KIF22 degraders and uses thereof

Abstract

The present disclosure relates generally to KIF22 degraders, compositions thereof, and methods of using said compounds and compositions thereof. More specifically, the present disclosure relates to KIF22 degraders for use for treating disease mediated by KIF22, such as cancer.

Description

Attorney Docket No. 57547-738.601KIF22 DEGRADERS AND USES THEREOFCROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application Serial No. 63 / 761,441 filed February 21, 2025 which is hereby incorporated by reference in their entirety.BACKGROUND OF THE INVENTION

[0002] Kinesin superfamily proteins (KIFs) are microtubule-dependent molecular engine proteins that transport organelles, protein complexes, messenger RNA and chromosomes in a microtubule and ATP-dependent manner. These proteins firmly control the intracellular transportation of a variety of important functional molecules.

[0003] KIF22, also known as motor protein-like DNA binding protein (Kid), is an engine based on the positive end-oriented microtubules, which is related to both microtubules and chromosomes. The affinity of KIF22 with microtubules is controlled by cyclin-dependent kinase 1 (CDK1)-mediated phosphorylation. Phosphorylation of KIF22 at Thr463 reduces the affinity of KIF22 for microtubules but increases its affinity for chromosomes. KIF22 is involved in the entire process of mitosis. In the pro -metaphase, it spreads along the axis structure and chromosomes. As mitosis continues, it is collected on the metaphase plate and given metaphase constraints, pushing the chromosome arm to the equator of the spindle. In the later stage, KIF22 moves to the spindle pole on the side of the chromosome and mediates chromosome compression to prevent the formation of multinucleated cells. KIF22 plays a role as a motor protein in the process of mitosis and tumorigenesis. Thus, there is a need for new compounds for use in treating diseases mediated by KIF22.BRIEF SUMMARY OF THE INVENTION

[0004] Described herein are KIF22 degraders that are useful in treating cancer.

[0005] Disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:(R14)mFormula (I) as disclosed herein.

[0006] Also disclosed herein is a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.Attorney Docket No. 57547-738.601

[0007] Also disclosed herein is a method of treating cancer in a subject, comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition disclosed herein.

[0008] Also disclosed herein is a method of inhibiting KIF22 in a subject, comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition disclosed herein.INCORPORATION BY REFERENCE

[0009] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference for the specific purposes identified herein.DETAILED DESCRIPTION OF THE INVENTIONDefinitions

[0010] In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments. However, one skilled in the art will understand that the invention may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring descriptions of the embodiments. Unless the context requires otherwise, throughout the specification and claims which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is, as “including, but not limited to.” Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

[0011] Reference throughout this specification to “some embodiments” or “an embodiment” means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Also, as used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. It should also be noted that the term “or” is generally employed in its sense including “and / or” unless the content clearly dictates otherwise.

[0012] The terms below, as used herein, have the following meanings, unless indicated otherwise:

[0013] “Oxo” refers to =0.

[0014] “Amino” refers to -NH2.

[0015] “Hydroxy” refers to -OH.

[0016] “Carboxyl” refers to -COOH.

[0017] “Alkyl” refers to a straight- chain or branched- chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, more preferably one to six carbon atoms. Examples include, but are notAttorney Docket No. 57547-738.601limited to methyl, ethyl, n-propyl, isopropyl, 2-methyl-l -propyl, 2-methyl-2-propyl, 2-methyl-l -butyl, 3-methyl-1 -butyl, 2-methyl-3-butyl, 2, 2-dimethyl-l -propyl, 2-methyl-l -pentyl, 3 -methyl- 1 -pentyl, 4-methyl-l-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-l-butyl, 3,3-dimethyl-l-butyl, 2-ethyl-l -butyl, n-butyl, isobutyl, sec-butyl, t- butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups, such as heptyl, octyl and the like. Whenever it appears herein, a numerical range such as “Ci-Ce alkyl”, means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. In some embodiments, the alkyl is a C1-C10alkyl. In some embodiments, the alkyl is a Ci-Ce alkyl. In some embodiments, the alkyl is a Ci-Cs alkyl. In some embodiments, the alkyl is a C1-C4alkyl. In some embodiments, the alkyl is a C1-C3 alkyl. Unless stated otherwise specifically in the specification, an alkyl group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the alkyl is optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkyl is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkyl is optionally substituted with halogen.

[0018] “Alkenyl” refers to a straight-chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms. The group may be in either the cis or trans or Z or E conformation about the double bond(s) and should be understood to include both isomers. Examples include but are not limited to ethenyl (-CH=CH2), 1 -propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl and the like. Whenever it appears herein, a numerical range such as “C2-C6 alkenyl”, means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated. Unless stated otherwise specifically in the specification, an alkenyl group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the alkenyl is optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkenyl is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkenyl is optionally substituted with halogen.

[0019] “Alkynyl” refers to a straight- chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl and the like. Whenever it appears herein, a numerical range such as “C2-C6 alkynyl”, means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated. Unless stated otherwise specifically in the specification, an alkynyl groupAttorney Docket No. 57547-738.601may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the alkynyl is optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkynyl is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkynyl is optionally substituted with halogen.

[0020] “Alkylene” refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the alkylene is optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkylene is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen.

[0021] “Alkoxy” refers to a radical of the formula -Oalkyl where alkyl is defined as above. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the alkoxy is optionally substituted with one or more halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkoxy is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen.

[0022] “Aryl” refers to a radical derived from a hydrocarbon ring system comprising 6 to 30 carbon atoms and at least one aromatic ring. The aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems. In some embodiments, the aryl is a 6- to 10-membered aryl. In some embodiments, the aryl is a 6-membered aryl (phenyl). Aryl radicals include, but are not limited to anthracenyl, naphthyl, phenanthrenyl, azulenyl, phenyl, chrysenyl, fluoranthenyl, fluorenyl, as-indacenyl, s-indacenyl, indanyl, indenyl, phenalenyl, phenanthrenyl, pleiadenyl, pyrenyl, and triphenylenyl. Unless stated otherwise specifically in the specification, an aryl may be optionally substituted, for example, with one or more halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the aryl is optionally substituted with one or more halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the aryl is optionally substituted with one or more halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen.

[0023] “Cycloalkyl” refers to a partially or fully saturated, monocyclic, or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom), spiro, and / or bridged ring systems. In some embodiments, the cycloalkyl is fullyAttorney Docket No. 57547-738.601saturated. Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (e.g., C3-C15 fully saturated cycloalkyl or C3-C15 cycloalkenyl), from three to ten carbon atoms (e.g., C3-C10fully saturated cycloalkyl or C3-C10cycloalkenyl), from three to eight carbon atoms (e.g., C3-C8 fully saturated cycloalkyl or C3-C8 cycloalkenyl), from three to six carbon atoms (e.g., C3-C6 fully saturated cycloalkyl or C3-C6 cycloalkenyl), from three to five carbon atoms (e.g., C3-C5 fully saturated cycloalkyl or C3-C5 cycloalkenyl), or three to four carbon atoms (e.g., C3-C4 fully saturated cycloalkyl or C3-C4 cycloalkenyl). In some embodiments, the cycloalkyl is a 3- to 10-membered fully saturated cycloalkyl or a 3- to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3- to 6-membered fully saturated cycloalkyl or a 3- to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5- to 6-membered fully saturated cycloalkyl or a 5- to 6-membered cycloalkenyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, norbomyl, decalinyl, bicyclo[3.3.0]octyl, bicyclo[4.3.0]nonyl, cisdecalinyl, trans- decalinyl, bicyclo[2.1. l]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2] octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, and bicyclo[3.3.2]decyl, bicyclo[1.1.1]pentyl, bicyclo[3.1.0]hexyl, bicyclo[3.1.1]heptyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, Spiro[4.2]heptyl, spiro[4.3]octyl, spiro [5.2] octyl, spiro [3.3] heptyl, and spiro[5.3]nonyl. Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless stated otherwise specifically in the specification, a cycloalkyl is optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, a cycloalkyl is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a cycloalkyl is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl is optionally substituted with halogen.

[0024] “Halo” or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.

[0025] “Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 2-fluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

[0026] “Haloalkoxy” refers to -O-haloalkyl, with haloalkyl as defined above.

[0027] “Hydroxy alkyl” refers to an alkyl radical, as defined above, that is substituted by one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl includes, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

[0028] “Aminoalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substitutedAttorney Docket No. 57547-738.601with one, two, or three amines. Aminoalkyl includes, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.

[0029] “Deuteroalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more deuteriums. In some embodiments, the alkyl is substituted with one deuterium. In some embodiments, the alkyl is substituted with one, two, or three deuteriums. In some embodiments, the alkyl is substituted with one, two, three, four, five, or six deuteriums. Deuteroalkyl includes, for example, CD3, CH2D, CHD2, CH2CD3, CD2CD3, CHDCD3, CH2CH2D, or CH2CHD2. In some embodiments, the deuteroalkyl is CD3.

[0030] “Heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a Ci-Ce heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, or combinations thereof wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a Ci-Ce heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or two atoms selected from the group consisting of oxygen, nitrogen, and sulfur wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyl are, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, -CH(CH3)OCH3, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3, or -CH2CH2N(CH3)2. Unless stated otherwise specifically in the specification, a heteroalkyl is optionally substituted for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, a heteroalkyl is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heteroalkyl is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.

[0031] “Heterocycloalkyl” refers to a 3- to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, silicon, and sulfur. In some embodiments, the heterocycloalkyl is fully saturated. In some embodiments, the heterocycloalkyl is C-linked. In some embodiments, the heterocycloalkyl is N-linked. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocycloalkyl comprises one to three nitrogens. In some embodiments, the heterocycloalkyl comprises one or two nitrogens. In some embodiments, the heterocycloalkyl comprises one nitrogen. In some embodiments, the heterocycloalkyl comprises one nitrogen and one oxygen. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom), spiro, or bridged ring systems; and theAttorney Docket No. 57547-738.601nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized. Representative heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (e.g., C2-C15 fully saturated heterocycloalkyl or C2-C15 heterocycloalkenyl), from two to ten carbon atoms (e.g., C2-C10 fully saturated heterocycloalkyl or C2-C10 heterocycloalkenyl), from two to eight carbon atoms (e.g., C2-C8 fully saturated heterocycloalkyl or C2-C8 heterocycloalkenyl), from two to seven carbon atoms (e.g., C2-C7 fully saturated heterocycloalkyl or C2-C7 heterocycloalkenyl), from two to six carbon atoms (e.g., C2-C6 fully saturated heterocycloalkyl or C2-C7 heterocycloalkenyl), from two to five carbon atoms (e.g., C2-C5 fully saturated heterocycloalkyl or C2-C5 heterocycloalkenyl), or two to four carbon atoms (e.g., C2-C4 fully saturated heterocycloalkyl or C2-C4 heterocycloalkenyl). Examples of such heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl) 1,3] dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1 -di oxo- thiomorpholinyl, 1,3-dihydroisobenzofuran-l-yl, 3-oxo-1,3-dihydroisobenzofuran-l-yl, methyl-2-oxo-l,3-dioxol-4-yl, and 2-oxo-l,3-dioxol-4-yl. The term heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the di saccharides, and the oligosaccharides. In some embodiments, heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring). In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3 - to 7-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to 7-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5 - to 6-membered heterocycloalkenyl. Unless stated otherwise specifically in the specification, a heterocycloalkyl is optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the heterocycloalkyl is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heterocycloalkyl is optionally substituted with one or more halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen.Attorney Docket No. 57547-738.601

[0032] “Heteroaryl” refers to a 5- to 14-membered ring system radical comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heteroaryl comprises one to three nitrogens. In some embodiments, the heteroaryl comprises one or two nitrogens. In some embodiments, the heteroaryl comprises one nitrogen. In some embodiments, the heteroaryl is C-linked. In some embodiments, the heteroaryl is N-linked. The heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quatemized. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl comprising 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. In some embodiments, the heteroaryl is a 5 - to 6-membered heteroaryl comprising 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. In some embodiments, the heteroaryl is a 6-membered heteroaryl comprising 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. In some embodiments, the heteroaryl is a 5 -membered heteroaryl comprising 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiadiazolyl, benzo[b][l,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1 -phenyl- 1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise specifically in the specification, a heteroaryl is optionally substituted, for example, with one or more halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the heteroaryl is optionally substituted with one or more halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heteroaryl is optionally substituted with one or more halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.

[0033] The term “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occursAttorney Docket No. 57547-738.601and instances in which it does not. For example, “optionally substituted alkyl” means either “alkyl” or “substituted alkyl” as defined above. Further, an optionally substituted group may be un- substituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), mono- substituted (e.g., -CH2CH2F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc ).

[0034] The term “one or more” when referring to an optional substituent means that the subject group is optionally substituted with one, two, three, or four, or more substituents. In some embodiments, the subject group is optionally substituted with one, two, three, or four substituents. In some embodiments, the subject group is optionally substituted with one, two, or three substituents. In some embodiments, the subject group is optionally substituted with one or two substituents. In some embodiments, the subject group is optionally substituted with one substituent. In some embodiments, the subject group is optionally substituted with two substituents. In some embodiments, the subject group is optionally substituted with three substituents.

[0035] The terms “treat,” “treated,” “treatment,” or “treating” as used herein refers to therapeutic treatment, wherein the object is to slow (lessen) an undesired physiological condition, disorder, or disease, or to obtain beneficial or desired clinical results. For the purposes described herein, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of the extent of the condition, disorder or disease; stabilization (i.e., not worsening) of the state of the condition, disorder or disease; delay in onset or slowing of the progression of the condition, disorder or disease; amelioration of the condition, disorder or disease state; and remission (whether partial or total), whether detectable or undetectable, or enhancement or improvement of the condition, disorder or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment. The terms “treat,” “treated,” “treatment,” or “treating” as well as words stemming therefrom, as used herein, do not necessarily imply 100% or complete treatment. Rather, there are varying degrees of treatment of which one of ordinary skill in the art recognizes as having a potential benefit or therapeutic effect. In this respect, the disclosed methods can provide any amount of any level of treatment of the disorder in a mammal. For example, a disorder, including symptoms or conditions thereof, may be reduced by, for example, about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, or about 10%.

[0036] The terms “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of a compound disclosed herein being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated, e.g., cancer or an inflammatory disease. In some embodiments, the result is a reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an “effective amount” for therapeutic uses is the amount of the composition comprising a compound disclosed herein required to provide a clinically significant decrease in disease symptoms. In some embodiments, an appropriate “effective” amount in any individual case is determined using techniques, such as a dose escalation study.Attorney Docket No. 57547-738.601Compounds

[0037] Described herein are KIF22 degraders that are useful for the treatment of cancer.

[0038] Disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:Formula (I);wherein:X1is N or CR1;R1is hydrogen, halogen, -CN, -OH, -ORa, -SH, -SRa, -NRbRc, Ci-Cealkyl, or Ci-Ceheteroalkyl; wherein the alkyl and heteroalkyl is independently optionally substituted with one or more R’;X2is N or CR2;R2is hydrogen, halogen, -CN, -OH, -ORa, -SH, -SRa, -NRbRc, Ci-Cealkyl, or Ci-Ceheteroalkyl; wherein the alkyl and heteroalkyl is independently optionally substituted with one or more R’;X3is N or CR3;R3is hydrogen, halogen, -CN, -OH, -ORa, -SH, -SRa, -NRbRc, Ci-Cealkyl, or Ci-Ceheteroalkyl; wherein the alkyl and heteroalkyl is independently optionally substituted with one or more R’;X4is N or CR4;R4is hydrogen, halogen, -CN, -OH, -ORa, -SH, -SRa, -NRbRc, Ci-Cealkyl, or Ci-Ceheteroalkyl; wherein the alkyl and heteroalkyl is independently optionally substituted with one or more R’;R5and R6are independently hydrogen, halogen, Ci-Cealkyl, or Ci-Cehaloalkyl;Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;each R7is halogen, -CN, -OH, -ORa, -SH, -SRa, -NRbRc, Ci-Cealkyl, or Ci-Ceheteroalkyl; wherein each allyl and heteroalkyl is independently optionally substituted with one or more R’;and / or two R7are taken together to form an oxo;p is 0, 1, 2, 3, or 4;L1is -O-, -S-, -NR9-, -C(R10)2-, -C(=O)NR9-*, -S(=O)2NR9-*, -NR9S(=O)2-*, -NR9C(=O)-*, - C(=O)NR9S(=O)2-*, -S(=O)2NR9C(=O)-*, -O-C(R10)2-*, -C(R10)2-O-*, -NR9-C(R10)2-*, -C(R10)2-NR9-*, -S(=O)2C(R10)2-*, or -C(R10)2S(=O)2-*, wherein * represent the attachment point to R8;R9is hydrogen or Ci-Cealkyl independently optionally substituted with one or more R’;each R10is independently hydrogen, halogen, Ci-Cealkyl, Ci-Cehaloalkyl, or Ci-Ceheteroalkyl;Attorney Docket No. 57547-738.601HBHRl1)nR8is , C1-C6alkyl, or C1-C6haloalkyl;Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;each R11is independently halogen, -CN, -NO2, -OH, -ORa, -SH, -SRa, -NRbRc, Ci-Cealkyl, orCi-Ceheteroalkyl, wherein each alkyl and heteroalkyl is independently optionally substituted with one or more R’;and / or two R11are taken together to form an oxo;n is 0, 1, 2, 3, or 4;R12is hydrogen, halogen, -OH, -ORa, -NRbRc, Ci-Cealkyl, C2-Cealkenyl, C2-Cealkynyl, Ci-Cehaloalkyl, or Ci-Ceheteroalkyl;L2is absent, -OC(=O)-*, -C(=O)O-*, -CH2C(=O)-*, -C(=O)CH2-*, -NR13C(=O)-*, or -C(=O)NR13-*;wherein * represent the attachment point to Ring C;R13is hydrogen or Ci-Cealkyl;Ring C is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;each R14is independently halogen, -CN, -NO2, -OH, -ORa, -SH, -SRa, -NRbRc, Ci-Cealkyl, orCi-Ceheteroalkyl, wherein each alkyl and heteroalkyl is independently optionally substituted with one or more R’;and / or two R14are taken together to form an oxo;and / or R13and one R14are taken together with the atom to which they are attached to form a heterocycloalkyl independently optionally substituted with one or more R”;m is 0, 1, 2, 3, or 4;each L3is independently -O-, -S-, -S(=O)-, -S(=O)2-, -NR15-, -C(=O)-, Ci-Cioalkylene, Ci-Cioheteroalkylene;C2-Cealkenylene, C2-Cealkynylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene; wherein each alkylene, alkenylene, alkynylene, and heteroalkylene is independently optionally substituted with one or more R’ and wherein each cycloalkylene, heterocycloalkylene, arylene, and heteroarylene is independently optionally substituted with one or more R”;each R15is independently hydrogen, Ci-Cealkyl, Ci-Ceheteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, and alkynyl is independently optionally substituted with one or more R’ and wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”;s is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20;| — M* is an E3 ubiquitin ligase targeting agent;each Rais independently Ci-Cealkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L- heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, and alkynyl is independently optionally substituted with one or more R’ and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”;Attorney Docket No. 57547-738.601each Rband Rcare independently hydrogen, Ci-Cealkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L- cycloalkyl, -L-heterocycloalkyl, -L-aryl, or-L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, and alkynyl is independently optionally substituted with one or more R’ and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”; or Rband Rcare taken together with the atom to which they are attached to form a heterocycloalkyl independently optionally substituted with one or more R”;L is absent or Ci-Galkylene optionally substituted with one or more R’; andeach R’ is independently halogen, -CN, -OH, -OCi-Csalkyl, -S(=O)Ci-C3alkyl, -S(=O)2Ci-C3alkyl, - S(=O)2NH2, -S(=O)2NHCi-C3alkyl, -S(=O)2N(Ci-C3alkyl)2, -NH2, -NHCi-C3alkyl, -N(Ci-C3alkyl)2, - NHC(=O)OCi-C3alkyl, -C(=O)Ci-C3alkyl, -C(=O)OH, -C(=O)OCi-C3alkyl, -C(=O)NH2, - C(=O)N(Ci-C3alkyl)2, or -C(=O)NHCi-C3alkyl; wherein each alkyl is independently optionally substituted with one or more halogen;and / or two R’ on the same atom are taken together to form an oxo; andeach R” is independently halogen, -CN, -OH, -OCi-Csalkyl, -S(=O)Ci-C3alkyl, -S(=O)2Ci-C3alkyl, - S(=O)2NH2, -S(=O)2NHCi-C3alkyl, -S(=O)2N(Ci-C3alkyl)2, -NH2, -NHCi-C3alkyl, -N(Ci-C3alkyl)2, - NHC(=O)OCi-C3alkyl, -C(=O)Ci-C3alkyl, -C(=O)OH, -C(=O)OCi-C3alkyl, -C(=O)NH2, - C(=O)N(Ci-C3alkyl)2, -C(=O)NHCi-C3alkyl, Ci-C3alkyl, Ci-C3heteroalkyl, Ci-C6cycloalkyl, or 3- to 6- membered heterocycloalkyl; wherein each alkyl is independently optionally substituted with one or more halogen;and / or two R” on the same atom are taken together to form an oxo.

[0039] In some embodiments of a compound of Formula (I), R5and R6are independently hydrogen or Ci-Cealkyl. In some embodiments of a compound of Formula (I), R5and R6are independently hydrogen.

[0040] In some embodiments of a compound of Formula (I), Ring A is aryl or heteroaryl. In some embodiments of a compound of Formula (I), Ring A is phenyl.

[0041] In some embodiments of a compound of Formula (I), L1is -O-, -C(=O)NR9-*, -S(=O)2NR9-*, -NR9S(=O)2-*, or -NR9C(=O)-*, wherein * represent the attachment point to R8. In some embodiments of a compound of Formula (I), L1is -S(=O)2NR9-* or -NR9S(=O)2-*, wherein * represent the attachment point to R8. In some embodiments of a compound of Formula (I), L1is -S(=O)2NR9-* wherein * represent the attachment point to R8. In some embodiments of a compound of Formula (I), L1is -NR9S(=O)2-*, wherein * represent the attachment point to R8.

[0042] In some embodiments of a compound of Formula (I), R9is Ci-Cealkyl independently optionally substituted with one or more R’. In some embodiments of a compound of Formula (I), R9is hydrogen or Ci-Cealkyl. In some embodiments of a compound of Formula (I), R9is hydrogen.Attorney Docket No. 57547-738.601HB

[0043] In some embodiments of a compound of Formula (I), R8is- ' or Ci-Cealkyl. InI- / B \- (Rii)nsome embodiments of a compound of Formula (I), R8is - '. In some embodiments of a compound of Formula (I), R8is Ci-Cealkyl.

[0044] In some embodiments of a compound of Formula (I), X1is CR1. In some embodiments of a compound of Formula (I), X1is N.

[0045] In some embodiments of a compound of Formula (I), X2is CR2. In some embodiments of a compound of Formula (I), X2is N.

[0046] In some embodiments of a compound of Formula (I), X3is CR3. In some embodiments of a compound of Formula (I), X3is N.

[0047] In some embodiments of a compound of Formula (I), X4is CR4. In some embodiments of a compound of Formula (I), X4is N.

[0048] In some embodiments of a compound of Formula (I), R3is hydrogen, halogen, or Ci-Cealkyl independently optionally substituted with one or more R’. In some embodiments of a compound of Formula (I), R3is hydrogen or Ci-Cealkyl independently optionally substituted with one or more R’. In some embodiments of a compound of Formula (I), R3is hydrogen or Ci-Cealkyl. In some embodiments of a compound of Formula (I), R3is hydrogen.

[0049] In some embodiments of a compound of Formula (I), R4is hydrogen, halogen, or Ci-Cealkyl independently optionally substituted with one or more R’. In some embodiments of a compound of Formula (I), R4is hydrogen or Ci-Cealkyl independently optionally substituted with one or more R’. In some embodiments of a compound of Formula (I), R4is hydrogen or Ci-Cealkyl. In some embodiments of a compound of Formula (I), R4is hydrogen.

[0050] In some embodiments of a compound of Formula (I), R12is -OH, Ci-Cealkyl, Ci-Cedeuteroalkyl, or C2-Cealkynyl. In some embodiments of a compound of Formula (I), R12is -OH or Ci-Cealkyl. In some embodiments of a compound of Formula (I), R12is Ci-Cealkyl. In some embodiments of a compound of Formula (I), R12is Ci-Cealkyl or Ci-Cedeuteroalkyl.

[0051] In some embodiments of a compound of Formula (I), the compound is of Formula (la):(R7)PFormula (la).Attorney Docket No. 57547-738.601

[0052] In some embodiments of a compound of Formula (I) or (la), L2is absent, -OC(=O)-*, -CH2C(=O)-*, or -NR13C(=O)-*; wherein * represent the attachment point to Ring C. In some embodiments of a compound of Formula (I) or (la), L2is -OC(=O)-*, -CH2C(=O)-*, or -NR13C(=O)-*; wherein * represent the attachment point to Ring C. In some embodiments of a compound of Formula (I) or (la), L2is -OC(=O)-* or -CH2C(=O)-*; wherein * represent the attachment point to Ring C. In some embodiments of a compound of Formula (I) or (la), L2is -OC(=O)-*; wherein * represent the attachment point to Ring C. In some embodiments of a compound of Formula (I) or (la), L2is -CH2C(=O)-*; wherein * represent the attachment point to Ring C. In some embodiments of a compound of Formula (I) or (la), L2is absent.

[0053] In some embodiments of a compound of Formula (I) or (la), Ring C is heterocycloalkyl, aryl, or heteroaryl. In some embodiments of a compound of Formula (I) or (la), Ring C is heterocycloalkyl. In some embodiments of a compound of Formula (I) or (la), Ring C is heteroaryl. In some embodiments of a compound of Formula (I) or (la), Ring C is phenyl.

[0054] In some embodiments of a compound of Formula (I) or (la), the compound is of Formula (lb): / R7^Formula (lb).

[0055] In some embodiments of a compound of Formula (I) or (la), the compound is of Formula (Ic): / R7^Formula (Ic).

[0056] In some embodiments of a compound of Formula (I) or (la)-(Ic), R1is hydrogen, halogen, or Ci-Cealkyl independently optionally substituted with one or more R’. In some embodiments of a compound of Formula (I) or (la)-(Ic), R1is hydrogen or Ci-Cealkyl independently optionally substituted with one or more R’. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), R1is hydrogen or Ci-Cealkyl. In some embodiments of a compound of Formula (I) or (la)-(Ic), R1is hydrogen. In some embodiments of a compound of Formula (I) or (la)-(Ic), R1is Ci-Cealkyl.Attorney Docket No. 57547-738.601

[0057] In some embodiments of a compound of Formula (I) or (la)-(Ic), R2is hydrogen, halogen, or Ci-Cealkyl independently optionally substituted with one or more R’. In some embodiments of a compound of Formula (I) or (la)-(Ic), R2is hydrogen or Ci-Cealkyl independently optionally substituted with one or more R’. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), R2is hydrogen or Ci-Cealkyl. In some embodiments of a compound of Formula (I) or (la)-(Ic), R2is hydrogen. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), R2is Ci-Cealkyl. In some embodiments of a compound of Formula (I) or (la)-(Ic), R2is hydrogen or halogen. In some embodiments of a compound of Formula (I) or (la)-(Ic), R2is halogen.

[0058] In some embodiments of a compound of Formula (I) or (la)-(Ic), each R7is halogen, -CN, -OH, -ORa, or Ci-Cealkyl. In some embodiments of a compound of Formula (I) or (la)-(Ic), each R7is halogen, -OH, -ORa, or Ci-Cealkyl. In some embodiments of a compound of Formula (I) or (la)-(Ic), each R7is halogen, -OH, or -ORa. In some embodiments of a compound of Formula (I) or (la)-(Ic), each R7is halogen.

[0059] In some embodiments of a compound of Formula (I) or (la)-(Ic), p is 0, 1, or 2. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), p is 0 or 1. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), p is 0. In some embodiments of a compound of Formula (I) or (la)-(Ic), p is 1. In some embodiments of a compound of Formula (I) or (la)-(Ic), p is 2.

[0060] In some embodiments of a compound of Formula (I) or (la)-(Ic), each R14is independently halogen, -ORa, or Ci-Cealkyl. In some embodiments of a compound of Formula (I) or (la)-(Ic), each R14is independently halogen or -ORa. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), each R14is independently -ORa. In some embodiments of a compound of Formula (I) or (la)-(Ic), each R14is independently halogen.

[0061] In some embodiments of a compound of Formula (I) or (la)-(Ic), m is 0, 1, or 2. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), m is 0 or 1. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), m is 0. In some embodiments of a compound of Formula (I) or (la)-(Ic), m is 1. In some embodiments of a compound of Formula (I) or (la)-(Ic), m is 2.

[0062] In some embodiments of a compound of Formula (I) or (la)-(Ic), Ring B is cycloalkyl or heterocycloalkyl. In some embodiments of a compound of Formula (I) or (la)-(Ic), Ring B is aryl or heteroaryl. In some embodiments of a compound of Formula (I) or (la)-(Ic), Ring B is heteroaryl.

[0063] In some embodiments of a compound of Formula (I) or (la)-(Ic), Ring B is 5- to 6-membered heteroaryl comprising one, two, or three heteroatoms selected from the group selected from O, S, and N. In some embodiments of a compound of Formula (I) or (la)-(Ic), Ring B is 6-membered heteroaryl comprising one or two heteroatoms that are N. In some embodiments of a compound of F ormula (I) or (la) - (I c), Ring B is pyridinyl, pyrimidinyl, or pyrazinyl. In some embodiments of a compound of Formula (I) or (la)-(Ic), Ring B is pyridinyl.

[0064] In some embodiments of a compound of Formula (I) or (la)-(Ic), Ring B is 5-membered heteroaryl comprising one, two, or three heteroatoms selected from the group selected from O, S, and N. In some embodiments of a compound of Formula (I) or (la)-(Ic), Ring B is thiophenyl, furanyl, pyrrolyl, thiazolyl,Attorney Docket No. 57547-738.601oxazolyl, imidazolyl, isothiazolyl, isoxazolyl, pyrazolyl, thiadiazolyl, oxadiazolyl, or triazolyl. In some embodiments of a compound of Formula (I) or (la)-(Ic), Ring B is thiazolyl, oxazolyl, imidazolyl, isothiazolyl, isoxazolyl, pyrazolyl, thiadiazolyl, or oxadiazolyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), Ring B is thiazolyl, isothiazolyl, or pyrazolyl. In some embodiments of a compound of Formula (I) or (la)-(Ic), Ring B is thiazolyl or isothiazolyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), Ring B is thiazolyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), Ring B is isothiazolyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), Ring B is pyrazolyl.

[0065] In some embodiments of a compound of Formula (I) or (la)-(Ic), each R11is independently halogen, -CN, -OH, -ORa, -NRbRc, or Ci-Cealkyl. In some embodiments of a compound of Formula (I) or (la)-(Ic), each R11is independently halogen, -OH, -ORa, -NRbRc, or C1-C6alkyl. In some embodiments of a compound of Formula (I) or (la)-(Ic), each R11is independently halogen or Ci-Cealkyl. In some embodiments of a compound of Formula (I) or (la)-(Ic), each R11is independently Ci-Cealkyl.

[0066] In some embodiments of a compound of Formula (I) or (la)-(Ic), n is 0, 1, or 2. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), n is 0 or 1. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), nis 0. In some embodiments of a compound of Formula (I) or (la)-(Ic), n is 1. In some embodiments of a compound of Formula (I) or (la)-(Ic), n is 2.Attorney Docket No. 57547-738.601

[0068] In some embodiments of a compound of Formula (I) or (la)-(Ic), each L3is independently -O-, -NR15-, -C(=O)-, Ci-Cioalkylene, Ci-Cioheteroalkylene, cycloalkylene, heterocycloalkylene, or arylene; wherein each alkylene and heteroalkylene is independently optionally substituted with one or more R’ and wherein each cycloalkylene, heterocycloalkylene, and arylene is independently optionally substituted with one or more R”

[0069] In some embodiments of a compound of Formula (I) or (la)-(Ic), each L3is independently -O-, -NR15-, -C(=O)-, Ci-Cioalkylene, Ci-Cioheteroalkylene, cycloalkylene, heterocycloalkylene, or arylene. In some embodiments of a compound of Formula (I) or (la)-(Ic), each L3is independently -O-, -NR15-, Ci-Cioalkylene, Ci-Cioheteroalkylene, cycloalkylene, or heterocycloalkylene. In some embodiments of a compound of Formula (I) or (la)-(Ic), each L3is independently -O-, -NR15-, Ci-Cioalkylene, or heterocycloalkylene. In some embodiments of a compound of Formula (I) or (la)-(Ic), each L3is independently -O-, -NR15-, or heterocycloalkylene. In some embodiments of a compound of Formula (I) or (la)-(Ic), each L3is independently -O- or heterocycloalkylene. In some embodiments of a compound of Formula (I) or (la)-(Ic), each L3is independently -NR15- or heterocycloalkylene.

[0070] In some embodiments of a compound of Formula (I) or (la)-(Ic), each L3is independently -O-, -NR15-, -C(=O)-, Ci-Cealkylene, Ci-Ceheteroalkylene, Cs-Ciocycloalkylene, 3- to 10-membered heterocycloalkylene comprising one, two, or three heteroatoms selected from the group consisting of N, O, and S, or phenylene. In some embodiments of a compound of Formula (I) or (la)-(Ic), each L3is independently -O-, -NR15-, Ci-Cealkylene, Ci-Ceheteroalkylene, Cs-Cwcycloalkylene, or 3- to 10-membered heterocycloalkylene comprising one, two, or three heteroatoms selected from the group consisting of N, O, and S. In some embodiments of a compound of Formula (I) or (la)-(Ic), each L3is independently -O-, -NR15-, Ci-Cealkylene, or 3- to 10-membered heterocycloalkylene comprising one, two, or three heteroatoms selected from the group consisting of N, O, and S. In some embodiments of a compound of Formula (I) or (la)-(Ic), each L3is independently -O-, -NR15-, or 3- to 10-membered heterocycloalkylene comprising one, two, or three heteroatoms selected from the group consisting of N, O, and S. In some embodiments of a compound of Formula (I) or (la)-(Ic), each L3is independently -O- or 3- to 10-membered heterocycloalkylene comprising one, two, or three heteroatoms selected from the group consisting of N, O,Attorney Docket No. 57547-738.601and S. In some embodiments of a compound of Formula (I) or (la)-(Ic), each L3is independently -NR15- or 3- to 10-membered heterocycloalkylene comprising one, two, or three heteroatoms selected from the group consisting of N, O, and S.

[0071] In some embodiments of a compound of Formula (I) or (la)-(Ic), each L3is independently -O-, -NR15-, -C(=O)-, Ci-Cealkylene, Ci-Ceheteroalkylene, Cs-Cecycloalkylene, 3- to 10-membered heterocycloalkylene comprising one, two, or three heteroatoms selected from the group consisting of N and O, or phenylene. In some embodiments of acompound of Formula (I) or(Ia)-(Ic), each L3is independently -O-, -NR15-, Ci-Cealkylene, Ci-Ceheteroalkylene, Cs-Cecycloalkylene, or 3- to 10-membered heterocycloalkylene comprising one, two, or three heteroatoms selected from the group consisting of N and O. In some embodiments of a compound of Formula (I) or (la)-(Ic), each L3is independently -O-, -NR15-, Ci-Cealkylene, or 3- to 10-membered heterocycloalkylene comprising one, two, or three heteroatoms selected from the group consisting of N and O. In some embodiments of a compound of Formula (I) or (la)-(Ic), each L3is independently -O-, -NR15-, or 3- to 10-membered heterocycloalkylene comprising one, two, or three heteroatoms selected from the group consisting of N and O. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), each L3is independently -O- or 3- to 10-membered heterocycloalkylene comprising one, two, or three heteroatoms selected from the group consisting of N and O. In some embodiments of a compound of Formula (I) or (la)-(Ic), each L3is independently -NR15- or 3- to 10-membered heterocycloalkylene comprising one, two, or three heteroatoms selected from the group consisting of N and O.

[0072] In some embodiments of a compound of Formula (I) or (la)-(Ic),each L3is independently heterocycloalkylene; oreach L3is independently -O- or Ci-Cioalkylene; oreach L3is independently -O- or Ci-Cioheteroalkylene; oreach L3is independently -O- or cycloalkylene; oreach L3is independently -O- or heterocycloalkylene; oreach L3is independently -NR15- or Ci-Cioalkylene; oreach L3is independently -NR15- or Ci-Cioheteroalkylene; oreach L3is independently -NR15- or cycloalkylene; oreach L3is independently -NR15- or heterocycloalkylene; oreach L3is independently -O-, -NR15-, or Ci-Cioalkylene; oreach L3is independently -O-, -NR15-, or Ci-Cioheteroalkylene; oreach L3is independently -O-, -NR15-, or cycloalkylene; oreach L3is independently -O-, -NR15-, or heterocycloalkylene; oreach L3is independently -O-, Ci-Cioalkylene, or cycloalkylene; oreach L3is independently -O-, Ci-Cioalkylene, or heterocycloalkylene; oreach L3is independently -O-, Ci-Cioalkylene, heterocycloalkylene, or arylene.

[0073] In some embodiments of a compound of Formula (I) or (la)-(Ic),Attorney Docket No. 57547-738.601each L3is independently heterocycloalkylene; oreach L3is independently -O- or Ci-C4alkylene; oreach L3is independently -O- or Ci-Ceheteroalkylene; oreach L3is independently -O- or cycloalkylene; oreach L3is independently -O- or heterocycloalkylene; oreach L3is independently -NR15- or Ci-C4alkylene; oreach L3is independently -NR15- or Ci-Ceheteroalkylene; oreach L3is independently -NR15- or cycloalkylene; oreach L3is independently -NR15- or heterocycloalkylene; oreach L3is independently -O-, -NR15-, or Ci-C4alkylene; oreach L3is independently -O-, -NR15-, or Ci-C4heteroalkylene; oreach L3is independently -O-, -NR15-, or cycloalkylene; oreach L3is independently -O-, -NR15-, or heterocycloalkylene; oreach L3is independently -O-, Ci-C4alkylene, or cycloalkylene; oreach L3is independently -O-, Ci-C4alkylene, or heterocycloalkylene; oreach L3is independently -O-, Ci-C4alkylene, heterocycloalkylene, or arylene.

[0074] In some embodiments of a compound of Formula (I) or (la)-(Ic),each L3is independently 4- to 10-membered heterocycloalkylene comprising one or two heteroatoms selected from the group consisting of N, O, and S; oreach L3is independently -O- or Ci-C4alkylene; oreach L3is independently -O- or Ci-Ceheteroalkylene; oreach L3is independently -O- or C3-C6cycloalkylene; oreach L3is independently -O- or 4- to 10-membered heterocycloalkylene comprising one or two heteroatoms selected from the group consisting of N, O, and S; oreach L3is independently -NR15- or Ci-C4alkylene; oreach L3is independently -NR15- or Ci-Ceheteroalkylene; oreach L3is independently -NR15- or C3-C6cycloalkylene; oreach L3is independently -NR15- or 4- to 10-membered heterocycloalkylene comprising one or two heteroatoms selected from the group consisting of N, O, and S; oreach L3is independently -O-, -NR15-, or Ci-C4alkylene; oreach L3is independently -O-, -NR15-, or Ci-C4heteroalkylene; oreach L3is independently -O-, -NR15-, or C3-C6cycloalkylene; oreach L3is independently -O-, -NR15-, or 4- to 10-membered heterocycloalkylene comprising one or two heteroatoms selected from the group consisting of N, O, and S; oreach L3is independently -O-, C1-C4alkylene, or C3-C6cycloalkylene; oreach L3is independently -O-, Ci-C4alkylene, or 4- to 10-membered heterocycloalkylene comprising one or two heteroatoms selected from the group consisting of N, O, and S; orAttorney Docket No. 57547-738.601each L3is independently -O-, C1-C4alkylene, 4- to 10-membered heterocycloalkylene comprising one or two heteroatoms selected from the group consisting of N, O, and S, or phenylene.

[0075] In some embodiments of a compound of Formula (I) or (la)-(Ic),each L3is independently 4- to 6-membered heterocycloalkylene comprising one or two heteroatoms selected from the group consisting of N, O, and S; oreach L3is independently -O- or Ci-C4alkylene; oreach L3is independently -O- or Ci-Ceheteroalkylene; oreach L3is independently -O- or C3-C6cycloalkylene; oreach L3is independently -O- or 4- to 6-membered heterocycloalkylene comprising one or two heteroatoms selected from the group consisting of N, O, and S; oreach L3is independently -NR15- or Ci-C4alkylene; oreach L3is independently -NR15- or Ci-Ceheteroalkylene; oreach L3is independently -NR15- or C3-C6cycloalkylene; oreach L3is independently -NR15- or 4- to 6-membered heterocycloalkylene comprising one or two heteroatoms selected from the group consisting of N, O, and S; oreach L3is independently -O-, -NR15-, or Ci-C4alkylene; oreach L3is independently -O-, -NR15-, or Ci-C4heteroalkylene; oreach L3is independently -O-, -NR15-, or C3-C6cycloalkylene; oreach L3is independently -O-, -NR15-, or 4- to 6-membered heterocycloalkylene comprising one or two heteroatoms selected from the group consisting of N, O, and S; oreach L3is independently -O-, C1-C4alkylene, or C3-C6cycloalkylene; oreach L3is independently -O-, Ci-C4alkylene, or 4- to 6-membered heterocycloalkylene comprising one or two heteroatoms selected from the group consisting of N, O, and S; oreach L3is independently -O-, Ci-C4alkylene, 4- to 6-membered heterocycloalkylene comprising one or two heteroatoms selected from the group consisting of N, O, and S, or phenylene.

[0076] In some embodiments of a compound of Formula (I) or (la)-(Ic), each R15is independently hydrogen or Ci-Cealkyl. In some embodiments of a compound of Formula (I) or (la)-(Ic), each R15is independently hydrogen. In some embodiments of a compound of Formula (I) or (la)-(Ic), each R15is independently C1-C6alkyl.

[0077] In some embodiments of a compound of Formula (I) or (la)-(Ic), s is 1, 2, 3, 4, 5, or 6. In some embodiments of a compound of Formula (I) or (la)-(Ic), s is 1, 2, 3, or 4. In some embodiments of a compound of Formula (I) or (Ia)-(Ic), s is 1, 2, or 3. In some embodiments of a compound of Formula (I) or (la)-(Ic), s is 2, 3, 4, 5, or 6. In some embodiments of a compound of Formula (I) or (la)-(Ic), s is 2, 3, 4, or 5. In some embodiments of a compound of Formula (I) or (la)-(Ic), s is 2, 3, or 4. In some embodiments of a compound of Formula (I) or (la)-(Ic), s is 2 or 3. In some embodiments of a compound of Formula (I) or (la)-(Ic), s is 2. In some embodiments of a compound of Formula (I) or (la)-(Ic), s is 3. In some embodiments of a compound of Formula (I) or (la)-(Ic), s is 4. In some embodiments of a compound ofAttorney Docket No. 57547-738.601Formula (I) or (la)-(Ic), s is 5. In some embodiments of a compound of Formula (I) or (la)-(Ic), s is 6. In some embodiments of a compound of Formula (I) or (la)-(Ic), s is 7. In some embodiments of a compound of Formula (I) or (la)-(Ic), s is 8.

[0078] In some embodiments of a compound of Formula (I) or (la)-(Ic),— M

[0079] In some embodiments of a compound of Formula (I) or (la)-(Ic),* is a cereblon E3 ligase, a VHL E3 ligase, a MDM2 ligase, a TRIM24 ligase, a TRI M21 ligase, a KE API ligase, or an IAP ligase. In I — Msome embodiments of a compound of Formula (I) or (la)-(Ic),’ is a cereblon E3 ligase.| — M

[0080] In some embodiments of a compound of Formula (I) or (la)-(Ic),’ is(R16)tIFormula (A);wherein:Y is CH, C[CH3], orN;Attorney Docket No. 57547-738.601W is absent, -0-, -NRb-, or -C(=O)NRb-;Ring D is absent, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;each R16is independently halogen, -CN, -OH, -ORa, -NRbRc, Ci-Cealkyl, -L-cycloalkyl, -L- heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl is independently optionally substituted with one or more R’ and wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”;and / or two R10on the same atom are taken together to form an oxo; andt is 0, 1, 2, 3, 4, 5, or 6.

[0081] In some embodiments of a compound of Formula (A), Y is CH. In some embodiments of a compound of Formula (A), Y is C[CHs]. In some embodiments of a compound of Formula (A), Y is N.

[0082] In some embodiments of a compound of Formula (A), W is absent. In some embodiments of a compound of Formula (A), W is -O-. In some embodiments of a compound of Formula (A), W is -NRb-. In some embodiments of a compound of Formula (A), W is -C(=O)NRb-.

[0083] In some embodiments of a compound of Formula (A), Ring D is heterocycloalkyl. In some embodiments of a compound of Formula (A), Ring D is aryl or heteroaryl. In some embodiments of a compound of Formula (A), Ring D is phenyl.

[0084] In some embodiments of a compound of Formula (A), each R16is independently halogen, -CN, -OH, -ORa, -NRbRc, Ci-Cealkyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein each alkyl is independently optionally substituted with one or more R’ and wherein each cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more R”; and / or two R16on the same atom are taken together to form an oxo. In some embodiments of a compound of Formula (A), each R16is independently halogen, -ORa, or Ci-Cealkyl; and / ortwo R16on the same atom are taken together to form an oxo. In some embodiments of a compound of Formula (A), each R16is independently halogen, -ORa, or Ci-Cealkyl. In some embodiments of a compound of Formula (A), each R16is independently halogen or Ci-Cealkyl. In some embodiments of a compound of Formula (A), each R16is independently halogen or -ORa. In some embodiments of a compound of Formula (A), two R16on the same atom are taken together to form an oxo.

[0085] In some embodiments of a compound of Formula (A), t is 0, 1, or 2. In some embodiments of a compound of Formula (A), t is 0 or 2. In some embodiments of a compound of Formula (A), t is 1 or 2. In some embodiments of a compound of Formula (A), t is 0. In some embodiments of a compound of Formula (A), t is 1. In some embodiments of a compound of Formula (A), t is 2. In some embodiments of a compound of Formula (A), t is 2, 3, or 4. In some embodiments of a compound of Formula (A), t is 3 or 4. In some embodiments of a compound of Formula (A), t is 2, 3, 4, 5 or 6. In some embodiments of a compound of Formula (A), t is 4, 5 or 6.Attorney Docket No. 57547-738.601

[0086] In some embodiments of a compound of Formula (I), (la)-(Ic), or (A), I isoHO? a?"Attorney Docket No. 57547-738.601

[0088] In some embodiments of a compound disclosed herein, each Rais independently Ci-Cealkyl, Ci-Ceheteroalkyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein each alkyl and heteroalkyl is independently optionally substituted with one or more R’ and each cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more R” In some embodiments of a compound disclosed herein, each Rais independently Ci-Cealkyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein each alkyl is independently optionally substituted with one or more R’ and each cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more R” In some embodiments of a compound disclosed herein, each Rais independently Ci-Cealkyl, -L-cycloalkyl, or -L-heterocycloalkyl. In some embodiments of a compound disclosed herein, each Rais independently Ci-Cealkyl or -L-cycloalkyl; wherein each alkyl is independently optionally substituted with one or more R’ and each cycloalkyl is independently optionally substituted with one or more R” In some embodiments of a compound disclosed herein, each Rais independentlyCi-Cealkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound disclosed herein, each Rais independently Ci-Cealkyl or cycloalkyl; wherein each alkyl is independently optionally substituted with one or more R’ and each cycloalkyl is independently optionally substituted with one or more R” In some embodiments of a compound disclosed herein, each Rais independently Ci-Cealkyl or -L-cycloalkyl. In some embodiments of a compound disclosed herein, each Rais independently Ci-Cealkyl or cycloalkyl. In some embodiments of a compound disclosed herein, each Rais independently Ci-Cealkyl.

[0089] In some embodiments of a compound disclosed herein, each Rband Rcare independently hydrogen, Ci-Cealkyl, Ci-Ceheteroalkyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein each alkyl and heteroalkyl is independently optionally substituted with one or more R’ and each cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more R” In some embodiments of a compound disclosed herein, each Rband Rcare independently hydrogen, Ci-Cealkyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein each alkyl is independently optionally substituted with one or more R’ and each cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more R” In some embodiments of a compound disclosed herein, each Rband Rcare independently hydrogen, Ci-Cealkyl, -L-cycloalkyl, or -L-heterocycloalkyl. In some embodiments of a compound disclosed herein, each Rband Rcare independentlyAttorney Docket No. 57547-738.601hydrogen, Ci-Cealkyl or -L-cycloalkyl; wherein each alkyl is independently optionally substituted with one or more R’ and each cycloalkyl is independently optionally substituted with one or more R” In some embodiments of a compound disclosed herein, each Rband Rcare independently hydrogen, Ci-Cealkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound disclosed herein, each Rband Rcare independently hydrogen, Ci-Cealkyl, or cycloalkyl; wherein each alkyl is independently optionally substituted with one or more R’ and each cycloalkyl is independently optionally substituted with one or more R” In some embodiments of a compound disclosed herein, each Rband Rcare independently hydrogen, Ci-Cealkyl, or -L-cycloalkyl. In some embodiments of a compound disclosed herein, each Rband Rcare independently hydrogen, Ci-Cealkyl, or cycloalkyl. In some embodiments of a compound disclosed herein, each Rband Rcare independently hydrogen or Ci-Cealkyl. In some embodiments of a compound disclosed herein, each Rband Rcare hydrogen. In some embodiments of a compound disclosed herein, each Rband Rcare independently Ci-Cealkyl.

[0090] In some embodiments of a compound disclosed herein, Rband Rcare taken together with the atom to which they are attached to form a heterocycloalkyl independently optionally substituted with one or more R” In some embodiments of a compound disclosed herein, Rband Rcare taken together with the atom to which they are attached to form a heterocycloalkyl.

[0091] In some embodiments of a compound disclosed herein, L is absent. In some embodiments of a compound disclosed herein, L is Ci-Galkylene optionally substituted with one or more R. In some embodiments of a compound disclosed herein, L is Ci alkylene optionally substituted with one or more R. In some embodiments of a compound disclosed herein, L is C2alkylene optionally substituted with one or more R. In some embodiments of a compound disclosed herein, L is CLalk lene optionally substituted with one or more R. In some embodiments of a compound disclosed herein, L is -CH2-, -CH2CH2-, or -CH2CH2CH2-. In some embodiments of a compound disclosed herein, L is absent or -CH2-. In some embodiments of a compound disclosed herein, L is -CH2-. In some embodiments of a compound disclosed herein, L is -CH2CH2-. In some embodiments of a compound disclosed herein, L is -CH2CH2CH2-.

[0092] In some embodiments of a compound disclosed herein, each R’ is independently halogen, -CN, -OH, -OCi -Galkyl. -NH2, -NHCi -Galk l. or -N(Ci-C3alkyl)2; wherein each alkyl is independently optionally substituted with one or more halogen; and / or two R’ on the same atom are taken together to form an oxo. In some embodiments of a compound disclosed herein, each R’ is independently halogen, -CN, -OH, -OCi -Galkyl. or -NH2; wherein each alkyl is independently optionally substituted with one or more halogen; or two R’ on the same atom are taken together to form an oxo. In some embodiments of a compound disclosed herein, each R’ is independently halogen, -CN, -OH, or -NH2; or two R’ on the same atom are taken together to form an oxo. In some embodiments of a compound disclosed herein, each R’ is independently halogen; or two R’ on the same atom are taken together to form an oxo. In some embodiments of a compound disclosed herein, each R’ is independently halogen.

[0093] In some embodiments of a compound disclosed herein, each R” is independently halogen, -CN, -OH, -OCi-Csalkyl, -NH2, -NHCi-Csalkyl, -N(Ci-C3alkyl)2, Ci-Csalkyl, Ci-Csheteroalkyl, Ci-Cecycloalkyl,Attorney Docket No. 57547-738.601or 3- to 6-membered heterocycloalkyl; wherein each alkyl is independently optionally substituted with one or more halogen; and / or two R” on the same atom are taken together to form an oxo. In some embodiments of a compound disclosed herein, each R” is independently halogen, -CN, -OH, -OCi-Csalkyl, -NH2, Ci-Csalkyl, Ci-Csheteroalkyl, Ci-Cecycloalkyl, or 3- to 6-membered heterocycloalkyl; wherein each alkyl is independently optionally substituted with one or more halogen; and / or two R” on the same atom are taken together to form an oxo. In some embodiments of a compound disclosed herein, each R” is independently halogen, -CN, -OH, -OCi-Csalkyl, -NH2, Ci-Csalkyl, or Ci-Csheteroalkyl; II wherein each alkyl is independently optionally substituted with one or more halogen; and / or two R” on the same atom are taken together to form an oxo. In some V emboZ\ <diments of a compound disclosed herein, each R” is independently halogen, -CN, -OH, -OCi-Csalkyl, -NH42 3, Ci-Csalkyl, Ci-Cshal 4oalkyl, or Ci-Csheteroalkyl; and / or two R” on the same atom are taken together to form an oxo. In som 0e 0 embodiments of a compound disclosed herein, each R” is independently halogen, Ci -Galk l C. osr Ci -Ghaloalkyk and / or two R” on the same atom are taken together to form an oxo.f0T°

[0094] In some embodiments of a compound disclosed 0 0 herein, each R” is independently halogen, Ci-Csalkyl, or Ci-Cshaloalkyl. In some embodiments of a com / 0pound disclosed herein, each R” is independently halogen or Ci-Galk l. In some embodiments of V V a compound disclosed herein, each R” is independently halogen. cTJ 10

[0095] In some embodiments of a compound disclosed herein, the compo ^^^und,0 or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is selected from a compound of Table 1:TABLE 1Ex. Structure12if ''f0L i / "" S 11N345Attorney Docket No. 57547-738.601Attorney Docket No. 57547-738.6012122 o? Y A R A 0YRY xrX231. Ye” Y Y R / o^24IcY R o0R\HRS> $YRZ25O■ ■ YY'n? RR oO-:.« O26 \R ' \ °\ A? 5 / YLA-AV” — o / A 27 R Cr SRRY-c y j1i RRR, CI YV>'0NSY08 V RR YY ^l r r("~ 2CH OCR- A. ' bff NJ. / °\ _ 29f X Y k Y YA^Xi £YX030 A aXr Y '3132 { R A”CAI^CR / A / ^Z° \^^" Y~YRO^”RRR^ 3334HR A XAttorney Docket No. 57547-738.601Attorney Docket No. 57547-738.6014950iTP?, \51 piP / i PPPXPP^- / °GX PP^ / ^HX^PP J8 CPJP > ) M52 X J \ / - 8 o _° p ^op pp G gp^p J rpy., o o 53 pp.PAP ■pv O nx CVCr °o o o pp54 9 C o ° / 55 J d o G d...< PPxP pp X o QP> O^XPJP^P,, PP^G PPP.p56r\ ' X 57 I P “-^ / '-.'''PP P~xf — PP"^PPPppP< ^P~P~°^P~ / ,xP) ° 5859 CJ.. P? Xp GP oXPPP^P,, PP-A''~ / ''«P| PPP.60 G..., Pr X f GP oXPPP^P,, PP-. / ''~ / '~i!PPP.6162(P PO «63 x txPkPP 11x «PP.^^»^X^PAttorney Docket No. 57547-738.60164o 6566 p >67 L c o68 Q y fyjxy of yy yJO - 69y°O / 70 ' \**50zy j1' o 71 Xy ry V n A jy Ly^yy CY-C y 72 ° __r~ / II73 / ^sa / '"' X)" CKi zC Xu iX / -^oXyy r74 xxyyy. yi.75 cpy x^yy 76' ■ ■ ■■ - Z '.. ' x 77 y yyw n i yy y x yyy rAttorney Docket No. 57547-738.601Attorney Docket No. 57547-738.601Attorney Docket No. 57547-738.601Attorney Docket No. 57547-738.601120121122 QftpX. ppX1^ 123 p JP Pp2A p) -.... P. Y V4 <124 p ^ J.P)'J) Tyyw p Xr JJiyjyjy.o125 O M XXrr O o O Ql O y126QA py^UU r^X i P 5 0 cO '“O. \ 127 ftA128 A " vc 1^ 1 / -- yX / \A»XXNA X / PANP(J T 129130V O131 V ripk A, A, O ft>- AK0A~~_ I132 \fp>£^AyJvv° PPfX ■ft ‘ AAA. ft'- ' 133yy \134 ri> Cp TVJVV 1 rV / n_n\\Uy « IJy \iyo / -yAJ ArxAttorney Docket No. 57547-738.6011361371 kn "" X A I AA?\ / X138 / \ x y~ V" x V^rx7 / A ° rN;\ r o.' J ^ f° ^ k 2 — A^1* A o1A139 f X A°. fX X 1 I:x XxAAAk / A.W \ X A “- ~ ^ k* AA A xx- / xz, A X \ _o? °- / 0—° ■ " Xx 1, ° —■ o 140AAAJ AA A o A’JJ x o141 Clx. AAx Cy CAx AC °. 1 Ak / x C AkX O OX 7 \ —0xAAX O \° A A142 X Vy o AB“ A. X.- “ f ix A X.. ° r' A xlT i t / T kA Ak X X A rk / A° AAfx 143 r kxx>x< Xxx A' vAAXX kZkX X(XA \ AzA° 0 ■144145146CAx. x>. i Ak / x 147 'I?T xAX / A-z AX / A |XjX^°^x,x xAjA XkAi o148149150Attorney Docket No. 57547-738.601151«- / < X J VW’ / xl 1 152 X / pX0L Jk / XNV \> X. X X P Hl^XO 153 or Y’ 154 A A0P »- "^ - / \ Pl \ / / » 1 j 1i V rA A “°\ / .155 1 jX))x xz A> Y t)iX ^■G v o f rXT>p°.1561L 1 rv C o Xi \VXxXo xof \ I nJ' 0 I / Y / " o==«t °= X » \ / / '- X P / ^ V157 r cX?r i " X vv i' 158 "A° Q HL / y',x / V— ' \ \ / X 1 OC A -Z rA AX 59 xX -x °vs~YP“V)Y X i X p XjX 160161 x s0XX rr X xX^ o xN'- xA ' 'X 1OX X'Y P lOfYO O r0162 O II 1 Ol / OU1UJO n 0\ i0i ( '', O J / JlXl « i °x163 X XX'^ X^XX7X \'X O'^X=^X^Q-xNA JVX / VVY x 164165Attorney Docket No. 57547-738.601166A Af AXx-XXA° 167\X H~O~~S \ Xl ' xxx • y z- — OXA^AA t A A^zx vv / \=O 168 ABXL A A A Ao X XAy oA T A ' 1 \ T169 X A A o. zz""- A / o o0- —° A A _ _,°v170 5 bA3o AO HAx \o===A o o AA °J“'‘" 'C Cz \M A AX rrC’° ° '5SS¥171x=A^5) AT - o ol A vx<\= Z o\Z b X"' o172 o d dr A° o ^^ ^44SSSSO\ z v> 173 AAJX b AA174 / \ bCl / « i..175 F ^AxXzx kAA / x AoA AYV- / A xAAAXNA / xk l J! 1 X. J 176 / \ / " Az'^xv i \ Az z b>bh / N'0^^o^X"■> OXoPXX177178179180Attorney Docket No. 57547-738.601Attorney Docket No. 57547-738.601Attorney Docket No. 57547-738.601210211212213214on 215216J217, \218■?- / \ <Attorney Docket No. 57547-738.601Attorney Docket No. 57547-738.601Attorney Docket No. 57547-738.601Attorney Docket No. 57547-738.601Attorney Docket No. 57547-738.601Attorney Docket No. 57547-738.601274275276o hh o o BoA278 V V 0o AX A O) \..279 jpUUp o / = —fyXX PlA o o I..b5Zr fX rCr PIAf cr 280 o i i ifff£ t XX X Bfp IP B S p xl iA o AAA. A □ o 7 « i hi i I I I 282 j"1ipv° p / j, / ^hpi cX c cXX c cXB X Ch (5283284285286287288289Attorney Docket No. 57547-738.601290291292293tr294295296b 297298299 C^"HC^~(°300Attorney Docket No. 57547-738.601A301302.7.0.: 1. ■ X303b304 QxX. ’ ctxF 305 ■; • ■ ' ' ■.0Xozf \HXO306° ° WA L ujA 307 1 / / — \ / ° " V'-'X\ —A\ / 308309f NX V 1 Vx / K » / X / 01310’1311 O-Attorney Docket No. 57547-738.601Attorney Docket No. 57547-738.601325 \ XX, i i■ V O XXi \\ U \AV XV v H X0326 ° 9 i VI327 OYX XvX°' 9Z328329 \ xX 0 x Yj iXX9Xx999 «9%z° i r^, 9'^9s7'T"'YNVV X9V“X ^LX XTOX X XV XV °330 \ XX > XX / « i XX H0M. X iJXXXXAXX 331 XXKVXX^Vy c°^ X K332V T " v XXVXX / -^ u~Xc-" P333\ XXx s j334 Xw w Xa 335 < A9OVXXVXX 336 AxVxxVXx 337338 xXo^xXvXx\ XX, j 1 ^ XX / \ / \ N^^ VV T XVXx^x>^ XXN9 339V340 1 — \ z \N^w XXZ1 1 ^X9X-\V^ / TNV / Vv 1 V 9XNTA^ V T rN X\ / X.Attorney Docket No. 57547-738.601Attorney Docket No. 57547-738.601Attorney Docket No. 57547-738.601370dd-XV / 0=— \ / \ Z - N / H ^° 371 XAxX V / XX^ X1JX 0 - 372 0 L X.A.\ z° - °373lX x-X-XJXXLXy o \) XciXjo« \xc / ’I';ro N-_ X \=X / | r O| '^Z 1 °'v \'A V-\ F » / Y. A r 374H / N—11 / X 1 XxAX MX_ / H - d X X / A Y 0 o - 0 V-N J. O\ J0AA X \f\0II 0 I1 — 0X0 -O dd [ / vX \ _ o Z A d.3751 ■3760X / H X> XX XXJI / ii i / / 377 ci / 0 JCX »ZA378 XI / ii i XXx °O oXy~ANX Z T ZA I. Y ZX L "'-'X" A JX ONXX^BX 0x X XXXOAiYAAA _J \ 379 \ Ly- V / 380381Attorney Docket No. 57547-738.601ClJ?382 o f YY"Cr ’M / / " Y YZ \ '^' TY0383 Y XA X T s |oA XAX^^A°AAY° p-Mo YY YrYZ'^' Y0384 CX YX X AY, S IA T il YZ AX / X A3^ ^ o Y / -o^ CAX A AT) o! YY J 385 o TT o ^TZA^ / ^ 1XXT \\ ’C' '^ AZ\ T| Y / ' 7 Y~ / AYYZY / X^ 0\ Y 0 PY xo A / VZY 386 Jtx€Gx l -Q \Y<^ ' ° A XXJAX YA T T TAYAb 387 r t OxZx I -Q i / AT?1A= XX / tA°^^° / VZY r—N\ \ 1 dY ~NH388 €rs / «x l -O v / A YA« lAxxXX AA / 389HN- — T 390r,i" Yi" Y'N / YY 1T iY Y JYT I / Y A / " 1 " Y'-zp I ^ IS / T'x)T391, TA X / CXCA-AYA\\ O - 392Attorney Docket No. 57547-738.601Attorney Docket No. 57547-738.601403X z\ ddjd / ^ppdy0pd404z<»Xi^^^2X XJN^ dd^V / _ / *1405 " p\ °406 v507 d°=F Jpnojc d^ ° °A / ^x.p ( / id 0Tp0 C^°0407 i U w B i P r i 0jzz'^d^^Nd^^ Ci Vd o / Pd''",° / rddr^ y^1 d- IP / P I / X40 J v8 rdv / / ^ d h. ^'N>p-°'P^ / PP ° MT°pydN^V\ o^13213211^ PA^ H" P / ? -P d^\ / CY oPpp yd / «409 dAJ^.py_ / ° vT’ / yd" TA-\ 410411412Fi d^d / ? dXjv d0dd^ rN'>v0^o^ Id / ^ i pdjx / xQx413Attorney Docket No. 57547-738.601414415416A p1Y. A ==Q417 dX A. AA / s\ < / X H O^. N. ^0 418 \A- ° O.. i r if ^^ T^CC.. Ood A419 ddA dXAy.p. ° ' kJ vr420o LJA / X Y i \ o u? i b-V T^> AV J ° —p421 AY / APA'A,. J 1 Yu vA A T Id-dCY^S T J 1 ° ' IJ422 '■. ■ A:. ■ - 10' IX423 Y'i • ' PdA d / WkAA ‘424425 Y'i • PlPA Y / PdPALP7 1■1NH426 - T1 « ' Xd °K A YY^~~~s / <"~Y \ 1 A Z -~T P '°Z\ A-, Z 1-.. „ / JzudAttorney Docket No. 57547-738.601427\ Xi ✓ 1 J n^Sx. 428yy99A 99 ' ‘ X1429 \ XX i / “ n^^XX oy9y 99 999 X XX ■• 01’ Xk9.. \ Xi i 9 ui^\x 430ruX XX°XXL Xbo<b. 5 2 4319 ^X^X^Xi s i A JL o / \ “° A T ] 1 \Z jk r-N^^ / V^NH 432 b “ b’0 0XXX / “'^X^° || XT X / ^ \ o o —xcr 0 b.. 0\ NH c? ° 433cy^cQ, yAS-^o434 XbX °?% w i °1XX / \ XX i ) z-XX° / \ ^ V^ yZ k <9 I \ / 435 9 999 99y '^9'*-° VA- / \ ° AA,436437438439 ^xXLa‘nXAttorney Docket No. 57547-738.601Attorney Docket No. 57547-738.601451o °452453454455456457458459460461462463Attorney Docket No. 57547-738.601464465o y zzF / \ o 466° O ’0H467 3 - OyNyOp. X Hz468 c^° O^N^O ^3 ■* H 469 5\H ZF\__ °YNY° 470471HF O N O472H_ O^N^O 473H474Attorney Docket No. 57547-738.601Attorney Docket No. 57547-738.601HFV \ °YNY° 485HFV-\O N O486F HF^FV^\aYNY° 487.HF\-x O N O 488HFV-\ °N 0489490 c4- V,j5"v b / # ‘o 0r^x0491o' "0492493495497' A x-' X - - 'Attorney Docket No. 57547-738.6010 \ NH 499 <No5006' 'o1, NH 501502HNV 0 H503n R D H 504D D5F\-x V L. Y° 05S; A^Vrr° 506H507 A; A5y.\^£x?iT' 508 n" - iJborCc°ti, noHAttorney Docket No. 57547-738.601509510oH5110HcH512oH5130OyO514o0 1515 Oy°' '"'od^yx°a51600517H518Attorney Docket No. 57547-738.601

[0096] The absolute label (abs) is added to a chiral center to denote that it is unambiguously a pure sample of the drawn stereoisomer.

[0097] The OR label (or) denotes a pure substance, but the absolute configuration of the stereochemical center is unknown. After chiral separation with pure structures isolated, multiple OR labels (OR indicates purity) with the same numerical value will indicates that a sample is one of a pair of pure enantiomers (but the absolute configuration of the stereochemical center is unknown).

[0098] The AND label (and) denotes both isomers are present at the depicted stereochemical center. Assigning different numerical values to the AND labels denotes that they are independent of each other. The use of AND labels with the same values indicate that the two stereocenters are relative to each other and can only change in concert.Further Forms of Compounds Disclosed HereinIsomers / Stereoisomers

[0099] In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the corresponding mixtures thereof. In some situations, the compounds described herein possess one or more chiral centers and each center independently exists in the R configuration or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds,Attorney Docket No. 57547-738.601separating the diastereomers and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation / resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.Labeled compounds

[0100] In some embodiments, the compounds described herein exist in their isotopically-labeled forms. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chlorine, such as2H,3H,13C,14C,15N,18O,17O,31P,32P,35S,18F, and36C1, respectively. Compounds described herein, and the pharmaceutically acceptable salts, solvates, or stereoisomers thereof which contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds, for example those into which radioactive isotopes such as3H and14C are incorporated, are useful in drug and / or substrate tissue distribution assays. Tritiated, i.e.,3H and carbon- 14, i.e.,14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavy isotopes such as deuterium, i.e.,2H, produces certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. In some embodiments, one or more hydrogen in a compound disclosed herein has been replaced by a deuterium atom. In some embodiments, one or more alkyl substituents in a compound disclosed herein has been replaced by a deuteroalkyl substituents.

[0101] In some embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.Pharmaceutically acceptable salts

[0102] In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.Attorney Docket No. 57547-738.601

[0103] In some embodiments, the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or a solvate, or stereoisomer thereof, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.

[0104] Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid or inorganic base, such salts including, but not limited to, acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-l,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, gluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne- 1,6-dioate, hydroxybenzoate, y-hy dr oxy butyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate metaphosphate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1 -napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3 -phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenyl acetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylate, undecanoate, and xylenesulfonate.

[0105] Further, the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-l -carboxylic acid, glucoheptonic acid, 4,4’-methylenebis-(3-hydroxy-2-ene-l-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid and muconic acid. In some embodiments, other acids, such as oxalic, while not in themselves pharmaceutically acceptable, are employed in the preparation of salts useful as intermediates in obtaining the compounds disclosed herein, solvate, or stereoisomer thereof and their pharmaceutically acceptable acid addition salts.

[0106] In some embodiments, those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptableAttorney Docket No. 57547-738.601metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N+(C1-C4alkyl)4hydroxide, and the like.

[0107] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. It should be understood that the compounds described herein also include the quatemization of any basic nitrogencontaining groups they contain. In some embodiments, water or oil -soluble or dispersible products are obtained by such quatemization.Solvates

[0108] In some embodiments, the compounds described herein exist as solvates. The invention provides for methods of treating diseases by administering such solvates. The invention further provides for methods of treating diseases by administering such solvates as pharmaceutical compositions. In some embodiments, the disease or condition is selected from breast cancer, lung cancer, bladder cancer, and head and neck squamous cell carcinoma (HNSCC). In some embodiments, the disease or condition is breast cancer. In some embodiments, the disease or condition is triple negative breast cancer.

[0109] Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein can be conveniently prepared from an aqueous / organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran or methanol. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.Preparation of the Compounds

[0110] The compounds used in the reactions described herein are made according to organic synthesis techniques known to those skilled in this art, starting from commercially available chemicals and / or from compounds described in the chemical literature. “Commercially available chemicals” are obtained from standard commercial sources including Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, U. K.), BDH, Inc. (Toronto, Canada), Bionet (Cornwall, U. K.), Chem Service Inc. (West Chester, PA), Crescent Chemical Co. (Hauppauge, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, U. K.), LancasterAttorney Docket No. 57547-738.601Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Cornwall, U.K.), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and Wako Chemicals USA, Inc. (Richmond, VA).

[0111] Suitable reference books and treatises that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, “Synthetic Organic Chemistry”, John Wiley & Sons, Inc., New York; S. R. Sandler et al., “Organic Functional Group Preparations,” 2nd Ed., Academic Press, New York, 1983; H. O. House, “Modem Synthetic Reactions”, 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L. Gilchrist, “Heterocyclic Chemistry”, 2nd Ed., John Wiley & Sons, New York, 1992; J. March, “Advanced Organic Chemistry: Reactions, Mechanisms and Structure”, 4th Ed, Wiley -Interscience, New Y ork, 1992. Additional suitable reference books and treatises that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, Fuhrhop, J. and Penzlin G. “Organic Synthesis: Concepts, Methods, Starting Materials”, Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R. V. “Organic Chemistry, An Intermediate Text” (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, R. C. “Comprehensive Organic Transformations: A Guide to Functional Group Preparations” 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. “Advanced Organic Chemistry: Reactions, Mechanisms, and Structure” 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (editor) “Modem Carbonyl Chemistry” (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. “Patai’s 1992 Guide to the Chemistry of Functional Groups” (1992) Interscience ISBN: 0-471-93022-9; Solomons, T. W. G. “Organic Chemistry” 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J. C., “Intermediate Organic Chemistry” 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; “Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann’s Encyclopedia” (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; “Organic Reactions” (1942-2000) John Wiley & Sons, in over 55 volumes; and “Chemistry of Functional Groups” John Wiley & Sons, in 73 volumes.

[0112] Specific and analogous reactants are optionally identified through the indices of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries, as well as through on-line. Chemicals that are known but not commercially available in catalogs are optionally prepared by custom chemical synthesis houses, where many of the standard chemical supply houses (e.g., those listed above) provide custom synthesis services. A reference for the preparation and selection of pharmaceutical salts of the compounds described herein is P. H. Stahl & C. G. Wermuth “Handbook of Pharmaceutical Salts,” Verlag Helvetica Chimica Acta, Zurich, 2002.Methods of TreatmentAttorney Docket No. 57547-738.601

[0113] Disclosed herein are methods for treating a disease or condition in a subject in need thereof, including administering to the subject a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0114] Disclosed herein are methods for treating a disease or condition mediated by KIF22 in a subject in need thereof, including administering to the subject a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the disease or condition mediated by KIF22 is cancer.

[0115] In some embodiments, the disease or condition is cancer. In some embodiments, the disease or condition is a cellular proliferation disorder, including uncontrolled cell growth, aberrant cell cycle regulation, centrosome abnormalities (structural and or numeric, fragmentation), a solid tumor, hematopoietic cancer, and hyperproliferative disorder, such as thyroid hyperplasia (such as Grave's disease), and cyst (such as hypervascularity of ovarian stroma, characteristic of polycystic ovarian syndrome (Stein-Leventhal syndrome)). Solid and hematological derived tumors, such as carcinomas, may include but are not limited to cancer of the anus, bladder, breast, colon, small intestine, appendix, kidney, renal pelvis, ureter, urothelium, liver, lung (including squamous cell and small cell lung cancer), pleura, esophagus, head and neck, nasopharynx, oropharynx, hypopharynx, oral cavity, larynx, biliary tract, gall-bladder, ovary, testicle, germ cell, uterus, pancreas, stomach, cervix, thyroid, prostate, salivary gland, and skin (including squamous cell carcinoma), hematopoietic tumors of lymphoid lineage (including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell-lymphoma, Hodgkin's lymphoma, nonHodgkin's lymphoma, hairy cell lymphoma and Burkett's lymphoma), hematopoietic tumors of myeloid lineage (including acute and chronic myelogenous leukemias, myelodysplastic syndrome and promyelocytic leukemia), hematopoietic tumors of any lineage, myeloma, tumors of mesenchymal origin (including fibrosarcoma and rhabdomyosarcoma, and other sarcomas, e.g., soft tissue and bone), tumors of the central and peripheral nervous system (including astrocytoma, neuroblastoma, glioma and schwannomas), tumor of neuroendocrine origin, tumor of endocrine origin, small cell tumors, tumors of unknown primary, other tumors (including retinoblastoma, melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratoacanthoma, thyroid follicular cancer, Ewing's sarcoma, Kaposi's sarcoma), and other cancer-related disorders that are a consequence of cancer presence or progression such as tumor-induced pleural or pericardial effusions, and malignant ascites.

[0116] Also disclosed herein is a method of inhibiting KIF22 in a subject, comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition disclosed herein.

[0117] In some embodiments, the inhibition of KIF22 occurs in a tumor cell in the subject in need thereof.

[0118] Also disclosed herein is a method of degrading KIF22 in a subject, comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition disclosed herein.Attorney Docket No. 57547-738.601Routes of Administration

[0119] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration. In addition, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections.Pharmaceutical Compositions / Formulations

[0120] The compounds described herein are administered to a subject, either alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice. In one embodiment, the compounds disclosed herein may be administered to animals. The compounds can be administered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal, and topical routes of administration.

[0121] In another aspect, provided herein are pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and at least one pharmaceutically acceptable excipient. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’ s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N. Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkinsl999), herein incorporated by reference for such disclosure.EXAMPLESPreparation 1: N-{4-[(3-amino-3,7-dimethyl-2-oxo-2,3-dihydro-lH-indol-l-yl)methyl]phenyl}pyridine-4-sulfonamideAttorney Docket No. 57547-738.601Step 14M HCI in Dioxane, rt, 3 h Step 4Step 1:

[0122] To a mixture of 7-methylisatin (20.0 g, 124 mmol, 1.0 eq) and cesium carbonate (60.6 g, 186 mmol, 1.5 eq) in anhydrous dimethylacetamide (DMAc, 500 mL, 0.25 M) was added 4-bromobenzyl bromide (32.6 g, 130 mmol, 1.05 eq) portion-wise. The reaction mixture was stirred overnight at room temperature. The reaction was quenched with water and the precipitate was collected and washed with water. The product dried thoroughly under vacuum to afford l-[(4-bromophenyl)methyl]-7-methyl-2,3-dihydro-lH-indole-2, 3-dione (37.7 g, 87%) as orange solid.Step 2:

[0123] A mixture of l-[(4-bromophenyl)methyl]-7-methyl-2,3-dihydro-lH-indole-2, 3-dione (7.50 g, 21.6 mmol, 1.0 eq) and N-Boc-imino-(triphenyl)phosphorane (8.96 g, 23.7 mmol, 1.1 eq) in anhydrous dioxane (72 mL) was stirred overnight at 100 °C. The solvent was removed in vacuo and the crude product was recrystallized from hot dioxane to afford tert-butyl N-[(3E / Z)-l-[(4-bromophenyl)methyl]-7-methyl-2-oxo-2, 3-dihydro-lH-indol-3-ylidene] carbamate (5.96 g, 64%) as an orange solid.Step 3:

[0124] A degassed suspension of tert-butyl N-[(3E / Z)-l-[(4-bromophenyl)methyl]-7-methyl-2-oxo-2,3-dihydro- lH-indol-3-ylidene] carbamate (3.0 g, 6.289 mmol, 1.0 eq) in anhydrous THF (63 mL, 0.1 M) was cooled to -78 °C and methylmagnesium bromide solution 3 M in Et20 (4.41 mL, 12.6 mmol, 2.0 eq) was added dropwise while maintaining the temperature below -70 °C. After 2 h, the reaction mixture was allowed to warm to room temperature and stirred for an additional 2 h. The mixture was cooled to 0 °C, quenched slowly with water and extracted with EtOAc. The organic layer was dried, filtered and concentrated. The crude material was purified by FCC (EtOAc in Cyclohexane, 0% to 30%) to afford tertbutyl N-{l-[(4-bromophenyl)methyl]-3,7-dimethyl-2-oxo-2,3-dihydro-lH-indol-3-yl}carbamate (2.12 g, 72%) as a white solid.Step 4:

[0125] To a round bottom flask charged with tert-butyl N-{l-[(4-bromophenyl)methyl]-3,7-dimethyl-2-oxo-2, 3-dihydro-lH-indol-3-yl}carbamate (1.6 g, 3.41 mmol, 1.0 eq) was added 4 M HCI in dioxane (12Attorney Docket No. 57547-738.601mL). The reaction mixture was stirred at room temperature for 3 h. The solvent was removed in vacuo and the residue was basified with 5 M NaOH. The mixture was extracted with EtOAc and the organic layer was dried, filtered and concentrated. The residue was purified by FCC (EtOAc in Cyclohexane, 0% to 50%) to afford 3-amino-l-[(4-bromophenyl)methyl]-3,7-dimethyl-2,3-dihydro-lH-indol-2-one (1.22 g, 98%) as a white solid.Step 5:

[0126] A vial was charged with 3-amino-l-[(4-bromophenyl)methyl]-3,7-dimethyl-2,3-dihydro-lH-indol- 2-one (300 mg, 0.808 mmol, 1.0 eq), 4-pyridinesulfonamide (192 mg, 1.21 mmol, 1.5 eq), potassium carbonate (279 mg, 2.02 mmol, 2.5 eq), tBuXPhos (69 mg, 0.162 mmol, 0.2 eq), tris(dibenzylideneacetone)dipalladium(0) (89 mg, 0.097 mmol, 0.12 eq), and suspended in dioxane (5.4 mL). The reaction mixture was stirred at 90°C overnight under argon. The reaction mixture was diluted with EtOAc / iPrOH (9:1) and filtered through celite. The filtrate was concentrated in vacuo and the crude material was purified by FCC (MeOH in DCM, 0% to 5%) to afford N-{4-[(3-amino-3,7-dimethyl-2-oxo-2,3-dihydro-lH-indol-l-yl)methyl] phenyl} pyridine-4-sulfonamide (204 mg, 59%) as an orange solid. MS (ESI):[M+H]+found 423.35, [M-H]’ found 421.00. 'H NMR (300 MHz, DMSO-d6) 8 8.81 - 8.76 (m, 2H), 7.64 -7.58 (m, 2H), 7.27 - 7.21 (m, 1H), 7.04 (s, 4H), 6.96 - 6.87 (m, 2H), 5.00 (d, J= 2.8 Hz, 2H), 2.08 (s, 3H), 1.34 (s, 3H).Preparation 2: N-{4-[(3-amino-3,7-dimethyl-2-oxo-2,3-dihydro-lH-indol-l-yl)methyl| phenyl Jpyridine- 3-sulfonamide3M MeMgBr in Et2O, K2CO3, MgBr2-Et2O tBuXphos, Pd2dba3, THF, -78°C, 4 h Dioxane, 80°C, o / n Step 1 Step 2SOCI2, TEA, aq. NH3, Dioxane, DCM, rt 65°C, o / n Step 3 Step 4Step 1:

[0127] To a mixture of 1-[(4-bromophenyl)methyl]-7-methyl-2,3-dihydro-1H- indole-2, 3-dione (20.0 g, 58.8 mmol, 1.0 eq) in anhydrous THF (294 mL) was added 3 M MeMgBr in Et20 (39.2 mL, 118 mmol) dropwise at -78°C. The reaction mixture was stirred at -78°C for 2 h and was allowed to warm to room temperature for an additional 2 h. The reaction was quenched with saturated ammonium chloride solution and extracted with DCM. The organic layer was washed with brine, dried, and evaporated. The crude product was recrystallized from hot DCM to afford l-[(4-bromophenyl)methyl]-3-hydroxy-3,7-dimethyl-2,3-dihydro-lH-indol-2-one (11.0 g, 52%) as a yellow solid.Attorney Docket No. 57547-738.601Step 2:

[0128] A pressure vessel was charged with l-[(4-bromophenyl)methyl]-3-hydroxy-3,7-dimethyl-2,3-dihydro-lH-indol-2-one (2.8 g, 7.28 mmol, 1.0 eq), 3-pyridinesulfonamide (1.38 g, 8.73 mmol, 1.2 eq), potassium carbonate (2.01 g, 14.6 mmol, 2.0 eq), tBuXPhos (0.556 g, 1.31 mmol, 0.18 eq), tris(dibenzylideneacetone)dipalladium(0) (400 mg, 0.437 mmol, 0.06 eq), and suspended in dioxane (73 mL). The reaction mixture was degassed and the reactor was sealed. The reaction was carried out at 80 °C overnight. The reaction mixture was filtered through celite and washed with EtOAc. The filtrate was concentrated in vacuo and the crude material was purified by FCC (MeOH in DCM, 0% to 5%) to afford N-{4-[(3-hydroxy-3,7-dimethyl-2-oxo-2,3-dihydro-lH-indol-l-yl)methyl]phenyl}pyridine-3-sulfonamide (2.36 g, 69%) as a white solid.Step 3:

[0129] To a cooled solution of N-{4-[(3-hydroxy-3,7-dimethyl-2-oxo-2,3-dihydro-lH-indol-l-yl)methyl]phenyl}pyridine-3-sulfonamide (2.36 g, 5.02 mmol, 1.0 eq) in DCM (50 mL) was added thionyl chloride (0.874 mL, 12.05 mmol, 2.4 eq) and triethylamine (3.08 mL, 22.1 mmol, 4.0 eq) dropwise at 0°C. The reaction mixture was stirred at room temperature for 2 h. The reaction was quenched with brine and the layers were separated. The organic layer was washed with brine, dried, and evaporated to afford N-{4-[(3-chloro-3,7-dimethyl-2-oxo-2,3-dihydro-lH-indol-l-yl)methyl]phenyl}pyridine-3-sulfonamide (2.37 g, 100%) as a brown oil. MS (ESI): [M+H]+found 441.85, 443.85, [M-H]’found 439.95, 441.65.Step 4:

[0130] A solution of N-{4-[(3-chloro-3,7-dimethyl-2-oxo-2,3-dihydro-lH-indol-l-yl)methyl]phenyl}pyridine-3-sulfonamide (2.38 g, 5.088 mmol) in dioxane (5 mL) and NH3 H2O (25%, 40 mL) was stirred at 65°C overnight. The solvents were removed in vacuo and the crude material was purified by FCC (DCM / MeOH: 0-7%) to afford N-{4-[(3-amino-3,7-dimethyl-2-oxo-2,3-dihydro-lH-indol-l-yl)methyl]phenyl}pyridine-3-sulfonamide (500 mg, 20%) as a white solid. MS (ESI): [M+H]+found 422.95;[M-H]- found 421.00.1HNMR(300 MHz, DMSO-de) 58.82 (dd, J= 2.4, 0.8Hz, 1H), 8.76 (dd, J= 4.9, 1.6 Hz, 1H), 8.06 (ddd, J= 8.1, 2.4, 1.5 Hz, 1H), 7.58 (ddd, J= 8.1, 4.8, 0.9 Hz, 1H),7.25 (dd, J = 5.9, 3.0 Hz, 1H), 7.05 (s, 4H), 6.95 - 6.90 (m, 2H), 5.01 (s, 1H), 5.00 (s, 1H), 2.07 (s, 3H), 1.34 (s, 3H).Preparation 3: benzyl 4-hydroxy-3-methoxybenzoate

[0131] A mixture of vanillic acid (5.0 g, 29.7 mmol, 1.0 eq) and potassium bicarbonate (3.57 g, 35.7 mmol, 1.2 eq) were stirred at room temperature for 15 min. To the mixture was added benzyl bromide (5.60 g, 32.7 mmol, 1.1 eq) dropwise and the reaction mixture was stirred at 40 °C for 3 h. The reaction mixture was diluted with MTBE, washed with water and brine, dried, filtered, and concentrated. The residue was purified by FCC (EtOAc in cyclohexane) to afford benzyl 4-hydroxy-3-methoxybenzoate (6.52 g, 25.3Attorney Docket No. 57547-738.601mmol, 85%) as a colorless oil. MS (ESI): [M-H]‘found 256.90. 'H NMR (400 MHz, Chloroform-d) 5 7.71 (dd, J = 8.3, 1.9 Hz, 1H), 7.60 (d, J = 1.9 Hz, 1H), 7.50 - 7.31 (m, 5H), 6.96 (d, J = 8.3 Hz, 1H), 6.02 (s, 1H), 5.37 (s, 2H), 3.97 (s, 3H).Preparation 4: benzyl 3-fluoro-4-hydroxybenzoateNaH, NMP, 40°C, o / n

[0132] To a solution of 3-fluoro-4-hydroxybenzoic acid (2.0 g, 12.8 mmol, 1.0 eq) in anhydrous NMP (25.6 mL, 0.5 M) was added sodium hydride 60% in mineral oil (0.338 g, 14.1 mmol, 1.1 eq) and the resulting mixture was stirred at 40 °C for 1 h. To the suspension was added benzyl bromide (2.41 g, 14.1 mmol, 1.1 eq) dropwise at 40 °C and the reaction was continued overnight at 40 °C. The mixture was poured into water (100 mL) and extracted with 25% EtOAc in cyclohexane (3 x 75 mL). The combined organic layers were washed with brine (1 x 100 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by FCC (EtOAc in cyclohexane 0-30%) to afford benzyl 3-fluoro-4-hydroxybenzoate (1.68 g, 6.82 mmol, 53%) as ayellow solid. MS (ESI): [M-H]’found 244.90.1H NMR (400 MHz, DMSO-d6) 510.90 (s, 1H), 7.73 - 7.65 (m, 2H), 7.49-7.43 (m,2H), 7.43 - 7.38 (m, 2H), 7.38 - 7.31 (m, 1H), 7.11 - 7.02 (m, 1H), 5.31 (s, 2H).Preparation 5: 4-{2-[3-(2,6-dioxopiperidin-3-yl)phenyl]ethoxy}-3-methoxybenzoic acidOHStep 1:

[0133] 2,6-Bis(benzyloxy)-3-bromopyridine (0.4 g, 1.08 mmol, 1.0 eq), 2-[3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]ethan-l-ol (0.295 g, 1.19 mmol, 1.1 eq), cesium carbonate (0.704 g, 2.16 mmol, 2.0 eq) and [l,r-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) DCM complex (Pd(dppf)Ch DCM, 0.088 g, 0.108 mmol, 0.1 eq) was suspended in dioxane (6.0 mL) and water (0.6 mL). The reaction mixture was degassed and the vial was refilled with argon. The reaction was carried out at 100Attorney Docket No. 57547-738.601°C for 5 h. The reaction mixture was diluted with EtOAc and filtered through a pad of Celite. The filtrate was concentrated under reduced pressure and the crude material was purified by FCC (Hex / EtOAc) to give 2-{3-[2,6-bis(benzyloxy)pyridin-3-yl]phenyl}ethan-l-ol (0.467 g, 1.07 mmol, 99%) as an orange oil. Step 2:

[0134] 2-{3-[2,6-Bis(benzyloxy)pyridin-3-yl]phenyl}ethan-l-ol (0.417 g, 0.953 mmol, 1.0 eq), benzyl 4-hydroxy-3-methoxybenzoate (0.271 g, 1.048 mmol, 1.1 eq) and triphenylphosphine (TPP, 0.35 g, 1.33 mmol, 1.4 eq) were dissolved in anhydrous DCM (8 mL). To the mixture was added diisopropyl azodicarboxylate (DIAD, 0.25 g, 1.238 mmol, 1.3 eq) dropwise at 0 °C. The reaction mixture was stirred at room temperature overnight under argon. The mixture was diluted with DCM, washed with water and brine, dried over Na2SO4, and evaporated. The crude material was purified by FCC (Hex / EtOAc) to afford benzyl 4-(2-{3-[2,6-bis(benzyloxy)pyridin-3-yl]phenyl}ethoxy)-3-methoxybenzoate (0.621 g, 0.858 mmol, 90%).Step 3:

[0135] Benzyl 4-(2-{3-[2,6-bis(benzyloxy)pyridin-3-yl]phenyl}ethoxy)-3-methoxybenzoate (0.1 g, 0.138 mmol, 1.0 eq) was dissolved in THF (1.0 mL) and zPrOH (1.0 mL). To the mixture was added 10% Pd / C (0.029 g) and the reaction mixture was stirred at room temperature for 4 h under hydrogen (1 atm). The mixture was diluted with dioxane / DMF (9:1) mixture and filtered through a pad of Celite. The volatiles were removed in vacuo to afford 4- { 2- [3 -(2, 6-dioxopiperi din-3 -yl)phenyl] ethoxy} -3 -methoxy benzoic acid (0.178 g, 0.395 mmol, 66%) as off-white solid. MS (ESI): [M-H]’found 382.00.1H NMR (300 MHz, DMSO-d6) 8 12.63 (s, 1H), 10.84 (s, 1H), 7.53 (dd, J = 8.4, 2.0 Hz, 1H), 7.44 (d, J = 2.0 Hz, 1H), 7.34 -7.17 (m, 3H), 7.12- 7.02 (m, 2H), 4.24 (t, J = 6.9 Hz, 2H), 3.88 - 3.74 (m, 4H), 3.06 (t, J = 6.9 Hz, 2H), 2.89 (s, 1H), 2.73 (d, J = 0.6 Hz, 1H), 2.65 (dt, J = 11.5, 5.5 Hz, 1H), 2.17 (td, J = 11.7, 4.1 Hz, 1H), 2.05 (dq, J = 8.7, 4.9 Hz, 1H)Preparation 6: 4-{2-[3-(2,6-dioxopiperidin-3-yl)phenoxy]ethoxy}-3-methoxybenzoic acidOHAttorney Docket No. 57547-738.601Step 1:

[0136] To degassed mixture of (3-hydroxyphenyl)boronic acid (1.86 g, 13.5 mmol, 1.0 eq), 2,6-bis(benzyloxy)-3-bromopyridine (5.0 g, 13.5 mmol, 1.0 eq) and potassium phosphate tribasic (8.6 g, 40.5 mmol, 3.0 eq) in dioxane (67.52 mL) and water (13.5 mL) was added [1,1 ’ -bis(diphenylphosphino)ferrocene]dichloropalladium(II) DCM complex (Pd(dppf)C12'DCM, 1.10 g, 1.35 mmol, 0.1 eq) and the resulting mixture was heated to 110 °C overnight. The mixture was poured into water (200 mL) and the product was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (1 x 100 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by FCC (EtOAc in cyclohexane, 0-30%) to afford 3-[2,6-bis(benzyloxy)pyridin-3-yl]phenol (4.28 g, 10.3 mmol, 76%) as yellow crystals.Step 2:

[0137] To degassed mixture of 3- [2, 6-bis(benzyloxy)pyri din-3 -yl] phenol (1.5 g, 3.91 mmol, 1.0 eq), 2-((tert-Butyldimethylsilyl)oxy)ethanol (0.759 g, 4.303 mmol, 1.1 eq) and triphenylphosphine (1.24 g, 4.73 mmol, 1.21 eq) in anhydrous THF (19.6 mL) was added diisopropyl azodicarboxylate (DIAD, 1.03 g, 5.08 mmol, 1.3 eq) and the resulting mixture was stirred overnight at 60 °C. The mixture was poured into water (100 mL) and the product was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (1 x 100 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by FCC (EtOAc in cyclohexane, 0-30%) to afford 2,6-bis(benzyloxy)-3-(3-{2-[(tert-butyldimethylsilyl)oxy] ethoxy} phenyl)pyridine (2.0 g, 3.51 mmol, 90%) as yellow solid.Step 3:

[0138] To solution of 2,6-bis(benzyloxy)-3-(3- {2-[(tert-butyldimethylsilyl)oxy]ethoxy}phenyl)pyridine (1.78 g, 3.12 mmol, 1.0 eq) in anhydrous THF (15.6 mL) was added 1 M TBAF in THF (4.68 mL, 4.68 mmol, 1.5 eq) and the resulting mixture was stirred at room temperature overnight. The mixture was poured into water (70 mL) and the product was extracted with 50% EtOAc in cyclohexane (3 x 50 mL). The combined organic layers were washed with water (3 x 50 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by FCC (EtOAc in cyclohexane, 0-35%) to afford 2-{3-[2,6-bis(benzyloxy)pyridin-3-yl]phenoxy}ethan-l-ol (1.3 g, 3.04 mmol, 97%) as a pale yellow solid.Step 4:

[0139] To solution of triphenylphosphine (0.295 g, 1.12 mmol, 1.6 eq), benzyl 4-hydroxy-3-methoxybenzoate (0.19 g, 0.737 mmol, 1.05 eq) and2-{3-[2,6-bis(benzyloxy)pyridin-3-yl]phenoxy}ethan-l-ol (0.3 g, 0.702 mmol, 1.0 eq) in anhydrous THF (3.5 mL) was added diisopropyl azodicarboxylate (DIAD, 0.227 g, 1.12 mmol, 1.6 eq) and the resulting mixture was stirred at 60 °C overnight. The mixture was poured into water (50 mL) and the product was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (1 x 50 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by FCC (EtOAc in cyclohexane, 0-30%) to afford benzyl 4-(2-{3-[2,6-bis(benzyloxy)pyridin-3-yl]phenoxy}ethoxy)-3-methoxybenzoate (0.3 g, 0.449 mmol, 64%) as a yellow solid.Attorney Docket No. 57547-738.601Step 5:

[0140] Benzyl 4-(2-{3-[2,6-bis(benzyloxy)pyridin-3-yl]phenoxy}ethoxy)-3-methoxybenzoate (0.255 g, 0.382 mmol, l. Oeq) was dissolved in THF (7.6 mL) and zPrOH (7.6 mL) and to the mixture was added 10% Pd / C (0.081 g). The reaction mixture was stirred at room temperature overnight under hydrogen (1 atm). The mixture was diluted with dioxane / DMF (9:1) mixture and filtered through a pad of Celite. Volatiles were removed in vacuo to afford 4-{2-[3-(2,6-dioxopiperidin-3-yl)phenoxy]ethoxy}-3-methoxybenzoic acid(0.165 g, 0.372 mmol, 97%). MS (ESI): [M+H] + found 399.90, [M-H]’found 397.95. 'H NMR (400 MHz, DMSO-d6) 5 12.72 (s, 1H), 10.83 (s, 1H), 7.57 (dd, J = 8.4, 2.0 Hz, 1H),7.47 (d, J = 2.0 Hz, 1H), 7.27 (t, J = 7.9 Hz, 1H), 7.12 (d, J = 8.4 Hz, 1H), 6.91 (dd, J = 8.0, 2.6 Hz, 1H), 6.87 (t, J = 2.1 Hz, 1H), 6.82 (d, J = 7.6 Hz, 1H), 4.42 - 4.29 (m, 4H), 3.81 (s, 4H), 2.71 - 2.61 (m, 1H), 2.23 (qd, J = 11.9, 4.3 Hz, 1H), 2.04 (dq, J = 13.8, 5.1 Hz, 1H).

[0141] The following compounds were prepared following general method described for 4-{2-[3-(2,6-dioxopiperidin-3-yl)phenoxy]ethoxy}-3-methoxybenzoic acid:Structure MW LC-MS (m / z)443.45 442.00) ~ NH / -o oX471.51 470.00 oO / =( / - 'HO OHo\y / yo387.36 387.95o0-?GNH425.44 423.95H0" ^0-0 °425.44 424.20Attorney Docket No. 57547-738.601Preparation 7: 4-{3-[3-(2,6-dioxopiperidin-3-yl)phenoxy]propoxy}-3-methoxybenzoic acidStep 1:

[0142] To mixture of 3-[2,6-bis(benzyloxy)pyridin-3-yl]phenol (0.5 g, 1.30 mmol, 1.0 eq) and cesium carbonate (0.637 g, 1.96 mmol, 1.5 eq) in anhydrous DMF (6.5 mL) was added 3 -bromo- 1 -propanol (0.217 g, 1.56 mmol, 1.2 eq) at room temperature and the resulting mixture was heated at 80 °C overnight. The mixture was poured into water (100 mL) and the product was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (1 x50 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by FCC (EtOAc in cyclohexane, 0-35%) to afford 3-{3-[2,6-bis(benzyloxy)pyridin-3-yl]phenoxy}propan-l-ol (0.46 g, 1.04 mmol, 80%) as pale-yellow oil.Step 2:

[0143] To solution of triphenylphosphine (0.257 g, 0.978 mmol, 1.6 eq), benzyl 4-hydroxy-3-methoxybenzoate (0.166 g, 0.642 mmol, 1.05 eq), 3-{3-[2,6-bis(benzyloxy)pyridin-3-yl]phenoxy}propan-l-ol (0.27 g, 0.612 mmol, l. Oeq) in anhydrous THF (3 mL) was added diisopropyl azodicarboxylate (DIAD, 0.198 g, 0.978 mmol, 1.6 eq) and the resulting mixture was stirred at 60 °C overnight. The mixture was poured into water (50 mL) and the product was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (1 x 50 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by FCC (EtOAc in cyclohexane, 0-30%) to afford benzyl 4-(3-{3-[2,6-bis(benzyloxy)pyridin-3-yl]phenoxy}propoxy)-3-methoxybenzoate (0.27 g, 0.396 mmol, 65%) as a pale yellow solid.

[0144] Step 3:Benzyl 4-(3-{3-[2,6-bis(benzyloxy)pyridin-3-yl]phenoxy}propoxy)-3-methoxybenzoate (0.270 g, 0.396 mmol, 1.0 eq) was dissolved in THF (7.9 mL) and zPrOH (7.9 mL) and to the mixture was added 10% Pd / C (0.084 g). The reaction mixture was stirred at room temperature overnight under hydrogen (1 atm). The mixture was diluted with dioxane / DMF (9:1) and filtered through a pad of Celite. The volatiles were removed in vacuo to afford 4-{3-[3-(2,6-dioxopiperidin-3-yl)phenoxy]propoxy}-3-methoxybenzoic acid (0.15 g, 0.345 mmol, 87%) as an off-white solid. MS (ESI): [M+H]+found 413.95, [M-H]‘found 412.00.Attorney Docket No. 57547-738.6011H NMR (400 MHz, DMSO-d6) 8 12.66 (s, 1H), 10.82 (s, 1H), 7.55 (dd, J = 8.4, 2.0 Hz, 1H), 7.45 (d, J = 2.0 Hz, 1H), 7.24 (t, J = 7.9 Hz, 1H), 7.09 (d, J = 8.5 Hz, 1H), 6.87 (dd, J = 8.0, 2.5 Hz, lH), 6.82 (t, J = 2.1 Hz, 1H), 6.79 (d, J = 7.6 Hz, 1H), 4.20 (t, J = 6.2 Hz, 2H), 4.13 (t, J = 6.2 Hz, 2H), 3.80 (s, 4H), 2.71 - 2.58 (m, 1H), 2.45 (t, J = 4.2 Hz, 1H), 2.20 (p, J = 6.7, 6.1 Hz, 3H), 2.02 (dq, J = 13.6, 4.9 Hz, 1H).Preparation 8: 4-({l-[3-(2,6-dioxopiperidin-3-yl)phenyl]azetidin-3-yl}oxy)-3-methoxybenzoic acidStep 1:

[0145] A pressure reactor was charged with 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-l,3,2-di oxaborolan-2-yl)pyri dine (5.0 g, 12.0 mmol, 1.0 eq), l-bromo-3-iodobenzene (4.41 g, 2 mL, 15.6 mmol, 1.3 eq) and potassium phosphate (5.09 g, 24.0 mmol, 2.0 eq). The reactants were suspended in dioxane (60 mL) and water (30 mL) and the mixture was degassed thoroughly. To the mixture was added [1,1’ -bis(diphenylphosphino)ferrocene]dichloropalladium(II) DCM complex (Pd(dppf)C12'DCM, 0.978 g, 1.20 mmol, 0.1 eq) and the mixture was purged again with argon. The reactor was sealed and the mixture was stirred at 110 °C for 3 h. The mixture was passed through celite and washed with EtOAc. The combined filtrates were concentrated and the residue was partitioned between EtOAc and water. The layers were separated and the organic layer was washed with brine, dried, filtered and concentrated. The residue was purified by FCC (EtOAc in cyclohexane, 0-5%) to afford 2,6-bis(benzyloxy)-3-(3-bromophenyl)pyridine (4.45 g, 75%) as a pale-yellow oil.Step 2:

[0146] A mixture of [(2,6-dimethylphenyl)carbamoyl]formic acid (0.062 g, 0.323 mmol, 0.2 eq), 3-hydroxyazeti dine hydrochloride (0.265 g, 2.42 mmol, 1.5 eq), copper(I) iodide (0.031 g, 0.161 mmol, 0.1 eq), potassium phosphate (1.03 g, 4.84 mmol, 3.0 eq) and 2,6-bis(benzyloxy)-3-(3-bromophenyl)pyridine (0.8 g, 1.613 mmol, l. Oeq) in anhydrous DMSO (8.74 mL) was purged with argon and then stirred at 105 °C overnight. Solids were filtered off and the filtrate was diluted with EtOAc and washed with 10% aqueous NaH2PO4 and 5% aqueous LiCl. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by FCC (EtOAc in hexane, 10 to 50%) to afford l-{3-[2,6-bis(benzyloxy)pyridin-3-yl]phenyl}azetidin-3-ol (0.666 g, 1.47 mmol, 91%)Attorney Docket No. 57547-738.601Step 3:

[0147] To a suspension of benzyl 4-hydroxy-3-methoxybenzoate (0.452 g, 1.75 mmol, 1.2 eq), 1-{3-[2,6-bis(benzyloxy)pyridin-3-yl]phenyl}azetidin-3-ol (0.660 g, 1.46 mmol, 1.0 eq) and 1,1'- O(azodicarbonyl)dipiperidine (ADDP, 0.921 g, 3.65 mmol, 2.5 eq) in anhydrous THF (13 mL) was added tri butylphosphine (0.912 mL, 3.65 mmol, 2.5 eq) and the resulting mixture was stirred at 60 °C overnight. The mixture was poured into water and the product was extracted with EtOAc. The combined organic layerswere washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by FCC (EtOAc in cyclohexane, 0-50%) to afford benzyl 4-[(l-{3-[2,6-bis(benzyloxy)pyridin-3- ^^zyl]phenyl}azetidin-3-yl)oxy]-3-methoxybenzoate (0.31 g, 0.448 mmol, 31%) as a clear oil.Step 4: 4-({l-[3-(2,6-dioxopiperidin-3-yl)phenyl]azetidin-3-yl}oxy)-3-methoxybenzoic acido

[0148] Benzyl 4-[(l-{3-[2,6-bis(benzyloxy)pyridin-3-yl]phenyl}azetidin-3-yl)oxy]-3-methoxybenzoate \ xz(0.31 g, 0.448 mmol, 1.0 eq) was dissolved in THF (3 mL) and zPrOH (3 mL) and 10% Pd / C (0.095 g) was oadded. The reaction mixture was stirred at room tem *p derature overnight under hydrogen (1 atm). The mixture / / xzzwas diluted with ethyl acetate and filtered thro \ / u°^gh a pad of Celite. The volatiles were removed in vacuo and the residue was purified by FCC (iPrOH in cyclohexane, 0-50%) to afford 4-({l-[3-(2,6-dioxopiperidin-3-yl)phenyl]azetidin-3-yl}oxy)-3-methoxybe °nzoic acid (0.183 g, 0.410 mmol, 92%) as an off-white solid. MS 0 x(ESI): [M+H]+found 411.10, [M-H]’found 408.80. / o A

[0149] The following compounds were prepared following general method described for 4-({ l-[3-(2,6- o o —dioxopiperidin-3-yl)phenyl]azetidin-3-yl}oxy)-3-methoxybenzoic acid:Structure MW LC-MS (m / z) oX oX498.53 497.55424.45 425.40, 422.85438.48 439.35, 436.85450.49 451.45, 449.15Attorney Docket No. 57547-738.601Preparation 9: N-{4-[(3-hydroxy-3,7-dimethyl-2-oxo-2,3-dihydro-1H-indol-1-yl)methyl]phenyl}-N-{[2-(trimethylsilyl)ethoxy]methyl}pyridine-4-sulfonamideStep 1:

[0150] A pressure vessel was charged with l-[(4-bromophenyl)methyl]-3-hydroxy-3,7-dimethyl-2,3-dihydro-lH-indol-2-one (2.0 g, 5.20 mmol, 1.0 eq), 4-pyridinesulfonamide (0.987 g, 6.24 mmol, 1.2 eq), potassium carbonate (1.44 g, 10.4 mmol, 2.0 eq), tBuXPhos (0.398 g, 0.936 mmol, 0.18 eq), tris(dibenzylideneacetone)dipalladium(0) (0.285 g, 0.312 mmol, 0.06 eq) and suspended in dioxane (52 mL). The reaction mixture was degassed and the reactor was sealed. The reaction was carried out at 80 °C overnight. The reaction mixture was filtered through celite and washed with EtOAc. The filtrate was concentrated in vacuo. The crude material was purified by FCC (MeOH in DCM, 0% to 10%) to afford N-{4-[(3-hydroxy-3,7-dimethyl-2-oxo-2,3-dihydro-lH-indol-l-yl)methyl]phenyl}pyridine-4-sulfonamide (1.58 g, 65%) as a white solid.Step 2:

[0151] To a cooled solution of N-{4-[(3-hydroxy-3,7-dimethyl-2-oxo-2,3-dihydro-lH-indol-l-yl)methyl]phenyl}pyridine-4-sulfonamide (0.8 g, 1.7 mmol, 1.0 eq) and N, N-diisopropylethylamine (DIPEA) (0.592 mL, 3.4 mmol, 2.0 eq) in anhydrous DCM (20 mL) was added ((2-(chloromethoxy)ethyl)trimethylsilane (0.312 g, 1.87 mmol, 1.1 eq) at 0 °C. The reaction mixture was stirred at room temperature overnight under argon. The reaction mixture was diluted with DCM, washed with NH4CI solution and brine, dried over ISfeSCL, and evaporated. The crude material was purified by FCC (MeOH in DCM) to afford N-{4-[(3-hydroxy-3,7-dimethyl-2-oxo-2,3-dihydro-lH-indol-l-yl)methyl]phenyl}-N-{[2-(trimethylsilyl)ethoxy]methyl}pyridine-4-sulfonamide (0.646 g, 0.992 mmol, 58%) as a beige solid. MS (ESI): [M+H] + found 554.90. 'H NMR (300 MHz, DMSO-d6) 8 8.88 - 8.75 (m, 2H), 7.63 - 7.53 (m, 2H), 7.29 - 7.09 (m, 5H), 7.00 - 6.93 (m, 2H), 6.03 (s, 1H), 5.09 (d, J = 4.1 Hz, 4H), 3.59 - 3.50 (m, 2H), 2.13 (s, 3H), 1.44 (d, J = 5.7 Hz, 3H), 0.87 - 0.77 (m, 2H), -0.06 (s, 9H).

[0152] The following compounds were prepared following general method described for N-{4-[(3-hydroxy-3,7-dimethyl-2-oxo-2,3-dihydro-lH-indol-l-yl)methyl]phenyl}-N-{[2-(trimethylsilyl)ethoxy]methyl}pyridine-4-sulfonamide:Attorney Docket No. 57547-738.601Structure MW LC-MS (m / z)1. 574.74 572.80P / O ZPreparation 10: 3-(3-{3-[(2-{l-[(4-aminophenyl)methyl]-3,7-dimethyl-2-oxo-2,3-dihydro-lH-indol-3-yl}-7-methoxy-l-oxo-l,2-dihydroisoquinolin-6-yl)oxy]propoxy}phenyl)piperidine-2, 6-dione XX) / N coStep 1:

[0153] To a cooled suspension of methyl 4-hydroxy-3-methoxybenzoate (0.222 g, 1.22 mmol, 1.1 eq), 3-{3-[2,6-bis(benzyloxy)pyridin-3-yl]phenoxy}propan-l-ol (0.5 g, 1.11 mmol, 1.0 eq), and 1,1'-(azodicarbonyl)dipiperidine (ADDP, 0.56 g, 2.22 mmol, 2.0 eq) in anhydrous THF (5.55 mL) was added tributylphosphine (0.554 mL, 2.22 mmol, 2.0 eq) and the resulting mixture was stirred at 50 °C overnight. The mixture was poured into water and the product was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified byAttorney Docket No. 57547-738.601FCC (EtOAc in cyclohexane, 0-30%) to afford Methyl 4-(3-{3-[2,6-bis(benzyloxy)pyridin-3-yl] phenoxy }propoxy)-3-methoxybenzoate (0.65 g, 1.052 mmol, 95%) as pale beige solid.Step 2:

[0154] To a solution of methyl 4-(3-{3-[2,6-bis(benzyloxy)pyridin-3-yl]phenoxy}propoxy)-3-methoxy benzoate (0.45 g, 0.728 mmol, 1.0 eq) in THF (3.64 mL) was added a solution of lithium hydroxide monohydrate (0.092 g, 2.18 mmol, 3.0 eq) in water (1.82 mL). The reaction was continued at 50 °C overnight. THF was removed in vacuo. The residue was acidified with 1 M HC1, extracted with EtOAc, dried, fdtered and concentrated to afford 4-(3-{3-[2,6-bis(benzyloxy)pyridin-3-yl]phenoxy}propoxy)-3-methoxy benzoic acid (0.425 g, 0.704 mmol, 97%)Step 3:

[0155] 4-(3-{3-[2,6-Bis(benzyloxy)pyridin-3-yl]phenoxy}propoxy)-3-methoxybenzoic acid (0.25 g, 0.414 mmol, 1.0 eq), 3-amino-l-[(4-bromophenyl)methyl]-3,7-dimethyl-2,3-dihydro-lH-indol-2-one (0.177 g, 0.435 mmol, 1.05 eq), 1 -hydroxy benzotriazole hydrate (0.07 g, 0.456 mmol, 1.1 eq), N, N-diisopropylethylamine (DIPEA, 0.216 mL, 1.24 mmol, 3.0 eq) and l-ethyl-3-(3-dimethylaminopropyl)carbodiimi de hydrochloride (EDCI HC1, 0.119 g, 0.621 mmol, 1.5 eq) were dissolved in anhydrous DMF (2.1 mL). The reaction mixture was stirred at room temperature overnight under argon. The mixture was diluted with water and extracted with EtOAc / iPrOH (9:1) and the organic layer was washed with brine, dried over Na2SO4, and evaporated. The crude product was purified by FCC (EtOAc in cyclohexane) to afford 4-(3-{3-[2,6-bis(benzyloxy)pyridin-3-yl]phenoxy}propoxy)-N-{l-[(4-bromophenyl)methyl]-3,7-dimethyl-2-oxo-2,3-dihydro-lH-indol-3-yl}-3-methoxybenzamide (0.37 g, 0.383 mmol, 92%).Step 4:

[0156] To degassed solution of vinyl carbonate (0.165 g, 1.91 mmol, 5.0 eq), 4-(3-{3-[2,6-bis(benzyloxy)pyridin-3-yl]phenoxy}propoxy)-N-{l-[(4-bromophenyl)methyl]-3,7-dimethyl-2-oxo-2,3-dihydro-lH-indol-3-yl}-3-methoxybenzamide (0.37 g, 0.383 mmol, 1.0 eq) in anhydrous 1,2-di chloroethane (3.83 mL) was added tris(acetonitrile)pentamethylcyclopentadienylrhodium(III) hexafluoroantimonate (0.032 g, 0.038 mmol, 0.1 eq) and the resulting mixture was stirred at 80 °C overnight. The volatiles were removed in vacuo and the crude mixture was purified by FCC (EtOAc in cyclohexane, 0-75%) to give 6-(3-{3-[2,6-bis(benzyloxy)pyridin-3-yl]phenoxy}propoxy)-2-{1-[(4-bromophenyl)methyl]-3,7-dimethyl-2-oxo-2,3-dihydro-1H-indol-3-yl}-7-methoxy-1,2-dihydroisoquinolin-1-one (0.33 g, 0.332 mmol, 87%), as a pale beige solid.1H NMR (300 MHz, DMSO-d6) δ 7.84 (d, J = 7.9 Hz, 1H), 7.76 (d, J= 8.1 Hz, 1H), 7.65 - 7.55 (m, 2H), 7.51 -7.20 (m, 16H), 7.18 -7.14 (m, 1H), 7.13 - 7.07 (m, 1H), 6.98 (d, J = 5.1 Hz, 1H), 6.97 -6.82 (m, 4H), 6.73 (d, J = 7.8 Hz, 1H), 6.54 (d, J = 8.2 Hz, 1H), 5.39 (s, 4H), 5.16 (s, 2H), 4.26 (t, J = 6.1 Hz, 2H), 4.12 (t, J = 5.9 Hz, 2H), 3.80 (s, 3H), 2.21 (s, 6H), 1.82 (s, 3H).Step 5:

[0157] A pressure reactor was charged with XPhos (0.049 g, 0.102 mmol, 0.4 eq), benzophenone imine (0.06 g, 0.333 mmol, 1.3 eq), potassium carbonate (0.106 g, 0.768 mmol, 3.0 eq), 6-(3-{3-[2,6-Attorney Docket No. 57547-738.601bis(benzyloxy)pyridin-3-yl]phenoxy}propoxy)-2-{l-[(4-bromophenyl)methyl]-3,7-dimethyl-2-oxo-2,3-dihydro-lH-indol-3-yl}-7-methoxy-l,2-dihydroisoquinolin-l-one (0.254 g, 0.256 mmol, 1.0 eq) and suspended in anhydrous dioxane (2.56 mL). To the mixture was added tris(dibenzylideneacetone)dipalladium(0) (0.059 g, 0.064 mmol, 0.25 eq) and the resulting mixture was degassed and the vial was sealed. The reaction was carried out at 100 °C overnight. The solvent was removed under vacuum and the residue was suspended in MeOH (1 mL). To the solution was added sodium acetate (0.063 g, 0.768 mmol, 3.0 eq) and hydroxylamine hydrochloride (0.053 g, 0.768 mmol, 3.0 eq). The reaction was continued at room temperature overnight. After the reaction was completed, the volatiles were removed in vacuo and the residue was purified by FCC (EtOAc in cyclohexane, 0-100%) to afford 2-{1-[(4-aminophenyl)methyl]-3,7-dimethyl-2-oxo-2,3-dihydro-1H-indol-3-yl}-6-(3-{3-[2,6-bis(benzyloxy)pyridin-3-yl]phenoxy}propoxy)-7-methoxy-1,2-dihydroisoquinolin-1-one (0.165 g, 0.16 mmol, 63%) as a pale beige solid.Step 6:

[0158] 2-{l-[(4-Aminophenyl)methyl]-3,7-dimethyl-2-oxo-2,3-dihydro-lH-indol-3-yl}-6-(3-{3-[2,6-bis(benzyloxy)pyridin-3-yl]phenoxy}propoxy)-7-methoxy-l,2-dihydroisoquinolin-l-one (0.080 g, 0.077 mmol, 1.0 eq) was dissolved in THF (1.55 mL) and zPrOH (1.55 mL) and 10% Pd / C (0.082 g) was added. The reaction mixture was stirred at room temperature overnight under hydrogen (1 atm). The mixture was diluted with THF and filtered through a pad of Celite. The volatiles were removed in vacuo to give crude 3-(3-{3-[(2-{l-[(4-aminophenyl)methyl]-3,7-dimethyl-2-oxo-2,3-dihydro-lH-indol-3-yl}-7-methoxy-l-oxo-l,2-dihydroisoquinolin-6-yl)oxy]propoxy}phenyl)piperidine-2, 6-dione (0.060 g, 0.068 mmol, 88%) as apale beige solid. MS (ESI): [M+H]+found 701.45.1H NMR (300 MHz, DMSO-d6) δ 10.82 (s, 1H), 7.82 (d, J = 8.0Hz, 1H), 7.43 (s, 1H), 7.31 -7.19 (m, 3H), 7.12 - 7.00 (m, 2H), 6.95 (t, J = 4.7 Hz, 1H), 6.85 (d, J = 10.2 Hz, 4H), 6.84-6.75 (m, 4H), 6.72(d, J = 7.9Hz, 1H), 6.65 (s, 1H), 6.61 - 6.50 (m, 2H), 5.28 - 4.79 (m, 4H), 4.27 (d, J = 4.6 Hz, 2H), 4.15 (t, J = 5.9 Hz, 3H), 3.81 (s, 3H), 2.29 (s, 3H), 2.24 (d, J = 6.0 Hz, 2H), 2.18 (s, 3H), 2.02 (dd, J = 12.6, 5.2 Hz, 1H), 1.80 (s, 3H).Preparation 11: 4-({3-[4-(4-hydroxy-3-methoxyphenyl)-lH-l,2 -triazol-l-yl]-3,7-dimethyl-2-oxo-2,3-dihydro-lH-indol-l-yl}methyl)-N-(2-methylpyridin-3-yl)-N-{[2-(trimethylsilyl)ethoxy]methyl}benzene-l-sulfonamideAttorney Docket No. 57547-738.601Step 1:

[0159] To a cooled solution of dimethyl (l-diazo-2-oxo-propyl)phosphonate (1.49 mL, 9.91 mmol, 1.2 eq), 4-benzyloxy-3-methoxybenzaldehyde (2.0 g, 8.25 mmol, 1.0 eq) in anhydrous MeOH (41 mL) was added potassium carbonate (2.28 g, 16.5 mmol, 2.0 eq) at 0 °C. The reaction was continued and allowed to slowly reach room temperature overnight. The mixture was diluted with water (150 mL) and extracted with MTBE (3 x 50 mL). The combined organic layers were washed with brine, dried over Na2SO4, and evaporated. The crude material was purified by FCC (EtOAc in cyclohexane, 0-15%) to afford 1-(benzyloxy)-4-ethynyl-2-methoxybenzene (1.62 g, 6.73 mmol, 82%) as pale beige solid.1H NMR (400 MHz, DMSO-d6) δ 7.48 - 7.29 (m, 5H), 7.07 - 6.99 (m, 3H), 5.11 (s, 2H), 4.03 (s, 1H), 3.78 (s, 3H).Step 2:

[0160] A degassed suspension of copper(II) sulfate pentahydrate (0.047 g, 0.19 mmol, 0.2 eq), sodium ascorbate (0.075 g, 0.38 mmol, 0.4 eq), 4-[(3-azido-3,7-dimethyl-2-oxo-2,3-dihydro-lH-indol-l-yl)methyl]-N-(2-methylpyridin-3-yl)benzene-l -sulfonamide (0.45 g, 0.95 mmol, 1.0 eq) and l-(benzyloxy)-4-ethynyl-2-methoxybenzene (0.274 g, 1.14 mmol, 1.2 eq) in acetonitrile (9.5 mL) and water (4.75 mL) was stirred at 65 °C overnight. The mixture was diluted with DCM, washed with water, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by FCC (MeOH in DCM, 0-5%) to give 4-[(3-{4-[4-(benzyloxy)-3-methoxyphenyl]-lH-l,2,3-triazol-l-yl}-3,7-dimethyl-2-oxo-2,3-dihydro-lH-indol-l-yl)methyl]-N-(2-methylpyridin-3-yl)benzene-l -sulfonamide (0.65 g, 0.918 mmol, 97%) as pale beige solid. > HNMR (300 MHz, DMSO-d6) 9.89 (s, 1H), 8.91 (s, 1H), 8.25 (s, 1H), 7.66 (d, J = 8.3 Hz, 2H), 7.52 -7.31 (m, 10H), 7.25 (d, J = 7.1 Hz, 1H), 7.14(d, J = 8.4 Hz, 3H), 7.03 (t, J = 7.5 Hz, 1H), 5.33 (d, J = 5.5 Hz, 2H), 5.12 (s, 2H), 3.85 (s, 3H), 2.19 (s, 3H), 2.16 (s, 3H), 2.10 (s, 3H).Step 3:

[0161] To a cooled solution of 4-[(3-{4-[4-(benzyloxy)-3-methoxyphenyl]-lH-l,2,3-triazol-l-yl}-3,7-dimethyl-2-oxo-2,3-dihydro-lH-indol-l-yl)methyl]-N-(2-methylpyridin-3-yl)benzene-l-sulfonamide (0.65Attorney Docket No. 57547-738.601g, 0.918 mmol, 1.0 eq) and N,N-Diisopropylethylamine (DIPEA, 0.48 mL, 2.75 mmol, 3.0 eq) in anhydrous DCM (9.2 mL) was added ((2-(chloromethoxy)ethyl)trimethylsilane (0.184 g, 1.10 mmol, 1.2 eq) at 0 °C. The reaction mixture was stirred at room temperature overnight under argon. The reaction mixture was diluted with DCM, washed with 5% citric acid and brine, dried over Na2SO4, and evaporated. The crude material was purified by FCC (MeOH in DCM) to afford 4-[(3-{4-[4-(benzyloxy)-3-methoxyphenyl]-lH-1,2,3-triazol-l -yl } -3,7-dimethyl-2-oxo-2,3-dihydro-lH-indol-l -yl)methyl] -N-(2-methylpyridin-3-yl)-N-{ [2-(trimethylsilyl)ethoxy]methyl} benzene- 1 -sulfonamide (0.695 g, 0.769 mmol, 84%) as a pale beige solid. MS (ESI): [M+H]+found 831.90.1H NMR (300 MHz, DMSO-d6) 8 8.92 (s, 1H), 8.43 (s, 1H), 7.71 (d, J = 8.6 Hz, 2H), 7.61 -7.29 (m, 9H), 7.30 -7.09 (m, 5H), 7.04 (t, J = 7.6 Hz, 1H), 5.49 - 5.26 (m, 2H), 5.12 (s, 4H), 3.85 (s, 3H), 3.55 (t, J = 8.3 Hz, 2H), 2.31 (s, 3H), 2.23 (s, 3H), 2.17 (s, 3H), 0.79 (dd, J = 9. 1, 7.3 Hz, 2H), -0.06 (s, 9H).Step 4:

[0162] 4-[(3-{4-[4-(Benzyloxy)-3-methoxyphenyl]-lH-l,2,3-triazol-l-yl}-3,7-dimethyl-2-oxo-2,3-dihydro- IH-indol- l-yl)methyl] -N-(2-methylpyridin-3-yl)-N- { [2-(trimethylsilyl)ethoxy] methyl} benzene- 1 -sulfonamide (0.695 g, 0.769 mmol, 1.0 eq) was dissolved in THF (15.5 mL) and MeOH (7.7 mL) and 10% Pd / C (0.286 g) was added. The reaction mixture was stirred at room temperature overnight under hydrogen (1 atm). The mixture was diluted with THF and filtered through a pad of Celite. The volatiles were removed in vacuo and the crude material was purified by FCC (MeOH in DCM, 0-3%) to give 4-({3-[4-(4-hydroxy-3-methoxyphenyl)-lH-l,2,3-triazol-l-yl]-3,7-dimethyl-2-oxo-2,3-dihydro-lH-indol-l-yl}methyl)-N-(2-methylpyridin-3-yl)-N-{[2-(trimethylsilyl)ethoxy]methyl}benzene-l-sulfonamide (0.580 g, 0.72 mmol, 94%) as a pale beige solid. MS (ESI): [M+H] found 742.05. > HNMR (300 MHz, DMSO-d6) 89.19(s, 1H), 8.85 (s, 1H), 8.44 (dd, J = 4.4, 2.1 Hz, 1H), 7.72 (d, J = 8.5 Hz, 2H), 7.54 (d, J = 8.7 Hz, 2H), 7.44 (d, J = 2.0 Hz, 1H), 7.34 (dd, J = 8.1,2.0 Hz, 1H), 7.29 - 7.24 (m, 1H), 7.23 - 7.12 (m, 3H), 7.04 (t, J = 7.5 Hz, 1H), 6.85 (d, J = 8.2 Hz, 1H), 5.37 (d, J = 7.2 Hz, 2H), 5.02 (s, 2H), 3.85 (s, 3H), 3.56 (t, J = 8.3 Hz, 2H), 2.32 (s, 3H), 2.23 (s, 3H), 2.17 (s, 3H), 0.84 - 0.74 (m, 2H), -0.06 (s, 9H).Preparation 12: 3-(4-hydroxy-l-oxo-2,3-dihydro-lH-isoindol-2-yl)-l-{ [2-(trimethylsilyl)ethoxy]methyl}piperidine-2, 6-dioneAttorney Docket No. 57547-738.601Step 1:

[0163] To a solution of 3-(4-hydroxy-1-oxo-1,3-dihydroisoindol-2-yl)piperidine-2,6-dione (3.0 g, 11.5 mmol, 1.0 eq) and DMAP (0.141 g, 1.15 mmol, 0.1 eq) in anhydrous pyridine (30 mL) was added di-tert-butyl dicarbonate (2.77 g, 12.7 mmol, 1.1 eq) and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with ice-cold water (7.5 mL) and acidified to pH 5-6 with 1 M HC1 solution. The resultant precipitate was collected, rinsed with water, and dried to afford tert-butyl 2-(2,6-dioxopiperidin-3-yl)-l-oxo-2,3-dihydro-lH-isoindol-4-yl carbonate (3.74 g, 10.4 mmol, 90%) as a white solid.Step 2:

[0164] To a cooled solution of tert-butyl 2-(2,6-dioxopiperidin-3-yl)-l-oxo-2,3-dihydro-lH-isoindol-4-yl carbonate (3.74 g, 10.4 mmol, 1.0 eq) in anhydrous DMF (74.8 mL) was added sodium hydride (60% in mineral oil, 0.457 g, 11.4 mmol, 1.1 eq) portion -wise and the reaction mixture was stirred for 30 min at 0 °C To the mixture was added (2-(chloromethoxy)ethyl)trimethylsilane (1.90 g, 11.4 mmol, 1.1 eq) dropwise and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with 5% NaH2PO4 aqueous solution and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over Na2SO4, and evaporated. The crude material was purified by FCC (EtOAc in cyclohexane, 0-70%) to give tert-butyl 2-(2,6-dioxo-l-{[2-(trimethylsilyl)ethoxy]methyl}piperidin-3-yl)-l-oxo-2, 3-dihydro-lH-isoindol-4-yl carbonate (3.78 g, 7.70 mmol, 74%) as a pale beige solid.

[0165] Step 3:To a solution of tert-butyl 2-(2,6-dioxo-1-{[2-(trimethylsilyl)ethoxy]methyl}piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-yl carbonate (3.78 g, 7.70 mmol, 1.0 eq) in DCM (75.5 mL) was added piperidine (18.9 mL). The reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with DCM, washed with 10% citric acid and brine, dried over Na2SO4. and evaporated. The crude material was purified by FCC (EtOAc in cyclohexane, 0-100%) to afford 3-(4-hydroxy-l-oxo-2,3-dihydro-lH-isoindol-2-yl)-l-{[2-(trimethylsilyl)ethoxy]methyl}piperidine-2, 6-dione (2.80 g, 7.16 mmol, 93%) as a white solid.Attorney Docket No. 57547-738.601Preparation 13: 3,7-dimethyl-l-({4-[(2-methylpyridin-3-yl)({[2- (trimethylsilyl)ethoxy]methyl})sulfamoyl]phenyI}methyI)-2-oxo-2,3-dihydro-lH-indol-3-yI 4-hydroxy- 3-methoxybenzoatePyridine, DCM, O°C-rt, o / n SEMCI, DIPEA, DCM, O°C-rt, 2 h Step 4Step 5H2(1 atm), Pd / C, MeOH, rt, o / n Step 6Step 1:

[0166] A flame-dried reactor was charged with l-[(4-bromophenyl)methyl]-3-hydroxy-3,7-dimethyl-2,3-dihydro-lH-indol-2-one (5.0 g, 13.8 mmol, 1.0 eq), N, N-diisopropylethylamine (DIPEA, 5.99 mL, 34.3 mmol, 2.5 eq), and XantPhos (2.38 g, 4.12 mmol, 0.3 eq). The reactants were dissolved in anhydrous dioxane (69 mL) and the mixture was degassed and refilled with argon. To the mixture was added tris(dibenzylideneacetone)dipalladium(0) (1.26 g, 1.37 mmol, 0.1 eq) and benzyl mercaptan (1.79 g, 14.4 mmol, 1.05 eq). The reaction mixture was stirred at 110 °C overnight. The mixture was filtered through a pad of celite and the volatiles were removed in vacuo. The crude material was purified by FCC (MTBE in DCM, 0-10%) to afford l-{[4-(benzylsulfanyl)phenyl]methyl}-3-hydroxy-3,7-dimethyl-2,3-dihydro-lH-indol-2-one (5.03 g, 9.74 mmol, 71%).Step 2:

[0167] To a solution of l-{[4-(benzylsulfanyl)phenyl]methyl}-3-hydroxy-3,7-dimethyl-2,3-dihydro-lH-indol-2-one (2.2 g, 4.24 mmol, 1.0 eq), DMAP (1.03 g, 8.47 mmol, 2.0 eq) and 4-(benzyloxy)-3-methoxybenzoic acid (1.42 g, 5.51 mmol, 1.3 eq) in anhydrous DCM (21 mL) was added DCC (1.75 g, 8.47 mmol, 2.0 eq) and the mixture was stirred at 40 °C overnight. The solids were filtered off and the filtrate was concentrated. The crude material was purified by FCC (EtOAc in cyclohexane, 0-20%) to give 1- { [4-(benzylsulfanyl)phenyl]methyl}-3,7-dimethyl-2-oxo-2,3-dihydro-lH-indol-3-yl 4-(benzyloxy)-3-methoxybenzoate (2.98 g, 3.56 mmol, 84%).Attorney Docket No. 57547-738.601Step 3:

[0168] To a cooled solution of l-{[4-(benzylsulfanyl)phenyl]methyl}-3,7-dimethyl-2-oxo-2,3-dihydro-lH-indol-3-yl 4-(benzyloxy)-3-methoxybenzoate (2.98 g, 3.55 mmol, 1.0 eq), glacial acetic acid (0.304 mL, 5.32 mmol, 1.5 eq) in ACN (101 mL) and water (2.4 mL) was added l,3-dichloro-5,5-dimethylhydantoin (1.01 g, 5.14 mmol, 1.45 eq) portion-wise. The reaction mixture was stirred at 0 °C for 2 h, then at room temperature for 20 min. The mixture was diluted with EtOAc and washed with water. The organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by FCC (EtOAc in cyclohexane, 0-20%) to give l-{[4-(chlorosulfonyl)phenyl]methyl}-3,7-dimethyl-2-oxo-2,3-dihydro-lH-indol-3-yl 4-(benzyloxy)-3-methoxybenzoate (1.87 g, 3.09 mmol, 87%).Step 4:

[0169] To a solution of 1 - { [4-(chlorosulfonyl)phenyl]methyl}-3,7-dimethyl-2-oxo-2,3-dihydro- IH-indol- 3-yl 4-(benzyloxy)-3-methoxybenzoate (2.95 g, 4.87 mmol, 1.0 eq) in anhydrous DCM (24 mL) was added anhydrous pyridine (0.786 mL, 9.73 mmol, 2.0 eq) at 0°C followed by 3-aminopicoline (1.05 g, 9.73 mmol, 2.0 eq). The reaction mixture was stirred at room temperature overnight. The solids were filtered off, washed with DCM and the filtrate was concentrated. The crude material was purified by FCC (MeOH in DCM) to give 3,7-dimethyl-l-({4-[(2-methylpyridin-3-yl)sulfamoyl]phenyl}methyl)-2-oxo-2,3-dihydro-lH-indol-3-yl 4-(benzyloxy)-3-methoxybenzoate (2.05 g, 3.02 mmol, 62%).Step 5:

[0170] To a cooled solution of 3,7-dimethyl-l-({4-[(2-methylpyridin-3-yl)sulfamoyl]phenyl}methyl)-2-oxo-2, 3-dihydro-lH-indol-3-yl 4-(benzyloxy)-3-methoxybenzoate (2.05 g, 3.02 mmol, 1.0 eq) andN, N-diisopropylethylamine (DIPEA, 1.58 mL, 9.07 mmol, 3.0 eq) in anhydrous DCM (25 mL) was added (2-(chloromethoxy)ethyl)trimethylsilane (1.01 g, 6.05 mmol, 2.0 eq) dropwise at 0°C. The reaction mixture was stirred at room temperature for 2 h. The volatiles were removed in vacuo and the crude material was purified by FCC (EtOAc in cyclohexane, 0-50%) to afford 3,7-dimethyl-l-({4-[(2-methylpyridin-3-yl)({[2-(trimethylsilyl)ethoxy]methyl})sulfamoyl]phenyl}methyl)-2-oxo-2,3-dihydro-lH-indol-3-yl 4-(benzyloxy)-3 -methoxy benzoate (1.73 g, 2.15 mmol, 71%).Step 6:

[0171] To a solution of 3,7-dimethyl-l-({4-[(2-methylpyridin-3-yl)({[2- (trimethylsilyl)ethoxy]methyl})sulfamoyl]phenyl}methyl)-2-oxo-2,3-dihydro-lH-indol-3-yl 4-(benzyloxy)-3 -methoxy benzoate (1.53 g, 1.89 mmol, 1.0 eq) in MeOH (38 mL) was added 10% Pd / C (0.504 g). The reaction mixture was stirred at room temperature overnight under hydrogen (1 atm). The mixture was filtered through a pad of Celite and the volatiles were removed in vacuo to give 3,7-dimethyl-l-({4-[(2-methylpyridin-3-yl)({[2-(trimethylsilyl)ethoxy]methyl})sulfamoyl]phenyl}methyl)-2-oxo-2,3-dihydro-lH-indol-3-yl 4-hydroxy-3-methoxybenzoate (1.28 g, 1.67 mmol, 88%). MS (ESI): [M+H]+found 718.60, [M-H]- found 716.20.Preparation 14: 2-{3-[2,6-bis(benzyloxy)pyridin-3-yl]-2-methylphenyl}-2-azaspiro[3.3]heptan-6-olAttorney Docket No. 57547-738.601K3PO4, DMPAO, Cui, DMSO, 100°C, o / n Step 2OBn Step 1:

[0172] A pressure reactor was charged with 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (1.0 g, 2.4 mmol, 1.0 eq), l-bromo-3-iodo-2-methylbenzene (0.925 g, 3.11 mmol, 1.3 eq) and potassium phosphate (1.02 g, 4.79 mmol, 2.0 eq). The reactants were suspended in anhydrous dioxane (12.0 mL) and water (6.0 mL) and the mixture was degassed thoroughly. To the degassed mixture was added [l,r-bis(diphenylphosphino)ferrocene]dichloropalladium(II) DCM complex (Pd(dppf)Ch DCM, 0.196 g, 0.240 mmol, 0.1 eq) and the mixture was purged again with argon. The reactor was sealed and the mixture was stirred at 110 °C for 3 h. The mixture was passed through celite, washed with EtOAc and the filtrate was concentrated. The residue was then partitioned between EtOAc and water and the organic layer was washed with brine, dried, filtered and concentrated. The crude material was purified by FCC (DCM in cyclohexane, 0-5%) to afford 2,6-bis(benzyloxy)-3-(3-bromo-2-methylphenyl)pyridine (0.908 g, 82%) as a colorless oil.Step 2:

[0173] A mixture of [(2,6-dimethylphenyl)carbamoyl]formic acid (0.067 g, 0.348 mmol, 0.2 eq), 2-azaspiro[3.3]heptan-6-ol hydrochloride (0.468 g, 3.13 mmol, 1.8 eq), copper(I) iodide (0.033 g, 0.174 mmol, 0.1 eq), potassium phosphate (1.84 g, 8.69 mmol, 5.0 eq) and 2,6-bis(benzyloxy)-3-(3-bromo-2-methylphenyl)pyridine (0.8 g, 1.74 mmol, 1.0 eq) in anhydrous DMSO (6 mL) was degassed, purged with argon and stirred at 100 °C overnight under inert atmosphere. Solids were filtered off and the filtrate was diluted with MTBE, washed with 5% ammonia and 5% aqueous LiCl solutions. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by FCC (EtOAc in cyclohexane, 0 to 20%) to afford 2-{3-[2,6-bis(benzyloxy)pyridin-3-yl]-2-methylphenyl}-2-azaspiro[3.3]heptan-6-ol (0.344 g, 0.695 mmol, 40%). MS (ESI): [M+H]+found 493.55, [M-H found 491.30.

[0174] The following compounds were prepared following general method described for 2-{3-[2,6-bis(benzyloxy)pyridin-3-yl]-2-methylphenyl}-2-azaspiro[3.3]heptan-6-ol:Attorney Docket No. 57547-738.601Structure MW LC-MS (m / z)H°—478.59 479.50, 477.00BnO—zZ \\N=ZOBnFZ496.58 495.05BnO-~ / Z ~AN=ZOBnHO- / \ y-466.58 467.45, 465.05BnO— z / AN= / OBnHO^ / \466.58 467.45BnO N OBnPreparation 15: tert-butyl / V-(4-{ [3-(6-hydroxy-7-methoxy-l-oxo-l,2-dihydroisoquinolin-2-yl)-3,7-dimethyl-2-oxo-2,3-dihydro-lH-indol-l-yl]methyl}phenyl)-N-methylcarbamateStep 1:

[0175] To a mixture of 1 -hydroxybenzotriazole hydrate (0.232 g, 1.51 mmol, 1.1 eq), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI HC1, 0.528 g, 2.75 mmol, 2.0 eq), 4-(benzyloxy)-3 -methoxy benzoic acid (0.391 g, 1.51 mmol, 1.1 eq) and 3-amino-l-[(4-bromophenyl)methyl]-3,7-dimethyl-Attorney Docket No. 57547-738.6012,3-dihydro-lH-indol-2-one (0.5 g, 1.38 mmol, 1.0 eq) in anhydrous DMF (7 mL) was added N, N-diisopropylethylamine (DIPEA, 1.2 mL, 6.88 mmol, 5.0 eq) and the resulting mixture was stirred at room temperature for 15 h. The mixture was diluted with water and extracted with EtOAc / iPrOH (9: 1). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude material was purified by FCC (EtOAc in cyclohexane, 0-75%) to give 4-(benzyloxy)-N-{l-[(4-bromophenyl)methyl] -3,7-dimethyl-2-oxo-2,3-dihy dro- lH-indol-3-yl } -3-methoxybenzamide (0.76 g, 1.23 mmol, 90%) as a light beige solid. MS (ESI): [M+H]+found 584.95, 586.75.1HNMR(400 MHz, DMSO-dr,) 89.03 (s, 1H), 7.60 - 7.51 (m, 3H), 7.50 - 7.44 (m, 3H), 7.44 - 7.37 (m, 4H), 7.37 - 7.31 (m, 1H), 7.13 (d, J = 8.6 Hz, 1H), 7.08 (dd, J = 7.0, 1.9 Hz, 1H), 6.97 - 6.85 (m, 2H), 5.22-5.05 (m,4H), 3.83 (s, 3H),2.18 (s, 3H), 1.55 (s, 3H).Step 2:

[0176] A flame-dried pressure vessel was charged with vinyl carbonate (0.255 g, 2.97 mmol, 3.0 eq) and 4-(benzyloxy)-N-{l-[(4-bromophenyl)methyl]-3,7-dimethyl-2-oxo-2,3-dihydro-lH-indol-3-yl}-3-methoxybenzamide (0.61 g, 0.99 mmol, 1.0 eq) and the components were suspended in 1,2-di chloroethane (DCE, 10 mL). The suspension was degassed thoroughly and backfilled with argon. To the mixture was added tris(acetonitrile)pentamethylcyclopentadienylrhodium(III) hexafluoroantimonate (0.041 g, 0.049 mmol, 0.05 eq) and the mixture was degassed again. The vial was sealed and the reaction mixture was stirred at 70 °C for 24 h. The mixture was filtered through a pad of Celite and volatiles were removed in vacuo. The crude mixture was purified by FCC (EtOAc in cyclohexane, 0-75%) to give 6-(benzyloxy)-2-{l-[(4-bromophenyl)methyl]-3,7-dimethyl-2-oxo-2,3-dihydro-lH-indol-3-yl}-7-methoxy-l,2-dihydroisoquinolin-l-one (0.51 g, 0.778 mmol, 79%) as apale beige solid. MS (ESI): [M-H found 607.85, 608.85.1HNMR(400MHz, DMSO-d6) 87.85 (d, J = 7.8 Hz, 1H), 7.64 - 7.57 (m, 2H), 7.54 - 7.39 (m, 7H), 7.38 (d, J = 7.8 Hz, 2H), 7.01 -6.93 (m, 1H), 6.90-6.81 (m,2H), 6.73 (d, J = 7.6 Hz, 1H), 5.30 - 5.20 (m, 2H), 5.17 (s, 2H), 3.83 (s, 3H), 2.22 (s, 3H), 1.83 (s, 3H).Step 3:

[0177] To a pressure reactor containing a mixture of 4-(benzyloxy)-N-{l-[(4-bromophenyl)methyl]-3,7-dimethyl-2-oxo-2,3-dihydro-lH-indol-3-yl}-3-methoxybenzamide (0.23 g, 0.351 mmol, 1.0 eq) and methylamine (33%wt in EtOH, 8.43 mL, 67.7 mmol, 200 eq) in THF (3.5 mL) was added copper(II) sulfate pentahydrate (0.096 g, 0.386 mmol, 1.1 eq). The vessel was sealed and the reaction mixture was stirred at 110 °C overnight. The volatiles were removed in vacuo and the residue was taken up in DCM. The solids were filtered off and the filtrate was concentrated. The crude material was purified by FCC (MeOH in DCM, 0-7%) to give 6-(benzyloxy)-2-(3,7-dimethyl-l-{[4-(methylamino)phenyl]methyl}-2-oxo-2,3-dihydro-lH-indol-3-yl)-7-methoxy-l,2-dihydroisoquinolin-l-one (0.2 g, 0.339 mmol, 97%) as yellow glassy solid. MS (ESI): [M+H]+found 560.55. 'H NMR (400 MHz, DMSO-d6) 87.84 (d, J = 7.8 Hz, 1H), 7.53 - 7.48 (m, 2H), 7.47-7.35 (m, 5H), 7.11 (d, J = 8.6 Hz, 2H), 6.99 - 6.92 (m, 1H), 6.84 (q, J = 3.3, 2.5 Hz, 2H), 6.72 (d, J = 7.7 Hz, 1H), 6.59-6.51 (m, 2H), 5.59 (q, J = 5.1 Hz, 1H), 5.29- 5.18 (m, 2H), 5.12 (d, J = 16.8 Hz, 1H), 4.94 (d, J = 16.7 Hz, 1H), 3.82 (s, 3H), 2.66 (d, J = 5.1 Hz, 3H), 2.30 (s, 3H), 1.81 (s, 3H).Attorney Docket No. 57547-738.601Step 4:

[0178] To a solution of di-tert-butyl dicarbonate (0.531 g, 2.43 mmol, 4.0 eq), DMAP (0.149 g, 1.22 mmol, 2.0 eq), 6-(benzyloxy)-2-(3.7-di methyl- l-{[4-(methylamino)phenyl]methyl}-2-oxo-2,3-dihydro- 1H-indol-3-yl)-7-methoxy-l,2-dihydroisoquinolin-l-one (0.37 g, 0.608 mmol, 1.0 eq) in anhydrous ACN (6 mL) was added tri ethylamine (0.17 mL, 1.22 mmol, 2.0 eq). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated and crude material was purified by FCC (EtOAc in cyclohexane, 0-75%) to give tert-butyl N-[4-({3-[6-(benzyloxy)-7-methoxy-l-oxo-l,2-dihydroisoquinolin-2-yl]-3,7-dimethyl-2-oxo-2,3-dihydro-lH-indol-l-yl}methyl)phenyl]-N-methylcarbamate (0.37 g, 0.505 mmol, 83%) as ayellow glassy solid. MS (ESI): [M+H]+found 660.65, [M-tBu+H]+ 604.25, [M-Boc+H]+560.05.! HNMR(300 MHz, DMSO-d6) 8 7.85 (d, J = 7.9 Hz, 1H), 7.55 -7.34 (m, 9H), 7.29 (d, J = 8.6 Hz, 2H), 7.02 - 6.93 (m, 1H), 6.86 (d, J = 5.9 Hz, 2H), 6.73 (d, J = 7.7 Hz, 1H), 5.27 - 5.08 (m, 4H), 3.82 (s, 3H), 3.18 (s, 3H), 2.24 (s, 3H), 1.83 (s, 3H), 1.38 (s, 9H).Step 5:

[0179] To a solution of tert-butyl N-[4-({3-[6-(benzyloxy)-7-methoxy-l-oxo-l,2-dihydroisoquinolin-2-yl]-3,7-dimethyl-2-oxo-2,3-dihydro-lH-indol-l-yl}methyl)phenyl]-N-methylcarbamate (0.370 g, 0.505 mmol, 1.0 eq) in THF (7.5 mL) and zPrOH (2.5 mL) was added 10% Pd / C (0.370 g). The reaction mixture was stirred at room temperature overnight under hydrogen (1 atm). The mixture was diluted with THF and filtered through a pad of Celite. The volatiles were removed in vacuo to afford tert- butyl N-(4-{[3-(6-hydroxy-7-methoxy- 1-oxo- l,2-dihydroisoquinolin-2-yl)-3,7-dimethyl-2-oxo-2,3-dihydro-lH-indol-l-yl] methyl }phenyl)-N-methylcarbamate (0.240 g, 0.398 mmol, 79%) as a beige glassy solid. MS (ESI):[M+H]+found 570.55, [M-H]’ found 568.20. TfNMRpOO MHz, DMSO-d6) 87.77(d, J= 7.8 Hz, 1H), 7.47 - 7.37 (m, 3H), 7.28 (d, J= 8.5 Hz, 2H), 7.00 (s, 1H), 6.96 (dd, J= 5.6, 3.7 Hz, 1H), 6.86(q, J= 2.8, 2.2 Hz 2H), 6.64 (d, J= 7.7 Hz, 1H), 5.21 (d, J= 17.6Hz, 1H), 5.13 (d, J= 17.5 Hz, 1H), 3.82 (s, 3H), 3.18 (s, 3H), 2.23 (s, 3H), 1.81 (s, 3H), 1.38 (s, 9H).Preparation 16: 4-{[3-(6-hydroxy-7-methoxy-l-oxo-l,2-dihydroisoquinolin-2-yl)-3,7-dimethyl-2-oxo-2,3-dihydro-lH-indol-l-yl]methyl}-N-(2-methylpyridin-3-yl)-N-{[2- (trimethylsilyl)ethoxy]methyl}benzene-l-sulfonamideStep 1:Attorney Docket No. 57547-738.601

[0180] To mixture 1 -hydroxy benzotriazole hydrate (0.597 g, 3.90 mmol, 1.1 eq), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.36 g, 7.09 mmol, 2.0 eq), 4-(benzyloxy)-3-methoxybenzoic acid (1.01 g, 3.90 mmol, 1.1 eq), and 4-[(3-amino-3,7-dimethyl-2-oxo-2,3-dihydro-lH-indol-l-yl)methyl]-N-(2-methylpyridin-3-yl)-N-{[2-(trimethylsilyl)ethoxy]methyl}benzene-l-sulfonamide (2.02 g, 3.54 mmol, 1.0 eq) in anhydrous DMF (18 mL) was added N, N-diisopropylethylamine (3.09 mL, 17.7 mmol, 5.0 eq) and the resulting mixture was stirred at room temperature for 15 h. The mixture was diluted with water and extracted with EtOAc / iPrOH (9:1). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude material was purified by FCC (EtOAc in cyclohexane, 0-75%) to give 4-(benzyloxy)-N-[3,7-dimethyl-l-({4-[(2-methylpyridin-3-yl)({[2-(trimethylsilyl)ethoxy]methyl})sulfamoyl]phenyl}methyl)-2-oxo-2,3-dihydro-lH-indol-3-yl]-3-methoxybenzamide (2.68 g, 3.25 mmol, 92%) as white solid. MS (ESI): [M+H]+found 807.90; [M-H]'found 805.50.1HNMR(400 MHz, DMSO-d6) 89.06 (s, 1H), 8.43 (dd, J = 4.5, 1.9 Hz, 1H), 7.68 (s,4H), 7.54 (dd, J = 8.5, 2.1 Hz, 1H), 7.46 (dd, J = 7.2, 1.7 Hz, 3H), 7.43 - 7.38 (m, 2H), 7.37 - 7.30 (m, 1H), 7.19 (qd, J = 8.3, 3.4 Hz, 2H), 7.14 - 7.05 (m, 2H), 6.93 (dt, J = 14.6, 6.9 Hz, 2H), 5.32 (d, J = 18.3 Hz, 1H), 5.22 (d, J = 18.0 Hz, 1H), 5.17 (s, 2H), 5.12 - 4.80 (m, 2H), 3.82 (s, 3H), 3.57 (t, J = 8.2 Hz, 2H), 2.32 (s, 3H), 2.14 (s, 3H), 1.57 (s, 3H), 0.85 - 0.76 (m, 2H), -0.06 (s, 9H).Step 2:

[0181] A flame-dried pressure vessel was charged with vinyl carbonate (1.05 g, 12.1 mmol, 20 eq), 4-(benzyloxy)-N-[3,7-dimethyl-l-({4-[(2-methylpyridin-3-yl)({[2- (trimethylsilyl)ethoxy] methyl} )sulfamoyl] phenyl } methyl)-2-oxo-2,3-dihy dro- lH-indol-3-yl] -3-methoxybenzamide (0.500 g, 0.607 mmol, 1.0 eq) and the components were suspended in 1,2-dichloroethane (6 mL). The suspension was degassed thoroughly and backfdled with argon. To the mixture was added tris(acetonitrile)pentamethylcyclopentadienylrhodium(III) hexafluoroantimonate (1.01 g, 1.21 mmol, 2 eq). The reaction mixture was degassed, sealed, and stirred at 90 °C for 24 h. The mixture was filtered through a pad of Celite. The volatiles were removed in vacuo and the residue was taken up in anhydrous DCM (5.7 mL). To the solution was added N, N-diisopropylethylamine (0.497 mL, 2.85 mmol, 5.0 eq) followed by (2-(chloromethoxy)ethyl)trimethylsilane (0.190 g, 1.142 mmol, 2.0 eq) dropwise at 0 °C. The reaction mixture was stirred at room temperature overnight. The mixture was diluted with DCM and washed with 5% citric acid solution and brine. The organic layer was dried, filtered, and concentrated. The crude material was purified by FCC (EtOAc in cyclohexane, 0-50%) to afford 4-({3-[6-(benzyloxy)-7-methoxy- 1 -oxo- 1,2-dihydroisoquinolin-2-yl]-3,7 -dimethyl-2-oxo-2, 3 -dihydro- IH-indol- 1 -yl } methyl)-N-(2-methylpyridin-3-yl)-N-{[2-(trimethylsilyl)ethoxy]methyl}benzene-l-sulfonamide (0.300 g, 0.325 mmol, 57%).Step 3:

[0182] To a solution of 4-({3-[6-(benzyloxy)-7-methoxy-l-oxo-l,2-dihydroisoquinolin-2-yl]-3,7-dimethyl-2-oxo-2,3-dihydro-lH-indol-l-yl}methyl)-N-(2-methylpyridin-3-yl)-N-{[2-(trimethylsilyl)ethoxy]methyl}benzene-l-sulfonamide (0.300 g, 0.325 mmol, 1.0 eq) in THF (6 mL) andAttorney Docket No. 57547-738.601MeOH (2 mL) was added 10% Pd / C (0.100 g). The reaction mixture was stirred at room temperature overnight under hydrogen (1 atm). The mixture was diluted with THF and filtered through a pad of Celite. The volatiles were removed in vacuo. The crude material was purified by FCC (EtOAc in cyclohexane, 0-100%) to give 4-{[3-(6-hydroxy-7-methoxy-l-oxo-l,2-dihydroisoquinolin-2-yl)-3,7-dimethyl-2-oxo-2,3-dihydro- IH-indol- l-yl]methyl} -N-(2-methylpyridin-3-yl)-N- {[2-(trimethylsilyl)ethoxy] methyl} benzene- 1 -sulfonamide (0.160 g, 0.198 mmol, 61%) as a light yellow solid. MS (ESI): [M+H]+found 742.15, [M-H]’ found 739.20.1HNMR(400MHz, DMSO-d6) 8 10.17 (s, 1H), 8.44 (dd, J = 4.5, 2.0 Hz, 1H), 7.79 (d, J = 7.9 Hz, 1H), 7.72 (s, 4H), 7.45 (s, 1H), 7.20 (t, J = 3.4 Hz, 2H), 7.03 - 6.95 (m, 2H), 6.91 - 6.83 (m, 2H), 6.66 (d, J = 8.0 Hz, 1H), 5.31 (s,2H), 5.06 (s, 2H),3.83 (s, 3H), 3.58 (t, J = 8.4 Hz, 2H), 2.34 (s, 3H), 2.17 (s, 3H), 1.84 (s, 3H), 0.85 - 0.78 (m, 2H), -0.05 (s, 9H).Preparation 17: 4-[(3-ethynyl-3-hydroxy-7-methyl-2-oxo-2,3-dihydro-lH-indol-l-yl)methyl]-N-(2-methylpyridin-3-yl)-N-{[2-(trimethylsilyl)ethoxy]methyl}benzene-l-sulfonamideStep 1:

[0183] A mixture of ethylene glycol (6.96 mL, 125 mmol, 5.0 eq), p -toluenesulfonic acid monohydrate (0.475 g, 2.50 mmol, 0.1 eq) and l-[(4-bromophenyl)methyl]-7-methyl-2,3-dihydro-lH-indole-2, 3-dione (8.68 g, 25.0 mmol, 1.0 eq) in anhydrous toluene was refluxed under Dean-Stark apparatus overnight. The mixture was diluted with DCM and washed with saturated aqueous NaHCO3. The organic layer was dried, filtered, and concentrated. The crude material was purified by FCC (EtOAc in cyclohexane, 0-50%) to give r-[(4-bromophenyl)methyl]-7'-methyl-r,2'-dihydrospiro[l,3-dioxolane-2,3'-indol]-2'-one (7.32 g, 18.5 mmol, 74%)Step 2:

[0184] A flame-dried reactor was charged with l'-[(4-bromophenyl)methyl]-7'-methyl-l',2'-dihydrospiro[l,3-dioxolane-2,3'-indol]-2'-one (4.68 g, 11.9 mmol, 1.0 eq), N, N- diisopropyl ethyl amine (5.19 ml, 29.7 mmol, 2.5 eq) and XantPhos (2.06 g, 3.56 mmol, 0.3 eq). The reaction components were taken up in anhydrous dioxane (47 mL) and the mixture was degassed and refilled with argon. To the mixture was added tris(dibenzylideneacetone)dipalladium(0) (1.09 g, 1.19 mmol, 0.1 eq) and benzyl mercaptan (1.48 g, 11.9 mmol, 1.0 eq). The reaction mixture was stirred at 110 °C overnight. The mixture was filtered through aAttorney Docket No. 57547-738.601pad of Celite and the filtrate was washed with EtOAc. The volatiles were removed in vacuo and the crude material was purified by FCC (EtOAc in cyclohexane, 0-20%) to give 1'- { [4-(benzylsulfanyl)phenyl]methyl}-7'-methyl-l',2'-dihydrospiro[l,3-dioxolane-2,3'-indol]-2'-one (3.64 g, 8.67 mmol, 73%).Step 3:

[0185] To a cooled solution of l'-{[4-(benzylsulfanyl)phenyl]methyl}-7'-methyl-l',2'-dihydrospiro[l,3-dioxolane-2,3'-indol]-2'-one (3.61 g, 8.42 mmol, 1.0 eq), glacial acetic acid (0.703 mL, 12.3 mmol, 1.45 eq) in a mixture of ACN (240 mL) and water (5.4 mL) was added l,3-dichloro-5,5-dimethylhydantoin (2.87 g, 14.6 mmol, 1.73 eq) portion- wise. The reaction was stirred at room temperature for 1 h. The mixture was diluted with EtOAc and washed with water. The organic layer was dried over Na2SO4, filtered and concentrated. The crude was purified by FCC (EtOAc in cyclohexane, 0-20%) to give 4-({7'-methyl-2'-oxo-l',2'-dihydrospiro[l,3-dioxolane-2,3'-indol]-l'-yl}methyl)benzene-l-sulfonyl chloride (2.9 g, 7.00 mmol, 83%).Step 4:

[0186] To asolution of anhydrous pyridine (1.70 mL, 21.0 mmol, 3.0 eq) and 3-aminopicoline (1.513 g, 14.0 mmol, 2.0 eq) in anhydrous DCM (72.5 mL) was added 4-({7'-methyl-2'-oxo-l',2'-dihydrospiro[l,3-dioxolane-2,3'-indol]-l'-yl}methyl)benzene-l-sulfonyl chloride (2.9 g, 7.00 mmol, 1.0 eq) at 0 °C. The reaction mixture was stirred at room temperature overnight. The mixture was diluted with DCM and washed with 10% NaFLPC. The organic layer was dried, filtered, and concentrated. The crude material was purified by FCC (MeOH in DCM, 0-10%) to give 4-({7'-methyl-2'-oxo-r,2'-dihydrospiro[l,3-dioxolane-2,3'-indol]-l'-yl}methyl)-N-(2-methylpyridin-3-yl)benzene-l -sulfonamide (2.2 g, 4.48 mmol, 64%).Step 5:

[0187] To asolution of 4-({7'-methyl-2'-oxo-l',2'-dihydrospiro[l,3-dioxolane-2,3'-indol]-l'-yl}methyl)-N-(2-methylpyridin-3-yl)benzene-l -sulfonamide (1.46 g, 2.98 mmol, 1.0 eq) in dioxane (22 mL) and acetone (22 mL) was added concentrated hydrochloric acid (1.79 mL, 20.9 mmol, 7.0 eq) and the mixture was stirred at 80 °C for 4 h. The solvents were removed in vacuo and the crude material was purified by FCC (MeOH in DCM, 0-10%) to give 4-[(7-methyl-2,3-dioxo-2,3-dihydro-lH-indol-l-yl)methyl]-N-(2-methylpyridin-3-yl)benzene-l-sulfonamide (0.950 g, 2.15 mmol, 72%).Step 6:

[0188] To a suspension of 4-[(7-methyl-2,3-dioxo-2,3-dihydro-lH-indol-l-yl)methyl]-N-(2-methylpyridin-3-yl)benzene-l -sulfonamide (0.45 g, 1.01 mmol, 1.0 eq) in anhydrous THF (4.5 mL) was added 0.5 M ethynylmagnesium bromide in THF (8.11 mL, 4.06 mmol, 4.0 eq) dropwise at 0°C. The reaction mixture was stirred at 0 °C for 3 h. The reaction was quenched with 10% NaH2PO4 and extracted with DCM. The organic layer was dried, filtered, and concentrated. The crude material was purified by FCC (MeOH in DCM, 0-6%) to give 4-[(3-ethynyl-3-hydroxy-7-methyl-2-oxo-2,3-dihydro-lH-indol-l-yl)methyl]-N-(2-methylpyridin-3-yl)benzene-l-sulfonamide (0.415 g, 0.881 mmol, 87%).Step 7:Attorney Docket No. 57547-738.601

[0189] To a solution of 4-[(3-ethynyl-3-hydroxy-7-methyl-2-oxo-2,3-dihydro-lH-indol-l-yl)methyl]-N-(2-methylpyridin-3-yl)benzene-l -sulfonamide (0.415 g, 0.881 mmol, 1.0 eq) and N, N-diisopropylethylamine (0.384 mL, 2.20 mmol, 2.5 eq) in anhydrous DCM (8 mL) was added (2-(chloromethoxy)ethyl)trimethylsilane (0.169 g, 1.01 mmol, 1.15 eq) dropwise at 0 °C. The reaction mixture was stirred at room temperature for 1 h. The mixture was diluted with DCM and washed with 10% NathPCh. The organic layer was dried, filtered, and concentrated. The crude material was purified by FCC (EtOAc in cyclohexane, 0-70%) to give 4-[(3-ethynyl-3-hydroxy-7-methyl-2-oxo-2,3-dihydro-lH-indol-l-yl)methyl] -N-(2-methylpyridin-3-yl)-N-{ [2-(trimethylsilyl)ethoxy]methyl (benzene- 1 -sulfonamide (0.340 g, 0.555 mmol, 63%).Preparation 18: 2-[2',6'-bis(benzyloxy)-3-methyl-[2,3'-bipyridin]-4-yl]-2-azaspiro[3.3]heptan-6-olK2CO3, RuPhos, Pd2dba3, DMAc 100°C, o / n Step 2OBn Step 1:

[0190] A pressure reactor was charged with 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (0.85 g, 2.04 mmol, 1.0 eq), 2-bromo-4-chloro-3-methylpyridine (0.505 g, 2.44 mmol, 1.2 eq) and sodium carbonate (0.648 g, 6.111 mmol, 3.0 eq). The reaction components were suspended in anhydrous dioxane (10.0 mL) and water (2.0 mL) and the mixture was degassed thoroughly. To the mixture was added Pd(dppf)Ch • DCM (0.166 g, 0.204 mmol, 0.1 eq) and the mixture was purged with argon. The reactor was sealed and the reaction mixture was stirred at 95 °C for 4 h. The mixture was passed through a pad of Celite and washed with EtOAc. The combined filtrates were concentrated. The residue was taken up in EtOAc and water. The layers were separated and the organic layer was washed with brine, dried, filtered and concentrated. The crude product was purified by FCC (EtOAc in cyclohexane, 0-5%) to afford 2',6'-bis(benzyloxy)-4-chloro-3-methyl-2,3'-bipyridine (0.64 g, 1.46 mmol, 72%).Step 2:

[0191] A pressure vessel was charged with 2', 6'-bis(benzyloxy)-4-chloro-3-methyl-2,3'-bipyridine (0.3 g, 0.684 mmol, 1.0 eq), 2-azaspiro[3.3]heptan-6-ol hydrochloride (0.205 g, 1.37 mmol, 2.0 eq), potassium carbonate (0.378 g, 2.73 mmol, 4.0 eq), 2-dicyclohexylphosphino-2',6'-diisopropoxy-l,l'-biphenyl (RuPhos, 0.064 g, 0.137 mmol, 0.2 eq), tris(dibenzylideneacetone)dipalladium(0) (0.063 g, 0.068 mmol, 0.1 eq) and the components were suspended in anhydrous dimethylacetamide (7 mL). The reaction mixture was degassed and the reactor was sealed. The reaction mixture was stirred at 100 °C overnight. The reaction mixture was diluted with EtOAc and filtered through a pad of Celite. The filtrate was washed with water, brine, dried, filtered and concentrated in vacuo. The crude material was purified by FCC (MeOH in DCM,Attorney Docket No. 57547-738.6010% to 5%) to give 2-[2',6'-bis(benzyloxy)-3-methyl-[2,3'-bipyridin]-4-yl]-2-azaspiro[3.3]heptan-6-ol (0.265 g, 0.51 mmol, 75%) as pale yellow solid.Preparation 19: 2-[2',6'-bis(benzyloxy)-[2,3'-bipyridin]-6-yl]-2-azaspiro[3.3]heptan-6-olStep 1:

[0192] A pressure reactor was charged with 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (0.5 g, 1.20 mmol, 1.0 eq), 2-bromo-6-fluoropyridine (0.274 g, 1.56 mmol, 1.3 eq) and potassium phosphate tribasic (0.509 g, 2.40 mmol, 2.0 eq). The reactants were suspended in dioxane (6.0 ml) and water (3.0 ml) and the mixture was degassed thoroughly. To the mixture was added 1,1'-bis(diphenylphosphino)ferrocene-palladium(ii)dichloride di chi oromethane (0.098 g, 0.12 mmol, 0.1 eq) and the mixture was purged with argon. The reactor was sealed and the reaction mixture was stirred at 110 °C overnight. The mixture was filtered through a pad of Celite and washed with EtOAc. The combined filtrates were diluted with EtOAc and water and the layers were separated. The organic layer was washed with brine, then dried, filtered, and concentrated. The crude product was purified by FCC (EtOAc in cyclohexane, 0-5%) to afford 2',6'-bis(benzyloxy)-6-fluoro-2,3'-bipyridine (0.453 g, 1.10 mmol, 92%).Step 2:

[0193] A pressure reactor was charged with 2',6'-bis(benzyloxy)-6-fluoro-2,3'-bipyridine (0.45 g, 1.09 mmol, 1.0 eq), 2-azaspiro[3.3]heptan-6-ol hydrochloride (0.328 g, 2.19 mmol, 2.0 eq), cesium carbonate (1.25 g, 3.83 mmol, 3.5 eq) and the components were suspended in anhydrous DMSO (5 mL). The reaction mixture was stirred at 120 °C for 6 h. The mixture was diluted with MTBE and washed with 1 M Li Cl. The organic layer was dried, filtered, and concentrated. The crude material was purified by FCC (EtOAc in cyclohexane, 0-30%) to afford 2-[2',6'-bis(benzyloxy)-[2,3'-bipyridin]-6-yl]-2-azaspiro[3.3]heptan-6-ol (395 mg, 0.821 mmol, 75%).Preparation 20: 6-[(2-{3-[2,6-bis(benzyloxy)pyridin-3-yl]phenyl}-2-azaspiro[3.3]heptan-6-yl)oxy]-5-methoxypyridine-3-carboxylic acidAttorney Docket No. 57547-738.601Step 1:

[0194] A pressure vessel was charged with 2-{3-[2,6-bis(benzyloxy)pyridin-3-yl]phenyl}-2-azaspiro[3.3]heptan-6-ol (0.25 g, 0.507 mmol, 1.0 eq), methyl 6-chloro-5-methoxynicotinate (0.102 g, 0.507 mmol, 1.0 eq), cesium carbonate (0.33 g, 1.01 mmol, 2.0 eq), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (XantPhos, 0.059 g, 0.101 mmol, 0.2 eq) and tris(dibenzylideneacetone)dipalladium(0) (0.070 g, 0.076 mmol, 0.15 eq). The reaction components were suspended in anhydrous dioxane (5 mL). The mixture was degassed and the reactor was sealed. The reaction mixture was stirred at 100 °C overnight. The reaction mixture was diluted with EtOAc / DCM (1:1) and filtered through a pad of Celite. The filtrate was concentrated in vacuo and the crude material was purified by FCC (EtOAc in cyclohexane) to give methyl 6-[(2-{3-[2,6-bis(benzyloxy)pyridin-3-yl]phenyl}-2-azaspiro[3.3]heptan-6-yl)oxy]-5-methoxypyridine-3-carboxylate (0.336 g, 0.496 mmol, 98%) as a pale yellow solid.Step 2:

[0195] To a solution of methyl 6-[(2-{3-[2,6-bis(benzyloxy)pyridin-3-yl]phenyl}-2-azaspiro[3.3]heptan-6-yl)oxy]-5-methoxypyridine-3-carboxylate (0.462 g, 0.682 mmol, 1.0 eq) in THF (7 mL) was added a solution of lithium hydroxide monohydrate (0.043 g, 1.02 mmol, 1.5 eq) in water (2 mL). The reaction mixture was stirred at room temperature overnight. The volatiles were removed in vacuo. The residue was acidified with 10% NaH₂PO₄ solution and extracted with EtOAc. The organic layer was dried, fdtered and concentrated to afford 6-[(2- {3-[2,6-bis(benzyloxy)pyridin-3-yl]phenyl}-2-azaspiro[3.3]heptan-6-yl)oxy]-5-methoxypyridine-3-carboxylic acid (0.397 g, 0.618 mmol, 91%).Preparation 21: 4-[(2-{3-[2,6-bis(benzyloxy)pyridin-3-yl]phenyl}-2-azaspiro[3.3]heptan-6-yl)oxy]-3-methoxybenzoic acidAttorney Docket No. 57547-738.601Step 1:

[0196] To a cooled suspension of methyl 4-hydroxy-3-methoxybenzoate (1.40 g, 7.66 mmol, 1.1 eq), 2- {3-|2.6-bis(benzyloxy)pyridin-3-yl|phenyl}-2-azaspiro|3.3|heptan-6-ol (3.4 g. 6.96 mmol. 1.0 eq), and 1,1'-(azodicarbonyl)dipiperidine (ADDP, 3.51 g, 13.9 mmol, 2.0 eq) in anhydrous THF (35 mL) was added tributylphosphine (3.5 mL, 13.9 mmol, 2.0 eq) and the resulting mixture was stirred at 60 °C overnight. The mixture was poured into water and the product was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by FCC (EtOAc in cyclohexane, 0-30%) to afford methyl 4-[(2-{3-[2, 6-bis(benzyloxy)pyridin-3-yl]phenyl} -2-azaspiro[3.3]heptan-6-yl)oxy]-3-methoxybenzoate (4.40 g, 6.61 mmol, 95%) as a colorless oil.Step 2:

[0197] To a solution of methyl 4-[(2-{3-[2,6-bis(benzyloxy)pyridin-3-yl]phenyl}-2-azaspiro[3.3]heptan-6-yl)oxy]-3-methoxybenzoate (4.40 g, 6.61 mmol, 1.0 eq) in THF (33 mL) was added a solution of lithium hydroxide monohydrate (836 mg, 19.9 mmol, 3.0 eq) in water (11 mL). The reaction mixture was stirred at 60 °C overnight. THF was removed in vacuo and the residue was acidified with 5% citric acid. The aqueous layer was extracted with EtOAc and the organic layer was dried, filtered and concentrated to afford 4-[(2-{3-[2,6-bis(benzyloxy)pyridin-3-yl]phenyl}-2-azaspiro[3.3]heptan-6-yl)oxy]-3-methoxybenzoic acid (4.10 g, 6.50 mmol, 98%) as a light yellow solid.

[0198] The following compounds were prepared following general method described for 4-[(2-{3-[2,6-bis(benzyloxy)pyridin-3-yl]phenyl}-2-azaspiro[3.3]heptan-6-yl)oxy]-3-methoxybenzoic acid:Attorney Docket No. 57547-738.601Preparation 22: N-(2-fluoro-4-{ [3-(6-hydroxy-7-methoxy-l-oxo-l,2-dihydroisoquinolin-2-yl)-3,7-dimethyl-2-oxo-2,3-dihydro-lH-indol-l-yl]methyl}phenyl)-l-methyl-N-{[2- (trimethylsilyl)ethoxy]methyl}-lH-pyrazole-5-sulfonamideDIPEA, DCM, H₂ (1 atm), Pd / C, 0°C-rt, o / n THF: MeOH, rt, o / n Step 4 Step 5Step 1:

[0199] To a mixture of 1 -hydroxybenzotriazole hydrate (0.510 g, 3.33 mmol, 1.1 eq), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.16 g, 6.06 mmol, 2.0 eq), 4-(benzyloxy)-3-methoxybenzoic acid (0.860 g, 3.33 mmol, 1.1 eq) and 3-amino-l-[(4-bromo-3-fluorophenyl)methyl]-3,7-dimethyl-2,3-dihydro-lH-indol-2-one (1.10 g, 3.03 mmol, 1.0 eq) in anhydrous DMF (15 mL) was added N, N-diisopropylethylamine (2.64 mL, 15.1 mmol, 5.0 eq) and the resulting mixture was stirred at room temperature overnight. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated in vacuo. The crude material was purified by FCC (EtOAc in cyclohexane, 0-75%) to give 4-(benzyloxy)-N-{l-[(4-bromo-3-Attorney Docket No. 57547-738.601Iluorophenyl)methy I |-3.7-dimethyl-2-oxo-2.3-dihydro- lH-indol-3-yl} -3-methoxybenzamide (1.60 g, 2.62 mmol, 87%) as pale yellow solid.Step 2:

[0200] A flame-dried pressure vessel was charged with vinyl carbonate (0.784 g, 9.11 mmol, 5.0 eq) and 4-(benzyloxy)-N-{l-[(4-bromo-3-fluorophenyl)methyl]-3,7-dimethyl-2-oxo-2,3-dihydro-lH-indol-3-yl}-3-methoxy benzamide (1.1 g, 1.82 mmol, 1.0 eq) and the reactants were suspended in 1,2-di chloroethane (11 mL). The suspension was degassed thoroughly and backfilled with argon. To the mixture was added tris(acetonitrile)pentamethylcyclopentadienylrhodium(III) hexafluoroantimonate (0.114 g, 0.137 mmol, 0.075 eq) and the mixture was degassed again. The vial was sealed and the reaction mixture was stirred at 80 °C for 24 h. The mixture was filtered through a pad of Celite. The volatiles were removed in vacuo and the crude material was purified by FCC (EtOAc in cyclohexane, 0-75%) to afford 6-(benzyloxy)-2-{l-[(4-bromo-3-fluorophenyl)methyl]-3,7-dimethyl-2-oxo-2,3-dihydro-lH-indol-3-yl}-7-methoxy-l,2-dihydroisoquinolin-l-one (950 mg, 1.48 mmol, 83%) as a pale yellow solid.Step 3:

[0201] A pressure vessel was charged with 6-(benzyloxy)-2-{1-[(4-bromo-3-fluorophenyl)methyl]-3,7-dimethyl-2-oxo-2,3-dihydro-1H-indol-3-yl}-7-methoxy-1,2-dihydroisoquinolin-1-one (1000 mg, 1.59 mmol, 1.0 eq), 1 -methyl- lH-pyrazole-5-sulfonami de (0.385 g, 2.39 mmol, 1.5 eq), potassium carbonate (0.661 g, 4.78 mmol, 3.0 eq), tBuXPhos (0.203 g, 0.478 mmol, 0.30 eq) and tris(dibenzylideneacetone)dipalladium(0) (0.219 g, 0.239 mmol, 0.15 eq). The reactants were suspended in dioxane (16 mL) and the reaction mixture was degassed. The reactor was sealed and the reaction mixture was stirred at 95 °C overnight. The reaction mixture was treated with sat. NH₄Cl solution and extracted with EtOAc. The combined organic layers were dried, fdtered, and concentrated. The crude material was purified by FCC (EtOAc in cyclohexane, 0-100%) to give N-[4-({3-[6-(benzyloxy)-7-methoxy-l-oxo-l,2-dihydroisoquinolin-2-yl]-3,7-dimethyl-2-oxo-2,3-dihydro- lH-indol-l-yl}methyl)-2-fluorophenyl]-l -methyl- IH-pyrazole- 5 -sulfonamide (1.05 g, 1.19 mmol, 75%) as pale beige solid.Step 4:

[0202] To a solution of N-[4-({3-[6-(benzyloxy)-7-methoxy-l-oxo-l,2-dihydroisoquinolin-2-yl]-3,7-dimethyl-2-oxo-2,3-dihydro-lH-indol-l-yl}methyl)-2-fluorophenyl]-l-methyl-lH-pyrazole-5-sulfonamide (1.05 g, 1.48 mmol, 1.0 eq) and N, N-diisopropylethylamine (1.29 mL, 7.42 mmol, 5.0 eq) in anhydrous DCM (15 mL) was added 2-(chloromethoxy)ethyl)trimethylsilane (0.371 g, 0.394 mL, 2.22 mmol, 1.5 eq) dropwise at 0 °C. The reaction mixture was stirred at room temperature overnight. The mixture was diluted with DCM and washed with 10% aq citric acid. The organic layer was dried, filtered and concentrated to afford N-[4-({3-[6-(benzyloxy)-7-methoxy-l-oxo-l,2-dihydroisoquinolin-2-yl]-3,7-dimethyl-2-oxo-2,3-dihydro- IH-indol- 1-yl} methyl)-2-fluorophenyl] - 1-methyl-N- { [2-(trimethylsilyl)ethoxy]methyl}-lH-pyrazole-5 -sulfonamide (1.12 g, 1.07 mmol, 90%) which was used in the next step without further purification.Step 5:Attorney Docket No. 57547-738.601

[0203] To a solution ofN-[4-({3-[6-(benzyloxy)-7-methoxy-l-oxo-l,2-dihydroisoquinolin-2-yl]-3,7-dimethyl-2-oxo-2, 3-dihydro- IH-indol- l-yl}methyl)-2-fluorophenyl] -l-methyl-N-{ [2- (trimethylsilyl)ethoxy]methyl}-lH-pyrazole-5-sulfonamide (1.12g, 1.34 mmol, 1.0 eq)inTHF (lOmL) and MeOH (2.5 mL) was added 10% Pd / C (0.142 g). The reaction mixture was stirred at room temperature overnight under hydrogen (1 atm). The mixture was diluted with THF and filtered through a pad of Celite. The volatiles were removed in vacuo and the crude material was purified by FCC (EtOAc in cyclohexane, 0-75%) to give N-(2-fluoro-4- {|3-(6-hydroxy-7-methoxy-l -oxo-1, 2-dihydroisoquinolin-2-yl)-3,7-dimethyl-2-oxo-2, 3-dihydro- IH-indol- 1 -yl]methyl} phenyl)- 1 -methyl-N- { [2-(trimethylsilyl)ethoxy] methyl} - 1H-pyrazole-5-sulfonamide (950 mg, 1.25 mmol, 95%) as a pale yellow solid.Preparation 23: N-{4-[(3-ethynyl-3-hydroxy-7-methyl-2-oxo-2, 3-dihydro- IH-indol- l-yl)methyl]-2-fluorophenyl}-l-methyl-N-{[2-(trimethylsilyl)ethoxy]methyl}-lH-pyrazole-5-sulfonamideStep 1:

[0204] A mixture of ethylene glycol (3.11 mL, 55.7 mmol, 10 eq), p -toluenesulfonic acid monohydrate (0.106 g, 0.557 mmol, 0.1 eq), and l-[(4-bromo-3-fluorophenyl)methyl]-7-methyl-2,3-dihydro-lH-indole-2, 3-dione (2.0 g, 5.57 mmol, 1.0 eq) in anhydrous toluene (20 mL) was refluxed under Dean-Stark apparatus overnight. The mixture was diluted with DCM and washed with saturated aqueous NaHCCh. The organic layer was dried, filtered, and concentrated. The crude material was purified by FCC (EtOAc in cyclohexane, 0-50%) to give l'-[(4-bromo-3-fluorophenyl)methyl]-7'-methyl-l',2'-dihydrospiro[l,3-dioxolane-2,3'-indol]-2'-one (1.8 g, 4.36 mmol, 78%).Step 2:

[0205] A pressure vessel was charged with l'-[(4-bromo-3-fluorophenyl)methyl]-7'-methyl-r,2'-dihydrospiro[l,3-dioxolane-2,3'-indol]-2'-one (1.0 g, 2.42 mmol, 1.0 eq), 1 -methyl- lH-pyrazole-5-sulfonamide (0.585 g, 3.63 mmol, 1.5 eq), potassium carbonate (0.837 g, 6.05 mmol, 2.5 eq), tBuXPhos (0.309 g, 0.727 mmol, 0.3 eq) and tris(dibenzylideneacetone)dipalladium(0) (0.333g, 0.363 mmol, 0.15 eq). The reactants were suspended in dioxane (15 mL) and the reaction mixture was degassed. The reactor wasAttorney Docket No. 57547-738.601sealed and the reaction mixture was stirred at 90 °C overnight. The mixture was concentrated in vacuo and the crude material was filtered through silica gel pad (EtOAc in cyclohexane, 0-100% and then MeOH in DCM) to give N-[2-fluoro-4-({7'-methyl-2'-oxo-T,2'-dihydrospiro[l,3-dioxolane-2,3'-indol]-T-yl}methyl)phenyl]-l-methyl-lH-pyrazole-5-sulfonamide (1.1 g, 2.20 mmol, 91%).Step 3:

[0206] To a solution ofN-[2-fluoro-4-({7'-methyl-2'-oxo-l',2'-dihydrospiro[l,3-dioxolane-2,3'-indol]-l'-yl}methyl)phenyl]-l-methyl-lH-pyrazole-5-sulfonamide (1.10 g, 2.33 mmol, 1.0 eq) in dioxane (15 mL) and acetone (15 mL) was added concentrated hydrochloric acid (1.6 mL, 18.6 mmol, 8.0 eq) and the reaction mixture was stirred at 80 °C for 4 h. The solvents were removed in vacuo and the crude material was purified by FCC (MeOH in DCM, 0-3%) to giveN-{2-fluoro-4-[(7-methyl-2,3-dioxo-2,3-dihydro-lH-indol- 1-yl)methyl]phenyl}-l-methyl-lH-pyrazole-5-sulfonamide (0.840 g, 1.80 mmol, 82%).Step 4:

[0207] To a suspension of N-{2-fluoro-4-[(7-methyl-2,3-dioxo-2,3-dihydro-lH-indol-l-yl)methyl]phenyl}-l-methyl-lH-pyrazole-5-sulfonamide (0.840 g, 1.96 mmol, 1.0 eq) in anhydrous THF (8.4 mL) was added ethynylmagnesium bromide (0.5 M in THF, 19.6 mL, 9.80 mmol, 5.0 eq) dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. The reaction was quenched with 10% NaH₂PO₄ and extracted with DCM. The combined organic layers were dried, filtered and concentrated to afford crude N-{4-[(3-ethynyl-3-hydroxy-7-methyl-2-oxo-2,3-dihydro-lH-indol-l-yl)methyl]-2-fluorophenyl}-l-methyl-lH-pyrazole-5-sulfonamide (0.900 g, 1.58 mmol, 88%) which was used in the next step without further purification.Step 5:

[0208] To a solution of N-{4-[(3-ethynyl-3-hydroxy-7-methyl-2-oxo-2,3-dihydro-lH-indol-l-yl)methyl]- 2-fhrorophenyl}-l-methyl-lH-pyrazole-5-sulfonamide (0.900 g, 1.98 mmol, 1.0 eq) andN, N-diisopropylethylamine (1.035 mL, 5.94 mmol, 3.0 eq) in anhydrous DCM (18 mL) was added (2-(chloromethoxy)ethyl)trimethylsilane (0.385 mL, 2.18 mmol, 1.1 eq) dropwise at 0 °C. The reaction mixture was stirred at room temperature for 1 h. The mixture was diluted with DCM and washed with sat. NaHCCh. The organic layer was dried, filtered and concentrated. The crude material was purified by FCC (EtOAc in cyclohexane, 0-30%) to give N-{4-[(3-ethynyl-3-hydroxy-7-methyl-2-oxo-2,3-dihydro-lH-indol-l-yl)methyl] -2-fluorophenyl} - 1 -methyl-N- { [2-(trimethylsilyl)ethoxy] methyl } - lH-pyrazole-5-sul fonamide (0.800 g, 1.23 mmol, 78%).Preparation 24: 7-{3-[2,6-bis(benzyloxy)pyridin-3-yl]phenyl}-2,7-diazaspiro[3.5]nonaneAttorney Docket No. 57547-738.601Step 1:

[0209] A mixture of [(2,6-dimethylphenyl)carbamoyl]formic acid (0.085 g, 0.439 mmol, 0.2 eq), 2-(tert-butoxycarbonyl)-2,7-diazaspiro[3.5]nonane (0.745 g, 3.29 mmol, 1.5 eq), copper(I) iodide (0.042 g, 0.220 mmol, 0.1 eq), potassium phosphate (1.40 g, 6.59 mmol, 3.0 eq) and 2,6-bis(benzyloxy)-3-(3-bromophenyl)pyridine (1.0 g, 2.22 mmol, 1.0 eq) in anhydrous DMSO (7.3 mL) was purged with argon and then stirred at 110 °C for 3 days. The mixture was diluted with EtOAc and filtered through a pad of Celite. The filtrate was washed with 10% aq NaH₂PO₄ and 5% aq LiCl. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude product was purified by FCC (EtOAc in hexane) to afford tert-butyl 7- {3-|2.6-bis(benzyloxy)pyridin-3-yl|phenyl}-2.7-diazaspiro|3.5|nonane-2-carboxylate (0.640 g, 1.09 mmol, 49%).Step 2:

[0210] To a solution of tert-butyl 7-{3-[2,6-bis(benzyloxy)pyridin-3-yl]phenyl}-2,7-diazaspiro[3.5]nonane-2-carboxylate (0.320 g, 0.541 mmol, l. Oeq) and 2, 6-luti dine (0.630 mL, 5.41 mmol, 10.0 eq) in anhydrous DCM (7 mL) was added trimethylsilyl trifluoromethanesulfonate (0.883 mL, 4.87 mmol, 9.0 eq) dropwise at 0 °C. The reaction mixture was stirred at room temperature for 20 min. The reaction was quenched with water and DCM was removed in vacuo. The precipitated was collected and washed with water to give 7-{3-[2,6-bis(benzyloxy)pyridin-3-yl]phenyl}-2,7-diazaspiro[3.5]nonane (332 mg, 0.519 mmol, 96%) as trifluoromethanesulfonic acid salt.Preparation 25: 3-(6-fhioro-4-oxo- 1, 2, 3-benzotriazin-3-yl)piperidine-2, 6-dioneStep 1:

[0211] A mixture of 2-amino-5-fluoro-benzoic acid (1.0 eq, 776 mg, 5.00 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.0 eq, 959 mg, 5.00 mmol) and 1-hydroxybenzotriazole (1.0 eq, 676 mg, 5.00 mmol) in DMF (5 mL) was stirred at RT for 5 min followed by the addition of N, N-diisopropylethylamine (3.3 eq, 2.9 mL, 16.5 mmol). The reaction mixture was stirred atAttorney Docket No. 57547-738.601RT overnight. To the mixture was added water and the precipitate was collected, washed with water, and dried to afford 2-amino-N-(2,6-dioxo-3-piperidyl)-5-fluoro-benzamide (0.536 g, 40%) as off-white solid. Step 2: 3-(6-fluoro-4-oxo-l, 2, 3-benzotriazin-3-yl)piperidine-2, 6-dione

[0212] To a suspension of 2-amino-N-(2,6-dioxo-3-piperidyl)-5-fluoro-benzamide (1.0 eq, 536 mg, 2.02 mmol) in acetic acid (12 mL) was added sodium nitrite (2.0 eq, 279 mg, 4.04 mmol). The reaction mixture was stirred at RT for 20 min. The reaction was quenched with water. The resulting precipitate was collected, washed with water, and dried to give 3-(6-fluoro-4-oxo-l, 2, 3-benzotriazin-3-yl)piperidine-2, 6-dione (492 mg, 1.78 mmol, 88%) as an off-white powder.

[0213] The following compound was prepared by following the same general method:Structure MW LC-MS (m / z)F O276.2 277.2 [M+H]+f l Y nPreparation 26: (S)-N-(2-fluoro-4-((3-hydroxy-3,7-dimethyl-2-oxoindolin-l-yl)methyl)phenyl)-l-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazole-5-sulfonamideStep 1 Step 2Step 1:

[0214] A mixture of (3S)-l-[(4-bromo-3-fluoro-phenyl)methyl]-3-hydroxy-3,7-dimethyl-indolin-2-one (314 mg, 0.862 mmol), 2-methylpyrazole-3-sulfonamide (166 mg, 1.03 mmol, 1.19 eq), t-BuXPhos Palladacycle Gen. 3 (71 mg, 0.0893 mmol, 0.104 eq) and anhydrous potassium carbonate (375 mg, 2.71 mmol, 3.15 eq) in 1,4-dioxane (4.6 mL) was heated to 95 °C for 4 h under argon. The reaction mixture was allowed to cool to room temperature. The mixture was diluted with ethyl acetate (25 mL) and filtered through a pad of Celite. The filtrate was evaporated and the residue was purified by gradient silica gel column chromatography (hexane: ethyl acetate, 100:0 to 0:100) to give the title compound (310 mg, 0.697 mmol, 81%) as a brown powder. LCMS (acidic condition) Rt = 2.60 min, ESMS m / z = 445.5 [M+H]+.Step 2:

[0215] To a solution of (S)-A-(2-fluoro-4-((3-hydroxy-3,7-dimethyl-2-oxoindolin-l-yl)methyl)phenyl)-l-methyl-lH-pyrazole-5-sulfonamide (307 mg, 0.691 mmol, 1.00 eq) and N,N-diisopropylethylamine (242 μL, 1.39 mmol, 2.01 eq) in DCM (4.5mL) was added 2-(trimethylsilyl)ethoxymethyl chloride (148 μL, 0.836 mmol, 1.21 eq) dropwise at 0 °C and the reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with water (5 mL) and extracted with dichloromethane (1 x 50 mL). The organic layer was washed with brine (1 x5 mL), dried over magnesium sulfate, filtered, and evaporated. The residue wasAttorney Docket No. 57547-738.601purified by gradient silica gel column chromatography (hexane:ethyl acetate, 100:0 to 0:100) to afford the title compound (234 mg, 0.407 mmol, 59%) as an off-white powder. LCMS (acidic condition) Rt = 3.54 & 3.56 min, ESMS m / z = 575.5 [M+H]+.

[0216] The following compounds were prepared by the same general method:Structure MW LC-MS (m / z)577.8 600.6 [M+Na]+^ 1 / SiT. o508.7 531.5 [M+Na]+.s; y |i \ \ro' ° OHAA A “■ 0 / 'zOSi522.7 545.5 [M+Na]+A A^'S'NYA / 6'xo0A / Si534.7 557.5 [M+Na]+Ar° L 4)s>' Y |i [AZo' °0Preparation 27Attorney Docket No. 57547-738.601NaCIO, HCI, DCM Step 2A CD3I, K2CO3, DMF, r.t. o / n Step 1Step 1:

[0217] To a stirred mixture of 3-(benzylsulfanyl)-2H-pyrazole (2 g, 10.5 mmol) and K₂CO₃ (4.36 g, 31.5 mmol) in DMF (20 mL) was added iodomethane-d3 (1.31 mL, 21 mmol) in portions at room temperature. The resulting mixture was stirred at room temperature overnight. The resulting mixture was quenched with water (10 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (1 x 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with (EA in PE, 30% to 70%) to afford 5-(benzylsulfanyl)-l-(2H3)methylpyrazole (955 mg, 44%) as a yellow oil and 3-(benzylsulfanyl)-l-(2H3)methylpyrazole (518 mg, 23%) as a white oil.Step 2A:

[0218] A solution of 10% sodium hypochlorite solution (2.29 mL, 3.38 mmol) and 2 M HCI (2.41 mL, 4.83 mmol) in DCM (2 mL) was stirred at room temperature for 1 min. To the mixture was added 5-(benzylsulfanyl)-l-(2H3)methylpyrazole (200 mg, 0.965 mmol) in portions at 0 °C. The resulting mixture was stirred at 0 °C for additional 30 min. The resulting mixture was extracted with CH2C12 (1 x 1 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used in the next step directly without further purification.Step 2B:

[0219] Using the same procedure used for step 2B, l-(2H3)methylpyrazole-3-sulfonyl chloride was isolated without purification.Example 17: N-(2-methyI-3-pyridyl)^l-[[rac-(3S)-3-[2-[4-[2-[3-(2,6-dioxo-3-piperidyl)phenoxy]ethoxy]-3-methoxy-phenyl]-2-oxo-ethyl]-3,7-dimethyl-2-oxo-indolin-l-yl]methyl]benzenesulfonamideAttorney Docket No. 57547-738.601OBnStep 1:

[0220] To a stirred solution of 3-hydroxyphenylboronic acid (2.42 g, 17.5 mmol) and 2,6-bis(benzyloxy)-3 -bromopyridine (5 g, 13.5 mmol) in 1,4-dioxane and H₂O (5.0 mL) were added K3PO4 (6.88 g, 32.4 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II (66.0 mg, 0.081 mmol) in portions at room temperature under nitrogen. The reaction mixture was stirred for additional 4 h at 100 °C. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with (EA in PE, 0% to 50%) to afford 3-[2, 6-bis(benzyloxy)pyridin-3-yl] phenol (5.1 g, 98%) as alight brown oil. MS (ESI): mass calcd. for C25H21NO3 383.15, m / z found 384 [M+H]+. LCMS (acidic condition): Rt = 0.974 min.Step 2:

[0221] To a stirred solution of 3-[2,6-bis(benzyloxy)pyridin-3-yl]phenol (1 g, 2.60 mmol) and 2-bromoethanol (221.8 pL, 3.13 mmol) in DMF (10 mL) was added CS2CO3 (2.56 g, 7.8 mmol) in portions at room temperature. The reaction mixture was stirred for additional 3 h at 65 °C. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3:1) to afford 2-(3-[2,6-bis(benzyloxy)pyridin-3-yl]phenoxyethanol (403.7 mg, 47%) as a yellow oil. MS (ESI): mass calcd. for C27H25NO4427.18, m / z found 428 [M+H]+. LCMS (acidic condition): Rt = 0.947 min.Step 3:

[0222] To a stirred solution of 2-(3-[2,6-bis(benzyloxy)pyridin-3-yl]phenoxyethanol (403 mg, 0.94 mmol) and TEA (393 pL, 2.83 mmol) inDCM (4 mL) were added DMAP (11.5 mg, 0.094 mmol) and TSC1 (180 mg, 0.94 mmol) in portions at room temperature. The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with (EA in PE, 0% to 50%) to afford 2-(3-[2,6-Attorney Docket No. 57547-738.601bis(benzyloxy)pyridin-3-yl]phenoxyethyl 4-methylbenzenesulfonate (452 mg, 82%) as a white oil. MS (ESI): mass calcd. for C34H31NO6S 581.19, m / z found 604 [M+Na]+. LCMS (acidic condition): Rt = 0.957 min.Step 4:

[0223] A solution of 2-(3-[2,6-bis(benzyloxy)pyridin-3-yl]phenoxyethyl 4-methylbenzenesulfonate (452 mg, 0.78 mmol) and Pd / C (452 mg, 4.2 mmol) in EtOH (5 mL) was stirred overnight at room temperature under hydrogen chloride atmosphere. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by reversed -phase flash chromatography. This resulted in 2-[3-(2,6-dioxopiperidin-3-yl)phenoxy]ethyl 4-methylbenzenesulfonate (262.3 mg, 84%) as a white solid. MS (ESI): mass calcd. for C20H21NO6S 403.11, m / z found 404 [M+H]+. LCMS (acidic condition): Rt = 0.685 min.Step 5:

[0224] To a stirred solution of 2-[3-(2,6-dioxopiperidin-3-yl)phenoxy]ethyl 4-methylbenzenesulfonate (30 mg, 0.074 mmol) and 4-([(3S)-3-[2-(4-hydroxy-3-methoxyphenyl)-2-oxoethyl]-3,7-dimethyl-2-oxoindol-l-yl]methyl-N-(2-methylpyridin-3-yl)benzenesulfonamide (39.6 mg, 0.067 mmol) in DMF (300 pL) was added K2CO3 (28.0 mg, 0.202 mmol) in portions at room temperature. The resulting mixture was stirred for additional 3 h at 60 °C. The mixture was cooled down to room temperature. The residue was purified by reversed-phase flash chromatography. This resulted in 4-([(3S)-3-[2-(4-(2-[3-(2,6-dioxopiperidin-3-yl)phenoxy]ethoxy-3-methoxyphenyl)-2-oxoethyl] -3,7 -dimethyl-2-oxoindol- 1 -yl] methyl-N-(2-methylpyridin-3-yl)benzenesulfonamide (15.2 mg, 26%). MS (ESI): mass calcd. for C45H44N4O9S 816.28, m / z found 716.3 [M+H]+. LCMS (basic condition): Rt= 1.005 min.! HNMR(400 MHz, DMSO-d6) 8 10.82 (s, 1H), 9.86 (s, 1H), 8.24 (s, 1H), 7.74 - 7.61 (m, 3H), 7.59 (d, J= 8.3 Hz, 2H), 7.43 - 7.33 (m, 2H), 7.26 (t, J= 7.9 Hz, 1H), 7.22 - 7.06(m, 3H), 6.95 - 6.76 (m, 5H), 5.26 (s, 2H), 4.36 (ddd, J= 32.0, 6.4, 3.6 Hz, 4H), 4.16 (d, J= 18.5 Hz, 1H), 3.88-3.81 (m, lH),3.79(s, 3H), 3.63 (d, J= 18.4 Hz, 1H), 2.71 -2.60 (m, 1H), 2.51 -2.46 (m, 1H), 2.30 - 2.18 (m, 1H), 2.12 (d, J= 2.6 Hz, 5H), 2.08 - 1.98 (m, 1H), 1.38 (s, 3H).Example 18: N-(2-methyl-3-pyridyl)-4- [ [rac-(3S)-3- [2- [4- [2- [2- [3-(2,6-dioxo-3-piperidyl)phenoxy]ethoxy]ethoxy]-3-methoxy-phenyl]-2-oxo-ethyl]-3,7-dimethyl-2-oxo-indolin-l-yl] methyl] benzenesulfonamideAttorney Docket No. 57547-738.601Step 1:

[0225] To a stirred solution of 3-[2,6-bis(benzyloxy)pyridin-3-yl]phenol (1 g, 2.61 mmol) and 2-(2-[(4-methylbenzenesulfonyl)oxy]ethoxyethanol (1.09 g, 4.17 mmol) in THF (10 mL) were added PPh3(1.03 g, 3.91 mmol) and DEAD (654 pL, 4.17 mmol) in portions at 0 °C under nitrogen. The reaction mixture was stirred for additional 1 h at 50 °C. The reaction was quenched with water (10 mL) at room temperature. The resulting mixture was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (2 x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with (EA in PE, 0% to 15%) to afford 2-(2-(3-[2,6-bis(benzyloxy)pyridin-3-yl]phenoxyethoxy)ethyl 4-methylbenzenesulfonate (1.6 g, 98%yield) as a white oil. MS (ESI): mass calcd. for C36H35NO7S 625.21, m / z found 648.2 [M+H]+. LCMS (acidic condition): Rt = 1.38 min.Step 2:

[0226] To a stirred solution of 2-(2-(3-[2,6-bis(benzyloxy)pyridin-3-yl]phenoxyethoxy)ethyl 4-methylbenzenesulfonate (300 mg, 0.479 mmol) in EtOH (3 mL) was added Pd / C (300 mg, 2.82 mmol) in portions at room temperature under hydrogen. The reaction mixture was stirred at room temperature overnight. The resulting mixture was filtered, the filter cake was washed with MeOH (5 x5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EAto afford 2-(2-[3-(2,6-dioxopiperidin-3-yl)phenoxy]ethoxyethyl 4-methylbenzenesulfonate (120 mg, 56%) as a white oil. MS (ESI): mass calcd. for C22H25NO7S 447.14, m / z found 448.2 [M+H]+. LCMS (acidic condition): Rt = 0.689 min.Step 3:

[0227] To a stirred solution of 2-(2-[3-(2,6-dioxopiperidin-3-yl)phenoxy]ethoxyethyl 4-methylbenzenesulfonate (34.4 mg, 0.076 mmol) and 4-([(3S)-3-[2-(4-hydroxy-3-methoxyphenyl)-2-oxoethyl]-3,7-dimethyl-2-oxoindol-l-yl]methyl-N-(2-methylpyridin-3-yl)benzenesulfonamide (30 mg, 0.051 mmol) inDMF (600 pL) was added K2CO3 (21.3 mg, 0.153 mmol) at room temperature. The resulting mixture was stirred for additional 2 h at 60 °C. The mixture was quenched with water (1 mL). The residue was purified by reversed-phase flash chromatography. This resulted in 4-([(3S)-3-(2-[4-(2-(2-[3-(2,6-dioxopiperi din-3-yl)phenoxy] ethoxy ethoxy)-3-methoxyphenyl]-2-oxoethyl-3,7-dimethyl-2-oxoindol-l-yl]methyl-N-(2-methylpyridin-3-yl)benzenesulfonamide (8.4 mg, 18.5% yield). MS (ESI): mass calcd. for C47H48N4O10S 860.31, m / zfound 861.65 [M+H]+. LCMS (basic condition): Rt = 1.012 min.! HNMR(400 MHz, DMSO-de) 810.822 (s, 1H), 9.874 (s, 1H), 8.232-8.222 (m, 1H), 7.677-7.656 (m, 3H), 7.638-7.576 (d, J = 8.2 Hz, 2H), 7.380-7.359 (m, 2H), 7.256-7.154 (m, 3H), 7.093-7.071 (d, J= 8.6 Hz, 1H), 6.907-6.784 (m, 5H), 5.258 (s, 2H), 4.220-4.172 (m, 2H), 4.125-4.093 (m, 2H), 3.857-3.793 (m, 8H), 3.642-3.596 (d, J = 18.5 Hz, 1H), 2.673-2.643 (m,2H), 2.448-2.402 (d, J= 4.2 Hz, 1H), 2.351-2.198 (m, 2H), 2.128 (s, 5H), 2.033-2.002 (m, 1H), 1.380 (s, 3H).Example 20: N-(2-methyI-3-pyridyl)^l-[[rac-(3S)-3-[2-[4-[2-[4-(2,6-dioxo-3-piperidyl)aniIino] ethoxy] -3-methoxy-phenyl]-2-oxo-ethyl]-3,7-dimethyl-2-oxo-indolin-l-yl]methyl]benzenesulfonamideAttorney Docket No. 57547-738.601Step 1:

[0228] To a stirred mixture of 3-(4-aminophenyl)piperidine-2, 6-dione hydrochloride (300 mg, 1.24 mmol) and anisaldehyde (169 mg, 1.24 mmol) in DCE (5 mL) were added NaBH(OAc)3 (792 mg, 3.73 mmol) in portions at room temperature. The resulting mixture was stirred for 1 h at room temperature. The reaction was quenched by the addition of water (1 mL) at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA in PE, 0% to 30%) to afford 3-(4-([(4-methoxyphenyl)methyl]aminophenyl)piperidine-2, 6-dione (380 mg, 94%) as an off-white solid. MS (ESI): mass calcd. for C19H20N2O3324.15, m / z found 323.00 [M-H]+. LCMS (acidic condition): Rt = 0.606 min.Step 2:

[0229] To a stirred solution of 3-(4-([(4-methoxyphenyl)methyl]aminophenyl)piperidine-2, 6-dione (380 mg, 1.17 mmol) and glycolaldehyde (70.3 mg, 1.17 mmol) in DCE (5 mL) was added NaBH(OAc)3 (744 mg, 3.51 mmol) in portions at room temperature. The resulting mixture was stirred for 1 h at room temperature. The reaction was quenched with water (1 mL) at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA in PE, 0% to 50%) to afford 3-(4-[(2-hydroxyethyl)[(4-methoxyphenyl)methyl]amino]phenylpiperidine-2,6-dione (400 mg, 93%) as a white solid. MS (ESI): mass calcd. for C21H24N2O4368. I7, m / z found 369.20 [M+H]+. LCMS (acidic condition): Rt = 0.561 min.Step 3:

[0230] To a stirred solution of 3-(4-[(2-hydroxyethyl)[(4-methoxyphenyl)methyl] amino] phenylpiperidine-2, 6-dione (400 mg, 1.08 mmol) and TEA (452 pL, 3.25Attorney Docket No. 57547-738.601mmol) in DCM (5 mL) was added TsCl (269 mg, 1.41 mmol,) DMAP (13 mg, 0.109 mmol) in portions at room temperature. The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA in PE, 0% to 50%) to afford 2-([4-(2,6-dioxopiperidin-3-yl)phenyl][(4-methoxyphenyl)methyl] aminoethyl 4-methylbenzenesulfonate (400 mg, 70%) as a white solid. MS (ESI): mass calcd. for C28H30N2O6S 522.18, m / z found 523.25 [M+H]+. LCMS (acidic condition): Rt = 0.801 min.Step 4:

[0231] To a stirred solution of 2-([4-(2,6-dioxopiperidin-3-yl)phenyl][(4-methoxyphenyl)methyl] aminoethyl 4-methylbenzenesulfonate (50 mg, 0.096 mmol) and K2CO3 (36 mg, 0.26 mmol) in DMF (500 pL) was added 4-([(3S)-3-[2-(4-hydroxy-3-methoxyphenyl)-2-oxoethyl]-3,7-dimethyl-2-oxoindol-l-yl]methyl-N-(2-methylpyridin-3-yl)-N-([2- (trimethylsilyl)ethoxy] methylbenzenesulfonamide (62 mg, 0.087 mmol) in portions at room temperature. The resulting mixture was stirred for 1 h at 60 °C. The reaction was quenched with water (1 mL) at room temperature. The residue was purified by reversed-phase flash chromatography. This resulted in 4-([(3S)-3-(2-[4-(2-([4-(2,6-dioxopiperidin-3-yl)phenyl][(4-methoxyphenyl)methyl]aminoethoxy)-3-methoxyphenyl]- 2-oxoethyl-3,7-dimethyl-2-oxoindol-l-yl]methyl-N-(2-methylpyridin-3-yl)-N-([2-(trimethylsilyl)ethoxy]methylbenzenesulfonamide (70 mg, 75%) as an off-white solid. MS (ESI): mass calcd. for CsgHevNsOioSSi 1065.44, m / z found 1066.55 [M+H]+. LCMS (basic condition-i- NH3. H2O): Rt = 1.209 min.Step 5:

[0232] To a stirred solution of 4-([(3S)-3-(2-[4-(2-([4-(2,6-dioxopiperidin-3-yl)phenyl][(4-methoxyphenyl)methyl] aminoethoxy )-3-methoxyphenyl]-2-oxoethyl-3,7-dimethyl-2-oxoindol- 1 -yl] methyl-N-(2-methylpyridin-3-yl)-N-([2-(trimethylsilyl)ethoxy]methylbenzenesulfonamide (50 mg, 0.047 mmol) was added TFA (1 mL) at room temperature. The resulting mixture was stirred for 1 h at 100 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography. This resulted in 4-([(3S)-3-(2-[4-(2-([4-(2,6-dioxopiperidin-3-yl)phenyl]aminoethoxy)-3-methoxyphenyl]-2-oxoethyl-3,7-dimethyl-2-oxoindol-l-yl]methyl-N-(2-methylpyri din-3-yl)benzenesulfonamide (13.6 mg, 35%). MS (ESI): mass calcd. for C45H45N5O8S 815.30, m / z found 816.25 [M+H]+. LCMS (basic condition): Rt= 1.437 min.1HNMR(400 MHz, DMSO-d6)8 10.74 (s, 1H), 9.88 (s, 1H), 8.22 (s, 1H), 7.66 (d, J = 8.1 Hz, 3H), 7.58 (d, J= 8.1 Hz, 2H), 7.45 - 7.30 (m, 2H), 7.23 - 7.00 (m, 3H), 7.00 - 6.75 (m, 4H), 6.61 (d, J = 8.3 Hz, 2H), 5.77 (t,.7= 5,8 Hz. 1H), 5.26 (s, 2H), 4.34 - 4.11 (m, 3H), 3.80 (s, 3H), 3.74 - 3.58 (m, 2H), 3.44 (d, J= 5.8 Hz, 2H), 2.61 (td, J= 11.2, 10.7, 5.4 Hz, 1H), 2.48 -2.34 (m, 1H), 2.13 (s, 7H), 2.10 - 1.93 (m, 1H), 1.38 (s, 3H).Example 21: N-(2-methyI-3-pyridyl)^l-[[rac-(3S)-3-[2-[4-[2-[3-(2,6-dioxo-3-piperidyl)aniIino] ethoxy] - 3-methoxy-phenyl]-2-oxo-ethyl]-3,7-dimethyl-2-oxo-indolin-l-yl]methyl]benzenesulfonamideAttorney Docket No. 57547-738.601O LDA, THF, -70 °C, 30 min, (BOC)2O, rt, 4 h K2CO3, ACN.75 °C, 6 h step 1 step 2Step 1:

[0233] To a stirred solution of 3 -nitrophenylacetonitrile (5 g, 30.4 mmol) in THF (70 mL) was added LDA (31 mL, 62.0 mmol, 2M / L in Hexane) dropwise at -70 °C under nitrogen. The resulting mixture was stirred for 30 min at -70 °C under nitrogen. To the above mixture was added BOC2O (8.75 g, 40.1 mmol) in THF (20 mL) dropwise over 10 min at -70 °C. The resulting mixture was stirred for additional 2 h at room temperature. The reaction was quenched with saturated NH4CI (200 mL ) at 0 °C. The resulting mixture was extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with brine (1 x 500 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA in PE, 0% to 25%) to afford tert -butyl 2-cyano-2-(3-nitrophenyl)acetate (3.4 g, 41%) as a brown oil. MS (ESI): mass calcd. for C13H14N2O4 262.10, m / z found 261.10 [M-H]+. LCMS (basic condition): Rt = 0.860 min.Step 2:

[0234] To a stirred solution of tert-butyl 2-cyano-2-(3-nitrophenyl)acetate (3.2 g, 12.2 mmol) and ethyl 3-bromopropanoate (4.42 g, 24.4 mmol) in acetonitrile was added benzyltri ethylazanium chloride (277.9 mg,Attorney Docket No. 57547-738.6011.220 mmol) at room temperature. To the above mixture was added K2CO3 (3.37 g, 24.4 mmol). The resulting mixture was stirred for additional 6 h at 75 °C. The mixture was allowed to cool down to room temperature. The reaction was quenched by the addition of water (100 mL) at room temperature. The resulting mixture was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (1 x 200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA in PE, 10% to 20%) to afford 1-tert-butyl 5-ethyl 2-cyano-2-(3-nitrophenyl)pentanedioate (3.2 g, 72%) as a brown oil. MS (ESI): mass calcd. for C18H22N2O6 362.15, no m / z found. LCMS (acidic condition): Rt = 0.849 min.Step 3:

[0235] A solution of 1-tert-butyl 5-ethyl 2-cyano-2-(3-nitrophenyl)pentanedioate (3.4 g, 9.38 mmol) in AcOH (34.0 mL) was treated with H2SO4 (410 pL, 7.7 mmol) for 2 min at room temperature. The resulting mixture was stirred for additional 3 h at 120 °C. The reaction was quenched by the addition of water / ice (400 mL) at room temperature. The aqueous layer was extracted with EtOAc (2 x 500 mL). The combined organic layers were washed with brine (1 x 200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used in next step directly without further purification. This resulted in 3-(3-nitrophenyl)piperidine-2, 6-dione (1.9 g, 84%) as a light brown solid. MS (ESI): mass calcd. for C11H10N2O4234.06, m / z found 235.05 [M+H]+. LCMS (acidic condition): Rt = 0.499 min.Step 4:

[0236] A solution of 3-(3-nitrophenyl)piperidine-2, 6-dione (2 g, 8.54 mmol) in MeOH (20 mL) was treated with Pd / C (2.00 g) for 3 min at room temperature under nitrogen. To the mixture was introduced H2 (gas). The reaction mixture was stirred at room temperature for 2 h under hydrogen. The resulting mixture was filtered, the filter cake was washed with MeOH (3 x 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA in PE, 10% to 25%) to afford 3-(3-aminophenyl)piperidine-2, 6-dione (1.03 g, 58%) as a yellow solid. MS (ESI): mass calcd. for C11H12N2O2204.09, m / z found 204.95 [M+H]+. LCMS (basic condition): Rt = 0.480 min.Step 5:

[0237] To a stirred solution of 3-(3-aminophenyl)piperidine-2, 6-dione (300 mg, 1.47 mmol) and anisaldehyde (200.0 mg, 1.47 mmol) in DCE (10 mL) was added NaBH(OAC)s (934.0 mg, 4.4 mmol) in portions at room temperature. The resulting mixture was stirred overnight at room temperature. The reaction was quenched with water (0.5 mL) and extracted with EtOAc (3 x 50 mL). The organic phase was washed with brine (1 x 50 mL), dried over anhydrous sodium sulfate, filtered, concentrated in vacuo. The residue was purified by silica gel column chromatography (EA in PE, 0% to 40%) to afford 3-(3-([(4-methoxyphenyl)methyl]aminophenyl)piperidine-2, 6-dione (446.5 mg, 94%) as a green solid. MS (ESI): mass calcd. for C19H20N2O3324.15, m / z found 325.15 [M+H]+. LCMS (acidic condition): Rt = 0.530 min.Step 6:Attorney Docket No. 57547-738.601

[0238] To a stirred mixture of 3-(3-([(4-methoxyphenyl)methyl]aminophenyl)piperidine-2, 6-dione (410 mg, 1.26 mmol) and l,4-dioxane-2,5-diol(121 mg, 1.01 mmol) in DCE (10 mL) were added NaBH(OAc)3 (803.6 mg, 3.79 mmol) in portions at room temperature. The resulting mixture was stirred overnight at room temperature. The reaction was quenched with water (0.5 mL) and extracted with EtOAc (3 x 50 mL). The organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated in vacuo. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography(EA in PE, 0% to 25%) to afford 3-(3-[(2-hydroxyethyl)[(4-methoxyphenyl)methyl] amino] phenylpiperidine-2, 6-dione (300 mg, 64%) as ayellow solid. MS (ESI): mass calcd. for C21H24N2O4 368.17, m / z found 369.30 [M+H]+. LCMS (acidic condition): Rt = 0.536 min. Step 7:

[0239] To a stirred solution of 3-{3-[(2-hydroxyethyl)[(4-methoxyphenyl)methyl] amino] phenyl }piperidine-2, 6-dione (460 mg, 1.25 mmol) and TEA (379.0 mg, 3.75 mmol) in DCM (5 mL) was added DMAP (15.3 mg, 0.125 mmol) at room temperature. To the above mixture was added TsCl (357.0 mg, 1.87 mmol) in portions over 10 min at 0 °C. The resulting mixture was stirred for additional 2 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (EA in PE, 0% to 20%) to afford 2-{[3-(2,6-dioxopiperidin-3-yl)phenyl] [(4-methoxyphenyl)methyl] amino} ethyl 4-methylbenzenesulfonate (260 mg, 40%) as an off-white solid. MS (ESI): mass calcd. for C28H30N2O6S 522.18, m / z found 523.25 [M+H]+. LCMS (acidic condition): Rt = 0.536 min.Step 8:

[0240] To a stirred solution of 4-([(3S)-3-[2-(4-hydroxy-3-methoxyphenyl)-2-oxoethyl]-3,7-dimethyl-2-oxoindol-l-yl]methyl-N-(2-methylpyridin-3-yl)benzenesulfonamide (20 mg, 0.034 mmol) and 2-([3-(2,6-dioxopiperidin-3-yl)phenyl][(4-methoxyphenyl)methyl] aminoethyl 4-methylbenzenesulfonate (35.7 mg, 0.068 mmol) in DMF(1.0 mL) was added K2CO3 (18.9 mg, 0.136mmol) at room temperature. The resulting mixture was stirred for 2h at 60 °C. The mixture was allowed to cool down to room temperature. The residue was purified by reversed-phase flash chromatography. This resulted in 4-([(3S)-3-(2- [4-(2-([3-(2,6-dioxopiperidin-3-yl)phenyl][(4-methoxyphenyl)methyl]aminoethoxy)-3-methoxyphenyl]-2-oxoethyl-3,7-dimethyl-2-oxoindol-l-yl]methyl-N-(2-methylpyridin-3-yl)benzenesulfonamide (20 mg, 63%) as a off-white solid. MS (ESI): mass calcd. for C53H53N5O9S 935.36, m / z found 936.30 [M+H]+. LCMS (acidic condition): Rt = 0.710 min.Step 9:

[0241] Into a8mL sealed tube were added 4-([(3S)-3-(2-[4-(2-([3-(2,6-dioxopiperidin-3-yl)phenyl][(4-methoxyphenyl)methyl] aminoethoxy )-3-methoxyphenyl]-2-oxoethyl-3,7-dimethyl-2-oxoindol- 1 -yl] methyl-N-(2-methylpyridin-3-yl)benzenesulfonamide (50 mg, 0.053 mmol) and TFA (1.0 mL) at room temperature. The resulting mixture was stirred for 1 h at 100 °C. The resulting mixture was concentrated under vacuum. The residue was purified by reversed-phase flash chromatography. This resulted in 4-([(3 S)-3-(2-[4-(2-([3-(2,6-dioxopiperidin-3-yl)phenyl |aminoethoxy)-3-methox phen l|-2-oxoeth l-3.7-dimeth l-2-Attorney Docket No. 57547-738.601oxoindol-l-yl]methyl-N-(2-methylpyridin-3-yl)benzenesulfonamide (12.3 mg, 28%). MS (ESI): mass calcd. for C45H45N5O8S 815.30, m / z found 816.25 [M+H]+. LCMS (acidic condition): Rt = 0.838 min.1HNMR (400 MHz, DMSO-de) 510.79 (s, lH),9.87 (s, 1H), 8.23 (s, 1H), 7.70 - 7.62 (m, 3H), 7.59 (d, J= 8.2 Hz, 2H), 7.41 - 7.34 (m, 2H), 7.22 - 7.12 (m, 2H), 7.12 - 7.01 (m, 2H), 6.90 (d, J= 7.5 Hz, 1H), 6.84 (t, J= 7.4 Hz, 1H), 6.54 (d, J= 8.5 Hz, 1H), 6.49 (s, 1H), 6.40 (d, J= 7.6 Hz, 1H), 5.82 (t, J= 5.8 Hz, 1H), 5.26 (s, 2H), 4.20 (t, J= 6.1 Hz, 2H), 4.13 (s, 1H), 3.80 (s, 3H), 3.77 -3.62 (m, 2H), 3.44 (d, J= 5.8 Hz, 2H), 2.62 (ddd, J= 16.4, 10.5, 5.4 Hz, 1H), 2.50 - 2.40 (m, 1H), 2.13 (s, 6H), 2.10 - 1.99 (m, 1H), 1.38 (s, 3H).Example 29: N-(2-methyl-3-pyridyl)-4- [ [rac-(3S)-3- [2- [4- [3- [3-(2,6-dioxo-3-piperidyl)phenoxy]propoxy]-3-methoxy-phenyl]-2-oxo-ethyl]-3,7-dimethyl-2-oxo-indolin-l-yl] methyl] benzenesulfonamideStep 1:

[0242] Into a 20 mL vial were added 4-[2,6-bis(benzyloxy)pyridin-3-yl]phenol (300 mg, 0.782 mmol, 1 equiv), DMF (5 mL), CS2CO3 (765 mg, 2.34 mmol, 3 equiv) and 2-(2-bromoethoxy)ethanol (158 mg, 0.93 mmol, 1.2 equiv) at room temperature. The reaction mixture was stirred at 70 °C overnight. The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (1x100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA in PE, 0% to 20%) to afford 2-(2-(4-[2,6-bis(benzyloxy)pyridin-3-yl] phenoxy ethoxy) ethanol (275 mg, 75%) as a colorless oil. MS (ESI): mass calcd. for C28H27NO4441.09, m / z found 442.25 [M+H]+. LCMS (acidic condition): Rt = 1.239 min.Step 2:Attorney Docket No. 57547-738.601

[0243] Into a 100 mL round-bottom flask were added 3-(3-[2,6-bis(benzyloxy)pyridin-3-yl]phenoxypropan-l-ol (275 mg, 0.62 mmol, 1 equiv), DCM (2 mL), TEA (189 mg, 1.87 mmol, 3 equiv), DMAP (1.52 mg, 0.012 mmol, 0.02 equiv) and TsCl (237 mg, 1.24 mmol, 2 equiv) at room temperature. The reaction mixture was stirred at room temperature overnight. The resulting mixture was filtered, the filter cake was washed with DCM (3 x 100 mL). The filtrate was concentrated under reduced pressure. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (EA in PE, 0% to 20%) to afford 3-(3-[2,6-bis(benzyloxy)pyridin-3-yl]phenoxypropyl 4-methylbenzenesulfonate (205 mg, 55%) as a colorless oil. MS (ESI): mass calcd. for C35H33NO6S 595.20, m / z found 618.25 [M+ Na]+. LCMS (acidic condition): Rt = 1.399 min.Step 3:

[0244] Into a 100 mL round-bottom flask were added 3-(3-[2,6-bis(benzyloxy)pyridin-3-yl] phenoxy propyl 4-methylbenzenesulfonate (204 mg, 0.342 mmol, 1 equiv), THF (5 mL) and Pd / C (204 mg, 1.92 mmol, 5.60 equiv) at room temperature. The reaction mixture was stirred at room temperature for 2 h under hydrogen. The resulting mixture was filtered, the filter cake was washed with MeOH and DCM (3 x 100 mL). The filtrate was concentrated under reduced pressure. This resulted in 3-[3-(2,6-dioxopiperidin-3-yl)phenoxy] propyl 4-methylbenzenesulfonate (139 mg, 97%) as a white solid. MS (ESI): mass calcd. for C21H23NO6S 417.12, m / z found 418.20 [M+H]+. LCMS (acidic condition): Rt = 0.89min.Step 4:

[0245] Into a 8 mL vial were added 4-([(3S)-3-[2-(4-hydroxy-3-methoxyphenyl)-2-oxoethyl]-3,7-dimethyl-2-oxoindol-l-yl]methyl-N-(2-methylpyridin-3-yl)benzenesulfonamide (50 mg, 0.085 mmol, 1 equiv), DMF (1.00 mL), K2CO3 (35.40 mg, 0.255 mmol, 3 equiv) and 3-[3-(2,6-dioxopiperidin-3-yl)phenoxy] propyl 4-methylbenzenesulfonate (42.7 mg, 0.102 mmol, 1.2 equiv) at room temperature. The reaction mixture was stirred at 60 °C overnight. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (1 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography. This resulted in 4-([(3S)-3- [2-(4-(3- [3-(2,6-dioxopiperidin-3-yl)phenoxy]propoxy-3-methoxyphenyl)-2-oxoethyl]-3,7-dimethyl-2-oxoindol-l-yl]methyl-N-(2-methylpyridin-3-yl)benzenesulfonamide (15 mg, 21%). MS (ESI): mass calcd. for C46H46N4O9S 830.30 m / z found 831.25 [M+H]+. LCMS (basic condition): Rt = 1.450 min. 'H NMR (400 MHz, DMSO-d6) 8 10.81 (s, 1H), 9.87 (s, 1H), 8.22 (d, J = 4.5Hz, 1H), 7.65 (td, J= 5.2, 2.7 Hz, 3H), 7.58 (d, J= 8.2 Hz, 2H), 7.36 (dd, J= 7.4, 1.8 Hz, 2H), 7.23 (t, J= 7.9 Hz, 1H), 7.16 (ddd, J= 12.8, 7.7, 3.1 Hz, 2H), 7.09 (d, J= 8.6 Hz, 1H), 6.92-6.75 (m, 5H),5.25 (s, 2H), 4.22 (t, J= 6.3 Hz, 2H), 4.18 - 4.08 (m, 3H), 3.85 - 3.78 (m, 1H), 3.79 (s, 3H), 3.61 (d, J= 18.5 Hz, 1H), 2.67 -2.57 (m, 1H),2.44 (d, J= 4.3 Hz, 1H), 2.23 - 2.14 (m, 3H), 2.12 (s, 6H), 2.10 - 1.96 (m, 1H), 1.37 (s, 3H).Example 34: N-(2-methyl-3-pyridyl)-4- [ [rac-(3S)-3- [2- [4- [3- [3-(2,6-dioxo-3-piperidyl)phenoxy] cyclobutoxy] -3-methoxy-phenyl]-2-oxo-ethyl] -3, 7-dimethyl-2-oxo-indolin-l-yl] methyl] benzenesulfonamideAttorney Docket No. 57547-738.601Step 1:

[0246] Into a 40 mL vial were added (1s,3s)-cyclobutane-1,3-diol (300 mg, 3.40 mmol, 1.00 equiv), TsCl (1.29 g, 6.81 mmol, 2.00 equiv), TEA (1.03 g, 10.215 mmol, 3.00 equiv), DCM (5 mL) and DMAP (8.32 mg, 0.068 mmol, 0.02 equiv) at room temperature. The resulting mixture was stirred overnight at room temperature. The resulting mixture was filtered, the filter cake was washed with DCM (3 x 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA in PE, 20% to 30%) to afford (ls,3s)-3-[(4-methylbenzenesulfonyl)oxy]cyclobutyl 4-methylbenzenesulfonate (950 mg, 70%) as a white solid. MS (ESI): mass calcd. for C18H20O6S2396.07, m / z found 414.05 [M+OH]+. LCMS (acidic condition): Rt = 1.066 min.Step 2:

[0247] Into a 40 mL vial were added (ls,3s)-3-[(4-methylbenzenesulfonyl)oxy]cyclobutyl 4-methylbenzenesulfonate (775 mg, 1.95 mmol, 1.5 equiv), 3-[2,6-bis(benzyloxy)pyridin-3-yl]phenol (499 mg, 1.30 mmol, 1.0 equiv), CS2CO3 (1273 mg, 3.91 mmol, 3.0 equiv) and DMF (7 mL) at room temperature. The resulting mixture was stirred for additional 2 h at 70 °C. The mixture was allowed to cool down to room temperature. The resulting mixture was quenched with water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with NaCl (1 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA in PE, 15% to 20%) to afford (lr,3r)-3-{3-[2,6-bis(benzyloxy)pyridin-3-yl] phenoxy (cyclobutyl 4-methylbenzenesulfonate (600 mg, 76%) as a light-yellow oil. MS (ESI): mass calcd. for C36H33NO6S 607.20, m / z found 630.25 [M+Na]+. LCMS (acidic condition): Rt = 1.434 min.Step 3:

[0248] Into a 40 mL vial were added (1r,3r)-3-{3-[2,6-bis(benzyloxy)pyridin-3-yl]phenoxy}cyclobutyl 4-methylbenzenesulfonate (570 mg, 0.938 mmol, 1.0 equiv), THF (6 mL) and Pd / C (570 mg) in portions at room temperature. The reaction mixture was stirred at room temperature for 2 h under hydrogen. TheAttorney Docket No. 57547-738.601resulting mixture was filtered, the filter cake was washed with THF (4 x 70 mL). The filtrate was concentrated under reduced pressure. The crude product (400 mg) was used in the next step directly without further purification. MS (ESI): mass calcd. For C22H23NO6S 429.12, m / z found 430.10 [M+H]+. LCMS (acidic condition): Rt = 0.946 min.Step 4:

[0249] Into a 8 mL vial were added 4-{[(3S)-3-[2-(4-hydroxy-3-methoxyphenyl)-2-oxoethyl]-3,7-dimethyl-2-oxoindol-l-yl]methyl}-N-(2-methylpyridin-3-yl)-N-{[2- (trimethylsilyl)ethoxy]methyl} benzenesulfonamide (95.3 mg, 0.133 mmol, 1.0 equiv), t-BuOK (22.4 mg, 0.200 mmol, 1.5 equiv) and DMSO (1 mL) in portions at room temperature. The reaction mixture was stirred at 100 °C for 15 min under nitrogen. To the mixture was added a solution of (lr,3r)-3-[3-(2,6-dioxopiperidin-3-yl)phenoxy] cyclobutyl 4-methylbenzenesulfonate (150 mg, 0.349 mmol, 2.5 equiv) in DMSO (0.5 mL) dropwise at 100 °C under nitrogen. The reaction mixture was stirred at 100 °C for additional 2 h under nitrogen. The mixture was allowed to cool down to room temperature. The resulting mixture was quenched with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with NaCl (1 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase flash to afford crude product. The crude product was purified by Prep-HPLC to afford 4-{[(3S)-3-[2-(4-{3-[3-(2,6-dioxopiperidin-3-yl)phenoxy]cyclobutoxy}-3-methoxyphenyl)-2-oxoethyl]-3,7-dimethyl-2-oxoindol-l-yl]methyl}-N-(2-methylpyridin-3-yl)benzenesulfonamide (6.5 mg, 3%). MS (ESI): mass calcd. for C19H18BrNO3, 842.30 m / z found 843.25 [M+H]+. LCMS (acidic condition): Rt = 0.897 min.1H NMR (400 MHz, DMSO-d6) 810.83 (s, 1H), 8.26 (s, 1H), 7.70 - 7.60 (m, 3H), 7.55 (d, J = 8.1 Hz, 2H), 7.39 (d, J = 1.9 Hz, 1H), 7.34 (dd, J = 8.0, 1.8 Hz, 1H), 7.25 (t, J = 7.9 Hz, 1H), 7.18 (d, J = 7.1 Hz, 1H), 7.08 (dd, J = 8.0, 4.6Hz, 1H), 6.99 (s, 2H), 6.87-6.72 (m,4H), 5.24 (s, 2H), 4.54 (dp, J = 36.0, 6.8 Hz, 2H), 4.16 (s, 1H), 3.81 (s, 4H), 3.65 (s, 1H), 3.18 (dt, J = 12.7, 6.6 Hz, 2H), 2.72 - 2.59 (m, 2H), 2.24 (dd, J = 12.1, 4.3 Hz, 1H), 2.14 (d, J = 4.2 Hz, 9H), 1.38 (s, 3H).Example 38: N-methyl-N- [4- [ [rac-(3S)-3- [2- [4- [2- [3-(2,6-dioxo-3-piperidyl)phenoxy] ethoxy] -3-methoxy-phenyl]-2-oxo-ethyl]-3,7-dimethyl-2-oxo-indolin-l-yl]methyl]phenyl]pyridine-4-carboxamideAttorney Docket No. 57547-738.601OBnStep 1:

[0250] To a stirred solution of 3-hydroxyphenylboronic acid (5.0 g, 36.2 mmol) and 2,6-bis(benzyloxy)-3 -bromopyridine (10.3 g, 27.9 mmol) in dioxane (200 mL) and H2O (20 mL) were added K3PO4 (14.2 g, 66.9 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium II (681 mg, 0.836 mmol) at room temperature under nitrogen. The reaction mixture was stirred at 100 °C for 3 h. The resulting mixture was filtered, the filter cake was washed with CH2CI2 (5 x 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with (EA in PE, 0% to 25%) to afford 3-[2,6-bis(benzyloxy)pyridin-3-yl]phenol (11 g, 99.8%) as ayellow oil. MS (ESI): mass calcd. for C25H21NO3 383.15, m / z found 384.15 [M+H]+. LCMS (acidic condition): Rt = 1.211 min.Step 2:

[0251] To a stirred solution of 3-[2,6-bis(benzyloxy)pyridin-3-yl]phenol (5 g, 13.040 mmol) and 2-bromoethanol (1.39 mL, 19.560 mmol) in DMF (50 mL) was added CS2CO3 (12.75 g, 39.12 mmol) at room temperature. The resulting mixture was stirred for additional overnight at 65 °C. The reaction was quenched with water (100 mL) at room temperature. The resulting mixture was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (1 x 200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with (EA in PE, 0% to 25%) to afford 2-(3-[2,6-bis(benzyloxy)pyridin-3-yl] phenoxyethanol (3.6 g, 65%) as a yellow oil. MS (ESI): mass calcd. for C27H25NO4427.18, m / z found 428.15 [M+H]+. LCMS (acidic condition): Rt = 1.219 min.Step 3:

[0252] To a stirred solution of 2-(3-[2,6-bis(benzyloxy)pyridin-3-yl]phenoxyethanol (3.6 g, 8.421 mmol) and TEA (3.51 mL, 25.3 mmol) in DCM (35 mL) were added TsCl (3.21 g, 16.8 mmol) and DMAP (20.6 mg, 0.168 mmol) at room temperature. The resulting mixture was stirred for additional 2.5 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with (EA in PE, 0% to 25%) to afford 2-(3-[2,6-Attorney Docket No. 57547-738.601bis(benzyloxy)pyridin-3-yl]phenoxyethyl 4-methylbenzenesulfonate (4.7 g, 96%) as a light-yellow oil. MS (ESI): mass calcd. for C34H31NO6S 581.19, m / z found 582.05 [M+H]+. LCMS (acidic condition): Rt = 1.073 min.Step 4:

[0253] To a stirred solution of 2-(3-[2,6-bis(benzyloxy)pyridin-3-yl]phenoxyethyl 4-methylbenzenesulfonate (4.7 g, 8.08 mmol)in 2,2,2-trifluoroethan-l-ol (50 mL) was added Pd / C (4.7 g) at room temperature under nitrogen. To the mixture was introduced hydrogen. The reaction mixture was stirred overnight at room temperature under hydrogen. The resulting mixture was filtered, the filter cake was washed with EtOAc (10x 10 mL). The filtrate was concentrated under reduced pressure. This resulted in 2-[3-(2,6-dioxopiperidin-3-yl)phenoxy]ethyl 4-methylbenzenesulfonate (2.87 g, 88%) as a white solid. The crude product was used directly in the next step without further purification. MS (ESI): mass calcd. for C20H21NO6S 403.11, m / z found 404.0 [M+H]+. LCMS (acidic condition): Rt = 0.668 min.Step 5:

[0254] To a stirred solution of N-(4-([(3S)-3-[2-(4-hydroxy-3-methoxyphenyl)-2-oxoethyl]-3,7-dimethyl- 2-oxoindol-l-yl]methylphenyl)-N-methylpyridine-4-carboxamide (800 mg, 1.46 mmol) in DMF (8 mL) were added 2-[3-(2,6-dioxopiperidin-3-yl)phenoxy]ethyl 4-methylbenzenesulfonate (763 mg, 1.89 mmol) and K2CO3 (603.5 mg, 4.37 mmol) at room temperature. The resulting mixture was stirred for additional 1 h at 60 °C. The residue was purified by reversed-phase flash chromatography. This resulted in N-(4-([(3S)-3-[2-(4-(2-[3-(2,6-dioxopiperidin-3-yl)phenoxy]ethoxy-3-methoxyphenyl)-2-oxoethyl]-3,7-dimethyl-2-oxoindol-l-yl]methylphenyl)-N-methylpyridine-4-carboxamide (503.6mg, 44%). MS (ESI): mass calcd. for C46H44N4O8 780.32, m / z found 781.6 [M+H]+. LCMS (basic condition): Rt = 1.016 min. 'H NMR (400 MHz, DMSO-d6) 810.83 (s, 1H), 8.44-8.43 (d, J = 4.6Hz, 2H), 7.68-7.65 (dd, J = 8.5, 2.0 Hz, 1H), 7.39-7.38 (d, J = 2.0 Hz, 1H), 7.32-7.13 (m, 9H), 6.92-6.81 (m, 5H), 5.11-5.09 (d, J = 3.2Hz, 2H), 4.41-4.40 (dd, J = 5.8, 2.9 Hz, 2H), 4.34-4.33 (m,2H), 4.16-4.11 (d, J= 18.5 Hz, 1H), 3.85-3.80 (m, 4H), 3.64-3.59 (d, J = 18.5 Hz, 1H), 3.38 (s, 3H), 2.71-2.66 (m, 1H), 2.50-2.47 (t, J= 4.2 Hz, 1H), 2.23-2.21 (qd, J= 12.0, 4.4 Hz, 1H), 2.08-2.03 (d, J = 20.5 Hz, 4H), 1.35 (s, 3H).Example 42: V(2-methyl-3-pyridyl)-l-||rac-(3S)-3-|2-|4-|3-|3-(2.6-dioxo-3-piperidyl)aiiiliiio|propoxy|- 3-methoxy-phenyl]-2-oxo-ethyl]-3,7-dimethyl-2-oxo-indolin-l-yl]methyl]benzenesulfonamideAttorney Docket No. 57547-738.601KOH, Pd2(dba)3, t-BuXPhos, SEMCI H2O, Dioxane, 100°C, 16h DIEA. DCM Step 2A Step 1ATFA, reflux Step 2o Step 1A:

[0255] To a stirred mixture of 4-((3-[2-(4-bromo-3-methoxyphenyl)-2-oxoethyl]-3,7-dimethyl-2-oxoindol-l-ylmethyl)-N-(2-methylpyridin-3-yl)benzenesulfonamide (1.39 g, 2.14 mmol, 1 equiv) in DCM (7 mL) and DIEA (981 pL, 5.63 mmol, 2.6 equiv) was added [2-(chloromethoxy)ethyl]trimethylsilane (751 pL, 4.24 mmol, 1.98 equiv) in portions at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with (EA in PE, 35% to 45%) to afford 4-((3-[2-(4-bromo-3-methoxyphenyl)-2-oxoethyl]-3,7-dimethyl-2-oxoindol-l-ylmethyl)-N-(2-methylpyridin-3-yl)-N-([2-(trimethylsilyl)ethoxy]methylbenzenesulfonamide (1.52 g, 91%) as a white solid. MS (ESI): mass calcd. for C38H44BrN3O6SSi 777.19, m / z found 778 [M+H]+. LCMS (acidic condition): Rt = 1.032 min.Step 2A:

[0256] To a stirred mixture of 4-((3-[2-(4-bromo-3-methoxyphenyl)-2-oxoethyl]-3,7-dimethyl-2-oxoindol-l-ylmethyl)-N-(2-methylpyridin-3-yl)-N-([2-(trimethylsilyl)ethoxy]methylbenzenesulfonamide (1.52 g, 1.95 mmol, 1 equiv) and KOH (328 mg, 5.86 mmol, 3 equiv) in dioxane (13 mL) and H2O (5 mL) was added t-BuXphos (82.8 mg, 0.195 mmol, 0.10 equiv) and Pd2(dba)s (178 mg, 0.195 mmol, 0.1 equiv) in portions at room temperature under nitrogen. The reaction mixture was stirred at 100 °C overnight under nitrogen. The resulting mixture was filtered, the filter cake was washed with ACN (3 x 5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography. This resulted in 4-((3-[2-(4-hydroxy-3-methoxyphenyl)-2-oxoethyl]-3,7-dimethyl-2-oxoindol-l-ylmethyl)-N-(2-methylpyridin-3-yl)-N-([2-(trimethylsilyl)ethoxy]methylbenzenesulfonamide (1.3 g, 93%) as a brown solid. MS (ESI): mass calcd. for C38H45N3O7SSi 715.27, m / z found 716 [M+H]+. LCMS (acidic condition): Rt = 0.965 min.Step 3A:Attorney Docket No. 57547-738.601

[0257] The crude product (1.3 g) was purified by Prep-SFC to afford 4-([(3S)-3-[2-(4-hydroxy-3-methoxyphenyl)-2-oxoethyl]-3,7-dimethyl-2-oxoindol-l-yl]methyl-N-(2-methylpyridin-3-yl)-N-([2-(trimethylsilyl)ethoxy]methylbenzenesulfonamide (502.4 mg, 38%) as ayellow solid. MS (ESI): mass calcd. for C38H45N3O7SSi 715.27, m / z found 716.3 [M+H]+. LCMS (acidic condition): Rt = 1.116 min.Step 1:

[0258] To a stirred mixture of 3-([3-(2,6-dioxopiperidin-3-yl)phenyl][(4-methoxyphenyl)methyl] aminopropyl 4-methylbenzenesulfonate (90 mg, 0.168 mmol, 1.2 equiv) and 4-([(3S)-3-[2-(4-hydroxy-3-methoxyphenyl)-2-oxoethyl]-3,7-dimethyl-2-oxoindol-l-yl]methyl-N-(2-methylpyridin-3-yl)-N-([2-(trimethylsilyl)ethoxy]methylbenzenesulfonamide (100 mg, 0.140 mmol, 1.0 equiv) in DMF (1 mL) was added K2CO3 (58 mg, 0.420 mmol, 3 equiv) in portions at room temperature. The resulting mixture was stirred for 2 h at 60 °C. The mixture was allowed to cool down to room temperature. The reaction was quenched with water at room temperature. The residue was purified by reversed-phase flash chromatography. This resulted in 4-([(3S)-3-(2-[4-(3-([3-(2,6-dioxopiperidin-3-yl)phenyl][(4-methoxyphenyl)methyl]aminopropoxy)-3-methoxyphenyl]-2-oxoethyl-3,7-dimethyl-2-oxoindol-l-yl]methyl-N-(2-methylpyridin-3-yl)-N-([2-(trimethylsilyl)ethoxy]methylbenzenesulfonamide (120 mg, 80%) as ayellow solid. MS (ESI): mass calcd. for C60H69N5O10SSi 1079.45, m / z found 1080 [M+H]+. LCMS (acidic condition): Rt = 1.276 min.Step 2:

[0259] A mixture of 4-([(3S)-3-(2-[4-(3-([3-(2,6-dioxopiperidin-3-yl)phenyl][(4-methoxyphenyl)methyl]aminopropoxy)-3-methoxyphenyl]-2-oxoethyl-3,7-dimethyl-2-oxoindol-l-yl]methyl-N-(2-methylpyridin-3-yl)-N-([2-(trimethylsilyl)ethoxy]methylbenzenesulfonamide (120 mg, 0.111 mmol, 1 equiv) in TFA (1.5 mL) was stirred for 2 h at 100 °C. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography. The crude product was purified by Prep-HPLC to afford 4-([(3S)-3-(2-[4-(3-([3-(2, 6-dioxopiperidin-3-yl)phenyl] aminopropoxy )-3-methoxyphenyl]-2-oxoethyl-3, 7-dimethyl-2-oxoindol-l-yl]methyl-N-(2-methylpyridin-3-yl)benzenesulfonamide (18.2 mg, 19%). MS (ESI): mass calcd. for C46H47N5O8S 829.97, m / z found 830.25 [M+H]+. LCMS (basic condition): Rt = 0.669 min. 'H NMR (400 MHz, DMSO-d6) 8 10.79 (s, 1H), 9.83 (s, 1H), 8.23 - 8.17 (m, 1H), 7.70- 7.62 (m, 3H), 7.58 (d, J= 8.2 Hz, 2H), 7.41 - 7.33 (m, 2H), 7.21 - 7.10 (m, 2H), 7.10 - 6.98 (m, 2H), 6.92 - 6.79(m, 2H), 6.48 (dd, J=8.3, 2.3Hz, 1H), 6.43 - 6.34 (m, 2H), 5.69 (t, J = 5.6 Hz, 1H), 5.25 (s, 2H), 4.21 - 4.11 (m, 3H), 3.81 (s, 3H), 3.74 - 3.56 (m, 2H), 3.17 (q, J= 6.4 Hz, 2H), 2.60 (ddd, J= 16.4, 10.3, 5.6 Hz, 1H), 2.48 - 2.38 (m, 1H), 2.13 (s, 6H), 2.03 (ddd, J= 19.5, 14.2, 5.5 Hz, 4H), 1.38 (s, 3H).Example 62: N-(2-methyl-3-pyridyl)-4- [ [rac-(3S)-3- [2- [4- [3- [3-(2,6-dioxo-3-piperidyl)anilino] cyclobutoxy] -3- methoxy-phenyl] -2-oxo-ethyl] -3, 7-dimethyl- 2-oxo- indolin-1-yl] methyl] benzenesulfonamideAttorney Docket No. 57547-738.601Step 1:

[0260] To a stirred mixture of 3-[2,6-bis(benzyloxy)pyridin-3-yl]aniline (1.0 g, 2.6 mmol) and 3-hydroxycyclobutan-l-one (225 mg, 2.6 mmol) in MeOH (15 mL) was added AcOH (449 pL, 7.8 mmol), NaBHsCN (492 mg, 7.84 mmol) in portions at 0 °C. The resulting mixture was stirred for 40 min at room temperature. The reaction was quenched with water (10 mL) and extracted with DCM (3 x 20 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous MgSCh. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA in PE, 0% to 50%) to afford 3-((3-[2,6-bis(benzyloxy)pyridin-3-yl]phenylamino)cyclobutan-l-ol (910 mg, 77%) as a yellow oil. MS (ESI): mass calcd. for C29H28N2O3 452.21, m / z found 453.20 [M+H]+. LCMS (acidic condition): Rt = 0.929 min.Step 2:

[0261] The crude product (1.0 g) was purified by Prep-Achiral-SFC to afford (E)-(benzyl N-[(1Z)-1-(benzyloxy)-2-(3- { [(1 s, 3s)-3-hydroxy cyclobutyl] amino} phenyl)prop- 1 -en- 1 -yl] ethanimidate) (300 mg, 30%) as a yellow solid.Step 3:

[0262] To a stirred solution of (ls,3s)-3-((3-[2,6-bis(benzyloxy)pyridin-3-yl]phenylamino)cyclobutan-l-ol (300 mg, 0.663 mmol) in CF3CH2OH (5 mL) was added Pd / C (300 mg, 2.8 mmol) in portions at room temperature. The reaction mixture was stirred at room temperature overnight under hydrogen. The resulting mixture was filtered, the filter cake was washed with DCM (4 x 20 mL). The filtrate was concentrated under reduced pressure. The crude product was used in the next step directly without further purification. MS (ESI): mass calcd. for C15H18N2O3274.13, no m / z found. LCMS (acidic condition): Rt = 1.123 min.Attorney Docket No. 57547-738.601Step 4:

[0263] To a stirred mixture of (3-(((ls,3s)-3-hydroxycyclobutyl)amino)phenyl)piperidine-2, 6-dione (230 mg, 0.83 mmol) and 4-methoxybenzyl chloride (131.3 mg, 0.83 mmol) in ACN (5 mL) was added DIEA (438 pL, 2.51 mmol), KI (13.9mg, 0.084 mmol) in portions at room temperature. The resulting mixture was stirred for 4 h at 60 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA in PE, 0% to 30%) to afford 3-(3-[(3-hydroxycyclobutyl)[(4-methoxyphenyl)methyl]amino]phenylpiperidine-2, 6-dione (130 mg, 39%) as a white solid. MS (ESI): mass calcd. for C23H26N2O4 394.19, no m / z found. LCMS (acidic condition): Rt = 1.226 min.Step 5:

[0264] To a stirred solution of 3-(3-([(4-methoxyphenyl)methyl][(ls,3s)-3-hydroxycyclobutyl]aminophenyl)piperidine-2, 6-dione (130 mg, 0.33 mmol) and TEA (137 pL, 0.99 mmol) in DCM (2 mL) was added DMAP (4.0 mg, 0.033 mmol), TsCl (81.6 mg, 0.429 mmol) in portions at room temperature. The resulting mixture was stirred for 3 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (E A in PE, 0% to 50%) to afford (ls,3s)-3-([3-(2,6-dioxopiperidin-3-yl)phenyl][(4-methoxyphenyl)methyl] aminocyclobutyl 4-methylbenzenesulfonate (160 mg, 88%) as a yellow solid. MS (ESI): mass calcd. for C30H32N2O6S 548.20, m / z found549.30 [M+H]+. LCMS (acidic condition): Rt = 0.863 min.Step 6:

[0265] To a stirred solution of (ls,3s)-3-([3-(2,6-dioxopiperidin-3-yl)phenyl][(4-methoxyphenyl)methyl]aminocyclobutyl 4-methylbenzenesulfonate (80 mg, 0.146 mmol) and 4-([(3S)-3- [2-(4-hydroxy-3-methoxyphenyl)-2-oxoethyl]-3,7-dimethyl-2-oxoindol-l-yl]methyl-N-(2-methylpyridin-3-yl)-N-([2-(trimethylsilyl)ethoxy]methylbenzenesulfonamide (94.9 mg, 0.133 mmol) in DMF (2 mL) was added K2CO3 (54.9 mg, 0.398 mmol) in portions at room temperature. The resulting mixture was stirred for 2 h at 100 °C. The reaction was quenched with water (1 mL) at room temperature. The residue was purified by reversed-phase flash chromatography. This resulted in 4-([(3S)-3-(2-(3-methoxy-4-[(lr,3r)-3-([3-(2,6-dioxopiperidin-3-yl)phenyl][(4-methoxyphenyl)methyl]aminocyclobutoxy]phenyl-2-oxoethyl)-3,7-dimethyl-2-oxoindol-l-yl]methyl-N-(2-methylpyridin-3-yl)-N-([2-(trimethylsilyl)ethoxy] methylbenzenesulfonamide (95 mg, 66%) as a purple solid.Step 7:

[0266] To a stirred solution of 4-([(3S)-3-(2-(3-methoxy-4-[(lr,3r)-3-([3-(2,6-dioxopiperidin-3-yl)phenyl][(4-methoxyphenyl)methyl]aminocyclobutoxy]phenyl-2-oxoethyl)-3,7-dimethyl-2-oxoindol-l-yl] methyl-N-(2-methylpyridin-3-yl)-N-([2-(trimethylsilyl)ethoxy] methylbenzenesulfonamide (90 mg, 0.082 mmol) was added TFA (1 mL) at room temperature. The resulting mixture was stirred for 1 h at 100 °C. The reaction was quenched with saturated NaHCO3(2 mL) at room temperature. The resulting mixture was extracted with DCM (2 x 4 mL). The combined organic layers were washed with brine (1 x 10 mL), driedAttorney Docket No. 57547-738.601over anhydrous MgSCL. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography. This resulted in 4-([(3S)-3-(2-(3-methoxy-4-[(lr,3r)-3-([3-(2,6-dioxopiperidin-3-yl)phenyl]aminocyclobutoxy]phenyl-2-oxoethyl)-3,7-dimethyl-2-oxoindol-l-yl]methyl-N-(2-methylpyridin-3-yl)benzenesulfonamide (7.3 mg, 10%). MS (ESI): mass calcd. for C47H47N5O8S 841.30, m / z found 842.20 [M+H]+. LCMS (acidic condition): Rt = 1.463 min.1H NMR (400 MHz, DMSO-de) 510.77 (s, 1H), 9.90 (s, 1H), 8.27 (d, J = 4.8Hz, 1H), 7.74-7.51 (m, 5H), 7.48 - 7.36 (m, 2H), 7.26 - 7.14 (m, 2H), 7.05 (t, J= 7.7 Hz, 1H), 6.85 (dt, J= 20.4, 7.9 Hz, 3H), 6.48-6.32 (m, 3H), 6.06 (s, 1H), 5.26 (s, 2H), 4.96 (t, J = 6.4 Hz, 1H),4.13 (d, J= 18.4Hz, 1H), 3.97 (s, lH),3.82(s, 3H), 3.71 (dd, J = 9.9, 5.4Hz, 1H), 3.61 (d, J= 18.4Hz, 1H), 2.64 (t, J= 12.6 Hz, 1H), 2.42 (d, J= 5.3 Hz, 5H), 2.22 - 1.98 (m, 8H), 1.38 (s, 3H).Example 63: N- [4- [ [rac-(3S)-3- [2- [4- [3- [3-(2,6-dioxo-3-piperidyl)phenoxy] propoxy] -3-methoxy-phenyl]-2-oxo-ethyl]-3,7-dimethyl-2-oxo-indolin-l-yl]methyl]phenyl]pyridine-4-sulfonamideStep 1A:

[0267] The crude product (16.6 g) was purified by Chiral-SFC to afford N-(4-{[(3R)-3- [2-(4-hydroxy-3-methoxyphenyl)-2-oxoethyl] -3,7-dimethyl-2-oxoindol- l-yl]methyl} phenyl)-N- { [2- (trimethylsilyl)ethoxy]methyl}pyridine-4-sulfonamide (7.8 g, 49%) as a white solid & N-(4-{[(3S)-3-[2-(4-hydroxy-3-methoxyphenyl)-2-oxoethyl]-3,7-dimethyl-2-oxoindol-l-yl]methyl}phenyl)-N-{[2- (trimethylsilyl)ethoxy]methyl}pyridine-4-sulfonamide (7.1 g, 45%) as a white solid. MS (ESI): mass calcd. for C37H43N3O7SSi 701.26, m / z found 702.35 [M+H]+. LCMS (acidic condition): Rt = 0.935 min.Step 1:

[0268] Into a 8 mL vial were added N-(4-([(3S)-3-[2-(4-hydroxy-3-methoxyphenyl)-2-oxoethyl]-3,7-dimethyl-2-oxoindol-l-yl]methylphenyl)-N-([2-(trimethylsilyl)ethoxy]methylpyridine-4-sulfonamide( assumed) (60 mg, 0.085 mmol, 1 equiv), 3-(3-(2,6-dioxopiperidin-3-yl)phenoxy)propyl 4-methylbenzenesulfonate (35.9 mg, 0.085 mmol, 1 equiv), K2CO3(35.4 mg, 0.255 mmol, 3 equiv) and DMF (1 mL) at room temperature. The reaction mixture was stirred at 60 °C for 1 h. The reaction was quenched with water (10 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used in the next step directly without further purification. MS (ESI): mass calcd. for C51H58N4O10SSi 946.36, m / z found 947.40 [M+H]+. LCMS (acidic condition): Rt = 0.972 min.Attorney Docket No. 57547-738.601Step 2:

[0269] Into a 8 mL vial were added N-(4-(|(3S)-3-|2-(4-(3-|3-(2.6-dioxopiperidin-3-yl)phenoxy|propoxy- 3-methoxyphenyl)-2-oxoethyl]-3,7-dimethyl-2-oxoindol-l-yl]methylphenyl)-N-([2-(trimethylsilyl)ethoxy]methylpyridine-4-sulfonamide (100 mg, 0.106 mmol, 1 equiv), DCM(lmL) and TFA (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 0.5 h. The mixture was evaporated and basified to pH 8 with saturated aqueous NaHCO3. The resulting mixture was extracted with CH2CI2 (2 x 10 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na2 S O4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (100 mg) was purified by Prep-HPLC to afford N-(4-([(3S)-3-[2-(4-(3-[3-(2,6-dioxopiperidin-3-yl)phenoxy]propoxy-3-methoxyphenyl)-2-oxoethyl]-3,7-dimethyl-2-oxoindol-l-yl]methylphenyl)pyridine- 4-sulfonamide(13.1 mg, 15%). MS (ESI): mass calcd. for C45H44N4O9S 816.28, m / z found 817.55 [M+H]+. LCMS (basic condition Hydroxine): Rt = 1.050 min.1H NMR(400 MHz, DMSO-d6) δ 10.82 (s, 1H), 10.56 (s, 1H), 8.81 - 8.75 (m, 2H), 7.66 - 7.59 (m, 3H), 7.36 (d, J= 2.0 Hz, 1H), 7.24 (t, J= 8.0 Hz, 3H), 7.15 (dd, J = 7.2, 1.6 Hz, 1H), 7.08 (dd, J= 17.0, 8.4 Hz, 3H), 6.88 - 6.85 (m, 2H), 6.84 - 6.78 (m, 3H), 5.14 - 5.00 (m, 2H), 4.22 (t, J= 6.3 Hz, 2H), 4.16 - 4.05 (m, 3H),3.79 (s, 4H), 3.58 (d, J= 18.4 Hz, 1H), 2.68 - 2.58 (m, 1H), 2.50 - 2.31 (m, 1H), 2.24 - 2.13 (m, 2H), 2.12 (s, 3H), 2.08 - 1.97 (m, 1H), 1.35 (s, 3H). Example 70: N- [4- [ [rac-(3S)-3- [2- [4- [3- [3-(2,6-dioxo-3-piperidyl)phenoxy] propoxy] -3-methoxy-phenyl]-2-oxo-ethyl]-6-fluoro-3,7-dimethyl-2-oxo-indolin-l-yl]methyl]phenyl]pyridine-4-sulfonamideAttorney Docket No. 57547-738.601Step 1A:

[0270] To a stirred solution of 4-thiopyridine (2.2 g, 19.8 mmol) in DCM (20 mL) was added HC1 (26.3 mL, 26.3 mmol) in portions at 0 °C. The resulting mixture was stirred for additional 5 min at 0 °C. To the above mixture was added NaCIO (80.4 mL, 118.7 mmol, 10%) in portions at 0 °C. The resulting mixture was stirred for additional 30 min at room temperature. The aqueous layer was extracted with CH₂Cl₂ (1 x 20 mL) and the organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product mixture was used in the next step [Step 5B] directly without further purification.Step IB:

[0271] To astirred solution of 3-fluoro-2-methyl-aniline (10g, 79.90 mmol) in DCM (100 mL) and TEA (12.2 mL, 87.9 mmol) were added methacryloyl chloride (8.35 g, 79.9 mmol) dropwise at 0 °C. The resulting mixture was stirred for additional 1 h at room temperature. The reaction was quenched with water (100 mL) and extracted with CH2CI2 (3 x 200 mL). The combined organic layers were washed with brine (2 x 500 mL), dried over anhydrous MgSCL. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with (EA in PE, 0% to 30%)Attorney Docket No. 57547-738.601to afford N-(3-fluoro-2-methylphenyl)-2-methylprop-2-enamide (3.9 g, 25%) as a white solid. MS (ESI): mass calcd. for C11H12FNO 193.09, m / z found 194 [M+H]+. LCMS (acidic condition): Rt = 0.787 min.Step 2B:

[0272] To a stirred solution of N-(3-fluoro-2-methylphenyl)-2-methylprop-2-enamide (8 g, 41.40 mmol) inTHF (100 mL) was added NaH (2.82 g, 70.4 mmol, 60%) in portions at 0 °C under nitrogen. The reaction mixture was stirred at 0 °C for 30 min. To the mixture was added tert-butyl N-[4-(bromomethyl)phenyl]carbamate (11.85 g, 41.4 mmol) in portions at 0 °C. The reaction mixture was stirred at room temperature overnight. The reaction was quenched with saturated NH4CI (100 mL) and extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with brine (l x 500 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with (EA in PE, 0% to 20%) to afford tert-butyl N-(4-{[N-(3-fluoro-2-methylphenyl)-2-methylprop-2-enamido]methyl}phenyl)carbamate (14 g, 84%) as a white solid. MS (ESI): mass calcd. for C23H27FN2O3398.20, m / z found 421.2 [M+Na]+. LCMS (acidic condition): Rt = 0.997 min.Step 3B:

[0273] To a stirred solution of tert-butyl N-(4-([N-(3-fluoro-2-methylphenyl)-2-methylprop-2-enamido]methylphenyl)carbamate (10 g, 25.09 mmol) and 4-(benzyloxy)-3-methoxybenzaldehyde (6.08 g, 25.09 mmol) in EtOAc (100 mL) was added TBHP (12.5 mL, 75.3 mmol) dropwise at room temperature under nitrogen. The reaction mixture was stirred at 105 °C overnight. The resulting mixture was washed with saturated NaHCOs (1 x 100 mL). The aqueous layer was extracted with EtOAc (1 x 100 mL). The combined organic layers were washed with brine (1 x 200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with (EA in PE, 0% to 35%) to afford tert-butyl N-(4-[(3-(2-[4-(benzyloxy)-3-methoxyphenyl]-2-oxoethyl-6-fluoro-3,7-dimethyl-2-oxoindol-l-yl)methyl]phenylcarbamate (4.4 g, 27%) as a yellow solid. MS (ESI): mass calcd. for C38H39FN2O6638.28, m / z found 661.3 [M+Na]+. LCMS (acidic condition): Rt = 0.783 min.Step 4B:

[0274] To a stirred solution of tert-butyl N-(4-[(3-(2-[4-(benzyloxy)-3-methoxyphenyl]-2-oxoethyl-6-fluoro-3,7-dimethyl-2-oxoindol-l-yl)methyl]phenylcarbamate (4.4 g, 6.89 mmol) in DCM (25 mL) was added TFA (25 mL, 337 mmol) dropwise at room temperature. The resulting mixture was stirred for additional 30 min at room temperature. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with EtOAc (50 mL) and washed with saturated NaHCOs (1 x 50 mL). The organic layers were washed with brine (1 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with (EA in PE, 0% to 50%) to afford l-[(4-aminophenyl)methyl]-3-(2-[4-(benzyloxy)-3-methoxyphenyl]-2-oxoethyl-6-fluoro-3,7-dimethylindol -2-one (2.3 g, 62%) as a brown solid.Attorney Docket No. 57547-738.601MS (ESI): mass calcd. for C33H31FN2O4538.23, m / z found 539.25 [M+H]+. LCMS (acidic condition): Rt = 0.866 min.Step 5B:

[0275] To a stirred solution of l-[(4-aminophenyl)methyl]-3-(2-[4-(benzyloxy)-3-methoxyphenyl]-2-oxoethyl-6-fluoro-3,7-dimethylindol-2-one (2.3 g, 4.27 mmol) and pyridine (1.73 mL, 21.35 mmol) in DCM (25 mL) was added pyridine-4-sulfonyl chloride (3.79 g, 21.35 mmol) in portions at 0 °C. The resulting mixture was stirred for additional 1 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed -phase flash chromatography. This resulted in N-(4-[(3-(2-[4-(benzyloxy)-3-methoxyphenyl]-2-oxoethyl-6-fluoro-3,7-dimethyl-2-oxoindol-l-yl)methyl]phenylpyridine-4-sulfonamide (2.7 g, 93%) as a yellow solid. MS (ESI): mass calcd. for C38H34FN3O6S 679.22, m / z found 680.2 [M+H]+. LCMS (acidic condition): Rt = 0.911 min.Step 6B:

[0276] To a stirred solution of N-(4-[(3-(2-[4-(benzyloxy)-3-methoxyphenyl]-2-oxoethyl-6-fluoro-3,7-dimethyl-2-oxoindol-l-yl)methyl]phenylpyridine-4-sulfonamide (4.0 g, 5.88 mmol) and in DCM (40 mL) and DIEA (2.70 mL, 15.47 mmol) were added SEMC1 (2.07 mL, 11.65 mmol) in portions at 0 °C. The resulting mixture was stirred for additional 30 min at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with (EAinPE, 0% to 50%) to afford N-(4-[(3-(2-[4-(benzyloxy)-3-methoxyphenyl]-2-oxoethyl-6-fluoro-3,7-dimethyl-2-oxoindol-l-yl)methyl]phenyl-N-([2-(trimethylsilyl)ethoxy]methylpyridine-4-sulfonamide (3.0 g, 63%) as a yellow solid. MS (ESI): mass calcd. for C44H48FN3O7SSi 809.30, m / z found 810.25 [M+H]+. LCMS (acidic condition): Rt = 1.047 min.Step 7B:

[0277] To a stirred solution of N-(4-[(3-(2-[4-(benzyloxy)-3-methoxyphenyl]-2-oxoethyl-6-fluoro-3,7-dimethyl-2-oxoindol-l-yl)methyl]phenyl-N-([2-(trimethylsilyl)ethoxy]methylpyridine-4-sulfonamide (1.3g, 1.6 mmol) in MeOH (15 mL) and DMF (2 mL) was added Pd / C (1.3 g, 12.2 mmol) in portions at room temperature under hydrogen. The reaction mixture was stirred at room temperature overnight. The resulting mixture was filtered, the filter cake was washed with CH2CI2 (10 x 5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography. This resulted in N-[4-((6-fluoro-3-[2-(4-hydroxy-3-methoxyphenyl)-2-oxoethyl]-3,7-dimethyl-2-oxoindol-l-ylmethyl)phenyl]-N-([2-(trimethylsilyl)ethoxy]methylpyridine-4-sulfonamide (511 mg, 44%) as a yellow solid. MS (ESI): mass calcd. for C37H42FN3O7SSi 719.25, m / z found 720.25 [M+H]+. LCMS (acidic condition): Rt = 1.019 min.Step 8B:

[0278] The crude product (1 g) was purified by Prep-HPLC to afford N-(4-([(3S)-6-fluoro-3-[2-(4-hydroxy-3-methoxyphenyl)-2-oxoethyl]-3,7-dimethyl-2-oxoindol-l-yl]methylphenyl)-N-([2-(trimethylsilyl)ethoxy]methylpyridine-4-sulfonamide (437 mg, 44%) as a light yellow solid.Attorney Docket No. 57547-738.601Step 1C:

[0279] Into a 25 mL round-bottom flask were added 3-[2,6-bis(benzyloxy)pyridin-3-yl]phenol (1.0 g, 2.60 mmol), 3-bromopropanol (283 pL, 3.13 mmol) in DMF (10 mL) and CS2CO3 (2.55 g, 7.82 mmol) at room temperature. The resulting mixture was stirred overnight at 70 °C. The reaction was quenched with water (10 mL) at room temperature. The resulting mixture was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with brine (2 x 40 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with (EA in PE, 0% to 25%) to afford 3-(3-[2,6-bis(benzyloxy)pyridin-3-yl]phenoxypropan-l-ol (1.12 g, 97%) as a light-yellow oil. MS (ESI): mass calcd. for C28H27NO4441.19, m / z found 442.2 [M+H]+. LCMS (acidic condition): Rt = 1.232 min.Step 2C:

[0280] Into a 50-mL round-bottom flask were added 3-(3-[2,6-bis(benzyloxy)pyridin-3-yl]phenoxypropan-l-ol (1.12 g, 2.5 mmol), TsCl (967 mg, 5.07 mmol), TEA (1057 pL, 7.6 mmol) and DMAP (6.2 mg, 0.051 mmol) at room temperature. The resulting mixture was stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with (EA in PE, 0% to 10%) to afford 3-(3-[2,6-bis(benzyloxy)pyridin-3-yl]phenoxypropyl 4-methylbenzenesulfonate (1.39 g, 92%) as a light-yellow oil. MS (ESI): mass calcd. for C35H33NO6S 595.20, m / z found 596.1 [M+H]+. LCMS (acidic condition): Rt = 1.094 min.Step 3C:

[0281] Into a 25-mL round-bottom flask were added 3-(3-[2,6-bis(benzyloxy)pyridin-3-yl]phenoxypropyl 4-methylbenzenesulfonate (1.28 g, 2.15 mmol), Pd / C (1.3 g, 12.03 mmol) and THF (12 mL) at room temperature. The reaction mixture was stirred at room temperature overnight under hydrogen. The resulting mixture was filtered, the filter cake was washed with EtOAc (3 x 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with (EA in PE, 0% to 50%) to afford 3-[3-(2,6-dioxopiperidin-3-yl)phenoxy]propyl 4-methylbenzenesulfonate (800 mg, 89%) as a light yellow solid. MS (ESI): mass calcd. for C21H23NO6S 417.12, m / z found 596.15 [M+H]+. LCMS (basic condition): Rt = 0.822 min.Step 1:

[0282] To a stirred solution of N-(4-([(3S)-6-fluoro-3-[2-(4-hydroxy-3-methoxyphenyl)-2-oxoethyl]-3,7-dimethyl-2-oxoindol-l-yl]methylphenyl)-N-([2-(trimethylsilyl)ethoxy]methylpyridine-4-sulfonamide (60 mg, 0.083 mmol) and 3-[3-(2,6-dioxopiperidin-3-yl)phenoxy]propyl 4-methylbenzenesulfonate (38.3 mg, 0.091 mmol) in DMF (1 mL) was added K2CO3 (34.6 mg, 0.249 mmol) at room temperature. The reaction mixture was stirred at 60 °C for 1.5 h. The residue was purified by reversed -phase flash chromatography. This resulted inN-(4-([(3S)-3-[2-(4-(3-[3-(2,6-dioxopiperidin-3-yl)phenoxy]propoxy-3-methoxyphenyl)-2-oxoethyl] -6-fluoro-3,7-dimethyl-2-oxoindol-l-yl]methylphenyl)-N-([2-(trimethylsilyl)ethoxy]methylpyridine-4-sulfonamide (57 mg, 71%) as alight yellow solid. MS (ESI): massAttorney Docket No. 57547-738.601calcd. for C51H57FN4O10SSi 964.35; 965.18, m / z found 966.6 [M+H]+. LCMS (basic condition): Rt = 1.206 min.Step 2:

[0283] To a stirred solution ofN-(4-([(3S)-3-[2-(4-(3-[3-(2,6-dioxopiperidin-3-yl)phenoxy]propoxy-3-methoxyphenyl)-2-oxoethyl]-6-fluoro-3,7-dimethyl-2-oxoindol-l-yl]methylphenyl)-N-([2-(trimethylsilyl)ethoxy]methylpyridine-4-sulfonamide (57 mg, 0.059 mmol) in DCM (500 pL) was added TFA (500 pL) dropwise at room temperature. The reaction mixture was stirred at room temperature for 30 min. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed -phase flash chromatography. This resulted in N-(4-([(3S)-3-[2-(4-(3-[3-(2,6-dioxopiperidin-3-yl)phenoxy]propoxy-3-methoxyphenyl)-2-oxoethyl]-6-fluoro-3,7-dimethyl-2-oxoindol-l-yl]methylphenyl)pyridine-4-sulfonamide (23.8 mg, 48%). MS (ESI): mass calcd. for C45H43FN4O9S 834.27, m / z found 835.2 [M+H]+. LCMS (acidic condition): Rt = 0.993 min.1H NMR (400 MHz, DMSO-d6) δ 10.82 (s, 1H), 10.56 (s, 1H), 8.80-8.79 (m, 2H), 7.65-7.61 (m, 3H), 7.36-7.35 (d, J = 2.0 Hz, 1H), 7.28-7.22 (m, 3H), 7.19-7.16 (dd, J= 8.2, 5.5 Hz, 1H), 7.10-7.08 (dd, J= 8.6, 2.1 Hz, 3H), 6.87-6.85 (dd, J= 8.2, 2.5 Hz, 1H), 6.82-6.78 (m, 2H), 6.75-6.70 (dd, J= 10.5, 8.1 Hz, 1H), 5.09 (s, 2H), 4.23-4.20 (t, J= 6.3 Hz, 2H), 4.15-4.10 (dd, J= 12.3, 6.1 Hz, 3H), 3.83 (s, 4H), 3.62(d, J= 18.5 Hz, 1H), 2.67-2.64 (m, 1H), 2.45 (d, J = 4.4 Hz, 1H), 2.21 (h, J= 9.0, 8.0 Hz, 3H), 2.04-1.98 (m, 4H), 1.35 (s, 3H).Example 83: N- [4- [ [3- [2-[4-[3-[3-(2,6-dioxo-3-piperidyl)phenoxy] propoxy] -3- methoxy-phenyl] -2-oxo-ethyl]-3,7-dimethyl-2-oxo-indolin-l-yl]methyl]-2-fhioro-phenyl]-2-methyl-pyrazole-3-sulfonamideY??Attorney Docket No. 57547-738.601Step 1:

[0284] Into a 100 mL round-bottom flask were added 2-fluoro-4-methylaniline (2.5 g, 20.0 mmol), BOC2O (5.23 g, 23.97 mmol) and EtOH (30 mL) at room temperature. The reaction mixture was stirred at room temperature for 6 h. The resulting mixture was concentrated under vacuum. The residue was purified by reversed-phase flash chromatography. This resulted in tert-butyl N-(2-fluoro-4-methylphenyl)carbamate (2.4 g, 53%) asayellowoil. MS (ESI): mass calcd. for C12H16FNO2225.12, no m / z found. LCMS (acidic condition): Rt = 0.853 min.Step 2:

[0285] To a stirred solution of tert-butyl N-(2-fluoro-4-methylphenyl)carbamate (15 g, 66.58 mmol, 1 equiv) andNBS (13.5 g, 75.9 mmol) in CCI4 (500 mL) was added 2-[(E)-2-(l-cyano-l-methylethyl)diazen-l-yl]-2-methylpropanenitrile (511 mg, 2 mmol) in portions at room temperature. The resulting mixture was stirred at 85 °C overnight. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered, the filter cake was washed with DCM (2 x 20 mL). The filtrate was concentrated under reduced pressure. The crude product was used in the next step directly without further purification. MS (ESI): mass calcd. for C12H16FNO2225.12, no m / z found. LCMS (acidic condition): Rt = 0.843 min. Step 3:

[0286] To a stirred solution of 2-methyl-N-(2-methylphenyl)prop-2-enami de (9.5 g, 54.21 mmol) in THF (100 mL) was added NaH (2.60 g, 65.05 mmol, 60%) in portions at 0 °C under nitrogen. The reaction mixture was stirred at 0 °C for 30 min. To the mixture was added tert-butyl N-[4-(bromomethyl)-2-fluorophenyl] carbamate (18.1 g, 59.6 mmol) in portions at 0 °C. The reaction mixture was stirred at room temperature overnight. The reaction was quenched with saturated aqueous NH4CI (100 mL) at 0 °C. The resulting mixture was extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with brine (1 x 400 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography. This resulted in tertbutyl N-(2-fluoro-4-{[2-methyl-N-(2-methylphenyl)prop-2-enamido]methyl}phenyl)carbamate (6.9 g, 32%)Attorney Docket No. 57547-738.601as ayellowoil. MS (ESI): mass calcd. for C23H27FN2O3 398.20, 399.10 m / z found [M+H]+. LCMS (acidic condition): Rt = 0.960 min.Step 4:

[0287] To a stirred solution of tert-butyl N-(2-fluoro-4-([2-methyl-N-(2-methylphenyl)prop-2-enamido]methylphenyl)carbamate (400 mg, 1.0 mmol) and 4-(benzyloxy)-3- methoxybenzaldehyde (486 mg, 2.00 mmol) in EtOAc (4 mL) was added TBHP (0.50 mL, 3.0mmol) in portions at room temperature. The reaction mixture was stirred at 105 °C overnight under nitrogen. The resulting mixture was washed with aqueous Na2CO3 (5 mL). The resulting mixture was extracted with EtOAc (2 x 5 mL). The combined organic layers were washed with brine (1 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA in PE, 0%to 50%) to afford tert -butyl N-(4-[(3-(2- [4-(benzyloxy)-3-methoxyphenyl] - 2-oxoethyl-3,7-dimethyl-2-oxoindol-l-yl)methyl]-2-fluorophenylcarbamate (350 mg, 47%) as a light yellow solid. MS (ESI): mass calcd. for C38H39FN2O6638.28, 639.30 m / z found [M+H]+. LCMS (acidic condition): Rt = 0.983 min.Step 5:

[0288] To a stirred solution of tert-butyl N-(4-[(3-(2-[4-(benzyloxy)-3-methoxyphenyl]-2-oxoethyl-3,7-dimethyl-2-oxoindol-l-yl)methyl]-2-fluorophenylcarbamate (350 mg, 0.54 mmol) in MeOH (4 mL) was added Pd / C (350 mg, 3.28 mmol) in portions at room temperature under hydrogen. The reaction mixture was stirred at room temperature for 1 h under hydrogen. The resulting mixture was filtered, the filter cake was washed with ACN (3 x 20 mL). The resulting mixture was concentrated under reduced pressure. This resulted in tert-butyl N-[2-fluoro-4-((3-[2-(4-hydroxy-3-methoxyphenyl)-2-oxoethyl]-3,7-dimethyl-2-oxoindol-l-ylmethyl)phenyl]carbamate (300 mg, 99%) as a brown solid. The product mixture was used in the next step directly without further purification. MS (ESI): mass calcd. for C31H33FN2O6548.23, 549.25 m / z found [M+H]+. LCMS (acidic condition): Rt = 0.934 min.Step 6:

[0289] To a stirred solution of tert-butyl N-[2-fluoro-4-((3-[2-(4-hydroxy-3-methoxyphenyl)-2-oxoethyl]-3,7-dimethyl-2-oxoindol-l-ylmethyl)phenyl]carbamate (300 mg, 0.54 mmol) and 3-[3-(2,6-dioxopiperidin- 3 -yl)phenoxy] propyl 4-methylbenzenesulfonate (273 mg, 0.66 mmol) in DMF (3 mL) was added K2CO3 (227 mg, 1.64 mmol) at room temperature. The resulting mixture was stirred at 60 °C for 2 h. The reaction was quenched with water (3 mL) at room temperature. The residue was purified by reversed-phase flash chromatography. This resulted in tert-butyl N-[4-((3-[2-(4-(3-[3-(2,6-dioxopiperidin-3-yl)phenoxy]propoxy-3-methoxyphenyl)-2-oxoethyl]-3,7-dimethyl-2-oxoindol-l-ylmethyl)-2-fluorophenyl]carbamate (200 mg, 46%) as alight brown solid. MS (ESI): mass calcd. for C45H48FN3O9793.34, 794.50 m / z found [M+H]+. LCMS (acidic condition): Rt = 1.012 min.Step 7:

[0290] Into a 25 mL round-bottom flask were added tert-butyl N-[4-((3-[2-(4-(3-[3-(2,6-dioxopiperidin-3-yl)phenoxy]propoxy-3-methoxyphenyl)-2-oxoethyl]-3,7-dimethyl-2-oxoindol-l-ylmethyl)-2-Attorney Docket No. 57547-738.601fluorophenyl] carbamate (200 mg, 0.25 mmol) and HCl / l,4-di oxane (5.98 mL, 197 mmol) at room temperature. The resulting mixture was stirred for 40 min at room temperature. The resulting mixture was concentrated under vacuum. The crude product was used in the next step directly without further purification. MS (ESI): mass calcd. for C40H40FN3O7693.29, 694.30 m / z found [M+H]+. LCMS (acidic condition): Rt = 0.890 min.Step 8:

[0291] To a stirred solution of 3-(3-(3-[4-(2-(l-[(4-amino-3-fluorophenyl)methyl]-3,7-dimethyl-2-oxoindol-3-ylacetyl)-2-methoxyphenoxy]propoxyphenyl)piperidine-2, 6-dione (30 mg, 0.043 mmol) in DCM (1 mL) were added pyridine (17 mg, 0.21 mmol). To the mixture was added 2-methylpyrazole-3-sulfonyl chloride (39.0 mg, 0.215mmol) dropwise at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography. The crude product (40 mg) was purified by Prep-HPLC to afford N-[4-((3-[2-(4-(3-[3-(2,6-dioxopiperidin-3-yl)phenoxy]propoxy-3-methoxyphenyl)-2-oxoethyl]-3,7-dimethyl-2-oxoindol-l-ylmethyl)-2-fluorophenyl]-2-methylpyrazole-3-sulfonamide (4.5 mg, 13%). MS (ESI): mass calcd. for C44H44FN5O9S 837.28, 838.20 m / z found [M+H]+. LCMS (basic condition+NH3·H2O): Rt = 0.638 min.1H NMR (400 MHz, DMSO-d6) δ 10.82 (s, 1H), 10.64 (s, 1H), 7.65-7.63 (d, J= 8.5 Hz, 1H), 7.47 (s, 1H), 7.43 (s, 1H), 7.32- 7.22 (m, 3H), 7.18-7.16(d, J= 7.4 Hz, 2H), 7.12-7.10 (d, J= 8.5 Hz, 1H), 6.90 -6.79 (m, 5H), 6.58 (s, 1H), 5.19-5.07 (d, J = 30.7 Hz, 2H), 4.24-4.21 (t, J= 6.3 Hz, 2H), 4.16-4.11 (dd, J = 12.9, 6.6 Hz, 3H), 4.04 (s, 3H), 3.97 (m, 4H), 3.64-3.59 (d, J= 9.3 Hz 1H), 2.65-2.61 (dd, J = 11.7, 5.3 Hz, 1H), 2.24 - 2.17 (m, 3H), 2.16 (s, 3H), 2.06-2.00 (dt, J= 13.6, 5.1 Hz, 1H), 1.35 (s, 3H).Example 88: N- [4- [ [3- [2- [4- [ [ 1- [3-(2,6-dioxo-3-piperidyl)phenyl] azetidin-3-yl] methoxy] -3-methoxy-phenyl]-2-oxo-ethyl]-3,7-dimethyl-2-oxo-indolin-l-yl]methyl]phenyl]-2-methyl-pyrazole-3-sulf on amideStep 1:

[0292] Into a 20 mL vial were added tert-butyl N-[4-((3-[2-(4-hydroxy-3-methoxyphenyl)-2-oxoethyl]-3,7-dimethyl-2-oxoindol-l-ylmethyl)phenyl]carbamate (80 mg, 0.151 mmol, 1 equiv), (l-[3-(2,6-dioxopiperidin-3-yl)phenyl]azetidin-3-ylmethyl 4-methylbenzenesulfonate (70 mg, 0.163 mmol, 1.08 equiv), K2CO3 (62 mg, 0.45 mmol, 3.00 equiv) and DMF (2 mL) at room temperature. The reaction mixture was stirred at 60 °C for 4 h. The reaction was quenched with water (ImL). The residue was purified byAttorney Docket No. 57547-738.601reversed-phase flash chromatography. This resulted in tert-butyl N-(4-[(3-(2-[4-((l-[3-(2,6-dioxopiperidin-3-yl)phenyl]azetidin-3-ylmethoxy)-3-methoxyphenyl]-2-oxoethyl-3,7-dimethyl-2-oxoindol-l-yl)methyl] phenylcarbamate (60 mg, 51%) as a light pink solid. MS (ESI): mass calcd. for C46H50N4O8786.36, m / z found 787.35 [M+H]+. LCMS (acidic condition): Rt = 0.913 min.Step 2:

[0293] Into a 25mL round-bottom flask were added tert-butyl N-(4-[(3-(2-[4-((l-[3-(2,6-dioxopiperidin-3-yl)phenyl]azetidin-3-ylmethoxy)-3-methoxyphenyl]-2-oxoethyl-3,7-dimethyl-2-oxoindol-l-yl)methyl] phenylcarbamate (40 mg, 0.051 mmol, 1 equiv), DCM (2 mL) and TFA (0.6 mL) at room temperature. The resulting mixture was stirred at room temperature for 30 min. The resulting mixture was concentrated under vacuum. The mixture was basified to pH 8 with saturated aqueous NaHCO3. The resulting mixture was extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine (1 x 25 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used in the next step directly without further purification. MS (ESI): mass calcd. for C41H42N4O6686.31, m / z found 687.30 [M+H]+. LCMS (acidic condition): Rt = 0.702 min. Step 3:

[0294] Into a 25 mL round-bottom flask were added 3-(3-(3-[4-(2-(l-[(4-aminophenyl)methyl]-3,7-dimethyl-2-oxoindol-3-ylacetyl)-2-methoxyphenoxymethyl]azeti din- l-ylphenyl)piperidine-2, 6-dione (37 mg, 0.054 mmol, 1 equiv), DCM (0.5 mL) and pyridine (1 mL) at room temperature. To the above mixture was added 2-methylpyrazole-3 -sulfonyl chloride (11.7 mg, 0.065 mmol, 1.2 equiv) in DCM (0.5 mL) dropwise at 0 °C. The reaction mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography. The crude product (40 mg) was purified by Prep-HPLC to afford N-(4-[(3-(2-[4-((l-[3-(2,6-dioxopiperidin-3-yl)phenyl]azetidin-3-ylmethoxy)-3-methoxyphenyl]-2-oxoethyl-3,7-dimethyl-2-oxoindol-l-yl)methyl]phenyl-2-methylpyrazole-3-sulfonamide (12.8 mg, 28%). MS (ESI): mass calcd. for C45H46N6O8S 830.31, m / z found 831.55 [M+H]+. LCMS (acidic condition): Rt = 1.543 min.1H NMR (400 MHz, DMSO-d6): δ 10.90 - 10.52 (m, 2H), 7.68 - 7.61 (m, 1H), 7.50- 7.45 (m, 1H), 7.39- 7.34 (m, 1H), 7.31 - 7.24 (m, 2H), 7.19 - 7.07 (m, 5H), 6.92 - 6.75 (m, 2H), 6.71 (d, J=2.1 Hz, 1H), 6.52 (d, J= 7.6 Hz, 1H), 6.39- 6.32 (m, 1H), 6.33 - 6.27 (m, 1H), 5.09 (d, J= 2.8 Hz, 2H), 4.31 (d, J= 7.1 Hz, 2H), 4.17 - 4.06 (m, 1H), 4.02 -3.90 (m, 5H), 3.85 - 3.70 (m, 4H), 3.68 - 3.55 (m, 3H), 3.18 - 3.10 (m, 1H), 2.67 - 2.57 (m, 1H), 2.47 -2.40 (m, 1H), 2.15 (s, 4H), 2.08 - 1.98 (m, 1H), 1.35 (s, 3H).Example 95: N-(2-methyl-3-pyridyl)-4-[[rac-(3S)-3-[2-[3-fluoro-4-[rac-(3S)-l-[3-(2,6-dioxo-3-piperidyl)phenyl]pyrrolidin-3-yl] oxy-phenyl] -2-oxo-ethyl] -3, 7-dimethyl- 2-oxo- indolin-1-yl] methyl] benzenesulfonamideAttorney Docket No. 57547-738.601Step 1:

[0295] To a stirred solution of (3R)-pyrrolidin-3-ol hydrochloride (655 mg, 5.30 mmol) and benzene, 1-bromo-3-iodo- (1.5 g, 5.30 mmol) in DMSO (15 mL) was added CS2CO3 (2.90 g, 8.90 mmol), L-Proline (61.0 mg, 0.53 mmol), Cui (121 mg, 0.63 mmol) in portions at room temperature. The reaction mixture was stirred at 130 °C overnight under nitrogen. The reaction was quenched with water (30 mL) at room temperature and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (2 x 200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography(EA in PE, 0% to 40%) to afford (3R)-l-(3-bromophenyl)pyrrolidin-3-ol (430 mg, 33%) as a yellow oil. MS (ESI): mass calcd. for: C10H12BrNO 241.01, m / z found 242.10; 244.05 [M+H]+. LCMS (acidic condition): Rt = 0.686 min. Step 2:

[0296] To a stirred solution of (3R)-l-(3-bromophenyl)pyrrolidin-3-ol (430 mg, 1.77 mmol) and 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (815 mg, 1.95 mmol) in dioxane (5 mL), H2O (1 mL) was added K2CO3 (736.3 mg, 5.3 mmol), Pd(dppf)C12. CH2C12 (43 mg, 0.053 mmol) at room temperature. The reaction mixture was stirred at 110 °C overnight under nitrogen. The resulting mixture was filtered, the filter cake was washed with DCM (3x10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA in PE, 0% to 40%) to afford (3R)-l-(3-[2,6-bis(benzyloxy)pyridin-3-yl]phenylpyrrolidin-3-ol (680 mg, 84%) as a yellow oil. MS (ESI): mass calcd. for: C29H28N2O3452.21, m / z found 453.20 [M+H]+. LCMS (acidic condition): Rt = 0.782 min.Step 3:Attorney Docket No. 57547-738.601

[0297] To a stirred solution of (3R)-l-(3-[2,6-bis(benzyloxy)pyridin-3-yl]phenylpyrrolidin-3-ol (680 mg, 1.50 mmol) in CF3CH2OH (10 mL) was added Pd / C (680 mg, 6.39 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight under hydrogen. The resulting mixture was filtered, the filter cake was washed with DCM (3 x 100 mL). The fdtrate was concentrated under reduced pressure. The crude product was used in the next step directly without further purification. MS (ESI): mass calcd. for: C15H18N2O3274.13, m / z found 275.20 [M+H]+. LCMS (acidic condition): Rt = 0.466 min.Step 4:

[0298] To a stirred solution of 3-(3-[(3R)-3-hydroxypyrrolidin-l-yl]phenylpiperidine-2, 6-dione (300 mg, 1.09 mmol) in DCM (3 mL) were added l,4-diazabicyclo[2.2.2] octane (155 mg, 1.38 mmol) and TsCl (231 mg, 1.21 mmol) in portions at 0 °C under nitrogen. The reaction mixture was stirred at room temperature overnight under nitrogen. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA in PE, 0% to 30%) to afford (3R)-l-[3-(2,6-dioxopiperidin-3-yl)phenyl]pyrrolidin-3-yl 4-methylbenzenesulfonate (200 mg, 42%) as a white solid. MS (ESI): mass calcd. for: C22H24N2O5S 428.14, m / z found 429.05 [M+H]+. LCMS (acidic condition): Rt = 0.759 min.Step 5:

[0299] To a stirred solution of (3R)-l-[3-(2,6-dioxopiperidin-3-yl)phenyl]pyrrolidin-3-yl 4-methylbenzenesulfonate (33 mg, 0.078 mmol) and 4-([(3S)-3-[2-(3-fluoro-4-hydroxyphenyl)-2-oxoethyl]-3,7-dimethyl-2-oxoindol-l-yl]methyl-N-(2-methylpyridin-3-yl)-N-([2-(trimethylsilyl)ethoxy]methylbenzenesulfonamide (50 mg, 0.071 mmol) in DMF (1 mL) was added K2CO3 (29 mg, 0.21 mmol) at room temperature. The resulting mixture was stirred at 60 °C for 5 h. The reaction was quenched with water (1 mL) at room temperature. The residue was purified by reversed-phase flash chromatography. This resulted in 4-([(3S)-3-[2-(4-([(3S)-l-[3-(2,6-dioxopiperidin-3-yl)phenyl]pyrrolidin-3-yl]oxy-3-fluorophenyl)-2-oxoethyl]-3,7-dimethyl-2-oxoindol-l-yl]methyl-N-(2-methylpyridin-3-yl)-N-([2-(trimethylsilyl)ethoxy]methylbenzenesulfonamide (60 mg, 88%) as a white solid. MS (ESI): mass calcd. for: C52H58FN5O8SSi 959.38, m / z found 960.30 [M+H]+. LCMS (basic condition+ NH3. H2O): Rt = 1.176 min.Step 6:

[0300] To a stirred solution of 4-([(3S)-3-[2-(4-([(3S)-l-[3-(2,6-dioxopiperidin-3-yl)phenyl]pyrrolidin-3-yl]oxy-3-fluorophenyl)-2-oxoethyl]-3,7-dimethyl-2-oxoindol-l-yl]methyl-N-(2-methylpyridin-3-yl)-N-([2-(trimethylsilyl)ethoxy]methylbenzenesulfonamide (40 mg, 0.042 mmol) in DCM (0.5 mL) was added TFA (0.5 mL) at room temperature. The resulting mixture was stirred at room temperature for 30 min. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography. This resulted in 4-([(3S)-3-[2-(4-([(3S)-l-[3-(2,6-dioxopiperidin-3-yl)phenyl]pyrrolidin-3-yl]oxy-3-fluorophenyl)-2-oxoethyl]-3,7-dimethyl-2-oxoindol-l-yl]methyl-N-(2-methylpyridin-3-yl)benzenesulfonamide (18.1 mg, 52%). MS (ESI): mass calcd. for: C46H44FN5O7S 829.29, m / z found 830.30 [M+H]+. LCMS (acidic condition): Rt = 1.592 min. > HNMR (400 MHz, DMSO-d6) 8 10.78 (d, J =Attorney Docket No. 57547-738.6012.1 Hz, 1H), 9.91 (s, 1H), 8.24 (d, J = 4.7 Hz, 1H), 7.80 (ddd, J= 21.4, 10.2, 2.0 Hz, 2H), 7.67 (d, J= 8.1 Hz, 2H), 7.59 (d, J= 8.2 Hz, 2H), 7.37 (tt, J= 6.2, 4.6, 3.6 Hz, 2H), 7.26 - 7.09 (m, 3H), 6.86 (dt, J= 14.9, 7.5 Hz, 2H), 6.56- 6.46 (m, 2H), 6.42 (d, J= 2.2 Hz, 1H), 5.37 (s, 1H), 5.33 - 5.18 (m, 2H), 4.16 (d, J = 18.5 Hz, 1H), 3.72 (ddd, J= 19.2, 8.7, 4.7 Hz, 2H), 3.62 (d, J= 18.5 Hz, 1H), 3.43 - 3.36 (m, 3H), 2.61 (dd, J= 11.3, 5.4 Hz, 1H), 2.45 - 2.32 (m, 2H), 2.29 - 1.95 (m, 9H), 1.37 (s, 3H).Example 98: N-(2-methyl-3-pyridyl)-4-[[rac-(3S)-3- [2- [4- [3- [3-(2,6-dioxo-3-piperidyl)-2- fluorophenoxy] cyclobutoxy] -3- methoxy-phenyl] -2-oxo-ethyl] -3, 7-dimethyl-2-oxo-indolin-l-y 1] methyl] benzenesulf onamideStep 1:

[0301] Into a 40-mL sealed tube were added 3-[2,6-bis(benzyloxy)pyridin-3-yl]-2-fluorophenol (1.8 g, 4.48 mmol, 1 equiv), (lr,3r)-3-[(4-methylbenzenesulfonyl)oxy]cyclobutyl 4-methylbenzenesulfonate (2.13 g, 5.38 mmol, 1.2 equiv), CS2CO3 (4.38 g, 13.4 mmol, 3 equiv) and DMF (15 mL) at room temperature. The reaction mixture was stirred at 70 °C for 3 h. The mixture was cooled to room temperature. The residue was purified by reversed-phase flash chromatography. This resulted in (ls,3s)-3-(3-[2,6-bis(benzyloxy)pyridin-3-yl]-2-fluorophenoxy cyclobutyl 4-methylbenzenesulfonate (1.5 g, 54%) as a yellow oil. MS (ESI): mass calcd. for C36H32FNO6S 625.19, m / z found 626.25 [M+H]+. LCMS (acidic condition): Rt = 1.090 min.Step 2:

[0302] Into a 100 mL round-bottom flask were added (ls,3s)-3-(3-[2,6-bis(benzyloxy)pyridin-3-yl]-2-fluorophenoxycyclobutyl 4-methylbenzenesulfonate (1.5 g, 2.39 mmol, 1 equiv), THF (10 mL) and Pd / C (1.5 g, 14.09 mmol, 5.9 equiv) at room temperature. The reaction mixture was stirred at room temperature overnight under hydrogen. The resulting mixture was filtered, the filter cake was washed with THF and EAAttorney Docket No. 57547-738.601(3 x 300 mL). The filtrate was concentrated under reduced pressure. This resulted in (ls,3s)-3-[3-(2,6-dioxopiperidin-3-yl)-2-fluorophenoxy]cyclobutyl 4-methylbenzenesulfonate (1.0 g, 93%) as a white solid. MS (ESI): mass calcd. for C22H22FNO6S 447.12, m / z found 448.15 [M+H]+. LCMS (acidic condition): Rt = 0.730 min.Step 3:

[0303] A solution of 4-([(3S)-3-[2-(4-hydroxy-3-methoxyphenyl)-2-oxoethyl]-3,7-dimethyl-2-oxoindol-l-yl]methyl-N-(2-methylpyridin-3-yl)-N-([2-(trimethylsilyl)ethoxy]methylbenzenesulfonamide (150 mg, 0.21 mmol, 1 equiv) in DMSO (3.00 mL) was treated with t-BuOK (28 mg, 0.25 mmol, 1.2 equiv) at 100 °C for 15 min followed by the addition of ( 1 s.3s)-3-|3-(2.6-dioxopiperidin-3-yl)-2-fluorophenox ] cyclobutyl 4-methylbenzenesulfonate (187 mg, 0.42 mmol, 2 equiv) in DMSO dropwise at 100 °C. The reaction mixture was stirred at 100 °C for 2 h. The mixture was cooled to room temperature. The residue was purified by reversed-phase flash chromatography. This resulted in 4-([(3S)-3-(2-(3-methoxy-4-[(lr,3r)-3-[3-(2,6-dioxopiperidin-3-yl)-2-fluorophenoxy]cyclobutoxy]phenyl-2-oxoethyl)-3,7-dimethyl-2-oxoindol-l-yl] methyl-N-(2-methylpyridin-3-yl)-N-([2-(trimethylsilyl)ethoxy] methylbenzenesulfonamide (90 mg, 43 %) as an off-white solid. MS (ESI): mass calcd. for C53H59FN4O10SSi 990.37, m / z found 991.40 [M+H]+. LCMS (acidic condition): Rt = 0.952 min.Step 4:

[0304] Into a 8-mL vial were added 4-([(3S)-3-(2-(3-methoxy-4-[(lr,3r)-3-[3-(2,6-dioxopiperidin-3-yl)-2-fluorophenoxy]cyclobutoxy]phenyl-2-oxoethyl)-3,7-dimethyl-2-oxoindol-l-yl]methyl-N-(2-methylpyridin-3-yl)-N-([2-(trimethylsilyl)ethoxy]methylbenzenesulfonamide (100 mg, 0. lOmmol, 1 equiv), DCM (2 mL) and trifluoroacetic acid (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under vacuum. The residue was purified by reversed-phase flash chromatography. This resulted in 4-([(3S)-3-(2-(3-methoxy-4-[(lr,3r)-3-[3-(2,6-dioxopiperidin-3-yl)-2-fluorophenoxy]cyclobutoxy]phenyl-2-oxoethyl)-3,7-dimethyl-2-oxoindol-l-yl]methyl-N-(2-methylpyridin-3-yl)benzenesulfonamide (35.5 mg, 41%). MS (ESI): mass calcd. for C47H45FN4O9S 860.29. m / z found 861.40 [M+H]+. LCMS (acidic condition): Rt = 0.896min.1HNMR(400 MHz, DMSO-d6) 810.89(s, 1H), 9.86 (s, 1H), 8.24 (d, J= 4.3 Hz, 1H), 7.66 (d, J= 8.5 Hz, 2H), 7.66 - 7.56 (m, 3H), 7.42 - 7.34 (m, 2H), 7.22 -7.12 (m, 2H), 7.07 (t, J= 8.0 Hz, 1H), 6.88 (tdd, J = 14.9, 9.3, 7.2Hz, 5H), 5.26 (s, 2H), 5.09 - 4.94 (m, 2H), 4.15 (d, J= 18.6 Hz, 1H), 4.06 (dd, J= 12.5, 4.9 Hz, lH),3.82(s, 3H), 3.62 (d, J= 18.5 Hz, 1H), 2.82- 2.62 (m, 5H), 2.56 (s, 1H), 2.23 (d, J= 4.0 Hz, 1H), 2.13 (d, J= 2.6 Hz, 6H), 2.05 - 1.99 (m, 1H), 1.38 (s, 3H).Example 101: N-(2- methyl- 3- pyridyl)-4- [ [rac-(3S)-3- [2- [4- [ [ 1- [3-(2,6-dioxo-3-piperidyl)phenyl]azetidin-3-yl]methoxy]-3-methoxy-phenyl]-2-oxo-ethyl]-3, 7-dimethyl- 2-oxo- indolin-1-yl] methyl] benzenesulfonamideAttorney Docket No. 57547-738.601Step 1:

[0305] To a stirred solution of 4-([(3S)-3-[2-(4-hydroxy-3-methoxyphenyl)-2-oxoethyl]-3,7-dimethyl-2-oxoindol-l-yl]methyl-N-(2-methylpyridin-3-yl)-N-([2-(trimethylsilyl)ethoxy]methylbenzenesulfonamide (45.6 mg, 0.064 mmol) and (l-[3-(2,6-dioxopiperidin-3-yl)phenyl]azetidin-3-ylmethyl 4-methylbenzenesulfonate (30 mg, 0.07 mmol) in DMF (500 pL) were added K2CO3 (26 mg, 0.19 mmol) dropwise at room temperature. The resulting mixture was stirred at 60 °C for additional 2 h. The residue was purified by reversed-phase flash chromatography. This resulted in 4-[(3-(2-[4-((l-[3-(2,6-dioxopiperidin-3-yl)phenyl |azetidin-3- lmethoxy)-3-methoxy phen l ]-2-oxoethyl-3,7-dimethyl-2-oxoindol-l -yl)methyl ]-N-(2-methylpyridin-3-yl)-N-([2-(trimethylsilyl)ethoxy]methylbenzenesulfonamide (34 mg, 55%) as a white solid. MS (ESI): mass calcd. for C53H61N5O9SSi 971.40, m / z found 972.95 [M+H]+. LCMS (basic condition): Rt = 1.205 min.Step 2:

[0306] To a stirred solution of 4-([(3S)-3-(2-[4-((l-[3-(2,6-dioxopiperidin-3-yl)phenyl]azetidin-3-ylmethoxy)-3-methoxy phenyl] -2-oxoethyl-3,7-dimethyl-2-oxoindol-l-yl]methyl-N-(2-methylpyridin-3-yl)-N-([2-(trimethylsilyl)ethoxy]methylbenzenesulfonamide (34 mg, 0.035 mmol) in DCM (500 pL) was added TFA (500 pL) dropwise at room temperature. The resulting mixture was stirred at room temperature for additional 30 min. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography. This resulted in 4-([(3S)-3-(2-[4-((l-[3-(2,6-dioxopiperidin-3-yl)phenyl |azetidin-3-ylmethoxy)-3-methoxy phenyl ]-2-oxoethyl-3,7-dimethyl-2-oxoindol-l -yl]methyl-N-(2-methylpyridin-3-yl)benzenesulfonamide (14.2 mg, 48%). MS (ESI): mass calcd. for C47H47N5O8S 841.31, m / z found 842.3 [M+H]+. LCMS (acidic condition): Rt = 0.815 min. 'H NMR (400 MHz, DMSO-d6) 8 10.79 (s, 1H), 9.90 (s, 1H), 8.23-8.22 (d, J = 4.7Hz, 1H), 7.67-7.65 (d, J = 8.3 Hz, 3H), 7.59-7.57 (d, J= 8.2 Hz, 2H), 7.38-7.36 (dd, J= 8.9, 1.8 Hz, 2H), 7.19-7.10 (m,4H), 6.90-6.84 (m, 2H), 6.53-6.51 (d, J= 7.5 Hz, 1H), 6.36-6.34 (dd, J= 8.1, 2.3 Hz, 1H), 6.30-6.29 (d,. / = 2.0 Hz. 1H), 5.25 (s, 2H), 4.31-4.29 (d, J= 7.1 Hz, 2H), 4.17-4.13 (d, J= 18.5Hz, 1H), 3.96-3.92 (td, J= 7.6, 3.3 Hz, 2H), 3.78-3.72 (m, 4H), 3.66-3.60 (m, 3H), 3.21-3.10 (m, 1H), 2.67-2.63 (m, 1H), 2.50-2.49 (m, 1H), 2.13 (s, 7H), 2.04-2.03 (dq, J = 13.8, 5.0 Hz, 1H), 1.38 (s, 3H).Example 102: N-(2-methyl-3-pyridyl)-4-[[rac-(3S)-3-[2-[4-[[l-[3-(2,4-dioxohexahydropyrimidin-l-yl)-l-methyl-indazol-6-yl]azetidin-3-yl]methoxy]-3-methoxy-phenyl]-2-oxo-ethyl]-3,7-dimethyl-2-oxo-Attorney Docket No. 57547-738.601indolin- 1-yl] methyl] benzenesulfonamideStep 1:

[0307] To a solution of l-(6-bromo-l-methylindazol-3-yl)-l,3-diazinane-2, 4-dione (200 mg, 0.619 mmol) and azetidin-3-ylmethanol hydrochloride (153 mg, 1.23 mmol) in 1,4-dioxane (5 mL) and 3-chloropyridine(l,3-bis[2,6-bis(heptan-4-yl)phenyl]-4,5-dichloro-2,3-dihydro-lH-imidazol-2-yldichloropalladium (30.1 mg, 0.031 mmol) were added CS2CO3 (90.7 mg, 0.260 mmol). The reaction mixture was stirred at 105 °C for 2 h under nitrogen. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered, the filter cake was washed with EtOAc (2 x 30 mL). The filtrate was concentrated under reduced pressure. The crude product / resulting mixture was used in the next step directly without further purification MS (ESI): masscalcd. for C16H19N5O3329.15, m / z found 330.10 [M+H]+. LCMS (acidic condition): Rt = 0.424 min.Step 2:

[0308] To a stirred solution of l-(6-[3-(hydroxymethyl)azetidin-l-yl]-l-methylindazol-3-yl-l,3-diazinane-2, 4-dione (160 mg, 0.48 mmol) and EtsN (203 pL, 1.45 mmol) in DCM (3 mL) was added DMAP (11.9 mg, 0.097 mmol) in portions at room temperature. To the above mixture was added 4-methylbenzenesulfonyl chloride (138 mg, 0.72 mmol) in portions at room temperature. The resulting mixture was stirred at room temperature for additional 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, (EA in PE, 10% to 20%) to afford (l-[3-(2,4-dioxo-3-([2-(trimethylsilyl)ethoxy]methyl-l,3-diazinan-l-yl)-l-methylindazol-6-yl] azeti din-3 -ylmethyl 4-methylbenzenesulfonate (130 mg, 43%) as an off-white solid. MS (ESI): mass calcd. for C23H25N5O5S 483.16, m / z found 484.05 [M+H]+. LCMS (acidic condition): Rt = 0.687 min.Step 3:

[0309] To a stirred solution of 4-([(3S)-3-[2-(4-hydroxy-3-methoxyphenyl)-2-oxoethyl]-3,7-dimethyl-2-oxoindol-l-yl]methyl-N-(2-methylpyridin-3-yl)-N-([2-(trimethylsilyl)ethoxy]methylbenzenesulfonamide (60 mg, 0.084 mmol) and (l-[3-(2,4-dioxo-l,3-diazinan-l-yl)-l-methylindazol-6-yl]azetidin-3-ylmethyl 4-Attorney Docket No. 57547-738.601methylbenzenesulfonate (44.6 mg, 0.092 mmol) in DMF (1 mL) was added K2CO3 (34.8 mg, 0.252 mmol) at room temperature. The resulting mixture was stirred at 60 °C for additional 2 h. The residue was purified by reversed-phase flash chromatography. This resulted in 4-([(3S)-3-(2-[4-((l-[3-(2,4-dioxo-l,3-diazinan-l-yl)-l-methylindazol-6-yl |azetidin-3- lmethoxy)-3-methoxyphen l|-2-oxoeth l-3.7-dimeth l-2-oxoindol- 1-yl]methyl-N-(2-methylpyridin-3-yl)-N-([2-(trimethylsilyl)ethoxy]methylbenzenesulfonamide (75 mg) as a white solid. MS (ESI): masscalcd. for C54H62N8O9SSi 1026.41, m / z found 1027.41 [M+H]+. LCMS (acidic condition): Rt = 0.790 min.Step 4:

[0310] To a stirred solution of 4-([(3S)-3-(2-[4-((l-[3-(2,4-dioxo-l,3-diazinan-l-yl)-l-methylindazol-6-yl]azetidin-3-ylmethoxy)-3-methoxyphenyl]-2-oxoethyl-3,7-dimethyl-2-oxoindol-l-yl]methyl-N-(2-methylpyridin-3-yl)-N-([2-(trimethylsilyl)ethoxy]methylbenzenesulfonamide (70 mg, 0.063 mmol) in DCM (2 mL) was added 2,2,2-trifluoroacetic acid (2 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under vacuum. The residue was purified by reversed-phase flash chromatography. This resulted in 4-([(3S)-3-(2-[4-((l-[3-(2,4-dioxo-l,3-diazinan-l-yl)-l-methylindazol-6-yl |azetidin-3-ylmethoxy)-3-methoxyphenyl ]-2-oxoethyl-3,7-dimethyl-2-oxoindol- 1-yl]methyl-N-(2-methylpyridin-3-yl)benzenesulfonamide (27 mg, 48%). MS (ESI): mass calcd. for C48H48N8O8S 896.33, m / z found 897.30. LCMS (acidic condition): Rt = 1.535 min.1H NMR (400 MHz, DMSO-de) 5 10.49 (s, lH), 8.18 (s, 1H), 7.71 - 7.63 (m, 3H), 7.57 (d, J = 8.2Hz, 2H),7.45 (s, 1H), 7.43 (s, 1H), 7.41 -7.32 (m, 2H), 7.19 (dd, J=7.2, 1.5 Hz, 1H), 7.12 (dd, J= 12.3, 8.1 Hz, 2H), 6.90(d, J= 6.8 Hz, 1H), 6.84 (t,.7= 7,4 Hz. 1H), 6.43 -6.34(m, 2H), 5.25 (s, 2H), 4.33 (d, J= 7.1 Hz, 2H), 4.15 (d, J= 18.5 Hz, 1H), 4.05 (t, J=7.7Hz, 2H), 3.89 (t, J= 6.7 Hz, 2H), 3.85 (s, 3H), 3.79 (s, 3H), 3.75 (dd, J= 7.6, 5.2 Hz, 2H), 3.62 (d, J= 18.5 Hz, 1H), 3.19(p, J= 6.8 Hz, 1H), 2.74 (t, J= 6.7 Hz, 2H), 2.13 (s, 6H), 1.38 (s, 3H).Example 105: N-(2-methyl-3-pyridyl)-4-[[rac-(3S)-3-[2-[4-[[l-[3-(2,4-dioxohexahydropyrimidin-l-yl)-l-methyl-indazol-6-yl ]^4- piperidyl |oxy |-3-methoxy-phenyl|-2-oxo-ethyl ]-3, 7 -dimethyl-2-oxo-indolin-l-yl] methyl] benzenesulfonamideAttorney Docket No. 57547-738.601Step 1:

[0311] To a stirred solution of l-(6-bromo-l-methylindazol-3-yl)-l,3-diazinane-2, 4-dione (500 mg, 1.54 mmol) and piperidin-4-ol (313 mg, 3.09 mmol) in dioxane (1 mL) were added CS2CO3 (1.51 g, 4.64 mmol) and 3-chloropyridine (l,3-bis[2,6-bis(heptan-4-yl)phenyl]-4,5-dichloro-2,3-dihydro-lH-imidazol-2-yldi chloropalladium (75.4 mg, 0.077 mmol) at room temperature under nitrogen. The reaction mixture was stirred at 105 °C overnight. The resulting mixture was concentrated under reduced pressure. The mixture was quenched with water (1 mL). The residue was purified by reversed-phase flash chromatography. This resulted in l-[6-(4-hydroxypiperidin-l-yl)-l-methylindazol-3-yl]-l,3-diazinane-2, 4-dione (200 mg, 37%) as a yellow solid. MS (ESI): mass calcd. for C17H21N5O3343.16, m / z found 344.05 [M+H]+. LCMS (acidic condition): Rt = 0.339 min.Step 2:

[0312] To a stirred solution of l-[6-(4-hydroxypiperidin-l-yl)-l-methylindazol-3-yl]-l,3-diazinane-2,4-dione (237 mg, 0.690 mmol) and Et3N (288 pL, 2.07 mmol) in DCM (2.5 mL) were added DMAP (16.9 mg, 0.138 mmol) and 4-methylbenzenesulfonyl chloride (197 mg, 1.03 mmol) at room temperature. The resulting mixture was stirred at room temperature overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with (EA in PE, 0% to 25%) to afford l-[3-(2,4-dioxo-l,3-diazinan-l-yl)-l-methylindazol-6-yl]piperidin-4-yl 4-methylbenzenesulfonate (112 mg, 33%) as an off-white solid. MS (ESI): mass calcd. for C24H27N5O5S 497.17, m / z found 498.2 [M+H]+. LCMS (acidic condition): Rt = 0.759 min.Step 3:

[0313] To a stirred solution of 4-([(3S)-3-[2-(4-hydroxy-3-methoxyphenyl)-2-oxoethyl]-3,7-dimethyl-2-oxoindol-l-yl]methyl-N-(2-methylpyridin-3-yl)-N-([2-(trimethylsilyl)ethoxy]methylbenzenesulfonamide (65 mg, 0.091 mmol) and l-[3-(2,4-dimethylidene-l,3-diazinan-l-yl)-l-methylindazol-6-yl]piperidin-4-yl 4-methylbenzenesulfonate (49.3 mg, 0.10 mmol) in DMF (200 pL) was added K2CO3 (37.7 mg, 0.27 mmol) dropwise at room temperature. The resulting mixture was stirred at 60 °C overnight. The mixture was quenched with water (1 mL). The residue was purified by reversed-phase flash chromatography. This resulted in4-([(3S)-3-(2-[4-((l-[3-(2,4-dioxo-l,3-diazinan-l-yl)-l-methylindazol-6-yl]piperidin-4-yloxy)-3-methoxyphenyl] -2-oxoethyl-3,7-dimethyl-2-oxoindol-l-yl]methyl-N-(2-methylpyridin-3-yl)-N-([2-(trimethylsilyl)ethoxy]methylbenzenesulfonamide (65 mg, 69%) as a white solid. MS (ESI): mass calcd. for C55H64N8O9SSi 1040.43, m / z found 1041.65 [M+H]+. LCMS (basic condition): Rt = 1.153 min.Step 4:

[0314] To a stirred solution of 4-([(3S)-3-(2-[4-((l-[3-(2,4-dioxo-l,3-diazinan-l-yl)-l-methylindazol-6-yl]piperidin-4-yloxy)-3-methoxyphenyl]-2-oxoethyl-3,7-dimethyl-2-oxoindol-l-yl]methyl-N-(2-methylpyridin-3-yl)-N-([2-(trimethylsilyl)ethoxy]methylbenzenesulfonamide (65 mg, 0.062 mmol) in DCM (1 mL) was added TFA (1 mL) dropwise at room temperature. The resulting mixture was stirred at room temperature for 30 min. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography. This resulted in 4-([(3S)-3-(2-[4-((l-[3-(2,4-dioxo-l,3-Attorney Docket No. 57547-738.601diazinan-l-yl)-l-methylindazol-6-yl]piperidin-4-yloxy)-3-methoxyphenyl]-2-oxoethyl-3,7-dimethyl-2-oxoindol-l-yl]methyl-N-(2-methylpyridin-3-yl)benzenesulfonamide (24.0 mg, 42.20%yield). MS (ESI): mass calcd. for C49H50N8O8S 910.35, m / z found 911.55 [M+H]+. LCMS (basic condition): Rt = 1.000 min.1HNMR(400MHz, DMSO-d6) 810.51 (s, 1H), 9.86 (s, 1H), 8.26-8.25 (dd, J= 4.8, 1.6 Hz, 1H), 7.67-7.63 (m, 3H), 7.60-7.58 (d, J= 8.3 Hz, 2H), 7.47-7.45 (d, J= 9.0 Hz, 1H), 7.42-7.41 (d, J= 2.0 Hz, 1H), 7.39-7.37 (dd, J=8.0, 1.6Hz, 1H), 7.20-7.15 (m, 3H), 6.95-6.93 (dd, J= 9.1, 2.0 Hz, 1H), 6.91-6.83 (m, 3H), 5.26 (s, 2H), 4.76-4.72 (dq, J= 8.3, 3.9 Hz, 1H), 4.17-4.13 (d, J= 18.5 Hz, 1H), 3.90 (d, J= 2.1 Hz, 5H), 3.80 (s, 3H), 3.66-3.61 (m, 3H), 3.19-3.15 (ddd, J= 12.6, 9.2, 3.2 Hz, 2H), 2.75-2.72 (t, J= 6.6 Hz, 2H), 2.13 (d, J= 4.4 Hz. 8H), 1.79 (d, J= 9.7 Hz, 2H), 1.39 (s, 3H).Example 106: N-(2- methyl- 3- pyridyl)-4- [ [rac-(3S)-3- [2- [4- [ [ 1- [3-(2,6-dioxo-3-piperidyl)- 1-methyl-indazol-6-yl]-4-piperidyl]oxy]-3-methoxy-phenyl]-2-oxo-ethyl]-3,7-dimethyl-2-oxo-indolin-l-yl] methyl] benzenesulfonamideStep 1:

[0315] To a stirred solution of 3-bromo-l-methylindazol-6-amine (2.0 g, 8.85 mmol) and 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (4.06 g, 9.73 mmol) in 1,4-dioxane (20 mL) and H2O (4 mL) was added K2CO3 (3.67 g, 26.5 mmol) and Pd(dppf)C12CH2Ch (0.22 g, 0.265 mmol) in portions at room temperature. The reaction mixture was stirred at 110 °C overnight under nitrogenAttorney Docket No. 57547-738.601The reaction was quenched with water (20 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (1 x 10 mL), dried over anhydrous Na2SO4. After fdtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with (EA in PE, 20% to 70%) to afford 3-[2,6-bis(benzyloxy)pyridin-3-yl]-l-methylindazol-6-amine (2.0 g, 51%) as an off-white solid. MS (ESI): mass calcd. for C27H24N4O2436.19, m / z found 437 [M+H]+. LCMS (acidic condition): Rt = 0.901 min.Step 2:

[0316] To a stirred solution of 3-[2,6-bis(benzyloxy)pyridin-3-yl]-l-methylindazol-6-amine (300 mg, 0.687 mmol) and 12 MHC1 (0.29 mL, 3.44 mmol) was added sodium nitrite (61.6 mg, 0.893 mmol) in H2O (4 mL) dropwise at 0 °C. The resulting mixture was stirred at 0 °C for 30 min. To the above mixture was added KI (148 mg, 0.893 mmol) in H2O (ImL ) dropwise at 0 °C. The resulting mixture was stirred at room temperature for additional 30 min. To the above mixture was added DCM (6 mL) dropwise at room temperature. The resulting mixture was stirred at 40 °C for additional 2 h. The resulting mixture was extracted with CH2C12 (2 x 30 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography. This resulted in 3-[2,6-bis(benzyloxy)pyridin-3-yl]-6-iodo-l-methylindazole (170 mg, 45%) as a brown solid. MS (ESI): mass calcd. for C27H22IN3O2547.08, m / z found 548 [M+H]+. LCMS (acidic condition): Rt = 1.118 min.Step 3:

[0317] To a solution of 3-[2,6-bis(benzyloxy)pyridin-3-yl]-6-iodo-l-methylindazole (350 mg, 0.639 mmol) and piperidin-4-ol (129mg, 1.28 mmol) in DMSO (3 mL) and L-Proline (17.7 mg, 0.153 mmol) was added CS2CO3 (625 mg, 1.92 mmol) and Cui (14.6 mg, 0.077 mmol) at room temperature. The reaction mixture was stirred at 130 °C overnight under nitrogen. The reaction was quenched with water (5 mL) and extracted with EtOAc (3x5 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with (EA in PE, 20% to 70%) to afford 1 -(3 - [2, 6-bis(benzyloxy)pyridin-3-yl]-l-methylindazol-6-ylpiperidin-4-ol (200 mg, 60%) as a brown solid. MS (ESI): mass calcd. for C32H32N4O3520.25, m / z found 521.15 [M+H]+. LCMS (acidic condition): Rt = 0.811 min.Step 4:

[0318] To a stirred solution of 4-([(3S)-3-[2-(4-hydroxy-3-methoxyphenyl)-2-oxoethyl]-3,7-dimethyl-2-oxoindol-l-yl]methyl-N-(2-methylpyridin-3-yl)-N-([2-(trimethylsilyl)ethoxy]methylbenzenesulfonamide (151 mg, 0.211 mmol) and l-(3-[2,6-bis(benzyloxy)pyridin-3-yl]-l-methylindazol-6-ylpiperidin-4-ol (100 mg, 0.192 mmol) in THF (2 mL) was added PPh3(75.6 mg, 0.288 mmol) and (E)-N-([(tert-butoxy)carbonyl]imino(tert-butoxy)formamide (70.7 mg, 0.307 mmol) in portions at 0 °C. The reaction mixture was stirred at room temperature for 1.5 h under nitrogen. The reaction mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography. This resulted in tert-butyl N-(4-([3-(2-(4-[(l-(3-[2,6-bis(benzyloxy)pyridin-3-yl]phenylpiperidin-4-yl)oxy]-3-Attorney Docket No. 57547-738.601methoxy phenyl-2-oxoethyl )-3.7-dimethyl-2-oxoindol- 1 -yl |methy 1-2- lluorophenyllcarbamate (100 mg, 42%) as ayellow solid. MS (ESI): mass calcd. for C70H75N7O9SSi 1217.51, m / z found 1218.75 [M+H]+. LCMS (acidic condition): Rt = 0.992 min.Step 5:

[0319] To a stirred solution of 4-([(3S)-3-(2-(4-[(l-(3-[2,6-bis(benzyloxy)pyridin-3-yl]-l-methylindazol-6-ylpiperidin-4-yl)oxy]-3-methoxyphenyl-2-oxoethyl)-3,7-dimethyl-2-oxoindol-l-yl]methyl-N-(2-methylpyridin-3-yl)-N-([2-(trimethylsilyl)ethoxy]methylbenzenesulfonamide (60 mg, 0.049 mmol) in CF3CH2OH (2 mL) was added Pd / C (60 mg, 0.564 mmol) in portions at room temperature. The reaction mixture was stirred overnight at room temperature under hydrogen. The resulting mixture was filtered, the filter cake was washed with CH2CI2 (7 x 5 mL). The filtrate was concentrated under reduced pressure. This resulted in 4-([(3S)-3-(2-[4-((l-[3-(2,6-dioxo-l,3-dihydropyridin-3-yl)-l-methylindazol-6-yl]piperi din-4-yloxy)-3-methoxyphenyl]-2-oxoethyl-3,7-dimethyl-2-oxoindol-l-yl]methyl-N-(2-methylpyridin-3-yl)-N-([2-(trimethylsilyl)ethoxy]methylbenzenesulfonamide (40 mg, crude) as a brown solid. The crude product was used in the next step directly without further purification.MS (ESI): mass calcd. for C56H65N7O9SSi 1039.43, m / z found 1040.35 [M+H]+. LCMS (acidic condition): Rt = 0.930 min.Step 6:

[0320] To a stirred solution of 4-([(3S)-3-(2-[4-((l-[3-(2,6-dioxopiperidin-3-yl)-l-methylindazol-6-yl]piperidin-4-yloxy)-3-methoxyphenyl]-2-oxoethyl-3,7-dimethyl-2-oxoindol-l-yl]methyl-N-(2-methylpyridin-3-yl)-N-([2-(trimethylsilyl)ethoxy]methylbenzenesulfonamide (50 mg, 0.048 mmol) in DCM (1 mL) was added trifluoroacetic acid (1 mL) dropwise at room temperature. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography. This resulted in 4-([(3 S)-3-(2- [4-(( 1 - [3-(2,6-dioxopiperidin-3-yl)- l-methylindazol-6-yl]piperidin-4-yloxy)-3-methoxyphenyl]-2-oxoethyl-3,7-dimethyl-2-oxoindol-l-yl]methyl-N-(2-methylpyridin-3-yl)benzenesulfonamide (8.4 mg, 19%). MS (ESI): mass calcd. for C50H51N7O8S 909.35, m / z found 910.50 [M+H]+. LCMS (basic condition): Rt = 1.581 min.1H NMR (400 MHz, DMSO-d6) 810.85 (s, 1H), 9.86 (s, 1H), 8.29 - 8.23 (m, 1H), 7.69 - 7.56 (m, 5H), 7.51-7.49 (d, J= 9.0 Hz, 1H), 7.43 - 7.34 (m, 2H), 7.23 - 7.13 (m, 3H), 6.98 - 6.81 (m, 4H), 5.26 (s, 2H), 4.73 (s, 1H), 4.28-4.24 (dd, J=9.2, 1H), 4.18-4.13 (d, J= 12.3 Hz, lH),3.90(s, 3H), 3.80 (s, 3H), 3.68 - 3.59 (m, 3H), 3.18-3.13(1,7= 10.1 Hz, 2H), 2.67 - 2.58 (m, 2H), 2.32-2.25 (m, 1H), 2.21 -2.04 (m, 9H), 1.80-1.77 (d, 7= 9.0 Hz, 2H), 1.38 (s, 3H).Example 107: N- [4- [ [3- [2-[4-[ [2- [3-(2,6-dioxo-3-piperidyl)phenyl] -2- azaspiro [3.3] heptan-6-yl] oxy] -3-methoxy-phenyl]-2-oxo-ethyl]-3,7-dimethyl-2-oxo-indolin-l-yl]methyl]-2-fluoro-phenyl]-2-methyl-pyrazole-3-sulfonamideAttorney Docket No. 57547-738.601Step 1:

[0321] To a stirred solution of N-[2-fluoro-4-((3-[2-(4-hydroxy-3-methoxyphenyl)-2-oxoethyl]-3,7-dimethyl-2-oxoindol-l-ylmethyl)phenyl] -2-methyl-N-([2-(trimethylsilyl)ethoxy]methylpyrazole-3-sulfonamide (70 mg, 0.097 mmol) and l-[3-(2,6-dioxopiperidin-3-yl)phenyl]piperidin-4-yl 4-methylbenzenesulfonate (53.8 mg, 0.122 mmol) in DMF (1 mL) was added K2CO3 (40.1 mg, 0.291 mmol) in portions at room temperature. The resulting mixture was stirred at 60 °C additional overnight. The reaction was poured into water (1 mL) at room temperature. The residue was purified by reversed-phase flash chromatography. This resulted in N-(4-[(3-(2-[4-((2-[3-(2,6-dioxopiperidin-3-yl)phenyl]-2-azaspiro[3.3]heptan-6-yloxy)-3-methoxyphenyl]-2-oxoethyl-3,7-dimethyl-2-oxoindol-l-yl)methyl]-2-fluorophenyl-2-methyl-N-([2-(trimethylsilyl)ethoxy]methylpyrazole-3-sulfonamide (30 mg, 31%) as a light yellow solid. MS (ESI): mass calcd. for CssHeiFNeOgSSi 1004.40, m / z found 1005.45 [M+H]+. LCMS (basic condition+NH3. H2O): Rt = 1.159 min.Step 2:

[0322] To a stirred solution ofN-(4-[(3-(2-[4-((2-[3-(2,6-dioxopiperidin-3-yl)phenyl]-2-azaspiro[3.3]heptan-6-yloxy)-3-methoxyphenyl]-2-oxoethyl-3,7-dimethyl-2-oxoindol-l-yl)methyl]-2-fluorophenyl-2-methyl-N-([2-(trimethylsilyl)ethoxy]methylpyrazole-3-sulfonamide (40 mg, 0.040 mmol) in DCM (1 mL) were added trifluoroacetic acid (1 mL) dropwise at room temperature. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The crude product (30 mg) was purified by Prep-HPLC to afford N-(4-[(3-(2-[4-((2-[3-(2,6-dioxopiperidin-3-yl)phenyl]-2-azaspiro[3.3]heptan-6-yloxy)-3-methoxyphenyl] -2-oxoethyl-3,7-dimethyl-2-oxoindol-l-yl)methyl]-2-fluorophenyl-2-methylpyrazole-3-sulfonamide (8.9 mg, 25%). MS (ESI): mass calcd. for C47H47FN6O8S 874.32, m / z found 875.80 [M+H]+. LCMS (basic condition): Rt = 0.963 min.1H NMR (400 MHz, DMSO-de) 5 10.80 (s, 1H), 10.64 (s, 1H), 7.62-7.59 (dd, J= 8.5, 1H), 7.47-7.46 (d, J= 2.1 Hz, 1H), 7.37-7.36 (d, J= 2.0 Hz, 1H), 7.34 - 7.23 (m, 2H), 7.22 - 7.14 (m, 2H), 7.13-7.09 (t, J= 7.8 Hz, 1H), 6.92 -6.81 (m, 3H), 6.59-6.58 (d, J= 2.1 Hz, 1H), 6.53-6.51 (d, J = 7.5 Hz, 1H), 6.33-6.31 (dd, J= 8.0, 1H), 6.26-6.25 (t, J= 1.9 Hz, 1H), 5.19-5.07 (d, J= 17.7 Hz, 2H), 4.81-4.74 (p, J = 6.8 Hz, 1H), 4.15-4.10 (d, J= 12.1 Hz, 1H), 3.97 (s, 3H), 3.87 (s, 2H), 3.82 - 3.70 (m, 6H), 3.64-3.59 (d, J = 14.1 Hz, 1H), 2.83-2.78 (dd, J = 12.4, 2H), 2.66-2.59 (td, J= 11.4, 1H), 2.44-2.42 (t, J= 6.4, 1H), 2.34-2.28 (t, J= 9.8 Hz, 2H), 2.15 (s, 4H), 2.13 - 1.96 (m, 1H), 1.34 (s, 3H).Attorney Docket No. 57547-738.601Example 108: 2-methyl-N-[4-[[rac-(3S)-3-[2-[4-[[l-[3-(2,6-dioxo-3-piperidyl)phenyl]azetidin-3-yl] methoxy] -3-methoxy-phenyl] -2-oxo-ethyl]-3,7-dimethyl-2-oxo-indolin- 1-yl] methyl] phenyl] pyrazole-3-sulfonamideStep 1:

[0323] Into a 40-mL vial were added tert-butyl N-(4-([(3S)-3-[2-(4-hydroxy-3-methoxyphenyl)-2-oxoethyl]-3,7-dimethyl-2-oxoindol-l-yl]methylphenyl)carbamate (550mg, 1.03 mmol, 1 equiv), (l-[3-(2,6-dioxopiperidin-3-yl)phenyl]azetidin-3-ylmethyl 4-methylbenzenesulfonate (444 mg, 1.03 mmol, 1 equiv), K2CO3 (429 mg, 3.11 mmol, 3.00 equiv) and DMF (5 mL) at room temperature. The reaction mixture was stirred at 60 °C for 4 h. The reaction was quenched with water (1 mL). The residue was purified by reversed-phase flash chromatography. This resulted in tert-butyl N-(4-([(3S)-3-(2-[4-((l-[3-(2,6-dioxopiperidin-3-yl)phenyl]azetidin-3-ylmethoxy)-3-methoxyphenyl]-2-oxoethyl-3,7-dimethyl-2-oxoindol-l-yl]methylphenyl)carbamate (450 mg, 55%) as alight purple solid. MS (ESI): mass calcd. for C46H50N4O8 786.36, m / z found 787.40 [M+H]+. LCMS (acidic condition): Rt = 0.921 min.Step 2:

[0324] Into a 100-mL round-bottom flask were added tert-butyl N-(4-([(3S)-3-(2-[4-((l-[3-(2,6-dioxopiperidin-3-yl)phenyl]azetidin-3-ylmethoxy)-3-methoxyphenyl]-2-oxoethyl-3,7-dimethyl-2-oxoindol-l-yl]methylphenyl)carbamate (280 mg, 0.36 mmol, 1 equiv), DCM (3 mL) and TFA (1 mL) at room temperature. The resulting mixture was stirred at room temperature for 30 min. The resulting mixture was concentrated under vacuum. The mixture was basified to pH 8 with saturated aqueous NaHCO3. The resulting mixture was extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine (1 x 25 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography. This resulted in 3-(3-[3-(4-(2-[ (3 S)- 1 -[(4-aminophenyl)methyl] -3,7-dimethyl-2-oxoindol-3-yl] acetyl-2-methoxyphenoxymethyl)azetidin-l-yl]phenylpiperidine-2, 6-dione (230 mg, 93%) as a purple solid. MS (ESI): mass calcd. for C41H42N4O6 686.31, m / z found 687.35 [M+H]+. LCMS (acidic condition): Rt = 1.050 min.Step 3:

[0325] Into a 100-mL round-bottom flask were added 3-(3-[3-(4-(2-[(3S)-l-[(4-aminophenyl)methyl]-3,7-dimethyl-2-oxoindol-3-yl] acetyl-2-methoxyphenoxymethyl)azetidin- 1 -yl]phenylpiperidine-2, 6-dione (1 g, 1.46 mmol, 1 equiv) and pyridine (3 mL) at room temperature. To the above mixture was added 2-Attorney Docket No. 57547-738.601methylpyrazole-3 -sulfonyl chloride (315.6 mg, 1.74 mmol, 1.2 equiv) in DCM (3 mL) dropwise at 0 °C. The reaction mixture was stirred at room temperature for 1 h. The residue was purified by reversed-phase flash chromatography. The crude product (700 mg) was purified by Prep-HPLC to affordN-(4-([(3S)-3-(2-[4-((l-[3-(2,6-dioxopiperidin-3-yl)phenyl]azetidin-3-ylmethoxy)-3-methoxyphenyl]-2-oxoethyl-3,7-dimethyl-2-oxoindol-l-yl]methylphenyl)-2-methylpyrazole-3-sulfonamide (385 mg, 32%). MS (ESI): mass calcd. for C45H46N6O8S 831.31, m / z found 831.45 [M+H]+. LCMS (acidic condition): Rt = 0.979 min.1H NMR (400 MHz, DMSO-de): d ppm 10.79 (s, 1H), 10.74 (s, 1H), 7.65 (dd, J= 8.4, 2.0 Hz, 1H), 7.47 (d, J= 2.1 Hz, 1H), 7.37 (d, J= 2.0 Hz, 1H), 7.28 (d, J= 8.2 Hz, 2H), 7.22 - 7.06 (m, 5H), 6.92 - 6.78 (m, 2H), 6.71 (d, J= 2.0Hz, 1H), 6.52 (d, J = 7.6Hz, 1H), 6.36 (dd, J= 8.1, 2.3 Hz, 1H), 6.30(t, J= 2.0 Hz, 1H),5. O9 (d, J=3.2 Hz, 2H), 4.31 (d, J=7.1 Hz, 2H), 4.11 (d, J= 18.5 Hz, 1H), 4.00 - 3.90 (m, 5H), 3.81 - 3.70 (m, 4H), 3.70 -3.55 (m, 3H), 3.18 -3.10 (m, 1H), 2.68- 2.57 (m, 1H), 2.51 - 2.41 (m, 1H), 2.15 (s, 4H), 2.10 - 1.98 (m, 1H), 1.36 (s, 3H).Example 109: N- [4- [ [3- [ 2- [ 4- [ [2- [3-(2,6-dioxo-3-piperidyl)phenyl] -2- azaspiro [3.3] heptan-6-yl] oxy] -3-methoxy-phenyl] -2-oxo-ethyl] -7-methyl-2-oxo-3-(trideuteriomethyl)indolin- 1-yl] methyl] -2-fluoro-phenyl]-2-methyl-pyrazole-3-sulfonamideo oStep 1:

[0326] To a stirred mixture of 2-(2H3)methyl-N-(2-methylphenyl)prop-2-enamide (3 g, 16.80 mmol, 1 equiv) in THF (30 mL) was added NaH (809 mg, 33.6 mmol, 2 equiv) in portions at 0 °C under nitrogen. The reaction mixture was stirred at 0 °C for 30 min under nitrogen. To the mixture was added 1-Attorney Docket No. 57547-738.601(bromomethyl)-4-methoxybenzene (3.38 g, 16.8 mmol, 1 equiv) dropwise at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The reaction was quenched with water / ice at 0 °C. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (1 x 60 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with (EA in PE, 10% to 30%) to afford N-[(4-methoxyphenyl)methyl]-2-(2H3)methyl-N-(2-methylphenyl)prop-2-enamide (4.5 g, 90%) as a yellow oil. MS (ESI): mass calcd. for C19H18D3NO2298.18, m / z found 299 [M+H]+. LCMS (acidic condition): Rt = 0.804 min.Step 2:

[0327] To a stirred mixture of N-[(4-methoxyphenyl)methyl]-2-(2H3)methyl-N-(2-methylphenyl)prop-2-enamide(9g, 30.1 mmol, 1 equiv) and 4-bromo-3-methoxybenzaldehyde (12.9 g, 60.3 mmol, 2 equiv) in ethyl acetate (90 mL) was added (acetyloxy )ferrio acetate (525 mg, 3.01 mmol, 0.10 equiv) and tert-butyl hydroperoxide (5.0-6.0 Min decane) (40.21 pL, 0.201 mmol, 3 equiv) dropwise at room temperature under nitrogen. The reaction mixture was stirred at 110 °C overnight under nitrogen. The reaction was quenched with aqueous Na2CO3at room temperature. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (1 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with (EA in PE, 20% to 30%) to afford 3-[2-(4-bromo-3-methoxyphenyl)-2-oxoethyl]-l-[(4-methoxyphenyl)methyl]-3-(2H3)methyl-7-methylindol-2-one (2.3 g, 15%) as ayellow solid MS (ESI): mass calcd. for C27H23D3BrNO4510.12, m / z found 511 [M+H]+. LCMS (acidic condition): Rt = 0.884 min.Step 3:

[0328] A mixture of 3-[2-(4-bromo-3-methoxyphenyl)-2-oxoethyl]-l-[(4-methoxyphenyl)methyl]-3-(2H3)methyl-7-methylindol-2-one (2.3 g, 4.49 mmol, 1 equiv) in trifluoroacetic acid (23 mL) was stirred at 100 °C for 1 h. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography. This resulted in 3-[2-(4-bromo-3-methoxyphenyl)-2-oxoethyl]-3-(2H3)methyl-7-methyl-lH-indol-2-one (1.2 g, 68%) as alight brown solid. MS (ESI): mass calcd. for C19H15D3BrNO3390.07, m / z found 391 [M+H]+. LCMS (acidic condition): Rt =0.925 min.Step 4:

[0329] To a stirred mixture of 3-[2-(4-bromo-3-methoxyphenyl)-2-oxoethyl]-3-(2H3)methyl-7-methyl-lH-indol-2-one (600 mg, 1.53 mmol, 1 equiv) and 4-(bromomethyl)-2-fluoro-l -nitrobenzene (538 mg, 2.3 mmol, 1.5 equiv) in DMF (10 mL) was added CS2CO3 (1499 mg, 4.6 mmol, 3 equiv) in portions at room temperature. The resulting mixture was stirred at 60 °C for 1 h. The mixture was allowed to cool down to room temperature. The reaction was quenched with water and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (1 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flashAttorney Docket No. 57547-738.601chromatography. This resulted in 3-[2-(4-bromo-3-methoxyphenyl)-2-oxoethyl]-l-[(3-fluoro-4-nitrophenyl)methyl]-3-(2H3)methyl-7-methylindol-2-one (360 mg, 43%) as a yellow solid. MS (ESI): mass calcd. for C26Hi9D3BrFN20s 543.09, m / z found 544 [M+H]+. LCMS (acidic condition): Rt = 0.904 min.Step 5:

[0330] To a stirred mixture of 3-[2-(4-bromo-3-methoxyphenyl)-2-oxoethyl]-l-[(3-fluoro-4-nitrophenyl)methyl]-3-(2H3)methyl-7-methylindol-2-one (366 mg, 0.67 mmol, 1 equiv) and NH4CI (143.8 mg, 2.69 mmol, 4 equiv) in EtOH (8 mL) were added H2O (1 mL) and Fe (150.1 mg, 2.68 mmol, 4 equiv) in portions at room temperature. The resulting mixture was stirred at 80 °C for 1 h. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered and the filter cake was washed with EtOAc (3 x 20 mL). The combined filtrates were concentrated under reduced pressure. The reaction was poured into water at room temperature. The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (1 x50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 1 -[(4-amino-3-fluorophenyl)methyl]-3-[2-(4-bromo-3-methoxyphenyl)-2-oxoethyl]-3-(2H3)methyl-7-methylindol-2-one (350 mg, 100%) as a light brown solid. The product was used in the next step directly without further purification. MS (ESI): mass calcd. for C26H2iD3BrFN2O3 513.11, m / z found 514 [M+H]+. LCMS (acidic condition): Rt = 0.847 min.Step 6:

[0331] To a stirred mixture of l-[(4-amino-3-fluorophenyl)methyl]-3-[2-(4-bromo-3-methoxyphenyl)-2-oxoethyl]-3-(2H3)methyl-7-methylindol-2-one (360 mg, 0.70 mmol, 1 equiv) in pyridine (5 mL) were added 2-methylpyrazole-3-sulfonyl chloride (632 mg, 3.50 mmol, 5 equiv) in DCM (0.5 mL) dropwise at 0 °C under nitrogen. The reaction mixture was stirred at room temperature for 1 h under nitrogen. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography. This resulted in N-[4-((3-[2-(4-bromo-3-methoxyphenyl)-2-oxoethyl]-3-(2H3)methyl-7-methyl-2-oxoindol-l-ylmethyl)-2-fluorophenyl]-2-methylpyrazole-3-sulfonamide (270 mg, 59%) as a yellow solid. MS (ESI): mass calcd. for C30H25D3BrFN4O5S 657.11, m / z found 658 [M+H]+. LCMS (basic condition): Rt = 0.705 min.Step 7:

[0332] To astirred mixture of N-[4-((3-[2-(4-bromo-3-methoxyphenyl)-2-oxoethyl]-3-(2H3)methyl-7-methyl-2-oxoindol-l-ylmethyl)-2-fluorophenyl]-2-methylpyrazole-3-sulfonamide (250 mg, 0.38 mmol, 1 equiv) and DIEA (147 mg, 1.14 mmol, 3 equiv) in DCM (2 mL) was added [2-(chloromethoxy)ethyl]trimethylsilane (127 mg, 0.76 mmol, 2 equiv) dropwise at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography. This resulted in N-[4-((3-[2-(4-bromo-3-methoxyphenyl)-2-oxoethyl]-3-(2H3)methyl-7-methyl-2-oxoindol-l-ylmethyl)-2-fluorophenyl]-2-methyl-N-([2-(trimethylsilyl)ethoxy]methylpyrazole-3-sulfonamide (260 mg, 87%) as a yellow solid. MS (ESI): mass calcd. for C36H39D3BrFN4O6SSi 787.20, m / z found 812 [M+Na]+. LCMS (acidic condition): Rt = 1.052 min.Attorney Docket No. 57547-738.601Step 8:

[0333] To astirred mixture of N-[4-((3-[2-(4-bromo-3-methoxyphenyl)-2-oxoethyl]-3-(2H3)methyl-7-methyl-2-oxoindol-l-ylmethyl)-2-fluorophenyl]-2-methyl-N-([2-(trimethylsilyl)ethoxy]methylpyrazole-3-sulfonamide (260 mg, 0.33 mmol, 1 equiv) and KOH (39 mg, 0.99 mmol, 3 equiv) and H2O (0.8 mL) in dioxane (2 mL) were added t-BuXPhos (14 mg, 0.033 mmol, 0.1 equiv) and Pd2(dba)s (30.18 mg, 0.033 mmol, 0.1 equiv) in portions at room temperature under nitrogen. The reaction mixture was stirred at 100 °C overnight under nitrogen. The mixture was allowed to cool down to room temperature. The reaction was quenched with water and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (1 x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed -phas...

Claims

Attorney Docket No. 57547-738.601CLAIMS WHAT IS CLAIMED IS:

1. A compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:(R14)mFormula (I);wherein:X1is N or CR1;R1is hydrogen, halogen, -CN, -OH, -ORa, -SH, -SRa, -NRbRc, Ci-Cealkyl, or Ci-Ceheteroalkyl; wherein the alkyl and heteroalkyl is independently optionally substituted with one or more R’;X2is N or CR2;R2is hydrogen, halogen, -CN, -OH, -ORa, -SH, -SRa, -NRbRc, Ci-Cealkyl, or Ci-Ceheteroalkyl; wherein the alkyl and heteroalkyl is independently optionally substituted with one or more R’;X3is N or CR3;R3is hydrogen, halogen, -CN, -OH, -ORa, -SH, -SRa, -NRbRc, Ci-Cealkyl, or Ci-Ceheteroalkyl; wherein the alkyl and heteroalkyl is independently optionally substituted with one or more R’;X4is N or CR4;R4is hydrogen, halogen, -CN, -OH, -ORa, -SH, -SRa, -NRbRc, Ci-Cealkyl, or Ci-Ceheteroalkyl; wherein the alkyl and heteroalkyl is independently optionally substituted with one or more R’;R5and R6are independently hydrogen, halogen, Ci-Cealkyl, or Ci-Cehaloalkyl;Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;each R7is halogen, -CN, -OH, -ORa, -SH, -SRa, -NRbRc, Ci-Cealkyl, or Ci-Ceheteroalkyl; wherein each allyl and heteroalkyl is independently optionally substituted with one or more R’;and / or two R7are taken together to form an oxo;p is 0, 1, 2, 3, or 4;L1is -O-, -S-, -NR9-, -C(R10)2-, -C(=O)NR9-*, -S(=O)2NR9-*, -NR9S(=O)2-*, -NR9C(=O)-*, - C(=O)NR9S(=O)2-*, -S(=O)2NR9C(=O)-*, -O-C(R10)2-*, -C(R10)2-O-*, -NR9-C(R10)2-*, -C(R10)2-NR9-*, -S(=O)2C(R10)2-*, or -C(R10)2S(=O)2-*, wherein * represent the attachment point to R8;R9is hydrogen or Ci-Cealkyl independently optionally substituted with one or more R’;each R10is independently hydrogen, halogen, Ci-Cealkyl, Ci-Cehaloalkyl, or Ci-Ceheteroalkyl;B B H(R,1)„, Ci-Cealkyl, or Ci-Cehaloalkyl;Attorney Docket No. 57547-738.601Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;each R11is independently halogen, -CN, -NO2, -OH, -ORa, -SH, -SRa, -NRbRc, Ci-Cealkyl, orCi-Ceheteroalkyl, wherein each alkyl and heteroalkyl is independently optionally substituted with one or more R’;and / or two R11are taken together to form an oxo;n is 0, 1, 2, 3, or 4;R12is hydrogen, halogen, -OH, -ORa, -NRbRc, Ci-Cealkyl, C2-Cealkenyl, C2-Cealkynyl, Ci-Cehaloalkyl, or Ci-Ceheteroalkyl;L2is absent, -OC(=O)-*, -C(=O)O-*, -CH2C(=O)-*, -C(=O)CH2-*, -NR13C(=O)-*, or -C(=O)NR13-*;wherein * represent the attachment point to Ring C;R13is hydrogen or Ci-Cealkyl;Ring C is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;each R14is independently halogen, -CN, -NO2, -OH, -ORa, -SH, -SRa, -NRbRc, Ci-Cealkyl, orCi-Ceheteroalkyl, wherein each alkyl and heteroalkyl is independently optionally substituted with one or more R’;and / or two R14are taken together to form an oxo;and / or R13and one R14are taken together with the atom to which they are attached to form a heterocycloalkyl independently optionally substituted with one or more R”;m is 0, 1, 2, 3, or 4;each L3is independently -O-, -S-, -S(=O)-, -S(=O)2-, -NR15-, -C(=O)-, Ci-Cioalkylene, Ci-Cioheteroalkylene;C2-Cealkenylene, C2-Cealkynylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene; wherein each alkylene, alkenylene, alkynylene, and heteroalkylene is independently optionally substituted with one or more R’ and wherein each cycloalkylene, heterocycloalkylene, arylene, and heteroarylene is independently optionally substituted with one or more R”;each R15is independently hydrogen, Ci-Cealkyl, Ci-Ceheteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, and alkynyl is independently optionally substituted with one or more R’ and wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”;s is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20;| — Mis an E3 ubiquitin ligase targeting agent;each Rais independently Ci-Cealkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L- heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, and alkynyl is independently optionally substituted with one or more R’ and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”;each Rband Rcare independently hydrogen, Ci-Cealkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L- cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, andAttorney Docket No. 57547-738.601alkynyl is independently optionally substituted with one or more R’ and each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”; or Rband Rcare taken together with the atom to which they are attached to form a heterocycloalkyl independently optionally substituted with one or more R”;L is absent or Ci-Ctialkylene optionally substituted with one or more R’; andeach R’ is independently halogen, -CN, -OH, -OCi-Csalkyl, -S(=O)Ci-C3alkyl, -S(=O)2Ci-C3alkyl, - S(=O)2NH2, -S(=O)2NHCi-C3alkyl, -S(=O)2N(Ci-C3alkyl)2, -NH2, -NHCi-C3alkyl, -N(Ci-C3alkyl)2, - NHC(=O)OCi-C3alkyl, -C(=O)Ci-C3alkyl, -C(=O)OH, -C(=O)OCi-C3alkyl, -C(=O)NH2, - C(=O)N(Ci-C3alkyl)2, or -C(=O)NHCi-C3alkyl; wherein each alkyl is independently optionally substituted with one or more halogen;and / or two R’ on the same atom are taken together to form an oxo; andeach R” is independently halogen, -CN, -OH, -OCi-Csalkyl, -S(=O)Ci-C3alkyl, -S(=O)2Ci-C3alkyl, - S(=O)2NH2, -S(=O)2NHCi-C3alkyl, -S(=O)2N(Ci-C3alkyl)2, -NH2, -NHCi-C3alkyl, -N(Ci-C3alkyl)2, - NHC(=O)OCi-C3alkyl, -C(=O)Ci-C3alkyl, -C(=O)OH, -C(=O)OCi-C3alkyl, -C(=O)NH2, - C(=O)N(Ci-C3alkyl)2, -C(=O)NHCi-C3alkyl, Ci-C3alkyl, Ci-C3heteroalkyl, Ci-C6cycloalkyl, or 3- to 6- membered heterocycloalkyl; wherein each alkyl is independently optionally substituted with one or more halogen;and / or two R” on the same atom are taken together to form an oxo.2 The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R5and R6are independently hydrogen.3 The compound of claim 1 or 2, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring A is aryl or heteroaryl.4 The compound of any one of claims 1-3, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring A is phenyl.5 The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:L1is -O-, -C(=O)NR9-*, -S(=O)2NR9-*, -NR9S(=O)2-*, or -NR9C(=O)-*, wherein * represent the attachment point to R8.6 The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:L1is -S(=O)2NR9-* or -NR9S(=O)2-*, wherein * represent the attachment point to R8.7 The compound of any one of claims 1-6, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R9is hydrogen.Attorney Docket No. 57547-738.601The compound of any one of claims 1-7, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:X1is CR1.

10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:X2is CR2.

11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:X3is CR3.

12. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R3is hydrogen.

13. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:X4is CR4.

14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R4is hydrogen.

15. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R12is -OH, Ci-Cealkyl, Ci-Cedeuteroalkyl, or C2-Cealkynyl.

16. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R12is Ci-C6alkyl.

17. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is of Formula (la):Attorney Docket No. 57547-738.601Formula (la).

18. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:L2is -OC(=O)-*, -CH2C(=O)-*, or -NR13C(=O)-*; wherein * represent the attachment point to Ring C.

19. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:L2is -OC(=O)-* or -CH2C(=O)-*; wherein * represent the attachment point to Ring C.

20. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring C is phenyl.

21. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is of Formula (lb):

22. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is of Formula (Ic):

23. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R1is hydrogen or Ci-Cealkyl.

24. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Attorney Docket No. 57547-738.601R1is Ci-Cealkyl.

25. The compound of any one of claims 1-24, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R2is hydrogen or halogen.

26. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R2is hydrogen.

27. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:R2is halogen.

28. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:each R7is halogen, -CN, -OH, -ORa, or Ci-Cealkyl.

29. The compound of any one of claims 1-28, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:each R7is halogen.

30. The compound of any one of claims 1-29, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:p is 0 or 1.

31. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:each R14is independently halogen, -ORa, or Ci-Cealkyl.

32. The compound of any one of claims 1-31, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:each R14is independently -ORa.

33. The compound of any one of claims 1-32, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:m is 0 or 1.

34. The compound of any one of claims 1-33, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:m is 1.

35. The compound of any one of claims 1-34, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring B is cycloalkyl or heterocycloalkyl.

36. The compound of any one of claims 1-34, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring B is aryl or heteroaryl.Attorney Docket No. 57547-738.60137. The compound of any one of claims 1-34, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring B is heteroaryl.

38. The compound of any one of claims 1-34, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring B is 5- to 6-membered heteroaryl comprising one, two, or three heteroatoms selected from the group selected from O, S, and N.

39. The compound of any one of claims 1-34, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring B is 6-membered heteroaryl comprising one or two heteroatoms that are N.

40. The compound of any one of claims 1-34, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring B is pyridinyl, pyrimidinyl, or pyrazinyl.

41. The compound of any one of claims 1-34, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring B is pyridinyl.

42. The compound of any one of claims 1-34, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring B is 5-membered heteroaryl comprising one, two, or three heteroatoms selected from the group selected from O, S, and N.

43. The compound of any one of claims 1-34, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring B is thiophenyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, isothiazolyl, isoxazolyl, pyrazolyl, thiadiazolyl, oxadiazolyl, or triazolyl.

44. The compound of any one of claims 1-34, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring B is thiazolyl, oxazolyl, imidazolyl, isothiazolyl, isoxazolyl, pyrazolyl, thiadiazolyl, or oxadiazolyl.

45. The compound of any one of claims 1-44, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:each R11is independently halogen, -CN, -OH, -ORa, -NRbRc, or Ci-Cealkyl.

46. The compound of any one of claims 1-45, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:each R11is independently Ci-Cealkyl.

47. The compound of any one of claims 1-46, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:n is 0, 1, or 2.Attorney Docket No. 57547-738.60148. The compound of any one of claims 1-46, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:n is 0 or 1.

49. The compound of any one of claims 1-34, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Attorney Docket No. 57547-738.60150. The compound of any one of claims 1-49, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:each L3is independently -O-, -NR15-, -C(=O)-, Ci-Cioalkylene, Ci-Cioheteroalkylene, cycloalkylene, heterocycloalkylene, or arylene; wherein each alkylene and heteroalkylene is independently optionally substituted with one or more R’ and wherein each cycloalkylene, heterocycloalkylene, and arylene is independently optionally substituted with one or more R” 51. The compound of any one of claims 1-50, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:each L3is independently -O-, -NR15-, -C(=O)-, C1-C10alkylene, C1-C10heteroalkylene, cycloalkylene, heterocycloalkylene, or arylene.

52. The compound of any one of claims 1-51, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:each L3is independently -O-, -NR15-, -C(=O)-, Ci-Cealkylene, Ci-Ceheteroalkylene, C3- Ciocycloalkylene, 3- to 10-membered heterocycloalkylene comprising one, two, or three heteroatoms selected from the group consisting of N, O, and S, or phenyl.

53. The compound of any one of claims 1-52, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:each L3is independently -O-, -NR15-, Ci-Cealkylene, or 3- to 10-membered heterocycloalkylene comprising one, two, or three heteroatoms selected from the group consisting of N, O, and S.Attorney Docket No. 57547-738.60154. The compound of any one of claims 1-53, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:each L3is independently -O- or 3- to 10-membered heterocycloalkylene comprising one, two, or three heteroatoms selected from the group consisting of N, O, and S.

55. The compound of any one of claims 1-50, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:each L3is independently heterocycloalkylene; oreach L3is independently -O- or Ci-Cioalkylene; oreach L3is independently -O- or Ci-Cioheteroalkylene; oreach L3is independently -O- or cycloalkylene; oreach L3is independently -O- or heterocycloalkylene; oreach L3is independently -NR15- or Ci-Cioalkylene; oreach L3is independently -NR15- or Ci-Cioheteroalkylene; oreach L3is independently -NR15- or cycloalkylene; oreach L3is independently -NR15- or heterocycloalkylene; oreach L3is independently -O-, -NR15-, or Ci-Cioalkylene; oreach L3is independently -O-, -NR15-, or Ci-Cioheteroalkylene; oreach L3is independently -O-, -NR15-, or cycloalkylene; oreach L3is independently -O-, -NR15-, or heterocycloalkylene; oreach L3is independently -O-, Ci-Cioalkylene, or cycloalkylene; oreach L3is independently -O-, Ci-Cioalkylene, or heterocycloalkylene; oreach L3is independently -O-, Ci-Cioalkylene, heterocycloalkylene, or arylene.

56. The compound of any one of claims 1-50, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:each L3is independently heterocycloalkylene; oreach L3is independently -O- or Ci-C4alkylene; oreach L3is independently -O- or Ci-Ceheteroalkylene; oreach L3is independently -O- or cycloalkylene; oreach L3is independently -O- or heterocycloalkylene; oreach L3is independently -NR15- or Ci-C4alkylene; oreach L3is independently -NR15- or Ci-Ceheteroalkylene; oreach L3is independently -NR15- or cycloalkylene; oreach L3is independently -NR15- or heterocycloalkylene; oreach L3is independently -O-, -NR15-, or Ci-C4alkylene; oreach L3is independently -O-, -NR15-, or Ci-C4heteroalkylene; oreach L3is independently -O-, -NR15-, or cycloalkylene; oreach L3is independently -O-, -NR15-, or heterocycloalkylene; orAttorney Docket No. 57547-738.601each L3is independently -O-, Ci-C4alkylene, or cycloalkylene; oreach L3is independently -O-, Ci-C4alkylene, or heterocycloalkylene; oreach L3is independently -O-, Ci-C4alkylene, heterocycloalkylene, or arylene.

57. The compound of any one of claims 1-56, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:each R15is independently hydrogen or Ci-Cealkyl.

58. The compound of any one of claims 1-57, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:each R15is independently hydrogen.

59. The compound of any one of claims 1-58, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:s is 1, 2, 3, 4, 5, or 6.

60. The compound of any one of claims 1-59, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:s is 1, 2, 3, or 4.

61. The compound of any one of claims 1-60, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:s is 1, 2, or 3.

62. The compound of any one of claims 1-50, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Attorney Docket No. 57547-738.60163. The compound of any one of claims 1-62, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:I — M’ is a cereblon E3 ligase, a VHL E3 ligase, a MDM2 ligase, a TRIM24 ligase, a TRIM21 ligase, a KEAPl ligase, or an IAP ligase.

64. The compound of any one of claims 1-63, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:| — M* is a cereblon E3 ligase.

65. The compound of any one of claims 1-64, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:(R16)tII - (D J— w — Y / ^>=Oj-M kNH’is ° Formula (A);wherein:Y is CH, C[CH3], or N;W is absent, -O-, -NRb-, or -C(=O)NRb-;Ring D is absent, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;each R16is independently halogen, -CN, -OH, -ORa, -NRbRc, Ci-Cealkyl, -L-cycloalkyl, -L- heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl is independently optionallyAttorney Docket No. 57547-738.601substituted with one or more R’ and wherein each cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R”;and / or two R10on the same atom are taken together to form an oxo; andt is 0, 1, 2, 3, 4, 5, or 6.

66. The compound of claim 65, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Y is CH.

67. The compound of claim 65, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Y is N.

68. The compound of any one of claims 65-67, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:W is absent.

69. The compound of any one of claims 65-68, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:W is -O-.

70. The compound of any one of claims 65-68, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:W is -NRb-.

71. The compound of any one of claims 65-68, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:W is -C(=O)NRb-.

72. The compound of any one of claims 65-71, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring D is heterocycloalkyl.

73. The compound of any one of claims 65-71, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring D is aryl or heteroaryl.

74. The compound of any one of claims 65-71, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ring D is phenyl.

75. The compound of any one of claims 65-74, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:each R16is independently halogen, -CN, -OH, -ORa, -NRbRc, Ci-Cealkyl, -L-cycloalkyl, or -L- heterocycloalkyl; wherein each alkyl is independently optionally substituted with one or more R’ and wherein each cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more R”; and / or two R16on the same atom are taken together to form an oxo.Attorney Docket No. 57547-738.60176. The compound of any one of claims 65-75, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:each R16is independently halogen, -ORa, or Ci-Cealkyl; and / or two R16on the same atom are taken together to form an oxo.

77. The compound of any one of claims 65-76, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:t is 0, 1, or 2.

78. The compound of any one of claims 65-76, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:t is 2, 3, or 4.

79. The compound of any one of claims 1-78, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Attorney Docket No. 57547-738.60180. The compound of any one of claims 1-78, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:

81. A compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, selected from a compound found in table 1.

82. A pharmaceutical composition comprising a compound of any one of claims 1-81, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

83. A method of treating cancer in a subject, comprising administering to the subject a compound of any one of claims 1-81, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition of claim 82.

84. A method of inhibiting KIF22 in a subject, comprising administering to the subject a compound of any one of claims 1-81, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition of claim 82.

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