KIF22 inhibitors and uses thereof

Abstract

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

Description

Attorney Docket No. 57547-742.601KIF22 INHIBITORS AND USES THEREOFCROSS-REFERENCE

[0001] This application claims the benefit of U. S. Provisional Application Serial No. 63 / 761,446 filed February 21, 2025 which is hereby incorporated by reference in its 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 (CDKl)-mediated phosphorylation. Phosphorylation of KIF22 at Thr463 reduces the affinity of KIF22for 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 inhibitors that are useful in treating cancer.

[0005] Disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:Formula (I) as defined 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. 57547-742.601

[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. 57547-742.601limited 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 aCi-Cio alkyl. 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 aCi-C4 alkyl. 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. 57547-742.601may 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. 57547-742.601saturated. 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, bicyclofl. l. l]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] “Hydroxyalkyl” 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. 57547-742.601with 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] “Heteroalky 1” 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] “HeterocycloaJkyl” 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),Attorney Docket No. 57547-742.601spiro, or bridged ring systems; and the nitrogen, 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[l,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-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-l-yl, 3-oxo-l,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 disaccharides, 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. 57547-742.601

[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. 57547-742.601and 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. 57547-742.601Compounds

[0037] Described herein are KIF22 inhibitors 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, -NO2, -OH, -ORa, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci-C6aminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;X2is N or CR2;R2is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, Ci-Cehydroxyalkyl, Ci-C6aminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;X3is N or CR3;R3is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci-C6aminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;X4is N or CR4;R4is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, Ci-Cehydroxyalkyl, Ci-C6aminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;Z is absent or -CH2-;Attomey Docket No. 57547-742.601W is absent or -CH2-;R5and R6are independently hydrogen, halogen, Ci-Cealkyl, or Ci-Cehaloalkyl;Y1is N or CR7;R7is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;Y2is N or CR8;R8is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl. C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;L1is -O-, -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 Ring A;R9is hydrogen or Ci-Cealkyl independently optionally substituted with one or more R;each R10is independently hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, or Ci-Cehaloalkyl; Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;each R11is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L- aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;or two R11are taken together to form an oxo;n is 0, 1, 2, 3, or 4;R12is hydrogen, halogen, -OH, -ORa, -NRcRd, Ci-Cealkyl, or Ci-Cehaloalkyl;L2is -O-, -CH2-, or -NR13-;U is O or NR14;L3is absent or -NR13-;R13is hydrogen or Ci-Cealkyl;R14is hydrogen, -CN, or -OH;Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;each R15is independently halogen, -L-CN, -NO2, -L-OH, -L-ORa, -L-OC(=O)Ra, -L-OC(=O)ORb, -L- OC(=O)NRcRd, -SH, -SRa, -L-S(=O)Ra, -L-S(=O)2Ra, -L-S(=O)2NRcRd, -L-NRcRd, -L-NRbC(=O)NRcRd, -L-NRbC(=O)Ra, -L-NRbC(=O)ORb, -L-NRbS(=O)2Ra, -L-C(=O)Ra, -L-C(=O)ORb, -L-C(=O)NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxy alkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Attorney Docket No. 57547-742.601Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;or two R15are taken together to form an oxo;m is 0, 1, 2, 3, or 4;each Rais independently Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxy alkyl, Ci-Ceaminoalkyl,Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L- heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;each Rbis independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxy alkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L- heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;each Rcand Rdare independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl,Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L- aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;or Rcand Rdare 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, -C(=O)NHCi-C3alkyl, Ci-C3alkyl, Ci-C3haloalkyl, Ci-C3hydroxyalkyl, Ci-Csaminoalkyl, Ci-Csheteroalkyl, Ci-Cecycloalkyl, or 3- to 6-membered heterocycloalkyl;or two R on the same atom are taken together to form an oxo.

[0039] In some embodiments of a compound of Formula (I), Z is absent. In some embodiments of a compound of Formula (I), Z is -CH2-.

[0040] In some embodiments of a compound of Formula (I), W is absent. In some embodiments of a compound of Formula (I), W is -CH2-.

[0041] In some embodiments, the compound of Formula (I) is of Formula (la), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:Attorney Docket No. 57547-742.601

[0042] In some embodiments, the compound of Formula (I) is of Formula (lb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:Formula (lb).

[0043] In some embodiments, the compound of Formula (I) is of Formula (Ic), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:

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

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

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

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

[0048] In some embodiments of a compound of Formula (I) or (la)-(Ic), Y1is N. In some embodiments of a compound of Formula (I) or (la)-(Ic), Y1is CR7.Attorney Docket No. 57547-742.601

[0049] In some embodiments of a compound of Formula (I) or (la)-(Ic), Y2is N. In some embodiments of a compound of Formula (I) or (la)-(Ic), Y2is CR8.

[0050] In some embodiments of a compound of Formula (I) or (la)-(Ic), R5and R6are independently hydrogen or Ci-Cealkyl. In some embodiments of a compound of Formula (I) or (la)-(Ic), R5and R6are hydrogen. In some embodiments of a compound of Formula (I) or (la)-(Ic), R5is hydrogen and R6is Ci-C6alkyl.

[0051] In some embodiments of a compound of Formula (I) or (la)-(Ic), U is O. In some embodiments of a compound of Formula (I) or (la)-(Ic), U is NR14. In some embodiments of a compound of Formula (I) or (la)-(Ic), U is N-OH.

[0052] In some embodiments, the compound of Formula (I) or (la) is of Formula (la- 1), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:R7R8Formula (la-1).

[0053] In some embodiments, the compound of Formula (I) or (lb) is of Formula (Ib-1), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:R7R8Formula (Ib-1).

[0054] In some embodiments, the compound of Formula (I) or (Ic) is of Formula (Ic-1), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:R7R8Formula (Ic-1).Attorney Docket No. 57547-742.601

[0055] In some embodiments of acompound of Formula (I), (Ia)-(Ic), or (la-l)-(Ic-l), L1is -C(=O)NR9-* or -NR9C(=O)-*

[0056] In some embodiments of acompound of Formula (I), (Ia)-(Ic), or (la-l)-(Ic-l), L1is -C(=O)NR9-*.

[0057] In some embodiments of acompound of Formula (I), (Ia)-(Ic), or (la-l)-(Ic-l), L1is -NR9C(=O)-*.

[0058] In some embodiments of acompound of Formula (I), (Ia)-(Ic), or (la-l)-(Ic-l), L1is -S(=O)2NR9-* or -NR9S(=O)2-*

[0059] In some embodiments of a compound of Formula (I), (Ia)-(Ic), or (la-l)-(Ic-l), L1is -S(=O)2NR9-*.

[0060] In some embodiments of a compound of Formula (I), (Ia)-(Ic), or (la-l)-(Ic-l), L1is -NR9S(=O)2-*.

[0061] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), L1is -C(=O)NR9S(=O)2-* or -S(=O)2NR9C(=O)-*.

[0062] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), L1is -C(=O)NR9S(=O)2-*.

[0063] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), L1is -S(=O)2NR9C(=O)-*.

[0064] In some embodiments of a compound of Formula (I), (Ia)-(Ic), or (la-l)-(Ic-l), L1-O-C(R10)2-* or -C(R10)2-O-*

[0065] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), L1-O-C(R10)2-*.

[0066] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), L1-C(R10)2-O-*.

[0067] In some embodiments of acompound of Formula (I), (Ia)-(Ic), or (la-l)-(Ic-l), L1-NR9-C(R10)2-* or -C(R10)2-NR9-*.

[0068] In some embodiments of acompound of Formula (I), (Ia)-(Ic), or (la-l)-(Ic-l), L1-NR9-C(R10)2-*

[0069] In some embodiments of acompound of Formula (I), (Ia)-(Ic), or (la-l)-(Ic-l), L1-C(R10)2-NR9-*

[0070] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), rein L1-S(=O)2C(R10)2-* or -C(R10)2S(=O)2-*.

[0071] In some embodiments of a compound of Formula (I), (Ia)-(Ic), or (la-l)-(Ic-l), L1-S(=O)2C(R10)2-*

[0072] In some embodiments of a compound of Formula (I), (Ia)-(Ic), or (la-l)-(Ic-l), L1-C(R10)2S(=O)2-*

[0073] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), L1is -C(R10)2-.

[0074] In some embodiments of acompound of Formula (I), (Ia)-(Ic), or (la-l)-(Ic-l), R9is hydrogen. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), R9is Ci-Cealkyl.

[0075] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), each R10is independently hydrogen or Ci-Cealkyl. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), each R10is independently hydrogen.Attorney Docket No. 57547-742.601

[0076] In some embodiments of a compound of Formula (I), (Ia)-(Ic), or (la-l)-(Ic-l), L2is -O-. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), L2is -CH2-. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), L2is -NR13-.

[0077] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), L3is absent. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), L3is -NR13-.

[0078] In some embodiments of a compound of Formula (la-l)-(Ic-l),NR13, or. In some embodiments of a compound of Formula (la-l)-(Ic-l),,0is

[0079] In some embodiments of a compound of Formula (I), (Ia)-(Ic), or (la-l)-(Ic-l), R13is hydrogen. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), R13is Ci-Cealkyl.

[0080] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), R1is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), R1is hydrogen, halogen, -CN, -ORa, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, or cycloalkyl. In some embodiments of acompound of Formula(I), (la)-(Ic), or (la-l)-(Ic-l), R1is hydrogen, halogen, or Ci-Cealkyl. In some embodiments of acompound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), R1is hydrogen. In some embodiments of acompound of Formula (I), (Ia)-(Ic), or (la-l)-(Ic-l), R1is halogen. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), R1is Ci-Cealkyl.

[0081] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), R2is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, or Ci-Cehaloalkyl. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), R2is hydrogen, halogen, or Ci-Cealkyl. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), R2is hydrogen. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), R2is halogen.

[0082] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), R3is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, or Ci-Cehaloalkyl. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), R3is hydrogen, halogen, or Ci-Cealkyl. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), R3is Ci-Cealkyl. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), R3is hydrogen.

[0083] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), R4is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, or Ci-Cehaloalkyl. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), R4is hydrogen, halogen, or Ci-Cealkyl. In some embodiments of aAttorney Docket No. 57547-742.601compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), R4is Ci-Cealkyl. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), R4is hydrogen.

[0084] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), R7is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, or Ci-Cehaloalkyl. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), R7is hydrogen, halogen, Ci-Cealkyl, or Ci-Cehaloalkyl. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), R7is hydrogen.

[0085] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), R8is hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, or Ci-Cehaloalkyl. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), R8is hydrogen, halogen, -ORa, -NRcRd, or Ci-Cealkyl. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), R8is hydrogen, halogen, -ORa, or -NRcRd. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), R8is halogen. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), R8is -ORa. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), R8is -NRcRd. The compound of any one of claims 1-50, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R8is hydrogen.

[0086] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), R12is hydrogen, -OH, or Ci-Cealkyl. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), R12is hydrogen. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), R12is -OH. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), R11is Ci-Cealkyl.

[0087] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), Ring B is aryl or heteroaryl.

[0088] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), Ring B is aryl.

[0089] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), Ring B is phenyl.

[0090] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), Ring B is heteroaryl.

[0091] In some embodiments of acompound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), Ring B is 5- or 6-membered heteroaryl comprising one, two, or three heteroatoms selected from the group consisting of N, O, and S.

[0092] In some embodiments of acompound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), Ring B is 5- or 6-membered heteroaryl comprising one, two, or three heteroatoms selected from the group consisting of N and O.

[0093] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), Ring B is 6-membered heteroaryl comprising one, two, or three heteroatoms that are N.

[0094] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), Ring B is 6-membered heteroaryl comprising one or two that are N.

[0095] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), Ring B is 6-membered heteroaryl comprising one that is N.Attorney Docket No. 57547-742.601

[0096] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), each R15is independently halogen, -L-CN, -L-OH, -L-ORa, -L-NRcRd, -L-NRbC(=O)NRcRd, -L-NRbC(=O)Ra, -L-NRbC(=O)ORb, -L-NRbS(=O)2Ra, -L-C(=O)Ra, -L-C(=O)ORb, -L-C(=O)NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R.

[0097] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), each R15is independently halogen, -L-CN, -L-OH, -L-ORa, -L-NRcRd, -L-NRbC(=O)Ra, -L-NRbS(=O)2Ra, -L-C(=O)Ra, -L-C(=O)ORb, -L-C(=O)NRcRd, Ci-C6alkyl, or Ci-C6haloalkyl.

[0098] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), each R15is independently halogen, -L-OH, -L-ORa, Ci-Cealkyl, or Ci-Cehaloalkyl.

[0099] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), each R15is independently halogen, -OH, -ORa, or Ci-Cealkyl.

[0100] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), each R15is independently -ORa.

[0101] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), each R15is independently -OCH3.

[0102] In some embodiments of acompound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), m is 0, 1, or 2. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), m is 1 or 2. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), m is 1. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), m is 2.

[0103] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), Ring A is heteroaryl.

[0104] In some embodiments of acompound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), Ring A is 5- to 6-membered heteroaryl comprising one, two, or three heteroatoms selected from the group consisting of N, O, and S.

[0105] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), Ring A is 5-membered heteroaryl comprising one, two, or three heteroatoms selected from the group consisting of N, O, and S.

[0106] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), Ring A is 6-membered heteroaryl comprising one, two, or three heteroatoms that are N.

[0107] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), Ring A is 6-membered heteroaryl comprising one or two heteroatoms that are N.

[0108] In some embodiments of acompound of Formula (I), (Ia)-(Ic), or (la-l)-(Ic-l), Ring A is pyridinyl or pyrimidinyl.

[0109] In some embodiments of a compound of Formula (I), (Ia)-(Ic), or (la-l)-(Ic-l), Ring A is pyridinyl.Attorney Docket No. 57547-742.601

[0110] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), each R11is independently halogen, -CN, -NO2, -OH, -ORa, -NRcRd, -NRbC(=O)Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R.

[0111] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), each R11is independently halogen, -CN, -NO2, -OH, -ORa, -NRcRd, -NRbC(=O)Ra, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceheteroalkyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R.

[0112] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), each R11is independently halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, or Ci-Ceheteroalkyl; wherein each alkyl and heteroalkyl is independently optionally substituted with one or more R.

[0113] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), each R11is independently halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, or Ci-Ceheteroalkyl.

[0114] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), each R11is independently halogen, Ci-Cealkyl, or Ci-Cehaloalkyl.

[0115] In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), n is 0, 1, or 2. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), n is 1 or 2. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), n is 1. In some embodiments of a compound of Formula (I), (la)-(Ic), or (la-l)-(Ic-l), n is 2.

[0116] In some embodiments of a compound disclosed herein, each Rais independently Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein each alkyl, heteroalkyl, 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, Ci-Cehaloalkyl, Ci-Cehydroxy alkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl; wherein each alkyl and heteroalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rais independently Ci-Cealkyl, Ci-Cehaloalkyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein each alkyl, 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, Ci-Cehaloalkyl, Ci-Cehy dr oxy alkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl. In some embodiments of a compound disclosed herein, each Rais independently Ci-Cealkyl or Ci-Cehaloalkyl. In some embodiments of a compound disclosed herein, each Rais independently Ci-Cealkyl. In some embodiments of a compound disclosed herein, each Rais independently Ci-Cehaloalkyl.Attorney Docket No. 57547-742.601

[0117] In some embodiments of a compound disclosed herein, each Rbis independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein each alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rbis independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl,Ci-Ceheteroalkyl; wherein each alkyl and heteroalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rbis independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rbis independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl,Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl. In some embodiments of a compound disclosed herein, each Rbis independently hydrogen, Ci-Cealkyl, or Ci-Cehaloalkyl. In some embodiments of a compound disclosed herein, each Rbis independently hydrogen or Ci-Cealkyl. In some embodiments of a compound disclosed herein, each Rbis independently hydrogen or Ci-Cehaloalkyl. In some embodiments of a compound disclosed herein, each Rbis hydrogen. In some embodiments of a compound disclosed herein, each Rbis independently Ci-Cehaloalkyl. In some embodiments of a compound disclosed herein, each Rbis independently Ci-Cealkyl.

[0118] In some embodiments of a compound disclosed herein, each Rcand Rdare independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein each alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rcand Rdare independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxy alkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl; wherein each alkyl and heteroalkyl is independently optionally substituted with one or more R. In some embodiments of a compound disclosed herein, each Rcand Rdare independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, -L-cycloalkyl, or -L-heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R.

[0119] In some embodiments of a compound disclosed herein, each Rcand Rdare independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxy alkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl. In some embodiments of a compound disclosed herein, each Rcand Rdare independently hydrogen, Ci-Cealkyl, or Ci-Cehaloalkyl. In some embodiments of a compound disclosed herein, each Rcand Rdare independently hydrogen or Ci-Cealkyl. In some embodiments of a compound disclosed herein, each Rcand Rdare independently hydrogen or Ci-Cehaloalkyl. In some embodiments of a compound disclosed herein, each Rcand Rdare hydrogen. In some embodiments of a compound disclosed herein, each Rcand Rdare independently Ci-Cehaloalkyl. In some embodiments of a compound disclosed herein, each Rcand Rdare independently Ci-Cealkyl.Attorney Docket No. 57547-742.601

[0120] In some embodiments of a compound disclosed herein, Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl independently optionally substituted with one or more R.

[0121] In some embodiments of a compound disclosed herein, L is absent. In some embodiments of a compound disclosed herein, L is C1-C6alkylene 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 C3alkylene 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 -CH2-. In some embodiments of a compound disclosed herein, L is -CH2CH2-. In some embodiments of a compound disclosed herein, L is -CH2CH2CH2-.

[0122] In some embodiments of a compound disclosed herein, each R is independently halogen, -CN, -OH, -OCi-C3alkyl, -NH2, -NHC1-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-C3haloalkyl, Ci-C3hydroxyalkyl, Ci-C3aminoalkyl, Ci-C3heteroalkyl, C1-C6cycloalkyl, or 3- to 6-membered heterocycloalkyl; 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, -OC1-C3alkyl, -NH2, -NHC1-C3alkyl, -N(C1-C3alkyl)2, C1-C3alkyl, C1-C3haloalkyl, C1-C3hydroxyalkyl, C1-C3aminoalkyl, C1-C3heteroalkyl, C1-C6cycloalkyl, or 3- to 6-membered heterocycloalkyl; 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, -OC1-C3alkyl, -NH2, C1-C3alkyl, C1-C3haloalkyl, C1-C6cycloalkyl, or 3- to 6-membered heterocycloalkyl; 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, -OC1-C3alkyl, -NH2, C1-C3alkyl, or C1-C3haloalkyl; 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, Ci-C3alkyl, orCi-C3haloalkyl; 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, Ci-C3alkyl, or Ci-C3haloalkyl. In some embodiments of a compound disclosed herein, each R is independently halogen or Ci-C3alkyl. In some embodiments of a compound disclosed herein, each R is independently halogen.

[0123] In some embodiments of a compound disclosed herein, the compound is selected from a compound of Table 1:TABLE 1Ex. Structure Name3-(2-(3,4-dimethoxyphenyl)-2- oxoethyl)-3-hydroxy-l-(4-(((2- 1 N-. \ \, methylpyrimidin-5-N=Z0O yl)oxy)methyl)benzyl)indolin-2-oneAttorney Docket No. 57547-742.601Ex. Structure Name3-(2-(3,4-dimethoxyphenyl)-2- oxoethyl)-3-hydroxy-l-(4-((2- 2methylpyrimi din-5 - yl)methoxy)benzyl)indolin-2-one [0J1 °h9 3-(2-(3,4-dimethoxyphenyl)-2- oxoethyl)-3-hydroxy-l-(4-((6- 3 P yIZOIZOx zCx / w methylpyridin-3- C w VAOZyl)methoxy)benzyl)indolin-2-one 3-(2-(3,4-dimethoxyphenyl)-2- oxoethyl)-3-hydroxy-l-(4-((2- 4c methylpyridin-4- 0 yl)methoxy)benzyl)indolin-2-one pA o° ro p 1 X 1 X 3-(2-(3,4-dimethoxyphenyl)-2- 0O 0°;5 oxoethyl)-3-hydroxy-l-(4-((2- 5methylpyrimidin-4- o Vd o o o Vo yl)methoxy)benzyl)indolin-2-one 00 O 1 oO TO / - 3-(2-(3,4-dimethoxyphenyl)-2- O O / - Q OH oxoethyl)-3-hydroxy-l-(4-(((6- 6 10H\ \ ° ° methylpyridin-3- \ 'N^v z^L, z \N0 / / X X / / I \ \ I ° ° V y0d0, 0o,o^J o ° V yl)methyl)amino)benzyl)indolin-2- one3-(2-(3,4-dimethoxyphenyl)-2- oxoethyl)-3-hydroxy-l-(4-(((2- 7 methylpyrimidin-5- 00 0 yl)methyl)amino)benzyl)indolin-2- o o IZone4-((3-(2-(3,4-dimethoxyphenyl)-2- )T U o Q\PHHoxoethyl)-3-hydroxy-2-oxoindolin-l- 8 y r 3 zS-^VN 'H Y 10 A-V 0 A Y II A 1 y l)methy 1) -N- (3 -methy li sothi azol -4- ° yl)benzenesulfonamide4-((3-(2-(3,4-dimethoxyphenyl)-2- oxoethyl)-3-hydroxy-2-oxoindolin-l- 9yl)methyl)-N-( 1 -methyl- IH-imidazol- 2-yl)benzenesulfonamide 4-((3-(2-(3,4-dimethoxyphenyl)-2- oxoethyl)-3-hydroxy-2-oxoindolin-l- 10yl)methyl)-N-(pyridin-4- yl)benzenesulfonamide 'N=l <\, P o 4-((3-(2-(3,4-dimethoxyphenyl)-2- 's' OH VL / = / oxoethyl)-3-hydroxy-2-oxoindolin-l- 11nHr ii00^^Nr y~ / \\ \0 0 yl)methyl)-N-(isothiazol-4- 0 yl)benzenesulfonamide4-((3-(2-(3,4-dimethoxyphenyl)-2- °<-Q° 00 Ooxoethyl)-3-hydroxy-2-oxoindolin-l- 12 f >- NH p p I WA Jyl)methyl)-N-(thiazol-2- y OH (3o yl)benzenesulfonamide Hrx-N^p / ^\ \ 4-((3-(2-(4-fluoro-3-methoxyphenyl)- N J V^x, \ # 0,o 2-oxoethyl)-3-hydroxy-2-oxoindolin- 130O H0 t 1 -yl)methyl)-N-(pyridin-4- yl)benzenesulfonamide0Attorney Docket No. 57547-742.601Ex. Structure NameH„ 4-((3-(2-(3-fluoro-4-methoxyphenyl)- k\ / / °w / =\ 2-oxoethyl)-3-hydroxy-2-oxoindolin- 14 GN / n MkHkv( 1 -yl)methyl)-N-(pyridin-3- Zx^ \\ F0 yl)benzenesulfonamide / / _p '-° o o (T 7 q p^ 4-((3-(2-(3,4-dimethoxyphenyl)-2- L Jk 's' M °H oxoethyl)-3-hydroxy-2-oxoindolin-l- 15IZ ZZOOx / / k.iCZco ' cn / v T \ y_ / A\ kH I wxkk'0yl)methyl)-N-(2-methylpyridin-4- o yl)benzenesulfonamide4-((3-(2-(3,4-dimethoxyphenyl)-2- oxoethyl)-3-hydroxy-2-oxoindolin-l- 16 c c c yl)methyl)-N-(4-methylpyridin-3- pk oro~ po- yl)benzenesulfonamide 1 1 X o X \ ) k Xp°Os 4-((3-(2-(3,4-dimethoxyphenyl)-2- ° A / / ° o / " oxoethyl)-3-hydroxy-2-oxoindolin-l- 17 o / 4 / / n o o / ^. °o yl)methyl)-N-(2-methoxypyridin-3- o o k i o yl)benzenesulfonamide o oPo / ° / ~ok^ 4-((3-(2-(3,4-dimethoxyphenyl)-2- 1 X ok X 1 ok^ oxoethyl)-3-hydroxy-2-oxoindolin-l- 1 Xk o 1 x 18 k o y^kX^O~k ok o yl)methyl)-N-(isoxazol-4- zVTVO~yl)benzenesulfonamide fl / fir CR°4-((3-(2-(3,4-dimethoxyphenyl)-2- 0- ° ff OHOs 4s^rkk i / kJk oxoethyl)-3-hydroxy-2-oxoindolin-l- 3 19 k ^NH V k / N" / J 3 yl)methyl)-N-(4-methylthiazol-5-OJ Nk 0 ZT o' ZWz T o' yl)benzenesulfonamide zi oz' ZT OZo1o 5-((3-(2-(3,4-dimethoxyphenyl)-2- / ki osP {[ 7 q \Z46 oA ■ iLJk *sC ^ oxoethyl)-3-hydroxy-2-oxoindolin-l- I 20 r n I y_ Z A\ k / yl)methyl)-N-(pyridin-3-yl)pyridine-HV^o2-sulfonamide o4-((3-(2-(3,4-dimethoxyphenyl)-2- oxoethyl)-3-hydroxy-2-oxoindolin-l- 21yl)methyl)-N-(2-hydroxypyridin-4- yl)benzenesulfonamide 4-((3-(2-(3,4-dimethoxyphenyl)-2- oxoethyl)-3-hydroxy-2-oxoindolin-l- 22 yl)methyl)-N-(l-methyl-2-oxo-l,2- dihydropyridin-4- yl)benzenesulfonamide 4-((3-(2-(3,4-dimethoxyphenyl)-2- N^k] OxP!j 7 0 o^k Jk 's4 \=k OH \\ / == / oxoethyl)-3-hydroxy-2-oxoindolin-l- 23 N v il f \k / 4 \yl)methyl)-N-(3-methylpyridin-4-Hkk'Oyl)benzenesulfonamide o4-((3-(2-(3,4-dimethoxyphenyl)-2- oxoethyl)-3-hydroxy-2-oxoindolin-l- 24yl)methyl)-N-(2-methoxypyridin-4- yl)benzenesulfonamide 4-((3-(2-(3,4-dimethoxyphenyl)-2- oxoethyl)-3-hydroxy-2-oxoindolin-l- 25yl)methyl)-N-(2-methylpyridin-3- yl)benzenesulfonamideAttorney Docket No. 57547-742.601Ex. Structure Name4-((3-(2-(3,4-dimethoxyphenyl)-2- oxoethyl)-3-hydroxy-2-oxoindolin-l- 26yl)methyl)-N-(6-methylpyridin-3- yl)benzenesulfonamide 4-((3-(2-(3,4-dimethoxyphenyl)-2- p oxoethyl)-3-hydroxy-2-oxoindolin-l- 27 AIZOx zXKX' X c / TT yl)methyl)-N-( 1 -methyl- IH-pyrazol- 5-yl)benzenesulfonamide 4-((3-(2-(3,4-dimethoxyphenyl)-2- oxoethyl)-3-hydroxy-2-oxoindolin-l- 28p p yl)methyl)-N-(pyridin-3- ^ OY roO-- 1 \ X z yl)benzenesulfonamide Ox / P PP \ / ° °^^ O 4-((3-(2-(3,4-dimethoxyphenyl)-2- r-N / SX^\ \ss= / fl V oxoethyl)-3-hydroxy-2-oxoindolin-l- 29 C PNHT 1 PPrvV O ok p o — o J o \ / / yl)methyl)-N-(oxazol-2- 0 yl)beo o^\ o o nzenesulfonamide XJ 1oO / \ - / N-(4-((3-(2-(3.4-dimeth 1\ O\* o* oxyphenyl)-2- / X x pO30 / x o 9\zP | i \ / ~ oJ 1 xf OJ° JO°, oxoethyl)-3-hydroxy-2-oxoindolin-l- yl)methyl)phenyl)-2-methylthiazole- N vsf A. JJ L A nxPv o- \\ A N / ===< OH 0 fu 5-sulfonamideAS HP / N-(4-((3-(2-(3,4-dimethoxyphenyl)-2- J oxoethyl)-3-hydroxy-2-oxoindolin-l- J b 31 yn yl)methyl)phenyl)-4- ZT O'. OZIZT o'xocxmethylisothiazole-5-sulfonamide L z- 0 P z N-(4-((3-(2-(3,4-dimethoxyphenyl)-2- j? XJC°" oxoethyl)-3-hydroxy-2-oxoindolin-l-N\Ax '9 n 32 [,s, A J 1 / \ B | yl)methyl)phenyl)-4-methylthiazole- / A' / == / OH 05-sulfonamideHwN-(4-((3-(2-(3,4-dimethoxyphenyl)-2- oxoethyl)-3-hydroxy-2-oxoindolin-l- -0'1 ^'v-' A £X°, 33yl)methyl)phenyl)-3- / kx. JJ 1 _ / \ H / / OH 0methylisothiazole-5-sulfonamideHMN-(4-((3-(2-(3,4-dimethoxyphenyl)-2- oxoethyl)-3-hydroxy-2-oxoindolin-l- 34yl)methyl)phenyl)-N, 1 -dimethyl- 1H- pyrazole-4-sulfonamide N-(4-((3-hydroxy-3-(2-(5- methylpyridin-3-yl)-2-oxoethyl)-2- bpP- N 35 oxoindolin-1-0°XX^rCp^P yl)methyl)phenyl)pyridine-3- o sulfonamideN-(4-((3-hydroxy-2-oxo-3-(2-oxo-2-IO^S-NX^ CbonV / ^Y (pyridin-3-yl)ethyl)indolin-l- 36yl)methyl)phenyl)pyridine-3- °Z'°sulfonamide oAttorney Docket No. 57547-742.601Ex. Structure NameR N-(4-((3-(2-(3,4-dimethoxyphenyl)-2- oxoethyl)-6-fluoro-3-hydroxy-7- 370Ju OH p- "s y ii r,={ methy 1 -2- oxoindolin- 1 - yl)methyl)phenyl) - 1 -methyl- 1 H- A! Jz° Mx o o \ pyr azol e- 5 - sulfonamide ox\zo N-(4-((3-(2-(3 / l-dimethoxyphenyl)-2- O ZE oxoethy 1) -3,7- dimethy 1-2- oxoindolin- 381 -yl)methyl)-2-methoxyphenyl)- 1 - _.Z'X\ / == / °00 B0\, methyl- lH-pyrazole-5-sulfonamide\ Qi OH N-(4-((3-(2-(3,4-dimethoxyphenyl)-2- pA o ro~ oxoethyl)-3-hydroxy-2-oxoindolin-l- 39 N-N H 1o p X 1 X A°\ / / A zN~^ A yl)methyl)phenyl)- 1 -ethyl- 1H- N-76?"o °° °* A 7O^pyr azol e- 5 - sulfonamide O O / o / N-(4-((3-(2-(3,4-dimethoxyphenyl)-2- / O oxoethyl) -3 -hydroxy -2- oxoindolin- 1 - 40 TOO / - Q O / - yl)methyl)phenyl)-2,4- Rb W <w<b o dimethylthiazole-5-sulfonamideHN^Z, 1 XJ. O^ N-(4-((3-(2-(3,4-dimethoxyphenyl)-2- oxoethyl)-3-hydroxy-2-oxoindolin-l- 41 r>oCO V cxrb\ / 0xH< p-0y l)methyl)pheny 1)-N, 3, 5 -trimethyl- 0 OZ i:—V \ lH-pyrazole-4-sulfonamide N-(4-((3-(2-(3,4-dimethoxyphenyl)-2- d oxoethy 1)- 3 -hydroxy -2- oxoindolin- 1- 42yl)methyl)phenyl)- lH-pyrazole-4-xwsulfonamided = °' z N-(4-((3-(2-(3,4-dimethoxyphenyl)-2- oxoethy 1)- 3 -hydroxy -2- oxoindolin- 1- 43yl)methyl)phenyl) - 1 -methyl- 1 H- pyrazole-4-sulfonamide A N-(4-((3-(2-(3,4-dimethoxyphenyl)-2- NA H C / °v / °~~ oxoethy 1)- 3 -hydroxy -2- oxoindolin- 1-N\ \AOH V / A 44yl)methyl)phenyl)-lH-imidazole-4- °^S'b QQ / NQ^ALAOsulfonamide0N-(4-((3-(2-(3,4-dimethoxyphenyl)-2- CNH / TA 1oxoethy 1)- 3 -hydroxy -2- oxoindolin- 1- u rv 45yl)methyl)phenyl)-lH-imidazole-2- °"° XXKnAv OH o sulfonamide0N-(4-((3-(2-(3,4-dimethoxyphenyl)-2- oxoethy 1)- 3 -hydroxy -2- oxoindolin- 1- 46yl)methyl)phenyl) - 1 -methyl- 1 H- pyr azol e- 5 - sulfonamide N-(4-((3-(2-(3,4-dimethoxyphenyl)-2- O / A oxoethy 1)- 3 -hydroxy -2- oxoindolin- 1- 47yl)methyl)phenyl)thiazole-2- oA A L _N° OH o sulfonamide 0Attorney Docket No. 57547-742.601Ex. Structure NameN-(4-((3-(2-(3,4-dimethoxyphenyl)-2- oxoethyl)-3-hydroxy-2-oxoindolin-l- 48o yl)methyl)phenyl)pyridine-3- sulfonamideN-(4-((3-(2-(3,4-dimethoxyphenyl)-2- V) ' QOHV^0- oxoethyl)-3-hydroxy-2-oxoindolin-l- 49 Ntf zzs ';.zr. r ii i y_ / A\ \ yl)methyl)phenyl) - 1 -methyl- 1 H- o o O X zr _X''^N'A / 0 imidazole-2-sulfonamide (R)-N-(4-((3-(2-(3,4- p e, dimethoxy phenyl) -2- oxoethyl) - 3 - QOHV^0'50 N O zs; O r p il W i o= y—< o* X \ <\Z zL hydroxy-2-oxoindolin-l- \ i0 1 'O yl)methyl)phenyl) - 1 -methyl- 1 H- I^<xO°oOj^ A imidazole-2-sulfonamide / I° r N-(4-((3-(2-(3 / l-dimethoxyphenyl)-2- tV O) O o iM ry J O° / < / oxoethyl)-3-hydroxy-2-oxoindolin-l- 51 o yl)methyl)phenyl) - 1 -methyl- 1 H- oO\ ° 'o XV-Oor^o-o / - 'X OHQ ° imidazole-5-sulfonamide o? 0(R)-N-(4-((3-(2-(3,4-\ o* 1 I dimethoxy phenyl) -2- oxoethyl) - 3 - oJ52 hydroxy-2-oxoindolin-l- yl)methyl)phenyl) - 1 -methyl- 1 H- v°imidazole-5-sulfonamide N-(5-((3-(2-(3 / l-dimethoxyphenyl)-2- d ' oxoethyl)-3-hydroxy-2-oxoindolin-l-z z 53yl)methyl)py ri din-2 -y 1)- 1 -methyl- 1 H- imidazole-2-sulfonamide L zN-(4-((3-(2-(3 / l-dimethoxyphenyl)-2- A Ioxoethyl)-3-hydroxy-2-oxoindolin-l-N%. Hvz>Q pr“ 54yl)methyl)-2-fluorophenyl)-l-methyl- AXXQVXVFX OH 6 lH-imidazole-2-sulfonamide 0N-(4-((3-(2-(3 / l-dimethoxyphenyl)-2- oxoethyl)-3-hydroxy-2-oxoindolin-l- 55 yl)methyl)phenyl)-2-oxo-2,3- dihy drobenzo| d | oxazole-6- sulfonamideN-(4-((3-(2-(3 / l-dimethoxyphenyl)-2- □4-& / =\ oxoethyl)-3-hydroxy-2-oxoindolin-l- 56 yl)methyl)phenyl) - 1 -methyl- 1 H-z■ '« Q MPH<L Z -°^N^N' Xzpyrazolo[3,4-b]pyridine-3- \ n < Xosulfonamide 0N— (7i N-(4-((3-(2-(3 / l-dimethoxyphenyl)-2- / / \=X Hoxoethyl)-3-hydroxy-2-oxoindolin-l- W srNv-\ ° 'o rj yxOHo / .o^. 57 yl)methyl)phenyl)-2-methyl-2H- pyrazolo[3,4-b]pyridine-3- V^VTX / n xxo sulfonamideoAttorney Docket No. 57547-742.601Ex. Structure NameHhKN-(4-((3-(2-(3 / l-dimethoxyphenyl)-2- oxoethyl)-3-hydroxy-2-oxoindolin-l- 58° 'o / v)HX z~'V°'' yl)methyl)phenyl)-lH-pyrrolo[2,3- b]pyridine-3-sulfonamide n AAOoN-(4-((3-(2-(3 / l-dimethoxyphenyl)-2- / H NQ °H oxoethyl)-3-hydroxy-2-oxo-2,3- 59 N-NMT rvA / / xdihydro-lH-pyrrolo[2,3-b]pyridin-l- < AS'NY K / M " ^A^ o' A O0 / ° yl)methyl)phenyl) - 1 -methyl- 1 H- pyr azol e- 5 - sulfonamide N-(4-((7-chloro-3-(2-(3,4- / H XA PHXVO dimethoxy phenyl) -2- oxoethyl) - 3 - 60 N-N " xA rA rXhydroxy-2-oxoindolin-l- ( / - / XI / M AU yl)methyl)phenyl) - 1 -methyl- 1 H- M W'-zA o?pyr azol e- 5 - sulfonamide N-(4-((3-(2-(3 / l-dimethoxyphenyl)-2- / H X l oH oxoethyl)-6-fluoro-3-hydroxy-2- 61 N-N T V-A / / r \ oxoindolin- 1 -yl)methyl)phenyl)- 1 - U-s' YAA " ^A^A 'b X) o / ° methyl- lH-pyrazole-5-sulfonamide N-(4-((3-(2-(3 / l-dimethoxyphenyl)-2- / AAu uvo oxoethyl)-3-hydroxy-7-methyl-2- 62 N-N H y y — / jr^ \Y k / H tf ^A oxoindolin- 1 -yl)methyl)phenyl)- 1 - A?Ao kU A o / ° methyl- lH-pyrazole-5-sulfonamide (R)-N-(4-((3-(2-(3,4- / H XX?” ^ro. dimethoxy phenyl) -2- oxoethyl) - 3 - 63 hydroxy-7-methyl-2-oxoindolin-l- A / YAA " ^A^A"o AU b0z° yl)methyl)phenyl) - 1 -methyl- 1 H- pyr azol e- 5 - sulfonamide (S)-N-(4-((3-(2-(3,4- / H JCA / ^VO dimethoxy phenyl) -2- oxoethyl) - 3 - 64 N-N " \ > AU\ / / Xhydroxy-7-methyl-2-oxoindolin-l- (LAs' Y k / A AU yl)methyl)phenyl) - 1 -methyl- 1 H- 6 / s° Az0 0 / pyr azol e- 5 - sulfonamide N-(4-((3-(2-(3 / l-dimethoxyphenyl)-2- / XXu kV° oxoethyl)-3-hydroxy-6-methyl-2- 65As' YA / A oxoindolin- 1 -yl)methyl)phenyl)- 1 - ^Ar'o A O 0 methyl- lH-pyrazole-5-sulfonamide FN-(4-((3-(2-(3 / l-dimethoxyphenyl)-2- oxoethyl)-5-fluoro-3-hydroxy-2- 66 N-NZ HCAOH / ^\k ' Ax J kA oxoindolin- 1 -yl)methyl)phenyl)- 1 - A 0A 0A k / A" / AXQ o AX0xmethyl- lH-pyrazole-5-sulfonamide / N-(4-((3-(2-(3 / l-dimethoxyphenyl)-2- ^N / H. M jAA / / M 70-oxoethy 1) -3,7- dimethy 1-2- oxoindolin- 671 -yl)methyl)-2-methoxyphenyl)- 1 -0o o x-^AA 'o Ovk / °\methyl- lH-imidazole-2-sulfonamide\Attorney Docket No. 57547-742.601Ex. Structure NameH ISkN-(4-((3-(2-(3,4-dimethoxyphenyl)-2- oxoethy 1) -3,7- dimethy 1-2- oxoindolin- 68 °"6 Yy ~ yJ / 2 l-yl)methyl)phenyl)-lH-pyrrolo[2,3- b]pyridine-3-sulfonamide n oo1 / N^N'N N-(4-((3-(2-(3,4-dimethoxyphenyl)-2- H oxoethy 1) -3,7- dimethy 1-2- oxoindolin-? S'N69 1 -yl)methyl)phenyl)- 1 -methyl- 1H-0° / \ pyrazolo[3,4-b]pyridine-3- 11 sulfonamide0N— C i N-(4-((3-(2-(3,4-dimethoxyphenyl)-2- / / vX H, _,W;s-N^ oxoethy 1) -3,7- dimethy 1-2- oxoindolin- 70 ° 6 y l-yl)methyl)phenyl)-2-methyl-2H- pyrazolo[3,4-b]pyridine-3- n sulfonamide0RN-(4-((3-(2-(3,4-dimethoxyphenyl)-2- Nf'X^N^^ F oxoethyl)-6,7-difluoro-3-hydroxy-2- 71 J* A <1 YVHP- oxoindolin- 1 -yl)methyl)phenyl)- 1 - 0 oMyJ^°xmethyl- lH-pyrazole-5-sulfonamide FyJN-(4-((3-(2-(3,4-dimethoxyphenyl)-2-FJO oxoethyl)-3-hydroxy-2-oxo-7- 72 / C==- / ^N / _X°H° (trifluoromethyl)indolin- 1 - 0 v\ / / o yl)methyl)phenyl) - 1 -methyl- 1 H- / =( H N==\ pyr azol e- 5 - sulfonamide VN- 0- F^N-(4-((3-(2-(3,4-dimethoxyphenyl)-2-FJQ oxoethyl)-3-hydroxy-2-oxo-7- 73 (trifluoromethyl)indolin- 1 - Yy°\ yl)methyl)phenyl) - 1 -methyl- 1 H- imidazole-2-sulfonamide / KN=\xl'KH0^Nx\ Jl H / =xN-(4-((3-(2-(2-fluoro-5- ^S'Ns^\ O methoxyphenyl)-2-oxoethyl)-3- 74 °Z'° < hydroxy-2-oxoindolin-l- yl)methyl)phenyl)pyridine-3- 0 F / ^ sulfonamideNN-(4-((3-(2-(2-fluoro-3- ^A Hmethoxyphenyl)-2-oxoethyl)-3- 750° t} WOH? hydroxy-2-oxoindolin-l- yl)methyl)phenyl)pyridine-3- sulfonamide0Attorney Docket No. 57547-742.601Ex. Structure NameM H N-(4-((3-(2-(4-(difluoromethoxy)-3- methoxyphenyl)-2-oxoethyl)-3- 76 Z^z A-V Qs -n hydroxy-2-oxoindolin-l- ^z z Won? i yl)methyl)phenyl)pyridine-3- / \ o^. / ; \ Owx AoFsulfonamideAFO zrO ZI N-(4-((3-(2-(4- (dimethylamino)phenyl)-2-oxoethyl)- 77 3-hydroxy-2-oxoindolin-l- z yl)methyl)phenyl) - 1 -methyl- 1 H- A pyr azol e- 5 - sulfonamide pZ oo p- ° 1° r I N-(4-((3-(2-(3- N-NZH AS 1 I v0o \? X\° / I^ (dimethylamino)phenyl)-2-oxoethyl)- 78 rCo=\jU 3-hydroxy-2-oxoindolin-l- o yl)methyl)phenyl) - 1 -methyl- 1 H- ft OH 0 Q0 Q^ z pyr azol e- 5 - sulfonamide M / X° z — N-(4-((3-(2-(4-(dimethylamino)-3-,N~N n # Ns ] I I -Z / x.o methoxyphenyl)-2-oxoethyl)-3- A N79 hydroxy-2-oxoindolin-l- 6' XXJQ ftO OH or ^ yl)methyl)phenyl) - 1 -methyl- 1 H- 0 pyr azol e- 5 - sulfonamide N-(4-((3-(2-(3-(dimethylamino)-4- ANVZH r\ Jfomethoxyphenyl)-2-oxoethyl)-3- 80 hydroxy-2-oxoindolin-l-0° ULNJTYVft OH Q yl)methyl)phenyl) - 1 -methyl- 1 H- 0 pyr azol e- 5 - sulfonamide.. / A"" N-(4-((3-(2-(3-(dimethylamino)-4- / ANV H A A F fluorophenyl)-2-oxoethyl)-3-hydroxy- 812-oxoindolin-l-yl)methyl)phenyl)-l- o" "° XXJO fto OHr^ methyl- lH-pyrazole-5-sulfonamide 0N-(4-((3-hydroxy-3-(2-(3- H A °>?N^ANX (methyl(pyridin-3-yl)amino)phenyl)- V=APHKV^< FT / )82 2-oxoethyl)-2-oxoindolin-l- yl)methyl)phenyl) - 1 -methyl- 1 H- 0 pyr azol e- 5 - sulfonamide N-(4-((3-hydroxy-3-(2-(3- H o i-Z55! (methyl(pyridin-4-yl)amino)phenyl)- \A< VA AA ft / N83 2-oxoethyl)-2-oxoindolin-l- yl)methyl)phenyl) - 1 -methyl- 1 H- o pyr azol e- 5 - sulfonamide N-(4-((3-hydroxy-3-(2-(3- (methyl(pyridin-2-yl)amino)phenyl)- 84 2-oxoethyl)-2-oxoindolin-l- yl)methyl)phenyl) - 1 -methyl- 1 H- pyr azol e- 5 - sulfonamide N-(4-((3-hydroxy-3-(2-(3- (methylsulfonamido)phenyl)-2- 85 oxoethyl)-2-oxoindolin-l- yl)methyl)phenyl) - 1 -methyl- 1 H-pyr azol e- 5 - sulfonamideAttorney Docket No. 57547-742.601Ex. Structure NameN-(4-((3-(2-(3-(lH-pyrazol-4- yl)phenyl)-2-oxoethyl)-3-hydroxy-2- 86oxoindolin- 1 -yl)methyl)phenyl)- 1 - methyl- lH-pyrazole-5-sulfonamide o0L°N~N XZN-(3-(2-(3-hy droxy- l-(4-((l-methyl- O zr H d\ 0 N~yZ I 1 H-py r azole) - 5 - sulfonamido)benzyl) - 87 Y fl [ y / ~\\ \0dz'b W 2- oxoindolin- 3 -y l)acety l)pheny 1) -N- 0 methylacetamide d6. N-(4-((3-hydroxy-3-(2-(3- A AA o morpholinophenyl)-2-oxoethyl)-2- 88 DZ Xo1 X oxoindolin- 1 -yl)methyl)phenyl)- 1 - ) V Ioo=\ methyl- lH-pyrazole-5-sulfonamide l C 4-((3-(2-(3,4-dimethoxyphenyl)-2- M / o o0CJ° ° oxoethy 1)- 3 -hydroxy -2- oxoindolin- 1- 89 )Pzyl)methyl)-N-(pyridin-4- \5 O Q ° °'\ 'zi ylsulfonyl)benzamide / / oo==4-((3-(2-(3,4-dimethoxyphenyl)-2- °"sPA O^ \o,o \ \ IJ oxoethy 1)- 3 -hydroxy -2- oxoindolin- 1- 90 NAA y=\ f iO o>>° yl)methyl)-N-(pyridin-3- dH0 ylsulfonyl)benzamide4-((3-(2-(3,4-dimethoxyphenyl)-2- x / ft r^v°xoxoethyl)-3-methyl-2-oxoindolin-l- 91 / =\H1 A K V ^AAX yl)methyl)-N-(pyridin-3- AJXx ( c,,ZIZIX CH3 O0 ylsulfonyl)benzamide dl o^ 4-((3-(2-(3,4-dimethoxyphenyl)-2- d °'oxoethyl)-3-methyl-2-oxoindolin-l- 92yl)methyl)-N-(pyridin-2- ylsulfonyl)benzamide N-((4-((3-(2-(3,4-dimethoxyphenyl)- o \ °X ^°"S>Y^^SSS il 2-oxoethyl)-3-hydroxy-2-oxoindolin- 93 XNH \ |1 MAX Jt d.l-yl)methyl)phenyl)sulfonyl)oxazole- P° &05 -carboxamideN-((4-((3-(2-(3,4-dimethoxyphenyl)- 0 °*S° < Xr"°2-oxoethyl)-3-hydroxy-2-oxoindolin- 94 XNH \ |i r y-v J' JNX xA / NdOHr l-yl)methyl)phenyl)sulfonyl)oxazole- C° o02-carboxamideN-((4-((3-(2-(3,4-dimethoxyphenyl)- 2-oxoethyl)-3-hydroxy-2-oxoindolin- 95 1- yl)methyl)phenyl)sulfonyl)isonicotina mi deN-((4-((3-(2-(3,4-dimethoxyphenyl)- o0<s° 2-oxoethyl)-3-hydroxy-2-oxoindolin- 96 YNHYI rVxJCr 1- yl)methyl)phenyl)sulfonyl)nicotinamideAttorney Docket No. 57547-742.601Ex. Structure NameN-((4-((3-(2-(3,4-dimethoxyphenyl)- 2-oxoethyl)-3-hydroxy-2-oxoindolin- 971- yl)methyl)phenyl)sulfonyl)benzamide P ( u o A\ ~ 0- 4-((4-(2-(3-hydroxy- 1-(4- (( 1 -methyl- O) zZT 1 H-py r azole) - 5 - sulfonamido)benzyl) - 98 t or W I'sll JH22-oxoindolin-3-yl)acetyl)-2- 0 methoxyphenoxy)methyl)benzamide N-(4-((3-(2-(4-(allyloxy)-3- 0 methoxyphenyl)-2-oxoethyl)-3- q-HNxz £;\ A oM OH1A z-v \°~ / — / / 99 n*o T n rp)DZ ¥ o o7 \\ / )~o hydroxy-2-oxoindolin-l- o\ o \ > I yl)methyl)phenyl) - 1 -methyl- 1 H- ) I0 / / ° O== pyr azol e- 5 - sulfonamide N-N^ r^\ O / / ) o o _ ^ ethyl 2-(4-(2-(3-hydroxy-l-(4-((l- (I I H / 0 O A ° o methyl-lH-pyrazole)-5- 100oA< °>- sulfonamido)benzyl)-2-oxoindolin-3- £'° ° yl)acetyl)-2-methoxyphenoxy)acetate 0 > °N-(4-((3-(2-(4-(cyanomethoxy)-3-ho / VvO~'VAOH oA / A / — =N methoxyphenyl)-2-oxoethyl)-3- 101 n*o T h ry OAyi A hydroxy-2-oxoindolin-l- yl)methyl)phenyl) - 1 -methyl- 1 H- 0 pyr azol e- 5 - sulfonamide N-(4-((3-(2-(4-(tert-butyl)-3- / N~NZd / 1 H / / / T~\ 7 L 1" methoxyphenyl)-2-oxoethyl)-3- 102 WNY% v< hydroxy-2-oxoindolin-l-0 0VA^NA A OH r''x^\0r" yl)methyl)phenyl) - 1 -methyl- 1 H- < T 0 pyr azol e- 5 - sulfonamide N-(4-((3-(2-(2-fluoro-4,5- (P| HFx^x O dimethoxy phenyl) -2- oxoethyl) - 3 - 103 hydroxy-2-oxoindolin-l- X OH » ° yl)methyl)phenyl)pyridine-3- O sulfonamideN-(4-((3-hydroxy-3-(2-(3- \A fVO, isopropoxy-4-methoxyphenyl)-2- 104 oxoethyl)-2-oxoindolin-l-0 0'x / '-X / OH i'r' ^^'o °'Y yl)methyl)phenyl)pyridine-3- o sulfonamideN-(4-((3-hydroxy-3-(2-(4- isopropoxy-3-methoxyphenyl)-2- 105 oxoethyl)-2-oxoindolin-l- yl)methyl)phenyl)pyridine-3- sulfonamideN-(4-((3-hydroxy-3-(2-(3- < \A¥\hA \ J / | Z AOisopropoxy-4-methoxyphenyl)-2- 106 oxoethyl)-2-oxoindolin-l- oz'o X^L^iO ^\ O OH (5l ^^o-^x yl)methyl)phenyl) - 1 -methyl- 1 H- 0 pyr azol e- 5 - sulfonamide N-(4-((3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-3-methyl-2-oxoindolin-l- 107yl)methyl)phenyl)pyrimidine-4- sulfonamideAttorney Docket No. 57547-742.601Ex. Structure NameN-(4-((3-(2-(3,4-dimethoxyphenyl)-2- 108 0 / kO oxoethyl)-3-methyl-2-oxoindolin-l- yl)methyl)phenyl)pyrimidine-2- O 0 X \0 sulfonamideA XN-(5-((3-(2-(3,4-dimethoxyphenyl)-2- p3X. C / kJw XX IWz (J oxoethyl)-3-methyl-2-oxoindolin-l- 109 °z'Zzi ° ZI fY°0yl)methyl)py ri din-2 -y 1)- 1 -methyl- 1 H- ° JX\\ 0 imidazole-2-sulfonamide 0n X x Cl / ° N-(4-((3-(2-(3Xdimethoxyphenyl)-2- p)X x X oxoethyl)-3-methyl-2-oxoindolin-l- 110 Oc- °oz xoxo ( / A yl)methyl)phenyl)pyridine-4- C VQo / s o= o sulfonamide1o / o Xo / X xN-(4-((3-(2-(3Xdimethoxyphenyl)-2- o O o111 Q X / O ° oxoethyl)-3-methyl-2-oxoindolin-l- / oo O °1° / '\\ yl)methyl)-2-fluorophenyl)pyridine- 4-sulfonamideN<oxX1 H C 7 o (S)-N-(4-((3-(2-(3,4- X X X XXxA / / K / X dimethoxy phenyl) -2- oxoethyl) - 3 - 112 xo o r XX iiX / CK 0Nr / -'X° po x X Jx ° methyl-2-oxoindolin-l-yl)methyl)-2- 0 fluorophenyl)pyridine-4-sulfonamide N-(4-((3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-3-methyl-2-oxoindolin-l- 113zO 32 dzOIZyl)methyl)phenyl)-2-methylpyridine- _ / O " 4-sulfonamideN-(4-((3-(2-(3Xdimethoxyphenyl)-2- tf o” oxoethy 1) -3,7- dimethy 1-2- oxoindolin- 1141 -yl)methyl)phenyl)pyridine-3- sulfonamide(S)-N-(4-((3-(2-(3,4- dimethoxyphenyl)-2-oxoethyl)-3,7- 115 dimethyl-2-oxoindolin-l- yl)methyl)phenyl) - 1 -methyl- 1 H- pyr azol e- 5 - sulfonamide N-(4-((3-(2-(3,4-dimethoxyphenyl)-2-C / 0oxoethyl)-3-methyl-2-oxoindolin-l- 116N^x x H^x \ x x. / CNA / CA^noz xo \) H I yl)methyl)phenyl)pyrazine-2- 0 sulfonamide1N-(4-((3-(2-(3,4-dimethoxyphenyl)-2- oxoethyl)-3-methyl-2-oxoindolin-l- 117 ^XA CAXC yl)methyl)phenyl)isothiazole-5- ° ° XXCVrXV sulfonamide W ooN-(4-((3-(2-(3,4-dimethoxyphenyl)-2- oxoethyl)-3-methyl-2-oxoindolin-l- 118 yl)methyl)-2- fluorophenyl)isothiazole-5- sulfonamideAttorney Docket No. 57547-742.601Ex. Structure NameN-(4-((3-(2-(4-fluoro-3- methoxyphenyl)-2-oxoethyl)-3- 119 methy 1 -2- oxoindolin- 1 - yl)methyl)phenyl) - 1 -methyl- 1 H- imidazole-2-sulfonamide X5PJ <? ozOW= (S)-N-(4-((3-(2-(4-fluoro-3- A ' ZT -n methoxyphenyl)-2-oxoethyl)-3- O ZE120 N <? o= r yvT \ methy 1 -2- oxoindolin- 1 - o o PT'Fyl)methyl)phenyl) - 1 -methyl- 1 H- " AL v o imidazole-2-sulfonamide G p A, Z^OV< °n □^ o / x N-(4-((3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-7-isopropyl-3-methyl-2- 121 ° VO; \ oxoindolin- 1 -yl)methyl)phenyl)- 1 - ^xyo methyl- lH-pyrazole-5-sulfonamide o O / '"o — J o° ° TO-\o / NG H J / / Qzo- N-(4-((3-(2-(3Tdimethoxyphenyl)-2- U T V^^YV^ rv / K / I oxoethy 1) -3,7- dimethy 1-2- oxoindolin- 122 X °d / S'b 'Ao71 -yl)methyl)phenyl)pyridine-4- Voo sulfonamide0 / - (S)-N-(4-((3-(2-(3,4- dimethoxyphenyl)-2-oxoethyl)-3,7- 123 dimethyl-2-oxoindolin-l- 9 yl)methyl)phenyl)pyridine-4- / O ZZC w sulfonamide(S)-N-(4-((3-(2-(3,4- A H JJ / °!Z°- dimethoxyphenyl)-2-oxoethyl)-3,7- 124 0 v Jv” '^yv » v / G dimethyl-2-oxoindolin-l- 6 / S"o U^Az'N'^ / / VVO yl)methyl)phenyl)pyridine-4- 0 sulfonamide(S)-N-(4-((3-(2-(3,4- dimethoxy phenyl) -2- oxoethyl) -3- 125 methyl-2-oxoindolin-l-yl)methyl)-2- fluorophenyl)- 1 -methyl - 1H- imidazole-2-sulfonamide, N-N H 9 z°- N-(4-((3-(2-(3,4-dimethoxyphenyl)-2- oxoethyl)-3-methyl-2-oxoindolin-l- 126 \ YAPX. zR^ T\H v i=< p / A KVv=G \ / O O GGG / NV7VV 'O yl)methyl)phenyl)- 1,4-dimethyl- 1H- 0 pyr azol e- 5 - sulfonamide LN—wN-(4-(l-(3-(2-(3, 4-dimethoxy phenyl)- ALA / 1 2-oxoethyl)-3-methyl-2-oxoindolin-l- 127 ° U N4 I A yl)ethyl)phenyl)- 1 -methyl- 1H- / H ’ pyr azol e- 5 - sulfonamide racemic arbitrarily assignedAttorney Docket No. 57547-742.601Ex. Structure NameN-(4-(l-(3-(2-(3, 4-dimethoxy phenyl)- O' % r vf A / AA 2-oxoethyl)-3-methyl-2-oxoindolin-l- 128 ° I 1 U I I yl)ethyl)phenyl)- 1 -methyl- 1H- / ^z _Al o / H ’ pyr azol e- 5 - sulfonamide ' / oAZ°w. O=,? A ' \ ZI -n i racemic arbitrarily assignedN-(4-((3-(2-(3 / l-dimethoxyphenyl)-2- oxoethyl)-7-methoxy-3-methyl-2- 129 AAAI Y K A / AK oxoindolin- 1 -yl)methyl)phenyl)- 1 - 0 01N0OXWA Q / methyl- lH-pyrazole-5-sulfonamide OA □OA oAJ oW AAA^^ o N-(4-((3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-3-methyl-2-oxoindolin-l- / o = Aos Aos 130 ° \ yl)methyl)-2-fluorophenyl)-l-methyl- lH-pyrazole-5-sulfonamide / IX. O o / Xo / o o o / (S)-N-(4-((3-(2-(3,4- o / o ° °-\ H A^ o dimethoxy phenyl) -2- oxoethyl) - 3 - / °z\ Q o AA TAZ A / A 131 methyl-2-oxoindolin-l-yl)methyl)-2-Z / ^x1 0 M / ' \\ / / — o o AANV ° 0A fluorophenyl)- 1 -methyl-lH-pyrazole- 0 5-sulfonamide zvAo'o AAN-(4-((3-(2-(3,4-dimethoxyphenyl)-2-N'sHA / 00A- oxoethyl)-3-methyl-2-oxoindolin-l- AA r \ / A- / \ 132yl)methyl)-2-fluorophenyl)-4- T 6 / S'b l AF W ' methylisothiazole-5-sulfonamide od(S)-N-(4-((3-(2-(3,4- / OX, OIZA C / xWdimethoxy phenyl) -2- oxoethyl) - 3 - / O " 133 methyl-2-oxoindolin-l-yl)methyl)-2- M°' HAZAZ’ fluorophenyl)-4-methylisothiazole-5- sulfonamideN-(4-((3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-3-methyl-2-oxoindolin-l- 134yl)methyl)phenyl)-3-methylpyridine- 2-sulfonamideN-(4-((3-(2-(4-fluoro-3- methoxyphenyl)-2-oxoethyl)-3- 135 methy 1 -2- oxoindolin- 1 - yl)methyl)phenyl)-4- methylisothiazole-5-sulfonamide (S)-N-(4-((3-(2-(4-fluoro-3- methoxyphenyl)-2-oxoethyl)-3- / " A H O?\ 7°- 136 methy 1 -2- oxoindolin- 1 - J n J. / ' \\ 0 — p I o oFyl)methyl)phenyl)-4- 0 methylisothiazole-5-sulfonamide N-(4-((3-(2-(3,4-dimethoxyphenyl)-2-oxoethy 1) -3,7- dimethy 1-2- oxoindolin- 1371 -yl)methyl)phenyl)-4- methylisothiazole-5-sulfonamide N-(4-((3-(2-(4-fluoro-3- 138 methoxyphenyl)-2-oxoethyl)-3- methy 1 -2- oxoindolin- 1 -Attorney Docket No. 57547-742.601Ex. Structure Name yl)methyl)phenyl) - 1 -methyl- 1 H- pyr azol e- 5 - sulfonamide (S)-N-(4-((3-(2-(4-fluoro-3- methoxyphenyl)-2-oxoethyl)-3- z^139 ^^ / W / CO / zz z / methy 1 -2- oxoindolin- 1 - P 00p> ° o o / oX, yl)methyl)phenyl) - 1 -methyl- 1 H- X XWC0 Zv> 7 >zO zr pyr azol e- 5 - sulfonamide O O O ZL zr ZIN-(4-((3-(2-(3 / l-dimethoxyphenyl)-2- G Q, oxoethyl)-3-methyl-2-oxoindolin-l- 140 No o r0 GG ilG / N\p Vz G'o yl)methyl)phenyl) - 1 -methyl- 1 H- G s G B,, o imidazole-2-sulfonamide OWZW~W W G G G G □ (S)-N-(4-((3-(2-(3,4- dimethoxy phenyl) -2- oxoethyl) - 3 - 141 G No,s; V G ML, G W G G / GO°Oois^o G 'kz \'O methyl -2- oxoindolin- 1 - yl)methyl)phenyl) - 1 -methyl- 1 H- o o o o O o O imidazole-2-sulfonamide O T / / oO / o oO T (S)-N-(4-((3-(2-(3,4- HHfp 9 / O / o / / ■" OO- / / o / - - - - dimethoxy phenyl) -2- oxoethyl) - 3 - 142 NA^;s; r il \ IG y » Z W\\W \ methyl -2- oxoindolin- 1 - O'X° GGG-Np yl)methyl)phenyl) - 1 -methyl- 1 H- 0 pyrazole-4-sulfonamide N-(4-((3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-3-methyl-2-oxoindolin-l- 143yl)methyl)phenyl)isothiazole-4- sulfonamide / " V u / W 0 N-(4-((3-(2-(3 / l-dimethoxyphenyl)-2- 1 < G M / L / G oxoethyl)-3-methyl-2-oxoindolin-l- 44 Xozil 1 y z \\ \0 GZG / NG VZ ~0 yl)methyl)phenyl) - 1 -methyl- 1 H- 0 pyr azol e- 5 - sulfonamide (R)-N-(4-((3-(2-(3,4- dimethoxy phenyl) -2- oxoethyl) - 3 - 145 methyl -2- oxoindolin- 1 - yl)methyl)phenyl) - 1 -methyl- 1 H- pyr azol e- 5 - sulfonamide N-(4-((3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-3-methyl-2-oxoindolin-l- 146yl)methyl)phenyl)pyridine-3- sulfonamideN-(4-((3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-3-methyl-2-oxoindolin-l- 147yl)methyl)phenyl)- 1 -ethyl- 1H- pyr azol e- 5 - sulfonamideN-(4-((3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-3-methyl-2-oxoindolin-l- 148yl)methyl)phenyl)imidazo[l,2- a]pyridine-3 -sulfonamideAttorney Docket No. 57547-742.601Ex. Structure NameX AA N-(4-((3-(2-(3,4-dimethoxyphenyl)-2-u X) O O-, oxoethyl)-3-methyl-2-oxoindolin-l- 149N\^ rv XXX yl)methyl)phenyl)imidazo[ 1,2- d / S'b a] pyrimidine- 3 - sulfonami de oN-(4-((7-bromo-3-(2-(3,4- JNX ' H o z InX / 9 dimethoxy phenyl) -2- oxoethyl) - 3 - 150 methyl -2- oxoindolin- 1 - 1 6 / so / XX'Q yl)methyl)phenyl) - 1 -methyl- 1 H- o pyr azol e- 5 - sulfonamide A N-(4-((3-(2-(3,4-dimethoxyphenyl)-2-AA^ OA- oxoethyl)-7-ethyl-3-methyl-2- 151oxoindolin- 1 -yl)methyl)phenyl)- 1 - Xo methyl- lH-pyrazole-5-sulfonamide / o"o / NX / H J I Q o N-(4-((3-(2-(3,4-dimethoxyphenyl)-2-oxoethy 1) -3,7- dimethy 1-2- oxoindolin- 152 U K. A^AA^XX / X oI' l OOAJ O / ° -\ 1 -yl)methyl)phenyl)-3- 0 CAY methylpyridine-4-sulfonamide NX AA Xx° (S)-N-(4-((3-(2-(3,4- y~NhX fx- / o dimethoxyphenyl)-2-oxoethyl)-3,7- 153NX^ -NA\XUJ XxX dimethyl-2-oxoindolin-l- 0% XUX yl)methyl)phenyl)imidazo[l,2- 0 a] pyrimidine- 3 - sulfonami de T 'NX ) tf <'91 zAA (R)-N-(4-((3-(2-(3,4- X^ H J / S o CA dimethoxyphenyl)-2-oxoethyl)-3,7- 154N\X -N^A M F XXX dimethyl-2-oxoindolin-l- d / S'b kAA^X ^ X / X yl)methyl)phenyl)imidazo[l,2- fz 0 a] pyrimidine- 3 - sulfonami de O / TX1N-(4-((3-(2-(3,4-dimethoxyphenyl)-2- 155 U.^vA O A oxoethyl)-3-methyl-2-oxoindolin-l- ° 'o X X X yl)methyl)phenyl)thiazole-5- W 0 sulfonamide05-cyano-N-(4-((3-(2-(3,4- dimethoxy phenyl) -2- oxoethyl) - 3 - 156 methyl -2- oxoindolin- 1 - yl)methyl)phenyl)furan-2- sulfonamide u>" A 1 N-(4-((3-(2-(3,4-dimethoxyphenyl)-2- oxoethyl)-3-methyl-2-oxoindolin-l- 157 O ry0° ° X X X - yl)methyl)phenyl) - 1 -methyl- 1 H- W o0 imidazole-5-sulfonamide (S)-N-(4-((3-(2-(3,4- C AN'.«JA A O py1dimethoxy phenyl) -2- oxoethyl) -3- 158 methyl-2-oxoindolin-l-yl)methyl)-2- ° XXX XXYF W o fluorophenyl)- 1 -methyl - 1H-0 imidazole-5-sulfonamideAttorney Docket No. 57547-742.601Ex. Structure NameNYH(R)-N-(4-((3-(2-(3,4- ry1dimethoxy phenyl) -2- oxoethyl) -3- 159 Y fy° methyl-2-oxoindolin-l-yl)methyl)-2- fluorophenyl)- 1 -methyl - 1H- F \\ ' O0 imidazole-5-sulfonamide p / \ CK N-(4-((3-(2-(3Ydimethoxyphenyl)-2-;w oxoethy 1) -3,7- dimethy 1-2- oxoindolin- 1601 -yl)methyl)phenyl)- 1 -methyl- 1H- imidazole-5-sulfonamide 8, N-(4-((3-(2-(3,4-dimethoxyphenyl)-2- oxoethyl)-3-methyl-2-oxoindolin-l- 161 )Z o yl)methyl)phenyl)- 1 -ethyl- 1H- imidazole-2-sulfonamide voN-(4-((3-(2-(3,4-dimethoxyphenyl)-2- O / '" rTHQ?\ o / / u.J? o / O / ox1 oxoethyl)-3-methyl-2-oxoindolin-l-' 162 o N ^S'^YAI l y ^AA yl)methyl)-2-fluorophenyl)-l-methyl- O' O A A / N Y A'P / oF V \Ti~ ° o / - lH-imidazole-2-sulfonamide o o 0N-(4-((3-(2-(4-fluoro-3- 0A>os=r xo^ > ° methoxyphenyl)-2-oxoethyl)-3- °JAYVO 163 methy 1 -2- oxoindolin- 1 - O / - yl)methyl)phenyl) - 1 -methyl- 1 H-y CT- CA° imidazole-5-sulfonamide (S)-N-(4-((3-(2-(4-fluoro-3- Y i_i f v 0 methoxyphenyl)-2-oxoethyl)-3- T Y T N A Mt A / A z — 164 YY I AY / V methy 1 -2- oxoindolin- 1 - / O \°^ P \ o o kY^NV Y / YCWyl)methyl)phenyl) - 1 -methyl- 1 H- o imidazole-5-sulfonamide L z K° zZ.-'j ’ All A N-(4-((3-(2-(3,4-dimethoxyphenyl)-2- L II OH, _ (oxoethy 1)- 3 -hydroxy -2- oxoindolin- 1 - 165 \ Y^AT °xyl)methyl)phenyl)-N-NA / NY^ \\N~A YY'YY YZ^ %0methylisoni cotinamide 0N-(4-((3-(2-(3,4-dimethoxyphenyl)-2- oxoethyl) -3 -hydroxy -2- oxoindolin- 1 - 166yl)methyl)phenyl)-3-methoxy-N- methylisoni cotinamide N-(4-((3-(2-(3,4-dimethoxyphenyl)-2- oxoethyl) -3 -hydroxy -2- oxoindolin- 1 - 167 Y!< Qz Zyl)methyl)phenyl)-N,2- YY Y.-NY Y Y°dimethylisoni cotinamide 0 0 0N-(4-((3-(2-(3,4-dimethoxyphenyl)-2- J l) k jl OH _ / oxoethy 1)- 3 -hydroxy -2- oxoindolin- 1- 168yl)methy l)phenyl) -N, 3- <^Y'CYQ7< Y dimethylisoni cotinamide N-(4-((3-(2-(3,4-dimethoxyphenyl)-2- oxoethyl)-6-fluoro-3,7-dimethyl-2- 169oxoindolin-l-yl)methyl)phenyl)-N- methylisoni cotinamideAttorney Docket No. 57547-742.601Ex. Structure Name| (T 7 o N-(4-((3-(2-(3 / l-dimethoxyphenyl)-2- 170 oxoethyl)-3-methyl-2-oxoindolin-l- o XAo yl)methyl)phenyl)-N- 0 methylisoni cotinamide N^II | °> N-(4-((3-(2-(3,4-dimethoxyphenyl)-2-oxoethy 1) -3,7- dimethy 1-2- oxoindolin- 171 o=\ V \ / z— 1 -yl)methy l)phenyl) -N- 0 methylisoni cotinamide (S)-N-(4-((3-(2-(3,4- dimethoxyphenyl)-2-oxoethyl)-3,7- 172 dimethyl-2-oxoindolin-l- / yl)methyl)phenyl)-N- * °c>methylisoni cotinamide \o=N^ii i M o N-(4-((3-(2-(3,4-dimethoxyphenyl)-2- oxoethyl)-3-hydroxy-2-oxoindolin-l- 173 VOHW oKo / M o / x / o y l)methyl)pheny l)-N-methy 1- 1,7- o naphthyridine-4-carboxamide O oN-(4-((3-(2-(3,4-dimethoxyphenyl)-2- 0A. oxoethyl)-3-methyl-2-oxoindolin-l- 174yl)methy l)phenyl) -N, 3- CM dimethylisoni cotinamide 3-amino-N-(4-((3-(2-(3,4- dimethoxy phenyl) -2- oxoethyl) - 3 - 175 7k¥? L 1 / jX methyl -2- oxoindolin- 1 - NH20 p wX^ O'"o yl)methyl)phenyl)-N- 0 methylisoni cotinamide N-(4-((3-(2-(3,4-dimethoxyphenyl)-2- cT oxoethyl)-3-methyl-2-oxoindolin-l- 176y l)methyl)pheny l)-N-methy 1- 1,7- NJC o CXJNZ^C^CC~O / 0 naphthyridine-4-carboxamide N-(4-((3-(2-(3,4-dimethoxyphenyl)-2- oxoethyl)-3-methyl-2-oxoindolin-l- 177 M o MCN^XM£J^Oyl)methyl)phenyl)-N-methyl- 1,8- naphthyridine-4-carboxamide 0J Nx^ J\ / N I — 4 / =\ ff o / °— N-(4-((3-(2-(3,4-dimethoxyphenyl)-2- 178NT^ ¥ M / A / =< oxoethy 1) -3,7- dimethy 1-2- oxoindolin- M o C^MCCQ71 -yl)methyl)phenyl)-N-methyl- 1,8- 0 naphthyridine-4-carboxamide N-(4-((3-(2-(3,4-dimethoxyphenyl)-2- M i r\ / XX / x^x - \? 0 _ z°— oxoethy 1) -3,7- dimethy 1-2- oxoindolin- 1791 -y l)methyl)pheny l)-N-methy 1- 1,7- M o LMiCM vCo / naphthyridine-4-carboxamide 0N-(4-((3-(2-(3,4-dimethoxyphenyl)-2- { Y 11JT 7 o oxoethy 1) -3,7- dimethy 1-2- oxoindolin- 180 n T il 1 -yl)methy l)phenyl) -N- W o methylquinoline-6-carboxamide oAttorney Docket No. 57547-742.601Ex. Structure NameN-(4-((3-(2-(4-hydroxy-3- A | # 7 o o-. methoxyphenyl)-2-oxoethyl)-3- 181 YA / methy 1 -2- oxoindolin- 1 - I N> yl)methyl)phenyl)-N- z 0z methylisoni cotinamide CX\ ) \1N-(4-((3-(2-(3 / l-dimethoxyphenyl)-2- oxoethy 1) -3,7- dimethy 1-2- oxoindolin- 182o=\o z — Y Y9AA 'Vk''v\\ 0 II U / 1 -yl)methyl)phenyl)-N-methyl- 1H- 0 pyrrolo[3,2-b]pyridine-6-carboxamide N-(4-((3-(2-(3,4-dimethoxyphenyl)-2- oxoethy 1) -3,7- dimethy 1-2- oxoindolin- 183 Y, 1 -yl)methyl)phenyl)-N-methyl- 1H- benzo [ d] i mi dazol e- 5 - carb oxami de N-(4-((3-(2-(3,4-dimethoxyphenyl)-2-1JAHjf / \po o ONo / o o oxoethy 1) -3,7- dimethy 1-2- oxoindolin- 184 n \ ii i V-XAL° ^AAX / N- Cv J.° ° 1 -yl)methyl)phenyl)-N-methyl- 1H-YX Y o O \5 W o indole-4-carboxamide \> 0 / OO / - \ ° / ° | NH l / Y N-(4-((3-(2-(3,4-dimethoxyphenyl)-2- / ° / ° ✓A / \ At A 0 oxoethy 1) -3,7- dimethy 1-2- oxoindolin- 185 \L 1 -yl)methyl)phenyl)-N-methyl- 1H- Ajf Y )Y / NY n 1 QA° O>° fyr pyrrolo[3,2-b]pyridine-7-carboxamide ° "" o YYAX / AN-(4-((3-(2-(3,4-dimethoxyphenyl)-2- \ ) / / A oxoethy 1) -3,7- dimethy 1-2- oxoindolin- Y r=< ' A4 / ? 186 z — 9 z — 1 -yl)methyl)phenyl)-N-methyl- 1H- FF / VY FKFV^r0- y^o z — ^°= \\ t JY / NY il 1 )o= \°^ pyrrolo[3,2-c]pyridine-3-carboxamide0o AAzO^ N-(4-((3-(2-(3,4-dimethoxyphenyl)-2- Cv\ ) z =Q z oxoethy 1) -3,7- dimethy 1-2- oxoindolin- vJzT 1871 -yl)methy l)phenyl) -N- methylquinoline-4-carboxamide N-(4-((3-(2-(3,4-dimethoxyphenyl)-2- oxoethy 1) -3,7- dimethy 1-2- oxoindolin- 1881 -yl)methy l)phenyl) -N- methy 1 quinoline- 5 - carb oxami de N-(4-((3-(2-(3,4-dimethoxyphenyl)-2-1AN'^VvNxA \J AA oxoethy 1) -3,7- dimethy 1-2- oxoindolin- 1891 -yl)methy l)phenyl) -N- ° XX^OAYCXmethylisoquinoline-7-carboxamide Y ° °N-(4-((3-(2-(3,4-dimethoxyphenyl)-2- oxoethy 1) -3,7- dimethy 1-2- oxoindolin- 1901 -yl)methyl)phenyl)-N-methyl- 1,8- naphthyridine-3 -carboxamide 2-amino-N-(4-((3-(2-(3,4- dimethoxy phenyl) -2- oxoethyl) - 3 - 191 methyl -2- oxoindolin- 1 - yl)methyl)phenyl)-N- methylisoni cotinamideAttorney Docket No. 57547-742.601Ex. Structure NameN-(4-((3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-3-methyl-2-oxoindolin-l- 192yl)methyl)phenyl) -3 -hydroxy -N- W OH ° X^xk^AN^ U / X x [[0’Z-r. o methylisoni cotinamide A Z- N-(4-((3- k \ / I — ) - M k 1 O y\ / °, z°- (2-(3 / l-dimethoxyphenyl)-2- O\= oxoethyl)-3-methyl-2-oxoindolin-l- 193 HO if 1 11 1 ¥— z \\ zK~ yl)methyl)phenyl)-2-hydroxy-N- omethylisoni cotinamide 03-amino-N-(4-((3-(2-(3,4- ikl i < J dimethoxyphenyl)-2-oxoethyl)-3,7- < xA / N^X\ U V°194 dimethyl-2-oxoindolin-l- T T | |1 fV\A Jyl)methyl)phenyl)-N- u oo methylisoni cotinamide XO^ (S)-3-amino-N-(4-((3-(2-(3,4- dimethoxyphenyl)-2-oxoethyl)-3,7- 195 dimethyl-2-oxoindolin-l- o / o yl)methyl)phenyl)-N- / methylisoni cotinamide N-(4-((3-(2-(3,4-dimethoxyphenyl)-2-oxoethy 1) -3,7- dimethy 1-2- oxoindolin- 196 XrXXX _Q° 1 -yl)methyl)phenyl)-N-methyl-3- °2No 'XkzNzAV'^O^nitroisoni cotinamide b02-((N-(4-((3-(2-(3,4- dimethoxy phenyl) -2- oxoethyl) - 3 - N~NZmethyl -2- oxoindolin- 1 - U8. U, C? fy°x 197yl)methyl)phenyl) - 1 -methyl- 1 H- A XXQoAV pyrazole)-5-sulfonamido)-N, N- U 00 dimethylacetamideN-(4-((3-(2-(3-hydroxy-4- N-NZH FX o OHmethoxyphenyl)-2-oxoethyl)-3- \^X zN^z^. yd / 198 methy 1 -2- oxoindolin- 1 - Fb UJ^ Vz^ozyl)methyl)phenyl) - 1 -methyl- 1 H- o pyr azol e- 5 - sulfonamide N-(4-((3-(2-(4-hydroxy-3- N-NZH FF q o^ methoxyphenyl)-2-oxoethyl)-3- \^x, N^y xx / K-Z A 199 methy 1 -2- oxoindolin- 1 - Fb X^OH yl)methyl)phenyl) - 1 -methyl- 1 H- 0 pyr azol e- 5 - sulfonamide N — M / ^X C) 2-(2-methoxy-4-(2-(3-methyl-l-(4- f i t! f ) o / _ / ° NH2((1 -methyl- lH-pyrazole)-5- VA / V / \ 200 sulfonamido)benzyl)-2-oxoindolin-3- yl)acetyl)phenoxy)acetamide 03-((2-methoxy-4-(2-(3-methyl-l-(4- f Y H O 0 / °~ / =y ((1 -methyl- lH-pyrazole)-5- WNvk Vf / K / A ZX A 201 H T h > y~y \ / / ° sulfonamido)benzyl)-2-oxoindolin-3-0XAZNZ / \ \\ ZXNIl2yl)acetyl)phenoxy)methyl)benzamide 0 0N-(4-((3-(2-(3-methoxy-4-(pyridin-4- < Zf H O 0 Z=\ ylmethoxy)phenyl)-2-oxoethyl)-3- 202 methy 1 -2- oxoindolin- 1 - xt'oYA Mz^SX^-O0XXzNz / yl)methyl)phenyl) - 1 -methyl- 1 H- 0 pyr azol e- 5 - sulfonamideAttorney Docket No. 57547-742.601Ex. Structure Name2-((N-(4-((3-(2-(4-(2- "" Nr"(dimethylamino)-2-oxoethoxy)-3- methoxyphenyl)-2-oxoethyl)-3- 203A N~UNZS. U LJ fv methy 1 -2- oxoindolin- 1 - yl)methyl)phenyl) - 1 -methyl- 1 H- °s° UJkrA'W o pyrazole)-5-sulfonamido)-N, N- odimethylacetamide2-(2-methoxy-4-(2-(3-methyl-l-(4- ((1 -methyl- lH-pyrazole)-5- u H n 1 O1) rS d"°203B sulfonamido)benzyl)-2-oxoindolin-3- / / \\ Il 1 v 1 < \^\ p ^Y1 yl)acetyl)phenoxy)-N, N- \\ o dimethylacetamide0N-(5-((3-(2-(3 / l-dimethoxyphenyl)-2- oxoethyl)-2-oxoindolin-l- 204 o" / 7 1 / yl)methyl)py ri din-2 -y 1)- 1 -methyl- 1 H- o / Px' ° imidazole-2-sulfonamide v °o 4-((3-(2-(3,4-dimethoxyphenyl)-2- A. ( oxoethyl)-2-oxoindolin- 1 -yl)methyl)- 205 \ Cr2-fluoro-N-(2-methylpyridin-3- PP>° yl)benzenesulfonamide cP PPV°N-(4-((3-(2-(3 / l-dimethoxyphenyl)-2- oxoethyl)-2-oxoindolin- 1 -yl)methyl)- 206y d01 LL ' ^d 2-fluorophenyl)- 1 -methyl- 1H- \ I u.32 imidazole-2-sulfonamide Xz. j,om cnz= ■' °ZtlT t, PP°N°'r r r\ i N-(4-((3-(2-(3 / l-dimethoxyphenyl)-2- oxoethyl)-2-oxoindolin- 1 -yl)methyl)- 207 M rvYXYYAY 2-fluorophenyl)- 1 -methyl-lH-rW o pyr azol e- 5 - sulfonamide 0NA 1 P / P z°- N-(4-((3-(2-(3 / l-dimethoxyphenyl)-2- oxoethyl)-2-oxoindolin-l- 208 r \ AC \o kJPN^f XPp yl)methyl)phenyl)-N- 0 methylisoni cotinamide [pl os / p O 5-((3-(2-(3,4-dimethoxyphenyl)-2- oxoethyl)-2-oxoindolin- 1 -yl)methyl)- 209 r n i \— JL / HNp^^N" / Yz0N-(pyridin-3-yl)pyridine-2- 0 sulfonamideN-(4-((3-(2-(3 / l-dimethoxyphenyl)-2- N~NZH P J F p— oxoethyl)-3-fluoro-2-oxoindolin-l- 210 zY zN^^> i V-A / =(yl)methyl)phenyl) - 1 -methyl- 1 H- <h> YPNi rCdoxo o pyr azol e- 5 - sulfonamide N-(4-((3-(2-(3 / l-dimethoxyphenyl)-2- v 0 H / f / cpoxoethyl)-3-fluoro-2-oxoindolin-l- 211 N^ zS |1 \ \ / Z \\ \<\ y o uPzN yl)methyl)phenyl) - 1 -methyl- 1 H-imidazole-5-sulfonamideAttorney Docket No. 57547-742.601Ex. Structure Name4-((3-(2-(4-fluoro-3-methoxyphenyl)- 2-oxoethyl)-3-methyl-2-oxoindolin-l- 212yl)methyl)-N-(2-methylpyridin-4- Z^\ yl)benzenesulfonamide p / / _ (S)-4-((3-(2-(3,4-dimethoxyphenyl)- 2-oxoethyl)-3-methyl-2-oxoindolin-l- 213 OIZO zCy / Co( n co yl)methyl)-2-fluoro-N-(2- methy Ipy ridin- 3 - yl)benzenesulfonamide (R)-4-((3-(2-(3,4-dimethoxyphenyl)- £ p 2-oxoethyl)-3-methyl-2-oxoindolin-l- 0 p- 214 yl)methyl)-2-fluoro-N-(2- \°°*s 7s methy Ipy ridin- 3 - yl)benzenesulfonamide / / u- u. / / u. 4-((3-(2-(3,4-dimethoxyphenyl)-2- o Q o / O / ° ° o O- °o / / Xoxoethyl)-3-methyl-2-oxoindolin-l- 215 / u u o o u o / / O / O yl)methyl)-N-(pyridin-4- o °1O / -\p Q o^ yl)benzenesulfonamide \p \ O QX*^ o °=4-((3-(2-(4-fluoro-3-methoxyphenyl)-p °= > °2-oxoethyl)-3-methyl-2-oxoindolin-l- 216 P ^^oyl)methyl)-N-(pyridin-4- y 0 Cy fy f / rr / -0 v zvo>yl)benzenesulfonamide 0P- (S)-4-((3-(2-(4-fluoro-3- methoxyphenyl)-2-oxoethyl)-3- 217 J 34 / OC methyl-2-oxoindolin-l-yl)methyl)-N- / OC Z o7W=° / OCu- o zi ozZT zi O oZzo zi Oz(pyridin-4-yl)benzenesulfonamideyp y o= \J— 4-((3-(2-(4-fluoro-3-methoxyphenyl)-,N=t Os / p PP 0 O-^ j 4 4 d & 0Z.—1■ Z N— Q 2-oxoethyl)-3-methyl-2-oxoindolin-l- 218 r H i y_ / A\yl)methyl)-N-(isothiazol-4- yl)benzenesulfonamide 0hko 3-(2-(3,4-dimethoxyphenyl)-2- ]P (T 7 o oxoethyl)- 1 -(4-(l -hydroxy- 1 - 219(pyridin-4-yl)ethyl)benzyl)-3- Hcr >ppmethylindolin-2-one 03-(2-(3,4-dimethoxyphenyl)-2- 220 oxoethyl)-3-methyl-l-(4-(l-(pyridin- 4-yloxy)ethyl)benzyl)indolin-2-one3-(2-(3,4-dimethoxyphenyl)-2- oxoethyl)- 1 -(4-(methoxy (pyridin-4- 221yl)methyl)benzyl)-3-methylindolin-2- one3-(2-(3,4-dimethoxyphenyl)-2- oxoethyl)-3-methyl-l-(4-((pyridin-4- 222ylmethyl)sulfonyl)benzyl)indolin-2- oneAttorney Docket No. 57547-742.601Ex. Structure Nameos / p 7 o 5-((3-(2-(3,4-dimethoxyphenyl)-2- oxoethyl)-3-methyl-2-oxoindolin-l- 223 1 V-v fi \ / yl)methyl)-N-(pyridin-3-yl)pyridine- Z^^\ Z 0 2-sulfonamide / / ^< 1 J° / 4-((3-(2-(3,4-dimethoxyphenyl)-2- oxoethyl)-3-methyl-2-oxoindolin-l- 224 ° °ZrIZ° Z Zx / / ..C z / w CK / / . yl)methyl)-N-(pyridin-3- yl)benzenesulfonamide 4-((3-(2-(3,4-dimethoxyphenyl)-2- oxoethyl)-3-methyl-2-oxoindolin-l- 225;: e e yl)methyl)-2-fluoro-N-(pyridin-3- OcA / = °x o yl)benzenesulfonamide v / VoO os= 4-((3-(2-(3,4-dimethoxyphenyl)-2- XD^ oxoethyl)-3-methyl-2-oxoindolin-l- 226 o o / " / oo / / " yl)methyl)-N-(5-methoxy-2- o o O J o / Xo / / o o methy Ipy ridin- 3 - / oOO / - o O / / -O / - yl)benzenesulfonamide M4-((3-(2-(3,4-dimethoxyphenyl)-2- > > ° ° oxoethyl)-3-methyl-2-oxoindolin-l- 227 X8x=sO~~ yl)methyl)-N-(2-methylpyridin-3- yl)benzenesulfonamide Cd O nr~--"°(S)-4-((3-(2-(3,4-dimethoxyphenyl)- 2-oxoethyl)-3-methyl-2-oxoindolin-l- 228d yl)methyl)-N-(2-methylpyridin-3- ) z, / 0CWT / 4 U-- ° o\ i O Z / zo yl)benzenesulfonamide zi oz4-((3-(2-(3,4-dimethoxyphenyl)-2- oxoethy 1) -3,7- dimethy 1-2- oxoindolin- 229 8T / ^^d OTZ- 1 -yl)methyl)-N-(pyridin-3- yl)benzenesulfonamide 4-((3-(2-(3,4-dimethoxyphenyl)-2- oxoethyl)-3-methyl-2-oxoindolin-l- 230yl)methyl)-N-(2,6-dimethylpyridin-3- yl)benzenesulfonamide \ _0^s"° 4-((3-(2-(3,4-dimethoxyphenyl)-2- oxoethyl)-3-methyl-2-oxoindolin-l- 231 NHYd] l y-'-x Jl dT yl)methyl)-N-(2,5-dimethylpyridin-3- \ U 00 yl)benzenesulfonamide4-((3-(2-(3,4-dimethoxyphenyl)-2- oxoethyl)-3-methyl-2-oxoindolin-l- 232yl)methyl)-N-(2,4-dimethylpyridin-3- yl)benzenesulfonamide 4-((3-(2-(3,4-dimethoxyphenyl)-2- oxoethyl)-3-methyl-2-oxoindolin-l- 233y l)methy 1) -N- (3 -methy li sothi azol -4- yl)benzenesulfonamideAttorney Docket No. 57547-742.601Ex. Structure NameN=(4-((3-(2-(3,4-dimethoxyphenyl)-2- xx 1 oxoethyl)-3-methyl-2-oxoindolin-l- 234 1 o / / 7 zx°i z ozHN'sV^ M f 1 yl)methyl)-N-(l,3-dimethyl-lH- «-^X / / Z I _ xx\ / Vi o pyrazol-5-yl)benzenesulfonamide 7 Ji0y i? ° zx_ 4-((3-(2-(3,4-dimethoxyphenyl)-2- Rw T° / x / ,Tw=o, oxoethy 1) -3,7- dimethy 1-2- oxoindolin- 235 1 -yl)methyl)-2-fluoro-N-(2- methy Ipy ridin- 3 - 0 p, yl)benzenesulfonamide C)T J,XA / o N-(5-chloro-2-methylpyridin-3-yl)-4- xxx^ o ((3-(2-(3,4-dimethoxyphenyl)-2- 236yoO y oxoethyl)-3-methyl-2-oxoindolin-l- yo yl)methyl)benzenesulfonamide o / Xo O o / 4-((3-(2-(3,4-dimethoxyphenyl)-2- O / o O oxoethyl)-3-methyl-2-oxoindolin-l- 237 o O / oO / / - - O / - yl)methyl)-N-(lH-pyrazolo[3,4- b]pyridin-5-yl)benzenesulfonamide 4-((3-(2-(3,4-dimethoxyphenyl)-2- oxoethyl)-3-methyl-2-oxoindolin-l- 238 CM y l)methy 1) -N- (3 -methy li sothi azol -4- yl)benzenesulfonamide _ °^ N-(2-chloropyridin-3-yl)-4-((3-(2- C ))( / R J° xxoLJ- (3,4-dimethoxyphenyl)-2-oxoethyl)- 239N4H ZT OZC XXlX^N^ / XerCCX0^ 3 -methy 1 -2- oxoindolin- 1 - Cl 1 o yl)methyl)benzenesulfonamide Z v—_ °<s"° XXO N-(2-bromopyridin-3-yl)-4-((3-(2- (3,4-dimethoxyphenyl)-2-oxoethyl)- 240N4 WNYX^ 0^ 3 -methy 1 -2- oxoindolin- 1 - Br UQ0 yl)methyl)benzenesulfonamide 4-((3-(2-(3,4-dimethoxyphenyl)-2- ^-S °^ Sc°x zX XX f Xl X X. 0n N oxoethyl)-3-methyl-2-oxoindolin-l- 241 H T |i r Vx JLN' / xkzNX" II yl)methyl)-N-(4-methylthiazol-5- \ W o0 yl)benzenesulfonamideBiros / p lN=L XX N-(2-bromo-5-methylpyridin-3-yl)-4- xy° ((3-(2-(3,4-dimethoxyphenyl)-2- 242 / J-NH T |1 xvx J JVxNV\ oxoethyl)-3-methyl-2-oxoindolin-l- / W o0 yl)methyl)benzenesulfonamide. N^ ^NxP 4-((3-(2-(3,4-dimethoxyphenyl)-2- oxoethyl)-3-methyl-2-oxoindolin-l- 243xMxN'M> A'X ffX ^^Xo^ yl)methyl)-N-(l,4-dimethyl-lH- W o0 pyrazol-5-yl)benzenesulfonamide0<?4-((3-(2-(3,4-dimethoxyphenyl)-2- s° _ <^x° oxoethyl)-3-methyl-2-oxoindolin-l- 244N^NHY1 rVxl ISs xx^zA yl)methyl)-N-(thiazol-5- W oo yl)benzenesulfonamideAttorney Docket No. 57547-742.601Ex. Structure Name4-((3-(2-(3,4-dimethoxyphenyl)-2- oxoethyl)-3-methyl-2-oxoindolin-l- 245 X Xo o yl)methyl)-N-(2-ethylpyridin-3- Z^\ O ' yl)benzenesulfonamide / / _Z 4-((3-(2-(3,4-dimethoxyphenyl)-2- oxoethy 1) -3,7- dimethy 1-2- oxoindolin- 246IZIZ°Os zx zCC w co1w-o, 1 -yl)methyl)-N-(pyridin-4-Z / / x1W~O-, yl)benzenesulfonamide L F 4-((3-(2-(3,4-dimethoxyphenyl)-2- oxoethyl)-3-methyl-2-oxoindolin-l- A247 O~ A y l)methy 1) -N- (5 - (i soxazol - 5 -y 1) -2- methy Ipy ridin- 3 - A A AO©O^s^O / yl)benzenesulfonamide J o o / " (S)-5-((3-(2-(3,4-dimethoxyphenyl)- O o2-oxoethyl)-3-methyl-2-oxoindolin-l- 248 o / / OoQ TO° °11o / -\\ yl)methyl)-N-(2-methylpyridin-3- OA= / / o / oo yl)pyridine-2-sulfonamide / (R)-5-((3-(2-(3,4-dimethoxyphenyl)- 2-oxoethyl)-3-methyl-2-oxoindolin-l- 249 Cy^ yl)methyl)-N-(2-methylpyridin-3- yl)pyridine-2-sulfonamide 3 4-((3-(2-(3,4-dimethoxyphenyl)-2- d<x\ Z Oz / OCX / °~ oxoethyl)-3-methyl-2-oxoindolin-l- '250 yl)methyl)-N-(5-(pyridin-3- yloxy)pyridin-3- yl)benzenesulfonamide oX 4-((3-(2-(3,4-dimethoxyphenyl)-2- oxoethyl)-3-methyl-2-oxoindolin-l- 251yl)methyl)-N-(6-hydroxypyridin-3- yl)benzenesulfonamide 4-((3-(2-(3,4-dimethoxyphenyl)-2- oxoethyl)-3-methyl-2-oxoindolin-l- 252 yl)methyl)-N-(5-(2- hydroxypropoxy)pyridin-3- yl)benzenesulfonamide 4-((3-(2-(3,4-dimethoxyphenyl)-2- oxoethyl)-3-methyl-2-oxoindolin-l- 253 y l)methy 1) -N- (5 -((tetr ahy dr ofuran- 3 - yl)oxy)pyridin-3- yl)benzenesulfonamide 4-((3-(2-(3,4-dimethoxyphenyl)-2- °\ ox zo 0 0^ oxoethyl)-3-methyl-2-oxoindolin-l- 254 / \ / V—N / / L^yr=:=\ yl)methyl)-N-(5-(2- H hy dr oxy ethoxy )pyri din-3 - 0 yl)benzenesulfonamide4-((3-(2-(3,4-dimethoxyphenyl)-2- oxoethyl)-3-methyl-2-oxoindolin-l- 255 yl)methyl)-N-(5-(2-hydroxy-2- methylpropoxy)pyridin-3-yl)benzenesulfonamideAttorney Docket No. 57547-742.601Ex. Structure Name4-((3-(2-(3,4-dimethoxyphenyl)-2- oxoethyl)-3-methyl-2-oxoindolin-l- 256 yl)methyl)-N-(2-methyl-5- ^^^Z I morpholinopyri din-3 - T J=\ ZX — Z wy yl)benzenesulfonamide TJ° z_ 4-((3-(2-(3,4-dimethoxyphenyl)-2- ^ °O oxoethyl)-3-methyl-2-oxoindolin-l- 257 Z_zc^o yl)methyl)-N-(5-hydroxypyridin-3- yl)benzenesulfonamide 4-((3-(2-(3,4-dimethoxyphenyl)-2- B,0 oxoethyl)-3-methyl-2-oxoindolin-l- 258 M0 J- o> yl)methyl)-N-(5-(dimethylamino)-2- AA^^^ Ome No^ thylpyridin-3- yl)benzenesulfonamide °* 7O o / O / / ^ O / '' / o o / / ''O o / 4-((3-(2-(3,4-dimethoxyphenyl)-2- o o oxoethyl)-3-methyl-2-oxoindolin-l- Q o o / / o w 259 yl)methyl)-N-(2-methyl-5-(4-O / - ON^ OA methylpiperazin- 1 -yl)pyridin-3- ON^ oN^I 1 yl)benzenesulfonamide oJ-vB zo^ rNs,^o / —4-((3-(2-(4,5-dimethoxy-2- O-- CM methy Ipheny 1) -2- oxoethyl) - 3 - 260 hydroxy-2-oxoindolin-l-yl)methyl)- N-(isothiazol-4- d B^WX' ° yl)benzenesulfonamide\cx / ~ °W I' O 3 y)f Z / / 5-((3-(2-(3,4-dimethoxyphenyl)-2- ZI OZx ° fY oxoethyl)-3-methyl-2-oxoindolin-l- A. zT / \ 261^ z / yl)methyl)-N-(4-methylthiazol-5- [zZo c I^ OJ 1 yl)pyridine-2-sulfonamide N-(5-((4-((3-(2-(3,4- dimethoxy phenyl) -2- oxoethyl) - 3 - <x Qri, methyl -2- oxoindolin- 1 - 262yl)methyl)phenyl)sulfonamido)-6- VD^NH'CJL BBCVBB methylpyridin-3-yl)-N- \ W oomethylacetamide0N-(5-bromo-2-methylpyridin-3-yl)-4- Br. O^' T X / 0((3-(2-(3,4-dimethoxyphenyl)-2- 263 ( VNHT ky N Q oxoethyl)-3-methyl-2-oxoindolin-l-N=\ '° \-sXXyl)methyl)benzenesulfonamide 0 / 4-((3-(2-(3,4-dimethoxyphenyl)-2- o^? Q 9 / ^z0- oxoethyl)-3-methyl-2-oxoindolin-l- 264 yl)methyl)-N-(5-(methoxymethyl)-2- CCHCX C / wlCo methylpyridin-3-xo yl)benzenesulfonamide 4-((3-(2-(3,4-dimethoxyphenyl)-2- oxoethyl)-3-methyl-2-oxoindolin-l- 265y l)methy 1) -N- (5 -methy li sothi azol -4- M xC C oi yl)benzenesulfonamide1Attorney Docket No. 57547-742.601Ex. Structure Name4-((3-(2-(3,4-dimethoxyphenyl)-2- oxoethyl)-3-methyl-2-oxoindolin-l- 266 yl)methyl)-N-(2-methyl-5- phenylpyridin-3- ^^^^^^ z Z Zii7 J 7 J yl)benzenesulfonamide 1 Jii1 J 4-((3-(2-(3,4-dimethoxyphenyl)-2- ° ° z Zx. oxoethyl)-3-methyl-2-oxoindolin-l- 267 *j^o yl)methyl)-N-(5-(isoxazol-4-yl)-2- g- methy Ipy ridin- 3 - yl)benzenesulfonamide s s e,,,_ °*s'° dJd o / — \,S-xr<2^\ \==4 [l id 4-((3-(2-(3,4-dimethoxyphenyl)-2- <\ / )-NH T n r ^x °x''y oxoethyl)-3-methyl-2-oxoindolin-l- 268 / \ n \ S°°0o*** 7 yl)methyl)-N-(2-propylpyridin-3- / 0 °^ T / ^X °J O\ / / o'O"° ~ yl)benzenesulfonamide o o O o / o°o \5 O / o / O / o N-(5-((4-((3-(2-(3,4- Q o>Q;OoO / / / / o - - - dimethoxy phenyl) -2- oxoethyl) - 3 - / 269 / ° methyl -2- oxoindolin- 1 - d r >>> °o:° yl)methyl)phenyl)sulfonamido)-6- methy Ipy ri din- 3 -yl) acetamide CK O->°0>°°O-- 4-((3-(2-(3,4-dimethoxyphenyl)-2- d oxoethyl)-3-methyl-2-oxoindolin-l- 270 \TC / ' ° yl)methyl)-N-(5-((l-methylpiperidin- J d Z / 'WI i °~i 4-yl)oxy)pyridin-3- i df )d^ 6wxWI^ ° °~' yl)benzenesulfonamide x ° 4-((3-(2-(3,4-dimethoxyphenyl)-2- xA dldiT^ ° °zA dfl dn "" oxoethy 1) -3,7- dimethy 1-2- oxoindolin- 271 j q ' l-yl)methyl)-2-methyl-N-(2- 0 cr z^^ methylpyridin-3- 1 yl)benzenesulfonamide4-((3-(2-(3,4-dimethoxyphenyl)-2- oxoethy 1) -3,7- dimethy 1-2- oxoindolin- 272 1 -yl)methyl)-2-ethyl-N-(2- methylpyridin-3- yl)benzenesulfonamide 4-((3-(2-(3,4-dimethoxyphenyl)-2- oxoethy 1) -3,7- dimethy 1-2- oxoindolin- 273l-yl)methyl)-N-(2-methylpyridin-3- yl)benzenesulfonamide (S)-4-((3-(2-(3,4-dimethoxyphenyl)- 2-oxoethyl)-3,7-dimethyl-2- 274 oxoindolin-l-yl)methyl)-N-(2- methylpyridin-3- yl)benzenesulfonamide (R)-4-((3-(2-(3,4-dimethoxyphenyl)- 2-oxoethyl)-3,7-dimethyl-2- 275 oxoindolin-l-yl)methyl)-N-(2- methylpyridin-3-yl)benzenesulfonamideAttorney Docket No. 57547-742.601Ex. Structure NameN-(2-aminopyridin-3-yl)-4-((3-(2- (3,4-dimethoxyphenyl)-2-oxoethyl)- 2763,7- dimethyl -2-oxoindolin- 1 - yl)methyl)benzenesulfonamide f zco=\- w N-(4-aminopyridin-3-yl)-4-((3-(2- O. P _y0^(3,4-dimethoxyphenyl)-2-oxoethyl)- 277 ° ° z z._I w.2° ^ 3,7- dimethyl -2-oxoindolin- 1 - NH2O yl)methyl)benzenesulfonamide 4-((3-(2-(4-fluoro-3-methoxyphenyl)- _ O r^F2-oxoethyl)-3-methyl-2-oxoindolin-l- 278 NH s'T5^, IN=< Wo^N° IT yl)methyl)-N-(2-methylpyridin-3- \ W o yl)benzenesulfonamide o / o = (S)-4-((3-(2-(4-fluoro-3- s°*oU3(" A F methoxyphenyl)-2-oxoethyl)-3- / u. o / " / u. PVNHY^ rU ij 279 methyl-2-oxoindolin-l-yl)methyl)-N- o o o / o / O / o (2-methylpyridin-3- \ W o / 0 yl)benzenesulfonamide o o o4-((3-(2-(4-fluoro-3-methoxyphenyl)- 2-oxoethyl)-3-methyl-2-oxoindolin-l- 280yl)methyl)-N-(4-methylthiazol-5- ir f yl)benzenesulfonamide O-- 4-((3-(2-(4-fluoro-3-methoxyphenyl)- 2-oxoethyl)-3-methyl-2-oxoindolin-l- 281 9 d d y l)methy 1) -N- (3 -methy li sothi azol -4-_WI'O> _^ O^T °t \I f yl)benzenesulfonamide O Z f £ o o'4-((3-(2-(3,4-dimethoxyphenyl)-2-n c \T / " \ Hwz- oxoethyl)-3-methyl-2-oxoindolin-l-z \=282 yl)methyl)-2-fluoro-N-(3- methylisothiazol-4- yl)benzenesulfonamide 4-((3-(2-(3,4-dimethoxyphenyl)-2- oxoethyl)-3-methyl-2-oxoindolin-l- 283 yl)methyl)-2-fluoro-N-(4- methylthiazol-5- yl)benzenesulfonamide 4-((3-(2-(3-(dimethylamino)-4- °.,9 4 methoxy phenyl) -2- oxoethyl) -3,7- 285 dimethyl-2-oxoindolin-l-yl)methyl)- n^-xiN= / N-(2-methylpyridin-3-xoyl)benzenesulfonamide (R)-4-((3-(2-(3-(dimethylamino)-4- methoxy phenyl) -2- oxoethyl) -3,7- 286 dimethyl-2-oxoindolin-l-yl)methyl)- Ir V o N-(2-methylpyridin-3-xo yl)benzenesulfonamide (S)-4-((3-(2-(3-(dimethylamino)-4- methoxy phenyl) -2- oxoethyl) -3,7- °'° y-v^287 dimethyl-2-oxoindolin-l-yl)methyl)- N=< \ N-(2-methylpyridin-3-x0 yl)benzenesulfonamideAttorney Docket No. 57547-742.601Ex. Structure NameN-(5-aminopyridin-3-yl)-4-((3-(2- (3,4-dimethoxyphenyl)-2-oxoethyl)- 2883 -methyl -2- oxoindolin- 1 - yl)methyl)benzenesulfonamide N-(5-amino-2-methylpyridin-3-yl)-4- ((3-(2-(3,4-dimethoxyphenyl)-2- 289oxoethyl)-3-methyl-2-oxoindolin-l- yl)methyl)benzenesulfonamide 2-amino-4-((3-(2-(3,4- dimethoxyphenyl)-2-oxoethyl)-3,7- 290 dimethyl-2-oxoindolin-l-yl)methyl)- N-(2-methylpyridin-3- yl)benzenesulfonamide N-(4-((3-(2-(3,4-dimethoxyphenyl)-2- N-VHHO / TS q o / / ^" oxoethyl)-7-(hydroxymethyl)-3- \^k -N^A\^^y==d / K-y \ o / o / / \ / 291 o o o methy 1 -2- oxoindolin- 1 - o o yl)methyl)phenyl) - 1 -methyl- 1 H- 0 Q pyr azol e- 5 - sulfonamide N-(4-((7-cyano-3-(2-(3,4- / " V H / A 9 \ ° / °- Vk VV zO~, 1 dimethoxy phenyl) -2- oxoethyl) - 3 - 292 ^o zCx-d / W1 H M methyl -2- oxoinO Ozz-- / ' \\ / z — n dolin- 1 - yl)methyl)phenyl) - 1 -methyl- 1 H- cA° O pyr azol e- 5 - sulfonamide d d.3dwx- O' N-(4-((7-cyclopropyl-3-(2-(3,4- z / / \xc / z °' OOW==<N> Z \0Z T dimethoxy phenyl) -2- oxoethyl) - 3 - i °1293 methyl -2- oxoindolin- 1 - K, / r nz: A^z z kx yl)methyl)phenyl) - 1 -methyl- 1 H-q eq eI I.d’ tz pyr azol e- 5 - sulfonamide N VNH p\\ / / 0N^dl H i — X N-(4-((3-(2-(3 / l-dimethoxyphenyl)-2- oxoethy 1) -3,7- dimethy 1-2- oxoindolin- 294 o '' / V l-yl)methyl)-3- ° A / 1 dj\ methylphenyl)pyridine-4-sulfonamide1o4-((4-(2-(3,4-dimethoxyphenyl)-2- o<° J3 oxoethyl)-3-oxo-3,4- 295 dihydroisoquinolin-2(lH)-yl)methyl)- QN" X^A\y N-(2-methylpyridin-3-XO W-'Oyl)benzenesulfonamide 14-((3-(2-(3,4-dimethoxyphenyl)-2- oxoethyl)-2-oxo-3,4-dihydroquinolin- 296 1 (2H)-yl)methyl)-N-(2- methylpyridin-3- yl)benzenesulfonamide (S)-4-((3-(2-(3,4-dimethoxyphenyl)- 2-oxoethyl)-2-oxo-3,4- 297N5=r ~N\ / dihydroquinolin- 1 (2H)-yl)methyl)-N- 'H(2-methylpyridin-3- yl)benzenesulfonamide arbitrarily assignedAttorney Docket No. 57547-742.601Ex. Structure Name(R)-4-((3-(2-(3,4-dimethoxyphenyl)- 2-oxoethyl)-2-oxo-3,4- 298 dihydroquinolin- 1 (2H)-yl)methyl)-N- (2-methylpyridin-3- arbitrarily assigned yl)benzenesulfonamide (Z)-4-((3-(2-(3,4-dimethoxyphenyl)- 2- (hydroxy imino) ethyl) -3,7 - dimethyl- 299A 2-oxoindolin-l-yl)methyl)-N-(2- methylpyridin-3- yl)benzenesulfonamide (E)-4-((3-(2-(3,4-dimethoxyphenyl)- 2- (hydroxy imino) ethyl) -3,7 - dimethyl- 299B 2-oxoindolin-l-yl)methyl)-N-(2- methylpyridin-3- yl)benzenesulfonamideN=\ / J / / O °U H n O 2-(3-hydroxy-2-oxo-l-(4-(pyridine-4- 300, S H I \ / z ^ ZXN o o Q sulfonamido)benzyl)indolin-3-yl)-N-00 UJU-N^fxoHzphenylacetamide\\1 o X 1O^Sc0 'T J oJ —N=\U H CR O O fU--- X 2-(3-hydroxy-2-oxo-l-(4-(pyridine-4- °? O301 <s A^ n \ \ / / sulfonamido)benzyl)indolin-3-yl)-N-0o N ' methyl-N-phenylacetamide od p Y*XOTT~ °\OvZ X2-(3-hydroxy-l-(4-((l-methyl-lH- 302 X ° pyrazole)-5-sulfonamido)benzyl)-2- f fiXix M °oxoindolin-3-yl)-N-phenylacetamide DHN-(2-fluorophenyl)-2-(3-hydroxy-2- n o n oxo- 1 -(4-(pyridine-4- 303sulfonamido)benzyl)indolin-3- °-bH Fyl)acetamide 0N=\H r Vx304 ^9HKN^ ex 2-(3-hydroxy-2-oxo-l-(4-(pyridine-4- -S n [ V Z N sulfonamido)benzyl)indolin-3-yl)-N-0'bH(pyridin-3-yl)acetamide 0ZN=\ ^N.w H r305 V=\? PHoKM / C^N' 2-(3-hydroxy-2-oxo-l-(4-(pyridine-4- sulfonamido)benzyl)indolin-3-yl)-N- 'S n r \ / Z N( 1 -methyl- lH-pyrazol-4-yl)acetamide0o UAUA\H0N=\N-(4-fluorophenyl)-2-(3-hydroxy-2- M H O 0 ( ) oxo- 1 -(4-(pyridine-4- 306 xS H i v z ^N sulfonamido)benzyl)indolin-3- °^b Uk / N^fHyl)acetamideO2-(3-hydroxy-l-(4-((l-methyl-lH- M H / / 7 0 \ },s' Y |I r V AN 307 imidazole)-5-sulfonamido)benzyl)-2- ° 'O H oxoindolin-3-yl)-N-phenylacetamide0Attorney Docket No. 57547-742.601Ex. Structure Name2-(3-hydroxy-2-oxo-l-(4-(thiazole-5- 308 sulfonamido)benzyl)indolin-3-yl)-N- phenylacetamideN-(4-((3-(2-(2,3-dihydro-4H- benzo [b] [ 1, 4] oxazin-4-y l)-2- 309 oxoethyl)-3-hydroxy-2-oxoindolin-l- yl)methyl)phenyl)pyridine-3- sulfonamide / =NN-(bicy clo[ 1.1.1] pentan- 1 -yl)-2-(3- W H OnO. 0 hydroxy-2-oxo-l-(4-(pyridine-3- 310 WOo-b H sulfonamido)benzyl)indolin-3- 0 yl)acetamide / =NO H C 9, O 2-(3-hydroxy-2-oxo-l-(4-(pyridine-3- 311 sulfonamido)benzyl)indolin-3-yl)-N- 'o O O (oxazol-2-yl)acetamide 0 oHZX c o / =N XO H A312 oJ oJ X 1 \ < °?. O 2-(3-hydroxy-2-oxo-l-(4-(pyridine-3- YO r / , —CO sulfonamido)benzyl)indolin-3-yl)-N- '0 UU oOh(thiazol-2-yl)acetamideN0=\, —(S)-2-(3-methyl-2-oxo-l-(4-(pyridine- 313A MHd O °< O r v ZO~~N 4-sulfonamido)benzyl)indolin-3-yl)- °" X / <x\obIZ IZVJ0HN-phenylacetamideN0=\OhCo 0 (R)-2-(3-methyl-2-oxo-l-(4- (pyridine-4- 313B ON>^> rO""o CC^O^Hsulfonamido)benzyl)indolin-3-yl)-N- o phenylacetamideN=\ x-^ N-methyl-2-(3-methyl-2-oxo-l-(4- 0HCo 0 (pyridine-4- 314,s n r \ / z^N0'b YY~^'N'Y / ' sulfonamido)benzyl)indolin-3-yl)-N- o phenylacetamide / =N2-(3-methyl-2-oxo-l-(4-(pyridine-3- 315 OhC 0ONY^ Y\ON sulfonamido)benzyl)indolin-3-yl)-N- °''b UMOHphenylacetamide0 / =Nx-^ N-methyl-2-(3-methyl-2-oxo-l-(4- O H o o (pyridine-3- 316 >*o YON0'oN / sulfonamido)benzyl)indolin-3-yl)-N- o phenylacetamide / =Nx-^o H c? o N-methyl-2-(2-oxo-l-(4-(pyridine-3- 317 Cs'No MON^ sulfonamido)benzyl)indolin-3-yl)-N- o o YYY / n~~v ' ' phenylacetamide0 / =Nx^O H O 0 O 2-(2-oxo- 1 -(4-(pyridine-3- 318 O'N^v rONsulfonamido)benzyl)indolin-3-yl)-N- °' o OoHphenylacetamide0Attorney Docket No. 57547-742.601Ex. Structure NameN-(2-fluorophenyl)-2-(2-oxo-l-(4- O H O ° O (pyridine-4- 319 rUO0'oH Fsulfonamido)benzyl)indolin-3- o yl)acetamideN=\2-(3,7-dimethyl-2-oxo- 1 -(4-(pyridine- 320 4-sulfonamido)benzyl)indolin-3-yl)- ° O ZI 'o kJOHN-phenylacetamide0N z —,M H p / / 7 0 \ ) 2-(3-methyl-l-(4-((l -methyl- 1H- 321 pyrazole)-5-sulfonamido)benzyl)-2- °' 'b J pyHoxoindolin-3-yl)-N-phenylacetamide 0IZ Q H A 0 0 2-(3-methyl-2-oxo-l-(4- 322 (phenylsulfonamido)benzyl)indolin-0Oh3-yl)-N-phenylacetamideO a / =N <° / 1 FP 0 2-(3-methyl-l-(4-(N-methylpyridine- 323 3 - sulfonami do)benzy 1) -2- oxoindolin-0b O pH3-yl)-N-phenylacetamide03,4-dimethoxy-N-(3-methyl-2-oxo-l- (4-(pyridine-3- 324sulfonamido)benzyl)indolin-3- yl)benzamide / N=\ p- 3,7-dimethyl-2-oxo-l-{[4-(pyridine- W H J / °4 / ={ 4-sulfonamido)phenyl] methyl} -2, 3- 325dihydro-lH-indol-3-yl 3,4- Axdimethoxybenzoate00 — 3,7 -dimethyl- 1 - { [4-(N- methylpyridine-4- 326 O 1 P / °\\ / ={ amido)phenyl]methyl} -2-oxo-2,3- T 1xo PP / Np dihydro-lH-indol-3-yl 3,4-0 dimethoxybenzoateor a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.Further Forms of Compounds Disclosed HereinIsomers / Stereoisomers

[0124] 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,Attorney Docket No. 57547-742.601mixtures 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, separating 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

[0125] 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,170,31P,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.

[0126] 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 saltsAttorney Docket No. 57547-742.601

[0127] 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.

[0128] 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.

[0129] 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.

[0130] 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,Attorney Docket No. 57547-742.601other 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.

[0131] 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 acceptable metal 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.

[0132] 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

[0133] 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.

[0134] 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

[0135] 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 CompanyAttorney Docket No. 57547-742.601(Rochester, NY), Fisher Scientific Co. (Pitsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, U. K.), Lancaster Synthesis (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).

[0136] 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.

[0137] 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.Attorney Docket No. 57547-742.601Methods of Treatment

[0138] 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.

[0139] 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.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, non-Hodgkin's lymphoma, hairy cell lymphoma and Burket'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.

[0140] 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.

[0141] In some embodiments, the inhibition of KIF22 occurs in a tumor cell in the subject in need thereof.Attorney Docket No. 57547-742.601Dosing

[0142] In certain embodiments, the compositions containing the compound(s) described herein are administered for prophylactic and / or therapeutic treatments. In certain therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient’s health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation and / or dose ranging clinical trial.

[0143] When used in patients, effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient’s health status and response to the drugs, and the judgment of the treating physician. In one aspect, prophylactic treatments include administering to a mammal, who previously experienced at least one symptom of or risk factor for the disease being treated and is currently in remission, a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, in order to prevent a return of the symptoms of the disease or condition.

[0144] In certain embodiments wherein the patient’s condition does not improve, upon the doctor’s discretion the compounds are administered chronically, that is, for an extended period of time, including throughout the duration of the patient’s life in order to ameliorate or otherwise control or limit the symptoms of the patient’s disease or condition.

[0145] Once improvement of the patient’s conditions has occurred, a maintenance dose is administered if necessary. Subsequently, in specific embodiments, the dosage, or the frequency of administration, or both, is reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. In certain embodiments, however, the patient requires intermittent or daily treatment on a longterm basis upon any recurrence of symptoms.

[0146] The amount of a given agent that corresponds to such an amount varies depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight, sex) of the subject or host in need of treatment, but nevertheless is determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated.Routes of Administration

[0147] 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.Attorney Docket No. 57547-742.601

[0148] In certain embodiments, a compound as described herein is administered in a local rather than systemic manner, for example, via injection of the compound directly into an organ, often in a depot preparation or sustained release formulation. In specific embodiments, long-acting formulations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection Furthermore, in other embodiments, the drug is delivered in a targeted drug delivery system, for example, in a liposome coated with organ specific antibody. In such embodiments, the liposomes are targeted to and taken up selectively by the organ. In yet other embodiments, the compound as described herein is provided in the form of a rapid release formulation, in the form of an extended-release formulation, or in the form of an intermediate-release formulation. In some embodiments, the compound described herein is administered topically.Pharmaceutical Compositions / F ormulat ions

[0149] 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.

[0150] 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.EXAMPLESGeneral procedures:

[0151] All final compounds were purified by either high-performance liquid chromatography (HPLC) or supercritical fluid chromatography (SFC) and were characterized by proton (¹H) NMR. All chemicals were purchased from commercial suppliers and used as received unless otherwise indicated. Proton nuclear magnetic resonance (¹H NMR) spectra were recorded on Bruker AVANCE 300 or 400 MHz spectrometers. Chemical shifts are expressed in 5 ppm and are calibrated to the residual solvent peak. Coupling constantsAttorney Docket No. 57547-742.601(J), when given, are reported in hertz. Multiplicities are reported using the following abbreviations: s = singlet, d = doublet, dd = doublet of doublets, t = triplet, q = quartet, m = multiplet (range of multiplet is given), br = broad signal, and dt = doublet of triplets.LC / MS conditions:

[0152] Method 1: Waters Cortecs Cl 8+ column, 2.7 pm, 2.1 mm x 30 mm; column temperature 45 °C; mobile phase, acetonitrile(+0.05% formic acid):water(+0.05% formic acid); gradient, 5% acetonitrile to 95% acetonitrile in 1.0 min, hold 1.0 min, total 2.5 min; flow rate 1.8 mL / min; UV detection (λ = 214, 254 nm).

[0153] Method 2: Shim-pack Scepter Cl 8- 120+ column, 3.0 pm, 3.0 mm x 33 mm; column temperature 40 °C; mobile phase, acetonitrile: water(+0.05% NH4HCO3); gradient, 5% acetonitrile to 95% acetonitrile in 2.0 min, total 2.0 min; flow rate 1.5 mL / min; UV detection (X = 220, 254 nm).

[0154] Method 3: HALO 90A Cl 8+ column, 2.0 pm, 3.0 mm x 30 mm; column temperature 40 °C; mobile phase, acetonitrile: water(+0.1% formic acid); gradient, 5% acetonitrile to 95% acetonitrile in 2.0 min, total 2.0 min; flow rate 1.2 mL / min; UV detection (X = 220, 254 nm).

[0155] Method 4: Agilent 6125; Column: Waters Cortecs C18+, 2.7um 30 mm; Mobile phase: ACN (0.05% FA)-Water (0.05% FA); Gradient: 5% ACN to 95% ACN in 1.0 min, hold 1.0 min, total 2.5 min; Flow 1.8 mL / min; Column Temp:45 degree.

[0156] Method 5: Shimadzu LCMS-2020 Single Quadrupole Liquid Chromatograph Mass Spectrometer, Waters Acquity UPLC BEH C18 column 130 A, 1.7 pm, 2.1 x 100 mm, column temperature 25°C; mobile phase, acetonitrile (+0.1% formic acid): water (+0.1% formic acid); flow rate 0.5 mL / min; UV detection at 254 nm and 280 nm

[0157] Method 6: Dionex UHPLC Ultimate 3000 with DAD detector / Thermo Scientific ISQ EC; Kinetex XB-C18 column 110A, 2.6 pm, 4.6 mm x 50 mm; column temperature 25°C; mobile phase, acetonitrile (+0.1% formic acid): water (+0.1% formic acid); flow rate 1.0 mL / min; UV detection at maximum absorption (λ range: 190-340 nm).Preparative HPLC methods:

[0158] Method A: Shimadzu LH-40 Prep HPLC. Column: Gemini 5 pmNX-C18 110 A, 150 x 21.2mm; Mobile Phase A: Water with 0.1% formic acid, Mobile Phase B: CAN with 0.1% formic acid; flow rate: 20ml / min; Gradient: 0% B to 100% B in 15min; UV Wave Length: 254nm; ELSD-LT II

[0159] Method B: Teledyne ACCQ Prep HP 150. Column: RediSep Prep C18, 100 A, 150 x 20 mm;; Mobile Phase A: Water with 0.1% formic acid, Mobile Phase B: CAN with 0.1% formic acid; flow rate: 20ml / min; Gradient: 0% B to 100% B in 15min; UV Wave Length: 254nm / 220nm

[0160] Method C: Column: YMC-Actus Triart C 18ExRS, 30*150 mm, 5pm; Mobile Phase A:Water(10mmol / L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 26% B to 56% B in 8 min; Wave Length: 254nm / 220nm nm; RTl(min): 6.85Attorney Docket No. 57547-742.601

[0161] Method D: Column: XselectCSH Prep OBD C18 Column, 30*150 mm, 5pm; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 22% B to 52% B in 8 min; Wave Length: 254nm / 220nm nm; RTl(min): 7.77

[0162] Method E: Daisogel-C18-10-100, 30 x 250 mm, 5 pm, mobile phase: ACN-H2O (0.1%FA), gradient: 5 ~ 95

[0163] Method F: HPLC Shimadzu Preparative System with Photodiode Array Detector - SPD-M20A / SPD-20a (Dual-wavelength detection); Gemini NX-C18 column, 5 pm, 21.2 mm x 250 mm; mobile phase, acetonitrile(+0.1% formic acid):water(+0.1% formic acid)

[0164] Method G: Waters Purification System; HPLC Photodiode Array Detector - Waters 2998, MS Detector - QDa detector; Gemini NX-C18 column, 5 pm, 21.2 mm x 250 mm; mobile phase, acetonitrile (+0.1% formic acid):water(+0.1% formic acid)Chiral HPLC methods:

[0165] Method A: Column: CHIRAL ART Cellulose-SB, 2*25 cm, 5 pm; Mobile Phase A: MtBE(0.5% 2M NH3-MeOH)— HPLC, Mobile Phase B: IPA— HPLC; Flow rate: 20ML / MIN mL / min; Gradient: isocratic 10; Wave Length: 254 / 220nmnm; RTl(min): 7.995; RT2(min): 9.744; Sample Solvent: EtOH— HPLC; Injection Volume: 0.5 mL

[0166] Method B: Lux A2, 5 pm, 21.2 mm x 250 mm; column temperature 25°C; mobile phase, isocratic 35:65 EtOH: CO2 (0.2% v / v NH3), flow rate 50 mL / min; UV detection at maximum absorptionPreparation of IntermediatePreparation of 3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-3-hydroxy-l-(4-((methylamino)methyl)benzyl) indolin-2-oneCBr4, PPh3, DCM, 0 °C, 30 min Step 1Step 1: Preparation of tert-butyl (4-(bromomethyl)benzyl)(methyl)carbamate

[0167] To a mixture of tert-butyl (4-(hydroxymethyl)benzyl)(methyl)carbamate (350 mg, 1.39 mmol) and PPh3 (73 mg, 0.28 mmol) in DCM (15 mL) at 0 °C was added CBr4 (920 mg, 2.77 mmol). The mixture was stirred at 0 °C for 30 minutes. The solvent was removed in vacuo to give the crude, which was purified byAttorney Docket No. 57547-742.601silica gel flash column chromatography (EtOAc in petroleum ether: 0-20%) to afford tert-butyl (4-(bromomethyl)benzyl)(methyl) carbamate (300 mg, 68.7% yield) as a light yellow solid.Step 2: Preparation of tert-butyl (4-((2,3-dioxoindolin-l-yl)methyl)benzyl)(methyl)carbamate

[0168] A mixture of tert-butyl (4-(bromomethyl)benzyl)(methyl)carbamate (300 mg, 0.96mmol), indoline-2, 3-dione (169 mg, 1.114 mmol) and Cs2CO3(930 mg, 2.85 mmol) in DCE (10 mL) was stirred at 50 °C overnight. The reaction mixture was poured into water and extracted with EtOAc (3 x 30 mL). The combined organic phases was concentrated in vacuo to give the crude product, which was purified by silica gel flash column chromatography (EtOAc in petroleum ether: 0-25%) to afford tert-butyl (4-((2,3-dioxoindolin-l-yl)methyl)benzyl)(methyl)carbamate (267 mg, 73.3% yield) as a white solid. ESI-LCMS calcd. for C22H24N2O4 [M+H]+ 380.17, found 381.17.Step 3: Preparation of tert-butyl (4-((3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-3-hydroxy-2-oxoindolin-l-yl)methyl)benzyl)(methyl)carbamate

[0169] A mixture of tert-butyl (4-((2,3-dioxoindolin-l-yl)methyl)benzyl)(methyl)carbamate (267 mg, 0.7 mmol), l-(3,4-dimethoxyphenyl)ethan-l-one (151.8 mg, 0.84 mmol) and Di ethylamine (204.4 mg, 2.8 mmol) in EtOH (10 mL) was stirred under nitrogen at 25 °C overnight. The solvent was removed in vacuo to give the crude, which was purified by silica gel flash column chromatography (EtOAc in petroleum ether: 0-30%) to afford tert-butyl (4-((3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-3-hydroxy-2-oxoindolin-l-yl)methyl)benzyl)(methyl)carbamate (180 mg, 45.9% yield) as yellow solid. ESI-LCMS mass calcd. for C32H36N2O7 [M+H]+ 560.25, found 561.25.Step 4: Preparation of 3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-3-hydroxy-l-(4-((methylamino)methyl)benzyl)indolin-2-one

[0170] Tert-butyl (4-((3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-3-hydroxy-2-oxoindolin-l-yl)methyl)benzyl)(methyl)carbamate (180 mg, 0.32 mmol) was dissolved in a mixed solvent (1,4-dioxane-HC1: DCM= 1:5, 12 mL) and the mixture was stirred under nitrogen at 25°C for 1 hour. The solvent was removed in vacuo to give the crude, which was purified by silica gel flash column chromatography (EtOAc in petroleum ether: from 0% to 20%)) to afford 3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-3-hydroxy-l-(4-((methylamino)methyl)benzyl)indolin-2-one (140 mg, 94% yield) as yellow solid. ESI-MS calcd. for C27H28N2O5 [M+H]+460.20, found 461.20.Preparation of l-(4-(dimethylamino)-3-methoxyphenyl)ethan- 1-oneStep 1: Preparation of 4-(dimethylamino)-N,3-dimethoxy-N-methylbenzaniide

[0171] To a stirred mixture of 4-(dimethylamino)-3-methoxybenzoic acid (300 mg, 1.537 mmol, 1 equiv.) and N, O-dimethylhydroxylamine hydrochloride (179.87 mg, 1.844 mmol, 1.2 equiv.) in DCM (5 mL) were added DIPEA (595.86 mg, 4.611 mmol, 3 equiv.) and HATU (876.49 mg, 2.305 mmol, 1.5 equiv.) inAttorney Docket No. 57547-742.601portions at room temperature. The resulting mixture was stirred at rt for Ih. The resulting mixture was extracted with CH2CI2 (3 x 10 mL). The combined organic layers were washed with brine (1x10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (60% EtOAc in PE) to afford 4-(dimethylamino)-N,3-dimethoxy-N-methylbenzamide (150 mg, 40.96%) as ayellow solid. MS (ESI): mass cal cd. for C12H18N2O3 238.29; [M+H] + found 239.10. LCMS (method 2): Rt = 0.601 min.Step 2: Preparation of l-[4-(dimethyIamino)-3- meth oxyphenyl] ethanone

[0172] To a stirred mixture of 4-(dimethylamino)-N,3-dimethoxy-N-methylbenzamide (160 mg, 0.671 mmol, 1 equiv.) in THF (5 mL) was added CH3MgBr (0.85 mL, 2.536 mmol, 3.78 equiv.) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred at rt for 2h under nitrogen atmosphere. The reaction was quenched with sat. NH4CI (aq.) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 20mL). The combined organic layers were washed with brine (1 x lOmL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA 1:1) to afford l-[4-(dimethylamino)-3-methoxyphenyl] ethanone (100 mg, 77.1%) as ayellow solid. MS (ESI): mass calcd. for C11H15NO2 193.25; [M+H]+found 194.10. LCMS (Method 4): Rt = 0.481 min.

[0173] The following intermediates were prepared by the same general method as for l-[4-(dimethylamino)-3-methoxyphenyl] ethanoneExact LC-MS [M+l] Structuremass (m / z)O194.23 195.10Preparation of 1- [3-(dimethylamino)-4- meth oxyphenyl] ethanone / NH

[0174] Into a 30mL vial were added l-(3-bromo-4-methoxyphenyl)ethanone (500 mg, 2.183 mmol, 1 equiv.), dimethylamine hydrochloride (177.98 mg, 2.183 mmol, 1.0 equiv.), Pd2(dba)3 (99.94 mg, 0.109 mmol, 0.05 equiv.), RuPhos (101.86 mg, 0.218 mmol, 0.1 equiv.), CS2CO3 (2133.51 mg, 6.549 mmol, 3 equiv.) and dioxane (5 mL) at room temperature. The resulting mixture was stirred at 100°C under nitrogen atmosphere overnight. The resulting mixture was filtered, the filter cake was washed with EtOAc (3x10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA=5: l)to afford 1- [3 -(dimethylamino) -4-methoxyphenyl] ethanone (150 mg, 35.6%)Attorney Docket No. 57547-742.601as ayellow oil. MS (ESI): mass calcd. for C11H15NO2193.25; [M+H]+found 194.10. LCMS (Method 4): Rt = 0.315 min.

[0175] The following intermediates were prepared by the same general method as for l-[3-(dimethylamino)-4-methoxyphenyl] ethanoneExact LC-MS [M+l] Structuremass (m / z)I 1uC 181.21 182.05Preparation of l-(3-morpholinophenyl)ethan- 1-oneOHStep 1: Preparation of l-(3-morpholinophenyl)ethan-l-ol

[0176] To a stirred solution of 3-(morpholin-4-yl)benzaldehyde (500 mg, 2.615 mmol, 1 equiv.) in THF (5 mL) was added MeMgBr (2614.65 pL, 7.845 mmol, 3 equiv.) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred at rt for Ih under nitrogen atmosphere. The reaction was quenched with sat. NH4CI (aq.) at 0°C. The resulting mixture was extracted with EtOAc (3 x lOmL). The combined organic layers were washed with brine (1x10 mL), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA =1 / 1) to afford l-(3-morpholinophenyl)ethan-l-ol (520 mg, 86%) as ayellow solid. MS (ESI): mass calcd. for C12H17NO2 207.27; [M+H]+ found 208.20.Step 2: Preparation of l-(3-morpholinophenyl)ethan-l-one

[0177] To a stirred solution of l-(3-morpholinophenyl)ethan-l-ol (520 mg, 2.509 mmol, 1 equiv.) in DCM (10 mL) was added Martin’s reagent (1.17 g, 2.760 mmol, 1.1 equiv.) in portions at room temperature. The resulting mixture was stirred at rt for Ih. The resulting mixture was extracted with EtOAc (3 x lOmL). The combined organic layers were washed with brine (1x10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA=l / l)to afford l-(3-morpholinophenyl)ethan-l-one (360 mg, 69.9%) as ayellow oil. MS (ESI): mass calcd. for C12H15NO2 205.26; [M+H]+ found 205.90.Preparation of 3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-3-hydroxy-l-(4- (hydroxymethyl) benzyl)ind olin-2- oneAttorney Docket No. 57547-742.601Step 1: Preparation of (4-(((tert-butyldiphenylsilyl)oxy)methyl)phenyl)methanol

[0178] To a mixture of 4-(hydroxymethyl)phenyl]methanol (5g, 36.19 mmol), imidazole (3.66 g, 36.19 mmol) in DCM(20 mL) was added l-l-tert-butyl-l-l-chloro-l-l,l-l-diphenylsilane (8.95 g, 32.58 mmol) slowly at 0°C under nitrogen. The reaction mixture was stirred at 25 °C for 12 hours. The solvent was removed in vacuo to give the crude, which was purified by silica gel flash column chromatography (EtOAc in petroleum ether: 0-20%) to afford (4-(((tert-butyldiphenylsilyl)oxy)methyl)phenyl)methanol (6 g, 44% yield) as a colorless oil. ESI-MS (ESI) calcd. for C24H28O2Si [M+H]+376.18, found 377.19.Step 2: Preparation of ((4-(bromomethyl)benzyl)oxy)(tert-butyl)diphenylsilane

[0179] To a mixture of (4-{1-[tert-butyl(phenyl)silyl]phenoxymethyl}phenyl)methanol (2.0 g, 5.3 mmol) and CBt4 (2.64 g, 7.95 mmol) in DCM (20 mL) was added PPh3(2.09 g, 7.95 mmol) slowly at 0°C under nitrogen. The reaction mixture was stirred at 0 °C for 30 mins. The solvent was removed in vacuo to give the crude, which was purified by silica gel flash column chromatography (EtOAc in petroleum ether: 0-20%) to afford ((4-(bromomethyl)benzyl)oxy)(tert-butyl)diphenylsilane (2.2 g, 94.2% yield) as ayellow oil. ESI-MS calcd. for C24H27BrOSi [M+H]+ 438.10 and 440.10, found 439.10 and 441.10.Step 3: Preparation of l-(4-(((tert-butyldiphenylsilyl)oxy)methyl)benzyl)indoline-2, 3-dione

[0180] A mixture of ((4-(bromomethyl)benzyl)oxy)(tert-butyl)diphenylsilane (2.2 g, 5.01 mmol), indoline-2, 3-dione (0.88 g, 6.01 mmol), CS2CO3 (3.26 g, 10.02 mmol) in DCE (20 mL) was stirred at 50 °C overnight. LCMS showed the reaction was finished. The reaction mixture was concentrated in vacuo. Then EtOAc (50 mL) was added and the mixture was washed with water (50 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated in vacuo. The residue was purified by silica gel flash column chromatography (EtOAc in petroleum ether: from 0% to 50%)) to afford l-(4-(((tert-butyldiphenylsilyl)oxy)methyl)benzyl)indoline-2, 3-dione (2.3 g, 90.86% yield) as yellow oil. ESI-MS calcd for C32H31NO3Si [M+H]+ 505.2, found 506.2.Step 4: Preparation of l-(4-(((tert-butyldiphenylsilyl)oxy)methyl)benzyl)-3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-3-hydroxyindolin-2-one

[0181] A mixture of ((4-(bromomethyl)benzyl)oxy)(tert-butyl)diphenylsilane (2.3 g, 4.5 mmol), l-(3,4-dimethoxyphenyl)ethan-l-one (0.97 g, 5.4 mmol), piperdine (0.57 g, 6.75 mmol) in EtOH (20 mL) was stirred at room temperature overnight. LCMS showed the reaction was finished. The reaction mixture was concentrated in vacuo, then EtOAc (20 mL) was added into the residue and the mixture was washed withAttorney Docket No. 57547-742.601water (20 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated in vacuo. The residue was purified by silica gel flash column chromatography (EtOAc in petroleum ether: from 0% to 50%)) to afford 1-(4-(((tert-butyldiphenylsilyl)oxy)methyl)benzyl)-3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-3-hydroxyindolin-2-one (2.0 g, 64.11% yield) as a yellow oil. ESI-MS calcd. for C42H43NO6Si [M+H]+685.26, found 686.29.Step 5: Preparation of 3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-3-hydroxy-l-(4-(hydroxymethyl) benzyl)ind olin-2- one

[0182] A solution of l-(4-(((tert-butyldiphenylsilyl)oxy)methyl)benzyl)-3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-3-hydroxyindolin-2-one (2.0 g, 2.9 mmol) in THF (20 mL) was cooled to 0°C under nitrogen. Then, HF / pyridine (1.44 g, 14.5 mmol) was added slowly. The reaction mixture was stirred at 25 °C for 4 hours. The solvent was removed in vacuo to give the crude, which was purified by silica gel flash column chromatography (MeOH in DCM: 0-10%) to afford 3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-3-hydroxy-l-(4-(hydroxymethyl)benzyl)indolin-2-one (0.75 g, 57.48% yield) as a yellow solid. ESI-MS calcd. for C26H25NO6 [M+H]+ 447.17, found 448.17.Preparation of 2,4,6-trichlorophenyl 3-methylpyridine-2-sulfonaten-BuLi, THF, ZnCI2

[0183] Into a lOOmL 3-necked round-bottom flask was added 2-bromo-3-methylpyridine (500 mg, 2.907 mmol, 1.0 equiv.) and THF (10 mL) at -78°C. To the above mixture was added n-BuLi in hexanes (1.16 mL, 2.907 mmol, 1.0 equiv.) dropwise at -78°C. The resulting mixture was stirred at -78°C for Ih. Then ZnCh (1.53 mL, 2.907 mmol, 1 equiv.) was added dropwise at -78°C. The resulting mixture was stirred at rt for Ih, followed by additon of 2,4,6-trichlorophenyl sulfurochloridate (860.17 mg, 2.907 mmol, 1.0 equiv.) at 0°C. The reaction mixture was stirred at 0°C for 2h, and then quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 x 35mL). The combined organic layers were washed with brine (1x50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / PE=l / 4) to afford 2,4,6-trichlorophenyl 3-methylpyridine-2-sulfonate (200 mg, 19.5%) as an off-white solid. MS (ESI): mass calcd. for C12H8C13NO3S 352.61; [M+H]+ found 351.80 & 353.75. LCMS (method 3): Rt = 1.028 min.Preparation of 3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-3-hydroxyindolin-2-oneoAttorney Docket No. 57547-742.601

[0184] To a solution of isatin (500 mg, 3.398 mmol, 1.0 equiv.) and l-(3,4-dimethoxyphenyl)ethanone (612.38 mg, 3.398 mmol, 1.0 equiv.) in EtOH (15 mL) was added diethylamine (421.86 pL. 4.078 mmol, 1.2 equiv.) at rt. The resulting mixture was stirred at rt overnight and then concentrated under reduced pressure. The residue was dissolved in EtOAc (20mL) and washed with 2x20 mL of brine. The organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to provide the crude product 3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-3-hydroxyindolin-2-one (1.1 g, 98.89%) as an orange solid, which was directly used in the next step without further purification. MS (ESI): mass calcd. for C18H17NO5327.1; [M+H]+ found 328.1.Preparation of l-(4-aminobenzyl)-3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-3-hydroxyindolin-2-oneStep 1: Preparation of tert-butyl (4-((2,3-dioxoindolin-l-yl)methyl)phenyl)carbamate

[0185] A mixture of tert-butyl (4-(bromomethyl)phenyl)carbamate (500 mg, 1.75 mmol), indoline-2,3-dione (258 mg, 1.75 mmol) and K2CO3 (290 mg, 2.11 mmol) in DMF (5 mL) was stirred at 60 °C for 3 hours. Water (50 mL) was added and the mixture was extracted with EtOAc (30 mL x 3). The combined organic phase was washed with brine (30 mL), dried with anhydrous Na2SO4, filtered and the solvent was removed in vacuo to give the crude, which was purified by silica gel flash column chromatography (EtOAc in petroleum ether: 0-20%) to afford tert-butyl (4-((2,3-dioxoindolin-l-yl)methyl)phenyl)carbamate (600 mg, 97.45% yield) as ayellow solid. ESI-MS calcd. for C20H20N2O4 [M+H]+352.14, found 353.39. Step 2: Preparation of tert-butyl (4-((3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-3-hydroxy-2-oxoindolin-l-yl)methyl)phenyl)carbamate

[0186] Amixture of tert-butyl (4-((2,3-dioxoindolin-l-yl)methyl)phenyl)carbamate (600 mg, 1.70 mmol), l-(3,4-dimethoxyphenyl)ethan-l-one (338 mg, 1.87 mmol) and piperidine (720 mg, 8.5 mmol) in EtOH (4 mL) was stirred at room temperature overnight. The solvent was removed in vacuo to give the crude, which was purified by silica gel flash column chromatography (MeOH in DCM: 0- 10%) to afford tert-butyl (4-((3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-3-hydroxy-2-oxoindolin-l-yl)methyl)phenyl)carbamate (600 mg, 66.16% yield) as ayellow solid. ESI-MS calcd. for C30H32N2O7 [M+H]+532.22, found 533.59.Step 3: Preparation of l-(4-aminobenzyl)-3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-3-hydroxyindolin-2-one

[0187] To a solution of tert-butyl (4-((3-(2-(3.4-dimethox phen l)-2-oxoethyl)-3-hydroxy-2-oxoindolin-l -yl)methyl) phenyl)carbamate (600 mg, 1.13 mmol) in DCM (6 mL) was added TFA (2 mL). The mixtureAttorney Docket No. 57547-742.601was stirred at room temperature for 30 minutes. LCMS showed the reaction was finished. The solvent was evaporated and the residue was redissolved in diethyl ether. The filtration provided 1 -(4-aminobenzyl)-3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-3-hydroxyindolin-2-one (450 mg, 92.36% yield) as ayellow solid. ESIMS calcd. for C25H24N2O5 [M+H]+ 432.17, found 433.48.

[0188] The following compounds were prepared by the same general method as l-(4-aminobenzyl)-3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-3-hydroxyindolin-2-one.Exact LC-MSStructure[M+l] (m / z) massH2Nn X'vCf 460.20 461.4YOHO x0460.20 461.4A / Az OH ''00420.15 421.4\\ FO / AF\ 0—H2NX^\ YY OH ’k / A420.15 421.40387.16 388.30H2N\^\ YY373.14 374.30FF<1FjQ_ / ~NJ / OHO500.16 501.4Ooryy>xH2N XAFYY L II OHzA' x' rY JH2N^A%XNA YA J Y V°\x468.15 469.4YY / 00Attorney Docket No. 57547-742.601Exact LC-MS Structuremass [M+l] (m / z) L II OH464.17 465.4 H2N^A\xnA Y'VjxI K> \) °468.2 469.3 s,J w 0ro~ 1 X\1° °^^r 466.92 467 } C \ \X / "ovp o —JP > 'zo o z XH N ^^C |A V / OH1n1 X1)\ \ ° ° 446.50 447 X ) X ) y ' |]> J> J ooCoPfyr450.47 451 P P M CM C z zI T433.46 434 W ec0 IFA nH2N T^AOH450.16 451 MVNY ^ VAOo '438.2 439.2C Ji OH 0 |443.5 444.2 H2N YX ^M iT^rNVo 0446.2 447.4Attorney Docket No. 57547-742.601Preparation of l-(4-amino-3-fluorobenzyI)-3-(2-(3,4-dimethoxyphenyl)-2-oxoethyI)-3-hydroxyindolin-2-onestep 1 step 2o Step 1: Preparation of l-(3-fluoro-4-nitrobenzyl)indoline-2, 3-dione

[0189] Into a 20 mL vial were added isatin (500 mg, 3.398 mmol, 1.0 equiv.), 4-(bromomethyl)-2-fluoro-1 -nitrobenzene (795.28 mg, 3.398 mmol, 1 equiv.), CS2CO3 (2214.45 mg, 6.796 mmol, 2 equiv.) and DCE (7 mL) at room temperature. The resulting mixture was stirred at 80°C for Ih. The resulting mixture was extracted with EtOAc (3 x 25mL). The combined organic layers were washed with brine (45 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA=5:1) to afford l-(3-fluoro-4-nitrobenzyl)indoline-2,3-dione(800mg, 78.41%) as ayellow solid. MS (ESI): mass calcd. for C15H9FN2O4 300.25; [M+H]+found 300.85. LCMS (Method 4): Rt = 0.88 min.Step 2: Preparation of 3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-l-(3-fluoro-4-nitrobenzyl)-3-hydroxyindolin-2-one

[0190] Into a30mL vial were added l-[(3-fluoro-4-nitrophenyl)methyl]indole-2, 3-dione (800 mg, 2.664 mmol, 1 equiv.), 1 -(3, 4-dimethoxyphenyl)ethanone (480.15 mg, 2.664 mmol, 1.0 equiv.), 1,4-diazabicyclo[2.2.2]octane (149.44 mg, 1.332 mmol, 0.5 equiv.) and H2O (10 mL) at rt. The resulting mixture was stirred at 80°C for 2h. The resulting mixture was extracted with EtOAc (3 x 25mL). The combined organic layers were washed with brine (1x45 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAc=l / 4) to afford 3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-l-(3-fluoro-4-nitrobenzyl)-3-hydroxyindolin-2-one (400 mg, 31.3%) as a tight yellow solid. MS (ESI): mass calcd. for C25H21FN2O7 480.45; [M+H]+ found 481.35. LCMS (Method 4): Rt = 0.87 min.Step 3: Preparation of l-(4-amino-3-fluorobenzyl)-3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-3-hydroxyindolin-2-one

[0191] Into a lOmL vial were added 3-[2-(3,4-dimethoxyphenyl)-2-oxoethyl]-l-[(3-fluoro-4-nitrophenyl)methyl]-3-hydroxyindol-2-one (190 mg, 0.395 mmol, 1 equiv.), Zn(155.13 mg, 2.370 mmol, 6 equiv.), NH4CI (126.92 mg, 2.370 mmol, 6.0 equiv.), EtOH (3 mL) and H2O (0.6 mL) at room temperature. The resulting mixture was stirred at 70°C for 30min. The resulting mixture was filtered, the filter cake was washed with MeOH (3x5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (column, Cl 8 silica gel; mobile phase, MeCN in WaterAttorney Docket No. 57547-742.601(0.1% FA), 10% to 100% gradient in 30 min; detector, UV 254 nm) to provide 1 -(4-amino-3-fluorobenzyl)-3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-3-hydroxyindolin-2-one (100 mg, 56.1%) as a pink solid. MS (ESI): mass calcd. for C25H23FN2O5 450.47; [M+H]+ found 451.10. LCMS (Method 4): Rt = 0.83 min.Preparation of 4-((3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-3-hydroxy-2-oxoindolin-l-yl)methyl)benzoic acidCS2CO3 Step 1Step 1: Preparation of tert-butyl 4-((2,3-dioxoindolin-l-yl)methylbenzoate

[0192] To a solution of tert-butyl 4-(bromomethyl)benzoate (1.00 eq, 1000 mg, 3.69 mmol), 2,3-indolinedione (1.20 eq, 651 mg, 4.43 mmol) in DMF (20mL) was added cesium carbonate (2.00 eq, 2403 mg, 7.38 mmol) in portions and the resulting mixture was stirred at 20 °C for 30 minutes. The reaction mixture was worked up with water (10 ml) and ethyl acetate (20 ml). Then the organic layer was washed twice with water (10 ml x 2), dried with anhydrous magnesium sulfate and concentrated under high vacuum. The crude product was purified by silica gel column chromatography with a gradient 0-40% ethyl acetate in hexanes to provide tert-butyl 4-((2,3-dioxoindolin-l-yl)methylbenzoate (1.16 g, 93% yield). LC-MS: m / z= 282.2 [M-56]+.Step 2: Preparation of tert-butyl 4-((3-2-(3,4=dimethoxyphenyl)-2-oxoetbyl)-3-hydroxy-2-oxoindolin-l-yl)methyl)benzoate

[0193] To a solution of 1-(3,4-dimethoxyphenyl)ethanone (1.50 eq, 401 mg, 2.22 mmol) and tert-butyl 4-[(2,3-dioxoindolin-l-yl)methyl]benzoate (1.00 eq, 500 mg, 1.48 mmol) was added diethylamine (1.00 eq, 0.15 mL, 1.48 mmol) and then anhydrous ethanol (2ml) at rt. The reaction was stirred and heated at 50 °C over the weekend. The reaction mixture was concentrated under vacuum. The resulting residue was purified by silica gel column chromatography eluting with 0-100% ethyl acetate in hexane to give tert-butyl 4-((3-2-(3,4=dimethoxyphenyl)-2-oxoethyl)-3-hydroxy-2-oxoindolin-l-yl)methyl)benzoate (631 mg, 82% yield). LC-MS: m / z= 518.4 [M+H]+.Step 3: Preparation of 4-((3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-3-hydroxy-2-oxoindolin-l-yl)methyl)benzoic acid

[0194] To a solution of tert-butyl 3-[[3-[2-(3,4-dimethoxyphenyl)-2-oxo-ethyl]-3-hydroxy-2-oxo-indolin-1-yl] methyl] benzoate (1.00 eq, 140 mg, 0.270 mmol) in DCM (3 mL) was added TFA (170 eq, 1.5 mL, 46.1 mmol). The resulting solution was stirred at rt for 50 minutes. The reaction mixture was neutralized withAttorney Docket No. 57547-742.60110% sodium bicarbonate, concentrated and was subjected to silica gel chromatography with 0-100% ethyl acetate in hexane and then 20% MeOH in DCM to provide 4-((3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-3-hydroxy-2-oxoindolin-l-yl)methyl)benzoic acid (75 mg, 61% yield). LC-MS: m / z= 462.4 [M+H]+. Preparation of 3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-3-methylindolin-2-oneStep 1: 7V-(4-methoxybenzyI)-N-phenyImethacryIamide

[0195] To solution of N-[(4-methoxyphenyl)methyl] aniline (1.00 eq, 1000 mg, 4.69 mmol) in DCM (8 mL) was added tri ethylamine (1.20 eq, 0.78 mL, 5.63 mmol) and then added dropwise 2-methylprop-2-enoyl chloride (1.00 eq, 0.46 mL, 4.69 mmol) at 0 °C. The reaction mixture was warmed to rt and stirred for 3.5 hours. Then reaction mixture was worked up with water (8 ml) and purified by silica gel column chromatography with 0-50% ethyl acetate in hexanes to provide A-(4-methoxybenzyl)-N-phenylmethacrylamide (1200 mg, 91% yield). LC-MS: m / z= 282.3 [M+H]+.Step 2: 3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-l-(4-methoxybenzyl)-3-methylindolin-2-one

[0196] To a sealed 50 ml reaction vial was added N-[(4-methoxyphenyl)methyl]-2-methyl-N-phenyl-prop- 2-enamide (1.00 eq, 883 mg, 3.14 mmol) in chlorobenzene (10 mL), 3,4-dimethoxybenzaldehyde (5.00 eq, 2608 mg, 15.7 mmol), TBHP 70% in water (3.00 eq, 1212 mg, 9.42 mmol)) and!ron(III) chloride (0.05 eq, 25 mg, 0.157 mmol). The resulting mixture was stirred at 120 °C under nitrogen atmosphere for 2h. The resulting mixture was filtered and the filter cake was washed with ethyl acetate (3x10 mL). The filtrate was concentrated under reduced pressure and then was purified by silica gel column chromatography to provide 3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-l-(4-methoxybenzyl)-3-methylindolin-2-one (1.1g, 79% yield). LC-MS: m / z= 446.4 [M+H]+.Step 3: 3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-3-methylindolin-2-one

[0197] The obtained 3-[2-(3,4-dimethoxyphenyl)-2-oxo-ethyl]-l-[(4-methoxyphenyl)methyl]-3-methyl-indolin-2-one (1.00 eq, 895 mg, 2.01 mmol) in TFA (147 eq, 9.0 mL, 295 mmol) in a sealed reaction vial was heated at 100 °C for 2 hours. The reaction solution was concentrated under reduce pressure. Then crude product was purified by silica gel column chromatography with 0-100% ethyl acetate in hexane to provide 3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-3-methylindolin-2-one (520 mg, 80% yield). LC-MS: m / z= 326.3 [M+H]+.Attorney Docket No. 57547-742.601

[0198] The following compounds were prepared by the same general method as 3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-3-methylindolin-2-one.Exact LC-MS [M+l] Structuremass (m / z)0 _ 0^339.39 340.15O313.33 314.11Preparation of 4-((3-(2-(3,4-dimethoxyphenyl)-2-oxoetbyl)-3-methyl-2-oxoindolin-l-yl)methyl)benzoic acid / u.O / oStep 1: Preparation of tert-butyl 4-((3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-3-methyl-2-oxoindolin-l-yl)methyl)benzoate

[0199] A mixture of 3-[2-(3,4-dimethoxyphenyl)-2-oxo-ethyl]-3-methyl-indolin-2-one (1.00 eq, 105 mg, 0.323 mmol) and cesium carbonate (2.00 eq, 210 mg, 0.645 mmol) in DMF (1ml) was stirred at rt for 5 minutes. Then tert-butyl 4-(bromomethyl)benzoate (2.00 eq, 175 mg, 0.645 mmol) was added. The resulting reaction mixture was stirred at rt for 2.5 hours, and worked up with water (5 ml) and ethyl acetate (5 ml). The organic layer was concentrated and subjected to silica gel column chromatography with 0-100% ethyl acetate in hexanes to provide tert-butyl 4-((3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-3-methyl-2-oxoindolin-1 -yl)methyl)benzoate (112 mg, 67% yield). LC-MS: m / z= 516.4 [M+H]+.Step 2: Preparation of 4-((3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-3-methyl-2-oxoindolin-l-yl)methyl)benzoic acid

[0200] To a solution of tert-butyl 4-[[3-[2-(3,4-dimethoxyphenyl)-2-oxo-ethyl]-3-methyl-2-oxo-indolin-l-yl] methyl] benzoate (1.00 eq, 104 mg, 0.202 mmol) in DCM (2 mL) was added TFA (163 eq, 1.0 mL, 32.9 mmol). The resulting solution was stirred at rt for 2 hours. The reaction mixture was concentrated to provide crude 4-((3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-3-methyl-2-oxoindolin-l-yl)methyl)benzoic acid (92 mg, 99% yield), which was used directly without further purification. LC-MS: m / z= 460.4 [M+H]+.Attorney Docket No. 57547-742.601

[0201] The following compounds were prepared by the same general method as tert-butyl 4-((3-(2-(3,4- dimethoxyphenyl)-2-oxoethyl)-3-methyl-2-oxoindolin-l-yl)methyl)benzoateO N)zO —, Structure Exact mass LC-MS [M+l] (m / z)HY / / Oy / Q "530.24 531.4\\ 0& 0J CkA Q I °V544.2 545.4A / 0504.2 505.4Preparation of l-(4-aminobenzyl)-3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-3-methylindolin-2-one

[0202] To solution of tert-butyl N-|4-| 13-| 2-(3.4-dimethoxyphenyl)-2-oxo-eth l |-3-methyl-2-oxo-indolin- 1-yl] methyl] phenyl]carbamate (1.00 eq, 78 mg, 0.147 mmol) in DCM (2mL) was added TFA (224 eq, 1.0 mL, 32.9 mmol). The resulting solution was stirred at rt for 15 minutes. Removal of the solvent under reduced pressure provided crude l-(4-aminobenzyl)-3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-3- methylindolin-2-one (94 mg, 97% yield) as its TFA salt, which was directly used in other reactions without further purification.

[0203] The following compounds were prepared by the same general method as l-(4-aminobenzyl)-3-(2- (3,4-dimethoxyphenyl)-2-oxoethyl)-3-methylindolin-2-oneStructure Exact mass LC-MS [M+l] (m / z)H _ O / °«444.2 445.4oPreparation of l-(4-amino-3-methoxybenzyl)-3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-3,7- dimethylindolin-2-oneAttorney Docket No. 57547-742.601

[0204] 3-[2-(3,4-dimethoxyphenyl)-2-oxo-ethyl]-l-[(3-methoxy-4-nitro-phenyl)methyl]-3,7-dimethyl-indolin-2-one (1.00 eq, 134 mg, 0.266 mmol) was stirred with Palladium on carbon 10%, wet, contains 67% water (0.531 eq, 15 mg, 0.141 mmol) in methanol (3ml) under hydrogen balloon at rt overnight. The catalyst was filtered off and washed with methanol. The filtrate was concentrated under vacuum to give l-[(4-amino-3-methoxy-phenyl)methyl]-3-[2-(3,4-dimethoxyphenyl)-2-oxo-ethyl]-3,7-dimethyl-indolin-2-one (118 mg, 93.62 % yield) as a white solid. MS (ESI): mass calcd for C28H30N2O5474.22; [M+H]+found 475.4. LCMS (method 1): Rt = 2.53 min.Preparation of 3-(2-(4-(benzyloxy)-3-methoxyphenyl)-2-oxoethyl)-3- methyl- 1 -(4-( methylamino) benzyl) indolin-2-oneNaH. THF TBHP Step 1 Step 2TFA DCMStep 3 Step 1: Preparation of tert-butyl methyl(4-((N-phenylmethacrylamido)methyl)phenyl)carbamate

[0205] To a stirred solution of tert-butyl (4-(bromomethyl)phenyl)(methyl)carbamate (252.39 mg, 1.566 mmol, 1.0 equiv.) in THF (3 mL) was added NaH (56.36 mg, 2.349 mmol, 1.5 equiv.) portionwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 0.5 h. Then tert-butyl N-phenylmethacrylamide (470.00 mg, 1.566 mmol, 1.00 equiv.) was added at 0 °C. The resulting mixture was stirred at rt for al h, quenched with water at room temperature and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (2x100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EA=4 / 1) to provide tert-butyl methyl(4-((N-phenylmethacrylamido)methyl) phenyl)carbamate (400 mg, 67.2%) as a yellow solid. MS (ESI): mass calcd. for C23H28N2O3 380.21; [M+H+Na]+found 403.25.Step 2: Preparation of tert-butyl (4-((3-(2-(4-(benzyloxy)-3-methoxyphenyl)-2-oxoethyl)-3-methyl-2-oxoindolin-l-yl)methyl)phenyl)(methyl)carbamate

[0206] To a stirred solution of tert-butyl methyl(4-((N-phenylmethacrylamido)methyl)phenyl)carbamate (1 g, 2.628 mmol, 1.0 equiv.) and 4-(benzyloxy)-3-methoxybenzaldehyde (1.27 g, 5.256 mmol, 2.0Attorney Docket No. 57547-742.601equiv.) in EtOAc (10 mL) was added TBHP (0.88 mL, 5.256 mmol, 2.0 equiv.) dropwiseat rt under nitrogen atmosphere. The resulting mixture was stirred at 105 °C under nitrogen atmosphere overnight. Then it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA=4 / l)to provide tert-butyl (4-((3-(2-(4-(benzyloxy)-3-methoxyphenyl)-2-oxoethyl)-3-methyl-2-oxoindolin-l-yl)methyl)phenyl)(methyl)carbamate (0.9 g, 55.2%) as a yellow solid. MS (ESI): mass calcd. for C38H40N2O6 620.29; [M+H+Na]+found 643.35.Step 3: Preparation of 3-(2-(4-(benzyloxy)-3-methoxyphenyl)-2-oxoethyl)-3-methyl-l-(4-(methyIamino)benzyI)indolin-2-one

[0207] To a stirred solution of tert-butyl (4-((3-(2-(4-(benzyloxy)-3-methoxyphenyl)-2-oxoethyl)-3-methyl-2-oxoindolin-l-yl)methyl)phenyl)(methyl)carbamate (5.6 g, 9.021 mmol, 1.0 equiv.) in DCM (45 mL) was added trifluoroacetaldehyde (15 mL) at rt. The resulting solution was stirred at rt for 30 min and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA=1:1) to afford 3-(2-(4-(benzyloxy)-3-methoxyphenyl)-2-oxoethyl)-3-methyl-l-(4-(methylamino) benzyl)indolin-2-one (3.9 g, 83.0%) as ayello cX O / / w'" solid. MS (ESI): mass calcd. for C33H32N2O4 520.24;J00 / [M+H]+ found 521.25.Q O

[0208] The following compounds were prepared by the same general method as for 3-(2-(4-(benzyloxy)-3-methoxyphenyl)-2-oxoethyl)-3-methyl-l-(4-(methylamino)benzyl)indolin-2-onefirStructure Exact mass LC-MS [M+l] (m / z)dP 1Z\ 476.2 477.3444.2 445.0O 0^H2N\rXX V \ / 458.22 459.250^ C / TV0430.19 431.30w 0□F1H2N^X448.18 449.15\\ 00Attorney Docket No. 57547-742.601Structure Exact mass LC-MS [M+l] (m / z) / TV 1H2N>^ VJ / TV°1 fl l yUkA 431.18 432.20\\ 00 / TV0444.20 445.20 XX-Q \\ < Y 0MA0H2NM^, \A fi VF418.17 419.15 XX-Q \\ < Y 0MA0Cr° 508.10 & XXHQC / ^ 509.25 & 511.3W O- 510.10ooy_n YY°..'i / ' < -'’ o '472.24 473.25 r NH2HiN.; C) j' A444.20 445.40Q Pr° 444.20 445.20W 00A?H2N_^ / TV0N506.22 507.20 X1JO «< I oAVoO>1H2Ny^ N r ^VZx\ Y / ^yo°'Bn 506.22 507.25\\ OoAttorney Docket No. 57547-742.601Structure Exact mass LC-MS [M+l] (m / z)\1460.20 461NH2Preparation of 4-((3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-3-methyl-2-oxoindolin-l-yl)methyl)benzenesulfonyl chlorideStep 1: Preparation of benzyl(4-(bromomethyl)phenyl)sulfane

[0209] To a solution of (4-(benzylthio)phenyl)methanol (2 g, 8.683 mmol, 1.0 equiv.) in Et20 (30 mL, 289.181 mmol, 33.30 equiv.) was added a solution of PBr 3 (0.41 mL, 4.341 mmol, 0.5 equiv.) in Et20 (10 mL) dropwise at 0 °C. The resulting mixture was stirred at 0 °C for Ih. Then hexane (50 mL) was added dropwise at 0 °C. The resulting mixture was stirred at 0 °C for additional Ih. The precipitated solids were collected by filtration and washed with hexane (4 x 4mL). The combined organic phase was concentrated under reduced pressure to provide benzyl(4-(bromomethyl)phenyl)sulfane (2 g, 78.55%) as a light brown solid, which was directly used in the next step without further purification.

[0210] The following intermediates were prepared under the same conditions as for benzyl(4-(bromomethyl)phenyl)sulfaneStructure Exact mass LC-MS [M+l] (m / z)JLFB' 292.99 &293.80 & 295.75294.99Step 2: Preparation of l-(4-(benzylthio)benzyl)-3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-3-methylindolin-2-one

[0211] A mixture of l-(benzylsulfanyl)-4-(bromomethyl)benzene (530 mg, 1.808 mmol, 1.5 equiv.), 3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-3-methylindolin-2-one (393 mg, 1.21 mmol, 1.0 equiv.) and CS2CO3 (785.23 mg, 2.411 mmol, 2 equiv.) in DMF was stirred at 60 °C for 2h. The reaction was quenched withAttorney Docket No. 57547-742.601water at room temperature. The resulting mixture was extracted with EtOAc (3 x lOOmL). The combined organic layers were washed with brine (2x10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA=1 / 1) to afford l-(4-(benzylthio)benzyl)-3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-3-methylindolin-2-one (440 mg, 67.9%) as a light yellow solid. MS (ESI): mass calcd. for C33H31NO4S 537.20; [M+H]+ found 538.25.Step 3: Preparation of 4-((3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-3-methyl-2-oxoindolin-l-yl)methyl)benzenesulfonyl chloride

[0212] To a stirred solution of l-(4-(benzylthio)benzyl)-3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-3-methylindolin-2-one (500 mg, 0.930 mmol, 1.0 equiv.) in ACN (5 mL) was added AcOH (266.43 pL, 4.650 mmol, 5.0 equiv.), H2O (150.78 pL, 8.370 mmol, 9.0 equiv.) and l,3-dichloro-5,5-dimethylimidazolidine-2, 4-dione (256.50 mg, 1.302 mmol, 1.4 equiv.) in portions at 0 °C under air atmosphere. The resulting mixture was stirred at 0 °C for 30 min and then quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3x5 mL). The combined organic layers were washed with brine (2x10 / °mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA=1:1) to afford 4-((3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-3-methyl-2-oxoindolin-l-yl)methyl)benzenesulfonyl chloride (387 mg, 81%) as a white solid. MS (ESI): mass calcd. for C26H24CINO6S 513.10; [M+H]+found 514.35. oT°

[0213] The following intermediates were prepared by the same general method as for 4-((3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-3-methyl-2-oxoindolin- 1 -yl)methyl)benzenesulfonyl chloridedxo / x_ Structure Exact mass LC-MS [M+l] (m / z)00514.1 515.10C| / T il TTxxTL A 531.1 532.25c| / T il T k^xTCTx 527.1 528.15 AAAc| / AF545.1 546.25 / T-VMil T ATxx TTLTC O"Attomey Docket No. 57547-742.601Structure Exact mass LC-MS [M+l] (m / z)572.1 573.10Preparation of 4-((3-(2-(3-(dimethylaniino)-4-methoxyphenyl)-2-oxoethyl)-3,7-dimethyl-2-oxoindolin-l-yl)methyl)benzenesulfonyl chlorideQAStep 1: Preparation of 3-(2-(3-bromo-4-methoxyphenyl)-2-oxoethyl)-l-(4-methoxybenzyl)-3,7-dimethylindolin-2-one

[0214] To a stirred solution of N-(4-methoxybenzyl)-N-(o-tolyl)methacrylamide (1 g, 3.385 mmol, 1.0 equiv.) and 3-bromo-4-methoxybenzaldehyde (1.46 g, 6.770 mmol, 2.0 equiv.)in EtOAc (lO mL) was added TBHP (2.03 mL, 10.155 mmol, 3.0 equiv.) and ferrous acetate (58.88 mg, 0.339 mmol, 0.1 equiv.) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 110°C under nitrogen atmosphere overnight. Then the mixture was filtered, and the filter cake was washed with EtOAc (3x10 mL). The filtrate was concentrated under reduced pressure. The resulting residue was extracted with EtOAc (3 x 20mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA=5 / 1) to afford 3-(2-(3-bromo-4-methoxyphenyl)-2-oxoethyl)-l-(4-methoxybenzyl)-3,7-dimethylindolin-2-one (400 mg, 23.2%) as a white solid. MS (ESI): mass calcd. for C27H26BrNO4507.10 and 509.10; [M+H]+ found 508.10 and 510.05.Step 2: Preparation of 3-(2-(3-(dimethylamino)-4-methoxyphenyl)-2-oxoethyl)-l-(4-methoxybenzyl)-3,7-dimethylindolin-2-one

[0215] To a stirred solution of 3-(2-(3-bromo-4-methoxyphenyl)-2-oxoethyl)-l-(4-methoxybenzyl)-3,7-dimethylindolin-2-one (3 g, 5.901 mmol, 1.0 equiv.) and dimethylamine (319.24 mg, 7.081 mmol, 1.2 equiv.) in toluene (30 mL) was added t-BuDavePhos (402.99 mg, 1.180 mmol, 0.2 equiv.) and t-BuOK (1.99Attorney Docket No. 57547-742.601g, 17.703 mmol, 3.0 equiv.) and Pd(dba)2 (339.30 mg, 0.590 mmol, 0.1 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 90 °C under nitrogen atmosphere overnight and then extracted with EtOAc (3 x lOmL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA=1 / 1) to afford 3-(2-(3-(dimethylamino)-4-methoxyphenyl)-2-oxoethyl)-l-(4-methoxybenzyl)-3,7-dimethylindolin-2-one (700 mg, 25.1%) as a yellow solid. MS (ESI): mass calcd. for C29H32N2O4 472.24; [M+H]+found 473.20.Step 3: Preparation of 3-(2-(3-(dimethylamino)-4-methoxyphenyl)-2-oxoethyl)-3,7-dimethylindolin-2-one

[0216] A solution of 3-(2-(3-(dimethylamino)-4-methoxyphenyl)-2-oxoethyl)-l-(4-methoxybenzyl)-3,7-dimethylindolin-2-one (700 mg, 1.481 mmol, 1 equiv.) in TFA (7 mL) was stirred at 100 °C overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, MeCN in Water (lOmmol / L NH4HCO3), 10% to 50% gradient in 10 min) to provide 3-(2-(3-(dimethylamino)-4-methoxyphenyl)-2-oxoethyl)-3,7-dimethylindolin-2-one (400 mg, 76.6%) as a yellow solid. MS (ESI): mass calcd. for C21H24N2O3 352.18;[M+H]+ found 353.25.Step 4: Preparation of l-(4-(benzylthio)benzyl)-3-(2-(3-(dimethylamino)-4-methoxyphenyl)-2-oxoethyl)-3,7-dimethylindolin-2-one

[0217] To a stirred solution of 3-(2-(3-(dimethylamino)-4-methoxyphenyl)-2-oxoethyl)-3,7-dimethylindolin-2-one (426 mg, 1.209 mmol, 1.0 equiv.) in DMF (4 mL) was added NaH (58.01 mg, 2.418 mmol, 2.0 equiv.) in portions at 0°C under nitrogen atmosphere. The mixture was stirred at 0 °C under nitrogen atmosphere for 30 min. Then a solution of l-(benzylsulfanyl)-4-(bromomethyl)benzene (354.43 mg, 1.209 mmol, 1.0 equiv.) in DMF (4 mL) was added dropwise at 0 °C. The resulting mixture was stirred at room temperature for Ih, then quenched with ice water at room temperature, and extracted with EtOAc (3 x lOmL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na2SO4. After filtration, the fdtrate was concentrated under reduced pressure. The residue was purified by prep-TLC (PE / EtOAc=l / 2) to afford l-(4-(benzylthio)benzyl)-3-(2-(3-(dimethylamino)-4-methoxyphenyl)-2-oxoethyl)-3,7-dimethylindolin-2-one (300 mg, 44%) as a yellow solid. MS (ESI): mass calcd. for C35H36N2O3S 564.24; [M+H]+ found 565.25.Step 5: Preparation of 4-((3-(2-(3-(dimethylamino)-4-methoxyphenyl)-2-oxoethyl)-3,7-dimethyl-2-oxoindolin-l-yl)methyl)benzenesulfonyl chloride

[0218] To a stirred solution of l-(4-(benzylthio)benzyl)-3-(2-(3-(dimethylamino)-4-methoxyphenyl)-2-oxoethyl)-3,7-dimethylindolin-2-one (200 mg, 0.354 mmol, 1.0 equiv.) in mixed water (1 mL) and AcOH (3 mL) was added 1 -chloropyrrolidine-2, 5-dione (141.87 mg, 1.062 mmol, 3.0 equiv.) in portions at 0 °C. Then the reaction solution was stirred at rt for Ih. The resulting mixture was extracted with CH2CI2 (3 x lOmL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by prep-TLC (PE / EA=1 / 3) to afford 4-((3-(2-(3-(dimethylamino)-4-methoxyphenyl)-2-oxoethyl)-3,7-dimethyl-2-oxoindolin-l-yl)methyl)benzenesulfonyl chloride (130 mg, 67.8%) as ayellow solid. MS (ESI): mass calcd. for C28H29CIN2O5S 540.15 and 542.15; [M+H]+ found 541.20 and 543.15.Preparation of 5-(isoxazol-5-yI)-2-methyIpyridin-3-amineStep 1: Preparation of l-(6-methyl-5-nitropyridin-3-yl)ethan-l-one

[0219] To a stirred solution of 5-bromo-2-methyl-3-nitropyridine (1.5 g, 6.912 mmol, 1.0 equiv.) and tributyl(l -ethoxy ethenyl) stannane (3.00 g, 8.294 mmol, 1.2 equiv.) in dioxane (15 mL) was added Pd(PPh3)4 (798.71 mg, 0.691 mmol, 0.1 equiv.) in portions at rt under nitrogen atmosphere. The resulting mixture was stirred at 100 °C under nitrogen atmosphere overnight. To the above mixture was added HC1 (15 mL) dropwise at rt. The resulting mixture was stirred for additional 30 min and then extracted with EtOAc (3 x 20mL). The combined organic layers were washed with brine (1x10 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA=1 / 1) to afford l-(6-methyl-5-nitropyridin-3-yl)ethan-l-one (1 g, 80.31%) as a yellow solid. MS (ESI): calcd. for C8H8N2O3 180.16; [M+H]+ found 181.00.Step 2: Preparation of (E / Z)-3-(dimethylamino)-l-(6-methyl-5-nitropyridin-3-yl)prop-2-en-l-one

[0220] A mixture of l-(6-methyl-5-nitropyridin-3-yl)ethan-l-one (1.0 g, 5.551 mmol, 1.0 equiv.) and (dimethoxymethyl)dimethylamine (859.85 mg, 7.216 mmol, 1.3 equiv.) in MeOH (10 mL) was stirred at 65 °C overnight. After concentration, the residue was purified by reversed-phase flash chromatography (column, C18; mobile phase, MeCN in Water (lOmmol / L NH4HCO3). 10% to 50% gradient in 10 min) to provide (E / Z)-3-(dimethylamino)-l-(6-methyl-5-nitropyridin-3-yl)prop-2-en-l-one (400 mg, 30.63%) as a yellow solid. MS (ESI): mass calcd. for C11H13N3O3 235.24; [M+H]+found 236.10.Step 3: Preparation of 5-(6-methyl-5-nitropyridin-3-yl)isoxazole

[0221] To a stirred solution of (E / Z)-3-(dimethylamino)-l-(6-methyl-5-nitropyridin-3-yl)prop-2-en-l-one (420 mg, 1.785 mmol, 1 equiv.) in MeOH (5 mL) was added NH2OH. HCI (136.47 mg, 1.964 mmol, 1.1 equiv.) in portions at rt. The resulting mixture was stirred at 65 °C for 4h. After concentration, the residue was purified by reversed-phase flash chromatography (column, Cl 8; mobile phase, MeCN in Water (0.1% FA), 10% to 50% gradient in 10 min) to provide 5-(6-methyl-5-nitropyridin-3-yl)isoxazole (140 mg, 38.22%) as ayellow solid. MS (ESI): mass calcd. for C9H7N3O3 205.17; [M+H]+found 206.10.Step 4: Preparation of 5-(isoxazol-5-yl)-2-methylpyridin-3-amineAttorney Docket No. 57547-742.601

[0222] To a stirred mixture of 5-(6-methyl-5-nitropyridin-3-yl)isoxazole (140 mg, 0.682 mmol, l. O equiv.) andNH4Cl (218.99 mg, 4.092 mmol, 6 equiv.) in EtOH (2 mL) was added H2O (0.4 mL) and Zn (267.67 mg, 4.092 mmol, 6 equiv.) in portions at rt. The reaction mixture was stirred at 70 °C for 4h. The resulting mixture was filtered, and the filter cake was washed with MeOH (3x10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (column, Cl 8 silica gel; mobile phase, MeCN in Water (lOmmol / L NH4HCO3), 10% to 50% gradient in 10 min) to provide 5-(isoxazol-5-yl)-2-methylpyridin-3-amine (60 mg, 50.2%) as ayellow solid. MS (ESI): mass cal cd. for C9H9N3O 175.19; [M+H]+ found 176.05.Preparation of 5-(pyridin-3-yIoxy)pyridin-3-aminePd / C / H2Step 2 Step 1: Preparation of 3-bromo-5-nitropyridine)pyridine

[0223] To a stirred solution of 3-bromo-5-nitropyridine (1 g, 4.926 mmol, 1.0 equiv.) and 3-hydroxypyri dine (702.73 mg, 7.389 mmol, 1.5 equiv.) in DMF (10 mL) was added K2CO3 (1.02 g, 7.389 mmol, 1.5 equiv.) in portions at rt. The resulting mixture was stirred at 100 °C overnight, and then extracted with EtOAc (3 x lOmL). The combined organic layers were washed with brine (1x10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA=1 / 1) to afford 3-nitro-5-(pyridin-3-yloxy)pyridine (230 mg, 21.5%) as ayellow solid. MS (ESI): mass calcd. for C10H7N3O3 217.18; [M+H]+found 218.00.Step 2: Preparation of 5-(pyridin-3-yloxy)pyridin-3-amine

[0224] A mixture of 3-nitro-5-(pyridin-3-yloxy)pyridine (220 mg, 1.013mmol, 1.0 equiv.) and Pd / C (220 mg, 2.067 mmol, 2.04 equiv.) in MeOH (5 mL) was stirred under hydrogen atmosphere at rt for Ih. The resulting mixture was filtered, and the filter cake was washed with MeOH (3x10 mL). The filtrate was concentrated under reduced pressure to provide -(pyridin-3-yloxy)pyridin-3-amine (160 mg, 84.38%) as a yellow solid, which was used directly in the next step without further purification. MS (ESI): mass calcd. for C10H9N3O 187.07; [M+H]+ found 187.95.

[0225] The following intermediates were prepared by the same general method as step 2 of preparative procedures of 5-(pyridin-3-yloxy)pyridin-3-amine starting with the corresponding nitro-intermediates Structure Exact mass LC-MS [M+l] (m / z)H°AINH110.12 Not found2OTBS{ V- NHN= / 2224.13 225.00Attorney Docket No. 57547-742.601Structure Exact mass LC-MS [M+l] (m / z) / — N^VNH2151.11 152.15N\z —hN206.15 207 / / NH2N=\ ' zZE rj179.11 179.95NHBoc223.13 224.10Ny^NH2Preparation of 1- [[4- [(2-methylpyrimidin-5-yl)methoxy]phenyl]methyl]indoline-2, 3-dioneStep 2Step 1: Preparation of l-[ [4- [tert-butyl(dimethyl)silyl] oxyphenyl] methyl] indoline-2, 3-dione

[0226] To a solution of |4-(bromomethyl)phenoxy |- / c / 7-butyl-dimethyl-silane (555 mg, 1.84 mmol, 1.03 eq) and 2,3-indolinedione (263 mg, 1.79 mmol, 1.00 eq) in A-di methyl formamide (4 mL) was added cesium carbonate (713 mg, 2.19 mmol, 1.22 eq). The reaction mixture was heated to 80 °C and stirred for 1 h. The reaction mixture was allowed to cool to room temperature. The mixture was diluted with ethyl acetate (75 mL) and washed with water (2 x 10 mL) and brine (1 x 10 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and evaporated. The residue was purified by gradient silica gel column chromatography eluting with hexane:ethyl acetate (100:0- >0: 100) to give the title compound (225 mg, 34%) as an orange powder. MS (ESI): mass calcd. for C2iH2sNO3Si 367.2; [M+H-TBS]+found 254.4. LCMS (Method 1): Rt = 3.97 min.Step 2: Preparation of l-[(4-hydroxyphenyl)methyl] indoline-2, 3-dione

[0227] To a solution of l-[[4-[fert-butyl(dimethyl)silyl]oxyphenyl]methyl]indoline-2, 3-dione (143 mg, 0.389 mmol, 1.00 eq) in tetrahydrofuran (2.5 mL) was added hydrogen fluoride pyridine solution (hydrogenAttorney Docket No. 57547-742.601fluoride -70%, pyridine -30%) (280 pL, 10.8 mmol, 1.1 g / mL, 27.7 eq) dropwise at 0 °C. The reaction mixture was stirred at room temperature for 5 h. To the reaction mixture was added tetrahydrofuran (1.0 mL) and the resulting mixture was stirred at room temperature overnight. The reaction was quenched with saturated sodium bicarbonate (10 mL) and extracted with ethyl acetate (1 x 50 mL). The organic layer was washed with water (1 x 10 mL) and brine (1 x 10 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and evaporated to afford the title compound (96 mg, 97%) as a dark orange powder. MS (ESI): mass calcd. for C15H11NO3 253.1; [M+H]+found 254.4. LCMS (Method 1): Rt = 2.47 min.Step 3: Preparation of l-[[4-[(2-methylpyrimidin-5-yl)methoxy]phenyl]methyl]indoline-2, 3-dione

[0228] To a solution of l-[(4-hydroxyphenyl)methyl]indoline-2, 3-dione (44 mg, 0.174 mmol, 1.00 eq), (2-methylpyrimidin-5-yl)methanol (46 mg, 0.371 mmol, 2.13 eq) and triphenylphosphine (1.87 eq, 85 mg, 0.324 mmol) in tetrahydrofuran (1.5 mL) was added diisopropyl azodicarboxylate (70 pL, 0.356 mmol, 1.027 g / mL, 2.05 eq). The reaction mixture was stirred at room temperature for 2.25 h. The reaction mixture 0was diluted with ethyl acetate (40 mL) and was washed with water (1 x 5 mL). The organic layer was washed with brine (1 x 5 mL), dried over anhydrous magnesium sulfate, filtered, and evaporated. The residue was purified by gradient silica gel column chromatography eluting with hexane:ethyl acetate (100:0- >0:100). The resulting product (110 mg) was purified by preparative HPLC (Method B, acidic) to give the title compound (31 mg, 50%) as an orange powder. MS (ESI): mass calcd. for C21H17N3O3 359.1; [M+H]+found 0360.3. LCMS (Method 1): Rt = 2.66 min.

[0229] The following compounds were prepared by the same general method as l-[[4-[(2-methylpyrimidin- 5-yl)methoxy]phenyl]methyl]indoline-2,3-dione.Structure Exact mass LC-MS [M+l] (m / z)358.1 359.3358.1 359.3yN nVy° 359.1 360.3N k / ° \ V / NAPreparation of N-(4-((2,3-dioxoindolin-l-yl)methyl)phenyl)-l-methyl-lH-pyrazole-5-sulfonamideAttorney Docket No. 57547-742.601Step 1O oStep 1: Preparation of 1-(4-aminobenzyl)indoline-2,3-dione

[0230] A solution of tert-butyl N-[4-[(2,3-dioxoindolin-l-yl)methyl]phenyl]carbamate (1.00 eq, 300 mg, 0.851 mmol) in mixed DCM (2 mL) and TFA (38.7 eq, 1.0 mL, 32.9 mmol) was stirred at rt for 15 minutes. The reaction mixture was rotovated. The desired product was precipitated by added dimethyl ether (10 ml) and rinsed with diethyl ether (3x5 ml) and filtered to provide 1 -(4-aminobenzyl)indoline-2, 3-dione (241 mg, 59% yield) as its TFA salt.oStep 2: Preparation of N-(4-((2,3-dioxoindolin-l-yl)methyl)phenyl)-l-methyl-lH-pyrazole-5-sulfonamide

[0231] To a solution of l-[(4-aminophenyl)methyl]indoline-2,3-dione;2,2,2-trifluoroacetic acid (1.00 eq, 241 mg, 0.502 mmol) and 2-methylpyrazole-3-sulfonyl chloride (1.20 eq, 109 mg, 0.602 mmol) in DCM (1 ml) was added pyridine (5.00 eq, 0.20 mL, 2.51 mmol). The resulting reaction solution was stirred at rt for 4 hours. The reaction mixture was concentrated and was subjected to pre HPLC column under acidic conditions (method B) to provide N-(4-((2,3-dioxoindolin-l-yl)methyl)phenyl)-l-methyl-lH-pyrazole-5-sulfonamide (170 mg, 85% yield).

[0232] The following compounds were prepared by the same general method as N-(4-((2,3-dioxoindolin-l-yl)methyl)phenyl)-l -methyl- lH-pyrazole-5-sulfonami de.Structure Exact mass LC-MS [M+l] (m / z)393.08 394.2Preparation of 4-((2,3-dioxoindolin-l-yl)methyl)benzenesulfonyl chlorideStep 1Step 3Step 1: Preparation of l-(4-bromobenzyl)indoline-2, 3-dioneAttorney Docket No. 57547-742.601

[0233] A mixture of indoline-2, 3-dione (10 g, 67.966 mmol, 1.0 equiv.) and K2CO3 (28.18 g, 203.898 mmol, 3 equiv.) in DCE (100 mL) was stirred at 80 °C under air atmosphere overnight. The resulting mixture was filtered, and the filter cake was washed with CH2CI2 (3x100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by trituration with EtOAc (100 mL). The precipitated solids were collected by filtration and washed with EtOAc (3x100 mL). The combined filtrate was concentrated under reduced pressure to provide l-(4-bromobenzyl)indoline-2, 3-dione (16 g, 74.5%) as a white solid. MS (ESI): mass calcd. for C15H10BrNO2 314.99 and 316.99; [M+H]+found 315.90 and 317.80.Step 2: Preparation of l-(4-(benzylthio)benzyl)indoline-2, 3-dione

[0234] To a stirred solution of l-(4-bromobenzyl)indoline-2, 3-dione (16 g, 50.608 mmol, 1 equiv.) and benzyl mercaptan (8.91 mL, 75.912 mmol, 1.5 equiv.) in dioxane (100 mL) was added DIPEA (17.63 mL, 101.216 mmol, 2 equiv.) and Xantphos (5.86 g, 10.122 mmol, 0.2 equiv.) and Pd2(dba)3 (3.48 g, 3.796 mmol, 0.1 equiv.) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100 °C overnight. The resulting mixture was filtered and the filter cake was washedwith EtOAc (3x10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 50% gradient in 10 min) to provide l-(4-(benzylthio)benzyl)indoline-2, 3-dione (6.72 g, 36.9%) as a red solid. MS (ESI): mass calcd. for C22H17NO2S 359.10; [M+H]+found 360.10.Step 3: Preparation of 4-((2,3-dioxoindolin-l-yl)methyl)benzenesulfonyl chloride

[0235] Into a 250 mL round-bottom flask was added l-(4-(benzylthio)benzyl)indoline-2, 3-dione (3 g, 8.346 mmol, 1 equiv.), ACN (30 mL), AcOH (2.39 mL, 41.730 mmol, 5 equiv.) and H2O (1.35 mL, 75.114 mmol, 9 equiv.) at room temperature, followed by addition of l,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (2.14 g, 10.850 mmol, 1.3 equiv.) in portions at 0 °C. The resulting mixture was stirred at 0 °C for additional 10 min. The resulting mixture was stirred at 40 °C under for Ih. The reaction was quenched by addition of Water / Ice (100 mL) at room temperature and extracted with EtOAc (2 x 100 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 (PE / EA=1 / 1) to afford 4-((2,3-dioxoindolin-l-yl)methyl)benzenesulfonyl chloride (2 g, 71.4%) as an orange solid. MS (ESI): mass calcd. for C15H10CINO4S 335.00; [M+H]+found 335.85.

[0236] The following intermediates were prepared by the same general method as for 4-((2,3-dioxoindolin-1 -yl)methyl)benzenesulfonyl chloride:Structure Exact mass LC-MS [M+l] (m / z)337 336.80Preparation of 4-(bromomethyl)-N-(2-methylpyridin-4-yl)benzenesulfonamideAttorney Docket No. 57547-742.601LiAIH4step 2Step 1: methyl 4-(N-(2-methylpyridin-4-yl)sulfamoyl)benzoate

[0237] To astirred solution of methyl 4-(chlorosulfonyl)benzoate (460.87 mg, 4.262 mmol, 1.0 equiv.) in DCM (10 mL) was added pyridine (1.03 mL, 12.786 mmol, 3.0 equiv.) dropwise at room temperature, followed by addition of methyl 4-(chlorosulfonyl)benzoate (1 g, 4.262 mmol, 1.0 equiv.) in portions at 0 °C. The resulting mixture was stirred at rt for 1 h and then concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under method D conditions to provide methyl 4-(N-(2-methylpyridin-4-yl)sulfamoyl)benzoate (1.2 g, 91.9%) as a white solid. MS (ESI): mass calcd. for C14H14N2O4S 306.07; [M+H]+found 307.30.Step 2: Preparation of 4-(hydroxymethyl)-N-(2-methylpyridin-4-yl)benzenesulfonamide

[0238] To a stirred solution of methyl 4-(N-(2-methylpyridin-4-yl)sulfamoyl)benzoate (605 mg, 1.975 mmol, 1 equiv.) in THF (6 mL) was added LiAlH4 (3.95 mL, 3.950 mmol, 2 equiv.) dropwise at 0 °C under N2 atmosphere. The resulting mixture was stirred at rt for 0.5 h and then quenched with water at room temperature. The mixture was acidified to pH = 3 with HC1 (2M). After concentration, the residue was purified by reversed-phase flash chromatography (column, Cl 8 silica gel; mobile phase, MeCN in Water (0.1% FA), 0% to 100% gradient in 15 min) to provide 4-(hydroxymethyl)-N-(2-methylpyridin-4-yl)benzenesulfonamide (233.7 mg, 42.5%) as a white solid MS (ESI): mass calcd. for C13H14N2O3S 278.07;[M+H]+found 279.05.Step 3: Preparation of 4-(bromomethyl)-N-(2-methylpyridin-4-yl)benzenesulfonamide

[0239] To astirred solution of 4-(hydroxymethyl)-N-(2-methylpyridin-4-yl)benzenesulfonamide (300 mg, 1.078 mmol, 1 equiv.) and PPh3 (565.43 mg, 2.156 mmol, 2 equiv.) in DCE (10 mL) was added tetrabromomethane (536.17 mg, 1.617 mmol, 1.5 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at rt for Ih under nitrogen atmosphere and then concentrated under vacuum. The residue was purified by prep-TLC (CH2C12 / MeOH=10:l) to afford 4-(bromomethyl)-N-(2-methylpyridin-4-yl)benzenesulfonamide (220 mg, 59.82%) as an off-white solid. MS (ESI): mass calcd. for C13H13BrN2O2S 339.99 and 341.99; [M+H]+ found 340.90 and 342.90.Preparation of l-(4-(bromomethyl)phenyl)-l-(pyridin-4-yl)ethan-l-olAttorney Docket No. 57547-742.601Step 1: Preparation of ((4-bromobenzyl)oxy)(tert-butyl)diphenylsilane

[0240] A solution of (4-bromophenyl)methanol (5 g, 26.733 mmol, 1 equiv.) in DMF was treated with TEA (4.06 g, 40.099 mmol, 1.5 equiv.) at room temperature for 2 min, followed by addition of TBDPSC1 (9.55 g, 34.753 mmol, 1.3 equiv.) at 0 °C. The resulting solution was stirred at rt overnight and then diluted with DCM (150 mL) and H2O (100 mL). The resulting mixture was washed with HC1 (2N, 40 mL), brine (2x100 mL), dried over anhydrous Na2SO4 and filtered. The fdtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (mobile phase: MeCN in H2O (0.1%FA) with gradient from 10% to 100%) to afford ((4-bromobenzyl)oxy)(tert-butyl)diphenylsilane (7 g, 61.6%) as a yellow oil.Step 2: Preparation of l-(4-(((tert-butyldiphenylsilyl)oxy)methyl)phenyl)-l-(pyridin-4-yl)ethan-l-ol

[0241] A solution of ((4-bromobenzyl)oxy)(tert-butyl)diphenylsilane (2 g, 4.701 mmol, 1 equiv.) in Et20 (20 mL) was treated with n-BuLi (331.26 mg, 5.171 mmol, 1.1 equiv.) at -78 °C under nitrogen atmosphere for 0.5h. Then a solution of 4-acetylpyridine (569.47 mg, 4.701 mmol, 1 equiv.) in THF (5mL) was added dropwise at -78 °C for Ih. The mixture was stirred at rt for additional Ih and then quenched by the addition of sat. NH4CI (aq.) (lOOmL). The aqueous layer was extracted with EtOAc (3x100 mL). The organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / PE:0~50%) to afford l-(4-(((tert-butyldiphenylsilyl)oxy)methyl)phenyl)-l-(pyridin-4-yl)ethan-l-ol (1.1 g, 50.0%) as ayellow solid. MS (ESI): mass calcd. for C30H33NO2Si 467.23; [M+H]+ found 468.10.Step 3: Preparation of l-(4-(hydroxymethyl)phenyl)-l-(pyridin-4-yl)ethan-l-ol

[0242] A solution of l-(4-(((tert-butyldiphenylsilyl)oxy)methyl)phenyl)-l-(pyridin-4-yl)ethan-l-ol (1.2 g, 2.566 mmol, 1.0 equiv.) andTBAF (1.21 g, 3.849 mmol, 1.5 equiv.) in THF was stirred at room temperature for an hour. The residue was purified by silica gel column chromatography (PE / EA=1 / 1) to afford l-(4-(hydroxymethyl)phenyl)-l-(pyridin-4-yl)ethan-l-ol (491 mg, 83.5%) as a white solid. ESI-LCMS calcd. for C14H15NO2 229.11; [M+H]+ found 230.00.Step 4: Preparation of l-(4-(bromomethyl)phenyl)-l-(pyridin-4-yl)ethan-l-ol

[0243] A solution of l-(4-(hydroxymethyl)phenyl)-l-(pyridin-4-yl)ethan-l-ol (50 mg, 0.218 mmol, 1.0 equiv.) in DCE was treated with PPh3 (85.80 mg, 0.327 mmol, 1.5 equiv.) and CBn (108.48 mg, 0.654Attorney Docket No. 57547-742.601mmol, 1.5 equiv.) at 0 °C for 5min and warmed to room temperature for 30 mins. The crude product was purified by prep-TLC (CTbCh / MeOH 15:1) to afford l-(4-(bromomethyl)phenyl)-l-(pyridin-4-yl)ethan-l-ol (30 mg, 47.2%) as a white solid. ESI-LCMS calcd. for C14H14BrNO 291.03 & 293.02; [M+H]+ found 291.90 & 293.90.Preparation of 4-(l-(4-(bromomethyl)phenyl)ethoxy)pyridineLiAIH4step 2PPh3CBr4, DCEstep 3 Step 1: Preparation of methyl 4-(l-(pyridin-4-yloxy)ethyl)benzoate

[0244] To a solution of methyl 4-(l-hydroxyethyl)benzoate (500 mg, 2.775 mmol, 1.0 equiv.) and 4-hydroxypyridine (263.87 mg, 2.775 mmol, 1.0 equiv.) in THF (5 mL) was added PPh3 (727.77 mg, 2.775 mmol, 1.0 equiv.) at 0°C. The resulting mixture was stirred at 0°C for Ih. To the above mixture were added DIAD (550.06 pL, 2.775 mmol, 1.0 equiv.) at room temperature. After the resulting mixture was stirred at rt overnight, it was concentrated under reduced pressure. The residue was purified by reversed -phase flash chromatography (mobile phase: MeCN in FhO (10 mmol / L NFUHCO3) with gradient from 5% to 100%) to provide methyl 4-(l-(pyridin-4-yloxy)ethyl)benzoate (698 mg, 97.8%) as a colorless oil. ESI-LCMS calcd. for C15H15NO3 257.11; [M+H]+ found 257.90.Step 2: Preparation of (4-(l-(pyridin-4-yloxy)ethyl)phenyl)methanol

[0245] To a solution of methyl 4-(l-(pyridin-4-yloxy)ethyl)benzoate (800 mg, 3.109 mmol, 1.0 equiv.) in THF (10 mL) was added LiAlH4(236.00 mg, 6.218 mmol, 2.0 equiv.) at 0°C. The resulting mixture was stirred at rt for 30 min under nitrogen atmosphere. The mixture was acidified to pH 5 with aq. HC1 (1.0 N). After concentration, the residue was purified by reversed-phase (Cl 8) flash chromatography (mobile phase: MeCN in H2O (lOmmol / L NHiHCCL) with gradient from 5% to 100%) to afford (4-(l-(pyridin-4-yloxy)ethyl)phenyl)methanol (320 mg, 44.9%) as a brown solid. ESI-LCMS calcd. for C14H15NO2 229.11, [M+H]+ found 230.10.Step 3: Preparation of 4-(l-(4-(bromomethyl)phenyl)ethoxy)pyridine

[0246] To solution of (4-(l-(pyridin-4-yloxy)ethyl)phenyl)methanol (100 mg, 0.436 mmol, 1 equiv.) in DCM (1 mL) was added PBrs (165.70 pL, 1.744 mmol, 4 equiv.) dropwise at 0°C. The resulting mixture was stirred at 0°C for 30 min, and then was quenched with water (5 mL) and extracted with CH2Q2 (3 x 10 mL). The combined organic layers were washed with brine (3x8 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to provide 4-(1-(4-(bromomethyl)phenyl)ethoxy)pyridine (98 mg, 76.90%) as a yellow solid, which was directly used in theAttorney Docket No. 57547-742.601next step without further purification. ESI-LCMS calcd. for C₁₄H₁₄BrNO 291.03 and 293.02; [M+H]+found 291.85 and 293.80.Preparation of 4-((4-(bromomethyl)phenyl)(methoxy)methyl)pyridineStep 1: Preparation of (4-(((tert-butyldiphenylsilyl)oxy)methyl)phenyl)(pyridin-4-yl)methanol

[0247] A solution of ((4-bromobenzyl)oxy)(tert-butyl)diphenylsilane (2 g, 4.701 mmol, 1.0 equiv.) in Et20 (20 mL) was treated with n-BuLi (331.2 mg, 5.171 mmol, 1.1 equiv.) at -78 °C for 0.5 h under nitrogen atmosphere, followed by the addition of a solution of isonicotinaldehyde (503.1 mg, 4.701 mmol, 1.0 equiv.) in THF (5mL) dropwise at -78°C for Ih. The resulting mixture was stirred at rt for additional Ih, quenched with sat. NEUCl (aq.) (100 mL) and extracted with EtOAc (3 x 100 mL). The organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / PE:0~50%) to provide (4-(((tert-butyldiphenylsilyl)oxy)methyl)phenyl)(pyridin-4-yl)methanol (1.0 g, 46.8% yield) as a yellow solid. MS (ESI): mass calcd. for C29H31NO2Si 453.21; [M+H]+ found 454.2.Step 2: Preparation of 4-((4-(((tert-butyldiphenylsilyl)oxy)methyl)phenyl)(methoxy)methyl)pyridine

[0248] To a solution of (4-(((tert-butyldiphenylsilyl)oxy)methyl)phenyl)(pyridin-4-yl)methanol (500 mg, 1.102 mmol, 1.0 equiv.) and Mel (102.92 pL, 1.653 mmol, 1.5 equiv.) in DMF (5 mL) was added NaH (39.67 mg, 1.653 mmol, 1.5 equiv.) in portions at 0°C over 2 min. The resulting mixture was stirred at 0 °C for additional Ih, then quenched with water (10 mL) at 0 °C and extracted with EtOAc (3 x lOmL). The combined organic layers were washed with brine (2x30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / PE:0~50%) to afford 4-((4-(((tert-butyldiphenylsilyl)oxy)methyl)phenyl) (methoxy)methyl)pyridine (140 mg, 27.2%) as a white solid. ESI-LCMS calcd. for C3oH33N02Si 467.23;[M+H]+ found 468.25.Step 3: Preparation of (4-[methoxy(pyridin-4-yl)methyl]phenylmethanol

[0249] To a solution of 4-((4-(((tert-butyldiphenylsilyl)oxy)methyl)phenyl)(methoxy)methyl)pyridine (140 mg, 0.299 mmol, 1.0 equiv.) in THF (5 mL) was added TBAF (141 mg, 0.448 mmol, 1.5 equiv. ). The resulting solution was stirred at rt for Ih. After concentration, the residue was purified by reversed -phase (C18) flash chromatography (mobile phase: MeCN in H2O (10 mmol / LN^HCCh) with gradient from 10% to 50%) to provide (4- [methoxy (pyridin-4-yl)methyl] phenylmethanol (73 mg, 100%) as ayellow solid. ESI-LCMS calcd. for C14H15NO2229.11; [M+H]+ found 230.10.Attorney Docket No. 57547-742.601Step 4: Preparation of 4-((4-(bromomethyl)phenyl)(methoxy)methyl)pyridine

[0250] To a solution of (4- [methoxy (pyridin-4-yl)methyl] phenylmethanol (60 mg, 0.262 mmol, 1 equiv.) in DCM (1 mL) was added PB (49.71 pL, 0.524 mmol, 2.0 equiv.) dropwise at 0 °C. The reaction mixture was stirred at 0°C for 30 min. The resulting mixture was basified to pH 8 with saturated NaHCCL (aq.) and extracted with EtOAc (3 x lOmL). The combined organic layers were washed with brine (2x10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to provide the crude product, which was directly used in the next step without further purification. ESI-LCMS calcd. for Ci4Hi4BrNO 291.03 & 293.02; [M+H]+ found 291.95 & 293.95.Preparation of 2-(3-hydroxy-2-oxo-l-(4-(pyridine-4-sulfonamido)benzyl)indolin-3-yl)acetic acidoStep 1: Preparation of l-(4-bromobenzyl)indoline-2, 3-dione

[0251] A suspension of 4-bromobenzyl bromide (25.00 g, 100.03 mmol, 1.0 eq), isatin (14.72 g, 100.03 mmol, 1.0 eq) and cesium carbonate (35.85 g, 110.03 mmol, 1.1 eq) in 1,2-dichloroethane (357 mL) was stirred at 80 °C for 3 h. The reaction mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure and the residue was treated with hexane to remove excess of benzyl bromide. The resulting solid material was dried under vacuum to provide l-(4-bromobenzyl)indoline-2,3-dione (29.36 g, 93%), which was directly used in the next step without further purification.Step 2: Preparation of N-(4-((2,3-dioxoindolin-l-yl)methyl)phenyl)pyridine-4-sulfonamide

[0252] A mixture of anhydrous potassium carbonate (0.586 g, 4.238 mmol, 2.0 eq), 4 -pyridinesulfonamide (0.503 g, 3.179 mmol, 1.5 eq), tBuXPhos (0.162 g, 0.381 mmol, 0.18 eq) and 1 -(4-bromobenzyl)indoline-2, 3-dione (0.670 g, 2.119 mmol, 1.0 eq) in anhydrous 1,4-dioxane (14 mL, 0.15 M) was degassed with argon for 5 minutes. Then tris(dibenzylideneacetone)dipalladium(0) (Pd2dba3, 0.116 g, 0.127 mmol, 0.06 eq) was added and the resulting mixture was stirred at 80 °C overnight. Upon completion, the reaction was cooled to room temperature, diluted with EtOAc, filtered through celite, washed with a mixed solvent DCM / MeOH (1:1) and concentrated. The residue was purified by silica gel column chromatography (MeOH / DCM: 0-10%) to provideN-(4-((2,3-dioxoindolin-l-yl)methyl)phenyl)pyridine-4-sulfonamide (0.562 g, 65%). MS (ESI): [M+H]+ found 394.2Step 3: Preparation of 2-(3-hydroxy-2-oxo-l-(4-(pyridine-4-sulfonamido)benzyl)indolin-3-yl)acetic acid

[0253] Amixture of malonic acid (0.285 g, 2.743 mmol, 2.0 eq), nickel(II) acetate tetrahydrate (0.102 g, 0.411 mmol, 0.3 eq) and N-(4-((2,3-dioxoindolin-l-yl)methyl)phenyl)pyridine-4-sulfonamide (0.562 g,Attorney Docket No. 57547-742.6011.371 mmol, 1.0 eq) in anhydrous THF (14 mL) was stirred at 70 °C for 2 days. Upon completion, the solution was filtered through celite, washed with EtOAc, and concentrated under reduced pressure. The residue was redissolved in 2-MeTHF, washed with water and brine, and dried over anhydrous Na2SO4. The evaporation of the solvent provided 2-(3-hydroxy-2-oxo-l-(4-(pyridine-4-sulfonamido)benzyl)indolin-3-yl)acetic acid (0.65 g, 89%), which was directly used in the next step without further purification. MS (ESI):[M+H]+ found 453.8.

[0254] The following intermediates were prepared by the same general method as for 2-(3-hydroxy-2-oxo-l-(4-(pyridine-4-sulfonamido)benzyl)indolin-3-yl)acetic acid.ft ft,,,Structure Exact mass LC-MS [M+l] (m / z)456.11 457.2456.11 456.8rOoH459.06 459.85° ONOz=NM H O ft453.10 453.8;451.80'boPreparation of 2-(3-methyl-2-oxo-l-(4-(pyridine-4-sulfonamido)benzyl)indolin-3-yl)acetic acidStep 1: Preparation of ethyl (E / Z)-2-(l-(4-bromobenzyl)-2-oxoindolin-3-ylidene)acetate

[0255] To a solution of l-(4-bromobenzyl)indoline-2, 3-dione (10.00 g, 31.63 mmol, 1.0 eq) in anhydrous THF (105 mL) was added ethyl (triphenylphosphoranylidene)acetate (11.02 g, 31.63 mmol, 1.0 eq) at rt. The resulting reaction solution was stirred at room temperature overnight. After concentration, the residue was purified by silica gel column chromatography (MeOH in DCM: 0-5%) to afford ethyl (E / Z)-2-(l-(4-bromobenzyl)-2-oxoindolin-3-ylidene)acetate (11.1 g, 91%) as a white solid.Attorney Docket No. 57547-742.601Step 2: Preparation of ethyl 2-(l-(4-bromobenzyl)-2-oxoindolin-3-yl)acetate

[0256] To a mixture of sodium borohydride (1.14 g, 30.19 mmol, 1.1 eq) in anhydrous tetrahydrofuran (265 mL) at 0 °C was added ethyl (E / Z)-2-(l-(4-bromobenzyl)-2-oxoindolin-3-ylidene)acetate (10.60 g, 27.44 mmol, 1.0 eq) portion wise. The resulting reaction mixture was stirred at 0 °C for 30 min. Upon completion, the mixture was quenched with 10% NaEUPC solution and extracted with DCM. The combined organic phases were dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (EtOAc in cyclohexane: 5-15%) to give ethyl 2-(l-(4-bromobenzyl)-2-oxoindolin-3-yl)acetate (5.62 g, 46%) as a white solid. MS (ESI): [M+H]+found 388.3 & 390.2.Step 3: Preparation of ethyl 2-(l-(4-bromobenzyl)-3-methyl-2-oxoindolin-3-yl)acetate

[0257] A solution of ethyl 2-(l-(4-bromobenzyl)-2-oxoindolin-3-yl)acetate (1.93 g, 3.88 mmol, 1.0 eq) in anhydrous DMF (38.0 ml) was purged with argon and cooled to 0 °C. Then sodium hydride (0.23 g, 5.82 mmol, 1.5 eq) was added, and the reaction mixture was stirred under argon for 10 min. Methyl iodide (0.29 ml, 4.65 mmol, 1.2 eq) was added dropwise. The resulting mixture was stirred at 0 °C for 1 h. Upon completion, the solution was quenched at 0 °C by addition of 5% NaEUPC solution and extracted with DCM. The combined organic fractions were dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (EtOAc in cyclohexane: 5-15%) to give ethyl 2-(l-(4-bromobenzyl)-3-methyl-2-oxoindolin-3-yl)acetate (1.45 g, 82%) as a yellow oil. MS (ESI):[M+H]+ found 401.85 & 403.65.Step 4: Preparation of ethyl 2-(3-methyl-2-oxo-1-(4-(pyridine-4-sulfonamido)benzyl)indolin-3-yl) acetate

[0258] A mixture of ethyl 2-(l-(4-bromobenzyl)-3-methyl-2-oxoindolin-3-yl)acetate (0.50 g, 1.09 mmol, 1.0 eq), anhydrous potassium carbonate (0.53 g, 3.83 mmol, 3.5 eq), / BuXPhos (0.18 g, 0.44 mmol, 0.4 eq) and 4-pyridinesulfonamide (0.21 g, 1.31 mmol, 1.2 eq) in 1,4-dioxane (10.0 mL) was degassed for 10 minutes. Tris(dibenzylideneacetone)dipalladium(0) (0.20 g, 0.22 mmol, 0.20 eq) was added. Then the reaction mixture was stirred at 100° C overnight. Full conversion was not achieved, so additional portions of / BuXPhos (0.06 g, 0.36 mmol, 0.13 eq), 4-pyridinesulfonamide (0.10 g, 0.66 mmol, 0.6 eq) and tris(dibenzylideneacetone)dipalladium(0) (0.08 g, 0.09 mmol, 0.08 eq) were added and the reaction mixture was stirred at 100 °C for 4 hours. Upon completion, the reaction mixture was diluted with EtOAc and filtered through celite. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (EtOAc in cyclohexane: 10-80%) to give ethyl 2-(3-methyl-2-oxo-l-(4-(pyridine-4-sulfonamido)benzyl)indolin-3-yl)acetate (335 mg, 64%) as a yellow solid. MS (ESI): [M+H]+found 480.3.Step 5: Preparation of 2-(3-methyl-2-oxo-l-(4-(pyridine-4-sulfonamido)benzyl)indolin-3-yl)acetic acid

[0259] To a solution of ethyl 2-(3-methyl-2-oxo-l-(4-(pyridine-4-sulfonamido)benzyl)indolin-3-yl)acetate (0.335 g, 0.70 mmol, 1.0 eq) in 1,4-dioxane (3.3 mL) and water (1.1 mL) was added lithium hydroxide monohydrate (0.07 g, 1.75 mmol, 2.5 eq). The resulting mixture was stirred at room temperature overnight,Attorney Docket No. 57547-742.601acidified with 0.5 M HC1 and extracted with EtOAc. The combined organic fractions were dried over anhydrous Na2SC>4 and concentrated in vacuum to give 2-(3-methyl-2-oxo-l-(4-(pyridine-4-sulfonamido)benzyl)indolin-3-yl)acetic acid as a white solid, which was directly used in the next step without further purification. MS (ESI): [M+H]+found 451.95.

[0260] The following compounds were prepared by the same general method as for 2-(3-methyl-2-oxo-l- °' ZX(4-(pyridine-4-sulfonamido)benzyl)indolin-3-yl)acetic acid.Structure Exact mass LC-MS [M+l] (m / z)N=\ p.,W H O J451.12 451.95o \°^o OX451.12 451.95Preparation of 2-(l-(4-bromobenzyl)-3,7-dimethyl-2-oxoindolin-3-yl)-N-phenylacetamiden —Step 1: Preparation of N-(o-tolyl)methacrylamide

[0261] To a solution of o-toluidine (2.98 mL, 28.00 mmol, 1.0 eq) and AA-diisopropylethylamine (4.88 mL, 28.00 mmol, 1.0 eq) in anhydrous DCM (60.0 mL) was added 2-methylprop-2-enoyl chloride (2.685 ml, 28.00 mmol, 1.0 eq) at 0 °C. The reaction solution was stirred at 0 °C for 4 h while the temperature was allowed to rise to room temperature. The reaction solution was diluted with DCM and washed with aqueous 10% NaELPCh. The organic layer was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give N-(o-tolyl)methacrylamide (4.28 g, 87%) as a white solid. MS (ESI): [M+H]+ found 175.95.Step 2: Preparation of N-(4-bromobenzyl)-N-(o-tolyl)methacrylamide

[0262] To asolution ofN-(o-tolyl)methacrylamide (4.28 g, 24.42 mmol, 1.0 eq) in anhydrous THF (81.42 mL, 0.3 M) at 0°C was added sodium hydride 60% dispersion in mineral oil (1.465 g, 36.637 mmol, 1.5 eq) portion wise. The resulting mixture was stirred at 0 °C for 5 minutes and then 4-bromobenzyl bromide (7.33 g, 29.31 mmol, 1.2 eq) was added. After the reaction mixture was stirred at room temperature overnight, it was diluted with 10% NaELPCh and extracted with EtOAc. The combined organic phases were washed with brine and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (EtOAc in cyclohexane: 0-10%) to provide N-(4-bromobenzyl)-N-(o-tolyl)methacrylamide as a white solid. MS (ESI): [M+H]+found 343.80 & 345.70.Attorney Docket No. 57547-742.601Step 3: Preparation of 2-(l-(4-bromobenzyl)-3,7-dimethyl-2-oxoindolin-3-yl)-N-phenylacetamide

[0263] To a dry high pressure reactor was charged with N-(4-bromobenzyl)-N-(o-tolyl)methacrylamide (5.15 g, 14.96 mmol, 1.0 eq), 4-phenylsemicarbazide (4.52 g, 29.92 mmol, 2.0 eq) and a 1:1 mixture of anhydrous MeCN (37.4 mL) and DCE (37.4 mL). Copper (II) carbonate (0.018 g, 0.15 mmol, 0.01 eq) and CDtert-butyl hydroperoxide (70 wt. % in H2O, 8.28 mL, 59.84 mmol, 4.0 eq) were added. The vessel was sealed and stirred at 70 °C for 4 h. The reaction mixture was cooled to room temperature and filtered through celite. The filtrate was concentrated under reduced pressure to give a dark brown foam, which was purified by silica gel flash column chromatography (EtOAc in cyclohexane: 0-30%) and repurified by reverse phase flash column chromatography to afford 2-(l-(4-bromobenzyl)-3,7-dimethyl-2-oxoindolin-3-yl)-N-phenylacetamide (1.17 g, 17%).0

[0264] The following intermediates were prepared by the same general method as for 2-(l-(4-bromobenzyl)-3,7-dimethyl-2-oxoindolin-3-yl)-N-phenylacetamide:Structure Exact mass LC-MS [M+l] (m / z)462.09 &, QZZ 462.90 & 464.85464.09448.08 &448.90 & 450.65450.08ptnPreparation of N-(4-((3- amino- 3-methyl-2-oxoindolin-l-yl)methyl)phenyl)pyridine-3-sulfonamideStep 4Step 3 Step 1: Preparation of N-(4-((2,3-dioxoindolin-l-yl)methyl)phenyl)pyridine-3-sulfonamide

[0265] Amixture of potassium carbonate (3.497 g, 25.304 mmol, 2.0 eq), pyridine-3-sulfonamide (2.00 g, 12.652 mmol, 1.0 eq), tBuXPhos (0.967 g, 2.277 mmol, 0.18 eq) and l-(4-bromobenzyl)indoline-2, 3-dione (4.00 g, 12.652 mmol, 1.0 eq) in dioxane (84 mL) was stirred under argon for 20 min. Then, tris(dibenzylideneacetone)dipalladium(0) (0.695 g, 0.759 mmol, 0.06 eq) was added. The resulting reaction mixture was stirred at 100 °C for 16 h. The suspension was filtered via celite, washed with DCM, and subsequently washed with 10% MeOH in DCM solution. The filtrate was concentrated under reduced pressure to afford N-(4-((2,3-dioxoindolin-l-yl)methyl)phenyl)pyridine-3-sulfonamide (3.74 g, 75%). MS (ESI): [M+H]+ found 393.80.Attorney Docket No. 57547-742.601Step 2: Preparation of N-(4-((3-hydroxy-3-methyl-2-oxoindolin-l-yl)methyl)phenyl)pyridine-3-sulfonamide

[0266] To a solution of N-(4-((2,3-dioxoindolin-l-yl)methyl)phenyl)pyridine-3-sulfonami de (1.92 g, 4.88 mmol, 1.0 eq) in anhydrous THF (134 mL) at -78°C was added 3M MeMgBr in Et20 (4.93 mL, 14.79 mmol) dropwise. The resulting reaction mixture was stirred at -78°C for 5 h. The it was quenched with saturated ammonium chloride solution and extracted with EtOAc. The combined organic phases were washed with brine, dried, and concentrated. The residue was purified by silica gel flash column chromatography (MeOH in DCM: 0-5%) to afford N-(4-((3-hydroxy-3-methyl-2-oxoindolin-l-yl)methyl)phenyl)pyridine-3-sulfonamide (0.714 g, 44%). MS (ESI): [M+H]+found 409.90.Step 3: Preparation of N-(4-((3-chloro-3-methyl-2-oxoindolin-l-yl)methyl)phenyl)pyridine-3-sulfonamide

[0267] To a cooled solution ofN-(4-((3-hydroxy-3-methyl-2-oxoindolin-l-yl)methyl)phenyl)pyridine-3-sulfonamide (2.014 g, 4.514 mmol, 1.0 eq) in DCM (60 mL) at 0 °C was added thionyl chloride (0.491 mL, 6.772 mmol, 2.4 eq) and triethylamine (1.573 mL, 11.285 mmol, 4.0 eq). The reaction mixture was stirred at 0 °C for 30 min, and subsequently quenched with brine. The organic phase was washed with brine, dried, and concentrated under reduced pressure to afford N-(4-((3-chloro-3-methyl-2-oxoindolin-l-yl)methyl)phenyl)pyridine-3-sulfonamide (1.83 g, 80%). MS (ESI): [M+H]+found 427.85 &429.70. Step 4: Preparation of N-(4-((3-amino-3-methyl-2-oxoindolin-l-yl)methyl)phenyl)pyridine-3-sulfonamide

[0268] A solution ofN-(4-((3-chloro-3-methyl-2-oxoindolin-l-yl)methyl)phenyl)pyridine-3-sulfonamide (1.83 g, 3.592 mmol) inNH3'H2O(25%, 36 mL) was stirred at room temperature for 16 h. The volatile was evaporated and the residue was purified by silica gel flash column chromatography (MeOH in DCM: 0-5%) to afford N-(4-((3-amino-3-methyl-2-oxoindolin-l-yl)methyl)phenyl)pyridine-3-sulfonamide (0.439 g, 30%). MS (ESI): [M+H]+ found 429.05.Preparation of 1-((2-(tert-butyl)-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)methyl)indoline-2,3-dioneStep 1 Step 2 Step 3 Step 4Step 5Step 1: Preparation of 4-bromo-N-(tert-butyl)-2-methylbenzenesulfonamide

[0269] To a solution of 4-bromo-2-methylbenzenesulfonyl chloride (5.00 g, 18.55 mmol) in DCM (50 mL) was added a solution of tert-butylamine (2.339 mL, 22.260 mmol) and triethylamine (3.120 mL, 22.260Attorney Docket No. 57547-742.601mmol) in DCM. The reaction mixture was stirred at 0 °C for 2 h and then at room temperature for 16 h. The resulting mixture was washed with 0.1 M HC1 solution and saturated NaHCCh. The organic layers were combined, dried and concentrated in vacuo to afford 4-bromo-N-(tert-butyl)-2-methylbenzenesulfonamide (4.845 g, yield 82%). MS (ESI): [M-Hp found 303.75 & 305.65.Step 2: Preparation of 4-bromo-2-(bromomethyl)-N-(tert-butyl)benzenesulfonamide

[0270] To a solution of 4-bromo-N-(tert-butyl)-2-methylbenzenesulfonamide (4.845 g, 15.189 mmol) in CCh (80 mL) was added N-Bromosuccinimide (2.703 g, 15.189 mmol) and 2,2'-Azobis(2-methylpropionitrile) (0.623 g, 3.797 mmol). The reaction mixture was stirred at 80 °C for 16 h. The solvent was evaporated and the residue was purified by silica gel flash column chromatography (EtOAc in hexane: 0-20%) to afford 4-bromo-2-(bromomethyl)-N-(tert-butyl)benzenesulfonamide (2.792 g, 41%).Step 3: Preparation of 5-bromo-2-(tert-butyl)-2,3-dihydrobenzo[d] isothiazole 1,1-dioxide

[0271] To a solution of 4-bromo-2-(bromomethyl)-N-tert-butylbenzenesulfonamide (2.792 g, 6.162 mmol) in DMF (40 mL) was added CS2CO3 (4.016 g, 12.325 mmol). The reaction mixture was stirred at room temperature for 3 h, diluted with water and extracted with Et20. The organic layers were combined, dried, and concentrated in vacuo to afford 5-bromo-2-(tert-butyl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (1.97 g, 80%). MS (ESI): [M-Hp found 301.75 & 303.70.Step 4: Preparation of 2-(tert-butyl)-5-(hydroxymethyl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide

[0272] A solution of 5-bromo-2-(tert-butyl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (1.969 g, 4.919 mmol) and (tributylstannyl)methanol (1.895 g, 5.903 mmol) in dioxane (25 mL) was degassed for 10 min. Then XPhos Pd G2 (0.387 g, 0.492 mmol) was added. The resulting reaction mixture was stirred at 80 °C for 16 h. After filtration through celite, the solvent was evaporated and the residue was purified by silica gel flash column chromatography (EtOAc in hexane: 0-100%) to afford 2-(tert-butyl)-5-(hydroxymethyl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (1.089 g, 81%). MS (ESI): [M+H]+found 256.15.Step 5: Preparation of (2-(tert-butyl)-l,l-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)methyl methanesulfonate

[0273] To a solution of 2-(tert-butyl)-5-(hydroxymethyl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (1.089 g, 4.009 mmol) in DCM (25 mL) was added tri ethylamine (0.843 mL, 6.014 mmol) and methanesulfonyl chloride (0.341 mL, 4.410 mmol) at 0 °C. The reaction mixture was stirred at room temperature overnight. The reaction solution was washed with brine, dried, filtered and concentrated under reduced pressure to afford (2-(tert-butyl)-l,l-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)methyl methanesulfonate (0.949 g, 86%).Step 6: Preparation of l-((2-(tert-butyl)-l,l-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)methyl)indoline-2, 3-dione

[0274] To a solution of (2-(tert-butyl)-l,l-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)methyl methanesulfonate (0.949 g, 3.466 mmol) in DMF (15 mL) at 0 °C was added sodium hydride (60% dispersion in mineral oil, 0.153 g, 3.813 mmol). The suspension was stirred at 0 °C for 30 min. Then isatin (0.510 g, 3.466 mmol) and tetrabutyl ammonium iodide (1.280 g, 3.466 mmol) were added. The resultingAttorney Docket No. 57547-742.601reaction mixture was stirred at room temperature for 16 h, quenched with water at 0 °C and extracted with DCM. The organic layers were combined, dried, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (EtOAc in hexane: 0-50%) to afford l-((2-(tert-butyl)-l,l-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)methyl)indoline-2, 3-dione (0.754 g, 52%).Preparation of l-[(4-bromophenyl)methyl]-3-hydroxy-3,7-dimethyl-2,3-dihydro-lH-indol-2-oneStep 1: l-[(4-bromophenyl)methyl]-7-methyl-2,3-dihydro-lH-indole-2, 3-dione

[0275] 7-Methylisatin (20.0 g, 124.1 mmol, 1.0 eq) and cesium carbonate (60.65 g, 186.15 mmol, 1.5 eq) were suspended in anhydrous Dimethylacetamide (DMAc, 500 mL, 0.25 M) to which 4-bromobenzyl bromide (32.57 g, 130.30 mmol, 1.05 eq) was added portion-wise. The reaction was left stirring overnight at rt. Upon completion, the reaction was quenched with water until precipitation was observed. Solids were filtered off, washed with water and dried on air. Solid material was collected and dried thoroughly under vacuum to afford l-[(4-bromophenyl)methyl]-7-methyl-2,3-dihydro-lH-indole-2, 3-dione as orange solid (37.7 g, 161.95 mmol, yield 87%).Step 2: l-[(4-bromophenyl)methyl]-3-hydroxy-3,7-dimethyl-2,3-dihydro-lH-indol-2-one

[0276] l-[(4-bromophenyl)methyl]-7-methyl-2,3-dihydro-lH-indole-2, 3-dione (20.00 g, 58.76 mmol, 1.0 eq) was suspended in anhydrous THF (294 mL) and cooled down to -78°C. Then, 3M MeMgBr in Et20 (39.17 mL, 117.51 mmol) was added dropwise and the reaction mixture was stirred at -78°C for 2h. Cooling bath was removed and the mixture was allowed to warm to rt for the next 2 h. The reaction was quenched with saturated ammonium chloride solution and extracted with DCM. The organic phase was washed with brine, dried and evaporated. Recrystallization from hot DCM afforded l-[(4-bromophenyl)methyl]-3-hydroxy-3,7-dimethyl-2,3-dihydro-lH-indol-2-one (11.04 g, 30.56 mmol, yield 52%) as a yellow solid.Example 1: Preparation of 3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-3-hydroxy-l-(4-(((2-methylpyrimidin-5-yl)oxy)methyl)benzyl)indolin -2-one

[0277] To a solution of 3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-3-hydroxy-l-(4-(hydroxymethyl)benzyl)indolin-2-one (50.0 mg, 0.112 mmol), 2-methylpyrimidin-5-ol (14.0 mg, 0.123 mmol) and PPh₃ (59.0 mg, 0.224 mmol) in DCM (5 mL) was added DIAD (45.0 mg, 0.224 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour under N2. LCMS showed the reaction was finished. DCM (10 mL) was added and the mixture was washed with water (10 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography, elutedAttorney Docket No. 57547-742.601with MeOH in DCM (from 0% to 5%) to afford 3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-3-hydroxy-1-(4-(((2-methylpyrimidin-5-yl)oxy)methyl)benzyl)indolin-2-one (24.0 mg, 39.81 % yield). 'H NMR (400 MHz, DMSO-de) 88.48 (s, 2H), 7.64(dd, J= 8.8, 2.0 Hz, 1H), 7.51 - 7.43 (m, 4H), 7.37 - 7.32 (m, 2H), 7.18 -7.13 (m, 1H), 7.05 (d, J= 8.4Hz, 1H), 6.92 (t, J = 7.6 Hz, 1H), 6.76 (d, J= 8.0 Hz, 1H), 6.24 (s, 1H), 5.21 (s, 2H), 4.96 - 4.86 (m, 2H), 4.17 (d, J = 17.6 Hz, 1H), 3.84 (s, 3H), 3.78 (s, 3H), 3.69 (d, J = 17.6 Hz, 1H), 2.53 (s, 3H). ESI-LCMS calcd. for C31H29N3O6 [M+H]+ 539.2, found 540.2.Example 2: Preparation of 3-[2-(3,4-dimethoxyphenyl)-2-oxo-ethyl]-3-hydroxy-l-[[4-[(2-methylpyrimidin-5-yl)methoxy]phenyl]methyl]indolin-2-one

[0278] To a suspension of l-[[4-[(2-methylpyrimidin-5-yl)methoxy]phenyl]methyl]indoline-2, 3-dione (30 mg, 0.0835 mmol, 1.00 eq) in ethanol (1 mL) was added l-(3,4-dimethoxyphenyl)ethanone (20 mg, 0. Ill mmol, 1.33 eq) and diethylamine (10 pL, 0.0967 mmol, 0.707 g / mL, 1.16 eq). The reaction mixture was heated to 50 °C and stirred for 22.5 h. To the reaction mixture was added ethanol (0.5 mL) and di ethylamine (5 pL, 0.0483 mmol, 0.707 g / mL, 0.579 eq) and the reaction mixture was stirred at 50 °C for 2.5 h. The reaction mixture was evaporated and the residue was purified by gradient silica gel column chromatography eluting with hexane:ethyl acetate (100:0- >0:100). The product was taken up in acetonitrile: water (9:1, 1 mL), flash frozen and lyophilized to afford the title compound (8.6 mg, 19%). MS (ESI): mass calcd. for C31H29N3O6539.2; [M+H]+found 540.3. LCMS (Method 1): Rt = 2.70 min.1H NMR (499 MHz, DMSO-d6) 88.78 (s, 2H), 7.63 (dd, J= 8.5, 2.0 Hz, 1H), 7.46 - 7.37 (m, 2H), 7.39 - 7.28 (m, 2H), 7.20 - 7.09 (m, 1H), 7.05 (d, J= 8.6 Hz, 1H), 7.03 - 6.99 (m, 2H), 6.95 - 6.87 (m, 1H), 6.76 (d, J= 7.8 Hz, 1H), 6.22 (s, 1H), 5.12 (s, 2H), 4.90 - 4.75 (m, 2H), 4.14 (d, J= 17.5 Hz, lH),3.83 (s, 3H), 3.78 (s, 3H),3.67 (d, J= 17.5 Hz, 1H), 2.62 (s, 3H).

[0279] The following compounds were prepared by the same general aldol condensation conditions as for preparation of 3-[2-(3,4-dimethoxyphenyl)-2-oxo-ethyl]-3-hydroxy-l-[[4-[(2-methylpyrimidin-5-y l)methoxy] phenyl] methyl] indolin-2-oneLC-MSEx. Exact mass ‘HNMR[M+l] (m / z)XH NMR (499 MHz, DMSO-de) 8 8.51 (d, J= 2.1 Hz, 1H), 7.78 - 7.72 (m, 1H), 7.68 - 7.58 (m, 2H), 7.42 - 7.36 (m, 2H), 7.37 - 7.30 (m, 2H), 7.26 (d, J= 7.9 Hz, 1H), 7.18 - 7.12 (m, 3 538.2 539.3 1H), 7.05 (d, J= 8.6 Hz, 1H), 7.02 - 6.95 (m, 2H), 6.93 - 6.87 (m, 1H), 6.76 (d, J= 7.8 Hz, 1H), 6.21 (s, 1H), 5.08 (s, 2H), 4.91 -4.69 (m, 2H), 4.13 (d, J= 17.5 Hz, 1H), 3.83 (s, 3H), 3.77 (s, 3H), 3.66 (d, J= 17.5 Hz, 1H), 2.46 (s, 3H).1H NMR (499 MHz, DMSO-de) 8 8.42 (d, J= 5.1 Hz, 1H), 7.67 - 7.60 (m, 1H), 7.43 - 7.37 (m, 2H), 7.37 - 7.30 (m, 2H), 4 538.2 539.37.29 (s, 1H), 7.23 - 7.20 (m, 1H), 7.20 - 7.09 (m, 1H), 7.05 (d,J = 8.5 Hz. 1H), 7.02 - 6.95 (m,2H), 6.95 - 6.85 (m, 1H), 6.77Attorney Docket No. 57547-742.601LC-MSEx. Exact mass ‘HNMR[M+l] (m / z)(d,.7=7, 8 Hz. 1H), 6.21 (s, 1H), 5.12(s, 2H), 4.93 - 4.74 (m, 2H), 4.14 (d, J= 17.5 Hz, 1H), 3.83 (s, 3H), 3.77 (s, 3H), 3.67 (d, J= 17.5 Hz, 1H), 2.48 (s, 3H).XH NMR (499 MHz, DMSO-d6) 8 8.70 (d, J= 5.1 Hz, 1H), 7.68 - 7.60 (m, 8H), 7.60- 7.51 (m,5H),7.47 - 7.37 (m, 3H), 7.37 - 7.28 (m, 2H), 7.18- 7.12(m, 1H), 7.05 (d, J= 8.5 Hz, 5 539.2 540.3 1H), 7.02 - 6.98 (m, 2H), 6.93 - 6.88 (m, 1H), 6.78 (d, J = 7.8Hz, 1H), 5.15 (s, 2H), 4.90 - 4.76 (m, 2H), 4.14 (d, J = 17.5 Hz, 1H), 3.83 (s, 3H), 3.78 (s, 3H), 3.67 (d, J= 17.5 Hz, 1H),2.62 (s, 3H)Example 6: Preparation of 3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-3-hydroxy-l-(4-(((6-methylpyridin-3-yl)methyl)amino)benzyl)indolin-2-one

[0280] To a mixture of l-(4-aminobenzyl)-3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-3-hydroxyindolin-2-one (70 mg, 0.161 mmol) and 6-methylnicotinaldehyde (23 mg, 0.193 mmol) in DCE (5ml) was added AcOH (1 mg, 0.016 mmol). The mixture was stirred at room temperature for 2 hours. Then the reaction was cooled to 0 °C and NaBH(OAc)3 (38 mg, 0.177 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with H2O and extracted with EtOAc (30 mL x 3). The combined organic phases was purified by prep-HPLC under method E condition to give 3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-3-hydroxy-1-(4-(((6-methylpyridin-3-yl)methyl)amino)benzyl)indolin-2-one (26 mg, 29.88%). 'H NMR (400 MHz, DMSO-d6)88.47 (d, J= 1.6 Hz, 1H), 7.75 (d, J= 0.8Hz. 1H), 7.62 (m, 1H), 7.30 (m, 3H), 7.13(m, 3H), 7.03 (d, J= 8Hz, 1H), 6.89 (t, J= 4Hz, 1H), 6.54 (t, J= 8Hz, 1H ), 6.54 (d, J= 8Hz, 2H), 6.25 (s, 1H), 6.16 (s, lH),4.74(d, J= 16 Hz, 1H), 4.63 (d, J= 16 Hz, 1H), 4.26 (s, 1H), 4.10(d, J= 17.6 Hz, 1H), 3.83 (s, 3H), 3.77 (s, 3H),3.63 (d, J= 16 Hz, 1H), 2.455 (s, 3H). ESI-LCMS calcd. for C32H31N3O5 [M+H]+ 537.23, found 538.62.

[0281] The following compounds were prepared by the same general method as for Preparation of 3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-3-hydroxy-l-(4-(((6-methylpyridin-3-yl)methyl)amino)benzyl)indolin-2-one):LC-MSEx. Exact mass ‘HNMR[M+l] (m / z)'H NMR (400 MHz, DMSO-d6) 8 8.65 (s, 2H), 7.62 (dd, J = 8.4, 1.6 Hz, 1H), 7.35 - 7.28 (m, 2H), 7.16 (d, J= 8.4 Hz, 2H), 7.13 (d, J= 8.0 Hz, 1H), 7.04 (d, J= 8.4 Hz, 1H), 6.89 (t, J = 7.2 Hz, 1H), 6.77 (d, J = 8.0Hz, 1H), 6.56 (d, J= 8.4 Hz, 2H), 7 538.2 539.36.24 (t, J= 6.0 Hz, 1H), 6.17 (s, 1H), 4.75 (d, J= 15.6 Hz, 1H), 4.64 (d, J= 15.6 Hz, 1H), 4.24 (d, J = 6.0 Hz, 2H), 4.11 (d, J= 17.6 Hz, 1H), 3.83 (s, 3H), 3.77 (s, 3H), 3.64 (d, J =17.6 Hz, 1H), 3.33 (s, 6H), 2.56 (s, 3H).Attorney Docket No. 57547-742.601Example 8: Preparation of 4-((3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-3-hydroxy-2-oxoindolin-l-yl)methyl)-N-(3-methylisothiazol-4-yl)benzenesulfonamideStep 1: Preparation of 4-((2,3-dioxoindolin-l-yl)methyl)-N-(3-methylisothiazol-4-yl)benzenesulfonamide

[0282] To a stirred solution of 3-methyl-l,2-thiazol-4-amine (34. OOmg, 0.298 mmol, 1.0 equiv.) in DCM (2 mL) was added pyridine (120.44 pL, 1.490 mmol, 5.0 equiv.) dropwise at room temperature, followed by addition of 4-((2,3-dioxoindolin-l-yl)methyl)benzenesulfonyl chloride (100 mg, 0.298 mmol, 1 equiv.) dropwise at 0 °C. The resulting mixture was stirred at room temperature for l. Oh and then concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (column, Cl 8 silica gel; mobile phase, MeCN in Water (0.1% FA), 0% to 100% gradient in 15 min) to provide 4-((2,3-dioxoindolin-l-yl)methyl)-N-(3-methylisothiazol-4-yl)benzenesulfonamide (60 mg, 48.7%) as a yellow solid. MS (ESI): mass calcd. for C19H15N3O4S2413.05; [M+H]+found 414.35.Step 2: 4-((3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-3-hydroxy-2-oxoindolin-l-yl)methyl)-N-(3-methylisothiazol-4-yl)benzenesulfonamide

[0283] To a stirred solution of 4-((2,3-dioxoindolin-l-yl)methyl)-N-(3-methylisothiazol-4-yl)benzenesulfonamide (50 mg, 0.121 mmol, 1 equiv.) and l-(3,4-dimethoxyphenyl)ethanone (21.79 mg, 0.121 mmol, 1 equiv.) in EtOH (500 pL, 8.607 mmol) was added diethylamine (15.01 pL, 0.145 mmol, 1.2 equiv.) in portions at room temperature. The resulting mixture was stirred at 50 °Cfor 4 h. The residue was purified by reversed-phase flash chromatography under method D conditions to provide 4-((3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-3-hydroxy-2-oxoindolin-l-yl)methyl)-N-(3-methylisothiazol-4-yl)benzenesulfonamide (13.8 mg, 19.2%). MS (ESI): mass calcd. for C29H27N3O7S2 593.13; [M+H]+found 594.10.1HNMR(400 MHz, DMSO-d6) 810.06(s, 1H), 8.42 (s, 1H), 7.70-7.62 (m, 5H), 7.38-7.32 (m, 2H), 7.17-7.13 (td, J = 7.7, 1.3 Hz, 1H), 7.056-7.04 (d, J = 8.5 Hz, 1H), 6.95-6.92 (t, J = 7.4Hz, 1H), 6.71-6.69 (d, J = 7.8 Hz, 1H), 6.25 (s, 1H), 4.99(s, 2H), 4.21-4.17 (d, J = 17.7 Hz, 1H), 3.83 (s, 3H), 3.78 (s, 3H), 3.71-3.67 (d, J = 17.6 Hz, 1H), 2.06 (s, 3H)

[0284] The following compounds were prepared by the same general method as for 4-((3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-3-hydroxy-2-oxoindolin-l-yl)methyl)-N-(3-methylisothiazol-4-yl)benzenesulfonamide (Example 8).LC-MSEx. Exact mass ‘HNMR[M+l] (m / z)1H NMR (400 MHz, Methanol-d4) 87.90 - 7.88 (m, 2H), 7.69 -7.61 (m, 3H), 7.39- 7.36 (m,2H), 7.20 - 7.17 (t, J = 7.8 Hz; 9 576.2 577.01H), 7.05 -6.98 (m, 2H), 6.76 - 6.74 (m, 2H), 6.67 (d, J = 2.2Hz, 1H), 5.11 - 4.97 (dd, 2H), 4.15 - 4.10 (d, J = 17.1 Hz,Attorney Docket No. 57547-742.601LC-MSEx. Exact mass ‘HNMR[M+l] (m / z)1H), 3.91 (d, J = 1.5 Hz, 3H), 3.84-3.78 (m, 4H), 3.78 (d, J =1.5 Hz, 3H)'H NMR (400 MHz, DMSO-d6) 8 7.97 (d, J = 6.1 Hz, 2H), 7.76 (d, J = 8.2 Hz, 2H), 7.64 (dd, J = 8.4, 2.0 Hz, 1H), 7.56 (d, J = 8.1 Hz, 2H), 7.36 (dd, J = 7.3, 1.3 Hz, 1H), 7.32 (d, J = 10 573.2 574.2 2.0 Hz, 1H), 7.16 (dd, J = 7.8, 1.3 Hz, 1H), 7.05 (d, J = 8.6 Hz,1H), 6.93 (d, J = 7.5 Hz, 1H), 6.91 - 6.85 (m, 2H),6.76 (d, J = 7.8 Hz, 1H), 6.25 (s, 1H), 4.94(d, J = 2.1 Hz, 2H), 4.18 (d, J = 17.8 Hz, 1H), 3.81 (d, J = 22.6 Hz, 6H), 3.73 - 3.62 (m, 1H).'H NMR (400 MHz, DMSO-d6) 8 10.76 (s, 1H), 8.38 (s, 1H), 8.25 (s, 1H), 7.76-7.74 (d, J = 8.0 Hz, 2H), 7.71-7.65 (d, J = 8.2 Hz, 3H), 7.37 - 7.35 (m, 2H), 7.15 11 579.1 580.0 (t, J = 7.8 Hz, 1H), 7.06-7.04 (d, J = 8.4 Hz, 1H), 6.91 (t, J =7.5 Hz, 1H), 6.74-6.72 (d, J = 7.9 Hz, 1H), 6.24 (s, 1H), 4.97 (s, 2H), 4.20-4.16 (d, J = 17.7 Hz, 1H), 3.83-3.71 (d, J = 21.5Hz, 6H), 3.66 (d, J = 17.7 Hz, 1H)'H NMR (400 MHz, DMSO-d6) 8 12.72 (s, 1H), 7.78 - 7.76 (m, 2H), 7.65 - 7.60 (t, J= 9.3 Hz, 3H), 7.37 - 7.34 (m, 2H), 7.24 - 7.23 (dd, J = 4.7, 2.0 Hz, 1H), 7.18 - 7.14 (t, J = 7.8 12 579.1 580.1 Hz, 1H), 7.06 - 7.04 (dd, J = 8.6, 2.0 Hz, 1H), 6.95 - 6.91 (t, J = 7.8 Hz, 1H), 6.82 -6.77 (m, 2H), 6.23 (d, J = 2.1 Hz, 1H), 4.96 (s, 2H), 4.19 - 4.13 (m, 1H), 3.84 - 3.78 (dd, J = 22.5, 2.1 Hz, 6H), 3.71 - 3.67 (d, J = 17.7 Hz, 1H).> HNMR (400 MHz, Methanol-d4) 87.98 (d, J = 6.5 Hz, 2H), 7.94 - 7.89 (m, 2H), 7.69 - 7.60 (m, 3H), 7.54 (dd, J = 8.3, 2.1 Hz, 1H), 7.38 (dd, J = 7.3, 1.3 Hz, 1H), 7.24 - 7.16 (m, 2H), 13 561.1 562.37.07 (d, J = 6.5 Hz, 2H), 7.01 (td, J = 7.5, 1.0 Hz, 1H), 6.74 (d, J = 7.8 Hz, 1H), 5.12 - 4.94 (m, 2H), 4.18 (s, 1H), 3.90 (s,3H), 3.82 (d, J = 17.4 Hz, 1H).'H NMR (400 MHz, DMSO-d6) 8 10.57 (s, 1H), 8.32 - 8.17 (m, 2H), 7.75 (d, J = 7.8 Hz, 2H), 7.60 (dd, J = 26.8, 8.7 Hz, 4H), 7.48 (d, J = 8.4 Hz, 1H), 7.41 - 7.31 (m, 2H), 7.25 (dd, J 14 561.2 562.2 = 8.3, 4.5 Hz, 1H), 7.16 (t, J = 7.9 Hz, 1H), 6.94 (t, J = 7.5 Hz,1H), 6.73 (d, J = 7.7 Hz, 1H), 6.28 (d, J = 3.1 Hz, 1H), 4.97 (s, 2H), 4.24 (d, J = 18.2 Hz, 1H),3.9O (d, J = 3.1 Hz, 3H), 3.74(d, J = 18.1 Hz, 1H).> HNMR (400 MHz, Methanol-d4) 87.93 - 7.86 (m, 2H), 7.83 (d, J = 7.0 Hz, 1H), 7.71 -7.61 (m, 3H), 7.42 - 7.34 (m, 2H), 7.18(td, J = 7.7, 1.2 Hz, 1H), 7.07 - 6.97 (m, 2H), 6.95 (dd, J 15 587.2 588.1= 6.9, 2.4Hz, 1H), 6.88 (d, J = 2.4 Hz, 1H), 6.73 (d, J = 7.8 Hz, 1H), 5.14- 4.94 (m, 2H),4.13 (d, J = 17.1 Hz, 1H), 3.91 (s, 3H), 3.84 (s, 3H), 3.80 (d, J = 17.1 Hz, 1H), 2.37 (s, 3H). 'H NMR- (400 MHz, DMSO-d6) 8 9.89 (s, 1H), 8.22 (d, J = 4.9 Hz, 1H), 8.07 (s, 1H), 7.64 (s, 5H), 7.37 (d, J = 7.3 Hz, 1H), 7.33 (s, 1H), 7.16 (t, J = 5.1 Hz, 2H), 7.05 (d, J = 8.5 Hz, 16 587.2 586.0 [M-l]1H), 6.94 (t, J = 7.5 Hz, 1H),6.69 (d, J = 7.8 Hz, 1H),6.25 (s, 1H), 5.00 (s, 2H), 4.19 (d, J = 17.7 Hz, 1H), 3.75 (dd, J = 45.1,20.8 Hz, 7H), 1.96 (s, 3H).1H NMR (400 MHz, Methanol-d4) 87.86 (dd, J = 5.0, 1.8 Hz, 1H), 7.78-7.70 (m, 3H), 7.67-7.62 (m, 3H), 7.42 - 7.34 (m, 17 603.2 604.02H), 7.19 (tt, J = 7.8, 1.2 Hz, 1H), 7.07 - 6.97 (m, 2H), 6.90(ddd, J = 7.7, 5.0, 0.8 Hz, 1H), 6.70 (d, J = 7.8 Hz, 1H), 5.10Attorney Docket No. 57547-742.601LC-MSEx. Exact mass ‘HNMR[M+l] (m / z)(d, J = 16.5 Hz, 1H), 4.97 (d, J = 16.5 Hz, 1H), 4.13 (d, J = 17.1 Hz, 1H), 3.94 -3.88 (m, 3H), 3.87 - 3.76 (m, 4H), 3.59(s, 3H).1H NMR (400 MHz, Methanol-d4) 88.49 (d, J = 1.1 Hz, 1H), 8.24 (s, 1H), 7.78-7.76 (d, J = 8.2 Hz, 2H), 7.70 - 7.66 (m, 3H), 7.39 -7.37 (m, 2H), 7.22-7.20 (dd, J = 8.4, 7.1 Hz, 1H), 18 563.2 564.0 7.18-6.99 (m, 2H), 6.77-6.72 (d, J = 7.8 Hz, 1H), 5.15-5.01(d, J = 16.6 Hz, 1H), 4.97-4.86 (d, J = 16.6 Hz, 1H), 4.16-4.12 (d, J = 17.2 Hz, 1H), 3.91 -3.84(d, J = 1.7 Hz, 3H), 3.84- 3.78(m, 4H).'H NMR (400 MHz, Methanol-d4) 88.66 (s, 1H), 7.81 - 7.66 (m, 5H), 7.43 -7.36 (m, 2H), 7.22 (td, J = 7.8, 1.3 Hz, 1H), 19 593.2 594.2 7.08 - 6.99 (m, 2H), 6.72 (d, J = 7.8 Hz, 1H), 5.17 (d, J = 16.5Hz, 1H), 5.03 (d, J = 16.5 Hz, 1H), 4.15 (d, J = 17.1 Hz, 1H),3.92 (s, 3H), 3.84 (s, 4H), 1.99 (s, 3H).1H NMR (400 MHz, Methanol-d4) 88.86- 8.84 (d, J = 2.1 Hz, 1H), 8.37 - 8.36 (d, J = 2.6 Hz, 1H), 8.22 - 8.21 (dd, J = 4.9, 1.4 Hz, 1H), 8.17 -8.14 (dd, J = 8.2, 2.2 Hz, 1H), 7.98 - 7.96 (d, J = 8.1 Hz, 1H), 7.74 - 7.71 (ddd, J = 8.4, 2.7, 1.4 Hz, 1H), 20 574.2 575.4 7.66-7.64 (dd, J = 8.5, 2.1 Hz, 1H), 7.38-7.36 (m,2H), 7.30- 7.20 (tn, 2H), 7.03 - 7.00 (m, 2H), 6.80 - 6.78 (d, J = 7.8 Hz, 1H), 5.22-5.18 (d, J = 16.6 Hz, 1H), 5.02 - 4.87 (d, J = 16.6 Hz, 1H), 4.18-4.13 (d, J = 17.3 Hz, 1H), 3.91 (s, 3H), 3.83 (s, 3H), 3.82 - 3.77 (d, J = 17.3 Hz, 1H).XH NMR (400 MHz, DMSO-d6) 811.11 (s, 2H), 10.88 (s, 1H), 7.84 – 7.70 (d, J = 8.1 Hz, 2H), 7.68 - 7.65 (d, J = 8.1 Hz, 2H), 7.64 - 7.63 (dd, J = 8.5, 2.0 Hz, 1H), 7.42 - 7.34 (m, 2H), 7.19-7.15 (td, J = 7.7, 1.4 Hz, 1H), 7.07 - 7.05 (d, J = 21 589.2 590.18.6 Hz, 1H), 6.96 - 6.92 (t, J = 7.4 Hz, 1H), 6.80 - 6.78 (d, J = 7.8 Hz, 1H), 6.25 (s, 1H), 5.97- 5.95 (d, J = 7.3 Hz, 1H),5.83 (s, 1H), 5.00 - 4.21 (d, J = 3.0 Hz, 2H), 4.17 - 3.79 (d, J = 17.7 Hz, 1H), 3.71 (s, 3H), 3.67 (s, 3H), 3.75 (s, 1H).1H NMR (400 MHz, Methanol-d4) 87.94 - 7.74 (m, 2H), 7.72 -7.67 (dd, J = 21.9, 8.3 Hz, 3H), 7.48 - 7.46 (dd, J = 8.1, 2.3 Hz, 1H), 7.40 - 7.21 (m, 2H), 7.19 - 7.17 (t, J = 7.9 Hz, 1H), 7.04 - 6.99 (tn, 2H), 6.74 - 6.72 (d, J = 7.8 Hz, 1H), 6.25 - 22 603.2 604.55.15 (q, J = 2.5 Hz, 2H), 5.11 - 5.03 (d, J = 16.6 Hz, 1H), 4.99 -4.87 (d, J = 16.6 Hz, 1H), 4.17 -4.13 (dd, J = 17.3, 2.1 Hz, 1H), 3.92 - 3.85 (d, J = 2.1 Hz, 3H), 3.83 - 3.79 (d, J = 2.1 Hz, 3H), 3.66 -3.59 (m, 1H), 3.50 - 3.15 (d, J = 2.1 Hz, 3H). > HNMR (400 MHz, Methanol-d4) 87.95 - 7.84 (m, 3H), 7.79 (d, J = 7.1 Hz, 1H), 7.70 - 7.58 (m, 3H), 7.42 - 7.34 (m, 2H), 7.31 (d, J = 7.0Hz, 1H), 7.19 (td, J = 7.8, 1.3 Hz, 1H), 7.07 - 23 587.2 588.2 6.96 (m, 2H), 6.74 (d, J = 7.8 Hz, 1H), 5.15 - 4.90 (m, 2H),4.12 (d, J = 17.1 Hz, 1H), 3.91 (s, 3H), 3.84 (s, 3H), 3.80 (d, J = 17.1 Hz, 1H), 2.19-2.15 (m, 3H), 1.57 -0.99 (m, 1H), 0.11(s, 1H),> HNMR (400 MHz, Methanol-d4) 87.88 (dd, J = 15.7, 6.9 Hz; 3H), 7.68 (dd, J = 12.6, 8.0 Hz, 3H), 7.38 (d, J = 8.2 Hz, 2H), 7.18 (t, J = 7.8 Hz, 1H), 7.02 (q, J = 7.9, 7.4 Hz, 2H), 6.71 (d, 24 603.2 604.4J = 6.9 Hz, 2H), 6.50 (s, 1H), 5.11 (d, J = 16.6 Hz, 2H), 4.14 (d, J = 17.1 Hz, 1H), 3.92 (s, 3H), 3.82 (dd, J = 14.8, 11.7 Hz,7H).Attomey Docket No. 57547-742.601LC-MSEx. Exact mass ‘HNMR[M+l] (m / z)1H NMR (400 MHz, Methanol-d4): 88.21 (dd, J = 4.8, 1.6 Hz, IH), 7.76-7.61 (m, 5H), 7.55 (dd, J = 8.1, 1.6 Hz, IH), 7.39 25 587.2 588 (dd, J = 4.9, 2.7 Hz, 2H), 7.26 - 7.13 (m, 2H), 7.07 - 6.98 (m,2H), 6.71 (d, J = 7.8 Hz, IH), 5.18 - 4.95 (m, 2H), 4.14 (d, J = 17.2 Hz, IH), 3.92 (s, 3H), 3.87 -3.71 (m, 4H), 2.18 (s, 3H). 'H NMR (400 MHz, Methanol-d4): 88.08 (d, J = 2.6 Hz, IH), 7.78 - 7.70 (m, 2H), 7.67 (td, J = 6.6, 3.2 Hz, 3H), 7.49 (dd, J = 8.4, 2.6 Hz, IH), 7.38 (dd, J = 8.1, 1.7 Hz, 2H), 7.24 - 7.13 26 587.2 588(m, 2H), 7.07- 6.97 (m,2H), 6.69 (d, J = 7.8 Hz, IH), 5.14 - 4.91 (m, 2H), 4.13 (d, J = 17.2 Hz, IH), 3.92 (s, 3H), 3.87 - 3.73 (m, 4H), 2.43 (s, 3H).XH NMR (400 MHz, DMSO-d6): 8 10.32 (s, IH), 7.81 - 7.60 (m, 5H), 7.38 (d, J = 7.3Hz, IH), 7.34 (s, IH), 7.28 - 7.23 (m, IH), 7.18 (t, J = 7.7 Hz, IH), 7.06 (d, J = 8.5 Hz, IH), 6.95 (t, 27 576.2 575 J = 7.5 Hz, IH), 6.74 (d, J = 7.8 Hz, IH), 6.26 (d, J = 2.1 Hz, IH), 5.60 (t, J = 1.9 Hz, IH), 5.02 (s, 2H), 4.20 (d, J = 17.9 Hz, IH), 3.84 (s, 3H), 3.78 (s, 3H), 3.71 (d, J = 17.6 Hz, IH),3.54 (d, J = 2.2 Hz, 3H).Example 28: Preparation of 4-((3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-3-hydroxy-2-oxoindolin-l-yl)methyl)-N-(pyridin-3-yl)benzenesulfonamideStep 1: Preparation of 4-((2,3-dioxoindolin-l-yl)methyl)-N-(pyridin-3-yl)benzenesulfonamide

[0285] To a solution of 4- [(2, 3-dioxoindol-l-yl)methyl] benzenesulfonyl chloride (100 mg, 0.298 mmol, 1.0 equiv.) in DCM (1 mL) was added pyridine (12 pL). 3-aminopyridine (84 mg, 0.893 mmol, 3.00 equiv.) and DCM (1 mL, 15.731 mmol, 52.82 equiv.) at 0 °C. The resulting mixture was stirred at room temperature for Ih and then concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (column, Cl 8 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 50% gradient in 10 min) to provide 4-((2,3-dioxoindolin-l-yl)methyl)-N-(pyridin-3-yl)benzenesulfonamide (68 mg, 58.0%) as a yellow solid. MS (ESI): mass calcd. for C20H15N3O4S 393.08; [M+H]+found 393.90. Step 2: Preparation of 4-((3-(2-(3,4-dimethoxyphenyl)-2-oxoetiiyl)-3-hydroxy-2-oxoindolin-l-yl)methyl)-N-(pyridin-3-yl)benzenesulfonamide

[0286] A solution of 4-((2,3-dioxoindolin-l-yl)methyl)-N-(pyridin-3-yl)benzenesulfonamide (50 mg, 0.127 mmol, 1 equiv.) and 1-(3,4-dimethoxyphenyl)ethanone (22.9 mg, 0.127 mmol, 1 equiv.) in water was stirred at 80 °C under nitrogen atmosphere for 2h. After concentration, the residue was purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 50% gradient in 10 min) to provide 4-((3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-3-hydroxy-2-oxoindolin-l-yl)methyl)-N-(pyridin-3-yl)benzenesulfonamide (10 mg, 13.7%).1H NMR (400 MHz, Methanol-d4) 5 8.23Attorney Docket No. 57547-742.601(dd, J = 7.5, 3.5 Hz, 2H), 7.82 - 7.75 (m, 2H), 7.71 - 7.59 (m, 4H), 7.41 - 7.34 (m, 2H), 7.30 (dd, J = 8.2, 4.8 Hz, 1H), 7.19 (t, J = 7.7 Hz, 1H), 7.07 - 6.97 (m, 2H), 6.69 (d, J = 7.7 Hz, 1H), 5.10 (d, J = 16.6 Hz, lH), 5.00 (s, 1H), 4.14 (d, J = 17.2 Hz, 1H), 3.88 (d, J = 28.3 Hz, 6H), 3.80 (d, J = 17.2 Hz, 1H). MS (ESI): mass calcd. for C30H27N3O7S 573. 2; [M+H]+found 574.1.Example 29: 4-((3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-3-hydroxy-2-oxoindolin-l-yl)methyl)-N-(oxazol-2-yl)benzenesulfonamideStep 1: Preparation of methyl 4-(N-(oxazol-2-yl)sulfamoyl)benzoate

[0287] To a stirred solution of oxazol-2-amine (1 g, 11.894 mmol, 1 equiv.) and pyridine (2.89 mL, 35.682 mmol, 3 equiv.) in DCM (2 mL) was added a solution of methyl 4-(chlorosulfonyl)benzoate (2.23 g, 9.515 mmol, 0.8 equiv.) in DCM (20 mL) dropwise at 0°C. The resulting mixture was stirred at room temperature overnight and then concentrated under vacuum. The residue was purified by reversed-phase flash chromatography (column, Cl 8 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 50% gradient in 20 min to provide methyl 4-(N-(oxazol-2-yl)sulfamoyl)benzoate (400 mg, 11.9%) as an off-white solid. MS (ESI): mass calcd. for C11H10N2O5S 282.03; [M+H]+ found 283.00.Step 2: Preparation of 4-(hydroxymethyl)-N-(oxazol-2-yl)benzenesulfonamide

[0288] To a stirred solution of methyl 4-(N-(oxazol-2-yl)sulfamoyl)benzoate (360 mg, 1.275 mmol, 1.0 equiv.) in THF (4 mL) was added LiAlH4 (2.55 mL, 2.550 mmol, 2 equiv.) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 30 min and then was quenched with Water at 0 °C. The resulting mixture was concentrated under vacuum. The residue was purified by reversed-phase flash chromatography (column, Cl 8 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 50% gradient in 10 min) to provide 4-(hydroxymethyl)-N-(oxazol-2-yl)benzenesulfonamide (120 mg, 37.0%) as a white solid. MS (ESI): mass calcd. for C10H10N2O4S 254.04; [M+H]+found 255.00.Step 3: Preparation of 4-(bromomethyl)-N-(oxazol-2-yl)benzenesulfonamide

[0289] To a stirred solution of 4-(hydroxymethyl)-N-(oxazol-2-yl)benzenesulfonamide (120 mg, 0.472 mmol, 1.0 equiv.) and PPh3 (247.58 mg, 0.944 mmol, 2 equiv.) in DCE (200 mL) was added CBr4 (234.77 mg, 0.708 mmol, 1.5 equiv.) in portions at 0 °C. The resulting mixture was stirred at room temperature for 2 h and then concentrated under vacuum. The residue was purified by silica gel column chromatographyAttorney Docket No. 57547-742.601(PE / EA=1 / 1) to afford 4-(bromomethyl)-N-(oxazol-2-yl)benzenesulfonamide (40 mg, 26.7%) as a white solid. MS (ESI): mass calcd. for C10H9BrN2O3S 315.95 and 317.95; [M+H]+ found 316.90 and 318.90.Step 4: Preparation of 4-((3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-3-hydroxy-2-oxoindolin-1-yl)methyl)-N-(oxazol-2-yl)benzenesulfonamide

[0290] To a solution of 3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-3-hydroxyindolin-2-one (41.28 mg, 0.126 mmol, 1 equiv. ) in DMF was added sodium hydride (60% in oil, 7.57 mg) at 0 °C. The resulting mixture was stirred for 15 min. 4-(bromomethyl)-N-(oxazol-2-yl)benzenesulfonamide (40 mg, 0.126 mmol, 1.0 equiv.) was added and the mixture was allowed to warm to rt for 2 h. The crude product was purified by prep-HPLC under method C conditions to afford 4-((3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-3-hydroxy-2-oxoindolin- l-yl)methyl)-N-(oxazol-2-yl)benzenesulfonamide (10.0 mg, 13.9%).XH NMR (400 MHz, DMSO-de) 5 12.12 (s, 1H), 7.83 -7.81 (d, J = 8.0 Hz, 2H), 7.65 - 7.60 (m, 4H), 7.37 - 7.33 (m, 2H), 7.26 (m, 1H), 7.18 -7.14 (t, J = 7.7 Hz, 1H), 7.06 - 7.04 (d, J = 8.4 Hz, 1H), 6.95 -6.91 (t, J = 7.4 Hz, 1H), 6.78 - 6.76 (d, J = 7.8 Hz, 1H), 6.24 (s, 1H), 4.97 (s, 2H), 4.20 - 4.15 (d, J = 17.7 Hz, 1H), 3.83 - 3.66 (dd, J = 47.3, 19.8 Hz, 7H) MS (ESI): mass calcd. for C28H25N3O8S 563.1; [M+H]+ found 564.0.Example 30: Preparation of N-(4-((3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-3-hydroxy-2-oxoindolin-l-yl)methyl)phenyl)-2-methylthiazole-5-sulfonamide

[0291] To a solution of 1-[(4-aminophenyl)methyl]-3-[2-(3,4-dimethoxyphenyl)-2-oxo-ethyl]-3-hydroxy-indolin-2-one (30 mg, 0.0694 mmol, 1.00 eq.) and pyridine (0.011 mL, 0.139 mmol, 2.00 eq) in DCM (0.50 mL) at rt was added 2-methylthiazole-5-sulfonyl chloride (21 mg, 0.104 mmol, 1.50 eq.). The resulting solution was stirred at rt for 30 min. After removing the solvent, the residue was purified by silica gel column chromatography (10-100% EtOAc in hexanes) to provide the desired product N-[4-[[3-[2-(3,4-dimethoxyphenyl)-2-oxo-ethyl] -3-hydroxy-2-oxo-indolin- 1 -yl] methyl] phenyl] -2-methyl-thiazole-5-sulfonamide (26 mg, 0.0438 mmol, 63.1 % yield).1H NMR (400 MHz, DMSO-d6) 8 3.4 (3H, s), 3.58 (1H, dd, J = 14 Hz), 3.65 (3H, s), 3.68 (3H, s), 4.04(lH, d, J = 6.4 H), 4.82 (2H, dd, J = 12 Hz), 6.21 (3H, s), 6.71 (1H, d, J = 6.4 Hz), 6.91 (1H, dd, J = 6.0 Hz), 7.2-7.15 (4H, m), 7.5-7.4 (4H, m), 7.6 (1H, d, J=6.0 Hz), 8.05 (1H, s), 10.6 (1H, s). ESI-LCMS calcd. for C29H27N3O7S2+ [M+H]+ 593.1, found 594.3.

[0292] The following compounds were prepared by the same general method as for preparation of N-(4-((3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-3-hydroxy-2-oxoindolin-l-yl)methyl)phenyl)-2-methylthiazole-5-sulfonamide (Example 30):LC-MSEx. Exact mass ‘HNMR[M+l] (m / z)> HNMR (400 MHz, DMSO-d6) 82.3 (3H, s), 3.60 (1H, dd, J 31 593.1 594.3 = 14 Hz), 3.75 (3H, s), 3.80 (3H, s), 4.20 (1H, dd, J = 14 Hz),4.82 (2H, dd, J = 12 Hz), 6.21 (3H, s), 6.71 (1H, d, J = 6.4Attorney Docket No. 57547-742.601LC-MSEx. Exact mass ‘HNMR[M+l] (m / z)Hz), 6.85 (1H, dd, J = 6.0 Hz), 7.15-7.0 (4H, m), 7.4-7.3 (4H, tn), 7.6 (1H, d, J=6.0 Hz), 8.46 (1H, s), 10.86 (1H, s) > HNMR (400 MHz, DMSO-d6) 82.36 (3H, s), 3.60 (1H, dd, J = 14Hz), 3.80 (3H, s), 3.85 (3H, s), 4.15 (1H, dd, J = 14 Hz), 32 593.1 594.3 4.83 (2H, dd, J = 12 Hz), 6.21 (3H, s), 6.61 (1H, d, J = 6.4 Hz), 6.90 (1H, dd, J = 6.0 Hz), 7.15-7.0 (4H, m), 7.4-7.3 (4H, m), 7.58 (1H, d, J=6.0 Hz), 9.13 (1H, s), 10.58 (1H, s) > HNMR (400 MHz, DMSO-d6) 82.39 (3H, s), 3.60 (1H, dd, J = 14Hz), 3.80 (3H, s), 3.85 (3H, s), 4.15 (1H, dd, J = 14 Hz), 33 593.1 594.3 4.80 (2H, dd, J = 12 Hz), 6.21 (3H, s), 6.71 (1H, d, J = 6.4 Hz), 6.91 (1H, dd, J = 6.0 Hz), 7.15-7.0 (4H, m), 7.4-7.3 (4H, m), 7.5 (1H, s), 7.60 (1H, d, J=6.0 Hz), 10.80 (1H, s)JH NMR (499 MHz, DMSO-d6) 8 8.16 (s, 1H), 7.64 (dd, J = 8.5, 1.9 Hz, 1H), 7.51 (s, 1H), 7.44 (d, J= 8.4 Hz, 2H), 7.36 (d, J= 7.2 Hz. 1H), 7.32 (d, J= 1.9 Hz, 1H), 7.17 (t, J= 7.8 Hz, 1H), 7.13 (d, J = 8.5 Hz, 2H), 7.05 (d, J= 8.6 Hz, 1H), 34 590.2 591.36.93 (t, J=7.4Hz, 1H), 6.78 (d, J = 7.8Hz, 1H),6.24 (s, 1H), 4.92 (d, J = 16.0 Hz, 1H), 4.87 (d, J= 16.0Hz, lH),4.16 (d, J = 17.6 Hz, 1H), 3.84 (s, 3H), 3.83 (s, 3H), 3.77 (s, 3H), 3.68 (d, J= 17.6 Hz, 1H), 3.09 (s, 3H)XH NMR (499 MHz, DMSO-d6) 8 10.48 (s, 1H), 8.86 (d, J = 1.4 Hz, 2H), 8.77 (dd, J= 4.8, 1.5 Hz, 1H), 8.62 (d, J= 1.6 Hz, 1H), 8.13 - 8.05 (m, 1H), 8.03 (s, 1H), 7.62 -7.49 (m, 35 528.2 529.3 1H), 7.42 -7.28 (m, 3H), 7.14 (td, J= 7.7, 1.2 Hz, 1H), 7.06 (d, J= 8.5 Hz, 2H), 6.98-6.86 (m, 1H), 6.69 (d, J= 7.8 Hz, 1H), 6.26 (s, 1H), 4.80 (s, 2H),4.19(d, J= 17.5 Hz, 1H),3.69 (d, J= 17.5 Hz, 1H), 2.34 (s, 3H).XH NMR (499 MHz, DMSO-d6) 8 10.48 (s, 1H), 9.06 (d, J = 1.8 Hz, 1H), 8.86 (d, J=2.1 Hz, 1H), 8.77 (ddd, J = 4.9, 3.3, 1.6 Hz, 2H), 8.21 (dt, J= 8.0, 1.9 Hz, 1H), 8.10 (dt, J= 8.1, 1.8 Hz, 1H), 7.58 (dd, J= 7.8, 4.9Hz, 1H), 7.52 (dd, J= 7.8, 36 514.1 515.34.9 Hz, 1H), 7.35 (dd, J= 16.4, 7.5 Hz, 3H), 7.14 (td, J= 7.7, 1.1 Hz, 1H), 7.06 (d, J= 8.5 Hz, 2H), 6.91 (t,. / = 7.2 Hz. 1H), 6.70 (d, J= 7.8 Hz, 1H), 6.28 (s, 1H), 4.80 (s, 2H), 4.21 (d, J = 17.6 Hz, 1H), 3.72 (d, J= 17.5 Hz, 1H).XH NMR (499 MHz, DMSO-d6) 810.76 (s, 1H), 7.64 (dd, J = 8.5, 2.0 Hz, 1H), 7.48 (d, J = 2.0Hz, 1H), 7.37 - 7.30 (m, 3H), 7.25 (dd, J= 8.1, 5.6 Hz, 1H), 7.11 (d, J= 8.5 Hz, 2H), 7.06 37 608.2 609.3(d, J= 8.6 Hz, 1H), 6.80 - 6.69 (m, 2H), 6.21 (s, 1H), 5.07 (m, 2H), 4.18 (d, J= 17.8 Hz, 1H), 3.93 (s, 3H), 3.84 (s, 3H), 3.79(s, 3H), 3.70 (d, J= 17.7 Hz, 1H), 1.99 (s, 3H).Example 38. N- [4- [ [3- [2-(3,4-dimethoxyphenyl)-2-oxo-ethyl] -3,7-dimethyl-2-oxo-indolin-l-yl] methyl] - 2-methoxy-phenyl]-2-methyl-pyrazole-3-sulfonamideoAttorney Docket No. 57547-742.601

[0293] To a solution of 1 -Methyl- lH-pyrazole-5-sulfonyl chloride (1.00 eq, 7.6 mg, 0.0421 mmol) and 1-[(4-amino-3-methoxy-phenyl)methyl]-3-[2-(3,4-dimethoxyphenyl)-2-oxo-ethyl]-3,7-dimethyl-indolin-2-one (1.00 eq, 20 mg, 0.0421 mmol) in DCM (1.0 ml) was added pyridine (2.00 eq, 0.0068 mL, 0.0843 mmol). The reaction was stirred at rt for Ih. The solvent was evaporated. The residue was purified by prep-HPLC under either conditions A, B, C or D to provide N-[4-[[3-[2-(3,4-dimethoxyphenyl)-2-oxo-ethyl]-3,7-dimethyl-2-oxo-indolin- 1-yl ]methyl |-2-methoxy-phenyl ]-2-methyl-pyrazole-3-sulfonamide (15 mg, 56.34% yield).1HNMR(499 MHz, DMSO-d6) 810.04 (s, IH), 7.65 (dd, J = 8.5, 2.0 Hz, IH), 7.39 (d, J = 2.0 Hz, IH), 7.29 (d, J = 2.0 Hz, IH), 7.22 (d, J = 8.1 Hz, IH), 7.15 (d, J = 6.4 Hz, IH), 7.10 - 7.04 (m, 2H), 6.92 (d, J = 7.9Hz, IH), 6.87 (d, J = 7.2Hz, IH), 6.82 (t, J = 7.4 Hz, IH), 6.44 (d, J = 2.0 Hz, lH),5.18 (d, J = 17.6 Hz, IH), 5.04 (d, J = 17.5 Hz, IH), 4.14 (d, J = 17.5 Hz, IH), 3.99 (s, 3H), 3.84 (s, 3H), 3.78 (s, IH), 3.62 (d, J= 17.5 Hz, IH), 3.50 (s, 3H), 2.15 (s, 3H), 1.34 (s, 3H). (ESI): mass calcd. for C30H30N4O7S 618.2;[M+H]+found 619.4. LCMS (method 1): Rt = 3.35 min.

[0294] The following compounds were prepared by the same general method as for N-[4-[[3-[2-(3,4-dimethoxyphenyl)-2-oxo-ethyl]-3,7-dimethyl-2-oxo-indolin-l-yl]methyl]-2-methoxy-phenyl]-2-methyl-pyrazole-3 -sulfonamide (Example 38). Single enantiomers were isolated by chiral SFC separation of the corresponding racemic final compound. The absolute stereochemistry was determined by co -crystal structures.LC-MSEx. Exact mass 'HNMR[M+l] (m / z)> HNMR (499 MHz, DMSO-d6) 8 11.05 (s, IH), 7.62 (dd, J = 8.5, 2.0 Hz, IH), 7.49 (d, J= 1.7Hz, IH), 7.42 - 7.22 (m,4H), 7.13 (d, J= 1.1 Hz, 2H), 7.04 (t, J= 7.8 Hz, 3H), 6.91 (d, J = 39 590.2 591.3 7.3 Hz, IH), 6.77 - 6.62 (m, 2H), 6.19 (s, IH), 4.83 (d, J =17.5 Hz, IH), 4.75 (d, J= 17.5 Hz, IH), 4.31 (d, J= 7.2 Hz, 2H), 4.13 (d, J= 17.5 Hz, IH), 3.83 (s, 3H), 3.77 (s, 3H), 3.65 (d, J = 17.5 Hz, IH), 1.26 (t, J = 7.2 Hz, 3H).'H NMR (499 MHz, DMSO-d6) 8 7.63 (dd, J = 8.5, 2.0 Hz, IH), 7.40- 7.30 (m, 4H), 7.17 -7.10 (m, IH), 7.10 - 7.00 (m, 3H), 6.91 (t, J=7.4Hz, IH), 6.69 (d, J = 7.8Hz, IH), 6.21 (s, 40 607.1 608.3IH), 4.85 (d, J= 16.0 Hz, IH), 4.79 (d, J= 16.0 Hz, 1H),4.15 (d, J= 17.6 Hz, IH), 3.83 (s, 3H), 3.78 (s, 3H), 3.67 (d, J =17.6 Hz, IH), 2.56 (s, 3H), 2.32 (s, 3H).> HNMR (499 MHz, DMSO-d6) 8 13.00 (s, IH), 7.64 (dd, J = 8.5, 2.0 Hz, IH), 7.43 (d, J= 8.5 Hz, 2H), 7.39 - 7.26 (m, 2H), 7.20- 7.08 (m, 3H), 7.05 (d, J = 8.6 Hz, IH), 6.92 (t, J= 7.5 41 604.2 605.3 Hz, IH), 6.65 (d, J= 7.8 Hz, IH), 6.26 (s, IH), 4.94 (d, J =16.5 Hz, IH), 4.88 (d, J= 16.5 Hz, IH), 4.16 (d, J= 17.6 Hz, IH), 3.83 (s, 3H), 3.77 (s, 3H), 3.69(d, J= 17.5 Hz, IH), 3.07 (s, 3H), 2.08 - 1.76 (m, 6H).> HNMR (400 MHz, DMSO-d6) 8 13.53 (s, IH), 10.05 (s, IH), 8.13-7.87 (s, 2H), 7.64 (dd, J = 8.5, 1.9 Hz, 1H),7.34 (dd, J = 8.1, 4.6 Hz, 4H), 7.16 - 7.09 (m, 4H), 6.92-6.89 (t, J = 7.5 Hz, 42 562.1 563.0IH), 6.72-6.70 (d, J = 7.8 Hz, 1H),6.2O (s, IH), 4.85-4.74 (q, J = 16.0 Hz, 2H), 4.16-4.12 (d, J= 17.5 Hz, IH), 3.83-3.68 (d, J = 23.9 Hz, 6H), 3.64 (d, J = 17.5 Hz, IH).> HNMR (400 MHz, Methanol-d4) 87.85 (s, IH), 7.65 (dd, J = 43 576.1 577.38.4, 2.0 Hz, IH), 7.61 (d, J = 0.8 Hz, IH), 7.41 - 7.39 (m,2H),Attorney Docket No. 57547-742.601LC-MSEx. Exact mass 'HNMR[M+l] (m / z)7.38-7.33 (tn, 2H), 7.20 (td, J = 7.7, 1.3 Hz, 1H), 7.14 - 7.12 (m, 2H), 7.04-6.99 (m, 2H), 6.78 (d, J = 7.9 Hz, 1H), 4.96 (d, J = 15.9Hz, 1H), 4.83 (s, 1H), 4.11 (d, J= 17.0 Hz, 1H), 3.90 (s, 3H), 3.81 - 3.76 (m, 4H), 3.72 (s, 3H).XH NMR (400 MHz, DMSO-d6) 8 12.69 (s, 1H), 10.15 (m, 1H), 7.77 (d, J = 4.3 Hz, 2H), 7.63-7.61 (d, J = 8.4 Hz, 1H), 7.32-7.27 (dd, J = 18.9, 8.8 Hz, 4H), 7.14-7.04 (td, J = 20.5, 44 562.1 562.9 19.3, 7.9 Hz, 4H), 6.92-6.90(t, J= 7.4 Hz, 1H), 6.73-6.71 (d, J = 7.9 Hz, 1H), 6.19 (s, 1H), 4.84-4.71 (q, J = 15.9 Hz, 2H), 4.15-4.11 (d, J = 17.4 Hz, 1H), 3.84-3.78 (d, J = 22.9 Hz, 6H),3.68-3.63 (d, J = 17.4 Hz, 1H).> HNMR (400 MHz, DMSO-d6) 8 13.44 (s, 1H), 10.63 (s, 1H), 7.63 (dd, J = 8.5, 2.0 Hz, 1H), 7.35 -7.31 (m, 4H), 7.28 - 7.04 45 562.1 563.2 (m, 6H), 6.91 (t, J = 7.4 Hz, 1H), 6.72 (d, J = 7.8 Hz, 1H),6.20 (s, 1H), 4.80 (q, J = 16.0 Hz, 2H), 4.14 (d, J = 17.6 Hz, 1H), 3.81 (d, J = 22.9 Hz, 6H), 3.66 (d, J = 17.6 Hz, 1H). 'H NMR (400 MHz, DMSO-d6) 8 10.77 (s, 1H), 7.64-7.61 (dd, J = 8.5, 2.0 Hz, 1H), 7.50-7.49 (d, J = 2.0 Hz, 1H), 7.37- 7.31 (m, 4H), 7.17-7.16 (td, J = 7.7, 1.3 Hz, 1H), 7.14-7.03 46 576.1 577.0 (m, 3H), 6.92-6.89 (td, J = 7.5, 1.0 Hz, 1H), 6.77-6.76 (d, J =2.0 Hz, 1H), 6.72-6.70 (d, J = 7.8 Hz, 1H), 6.20 (s, 1H), 4.82- 4.80 (m, 2H), 4.16-4.11 (d, J = 17.6 Hz, 1H), 3.91-3.77 (m,9H), 3.68-3.64 (d, J = 17.5 Hz, 1H).> HNMR (400 MHz, Methanol-d4) 87.94 (d, J = 3.1 Hz, 1H), 7.84 (d, J = 3.0 Hz, 1H), 7.67 - 7.65 (d, J = 8.5 Hz, 1H), 7.43 - 7.34 (q, J = 7.8, 6.8 Hz, 4H), 7.20 - 7.16 (d, J = 8.2 Hz, 3H), 47 579.2 580.4 7.04-6.97 (ddd, J = 15.2, 9.0, 2.8 Hz, 2H), 6.72 - 6.70 (m,1H), 4.92 (s, 2H), 4.11 - 4.07 (dd, J = 16.8, 2.9 Hz, 2H), 3.91 (d, J = 2.9 Hz, 3H), 3.84 (d, J = 2.9 Hz, 3H), 3.79 -3.75 (dd, J = 17.0, 2.8 Hz, 1H).'H NMR (400 MHz, DMSO-d6) 8 10.48 (s, 1H), 8.87-8.77 (dd, J = 40.2, 3.6 Hz, 2H), 8.11 - 8.09 (m, 1H), 7.63-7.61 (ddd, J = 18.6, 8.1, 3.3 Hz, 2H), 7.59 - 7.56 (m, 4H), 7.35- 48 573.1 574.0 7.31 (t, J = 7.7 Hz, 1H), 7.15-7.03 (t, J = 8.9 Hz, 3H), 6.93- 6.89 (t, J = 7.4 Hz, 1H), 6.69-6.67 (d, J = 7.8 Hz, 1H), 6.19 (s, 1H), 4.85-4.75 (m, 2H), 4.16-4.11 (d, J= 17.5 Hz, 1H),3.83- 3.78 (d, J = 23.5 Hz, 6H), 3.68-3.64 (d, J = 17.5 Hz, 1H).! HNMR(400 MHz, DMSO-d6) 8 9.93 (s, 1H), 8.18 (s, 1H), 7.68 - 7.59 (m, 2H), 7.37 - 7.27 (m, 4H), 7.18 - 7.01 (m, 4H), 49 576.1 577.2 6.91 (t, J = 7.4 Hz, 1H), 6.73 (d, J = 7.8 Hz, 1H), 6.20 (s, 1H),4.88 - 4.74 (m, 2H), 4.14 (d, J = 17.6 Hz, 1H), 3.88 - 3.74 (m,9H), 3.66 (d, J = 17.5 Hz, 1H)'H NMR (400 MHz, DMSO-d6) 8 10.08 (s, 1H), 8.19 (s, 1H), 7.68 - 7.60 (m, 2H), 7.38 - 7.29 (m, 4H), 7.15 - 7.07 (m, 4H), 50 576.1 577.2 6.91 (t, J = 7.4 Hz, 1H), 6.73 (d, J = 7.8 Hz, 1H), 6.20 (s, 1H),4.88 - 4.74 (m, 2H), 4.14 (d, J = 17.5 Hz, 1H), 3.84 - 3.79 (m,9H), 3.67 (d, J = 17.5 Hz, 1H).> HNMR (400 MHz, DMSO-d6) 8 10.67 (s, 1H), 7.83 (s, 1H), 7.64-7.61 (dd, J = 8.5, 2.1 Hz, 1H), 7.47 (s, 1H), 7.35 - 7.31 (m, 4H), 7.16-7.03 (dt, J = 33.4, 8.3 Hz, 4H), 6.92-6.88 (t, J = 51 576.2 576.97.4 Hz, 1H), 6.73-6.71 (d, J = 7.8Hz, 1H), 6.20 (s, 1H),4.85 - 4.75 (m, 2H), 4.15-4.11 (d, J = 17.5 Hz, 1H), 3.87 - 3.63 (m,10H).Attorney Docket No. 57547-742.601LC-MSEx. Exact mass 'HNMR[M+l] (m / z)'H NMR (400 MHz, Methanol-d4) 87.72 (s, 1H), 7.67-7.65 (dd, J = 8.5, 2.1 Hz, 1H), 7.46-7.42 (d, J = 1.2 Hz, 1H), 7.40 - 7.34(m, 4H), 7.20-7.18 (td, J = 7.8, 1.3 Hz, 1H), 7.16 - 7.12 52 576.2 577.4 (m, 2H), 7.04-6.97 (m, 2H), 6.73-6.71 (d, J = 7.8 Hz, 1H),4.97-4.93 (d, J = 15.9 Hz, 1H), 4.89-4.86 (d, J = 15.9 Hz, 1H) ’ 4.11-4.06 (d, J = 17.0 Hz, 1H), 3.91 (s, 3H), 3.84 (s, 3H), 3.80-3.75 (d, J = 17.0 Hz, 1H), 3.69 (s, 3H).> HNMR (400 MHz, DMSO-d6) 88.09 (s, 1H), 7.85 (d, J = 8.9 Hz, 1H), 7.63 (dd, J = 8.4, 2.0 Hz, 1H), 7.38 - 7.13 (m, 4H), 53 577.2 578.1 7.06 (s, 1H), 7.04 (s, OH), 6.97 - 6.81 (m, 3H), 6.21 (s, 1H),4.89 - 4.74 (m, 2H), 4.18 (d, J = 17.8 Hz, 1H), 3.87 - 3.75 (m, 9H), 3.66 (d, J = 17.8 Hz, 1H), 2.56 - 2.50 (m, 3H). > HNMR (400 MHz, DMSO-d6): 810.57 (s, 1H), 7.64 (dd, J = 8.7, 1.8 Hz, 1H), 7.38 (d, J = 16.1 Hz, 2H), 7.33 - 7.27 (m, 3H), 7.23 (d, J = 8.5 Hz, 1H), 7.16 (d, J = 7.7 Hz, 1H), 7.06 (d, 54 594.2 595.4 J = 8.5 Hz, 1H), 7.02 (s, 1H), 6.94 (t, J = 7.5 Hz, 1H),6.75 (d,J = 7.8 Hz, 1H), 6.24 (d, J = 1.1 Hz, 1H), 4.87 (s, 2H), 4.18 (d, J = 17.7Hz, lH), 3.84(s, 3H), 3.77 (d, J= 11.1 Hz, 6H), 3.68(d, J = 17.7 Hz, 1H).> HNMR (400 MHz, DMSO-d6) 8 12.11 (s, 1H), 10.24 (s, 1H), 7.66 - 7.58 (m, 2H), 7.55 (dd, J = 8.2, 1.8 Hz, 1H), 7.37 -7.28 (m, 4H), 7.20-7.10 (m,2H), 7.06 (dd, J = 8.4, 5.3 Hz, 3H), 55 629.2 630.46.91 (t, J = 7.5 Hz, 1H), 6.68 (d, J = 7.8 Hz, 1H), 6.19 (s, 1H), 4.86-4.73 (m, 2H), 4.14 (d, J = 17.6 Hz, 1H), 3.84 (s, 3H),3.78 (s, 3H), 3.66 (d, J = 17.6 Hz, 1H).> HNMR (499 MHz, DMSO-d6) 8 10.72 (s, 1H), 8.65 (dd, J = 4.5, 1.5 Hz, 1H), 8.18 (dd, J= 8.2, 1.6 Hz, 1H), 7.61 (dd, J = 8.5, 2.0 Hz, 1H), 7.40 - 7.27 (m, 5H), 7.20 - 7.08 (m, 2H), 56 627.2 628.47.08-7.01 (m, 2H), 7.00-6.85 (m, 1H),6.66 (d, J= 7.8 Hz, 1H), 6.18 (s, 1H), 4.76 (s, 2H), 4.13 (d, J= 15.5 Hz, 1H), 4.11 (s, 3H), 3.83 (s, 3H), 3.76 (s, 3H), 3.65 (d, J= 17.5 Hz, 1H). > HNMR (499 MHz, DMSO-d6) 8 10.98 (s, 1H), 8.67 (dd, J = 4.2, 1.7 Hz, 1H), 8.12 (dd, J= 8.5, 1.7 Hz, 1H), 7.61 (dd, J = 8.5, 2.0 Hz, 1H), 7.42 - 7.28 (m, 4H), 7.21 (dd, J= 8.5, 4.2 57 627.2 628.4 Hz, 3H), 7.11 (td, J=7.7, 1.2Hz, 1H), 7.03 (dd, J= 11.8, 8.5Hz, 3H), 6.97-6.84 (m, 1H), 6.59 (d, J= 7.8 Hz, 1H), 6.18 (s, 1H), 4.76 (m, 2H), 4.29 (s, 3H), 4.13 (d, J= 17.6 Hz, 1H), 3.83 (s, 3H), 3.76 (s, 3H), 3.64 (d, J= 17.5 Hz, 1H). 'H NMR (499 MHz, DMSO-d6) 8 12.56 (s, 1H), 10.18 (s, 1H), 8.31 (dd, J=4.7, 1.5 Hz, 1H), 8.19 - 8.00 (m, 2H), 7.61 (dd, J = 8.5, 2.0 Hz, 1H), 7.39 -7.28 (m, 2H), 7.25 (d, J= 8.6 Hz, 2H), 7.17 (dd, J= 8.0, 4.7 Hz, 1H), 7.14 - 7.08 (m, 1H), 7.04 58 612.2 613.3(dd, J=8.5, 5.2Hz, 3H), 6.89 (t, J= 7.2Hz, 1H), 6.66 (d, J = 7.8Hz, 1H), 6.16(s, 1H), 4.77(d, J= 16.0Hz, 1H),4.71 (d, J = 16.0Hz, 1H), 4.12(d, J= 17.6 Hz, 1H), 3.83 (s, 3H), 3.76(s, 3H), 3.64 (d, J= 17.5 Hz, 1H).H NMR (400 MHz, DMSO-d6) 8 10.78 (s, 1H), 8.09 - 8.07 (dd, J = 5.3, 1.6 Hz, 1H), 7.71 -7.69 (dd, J = 7.2, 1.6 Hz, 1H), 7.63 -7.61 (dd, J = 8.5, 2.0 Hz, 1H), 7.49 - 7.48 (d, J = 2.0 59 577.2 578.2 Hz, 1H), 7.35 -7.31 (m, 3H), 7.07 - 7.04 (dd, J = 8.4, 5.8 Hz,3H), 6.98 - 6.94 (dd, J = 7.2, 5.3 Hz, 1H), 6.77 - 6.76 (d, J = 2.0Hz, 1H), 6.40(s, 1H), 4.84(s, 2H), 4.21 - 4.16 (d, J = 17.9Hz, 1H), 3.92 (s, 3H), 3.84 (s, 3H), 3.78 (s, 4H).Attorney Docket No. 57547-742.601LC-MSEx. Exact mass 'HNMR[M+l] (m / z)! HNMR(400 MHz, DMSO-d6) 8 10.72 (s, 1H), 7.65 - 7.63 (dd, J = 8.5, 2.0 Hz, 1H), 7.49 - 7.49 (d, J = 2.0 Hz, 1H), 7.39 - 7.30 (tn, 4H), 7.20 -7.18 (dd, J = 8.2, 1.2 Hz, 1H), 7.07 - 60 611.2 611.2 7.05 (dd, J = 8.5, 6.4 Hz, 3H), 6.99 - 6.95 (t, J = 7.7 Hz, 1H),6.75 (d, J = 2.1 Hz, 1H), 6.39 (s, 1H), 5.16 (s, 2H), 4.24 - 4.19 (d, J = 17.9Hz, 1H), 3.91 (s, 3H), 3.84 (s, 3H), 3.79 (s, 3H),3.74 (d, J = 17.7 Hz, 1H).! HNMR(400 MHz, DMSO-d6) 8 10.79 (s, 1H), 7.63 - 7.32 (m, 6H), 7.11-7.04 (dd, J = 17.1, 8.2 Hz, 3H), 6.77 (s, 1H), 61 594.1 595.2 6.73 - 6.67 (m, 2H), 6.24 (s, 1H), 4.88 - 4.78 (m, 2H), 4.19- 4.14 (d, J = 17.7 Hz, 1H), 3.92 - 3.78 (m, 9H), 3.70-3.65 (d, J = 17.6 Hz, 1H).> HNMR (400 MHz, DMSO-d6) 8 10.77 (s, 1H), 7.65 (dd, J = 8.4, 2.1 Hz, 1H), 7.46 (d, J = 2.0 Hz, 1H), 7.34 (d, J = 2.0 Hz, 1H), 7.30 (d, J = 8.2 Hz, 2H), 7.22 (dd, J = 7.3, 1.4 Hz, 1H), 62 590.1 591.5 7.09 (dd, J = 9.8, 8.4 Hz, 3H), 6.93 -6.91 (m, 1H), 6.85-6.82(t, J = 7.5 Hz, 1H), 6.70 (d, J = 2.0 Hz, lH),6.15 (s, 1H), 5.15 - 4.94 (m, 2H), 4.14 (d, J = 17.6 Hz, 1H), 3.92 (s, 3H), 3.84 (s, 3H), 3.79 (s, 3H), 3.68 (d, J = 17.6 Hz, 1H), 2.12 (s, 3H). > HNMR (400 MHz, DMSO-d6) 88.28 (s, 1H), 7.65-7.63 (dd, J = 8.5, 2.0 Hz, 1H), 7.36 - 7.33 (m, 2H), 7.21-7.14 (dd, J = 7.4, 1.4 Hz, 1H), 7.07 (d, J = 8.1 Hz, 2H), 6.96-6.91 (d, J = 8.5 63 590.1 591.4 Hz, 1H), 6.85 -6.83 (m, 3H),6.81 (t, J = 7.4 Hz, 1H),6.55 (s,1H), 6.15 (s, 1H), 5.05-4.92 (q, J = 17.0 Hz, 2H), 4.14-4.10 (d, J = 17.6 Hz, 1H), 3.91 - 3.79 (m, 9H), 3.69-.64 (d, J = 17.6Hz, 1H), 2.15 (s, 3H).> HNMR (400 MHz, DMSO-d6) 88.28 (s, 1H), 7.65-7.63 (dd, J = 8.5, 2.0 Hz, 1H), 7.36 - 7.33 (m, 2H), 7.21-7.14 (dd, J = 7.4, 1.4 Hz, 1H), 7.07 (d, J = 8.1 Hz, 2H), 6.96-6.91 (d, J = 8.5 64 590.1 591.4 Hz, 1H), 6.85 -6.83 (m, 3H),6.81 (t, J = 7.4 Hz, 1H),6.55 (s,1H), 6.15 (s, 1H), 5.05-4.92 (q, J = 17.0 Hz, 2H), 4.14-4.10 (d, J = 17.6 Hz, 1H), 3.91 - 3.79 (m, 9H), 3.69-.64 (d, J = 17.6Hz, 1H), 2.15 (s, 3H).> HNMR (400 MHz, DMSO-d6) 8 10.75 (s, 1H), 7.63 (dd, J = 8.5, 2.0 Hz, 1H), 7.47 (d, J = 2.0 Hz, 1H), 7.37 - 7.29 (m, 3H), 7.21 (d, J = 7.4 Hz, 1H), 7.06 (dd, J = 8.3, 5.5 Hz, 3H), 6.77 - 65 590.2 591.26.69 (m, 2H), 6.34 (d, J = 176.7 Hz, 2H), 4.91 -4.58 (m, 2H), 4.10 (d, J = 17.5 Hz, 1H), 3.95 - 3.73 (m, 9H), 3.63 (d, J =17.5 Hz, 1H), 2.20 (s, 3H).> HNMR (400 MHz, DMSO-d6) 8 10.82 (s, 1H), 7.63 (dd, J = 8.5, 2.0 Hz, 1H), 7.49 (d, J = 2.1 Hz, 1H), 7.39 - 7.28 (m, 4H), 7.08 (dd, J = 8.4, 6.3 Hz, 3H), 6.99 (td, J = 9.1, 2.7 Hz, 1H), 66 594.2 595.46.77 (d, J = 2.1 Hz, 1H), 6.71 (dd, J = 8.6, 4.1 Hz, 1H), 6.34 (s, 1H), 4.89 - 4.75 (m, 2H), 4.18 (d, J = 17.7 Hz, 1H), 3.92 (s, 3H), 3.85 (s, 3H), 3.79 (s, 3H), 3.71 (d, J = 17.6 Hz, 1H). iHNMR(499 MHz, DMSO-d6) 8 10.78 (s, 1H), 7.72 - 7.57 (m, 2H), 7.49 (s, 1H), 7.43 - 7.29 (m, 4H), 7.21 - 7.11 (m, 1H), 7.08 (dd, J= 8.5, 3.2 Hz, 3H), 6.91 (t, J= 7.4 Hz, 1H), 6.76 (d, J=2.0 Hz. 1H), 6.71 (d, J = 7.8Hz, 1H),6.20 (s, 1H), 67 677.2 678.44.84 (d, J= 16.0 Hz, 1H), 4.78 (d, J= 16.0 Hz, 1H), 4.27 - 4.20 (m, 2H), 4.15 (d, J= 17.6 Hz, 1H), 3.93 (s, 2H), 3.91 (s, 3H), 3.82 (m, 2H), 3.80 (s, 3H), 3.67 (d, J= 17.6 Hz, 1H),2.63 (d, J= 4.7 Hz, 3H).Attorney Docket No. 57547-742.601LC-MSEx. Exact mass 'HNMR[M+l] (m / z)> HNMR (499 MHz, DMSO-d6) 8 12.55 (s, 1H), 10.12 (s, 1H), 8.31 (dd, J=4.7, 1.6Hz, 1H), 8.20- 8.01 (m,2H), 7.63 (dd, J = 8.5, 2.0 Hz, 1H), 7.33 (d, J = 2.0 Hz, 1H), 7.26 - 7.11 (m, 68 624.2 625.4 4H), 7.06 (dd, J= 11.0, 8.6 Hz, 3H), 6.82(dt, J= 14.7,7.1 Hz,2H), 5.04 (d, J= 17.5 Hz, 1H), 5.00 (d, J= 17.5 Hz, 1H),4. O8 (d, J= 18.5 Hz, 1H), 3.83(s, 3H), 3.77 (s, 3H), 3.57 (d, J =17.5 Hz, 1H), 2.07 (s, 3H), 1.33 (s, 3H).'H NMR (499 MHz, DMSO-d6) 8 8.66 (dd, J = 4.5, 1.5 Hz, 1H), 8.20 (dd, J= 8.2, 1.5 Hz, 1H),7.63 (dd, J= 8.5, 2.0 Hz, 1H), 7.41 - 7.31 (m, 2H), 7.19 (d, J= 8.4 Hz, 2H), 7.18-7.08 69 639.2 640.4 (tn, 3H), 7.05 (d, J= 8.6 Hz, 1H), 6.82 (dt, J= 14.8, 7.2 Hz,2H), 5.03 (m, 2H), 4.11 (s, 3H), 4.08 (d, J= 18.5 Hz, 1H), 3.84 (s, 3H), 3.78 (s, 3H), 3.57 (d, J= 18.5 Hz, 1H), 2.07 (s,3H), 1.32 (s, 3H).> HNMR (499 MHz, DMSO-d6) 8 10.93 (s, 1H), 8.67 (dd, J = 4.2, 1.7 Hz, 1H), 8.15 - 8.02 (m, 1H), 7.63 (dd, J= 8.5, 2.0 Hz, 1H), 7.34 (d, J= 2.0 Hz, 1H), 7.29 - 7.17 (m, 3H), 7.13 70 639.2 640.4 (dd, J= 6.7, 1.8 Hz, 1H), 7.05 (d, J= 8.5 Hz, 3H), 6.90 - 6.73(m, 2H), 5.02 (m, 2H), 4.32(s, 3H),4.08 (d, J=18.5 Hz, 1H), 3.84 (s, 3H), 3.78 (s, 3H), 3.57 (d, J =18.5 Hz, 1H), 1.96 (s,3H), 1.32 (s, 3H).> HNMR (499 MHz, DMSO-d6) 8 10.78 (s, 1H), 7.63 (dd, J = 8.5, 2.0 Hz, 1H), 7.49 (d, J= 2.1 Hz, 1H), 7.37 - 7.29 (m, 3H), 7.23 (dd, J= 8.1, 4.6 Hz, 1H), 7.19 - 7.04 (m, 3H), 6.96 (dt, J 71 612.2 613.3 = 10.9, 7.8 Hz, 1H), 6.77 (d, J= 2.0 Hz, 1H), 6.42 (s, 1H),4.95 (d, J= 16.5Hz, 1H), 4.90 (d, J= 16.5 Hz, 1H),4.22 (d, J = 18.0Hz, 1H), 3.90 (s, 3H), 3.84 (s, 3H), 3.76 (s, 3H), 3.74(d, J = 18.0 Hz, 1H).1H NMR (499 MHz, DMSO-d6) δ 10.69 (s, 1H), 7.78 - 7.71 (m, 1H), 7.64 (dd, J = 8.5, 2.0 Hz, 1H), 7.56 (dd, J = 8.2, 1.1 Hz, 1H), 7.47 (d, J= 2.0 Hz, 1H), 7.32 (d, J= 2.0 Hz, 1H), 7.22 (d, J= 8.5 Hz. 2H), 7.17 (t, J= 7.7 Hz, 1H),7.04 (dd, J= 72 644.2 645.315.1, 8.6Hz, 3H), 6.72 (d, J= 2.0 Hz, 1H), 6.47 (s, 1H), 5.07 (d, J= 17.8 Hz, 1H), 4.93 (d, J= 17.7 Hz, 1H), 4.30 (d, J = 18.0 Hz, 1H), 3.89 (s, 3H), 3.84 (s, 3H), 3.82 (d, J= 10.0 Hz,1H), 3.78 (s, 3H).'H NMR (499 MHz, DMSO-d6) 8 10.68 (s, 1H), 7.74 (d, J = 6.7 Hz, 1H), 7.64 (dd, J = 8.5, 2.0 Hz, 1H), 7.56 (d, J= 7.3Hz,1H), 7.36 (s, 1H), 7.32 (d, J= 2.0 Hz, 1H), 7.23 - 7.12 (m, 73 644.2 645.33H), 7.06 (d, J= 8.4 Hz, 3H), 7.00 (s, 1H), 6.47 (s, 1H), 5.07 (d, J= 17.7 Hz, 1H), 4.92 (d, J= 17.7 Hz, 1H), 4.29 (d, J = 18.0Hz, 1H), 3.84 (s, 3H), 3.82 (d, J= 10.4 Hz, 1H), 3.78 (s,3H), 3.73 (s, 3H).'H NMR (499 MHz, DMSO-d6) 8 10.48 (s, 1H), 8.86 (d, J = 2.1 Hz, 1H), 8.76 (dd, J= 4.8, 1.5 Hz, 1H), 8.09 (dt, J= 8.1, 1.8 Hz, 1H), 7.69- 7.52 (m, 1H), 7.42 - 7.26 (m, 4H), 7.26 - 74 561.1 562.3 7.18 (m, 1H), 7.15 (td, J = 1.1, 1.1 Hz, 1H), 7.12 - 7.01 (m,3H), 6.92 (t, J= 7.5 Hz, 1H), 6.71 (d, J = 7.8Hz, 1H), 6.26 (s, 1H), 4.82 (d, J = 16.0 Hz, 1H), 4.78 (d, J= 16.5 Hz, 1H), 4.04 (d, J = 15.5 Hz, 1H), 3.73 (s, 3H), 3.69 (d, J= 15.5 Hz, 1H). 'HNMR (499 MHz, DMSO-d6) 8 10.48 (s, 1H), 8.86 (d, J= 75 561.1 562.31.9 Hz, 1H), 8.77 (dd, J= 4.8, 1.6 Hz, 1H), 8.19 - 8.03 (m,Attorney Docket No. 57547-742.601LC-MSEx. Exact mass 'HNMR[M+l] (m / z)1H), 7.63- 7.53 (m, 1H), 7.40 (td, J= 8.1, 1.5 Hz, 1H), 7.38 - 7.30 (m, 3H), 7.24-7.08 (m, 3H), 7.09 - 7.01 (m, 2H), 6.96- 6.85 (m, 1H), 6.70 (d, J = 7.8 Hz, 1H), 6.25 (s, 1H), 4.80 (s, 2H), 4.02 (d, J= 18.0 Hz, 1H), 3.87 (s, 3H), 3.68 (d, J= 18.0Hz, 1H).> HNMR (499 MHz, DMSO-d6) 8 10.48 (s, 1H), 8.87 (d, J = 2.2 Hz, 1H), 8.77 (dd, J= 4.8, 1.5 Hz, 1H), 8.10 (dt, J= 8.1, 1.9 Hz, 1H), 7.64 - 7.55 (m, 2H), 7.50 (d, J = 1.9 Hz, 1H), 7.40- 7.30 (m, 3H), 7.28 (d, J = 8.3Hz, 1H), 7.14 (td, J= 7.7, 76 609.1 610.31.1 Hz, 1H), 7.12 - 7.03 (m, 2H), 6.91 (t, J= 7.4 Hz, 1H), 6.69 (d, J= 7.8 Hz, 1H), 6.24 (s, 1H), 5.76 (s, 1H), 4.83 (d, J = 16.0 Hz, 1H), 4.77 (d, J= 16.0 Hz, 1H), 4.20 (d, J= 17.8 Hz, 1H), 3.87 (s, 3H), 3.71 (d, J = 17.8 Hz, 1H).! HNMR(400 MHz, DMSO-d6) 8 10.79 (s, 1H), 7.76 - 7.69 (tn, 2H), 7.49 (d, J = 2.0 Hz, 1H), 7.37 (d, J = 8.2 Hz, 2H), 7.31 (dd, J = 7.4, 1.3 Hz, 1H), 7.13 (td, J = 7.7, 1.3 Hz, 1H), 77 559.1 560 7.07 (d, J = 8.3 Hz, 2H), 6.90 (t, J = 7.4 Hz, 1H), 6.76 (d, J =2.1 Hz, 1H), 6.69 (dd, J = 8.4, 3.8 Hz, 3H), 6.15 (s, 1H), 4.81 (s, 2H), 4.02 (d, J = 17.2 Hz, 1H), 3.92 (s, 3H), 3.55 (d, J =17.1 Hz, 1H), 3.01 (s, 6H).> HNMR (400 MHz, Methanol-d4) 87.46 - 7.41 (m, 3H), 7.38 -7.25 (tn, 3H), 7.20 - 7.11 (m, 4H), 7.00 (ddd, J = 7.3, 4.5, 78 559.1 560.1 2.2 Hz, 2H), 6.77 - 6.70 (m, 2H), 4.94 (d, J = 10.9 Hz, 2H),4.12 (d, J = 17.3 Hz, 1H), 3.86 (s, 3H), 3.83 (d, J = 17.2 Hz,1H), 2.96 (s, 6H).> HNMR (400 MHz, DMSO-d6): 810.96 (s, 1H), 7.54 (dd, J = 8.4, 2.0 Hz, 1H), 7.47 (d, J = 1.9 Hz, 1H), 7.37 - 7.30 (tn, 3H), 7.26 (d, J = 2.0 Hz, 1H), 7.14 (td, J = 7.7, 1.3 Hz, 1H), 7.05 (d, 79 589.2 590 J = 8.0 Hz, 2H), 6.91 (t, J = 7.4 Hz, 1H), 6.84 (d, J = 8.4 Hz,1H), 6.71 (d, J = 8.1 Hz, 2H), 6.17 (s, 1H), 4.80 (q, J = 16.0 Hz, 2H), 4.09 (d, J = 17.4 Hz, 1H),3.91 (s, 3H), 3.81 (s, 3H),3.62 (d, J = 17.3 Hz, 1H), 2.84 (s, 6H).> HNMR (400 MHz, Methanol-d4): 87.71 (dd, J = 8.5, 2.1 Hz, 1H), 7.48 - 7.39 (m, 4H), 7.36 (dd, J = 7.4, 1.2 Hz, 1H), 7.19 (td, J = 7.8, 1.3 Hz, 1H), 7.16-7.09 (m, 2H), 7.07 - 6.95 (m, 80 589.2 5902H), 6.76 - 6.69 (m, 2H), 5.03 - 4.89 (m, 2H), 4.08 (d, J = 16.9 Hz, 1H), 3.96 (s, 3H), 3.87 (s, 3H),3.78 (d, J = 16.9 Hz,1H), 2.74 (s, 6H).> HNMR (400 MHz, Methanol-d4): 8 7.54 (ddd, J = 8.4, 4.2, 2.2 Hz, 1H), 7.46 - 7.39 (m, 4H), 7.36 (dd, J = 7.4, 1.3 Hz, 1H), 7.20 (td, J = 7.8, 1.3 Hz, 1H), 7.17 - 7.08 (m, 3H), 7.00 81 577.2 578(td, J = 7.6, 1.0 Hz, 1H), 6.78 -6.69 (m,2H), 5.02 - 4.90 (m, 2H), 4.10 (d, J = 17.1 Hz, 1H), 3.86 (s, 3H), 3.79 (d, J = 17.1Hz, 1H), 2.85 (d, J = 0.9 Hz, 6H).> HNMR (400 MHz, Methanol-d4) 88.21 (d, J = 2.8 Hz, 1H), 8.11 (dd, J = 4.7, 1.4 Hz, 1H), 7.65 (dt, J = 7.8, 1.3 Hz, 1H), 7.55 (t, J = 2.1 Hz, 1H), 7.51 - 7.39 (m, 5H), 7.39 - 7.30 (m, 82 622.2 623.2 3H), 7.20 (td, J = 7.8, 1.3 Hz, 1H), 7.15 - 7.07 (m, 2H), 7.04 - 6.96 (tn, 1H), 6.77 -6.68 (m, 2H), 5.14 - 4.88 (m, 2H), 4.11 (d, J = 17.2 Hz, 1H), 3.85 (s, 3H), 3.79 (d, J = 17.2 Hz, 1H),3.37 (s, 3H).> HNMR (400 MHz, DMSO-d6) 8 11.28 (s, 1H), 8.16 (ddd, J = 83 622.2 623.28.7, 4.3, 2.2 Hz, 2H), 7.81 (dd, J = 7.3, 2.2 Hz, 1H),7.75 (q, JAttorney Docket No. 57547-742.601LC-MSEx. Exact mass 'HNMR[M+l] (m / z)= 2.1 Hz, 1H), 7.64- 7.52 (m, 2H), 7.47 (t, J = 2.2 Hz, 1H), 7.39-7.32(m, 3H), 7.16 (t, J = 7.7 Hz, 1H), 7.11 - 7.03 (m, 2H), 6.97- 6.88 (m, 1H), 6.78 - 6.70 (m, 2H), 6.68 - 6.61 (m, 2H), 6.24(s, 1H), 4.82(s, 2H),4.20(dd, J = 17.6, 2.0Hz, 1H), 3.91 (d, J = 2.1 Hz, 3H), 3.71 (dd, J = 17.6, 2.1 Hz, 1H), 2.77 - 2.58 (m, 3H).! HNMR(400 MHz, DMSO-d6) 8 10.77 (s, 1H), 8.20 - 8.12 (m, 1H), 7.72 (dd, J = 6.9, 1.8 Hz, 2H), 7.59 - 7.43 (m, 4H), 7.41 - 7.33 (m, 3H), 7.15 (td, J = 7.7, 1.3 Hz, 1H), 7.11 -7.04 84 622.2 623.5(m, 2H), 6.92 (t, J = 7.4 Hz, 1H), 6.78 - 6.69 (m, 3H), 6.63 (d, J = 8.5 Hz, 1H), 6.23 (s, 1H), 4.82 (s, 2H), 4.19 (d, J = 17.7 Hz, 1H), 3.91 (s, 3H), 3.70 (d, J = 17.7 Hz, 1H), 3.40 (s, 3H). > HNMR (400 MHz, DMSO-d6) 8 10.79 (s, 1H), 9.97 (s, 1H), 7.69 - 7.65 (m, 2H), 7.50 - 7.43 (m, 3H), 7.38 - 7.35 (m, 3H), 7.17-7.15 (td, J = 7.7, 1.3 Hz, 1H), 7.13 - 7.08 (m, 2H), 6.94- 85 609.2 610.1 6.90 (td, J = 7.6, 1.0 Hz, 1H), 6.77-6.76 (d, J = 2.1 Hz, 1H),6.73-6.71 (d, J = 7.8 Hz, 1H), 6.27 (s, 1H),4.83 (s, 2H), 4.16- 4.12 (d, J = 17.8 Hz, 1H), 3.92 (s, 3H), 3.71-3.67 (d, J = 17.8Hz, 1H), 3.01 (s, 3H).> HNMR (400 MHz, DMSO-d6) 8 13.00 (s, 1H), 10.78 (s, 1H), 8.32-8.09 (t, J = 1.9 Hz, 3H), 7.87-7.85 (dt, J = 7.8, 1.4 Hz, 1H), 7.69-7.67 (dt, J = 7.8, 1.4 Hz, 1H), 7.49-7.45 (m, 2H), 86 582.2 583.2 7.40-7.37 (m, 3H), 7.15-7.09(m, 3H), 6.94-6.92 (t, J= 7.5 Hz,1H), 6.78-6.77 (d, J = 2.1 Hz, 1H), 6.74-6.72 (d, J = 7.8 Hz, 1H), 6.24 (s, 1H), 4.84-4.83 (m, 2H), 4.28-4.23 (d, J = 17.8 Hz, 1H), 3.92 (s, 3H), 3.79-3.75 (d, J = 17.9 Hz, 1H)1H NMR (400 MHz, Methanol-d4) 87.99 - 7.93 (m, 1H), 7.83 (s, 1H), 7.65 -7.53 (m, 2H), 7.48 - 7.40 (m, 3H), 7.38 (dd, J = 7.5, 1.3Hz, 1H), 7.20 (td, J = 7.8, 1.3Hz, 1H), 7.16-7.09 (m, 87 587.2 588.22H), 7.04 - 6.96 (m, 1H), 6.76 (d, J = 7.9 Hz, 1H), 6.72 (d, J = 2.1 Hz, 1H), 5.00 (d, J = 15.9 Hz, 1H), 4.89 (s, 1H),4.17 (d, J = 17.2 Hz, 1H), 3.85 (s, 4H), 3.26 (s, 3H), 1.84 (s, 3H) > HNMR (400 MHz, Methanol-d4) 87.47 - 7.39 (m, 4H), 7.39 -7.31 (m, 3H), 7.25 -7.16 (m,2H), 7.16 - 7.09 (m, 2H), 7.00 88 601.2 602.2 (td, J = 7.6, 1.0 Hz, 1H), 6.78 -6.69 (m,2H),4.98 (d, J = 15.9 Hz, 1H), 4.90 (s, 1H), 4.11 (d, J = 17.3 Hz, 1H), 3.87 - 3.82(m, 7H), 3.22 - 3.13 (m, 4H).Example 89: Preparation of 4-((3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-3-hydroxy-2-oxoindolin-l-yl)methyl)-N-(pyridin-4-ylsulfonyl)benzamide

[0295] To solution of 4-[[3-[2-(3,4-dimethoxyphenyl)-2-oxo-ethyl]-3-hydroxy-2-oxo-indolin-l-yl]methyl]benzoic acid (1.00 eq, 50 mg, 0.108 mmol), 4-pyridinesulfonamide (1.10 eq, 19 mg, 0.119 mmol), DMAP (1.20 eq, 16 mg, 0.130 mmol) in DCM (3mL) was added EDC. HC1 (1.20 eq, 25 mg, 0.130 mmol) atAttorney Docket No. 57547-742.601rt. The reaction solution was heated to 45 °C for 3 hours, and then worked up with water (2 ml) and DCM (2 ml). The organic phase was dried, concentrated, and followed by silica gel column chromatography with ethyl acetate in hexane 60-100% then 20% methanol in ethyl acetate to provide 4-((3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-3-hydroxy-2-oxoindolin-l-yl)methyl)-N-(pyridin-4-ylsulfonyl)benzamide (lOmg, 15% yield).1H NMR (499 MHz, DMSO-d6)88.68 - 8.55 (m,2H), 7.85 (d, J= 8.3 Hz, 2H), 7.71 -7.66 (m, 2H), 7.64 (dd, J= 8.5, 2.0Hz, 1H), 7.40 (d, J=8.3 Hz, 2H), 7.39 - 7.31 (m, 2H), 7.13 (td, J= 7.7, 1.1 Hz, 1H), 7.05 (d, J= 8.6 Hz. 1H), 6.91 (t, J=7.2Hz, 1H), 6.71 (d, J = 7.8Hz, lH),6.24(s, 1H), 5.76(s, 1H), 5.02 - 4.72 (m, 2H),4.15 (d, J= 17.5 Hz, 1H), 3.84 (s, 3H), 3.78 (s, 3H), 3.68 (d, J= 17.5 Hz, 1H). ESI-LCMS calcd. for C31H27N3O8S 601.1; found [M-Hp 600.2.

[0296] The following compounds were prepared by the same general method as for 4-((3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-3-hydroxy-2-oxoindolin-l-yl)methyl)-N-(pyridin-4-ylsulfonyl)benzamide (Example 89) starting with either 4-| 13-| 2-(3.4-dimethox phenyl)-2-oxo-ethyl |-3-hydroxy-2-oxo-indolin- 1 -yl]methyl]benzoic acid or 4-[[3-[2-(3,4-dimethoxyphenyl)-2-oxo-ethyl]-3-methyl-2-oxo-indolin-l-yl]methyl]benzoic acid:LC-MSEx. Exact Mass ‘HNMR(m / z) [M-lp'H NMR (499 MHz, DMSO-d6) 8 8.49 (d, J = 4.0 Hz, 1H), 7.89 (s, 1H), 7.86 (d, J = 8.2 Hz, 3H), 7.64 (dd, J = 8.5, 2.0 Hz, 1H), 7.41 (d, J = 7.9 Hz, 3H), 7.36 - 7.28 (m, 2H), 7.14 (td, J = 7.8, 1.1 Hz, 1H), 7.06 (d, J = 8.6 Hz, 1H), 6.91 (t, J = 90 601.2 600.27.4 Hz, 1H), 6.71 (d, J = 7.8 Hz, 1H), 6.24 (s, 1H), 5.76 (s, 1H), 5.03 - 4.75 (m, 2H), 4.15 (d, J = 17.6 Hz, 1H), 3.84 (s, 3H), 3.78 (s, 3H), 3.68 (d, J = 17.5 Hz, 1H), 3.17 (d, J = 5.3 Hz, 1H), 2.18 - 1.72 (m, 1H), 1.18 (t, J = 7.1 Hz, 1H).'H NMR (499 MHz, DMSO-d6) 813.15 (s, 1H), 8.93 (s, 1H), 8.59 (d, J = 4.3 Hz, 1H), 8.21 (d, J = 7.7 Hz, 2H), 8.15 (d, J = 7.9 Hz, 1H), 7.85 (d, J = 8.3 Hz, 2H), 7.65 (dd, J = 8.5, 2.0 Hz, 1H), 7.44 (dd, J = 7.9, 4.8 Hz, 1H), 7.38 (d, J = 8.2 Hz, 2H), 91 599.2 600.3 7.34 (d, J = 2.0 Hz, 1H), 7.29 (d, J = 6.5 Hz, 1H), 7.14 - 7.01 (m, 2H), 6.98 (d, J = 7.7 Hz, 2H), 6.88 (t, J = 7.1 Hz, 1H), 6.75 (d, J = 7.8 Hz, 1H), 4.99 (d, J = 16.1 Hz, 1H), 4.89 (d, J = 16.1 Hz, 1H), 4.16 - 4.02 (m, 1H), 3.87-3.72 (m, 7H), 3.63 - 3.50 (m, 1H), 3.18 (s, 5H), 1.35 (s, 3H).> HNMR (499 MHz, DMSO-d6) 8 8.53 (s, 1H), 7.94 (s, 2H), 7.86 (d, J = 7.6 Hz, 3H), 7.65 (dd, J = 8.4, 1.9 Hz, 1H), 7.42 (s, 3H), 7.34 (d, J = 1.9 Hz, 1H), 7.29 (d, J = 7.2 Hz, 1H), 7.12 92 599.2 600.3 -7.03 (m, 2H), 6.89 (t, J = 7.4 Hz, 1H), 6.82 - 6.72 (m, 1H),5.00 (d, J = 15.9 Hz, 1H), 4.93 (s, 1H), 4.17 - 4.09 (m, 1H), 3.83 (s, 4H), 3.78 (s, 4H), 3.71 -3.53 (m, 2H), 3.33 (s, 65H),1.35 (s, 4H), 1.17 (t, J = 7.1 Hz, 1H).Example 93: Preparation of N-((4-((3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-3-hydroxy-2-oxoindolin-l-yl)methyl)phenyl)sulfonyl)oxazole-5-carboxamideAttorney Docket No. 57547-742.601step 2Step 1: Preparation of N-((4-((2,3-dioxoindolin-l-yl)methyl)phenyl)sulfonyl)oxazole-5-carboxamide

[0297] To a solution of 4-((2,3-dioxoindolin-l-yl)methyl)benzenesulfonami de (100 mg, 0.316 mmol, 1.0 equiv.), 1,3-oxazole-5-carboxylic acid (38 mg, 0.336 mmol, 1.1 equiv.) and DMAP (40 mg, 0.327 mmol, 1.04 equiv.) in DCM (1 mL) was added DIC (42 mg, 0.333 mmol, 1.1 equiv.) at room temperature. The resulting mixture was stirred at rt overnight and then concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (column, Cl 8 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 50% gradient in 10 min) to provide N-((4-((2,3-dioxoindolin-l-yl)methyl)phenyl)sulfonyl)oxazole-5-carboxamide (150 mg, 115.3%) as a white solid. MS (ESI): mass calcd. for C19H13N3O6S 411.05; [M+H]+ found 441.90.Step 2: Preparation of N-((4-((3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-3-hydroxy-2-oxoindolin-l-yl)methyl)phenyl)sulfonyl)oxazole-5-carboxamide

[0298] A mixture of N-((4-((2,3-dioxoindolin-l-yl)methyl)phenyl)sulfonyl)oxazole-5-carboxamide (50 mg, 0.122 mmol, 1.0 equiv.), N-(4-[(2,3-dioxoindol-l-yl)methyl]benzenesulfonyl-l,3-oxazole-5-carboxamide (50 mg, 0.122 mmol, 1.0 equiv.) and 4A molecular sieves (25 mg, 0.057 mmol, 0.47 equiv.) in THF (2 mL) was stirred at rt overnight. After filtration, the resulting mixture was concentrated under reduced pressure. The crude product was purified by prep-HPLC under method C conditions to provide N-((4-((3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-3-hydroxy-2-oxoindolin-l-yl)methyl)phenyl)sulfonyl)oxazole-5-carboxamide (22.5 mg, 31.2%). 'H NMR (400 MHz. Methanol-d4) 5 8.26 (s, 1H), 8.03 (d, J = 8.2 Hz, 2H), 7.74 - 7.64 (m, 4H), 7.43 - 7.34 (m, 2H), 7.24 - 7.15 (m, 1H), 7.07 -6.96 (m, 2H), 6.77 (d, J = 7.8 Hz, 1H), 5.07 (q, J = 16.5Hz, 2H), 4.12 (d, J = 17.1 Hz, 1H), 3.91 (d, J = 0.9 Hz, 3H), 3.84 (d, J = 1.4 Hz, 3H), 0.14- 0.08 (m, 1H). ESI-LCMS calcd. for C29H25N3O9S 591.1; [M+H]+ found 592.2.

[0299] The following compounds were prepared by the same general method as for N-((4-((3-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-3-hydroxy-2-oxoindolin-l-yl)methyl)phenyl)sulfonyl)oxazole-5-carboxamide (Example 93):LC-MSEx. Exact mass ‘HNMR[M+l] (m / z)1H NMR (400 MHz, Methanol-d4) 88.05 - 7.99 (m, 2H), 7.93 94 591.1 590.1 [M-H]+(s, 1H), 7.71 - 7.61 (m, 3H), 7.43 - 7.33 (m, 2H), 7.25 (s, 1H),Attomey Docket No. 57547-742.601LC-MSEx. Exact mass ‘HNMR[M+l] (m / z)7.19 (td, J = 7.8, 1.3 Hz, 1H), 7.09 - 6.95 (m, 2H), 6.76 (d, J = 7.8 Hz, 1H), 5.13 - 4.98 (m, 2H), 4.11 (d, J = 17.0 Hz, 1H), 3.91 (s, 3H), 3.84(s, 3H), 3.79 (d, J = 17.0 Hz, 1H), 1.31 (s,1H)'H NMR (400 MHz, DMSO-d6) 8 8.74 (d, J = 5.1 Hz, 2H), 7.96 (d, J = 8.1 Hz, 2H), 7.81 (d, J = 5.1 Hz, 2H), 7.71 - 7.61 (m, 3H), 7.41 -7.32 (m,2H), 7.17 (t, J = 7.8 Hz, 1H),7.05 (d, 95 601.2 602.1J = 8.5 Hz, 1H), 6.94 (t, J = 7.5 Hz, 1H), 6.80 (d, J = 7.8 Hz, 1H), 6.25 (s, 1H), 5.01 (s, 2H), 4.18 (d, J = 17.7 Hz, 1H), 3.81 (d, J = 23.3 Hz, 6H), 3.71 (t, J = 13.3 Hz, 1H)1H NMR (400 MHz, Methanol-d4) 88.74 - 8.73 (d, J = 2.2 H^ 1H), 8.29-8.27 (m, 1H), 8.18 - 8.12 (dt, J = 8.0, 2.0 Hz, 1H), 8.10- 7.77 (dd, J = 8.4, 1.9 Hz, 2H), 7.75 - 7.69 (d, J = 8.1 Hz, 2H), 7.67-7.49 (ddd, J = 41.7, 8.1, 3.4 Hz, 2H), 7.47 - 96 601.2 602.57.40 (m, 2H), 7.27 - 7.12 (m, 1H), 7.05 - 6.94 (m, 2H), 6.80- 6.78 (d, J = 7.8 Hz, 1H), 5.19 - 5.06(d, J = 16.6 Hz, 1H),5.02 - 4.86 (d, J = 16.6 Hz, 1H), 4.17 - 4.02 (d, J = 17.1 Hz, 1H), 3.91 (d, J = 1.9 Hz, 3H), 3.85 - 3.78 (m, 3H)1H NMR (400 MHz, Methanol-d4) 88.10 (d, J = 8.1 Hz, 2H), 7.82 (d, J = 7.8 Hz, 2H), 7.75 (d, J = 8.1 Hz, 2H), 7.68 (dd, J = 8.5, 1.9 Hz, 1H), 7.60 (t, J = 7.4 Hz, 1H), 7.47 (t, J = 7.6 Hz, 97 600.2 601.4 2H), 7.43 - 7.36 (m, 2H), 7.21 (t, J = 7.7 Hz, 1H), 7.07 - 6.98 (m, 2H), 6.79 (d, J = 7.9 Hz, 1H), 5.16 (d, J = 16.5 Hz, 1H), 5.05 (d, J = 16.6 Hz, 1H), 4.14 (d, J = 17.0 Hz, 1H), 3.91 (s,7H)Example 98: Preparation of 4-((4-(2-(3-hydroxy-l-(4-((l-methyI-lH-pyrazole)-5-sulfonamido) benzyl)- 2-oxoindolin-3-yl)acetyl)-methoxyphenoxy)methyl)benzamideoStep 1: Preparation of l-(4-benzyloxy-3-methoxy-phenyl)ethenone.

[0300] To a solution of l-(4-Hydroxy-3-methoxyphenyl)ethanone (1.00 eq, 100 mg, 0.60 mmol) and benzyl bromide (1.00 eq, 0.072 mL, 98%, 0.60 mmol) in DMF (2 mL) was added potassium carbonate (1.50 eq, 125 mg, 0.90 mmol). The reaction mixture was heated overnight at 60 °C and then poured in 20 ml of water, and extracted with EtOAc (10 mLx 2). The combined organic phases were washed with brine, driedAttorney Docket No. 57547-742.601over MgSO4, and concentrated under vacuum to provide desired compound (164 mg) used as is for the next step.Step 2: Preparation of 4-[[4-[2-[3-hydroxy-l-[[4-[(2-methylpyrazol-3-yl)sulfonylamino] phenyl] methyl] -2-oxo-indolin-3-yl] acetyl] -2-methoxy-phenoxy] methyl] benzamide

[0301] A solution of 4- [(4-acetyl-2-methoxy-phenoxy)methyl] benzamide (1.50 eq, 23 mg, 0.076 mmol), N-[4-[(2,3-dioxoindolin-l-yl)methyl]phenyl]-2-methyl-pyrazole-3-sulfonamide (1.00 eq, 20 mg, 0.051 mmol) and di ethylamine (1.00 eq, 0.0053 mL, 0.051 mmol) in anhydrous ethanol (1.5 ml) was stirred at 50 °C for 3 days. The solvent was evaporated. The residue was purified on silica gel column chromatography eluting with 0-5% MeOH in DCM to give 4-[[4-[2-[3-hydroxy-l-[[4-[(2-methylpyrazol-3-yl)sulfonylamino] phenyl] methyl] -2-oxo-indolin-3-yl] acetyl] -2-methoxy-phenoxy] methyl] benzamide (9.0 mg, 25.5 % yield). 'HNMR (499 MHz, DMSO-d6) 8 10.78 (s, 1H), 7.97 (s, 1H), 7.88 (d, J=8.3 Hz, 2H), 7.60 (dd, J=8.5, 1.9 Hz, 1H), 7.56 - 7.45 (m, 3H), 7.43 - 7.28 (m, 5H), 7.24- 6.98 (m, 3H), 6.90 (t, J=7.5 Hz, 1H), 6.77 (d, J=2.0Hz, 1H), 6.71 (d, J=7.8Hz, lH),6.20(s, 1H), 5.25 (s, 2H), 4.94 - 4.57 (m, 2H), 4.14 (d, J=17.7 Hz,lH), 3.91 (s, 3H), 3.80 (s, 3H), 3.66 (d, J=17.6 Hz, 1H), 3.17 (d, J=4.9 Hz, 1H). ESI-LCMS calcd. for C25H29N9O [M+H]+695.2, found 696.4.

[0302] The following compounds were prepared by the same general method as for 4-((4-(2-(3-hydroxy-l-(4-((l-methyl-lH-pyrazole)-5-sulfonamido) benzyl)-2-oxoindolin-3-yl)acetyl)-methoxyphenoxy)methyl)benzamide (Example 98):LC-MSEx. Exact mass 'HNMR(m / z) [M+l]+'H NMR (499 MHz, DMSO-d6) 8 7.59 (dd, J=8.5, 2.0 Hz, 1H), 7.46 (s, 1H), 7.40 - 7.27 (m, 4H), 7.14 (td, J=7.7, 1.1 Hz, 1H), 7.05 (d,.7=8.5 Hz, 3H), 6.90 (t, J=1.2 Hz, 1H), 6.71 (d, J=7.9 Hz, 2H), 6.19 (s, 1H), 6.12 - 5.94 (m, 1H), 5.40 (dd, 99 602.2 603.3.7=17.3, 1.7 Hz, 1H), 5.27 (dd, J=10.5, 1.5 Hz, 1H), 4.90- 4.69 (m, 2H), 4.65 (d, J=5.3 Hz, 2H), 4.13 (d, J=17.6 Hz, 1H), 3.90 (s, 3H), 3.79 (s, 3H), 3.65 (d, J=17.5 Hz, 1H), 3.32 (s, 21H),1.15 (t,.7=7,2 Hz. 1H).'H NMR (499 MHz, DMSO-d6) 8 7.57 (dd, J=8.5, 2.0 Hz, 1H), 7.48 (d,.7 2.0 Hz, 1H), 7.39 - 7.29 (m, 4H), 7.14 (td, J=7.7, 1.2 Hz, 1H), 7.07 (d, J=8.5Hz, 2H), 6.95 (d, J=8.6Hz; 100 634.2 635.4 1H), 6.93 - 6.86 (m, 1H), 6.75 - 6.67 (m, 1H), 6.20 (s, 1H),4.89 (s, 2H), 4.81 (q, J=16.0 Hz, 2H), 4.24 - 4.06 (m, 3H), 3.91 (s, 3H), 3.80 (s, 3H), 3.66 (d, J=17.6 Hz, 1H), 1.21 (t, J=7.1 Hz, 3H).'H NMR (499 MHz, DMSO-d6) 8 7.66 (dd, J=8.5, 2.0 Hz, 1H), 7.61 - 7.53 (m, 1H), 7.47 (dd, J=6.3, 2.0 Hz, 1H), 7.42 - 7.29 (m, 3H), 7.20 (d, J=8.5 Hz, 1H), 7.17 - 7.09 (m, 1H), 601.2101 602.3 7.09 - 7.01 (m, 3H), 6.91 (t, J=7.5 Hz, 1H), 6.81 - 6.67 (m,2H), 6.22 (s, 1H), 5.26 (s, 2H), 4.87 - 4.71 (m, 2H), 4.18 (d,.7=17.7 Hz, 1H), 3.91 (d,.7=2,6 Hz. 3H), 3.82 (s, 3H), 3.69 (d,.7=17.7 Hz, 1H).> HNMR (499 MHz, DMSO-d6) 8 10.79 (s, 1H), 7.87 (dd, J = 8.6, 2.2 Hz, 1H), 7.68 (d, J = 2.2 Hz, 1H), 7.49 (d, J = 2.1 Hz, 102 602.2 601.3 [M-l]- 1H), 7.38 (s, 1H), 7.36 - 7.30 (m, 2H), 7.14 (td, J = 7.7, 1.2Hz, 1H), 7.11 - 7.01 (m, 3H), 6.94 - 6.86 (m, 1H), 6.76 (d, J =Attorney Docket No. 57547-742.601LC-MSEx. Exact mass ‘HNMR(m / z) [M+l]+2.1 Hz, 1H), 6.71 (d, J = 7.8 Hz, lH),6.19(s, 1H), 4.81 (d, J = 2.8 Hz, 2H), 4.12 (d, J = 17.5 Hz, 1H), 3.90 (d, J = 11.1 Hz, 6H), 3.66 (d, J = 17.5 Hz, 1H), 1.99 (s, 1H), 1.32 (s, 9H), 1.23(s, 1H), 1.17 (t, J = 7.1 Hz, 1H).Example 103: Preparation of N-(4-((3-(2-(2-fluoro-4,5-dimethoxyphenyl)-2-oxoethyl)-3-hydroxy-2-oxoindolin-l-yl)methyl)phenyl)pyridine-3-sulfonamideo

[0303] A solution of l-(2-fluoro-4,5-dimethoxy-phenyl)ethanone (1.50 eq, 11 mg, 0.0534 mmol), N-[4- [(2,3-dioxoindolin-l-yl)methyl]phenyl]pyridine-3-sulfonamide (1.00 eq, 14 mg, 0.0356 mmol) and diethylamine (1.00 eq, 0.0037 mL, 0.0356 mmol) in anhydrous ethanol (1.5ml) was stirred at 45 °C overnight. The reaction mixture was concentrated and purified by silica gel column chromatography with 0- 100% ethyl acetate in hexane to provide N-(4-((3-(2-(2-fluoro-4,5-dimethoxyphenyl)-2-oxoethyl)-3-hydroxy-2-oxoindolin-l-yl)methyl)phenyl)pyridine-3-sulfonamide (11 mg, 52% yield). 'H NMR (499 MHz. DMSO-de) 8 10.49 (s, 1H), 8.86 (d, J = 2.3 Hz, 1H), 8.76 (dd, J = 4.8, 1.5 Hz, 1H), 8.09 (dt, J = 8.1, 1.9 Hz, 1H), 7.57 (dd, J = 8.0, 4.6 Hz, 1H),7.33 (d, J = 8.4 Hz, 3H), 7.21 - 7.12 (m, 1H), 7.10 - 6.97 (m, 4H), 6.92 (t, J = 7.5Hz, 1H), 6.71 (d, J = 7.8Hz, 1H), 6.21 (s, 1H), 4.84 (d, J = 16.1 Hz, 1H), 4.76 (d, J = 16.1 Hz, 1H), 4.06 - 3.96 (m, 1H),3.85 (s, 3H), 3.71 (s, 3H), 3.69 - 3.59(m, 1H), 3.33 (s, 18H), 1.99 (s, 1H), 1.17 (t, J = 7.1 Hz, 1H). ESI-LCMS calcd. for C30H26FN3O7S 591.1; found [M+H]+ 592.3.Example 104: Preparation of N-(4-((3-(2-(2-fluoro-4,5-dimethoxyphenyl)-2-oxoethyl)-3-hydroxy-2-oxoindolin-l-yl)methyl)phenyl)pyridine-3-sulfonamide

[0304] To a solution of l-[(4-aminophenyl)methyl]-3-hydroxy-3-[2-(3-isopropoxy-4-methoxy-phenyl)-2-oxo-ethyl]indolin-2-one;2,2,2-trifluoroacetic acid (1.00 eq, 48 mg, 0.0700 mmol) and pyridine-3-sulfonyl chloride (1.00 eq, 12 mg, 0.0700 mmol) in DCM (1ml) was added pyridine (8.00 eq, 0.045 mL, 0.560 mmol) at rt. The resulting solution was stirred at rt for 4 hours, quenched with water (1 ml) and extracted with DCM. The organic phase was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography eluting with 0-100% ethyl acetate in hexane to give N-(4-((3-(2-(2-fluoro-4,5-dimethoxyphenyl)-2-oxoethyl)-3-hydroxy-2-oxoindolin-l-yl)methyl)phenyl)pyridine-3-sulfonamide (6 mg, 14% yield).1HNMR(500MHz, MeOD) 88.84(d, J = 2.0Hz, 1H), 8.67 (dd, J = 4.9, 1.5 Hz, 1H), 8.06 (dt, J = 8.1, 2.0Hz, 1H), 7.64 (dd, J = 8.5, 2.1 Hz, 1H), 7.45 (dd, J=7.8, 4.6 Hz, 1H),7.43 - 7.32 (m, 5H), 7.17Attorney Docket No. 57547-742.601(d, J = 1.2 Hz, 1H), 7.14 - 7.06 (m, 2H), 7.06 - 6.94 (m, 2H), 6.69 (d, J = 7.8 Hz, 1H), 4.91 (s, 1H), 4.63 -4.45 (m, 1H), 4.15 - 3.98(m, 2H), 3.89(s, 3H),3.74(d, J = 17.0 Hz, 1H), 2.01 (s, 1H), 1.36 - 1.20 (m, 9H). ESI-LCMS calcd. for C32H31N3O7S 601.2; found [M+H]+ 602.3.

[0305] The following compounds were prepared by the same general method as for N-(4-((3-(2-(2-fluoro-4,5-dimethoxyphenyl)-2-oxoethyl)-3-hydroxy-2-oxoindolin-l-yl)methyl)phenyl)pyridine-3-sulfonamide (Example 104). Single enantiomers were obtained by chiral SFC separation from the corresponding recemic material.LC-MSEx. Exact mass H NMR(m / z) [M+l]+> HNMR (499 MHz, DMSO-d6) 8 10.48 (s, 1H), 8.87 (d, J = 2.0Hz, 1H), 8.77 (dd, J = 4.8, 1.5 Hz, 1H), 8.09 (dt, J = 8.1, 1.7 Hz, 1H), 7.66 - 7.49 (m, 2H), 7.38 - 7.25 (m, 4H), 7.13 (td, J = 7.7, 1.2 Hz, 1H), 7.05 (dd, J = 8.6, 4.6 Hz, 3H), 6.91 (t, J = 105 601.2 602.37.2 Hz, 1H), 6.68 (d, J = 7.8 Hz, 1H), 6.19 (s, 1H), 5.76 (s, 1H), 4.89 - 4.76 (m, 2H), 4.76 - 4.60 (m, 2H), 4.13 (d, J = 17.6 Hz, 1H), 3.76 (s, 3H), 3.65 (d, J = 17.6 Hz, 1H), 1.28 (d, J =6.0 Hz, 7H).> HNMR (499 MHz, DMSO-d6) 810.78 (s, 1H), 7.59 (dd, J = 8.5, 1.9 Hz, 1H), 7.49 (d, J = 1.9 Hz, 1H),7.41 - 7.34(m,3H), 7.34 - 7.29 (m, 2H), 7.14 (t, J = 7.7 Hz, 1H), 7.06 (dd, J = 13.5, 8.6 Hz, 4H), 6.91 (t, J = 7.5 Hz, 1H), 6.76 (d, J = 1.8 Hz, 1H), 6.71 (d, J = 7.8 Hz, 1H), 6.19 (s, 1H), 4.86 - 4.71 (m, 106 604.2 605.32H), 4.58 (dt, J = 12.1, 6.1 Hz, 2H), 4.13 (d, J = 17.6 Hz, 1H), 4.07 - 3.96 (m, 1H), 3.91 (s, 3H), 3.82 (s, 4H), 3.64 (d, J = 17.5 Hz, 1H), 3.38 (d, J = 7.0 Hz, 1H), 1.99 (s, 1H), 1.32 - 1.19 (m, 9H), 1.19 - 1.13 (m, 2H), 1.10 (dt, J = 11.4, 7.0 Hz,2H).> HNMR (400 MHz, Methanol-d4) 89.29 (d, J = 1.4 Hz, 1H), 8.97 (d, J = 5.1 Hz, 1H), 7.90 (dd, J = 5.1, 1.4 Hz, 1H), 7.67 (dd, J = 8.5, 2.0 Hz, 1H), 7.40 - 7.32 (m, 3H), 7.23 (d, J = 7.3 Hz, 1H), 7.21 -7.16 (m, 2H), 7.12 (td, J = 7.8, 1.2 Hz, 1H), 107 572.2 573.357.03 (d, J = 8.5 Hz, 1H), 6.96 (t, J = 7.5 Hz, 1H), 6.75 (d, J = 7.8 Hz, 1H), 5.01 - 4.91 (m, 2H), 4.02 (d, J = 17.9 Hz, 1H), 3.88 (d, J = 27.7 Hz, 6H), 3.91 (s, 3H), 3.84 (s, 3H), 3.64 (d, J = 17.9 Hz, 1H), 1.43 (s, 3H)> HNMR (400 MHz, Methanol-d4) 88.90 (d, J = 4.9 Hz, 2H), 7.65 (dd, J = 8.5, 2.0 Hz, 1H), 7.60 (t, J = 4.9 Hz, 1H), 7.35 (dd, J = 8.5, 2.0 Hz, 3H), 7.25 - 7.21 (m, 3H), 7.10 (td, J = 108 572.2 573.1 7.8, 1.3 Hz, 1H), 7.01 (d, J = 8.5 Hz, 1H), 6.94 (td, J= 7.6, 1.0 Hz, 1H), 6.74 (d, J = 7.8 Hz, 1H), 4.98 - 4.86 (m, 2H), 4.01 (d, J = 17.9 Hz, 1H), 3.90 (s, 3H), 3.83 (s, 3H), 3.63 (d, J =17.9 Hz, 1H), 1.42 (s, 3H).> HNMR (400 MHz, DMSO-d6) 813.64-13.39 (brs, 1H), 8.11 (s, 1H),7.85 - 7.82 (m, 1H), 7.64 (dd, J = 8.5, 2.0 Hz, 1H), 7.33 - 7.28 (m, 3H), 7.15 - 7.04 (m, 2H), 6.94 - 6.89 (m, 3H), 109 575.2 576.14.94 (d, J = 16.0 Hz, 1H), 4.75 (d, J = 16.0 Hz, 1H), 4.14 (d, J = 18.6 Hz, 1H), 3.84(s, 3H), 3.76 (two s, 6H), 3.58 (d, J = 18.5 Hz, 1H), 1.32 (s, 3H).> HNMR (400 MHz, Methanol-d4) 88.68-8.62 (m, 2H), 7.68 - 7.64 (m, 3H), 7.40 - 7.37 (m, 3H), 7.24 (d, J = 7.3 Hz, 1H), 110 571.2 572.27.12 (t, J = 6.8 Hz, 3H), 7.06 -6.94 (m, 2H), 6.75 (d, J = 7.7Hz, 1H), 5.01 (d, J = 15.9 Hz, 1H), 4.92 (s, 1H), 4.03 (d, J =Attorney Docket No. 57547-742.601LC-MSEx. Exact mass H NMR(m / z) [M+l]+17.8 Hz, 1H), 3.90 (s, 3H), 3.82 (s, 3H), 3.64 (d, J = 18.0 Hz,1H), 1.43 (s, 3H).'H NMR (400 MHz, DMSO-d6) 8 10.54 (s, 1H), 8.81 - 8.80 (tn, 2H), 7.65 - 7.62 (m, 3H), 7.32 - 7.29 (m, 3H), 7.22 (d, J = 4.8 Hz, 2H), 7.12 - 7.09 (m, 1H), 7.05 (d, J = 8.5 Hz, 1H), Ill 589.2 590.36.92 (t, J = 7.5 Hz, 1H), 6.77 (d, J = 7.8 Hz, 1H), 4.97 - 4.85 (m, 2H), 4.13 (d, J = 18.5 Hz, 1H), 3.84 (s, 3H), 3.77 (s, 3H),3.60 (d, J = 18.5 Hz, 1H), 1.34 (s, 3H).'H NMR (400 MHz, DMSO-d6) 8 10.54 (s, 1H), 8.81 - 8.80 (m, 2H), 7.64 - 7.62 (m, 3H), 7.31 - 7.28 (m, 3H), 7.22 (d, J = 5.1 Hz, 2H), 7.12 - 7.11 (m, 1H), 7.07 (d, J = 8.5 Hz, 1H), 112 589.2 590.16.91 (t, J = 7.5 Hz, 1H), 6.77 (d, J = 7.8 Hz, 1H), 4.97 - 4.84 (tn, 2H), 4.13 (d, J = 18.4 Hz, 1H),3.84 (s, 3H), 3.77 (s, 3H),3.60 (d, J = 18.4 Hz, 1H), 1.34 (s, 3H).> HNMR (400 MHz, DMSO-d6) 8 10.58 (s, 1H), 8.64 (d, J = 5.2 Hz, 1H), 7.64 (dd, J = 8.4, 2.0 Hz, 1H), 7.50 (d, J = 1.7 Hz; 1H), 7.44 (dd, J = 5.1, 1.7 Hz, 1H), 7.35 - 7.25 (m, 4H), 7.06 113 585.2 586.1 (t, J= 8.0 Hz, 4H), 6.89 (t, J = 7.4 Hz, 1H), 6.73 (d, J = 7.8Hz, 1H), 4.85 (q, J = 15.9 Hz, 2H),4.10(d, J = 18.4 Hz, 1H), 3.84 (s, 3H), 3.77 (s, 3H), 3.58 (d, J = 18.4 Hz, 1H), 2.49 (s,3H), 1.33 (s, 3H))> HNMR (400 MHz, DMSO-d6) 8 10.51 (s, 1H), 8.85 (d, J = 2.4 Hz, 1H), 8.77 (dd, J = 4.8, 1.6 Hz, 1H), 8.08 (dt, J = 8.1, 114 585.2 586.2 2.0 Hz, 1H), 7.69 - 7.53 (m, 1H), 7.35 (d, J = 2.0 Hz, 1H),7.26 (d, J = 8.3 Hz, 1H), 7.15 (dd, J = 7.0, 1.7Hz,2H), 7.12 - 7.03 (m, 1H), 6.98 (s, 3H), 6.89 - 6.77 (m, 2H), 5.08 > HNMR (400 MHz, Methanol-d4) 87.68 (dd, J = 8.4, 2.0 Hz, 1H), 7.45 -7.33 (m, 4H), 7.19 - 7.11 (m, 2H), 7.09 (dd, J = 6.9, 1.9 Hz, 1H), 7.02 (dd, J = 8.5, 0.9 Hz, 1H), 6.96 - 6.85 115 588.2 589.3(m, 2H), 6.71 (d, J = 2.1 Hz, 1H), 5.30 - 5.14 (m, 2H), 4.03 (d, J = 18.0 Hz, 1H), 3.93, 3.85 (two s, 6H), 3.83 (s, 3H), 3.65 (d, J = 18.0 Hz, 1H), 2.23 (s, 3H), 1.44 (s, 3H).> HNMR (400 MHz, DMSO-d6) 810.81 (s, 1H), 9.15 (s, 1H), 8.92 (d, J = 2.3 Hz, 1H), 8.84 (s, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.35 -7.25 (m, 4H), 7.12 (d, J = 8.2 Hz, 2H), 7.06 (t, J = 7.6 116 572.2 573.3Hz, 2H), 6.89 (t, J = 7.6 Hz, 1H), 6.73 (d, J = 7.8 Hz, 1H), 4.84 (q, J = 16.1 Hz, 2H), 4.10 (d, J = 18.4 Hz, 1H), 3.84 (s, 3H), 3.78 (s, 3H), 3.58 (d, J = 18.6 Hz, 1H),...

Claims

Attorney Docket No. 57547-742.601CLAIMS WHAT IS CLAIMED IS:

1. 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, -NO2, -OH, -ORa, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci-C6aminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;X2is N or CR2;R2is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci-C6aminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;X3is N or CR3;R3is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci-C6aminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;X4is N or CR4;R4is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci-C6aminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;Z is absent or -CH2-;W is absent or -CH2-;Attorney Docket No. 57547-742.601R5and R6are independently hydrogen, halogen, Ci-Cealkyl, or Ci-Cehaloalkyl;Y1is N or CR7;R7is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;Y2is N or CR8;R8is hydrogen, halogen, -CN, -NO2, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl. C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;L1is -O-, -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 Ring A;R9is hydrogen or Ci-Cealkyl independently optionally substituted with one or more R;each R10is independently hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, or Ci-Cehaloalkyl; Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;each R11is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L- aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;or two R11are taken together to form an oxo;n is 0, 1, 2, 3, or 4;R12is hydrogen, halogen, -OH, -ORa, -NRcRd, Ci-Cealkyl, or Ci-Cehaloalkyl;L2is -O-, -CH2-, or -NR13-;U is O or NR14;L3is absent or -NR13-;R13is hydrogen or Ci-Cealkyl;R14is hydrogen, -CN, or -OH;Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;each R15is independently halogen, -L-CN, -NO2, -L-OH, -L-ORa, -L-OC(=O)Ra, -L-OC(=O)ORb, -L- OC(=O)NRcRd, -SH, -SRa, -L-S(=O)Ra, -L-S(=O)2Ra, -L-S(=O)2NRcRd, -L-NRcRd, -L-NRbC(=O)NRcRd, -L-NRbC(=O)Ra, -L-NRbC(=O)ORb, -L-NRbS(=O)2Ra, -L-C(=O)Ra, -L-C(=O)ORb, -L-C(=O)NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxy alkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2- Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl,Attorney Docket No. 57547-742.601alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;or two R15are taken together to form an oxo;m is 0, 1, 2, 3, or 4;each Rais independently Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxy alkyl, Ci-Ceaminoalkyl,Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L- heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;each Rbis independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxy alkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L- heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;each Rcand Rdare independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl,Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L- aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;or Rcand Rdare 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, -C(=O)NHCi-C3alkyl, Ci-C3alkyl, Ci-C3haloalkyl, Ci-C3hydroxyalkyl, Ci-Csaminoalkyl, Ci-Csheteroalkyl, Ci-Cecycloalkyl, or 3- to 6-membered heterocycloalkyl;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 the compound of Formula (I) is of Formula (la):R6Y1=Y2(R11)nX 22'X x'IIX?RFormula (la).3 The compound of claim 1 or 2, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R5and R6are independently hydrogen or Ci-Cealkyl.4 The compound of any one of claims 1-3, or a pharmaceutically acceptable salt, solvate, orAttorney Docket No. 57547-742.601stereoisomer thereof, wherein R5and R6are hydrogen.

5. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound of Formula (I) or (la) is of Formula (la- 1):R7R8Formula (la-1).6 The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein L1is -C(=O)NR9-* or -NR9C(=O)-*.7 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-*.8 The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein L1is -C(=O)NR9S(=O)2-* or -S(=O)2NR9C(=O)-*.9 The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein L1-O-C(R10)2-* or -C(R10)2-O-*.10 The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein L1-NR9-C(R10)2-* or -C(R10)2-NR9-*.11 The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein L1-S(=O)2C(R10)2-* or -C(R10)2S(=O)2-*.12 The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein L1is -C(R10)2-.13 The compound of any one of claims 1-12, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R9is hydrogen.14 The compound of any one of claims 1-13, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R9is Ci-Cealkyl.15 The compound of any one of claims 1-14, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R10is independently hydrogen or Ci-Cealkyl.16 The compound of any one of claims 1-15, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R10is independently hydrogen.17 The compound of any one of claims 1-16, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein L2is -O-.18 The compound of any one of claims 1-16, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein L2is -CH2-.19 The compound of any one of claims 1-18, or a pharmaceutically acceptable salt, solvate, orAttorney Docket No. 57547-742.601stereoisomer thereof, wherein L3is absent.

20. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R1is hydrogen, halogen, -CN, -ORa, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, or cycloalkyl.

21. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R1is hydrogen, halogen, or Ci-Cealkyl.

22. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R2is hydrogen.

23. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R3is hydrogen.

24. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R4is hydrogen.

25. The compound of any one of claims 1-24, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R7is hydrogen.

26. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R8is hydrogen, halogen, -ORa, or -NRcRd.

27. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R8is hydrogen.

28. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R12is hydrogen, -OH, or Ci-Cealkyl.

29. The compound of any one of claims 1-28, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R12is Ci-Cealkyl.

30. The compound of any one of claims 1-29, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring B is phenyl.

31. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R15is independently halogen, -L-CN, -L-OH, -L-ORa, -L-NRcRd, -L-NRbC(=O)Ra, -L-NRbS(=O)2Ra, -L-C(=O)Ra, -L-C(=O)ORb, -L-C(=O)NRcRd, Ci-C6alkyl, or Ci-Cehaloalkyl.

32. The compound of any one of claims 1-31, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R15is independently halogen, -L-OH, -L-ORa, Ci-Cealkyl, or Ci-Cehaloalkyl.

33. The compound of any one of claims 1-32, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R15is independently halogen, -OH, -ORa, or Ci-Cealkyl.

34. The compound of any one of claims 1-33, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R15is independently -ORa.

35. The compound of any one of claims 1-34, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein m is 1 or 2.Attorney Docket No. 57547-742.60136. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is 5- to 6-membered heteroaryl comprising one, two, or three heteroatoms selected from the group consisting of N, O, and S.

37. The compound of any one of claims 1-36, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ring A is pyridinyl.

38. The compound of any one of claims 1-37, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein eachR11is independently halogen, -CN, -NO2, -OH, -ORa, -NRcRd, - NRbC(=O)Ra, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehy dr oxy alkyl, Ci-Ceheteroalkyl, -L-cycloalkyl, -L- heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R.

39. The compound of any one of claims 1-38, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R11is independently halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, or Ci-Ceheteroalkyl.

40. The compound of any one of claims 1-39, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R11is independently halogen, Ci-Cealkyl, or Ci-Cehaloalkyl.

41. The compound of any one of claims 1-40, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein n is 1 or 2.

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

43. A pharmaceutical composition comprising a compound of any one of claims 1-42, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

44. A method of treating cancer in a subj ect, comprising administering to the subj ect a compound of any one of claims 1-42, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition of claim 43.

45. A method of inhibiting KIF22 in a subject, comprising administering to the subject a compound of any one of claims 1-42, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition of claim 43.

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