS,7aS)-l-{2-[3-(2-{4-[(4-{[2-(2,6-dioxopiperidin-3-yl)-l,3- di oxo-2, 3-dihydro-lH-isoindol-4-yl]amino}piperi din- l-yl)methyl]piperi din- 1- yl}ethoxy)propyl]-6-[(lS) -l-{[4-(morpholin-4-yl)phenyl]formamido}ethyl]pyrimidin-4-yl}-N- methyl-octahydr o-lH-indole-2-carboxamide, 1-11. Yield: 5.0 mg, 12.5%; Appearance: yellow solid; 'H NMR (300 MHz, DMSO-J6) 8 8.42 - 8.35 (m, 1H), 7.90 - 7.71 (m, 3H), 7.71 - 7.54 (m, 1H), 7.23 - 7.18 (m, 1H), 7.10 - 7.08 (m, 1H), 6.98 - 6.92 (m, 2H), 6.31 - 6.21 (m, 1H), 5.19 - 5.00 (m, 1H), 4.98 - 4.68 (m, 2H), 4.41 - 4.15 (m, 2H), 3.71 - 3.32 (m, 10H), 3.32 - 3.10 (m, 6H), 3.01 - 2.82 (m, 2H), 2.80 - 2.72 (m, 2H), 2.61 - 2.59 (m, 4H), 2.30 - 2.25 (m, 1H), 2.19 - 2.03 (m, 5H), 2.02 - 1.81 (m, 1 1H), 1.80 - 1.63 (m, 6H), 1.50 - 1.40 (m, 3H), 1.42 - 1.30 (m, 6H), 1.31- 1.27 (m, 2H), 1.11 - 1.25 (m, 2H). HPLC purity: 93.5%; LCMS Calculated for C56H75N11O8: 1029.64; Observed: 1030.9 [M+H]+.Example 12. Synthesis of (2S,3aS,7aS)-l-(2-(3-(2-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-l,3- dioxoisoindolin-5-yl)piperazin-l-yl)ethoxy)ethoxy)propyl)-6-((S)-l-(4- morpholinobenzamido)ethyl)pyrimidin-4-yl)-N-methyloctahydro-lH-indole-2- carboxamide, 1-12.Attorney Docket No. 2013075-00110Step-1. Synthesis of (2S,3aS, 7aS)-l-(2-(3-(2-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindol in-5-yl)piperazin-l-yl)ethoxy)ethoxy)propyl)-6-((S)-l-(4-morpholinobenzamido)ethyl)pyrimidin- 4-yl)-N-methyloctahydro-lH-indole-2-carboxamide, 1-12:

[0391] Into a 50 mL round-bottom flask, was placed (2S,3aS,7aS)-l-(2-(3-(2-(2-(4-(2-(2,6- dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)piperazin-l-yl)ethoxy)ethoxy)prop-l-yn-l-yl)-6- ((S)-l-(4-morpholinobenzamido)ethyl)pyrimidin-4-yl)-N-methyloctahydro-lH-indole-2- carboxamide (80.0 mg, 83.4 pmol) in MeOH (1.6 mL) at room temperature. The reaction mixture was added Raney -Ni (28.5 mg, 333 pmol) at room temperature and then the reaction mixture was degassed and purged with hydrogen for three times. The resulting reaction mixture was stirred for 0.5 hour at room temperature under hydrogen atmosphere. The reaction mixture was filtered and the filtrate was concentrated in vacuum, and the residue was purified by Prep-HPLC with the following conditions (Column, Bridge Prep Cl 8 OBD Column, 19*150 mm, 5um; mobile phase, water (10 mol / L FA) and MeCN (35% up to 75% in 8 min); Detector, 220 nm; flow rate: 20 mL / min) to afford (2S,3aS,7aS)-l-(2-(3-(2-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-l,3- dioxoisoindolin-5-yl)piperazin-l-yl)ethoxy)ethoxy)propyl)-6-((S)-l-(4- morpholinobenzamido)ethyl)pyrimidin-4-yl)-N-methyloctahydro-lH-indole-2-carboxamide, 1-12. Yield: 28.0 mg, 34.8%; Appearance: Yellow solid; ’H NMR (400 MHz, DMSO-r / r,) 8 11 .02 (brs, 1H), 8.35 (d, J= 7.8 Hz, 1H), 7.78 (d, J = 8.4 Hz, 3H), 7.66 (d, J = 8.5 Hz, 1H), 7.36 - 7.29 (m, 1H), 7.26 - 7.19 (m, 1H), 6.97 (d, J= 8.5 Hz, 2H), 6.42 (brs, 1H), 5.11 - 5.02 (m, 1H), 4.92 - 4.80 (m, 1H), 4.26 (brs, 1H), 3.80 - 3.70 (m, 5H), 3.59 - 3.46 (m, 10H), 3.21 (t, J= 4.8 Hz, 5H), 2.95 - 2.81 (m, 1H), 2.62 - 2.52 (m, 12H), 2.30 - 2.10 (m, 1H), 2.05 - 1.95 (m, 2H), 1.93 - 1.86 (m, 4H), 1.73 - 1.53 (m, 3H), 1.52 - 1.37 (m, 5H), 1.33 - 1.18 (m, 4H). HPLC purity: 98.9%; LCMS Calculated for C51H66N10O9: 962.50; Observed: 963.4 [M+H]+.Example 13. Synthesis of 2-{5-cyclopropyl-4-[(2S)-2-methyl-4-(propane-2- sulfinyl)piperazin-l-yl]pyrrolo[2,l-f|[l,2,4]triazin-7-yl}pyridine-4-carbonitrile , 1-13.Attorney Docket No. 2013075-00110Step-1. Synthesis of (2S,3aS, 7aS)-l-[2-(3-{4-[(4-{[2-(2,6-dioxopiperidin-3-yl)-l,3-dioxo-2,3- dihydro-lH-isoindol-4-yl ]amino}piperidin-l-yl)methyl ]piperidin-l-yl}propyl)-6-[ ( 1 S)-l-{[ 4- (morpholin-4-yl)phenyl]formamido}ethyl]pyrimidin-4-yl]-N-methyl-octahydro-lH-indole-2- carboxamide , 1-13

[0392] Into a 50 mL round-bottom flask, was placed (2S,3aS,7aS)-l-[2-(3-{4-[(4-{ [2-(2,6- dioxopiperidin-3-yl)-l,3-di oxo-2, 3-dihydro-lH-isoindol-4-yl]amino}piperidin- 1- yl)methyl]piperidin- 1 -yl (prop- 1 -yn- 1 -y l)-6- [( 1 S)- 1 -{ [4-(morpholin-4- yl)phenyl]formamido}ethyl]pyrimidin-4-yl]-N-methyl-octahydro-lH-indole-2- carboxamide (90.0 mg, 91.6 pmol) in MeOH (3mL) was added Raney-Ni (25.0 mg, 723 pmol) at room temperature under nitrogen atmosphere and then the reaction mixture was degassed and purged with hydrogen for three times. The resulting reaction mixture was stirred for 12 hours under hydrogen atmosphere (1 atm). The reaction mixture was filtered and the filtrate was concentrated in vacuum. The residue was purified by prep-HPLC (FA buffer) to afford (2S,3aS,7aS)-l-[2-(3- {4-[(4-{[2-(2,6-dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihydro-lH-isoindol-4-yl]amino}piperidin-l- yl)methyl]piperidin- 1 -yl }propyl)-6-[( 1 S)- 1 -{ [4-(morpholin-4- yl)phenyl]formamido}ethyl]pyrimidin-4-yl]-N-methyl-octahydro-lH-indole-2-carboxamide, I- 13. Yield: 10.0 mg, 5.6%; Appearance: yellow solid; ’HNMR (300 MHz, DMSO-rf6) 8 11.10 (s, 1H), 9.49 - 9.21 (m, 1H), 8.65 - 8.37 (m, 1H), 7.78 (d, J= 8.5 Hz, 2H), 7.63 (t, J= 7.8 Hz, 1H), 7.24 - 7.18 (m, 1H), 7.10 (d, J = 7.0 Hz, 1H), 6.97 (d, J= 8.6 Hz, 2H), 6.59 - 6.37 (m, 1H), 6.29 - 6.21 (m, 1H), 5.17 - 5.02 (m, 1H), 4.98 - 4.84 (m, 1H), 4.45 - 4.23 (m, 1H), 3.89 - 3.78 (m, 1H), 3.77 - 3.67 (m, 4H), 3.68 - 3.55 (m, 2H), 3.55 - 3.40 (m, 10H), 3.24 - 3.16 (m, 5H), 3.15 - 2.99 (m, 4H), 2.99 - 2.80 (m, 3H), 2.70 - 2.68 (m, 2H),2.64 - 2.57 (m, 2H), 2.30 - 1.98 (m, 10H), 1.87 - 1.55 (m, 6H), 1.51 - 1.36 (m, 5H), 1.34 - 1.03 (m, 3H). HPLC purity: 95.1%; LCMS Calculated for C54H71N11O7: 985 55; Observed: 986 6 [M+H]+Attorney Docket No. 2013075-00110Example 14. Synthesis of (2S,3aS,7aS)-l-[2-(3-{2-[2-(4-{[2-(2,6-dioxopiperidin-3-yl)-l,3- dioxo-2,3-dihydro-lH-isoindol-4-yl] amino} piperidin-l-yl)ethoxy]ethoxy}prop-l-yn-l-yl)-6- [(lS)-l-{[4-(morpholin-4-yl)phenyl]formamido}ethyl]pyrimidin-4-yl]-N-methyl-octahydro- lH-indole-2-carboxamide, 1-14.Step-1. Synthesis of 2-(2, 6-dioxopiperidin-3-yl)-4-[ ( 1 -{2-[ 2-(prop-2-yn-l-yloxy) ethoxy] thyl }piperidin-4-yl)amino ]-2, 3-dihydro-lH-isoindole-l, 3-dione, INT-D.

[0393] Into a 8mL vial, was placed 2-(2,6-dioxopiperidin-3-yl)-4-fluoro-2,3-dihydro-lH- isoindole-1, 3-dione (300 mg, 1.08 mmol), l-{2-[2-(prop-2-yn-l-yloxy)ethoxy] ethyl}p iperidin- 4-amine (320 mg, 1.30 mmol), DIEA (416 mg, 3.23 mmol) and DMF (3 mb) at room temperature. The reaction mixture was stirred for 3.0 hours at 170°C in microwave reactivity meter. The mixture was allowed to cool down to room temperature and purified by prep-HPLC (NH3.H2O buffer) to give 2-(2,6-dioxopiperidin-3-yl)-4-[(l-{2-[2-(prop-2-yn-l-yloxy)ethoxy]ethyl}piperi din-4- yl)amino]-2,3-dihydro-lH-isoindole-l, 3-dione (150 mg, 310 pmol, 79.8% purity, 28.7% yield) as yellow solid.Step-2. Synthesis of (2S,3aS, 7aS)-J-[2-(3-{2-[2-(4-{[2-(2,6-dioxopiperidin-3-yl)-l,3-dioxo-2,3- dih ydro-lH-isoindol-4-y / ]amino}piperidin-l-yl)ethoxy]ethoxy}prop-l-yn-l-yl)-6-[(lS)-l-{[4- (morpholin-4-yl)phenyl]formamido}ethyl]pyrimidin-4-yl]-N-methyl-octahydro -lH-indole-2- carboxamide. 1-14.Attorney Docket No. 2013075-00110

[0394] To a solution of 2-(2,6-dioxopiperidin-3-yl)-4-[(l-{2-[2-(prop-2-yn-l-yloxy)ethoxy] ethyl}piperidin-4-yl)amino]-2,3-dihydro-lHisoindole-l, 3-dione (83.9 mg, 174 pmol), (2S,3aS,7aS)-l-{2-bromo-6-[(lS)-l-{[4-(morpholin-4-yl)phenyl]formamido}ethyl]p yrimidin-4- yl}-N-methyl-octahydro-lH-indole-2-carboxamide (50.0 mg, 87.4 pmol), Cui (3.30 mg, 17.4 pmol), DIEA (33.7 mg, 262 pmol) and Pd(PPh3)2Ch (6.11 mg, 8.74 pmol) in DMF (1 mL) at room temperature. After stirring for 2.0 hours at 80°C under nitrogen atmosphere, the resulting mixture was concentrated in vacuum. The residue was purified by prep-HPLC (NH3 H2O buffer) to afford (2S,3aS,7aS)-l-[2-(3-{2-[2-(4-{[2-(2,6-dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihydro-lH-isoindol- 4-yl]amino}piperidin-l-yl)ethoxy]ethox y}prop-l-yn-l-yl)-6-[(lS)-l-{[4-(morpholin-4- yl)phenyl]formamido}ethyl]pyrimidin-4-yl]-N-m ethyl -octahydro-lH-indole-2-carboxamide, I- 14. Yield: 25.0 mg, 40.6%. Appearance: Yellow solid; ’H NMR (300 MHz, DMSO-r / e) 8 11.05 (brs, 1H), 8.45 - 8.36 (m, 1H), 7.91 - 7.65 (m, 2H), 7.61 - 7.57 (m, 1H), 7.23 - 7.13 (m, 1H), 7.04 - 7.01 (m, 1H), 7.00 - 6.92 (m, 2H), 6.42 - 6.15 (m, 1H), 5.15 - 4.98 (m, 1H), 4.97 - 4.78 (m, 1H), 4.40 - 4.20 (m, 1H), 3.90 - 3.65 (m, 5H), 3.62 - 3.49 (m, 6H), 3.25 - 3.15 (m, 5H), 2.95 - 2.71 (m, 3H), 2.69 - 2.58 (m, 5H), 2.30 - 2.18 (m, 4H), 2.12 - 1.98 (m, 2H), 1.95 - 1.80 (m, 7H), 1.70 - 1.36 (m, 12H). HPLC purity: 93.9%; LCMS Calculated for C52H64N10O9: 972.51;Observed: 973.5 [M+H]+.Example 15. Synthesis of (2S,3aS,7aS)-l-(2-{3-[2-(4-{[2-(2,6-dioxopiperidin-3-yl)-l,3-dioxo- 2,3-dihydro-lH-isoindol-4-yl]amino}piperidin-l-yl)ethoxy]prop-l-yn-l-yl}-6-[(lS)-l-{[4- (morpholin-4-yl)phenyl]formamido}ethyl]pyrimidin-4-yl)-N-methyl-octah ydro-lH-indole- 2-carboxamide, 1-15.Step-1. Synthesis of (2S,3aS, 7aS)-l-(2-{3-[2-(4-{[2-(2,6-dioxopiperidm-3-yl)-l,3-dioxo-2,3- dihydro-lH-isoindol-4-yl]amino}piperidin-l-yl)ethoxy]prop-l-yn-l-yl}-6-[(lS)-l-{[4- (morpholin-4-yl)phenyl]formamido}ethyl]pyrimidin-4-yl)-N-methyl-octa hydro- lH-indole-2- carboxamide, 1-15Attorney Docket No. 2013075-00110

[0395] A mixture of 2-[(3-{4-[(2S,3aS,7aS)-2-(methylcarbamoyl)-octahydro-lH-indol-l -yl]- 6-[( 1 S)- 1 -{ [4-(morpholin-4-yl)phenyl]formamido } ethyl]pyrimidin-2-yl } prop-2-yn- 1 - yl)oxy]ethyl methanesulfonate (150 mg, 224 pmol), 2-(2,6-dioxopiperidin-3-yl)-4-[(piperidin-4- yl)amino]-2,3-dihydro-lH-isoindole-l, 3-dione (95.5 mg, 268 pmol) and DIEA (86.6 mg, 672 pmol) in DMF (2.0 mL) at room temperature. The reaction mixture was stirred for 12.0 hours at 100°C. The resulting mixture was concentrated in vacuum, the residue was purified by prep-HPLC (NH3.H2O buffer) to give (2S,3aS,7aS)-l-(2-{3-[2-(4-{[2-(2,6-dioxopiperidin-3-yl)-l,3-dioxo- 2,3-dihydro-lH-isoindol-4-yl]amino}piperidin-l-yl)ethoxy]prop-l-yn-l-yl}-6-[(lS)-l-{[4- (morpholin-4-yl)phenyl]formamido}ethyl]pyrimidin-4-yl)-N-methyl-octahydro-lH-indole-2- carboxamide, 1-15. Yield: 10.0 mg, 4.80%. Appearance: Yellow solid;1H NMR (400 MHz, DMSO-(fc) 8 11.51 - 10.25 (brs, 1H), 8.80 - 8.21 (m, 1H), 8.02 - 7.64 (m, 2H), 7.30 - 7.13 (m, 1H), 6.91 - 7.08 (m, 2H), 6.57 - 6.49 (m, 2H), 5.31 - 4.85 (m, 2H), 4.52 - 4.21 (m, 2H), 4.28 - 3.81 (m, 4H), 3.71 - 3.39 (m, 2H), 3.30 - 3.19 (m, 1H), 3.18 - 3.02 (m, 2H), 2.99 - 2.82 (m, 1H), 2.73 - 2.62 (m, 2H), 2.54 - 2.53 (m, 2H), 2.49 - 2.42 (m, 8H), 2.38 - 2.27 (m, 9H), 2.24 - 1.98 (m, 2H), 1.91 - 1.55 (m, 4H), 1.49 - 1.30 (m, 4H), 1.24 - 1.08 (m, 3H). HPLC purity: 95.8%;LCMS Calculated for CsoHeoNioOs: 928 54; Observed: 9294[M+H]+Example 16. Synthesis of (2S,3aS,7aS)-N-methyl-l-[2-(3-{2-[2-(4-{[2-(l-methyl-2,6- dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihydrolH-isoindol-4-yl]amino}piperidin-l- yl)ethoxy]ethoxy}propyl)-6-[(lS)-l-{[4-(morpholin-4- yl)phenyl]formamido}ethyl]pyrimidin-4-yl]-octahydro-lH-indole-2-carboxamide, 1-16.Attorney Docket No. 2013075-00110Step-1. Synthesis of 4-fluoro-2-(l-methyl-2, 6-dioxopiperidin-3-yl)-2,3-dihydro-lH-isoindole- 1,3- dione.

[0396] A mixture of 2-(2,6-dioxopiperidin-3-yl)-4-fluoro-2,3-dihydro-lH-isoindole-l,3-dione (500 mg, 1.81 mmol) and K2CO3 (678.0 mg, 5.43 mmol) in DMF (5.0 mL) at room temperature, to above mixture was added Mel (2.75 g, 7.24 mmol) at room temperature. The mixture was stirred for 12.0 hours at room temperature, quenched with water (5 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (NH3.H2O buffer) to give 4-fluoro-2-(l-methyl-2,6-dioxopiperidin-3-yl)-2,3-dihydro-lH- isoindole-1, 3-dione (400 mg, 1.37 mmol, 79.2% purity, 76.1% yield) as white solid.Step-2. Synthesis of tert-butyl 2-(l-methyl-2,6-dioxopipe ridin-3-yl)-4-[(l-{2-[2-(prop-2-yn-l- yloxy)ethoxy ] ethyl }piperidin-4-yl)amino ]-2, 3-dihydro-lHisoindole-l , 3 -dione.

[0397] Into a 8 mL vial, was placed 4-fluoro-2-(l-methyl-2,6-dioxopiperidin-3-yl)-2,3-dihydr o-lH-isoindole-1, 3-dione (400 mg, 1.37 mmol), DIEA (530 mg, 4.11 mmol) and l-{2-[2-(prop-2- yn-l-yloxy)ethoxy]ethyl}piperidin-4-amine (371 mg, 1.64 mmol) in DMF (5.0 mL) at room temperature. The reaction mixture was stirred for 3.0 hours at 170 °C in microwave reactivityAttorney Docket No. 2013075-00110 meter. The mixture was allowed to cool down to room temperature, quenched with water (5 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (NH3.H2O buffer) to give tert-butyl 2-(l-methyl-2,6-dioxopiperidin- 3-yl)-4-[(l-{2-[2-(prop-2-yn-l-yloxy)ethoxy]ethyl}piperidin-4-yl)amino]-2,3-dihydro- IHisoindole-l, 3-dione (200 mg, 402 pmol, 85.3% purity, 29.4% yield) as yellow solid.Step-3. Synthesis of (2S,3aS, 7aS)-N-methyl-l-[2-(3-{2-[2-(4-{[2-(l-methyl-2,6-di oxopiper idin- 3- yl)-l, 3-dioxo-2, 3-dihydro-lHisoindol-4-yl ]amino}piper idin- 1-yl) etho xy]ethoxy}prop-l-yn-l-yl)~ 6-[ (lS)-l-{[ 4-(morpholin-4-yl)phenyl ]formamido}ethyl ]p yrimidin-4-yl ] -octahydro- lHindole-2- carboxamide.

[0398] To a mixture of 2-(l-methyl-2,6-dioxopiperidin-3-yl)-4-[(l-{2-[2-(prop-2-yn-l-ylo xy)ethoxy]ethyl}piperidin-4-yl)amino]-2,3-dihydrolH-isoindole-l, 3-dione (200 mg, 402 pmol) and (2S,3aS,7aS)-l-[2-bromo-6-[(lS)-l-{[4-(morpholin-4- yl)phenyl]formamido}ethyl]pyrimidin-4-yl}-N-methyl-octahydro-lH-indole-2-carboxamide (275.0 mg, 482 pmol) in DMF (2.0 mL) was added DIEA (154 mg, 1.20 mmol), Cui (15.2 mg, 80.4 pmol) and Pd(PPh3)2Ch (28.1 mg, 40.2 pmol) at room temperature. After stirring for 2.0 hours at 80 °C under nitrogen atmosphere, the resulting mixture was quenched with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by silica gel column chromatography, eluted with ethyl acetate / petroleum ether (0- 100%, 15 min) to afford (2S,3aS,7aS)-N-methyl-l-[2-(3-{2-[2-(4-{[2-(l-methyl-2,6- dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihydro-lHisoindol-4-yl]amino}piperidin-l- yl)ethoxy] ethoxy } prop- 1 -yn- 1 -y l)-6 - [( 1 S)- 1 -{ [4-(morpholin-4- yl)phenyl]formamido}ethyl]pyrimidin-4-yl]-octahydro-lHindole-2-carboxamide (100 mg, 101 pmol, 89.5% purity, 25.2% yield) as a yellow solid.Step-4. Synthesis of(2S,3aS, 7aS)-N-methyl-l-[2-(3-{2-[2-(4-{[2-(l-methyl-2,6-dioxo piperidin-3- yl)-l,3-dioxo-2,3-dihydrolH-isoindol-4-yl]amino}piperidin-l-yl)ethoxy]e thoxy}propyl)-6-[( 1 S)- l-{[ 4-(morpholin-4-yl)phenyl ]formamido}ethyl Jpyramid in-4-yl / -octahydro- lH-indole-2- carboxamide, 1-16.Attorney Docket No. 2013075-00110

[0399] Into a 50 mL round-bottom flask, was placed (2S,3aS,7aS)-N-methyl-l -[2-(3-{2-[2-(4- {[2-(l-methyl-2,6-dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihydro-lH-isoindol-4-yl]amin o}piperidin- 1 -yl)ethoxy ]ethoxy [prop- 1 -yn- 1 -yl)-6-[( 1 S)- 1 - { [4-(morpholin-4-yl)phen yl]formamido}ethyl]pyrimidin-4-yl]-octahydro-lH-indole-2-carboxamide (100 mg, 101 pmol) in MeOH (2.0 mL) was added Pd / C (10 mg, 10%) at room temper under nitrogen atmosphere and then the reaction mixture was degassed and purged with hydrogen for three times. The resulting reaction mixture was stirred for 2.0 hours under hydrogen atmosphere. The reaction mixture was filtered and the filtrate was concentrated in vacuum. The residue was purified by prep-HPLC (NH3 H2O buffer) to afford (2S,3aS,7aS)-N-methyl-l-[2-(3-{2-[2-(4-{[2-(l-methyl-2,6-dioxopip eridin-3-yl)- 1,3 -di oxo-2, 3-dihydrolH-isoindol-4-yl]amino}piperidin-l-yl)ethoxy]etho xy[propyl)-6-[(lS)-l-{[4-(morpholin-4-yl)phenyl]formamido[ethyl]pyrimidin-4-yl]-o ctahydro- lH-indole-2-carboxamide, 1-16. Yield: 15.0 mg, 15.2%. Appearance: Yellow solid;1H NMR (400 MHz, DMSO-r / e) 8 8.34 - 8.30 (m, 1H), 7.77 - 7.70 (m, 2H), 7.56 - 7.48 (m, 1H), 7.20 - 7.11 (m, 1H), 7.02 - 6.98(m, 1H), 6.95 - 6.90 (m, 2H), 6.30 - 6.18 (m, 2H), 5.12 - 5.08 (m, 2H), 4.92 - 4.79 (m, 2H), 4.32 - 4.22 (m, 1H), 3.79 - 3.70 (m, 4H), 3.39 - 3.30 (m, 4H), 3.20 - 3.18 (m, 3H), 3.00 - 2.98 (m, 4H), 2.95 - 2.88 (m, 2H), 2.85 - 2.69 (m, 4H), 2.65 - 2.50 (m, 5H), 2.27 - 2.13 (m, 4H), 2.12 - 1.80 (m, 9H), 1.77 - 1.29 (m, 11H). HPLC purity: 98.0%; LCMSCalculated for C53H70N10O9: 990 55; Observed: 991 6 [M+H]+Example 17. Synthesis of (2S,3aS,7aS)-l-(2-(3-(4-((2-(2,6-dioxopiperidin-3-yl)-l,3- dioxoisoindolin-4-yl)amino)-[l,4'-bipiperidin]-l'-yl)prop-l-yn-l-yl)-6-((S)-l-(4- morpholinobenzamido)ethyl)pyrimidin-4-yl)-N-methyloctahydro-lH-indole-2- carboxamide, 1-17.Attorney Docket No. 2013075-00110Step-1. Synthesis of benzyl 4-{[ ( tert-butoxy)carbonyl]amino}-[ l,4'-bipiperidine ]- 1 '-carboxylate

[0400] A solution of tert-butyl N-(piperidin-4-yl)carbamate (10.0 g, 49.9 mmol) and benzyl 4- oxopiperidine-l-carboxylate (11.6 g, 49.9 mmol) in methanol (100 mb) followed by the addition of NaBH3CN (3.09 g, 49.9 mmol) at room temperature. The resulting mixture was stirred for 12 hours at room temperature. The reaction was quenched by the addition of water (2 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (50 mLx3). The combined organic layers were washed with brine (2x3 mL), dried over anhydrous Na2SO4, filtrated and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with ethyl acetate / petroleum ether (0% to 50%) to afford benzyl 4-{ [(ter / - butoxy)carbonyl]amino}-[l,4'-bipiperidine]-r-carboxylate (10.5 g, 25.1 mmol, 96% purity, 50% yield) as a white solid.Step-2. Synthesis of benzyl 4-amino-[l,4'-bipiperidine]- -carboxylate

[0401] A mixture of 2-([3-(benzyloxy)-6-[(2,6-dimethylphenyl)methyl]-4- (trifluoromethyl)pyridin-2-yl]methoxyacetonitrile (150 mg, 0.34 mmol) in DCM(2 mL) and TFA (2 mL) was stirred for 1.0 hour at room temperature. The resulting mixture was concentrated in vacuum to afford benzyl 4-amino-[l,4'-bipiperidine]-T-carboxylate (300 mg, crude) as a yellow solid, which was used for next step directly.Attorney Docket No. 2013075-00110Step-3. Synthesis of benzyl 4-{[2-(2,6-dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihydro-lH-isoindol-4- yl ]amino}-[ 1, 4' -bipiperidine ]-l '-carboxylate

[0402] Into a 2-L 3-necked round-bottom was placed benzyl 4-amino-[l,4'-bipiperidine]-l'- carboxylate (300 mg, 945 pmol), benzyl 4-amino-[l,4'-bipiperidine]-l'-carboxylate (300 mg, 945 pmol), DIEA (1 ml) and DMF (3 mL). The resulting mixture was stirred for 1.0 hour at 170°C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature, diluted with water (10 mL) and extracted with ethyl acetate (10 mLx3). The combined organic phase was washed with brine (500 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by silica gel column chromatography, eluted with ethyl acetate / petroleum ether (0% to 100%) to afford benzyl 4-{[2-(2,6-dioxopiperidin-3-yl)-l,3-dioxo-2,3- dihydro-lH-isoindol-4-yl]amino}-[l,4'-bipiperidine]-T-carboxylate (180 mg, 313 pmol, 85% purity, 33% yield) as a yellow solid.Step-4. Synthesis of 4-({[l,4'-bipiperidin]-4-yl}amino)-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro- IH-isoindole-l, 3-dione

[0403] A mixture of benzyl 4-{[2-(2,6-dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihydro-lH- isoindol-4-yl]amino}-[l,4'-bipiperidine]-T-carboxylate (180 mg, 313 pmol), TFA (68.8 mg, 626 pmol), Pd / C (18.0 mg, 10%) and Pd / (OH)2 (18.0 mg, 20%) in methanol (2 mL) was stirred for 16 hours at room temperature under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with methanol (3x5 mL). The filtrate was concentrated in vacuum to afford 4-({[l,4'-bipiperidin]-4-yl}amino)-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-lH-isoindole-l,3- dione (120 mg, crude) as a yellow solid, which was used for next step directly.Step-5. Synthesis of (2S,3aS, 7aS)-l-(2-(3-(4-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4- yl)amino)-[ l,4'-bipiperidi ]-l '-yl)prop-l-yn-l-yl)-6-( (S)-l-( 4- morpholinobenzamido)ethyl)pyrimidin-4-yl)-N-methyloctahydro-lH-indole-2-carboxamide, 1-17

[0404] A mixture of 4-({[l,4'-bipiperidin]-4-yl}amino)-2-(2,6-dioxopiperidin-3-yl)-2,3- dihydro-lH-isoindole-1, 3-dione (180 mg, 409 pmol), 3-{4-[(2S,3aS,7aS)-2-(methylcarbamoyl)- octahydro-lH-indol-l-yl]-6-[(lS)-l-{[4-(morpholin-4-yl)phenyl]formamido}ethyl]pyrimidin-2- yl}prop-2-yn-l-yl methanesulfonate (212 mg, 340 pmol) and K2CO3 (140 mg, 1.02 mmol) inAttorney Docket No. 2013075-00110MeCN (2 mL) was stirred for 16 hours at 80°C. The resulting mixture was quenched with water (10 mL) and extracted with ethyl acetate (10 mLx3). The combined organic phase was washed with brine (10 mL) , dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (formic acid buffer) to give (2S,3aS,7aS)-l-{2-[3-(4-{[2- (2,6-dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihydro-lH-isoindol-4-yl]amino}-[l,4'-bipiperidin]-r- yl)prop-l-yn-l-yl]-6-[(lS)-l-{[4-(morpholin-4-yl)phenyl]formamido}ethyl]pyrimidin-4-yl}-N- methyl-octahydro-lH-indole-2-carboxamide, 1-17. Yield: 25 mg, 7.6%; Appearance: Yellow solid; NMR (300 MHz, DMSO-r / c,) 6 11.11 (s, 1H), 8.47 (d, J= 7.7 Hz, 1H), 8.10 - 7.80 (m, 3H), 7.62 (m, J= 7.8 Hz, 1H), 7.22 (d, J= 8.6 Hz, 1H), 7.09 (d, J= 7.0 Hz, 1H), 6.97 (d, J= 8.6 Hz, 2H), 6.65 - 6.15 (m, 2H), 5.18 - 5.02 (m, 1H), 4.97 - 4.76 (m, 2H), 4.45 - 3.90 (m, 2H), 3.90 - 3.70 (m, 6H), 3.53 - 3.40 (m, 3H), 3.25 - 3.20 (m, 4H), 3.12 - 2.75 (m, 6H), 2.67 - 2.58 (m, 2H), 2.40 - 2.84 (m, 11H), 1.81 - 1.58 (m, 7H), 1.51 - 1.38 (m, 6H), 1.25 (m, 1H), HPLC purity: 93.4%; LCMS Calculated for C53H65N11O7: 967.51; Observed: 968.5 [M+H]+.Example 20. Synthesis of (2S,3aS,7a S)-l-[2-(3-{2-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-l,3- dioxo-2,3-dihydro-lH-isoindol-5-yl]piperazin-l-yl}methyl)piperidin-l-yl]ethoxy}propyl)-6- [(lS)-l-{[4-(morpholin-4-yl)phenyl]formamido}ethylJpyram idin-4-ylJ-N-methyl- octahydro-lH-indole-2-carboxamide, 1-20.Step-1. Synthesis of (2S,3aS, 7aS)-l-[2-(3-{2-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-l,3-dioxo-2,3- dihydro-lH-isoindol-5-yl]piperazin-l-yl}methyl)piperidin-l-yl]ethoxy}pro p-l-yn-l-yl)-6-[(lS)-1-{[ 4-(morpholin-4-yl)phenyl ]formamido}ethyl Jpyrimidin-4-yl / -N -methyl -octahydr o-lH -indole -2 -carboxamide.Attorney Docket No. 2013075-00110

[0405] A mixture of 2-(2,6-dioxopiperidin-3-yl)-5-{4-[(piperidin-4-yl)methyl]piperazin-l - yl}-2,3-dihydro-lH-isoindole-l, 3-dione (150 mg, 341 pmol), DIEA (131 mg, 1.02 mmol) and 2- (3-{4-[(2S,3aS,7aS)-2-(methylcarbamoyl)-octahydro-lH-indol-l-yl]-6-[(lS)-l-{ [4-(morpholin- 4-yl)phenyl]formamido}ethyl]pyrimidin-2-yl}propoxy)ethyl methanesulfonate (252 mg, 375 pmol) in DMF (2 mL) at room temperature, the reaction mixture was stirred for 12.0 hours at 100°C. The mixture was allowed to cool down to room temperature, quenched with water (10 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, fdtered and concentrated in vacuum. The residue was purified by prep-HPLC (TFA buffer) to give (2S,3aS,7aS)-l-[2-(3-{2-[4-({4-[2-(2,6- dioxopiperidin-3-yl)-l,3-di oxo-2, 3-dihydro-lH-isoindol-5-yl]piperazin- l-yl}methyl)piperi din- 1- yl]ethoxy [prop- 1 -yn- 1 -y l)-6- [( 1 S)- 1 - { [4-(morpholin-4-yl)phenyl]form amido} ethyl]pyrimidin-4- yl]-N-methyl-octahydro-lH-indole-2-carboxamide (40.0 mg, 39.5 pmol, 75.9% purity, 11.5% yield) as yellow solid.Step-2. Synthesis of (2S,3aS, 7ct S)-l-[2-(3-{2-[4-({4-[2-(2,6-dioxopiperidm-3-yl)-l,3-dioxo-2,3- dihydro-lH-isoindol-5-yl]piperazin-l-yl}methyl)piperidin-l-yl]ethoxy}pro pyl)-6-[(lS)-l-{[4- (morpholin-4-yl)phenyl]formamido}ethyl]pyrimidin-4-yl]-N-meth yl-octahydro- lH-indole-2- carboxamide, 1-20.

[0406] Into a 50 mL round-bottom flask was placed Zc / 'Z-butyl (2S,3aS,7aS)-l -[2-(3-{2-[4-({4- [2-(2, 6-dioxopiperidin-3-yl)-l, 3 -di oxo-2, 3-dihydro-lH-isoindol-5-yl]piperazin-l-yl} methyl)piperidin- 1 -yl]ethoxy [prop- 1 -yn- 1 -yl)-6-[( 1 S)- 1 -{ [4-(morpholin-4-yl)pheny l]formamido}ethyl]pyrimidin-4-yl]-N-methyl-octahydro-lH-indole-2-carboxamide (4 0.0 mg, 39.5 pmol) in MeOH (2.0 mL) was added Pd / C (10 mg, 10%) at room temperature under nitrogen atmosphere and then the reaction mixture was degassed and purged with hydrogen for three times. The resulting reaction mixture was stirred for 4.0 hours under hydrogen atmosphere. The reaction mixture was filtered and the filtrate was concentrated in vacuum, the residue was purified by prep- HPLC (NH4HCO3 buffer) to give (2S,3aS,7a S)-l-[2-(3-{2-[4-({4-[2-(2,6-dioxopiperidin-3-yl)- l,3-dioxo-2,3-dihydro-lH-isoindol-5-yl]piperazin-l-yl}methyl)piperidin-l-yl]ethoxy}propyl)-6- [(lS)-l-{[4-(morpholin-4-yl)phenyl]formamido}ethyl]pyrimidin-4-yl]-N-methyl-octahydro-lH- indole-2-carboxamide, 1-20. Yield: 11. 0 mg, 27.4%; Appearance: yellow solid;1H NMR (300 MHz, DMSO-zfc) 5 11.10 (s, 1H), 8.53 - 8.12 (m, 2H), 7.95 - 7.73 (m, 3H), 7.72 - 7.68 (m, 1H),Attorney Docket No. 2013075-001107.41 - 7.35 (m, 1H), 7.35 - 7.21 (m, 1H), 7.03 - 6.98 (m, 2H), 5.10 - 5.06 (m, 2H), 3.75 - 3.73 (m, 4H), 3.30 - 3.21 (m, 10H), 2.91 - 2.81 (m, 3H), 2.69 - 2.51 (m, 13H), 2.38 - 2.33 (m, 5H), 2.10 - 1.85 (m, 10H), 1.73 - 1.63 (m, 5H), 1.58 - 1.35 (m, 8H), 1.21 - 1.11 (m, 3H). HPLC purity: 95.1%; LCMS Calculated for C55H73N11O8: 1015.65; Observed: 1016.4[M+H]+.Example 21. Synthesis of (2S,3aS,7aS)-l-(2-{3-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-l,3-dioxo- 2,3-dihydro-lH-isoindol-5-yl]piperazin-l- yl}methyl)piperidin-l-yl]propyl}-6-[(lS)-l-{[4- (morpholin-4-yl)phenyl]formamido}ethyl]pyrimidin-4-yl)-N-methyl-octahydro-lH-indole- 2-carboxamide, 1-21.Step-1. Synthesis of (2S,3aS, 7aS)-l-(2-{3-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihy dro-lH-isomdol-5-yl]piperazm-l-yl}methyl)piperidin-l-yl]propyl}-6-[(lS)-l-{[4-(morpholin-4- yl)phenyl]formamido}ethyl]pyrimidin-4-yl)-N-methyl-octahydro-lH-indole-2-carboxamide, 1-21

[0407] Into a 50 mL round-bottom flask, was placed (2S,3aS,7aS)-l-(2-{3-[4-({4-[2-(2,6- dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihydro-lH-isoindol-5-yl]piperazin-l-yl}methyl)piperidin-l- yl]prop-l -yn-l -yl]-6-[(l S)-l-{[4-(morpholin-4-yl)phenyl]formamido}ethyl]pyrimidin-4-yl)- Nmethyl-octahydro-lH-indole-2-carboxamide (30.0 mg, 30.9 pmol) in MeOH (10 mL) was added Raney -Ni (9.91 mg, 92.7 pmol) at room temperature under nitrogen atmosphere and then the reaction mixture was degassed and purged with hydrogen for three times. The resulting reaction mixture was stirred for 12.0 hours under hydrogen atmosphere. The reaction mixture was filtered and the filtrate was concentrated in vacuum, the residue was purified by prep-HPLC (formic acid buffer) to give (2S,3aS,7aS)-l-(2-{3-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-l,3-dioxo-2,3-dihydro- lH-isoindol-5-yl]piperazin- 1 - yl }methyl)piperidin- 1 -yl]propyl }-6-[(lS)-l-{ [4-(morpholin-4- yl)phenyl]formamido}ethyl]pyrimidin-4-yl)-N-methyl-octahydro-lH-indole-2-carboxamide. I- 21, 3.0 mg, 9.7%; Appearance: Yellow solid; 'HN R (400 MHz, DMSO-rf6) 5 11.07 (s, 1H), 8.37 (d, J = 7.7 Hz, 1H), 7.90 - 7.80 (m, 1H), 7.79 (d, J= 8.7 Hz, 2H), 7.68 (d, J= 8.5 Hz, 1H),Attorney Docket No. 2013075-001101.33 (d, J = 2.1 Hz, 1H), 7.25 (d, J= 8.8 Hz, 1H), 6.98 (d, J = 8.8 Hz, 2H), 5.10 - 5.04 (m, 1H), 4.86 (t, J= 7.3 Hz, 1H), 3.74 - 3.66 (m, 5H), 3.43 - 3.34 (m, 4H), 3.22 - 3.16 (m, 4H), 2.83 - 2.77 (m, 3H), 2.59 - 2.55 (m, 9H), 2.51 - 2.44 (m, 3H), 2.40 - 2.21 (m, 4H), 2.16 -2.14 (m, 2H), 2.12 - 1.95 (m, 2H), 1.90 - 1.60 (m, 12H), 1.50 - 1.407 (m, 2H), 1.24 - 1.18 (m, 4H), 1.19 - 1.02 (m, 3H) HPLC purity: 97 6%; LCMS Calculated for C53H69N11O7 971 54; Observed: 972 6 [M+H]+.Example 22. Synthesis of (2S,3aS,7aS)-l-(2-(3-(2-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-l,3- dioxoisoindolin-5-yl)piperazin-l-yl)ethoxy)ethoxy)prop-l-yn-l-yl)-6-((S)-l-(4- morpholinobenzamido)ethyl)pyrimidin-4-yl)-N-methyloctahydro-lH-indole-2- carboxamide; bis(formic acid), 1-22.Step-1. Synthesis of tert-butyl 4-{2-[2-(prop-2-yn-l-yloxy)ethoxy]ethyl}piperazine-l-carboxylate

[0408] A mixture of / c / V-butyl piperazine- 1 -carboxylate (200 mg, 1.07 mmol), 2-[2-(prop-2- yn-l-yloxy)ethoxy]ethyl methanesulfonate (284 mg, 1.28 mmol) and DIEA (414 mg, 3.21 mmol) in MeCN (4.00 mL) was stirred at 80°C for 12.0 hours. The mixture was allowed to cool down to room temperature and concentrated in vacuum. The residue was purified by prep-HPLC (NH3.H2O buffer) to give terZ-butyl 4-{2-[2-(prop-2-yn-l-yloxy)ethoxy]ethyl }piperazine-l-carboxylate (400 mg, 1.28 mmol, 70% purity, 95% yield) as a white solid.Step-2. Synthesis of l-{2-[2-(prop-2-yn-l-yloxy)ethoxy]ethyl}piperazine

[0409] A solution of / c77-butyl 4-{2-[2-(prop-2-yn-l-yloxy)ethoxy]ethyl}piperazine-l- carboxylate (380 mg, 1.21 mmol) in TFA : DCM (1 :4, 5 mL) was stirred for 3.0 hours at roomAttorney Docket No. 2013075-00110 temperature. The resulting mixture was concentrated in vacuum to afford l -{2-[2-(prop-2-yn-l - yloxy)ethoxy]ethyl}piperazine (210 mg, crude) as a brown solid, which was used for next step directly.Step-3. Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-(4-{2-[2-(prop-2-yn-l- yloxy)ethoxy]ethyl}piperazin-l-yl)-2,3-dihydro-lH-isoindole-l, 3-dione

[0410] A mixture of l-{2-[2-(prop-2-yn-l-yloxy)ethoxy]ethyl}piperazine (200 mg, 942 pmol), 2-(2,6-dioxopiperidin-3-yl)-5-fluoro-2,3-dihydro-lH-isoindole-l, 3-dione (233 mg, 847 pmol) and DIEA (363 mg, 2.82 mmol) in DMF (5 mL) at room temperature. The final reaction mixture was irradiated with microwave radiation at 170°C for 3.0 hours. The reaction mixture was cooled to...

Claims

CLAIMS1. A compound of formula I:A-B-E3L or a pharmaceutically acceptable salt thereof, wherein:A is a moiety that binds to or associates with FIP200;B is a linker moiety; andE3L is a ubiquitin E3 ligase binding moiety.The compound of claim 1, wherein A is selected from formula II-l, II-2, II-3, or II-4:or a pharmaceutically acceptable salt thereof, wherein:G1is an optionally substituted Ce-Cn aryl or an optionally substituted 5- to 6-membered heteroaryl;X1is -S-, -N(R3)-, -O-, optionally substituted C1-C6aliphatic, or optionally substituted C3-C6 cycloaliphatic;X2is independently C(R3) or N, provided that, when X2is N, then X1is optionally substituted C1-C6aliphatic, or optionally substituted C3-C6 cycloaliphatic; when a bond between X3and X4is a single bond, then X3is N(R2a), and X4is C(O) when a bond between X3and X4is a double bond, then X3is C(R2b) and X4is C(R3), or N;each R1is independently selected from halogen, optionally substituted C1-C6aliphatic, and optionally substituted -O-C1-C6aliphatic; or two instances of R1come together with the atoms to which they are attached to form a n optionally substituted C6-C12 aryl ring, an optionally substituted C4-C6 cycloaliphatic ring, a 5- to 6- membered heteroaryl ring comprising 1 to 3 heteroatoms selected from N, O, and S, or an optionally substituted 5- to 6-membered heterocyclic ring comprising 1 to 3 heteroatoms selected from N, O, and S;R2ais optionally substituted C1-C6aliphatic;R2bis hydrogen, optionally substituted C1-C6aliphatic, optionally substituted -N(R3)-CI- C6 aliphatic, or optionally substituted -O-C1-C6aliphatic; each R3is independently selected from hydrogen, halogen, and optionally substituted Ci- C6 aliphatic;R4is selected from optionally substituted C6-C12 aryl, optionally substituted 5- to 12- membered heteroaryl ring comprising 1 to 3 heteroatoms selected from N, O, and S, optionally substituted 4- to 12-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, and optionally substituted C1-C6aliphatic;R?is an optionally substituted 4- to 6-membered heterocyclic ring, an optionally substituted 5- to 6-membered heteroaryl ring, an optionally C3-C6 cycloaliphatic ring, an optionally substituted C6-C12 aryl, or an optionally substituted Ci-Cg aliphatic;L1is a bond, -C(O)-, -S(O)-, -S(O)2-, or -NR3-; n is independently 0, 1, 2, 3, 4, 5, or 6; each of X5, X6, and X7is independently selected from the group consisting ofN and CH;R7is hydrogen, an optionally substituted -O-C1-C6aliphatic, -S(O)2R3, optionally substituted C1-C6aliphatic, an optionally substituted 4- to 12-membered heterocycle ring comprising 1 to 4 heteroatoms selected from N, O, and S, an optionally substituted C6-C12 aryl, or an optionally substituted 5- to 12-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and SG2is optionally substituted C6-C12 aryl, optionally substituted 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, optionally substituted 5- to 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, or optionally substituted C3-C6 cycloaliphatic;G3is optionally substituted 4- to 12-membered heterocycle ring comprising 1 to 4 heteroatoms selected from N, O, and S, optionally substituted 5- to 6-membered heteroaryl ring comprising 1 to 4 heteroatoms selected from N, O, and S, an optionally substituted C3-C6 cycloaliphatic ring or optionally substituted Ce-Ci2aryl;L2is a bond, -NR3-C(O)-, -C(O)-NR3-, optionally substituted C1-C6aliphatic, optionally substituted 4- to 6-membered heterocyclic, or optionally substituted C3-C6 cycloaliphatic;L3is -NR3-, -O-, -C(O)-, -NR3-C(O)-, -NR3-S(O)2-, -C(O)-NR3-, -S(O)2NR3-, -NR3- C(O)-NR3-, optionally substituted C1-C6aliphatic, or optionally substituted C3-C6 cycloaliphatic ring;* represents a point of attachment to moiety B; and wherein: when A is a moiety of formula II- 3 then R6is a bond, optionally substituted C1-C6aliphatic, optionally substituted 2- to 6-membered heteroaliphatic, optionally substituted 4- to 6-membered heterocycle comprising one 1 to 3 heteroatoms selected from N, O, and S, optionally substituted Ce-Ci2aryl, or optionally substituted C3-C6 cycloaliphatic; and R8is halogen, -OR3, -C(O)N(R3)2, -C(O)OR3, optionally substituted C1-C6aliphatic, optionally substituted C3-C6 cycloaliphatic, optionally substituted Ce-Ci2aryl; and when A is of formula II-4, then R6is H, halogen, optionally substituted C1-C6aliphatic, optionally substituted 2- to 6-membered heteroaliphatic, optionally substituted 4- to 6-membered heterocycle comprising one 1 to 3 heteroatoms selected from N, O, and S, optionally substituted Ce-Ci2aryl, or optionally substituted C3-C6 cycloaliphatic; and R8is a bond, -O-, -C(O)NR3-, -C(O)OR3, optionally substituted C1-C6aliphatic, optionally substituted C3-C6 cycloaliphatic, or optionally substituted Ce-Ci2aryl.

3. The compound of claim 2, wherein two R1come together, with the atoms to which they are attached, to form an optionally substituted Ce-Ci2aryl ring or a 5- to 6- membered heteroaryl ring comprising 1 to 3 heteroatoms selected from N, O, and S.

4. The compound of claim 2, wherein n is 2 and each R1is halogen.

5. The compound of claim 4, wherein each R1is chloride.

6. The compound of any one of claims 2-5, wherein a bond between X4and X3is a single bond.

7. The compound of any one of claims 2-5, wherein a bond between X4and X3is a double bond, X3is C(R2b), and X4is N.

8. The compound of any one of claims 2-7, wherein X1is S.

9. The compound of any one of claims 2-8, wherein R4is optionally substituted phenyl or optionally substituted 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S.

10. The compound of any one of claims 2-9, wherein a moiety:is:

11. The compound of any one of claims 2-10, wherein G1is phenyl or naphthyl.

12. The compound of any one of claims 2-11, wherein R? is optionally substituted 5- to 6- membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S.

13. The compound of any one of claims 2-12, wherein L1is C(O).

14. The compound of claim 2, wherein A is of formula II- 1 or II-2, X4is C(O), a bond between X4and X3is a single bond, G1is napthyl, X1is S, X2is C(R3), R4is optionally substituted phenyl, and R5is optionally substituted 5- to 6-membered heterocycle.

16. The compound of claim 2, wherein X5and X7are each N and X6is CH.

17. The compound of claim 2, wherein G3is an optionally substituted 4- to 12-membered heterocycle ring comprising 1 to 4 heteroatoms selected from N, O, and S.

18. The compound of claim 17, wherein G3is optionally substituted 4- to 6-membered heterocycle comprising 1 to 3 heteroatoms selected from N, O, and S.

19. The compound of claim 17, wherein G3is optionally substituted 6- to 12-membered bicyclic heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S.

20. The compound of any one of claims 2 or 16-19, wherein L2is optionally substituted Ci- Ce aliphatic.

21. The compound of any one of claims 2 or 16-19, wherein L2is a bond or selected from:

22. The compound of claim 21, wherein L2is:

23. The compound of any one of claims 2 or 16-22, wherein G2is optionally substituted Ce- C12 aryl or optionally substituted 5- to 6-membered heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S.

24. The compound of any one of claims 2 or 16-23, wherein R7is optionally substituted 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S.

25. The compound of claim 2, wherein A is of formula II-3 or II- 4, X5and X7are each N, X6is CH, G3is optionally substituted 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S, L2is optionally substituted C1-C6aliphatic, L3is - NR3-C(O)- or -C(O)-NR3-, G2is optionally substituted phenyl, and R7is optionally substituted 4- to 12-membered heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S.

26. The compound of claim 2, wherein a moiety:

27. The compound of claim 2, wherein a moiety:

28. The compound of claim 2, wherein A is selected from:

29. The compound of claim 2, wherein A is a moiety selected from:

30. The compound of any one of claims 2-29, wherein E3L is a moiety that binds a Von Hippel-Lindau tumor suppressor, an inhibitor of apoptosis protein, or cereblon.

31. The compound of claim 30, wherein E3L is a moiety that binds a Von-Hippel Lindau tumor suppressor.

32. The compound of claim 31, wherein E3L is a moiety that binds a Von-Hippel Lindau tumor suppressor and is represented by any one of the following structures:

33. The compound of claim 30, wherein E3L is a moiety that binds an inhibitor of apoptosis protein.

34. The compound of claim 33, wherein E3L is a moiety that binds an inhibitor of apoptosis protein and is represented by any one of the following structures:

35. The compound of claim 30, wherein E3L is a moiety that binds cereblon.

36. The compound of claim 35, wherein E3L is a moiety that binds cereblon and is represented by any one of the following structures:

37. The compound of claim 2, wherein the compound is represented by formula III- 1 :III-l38. The compound of claim 2, wherein the compound is represented by formula III-2:III-239. The compound of claim 2, wherein the compound is represented by formula III-3III-340. The compound of claim 2, wherein the compound is represented by formula III-4:III-441. The compound of claim 2, wherein the compound is represented by formula III-5 :III-542. The compound of claim 2, wherein the compound is represented by formula III-6:III-643. The compound of claim 2, wherein the compound is represented by formula III-7III-744. The compound of claim 2, wherein the compound is represented by formula III-8 :

45. The compound of claim 2, wherein the compound is represented by formula III-9 :III-946. The compound of claim 2, wherein the compound is represented by formula III- 10 :III- 1047. The compound of claim 2, wherein the compound is represented by formula III- 11 :Ill- 1148. The compound of claim 2, wherein the compound is represented by formula III- 12 :III- 1249. The compound of claim 2, wherein the compound is represented by formula III- 13 :Ill- 1350. The compound of claim 2, wherein the compound is represented by formula III- 14 :III- 1451. The compound of any one of claims 1-50, wherein B is a linker moiety that is an optionally substituted C2-30 aliphatic group wherein one or more carbons are optionally and independently replaced by -Cy-, -NRZ-, -N(RZ)C(O)-, -C(O)N(RZ)-, -N(RZ)C(O)O-, - OC(O)N(RZ)-, -N(RZ)C(O)N(RZ) -, -OC(O)O-, -O-, -C(O)-, -OC(O)-, - C(O)O-, -SO-, -SO2-, wherein each -Cy- is independently an optionally substituted 3-12 membered heterocycle ring having 1-3 heteroatoms selected from N, O, and S, an optionally substituted 3-8 membered heteroaryl ring having 1-4 heteroatoms selected from N, O, and S, an optionally substituted C3-C6 cycloalkyl, or an optionally substituted C6-C12aryl, and each Rzis independently H or an optionally substituted group selected from Ci- C20 aliphatic, or C3-C12 cycloaliphatic.

52. The compound of any one of claims 1-50, wherein B is selected from Table Bl.

53. The compound of claims 1 or 2, wherein the compound is selected from Table 1.

54. A pharmaceutical composition comprising a compound of any one of claims 1-53, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

55. A method of treating a disease, disorder, or condition in a subject comprising administering to the subject a compound of any one of claims 1-53 or a pharmaceutical composition of claim 54.

56. The method of claim 55, wherein the disease, disorder, or condition is selected from forms of cancer, Ischemia-Reperfusion injury following a stroke or myocardial infarction, a neurodegenerative disease, a bacterial infection, a viral infection and an inflammatory disease.

57. The method of claim 56, wherein the form of cancer is selected from pancreatic ductal adenocarcinoma, colorectal adenocarcinoma, multiple myeloma, lung adenocarcinoma, skin cutaneous melanoma, uterine corpus endometrioidcarcinoma, uterine carcinosarcoma, thyroid carcinoma, acute myeloid leukemia, bladder urothelial carcinoma, gastric adenocarcinoma, cervical adenocarcinoma, head and neck squamous cell carcinoma, or other Ras family-associated cancer.

58. The method of claim 57, wherein the method further comprises administering a RTK, RAS, RAF, MEK, ERK, or MAPK inhibitor.

59. The method of claim 57, wherein the method further comprises administering an immune checkpoint inhibitor.

60. The method of claim 59, wherein the immune checkpoint inhibitor is selected from a PD- 1 inhibitor, a PD-Ll inhibitor, a CTLA4 inhibitor, a LAG-3 inhibitor, and a TIGIT inhibitor.

61. The method of claim 57, wherein the method further comprises administering a T-cell engager or immunotherapy that binds to both a cancer cell and an immune cell.

62. The method of claim 61, wherein a T-cell engager or immunotherapy is a bispecific antibody.

63. The method of claim 62, wherein the bispecific antibody binds to CD3 on a T-cell and a target on a cancer cell.

64. The method of claim 56, wherein the neurodegenerative disease is selected from Alzheimer disease (AD), Parkinson disease (PD), and Huntington disease (HD).

65. The method of claim 56, wherein the bacterial infection is selected from Porphyromonas gingivalis and Brucella abortus.

66. The method of claim 56, wherein the viral infection is a coronavirus.

67. The method of claim 56, wherein the inflammatory disease is selected from Crohn’s disease and inflammatory bowel disease.

68. A method of inhibiting autophagy in a subject comprising administering to the subject a compound of any one of claims 1-53, or a pharmaceutical composition of claim 54.

69. Use of a compound of any one of claims 1-53 or a pharmaceutical composition of claim 54 for the treatment of a disease, disorder, or condition.

70. Use of a compound of any one of claims 1-53 or a pharmaceutical composition of claim 54 for inhibiting autophagy in a subject.

Images