Modulators of bcl6 as ligand directed degraders

Abstract

Provided herein are compounds and compositions thereof for modulating BCL6. In some embodiments, the compounds and compositions are provided for treatment of cancer or an autoimmune disease. In a particular embodiment, the compounds are of Formula (I):, wherein values for the variables are as described herein.

Description

MODULATORS OF BCL6 AS LIGAND DIRECTED DEGRADERS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to US Provisional Application No. 63 / 595,058, filed November 1, 2023, which is incorporated by reference herein in its entirety for any purpose. FIELD

[0002] The present disclosure relates generally to compounds, compositions, and methods for their preparation and use of the compounds and compositions for treating cancer or an autoimmune disease. BACKGROUND

[0003] BCL6 (B cell lymphoma 6) is a member of the BTB / POZ-zinc finger family that contains an N-terminal BTB / POZ domain and a zinc finger at the C-terminus. As a transcription factor for T follicular helper (Tfh) cells, BCL6 is required for germinal center (GC) formation of naïve B cells and hence antibody affinity maturation. BCL6 was initially discovered as an oncogene in diffuse large B-cell lymphomas (DLBCLs) and its role has been implicated in many types of diseases including B-acute lymphoblastic leukemia, chronic myeloid leukemia, breast cancer, and non-small lung cancer (NSCLC) (Cardenas et al., Clin Cancer Res 2017, 23, 885- 893). The N-terminal BTB / POZ domain binds to and recruits co-repressor molecules such as SMRT, NCOR1, and BCOR, to form class I and II histone deacetylase complexes, and the C- terminal zinc fingers bind to specific DNA recognition sequences (Yang et al., Cell Dev. Biol. 2019, 7, 272). Upon binding to its target genes and forming complexes, BCL6 reduces RNA expression of its targets, including several key tumor supressors. Overexpression of BCL6, common in malignanies such as Non-Hodgkin’s lymphoma (NHL), leads to ectopic repression of cell cycle and DNA repair checkpoint proteins, causing unrestricted cell proliferation and tumorgenesis.

[0004] GC reponses are known to result in increased production of pathogenic autoantibodies which are responsible for several diseases, suggesting that methods to suppress or degrade BCL6 hold potential therapeutic applicability. Structural characterization of the co- crystal structures of the BCL6 BTB / POZ domain and co-repressors has shown that binding occurs at the lateral grooves formed by the interface between BCL6 BTB / POZ homodimers (Melnick et al., Mol. Cell Biol.2002, 22, 1804-1818; Ghetu et al., Mol. Cell.2008, 29, 384-391). Since then, specific ligands that bind to this site have been investigated, purposed to exploit the binding affinity towards the lateral grooves to render BCL6 as a druggable target.

[0005] Protein degradation is a highly regulated and essential process that maintains cellular homeostasis. Selective identification and removal of damaged, misfolded, or excess proteins is achieved through the ubiquitin-proteasome pathway (UPP). The UPP is central to the regulation of almost all cellular processes. Ubiquitination of the protein is accomplished by an E3 ubiquitin ligase that binds to a protein and adds ubiquitin molecules to the protein, thus marking the protein for proteasome degradation.

[0006] Harnessing the UPP for therapeutic use has received significant interest (Zhou et al., Mol. Cell 2000, 6, 751-756). One promising therapy uses proteolysis targeting chimeras, commonly referred to as PROTACs, to effect removal of unwanted proteins by protein degradation (Scheepstra et al., Comp. Struct. Biotech. J.2019, 17, 160-176). PROTACS are ligand directed degraders that bring together an E3 ligase and a target protein that is to be degraded. These bivalent molecules usually consist of an E3 ligase ligand connected through a linker moiety to small molecule that binds to the target protein. A PROTAC positions the E3 ligase at the appropriate distance and orientation to the target protein, allowing the latter to be ubiquitinated. The ubiquitinated target protein is subsequently recognized by the proteasome, where it is degraded.

[0007] Accordingly, there is a need for compounds that target BCL6 for degradation. SUMMARY

[0008] Described herein, in certain embodiments, are compounds and compositions thereof for modulating BCL6. In various embodiments, the compounds and compositions thereof may be used for treatment of cancer.

[0009] The present embodiments can be understood more fully by reference to the detailed description and examples, which are intended to exemplify non-limiting embodiments.

[0010] Provided in an aspect is a compound of Formula (I):, or a pharmaceutically acceptable salt thereof, wherein values for variables (e.g., Ring A, L1, L2, R1, R2, R3, R4) are as described herein.

[0011] Provided in another aspect is a pharmaceutical composition comprising a compound described herein (e.g., a compound of Formula (I)-(IV) or Table 1, or a pharmaceutically acceptable salt of any of the foregoing) and a pharmaceutically acceptable excipient.

[0012] Provided in yet another aspect is a method of degrading B-cell lymphoma 6 protein (BCL6), comprising contacting BCL6 with an effective amount of a compound described herein(e.g., a compound of Formula (I)-(IV) or Table 1, or a pharmaceutically acceptable salt of any of the foregoing), e.g., in the form of a pharmaceutical composition.

[0013] Provided in yet another aspect is a method of treating a cancer or an autoimmune disease in a subject in need thereof, comprising administering to the subject an effective amount of a compound described herein (e.g., a compound of Formula (I)-(IV) or Table 1, or a pharmaceutically acceptable salt of any of the foregoing), e.g., in the form of a pharmaceutical composition.

[0014] Also provided herein is a compound described herein (e.g., a compound of Formula (I)-(IV) or Table 1, or a pharmaceutically acceptable salt of any of the foregoing) or a pharmaceutical composition comprising a compound described herein (e.g., a compound of Formula (I)-(IV) or Table 1, or a pharmaceutically acceptable salt of any of the foregoing) for a use described herein (e.g., degrading BCL6, such as in a cell and / or subject, such as a subject in need thereof; treating a cancer or an autoimmune disease in a subject in need thereof).

[0015] Also provided herein is a use of a compound described herein (e.g., a compound of Formula (I)-(IV) or Table 1, or a pharmaceutically acceptable salt of any of the foregoing) for the manufacture of a medicament for a use described herein (e.g., degrading BCL6, such as in a cell and / or subject, such as a subject in need thereof; treating a cancer or an autoimmune disease in a subject in need thereof). DETAILED DESCRIPTION Definitions

[0016] As used herein, the terms “comprising” and “including” can be used interchangeably. The terms “comprising” and “including” are to be interpreted as specifying the presence of the stated features or components as referred to, but does not preclude the presence or addition of one or more features, or components, or groups thereof. Additionally, the terms “comprising” and “including” are intended to include examples encompassed by the term “consisting of”. Consequently, the term “consisting of” can be used in place of the terms “comprising” and “including” to provide for more specific embodiments.

[0017] The term “consisting of” means that a subject-matter has at least 90%, 95%, 97%, 98% or 99% of the stated features or components of which it consists. In another embodiment the term “consisting of” excludes from the scope of any succeeding recitation any other features or components, excepting those that are not essential to the technical effect to be achieved.

[0018] As used herein, the term “or” is to be interpreted as an inclusive “or” meaning any one or any combination. Therefore, “A, B or C” means any of the following: “A; B; C; A and B;A and C; B and C; A, B and C”. An exception to this definition will occur only when a combination of elements, functions, steps or acts are in some way inherently mutually exclusive.

[0019] In the present description, any concentration range, percentage range, ratio range, or integer range is to be understood to include the value of any integer within the recited range and, when appropriate, fractions thereof (such as one tenth and one hundredth of an integer), unless otherwise indicated. Also, any number range recited herein relating to any physical feature, such as polymer subunits, size, or thickness, are to be understood to include any integer within the recited range, unless otherwise indicated. As used herein, the terms “about” and “approximately” mean ± 20%, ± 10%, ± 5%, or ± 1% of the indicated range, value, or structure, unless otherwise indicated.

[0020] “Amino” refers to the –NH2radical.

[0021] “Cyano” refers to the -CN radical.

[0022] “Nitro” refers to the -NO2 radical.

[0023] “Oxa” refers to the -O- radical.

[0024] “Oxo” refers to the =O radical.

[0025] “Thioxo” refers to the =S radical.

[0026] “Imino” refers to the =N-H radical.

[0027] “Oximo” refers to the =N-OH radical.

[0028] “Hydrazino” refers to the =N-NH2 radical.

[0029] “Alkyl” refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to fifteen carbon atoms (e.g., C1-C15 alkyl). In certain embodiments, an alkyl comprises one to thirteen carbon atoms (e.g., C1-C13 alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (e.g., C1-C8alkyl). In other embodiments, an alkyl comprises one to six carbon atoms (e.g., C1-C6 alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (e.g., C1- C5 alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (e.g., C1-C4 alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (e.g., C1-C3alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (e.g., C1-C2alkyl). In other embodiments, an alkyl comprises one carbon atom (e.g., C1 alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (e.g., C5-C15 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (e.g., C5-C8alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (e.g., C2-C5 alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (e.g., C3-C5 alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl),1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), and 1-pentyl (n-pentyl). The alkyl is attached to the rest of the molecule by a single bond. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)- N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2(where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0030] “Alkyl-OH” or “hydroxyalkyl” refers to an alkyl as defined above, wherein one or more hydrogen atoms are replaced by -OH. For example, “C1-C6 alkyl-OH” or “hydroxyalkyl” refers to a C1-C6alkyl which is substituted by one or more -OH groups. An alkyl-OH or hydroxyalkyl may contain multiple hydroxy groups that are attached to the same carbon atom or to multiple carbon atoms. Examples of hydroxyalkyl include, e.g., -CH2OH, -CH2CH2OH, and -CH2CH2C(CH3)2OH.

[0031] “Alkoxy” refers to a radical bonded through an oxygen atom of the formula -O-alkyl, where alkyl is as defined above.

[0032] “Alkenyl” refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. In certain embodiments, an alkenyl comprises two to eight carbon atoms. In other embodiments, an alkenyl comprises two to four carbon atoms. The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2,-N(Ra)C(O)ORa, -OC(O)- N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2 (where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0033] “Alkynyl” refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, having from two to twelve carbon atoms. In certain embodiments, an alkynyl comprises two to eight carbon atoms. In other embodiments, an alkynyl has two to four carbon atoms. The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)- N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2 (where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0034] “Aryl” refers to an aromatic monocyclic or multicyclic hydrocarbon ring systemradical having fromfive to eighteen carbon atoms, where at least one of the rings in the ring system is aromatic. Aryl includes, but is not limited to, phenyl, fluorenyl, indanyl, indenyl, tetralinyl, and naphthalenyl. Unless stated otherwise specifically in the specification, the term “aryl” or the prefix “ar” (such as in “aralkyl”) is meant to include aryl radicals optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2 (where t is 1 or 2), where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

[0035] “Aralkyl” refers to a radical of the formula -Rc-aryl where Rcis alkylene, for example, methylene, ethylene, and the like. The alkylene part of the aralkyl radical is optionally substituted as described above for alkyl. The aryl part of the aralkyl radical is optionally substituted as described above for aryl.

[0036] “Aralkenyl” refers to a radical of the formula -Rd-aryl where Rdis alkenylene. The aryl part of the aralkenyl radical is optionally substituted as described above for aryl. The alkenylene part of the aralkenyl radical is optionally substituted as defined above for alkenyl.

[0037] “Aralkynyl” refers to a radical of the formula -Re-aryl, where Reis alkynylene. The aryl part of the aralkynyl radical is optionally substituted as described above for aryl. Thealkynylene part of the aralkynyl radical is optionally substituted as defined above for alkynyl.

[0038] “Carbocyclyl” refers to a non aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, having from three to fifteen carbon atoms. In certain embodiments, a carbocyclyl has five to twelve carbon atoms (a five to twelve-membered carbocyclyl). In certain embodiments, a carbocyclyl has three to ten carbon atoms (a three to ten-membered carbocyclyl). In other embodiments, a carbocyclyl has five to seven carbon atoms (a five to seven-membered carbocyclyl). The carbocyclyl is attached to the rest of the molecule by a single bond. Carbocyclyl may be saturated (i.e., containing single C-C bonds only) or unsaturated (i.e., containing one or more C-C double bonds or triple bonds). A fully saturated carbocyclyl radical is also referred to as “cycloalkyl”. Examples of monocyclic cycloalkyl include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. An unsaturated carbocyclyl is also referred to as “cycloalkenyl”. Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7 dimethyl bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically in the specification, the term "carbocyclyl" is meant to include carbocyclyl radicals that are optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)- N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2 (where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each Rb is independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

[0039] “Carbocyclylalkyl” refers to a radical of the formula -Rc-carbocyclyl where Rcis alkylene. The alkylene chain and the carbocyclyl radical are optionally substituted as defined above for alkyl and carbocyclyl, respectively.

[0040] “Carbonyl” refers to a radical of the formula -C(O)RxRy, wherein Rxand Ryare independently selected from -OH, halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -Ra, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra) C(O)ORa, -OC(O)- N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2 (where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0041] “Deuteroalkyl” refers to alkyl, as defined above, wherein one or more hydrogen atoms is replaced by a corresponding number of deuterium atoms, e.g., -CD3, -CHD2, -CH2D, and the like.

[0042] “Ene” or “enyl,” when used as a suffix herein, means that the group being modified with the suffix is attached to the rest of the molecule through two or more points of attachment (typically, two), e.g., alkylene, heterocyclyene, carbocyclylene, arylene, heteroarylene, etc., wherein alkyl, heterocyclyl, carbocyclyl, aryl, and heteroaryl, respectively, are as defined herein. The group may be attached to the rest of the molecule through any two suitable atoms in the group.

[0043] “Halo” or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halo is chloro or fluoro. In some embodiments, halo is fluoro.

[0044] “Haloalkyl” refers to an alkyl, as defined above, that is substituted by one or more halo, as defined above, e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. In some embodiments, haloalkyl has one to six carbon atoms and is substituted by one or more halo (C1- C6 haloalkyl), or haloalkyl has one to five carbon atoms and is substituted by one or more halo (C1-C5 haloalkyl), or haloalkyl has one to three carbon atoms and is substituted by one or more halo (C1-C3haloalkyl). The halo radicals may be all the same, or the halo radicals may be different.

[0045]

[0046] “Heterocyclyl” refers to a 3 to 18 membered non-aromatic ring radical that comprises two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. Unless stated otherwise specifically in the specification, the heterocyclyl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused, bridged, or spirocyclic ring systems. The heteroatoms in the heterocyclyl radical may be optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocyclyl radical is partially or fully saturated. The heterocyclyl may be attached to the rest of the molecule through any atom of the ring(s). Examples of heterocyclyl include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, azetidinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2 oxopiperazinyl, 2 oxopiperidinyl, 2 oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4 piperidonyl, pyrrolidinyl, pyrazolidinyl, 2,6-diazaspiro[3.4]octanylene, 2,8-diazaspiro[4.5]decanylene, 8-azabicyclo[3.2.1]octanylene, octahydro-1H-pyrrolo[3,2-c]pyridinylene, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1 oxo thiomorpholinyl, and 1,1 dioxo thiomorpholinyl. Unless stated otherwise specifically in the specification, the term "heterocyclyl" is meant to include heterocyclyl radicals as defined above that are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2(where t is 1 or 2), where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

[0047] "Nitrogen-containing heterocyclyl” refers to a heterocyclyl, as defined above, containing at least one nitrogen, e.g., N-heterocyclyl, C-heterocyclyl. In some embodiments, nitrogen-containing heterocyclyl is N-heterocyclyl.

[0048] “N-heterocyclyl” or “N-attached heterocyclyl” refers to heterocyclyl, as defined above, containing at least one nitrogen and where the point of attachment of the heterocyclyl to the rest of the molecule is through a nitrogen atom in the heterocyclyl. An N-heterocyclyl radical is optionally substituted as described above for heterocyclyl. Examples of N- heterocyclyl include, but are not limited to, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, 1- pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl. When “N-heterocyclyl” is used in the context of N-heterocyclylene, a nitrogen serves as one point of attachment of the heterocyclylene to the rest of the molecule. Any other atom present in the heterocyclene ring may serve as a second point of attachment to the rest of the molecule.

[0049] “C-heterocyclyl” or “C-attached heterocyclyl” refers to heterocyclyl, as defined above, containing at least one heteroatom and where the point of attachment of the heterocyclyl to the rest of the molecule is through a carbon atom in the heterocyclyl. A C-heterocyclyl radical is optionally substituted as described above for heterocyclyl. Examples of C- heterocyclyl include, but are not limited to, 2-morpholinyl, 2- or 3- or 4-piperidinyl, 2- piperazinyl, 2- or 3-pyrrolidinyl, and the like.

[0050] “Heterocyclylalkyl” refers to a radical of the formula -Rc-heterocyclyl where Rcis alkylene. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkylene at the nitrogen atom. The alkylene part of the heterocyclylalkyl isoptionally substituted as defined above for alkyl. The heterocyclyl part of the heterocyclylalkyl is optionally substituted as defined above for heterocyclyl.

[0051] “Heterocyclylalkoxy” refers to a radical bonded through an oxygen atom of the formula -O-Rcheterocyclyl where Rcis alkylene. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkylene at the nitrogen atom. The alkylene part of the heterocyclylalkoxy is optionally substituted as defined above for alkyl. The heterocyclyl part of the heterocyclylalkoxy is optionally substituted as defined above for heterocyclyl.

[0052] “Heteroaryl” refers to a 3 to 18 membered monocyclic, bicyclic, tricyclic, or tetracyclic ring system radical consisting of two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur, where at least one of the rings in the ring system is aromatic. Heteroaryl includes fused and bridged ring systems. The heteroatom(s) in the heteroaryl radical is optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl is attached to the rest of the molecule through any atom of the ring(s). Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H- benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e. thienyl). Unless stated otherwise specifically in the specification, the term “heteroaryl” is meant to include heteroaryl radicals as defined above which are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2(where t is 1 or 2), where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

[0053] "Nitrogen-containing heteroaryl” refers to a heteroaryl, as defined above, containing at least one nitrogen, e.g., N-heteroaryl, C-heteroaryl.

[0054] “N-heteroaryl” refers to a heteroaryl as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl to the rest of the molecule is through a nitrogen atom in the heteroaryl ring system. An N-heteroaryl is optionally substituted as described above for heteroaryl. When “N-heteroaryl” is used in the context of N- heteroarylene, a nitrogen serves as one point of attachment of the heteroarylene to the rest of the molecule. Any other atom present in the heteroarylene ring may serve as a second point ofattachment to the rest of the molecule.

[0055] “C-heteroaryl” refers to a heteroaryl radical as defined above where the point of attachment of the heteroaryl to the rest of the molecule is through a carbon atom in the heteroaryl ring system. A C-heteroaryl is optionally substituted as described above for heteroaryl.

[0056] “Heteroarylalkyl” refers to a radical of the formula -Rc-heteroaryl, where Rcis alkylene. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkylene at the nitrogen atom. The alkylene part of the heteroarylalkyl is optionally substituted as defined above for alkyl. The heteroaryl part of the heteroarylalkyl is optionally substituted as defined above for heteroaryl.

[0057] “Heteroarylalkoxy” refers to a radical bonded through an oxygen atom of the formula -O-Rcheteroaryl, where Rcis alkylene. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkylene at the nitrogen atom. The alkylene part of the heteroarylalkoxy is optionally substituted as defined above for alkyl. The heteroaryl part of the heteroarylalkoxy is optionally substituted as defined above for heteroaryl.

[0058] Embodiments of the disclosure are meant to encompass pharmaceutically acceptable salts, tautomers, isotopologues, stereoisomers, and mixtures of stereoisomers of the compounds provided herein, such as the compounds of Formula (I).

[0059] As used herein, the term “pharmaceutically acceptable salt(s)” refers to a salt prepared from a pharmaceutically acceptable non-toxic acid or base including an inorganic acid and base and an organic acid and base. Suitable pharmaceutically acceptable base addition salts of the compounds of formula (I) include, but are not limited to metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, N,N’-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methyl-glucamine) and procaine. Suitable non-toxic acids include, but are not limited to, inorganic and organic acids such as acetic, alginic, anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, formic, fumaric, furoic, galacturonic, gluconic, glucuronic, glutamic, glycolic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phenylacetic, phosphoric, propionic, salicylic, stearic, succinic, sulfanilic, sulfuric, tartaric acid, and p-toluenesulfonic acid. Specific non-toxic acids include hydrochloric, hydrobromic, maleic, phosphoric, sulfuric, and methanesulfonic acids. Examples of specific salts thus include hydrochloride, formic, and mesylate salts. Others are well-known in the art, see for example, Remington’s Pharmaceutical Sciences, 18theds., Mack Publishing, Easton PA (1990) orRemington: The Science and Practice of Pharmacy, 19theds., Mack Publishing, Easton PA (1995).

[0060] As used herein and unless otherwise indicated, the term “stereoisomer” or “stereoisomerically pure” means one stereoisomer of a particular compound that is substantially free of other stereoisomers of that compound. For example, a stereoisomerically pure compound having one chiral center will be substantially free of the opposite enantiomer of the compound. A stereoisomerically pure compound having two chiral centers will be substantially free of other diastereomers of the compound. A typical stereoisomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomers of the compound, greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, or greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound. The compounds disclosed herein can have chiral centers and can occur as racemates, individual enantiomers or diastereomers, and mixtures thereof. All such isomeric forms are included within the embodiments disclosed herein, including mixtures thereof.

[0061] The use of stereoisomerically pure forms of the compounds disclosed herein, as well as the use of mixtures of those forms, are encompassed by the embodiments disclosed herein. For example, mixtures comprising equal or unequal amounts of the enantiomers of a particular compound may be used in methods and compositions disclosed herein. These isomers may be asymmetrically synthesized or resolved using standard techniques such as chiral columns or chiral resolving agents. See, e.g., Jacques, J., et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen, S. H., et al., Tetrahedron 33:2725 (1977); Eliel, E. L., Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, S. H., Tables of Resolving Agents and Optical Resolutions p.268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN, 1972); Todd, M., Separation Of Enantiomers : Synthetic Methods (Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2014); Toda, F., Enantiomer Separation: Fundamentals and Practical Methods (Springer Science & Business Media, 2007); Subramanian, G. Chiral Separation Techniques: A Practical Approach (John Wiley & Sons, 2008); Ahuja, S., Chiral Separation Methods for Pharmaceutical and Biotechnological Products (John Wiley & Sons, 2011).

[0062] “Tautomers” refers to isomeric forms of a compound that are in equilibrium with each other. The concentrations of the isomeric forms will depend on the environment the compound is found in and may be different depending upon, for example, whether the compound is a solid or is in an organic or aqueous solution. For example, in aqueous solution, pyrazoles may exhibit the following isomeric forms, which are referred to as tautomers of each other:.

[0063] As readily understood by one skilled in the art, a wide variety of functional groups and other stuctures may exhibit tautomerism and all tautomers of compounds of Formula (I) are within the scope of the present disclosure.

[0064] Polymers or similar indefinite structures arrived at by defining substituents with further substituents appended ad infinitum (e.g., a substituted aryl having a substituted alkyl which is itself substituted with a substituted aryl group, which is further substituted by a substituted heteroalkyl group, etc.) are not intended for inclusion herein. Similarly, the above definitions are not intended to include impermissible substitution patterns (e.g., methyl substituted with 5 fluorines or heteroaryl groups having two adjacent oxygen ring atoms). Such impermissible substitution patterns are well known to the skilled artisan.

[0065] It should also be noted the compounds disclosed herein can contain unnatural proportions of atomic isotopes at one or more of the atoms. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (3H), iodine-125 (125I), sulfur-35 (35S), or carbon-14 (14C), or may be isotopically enriched, such as with deuterium (2H), carbon-13 (13C), or nitrogen-15 (15N). As used herein, an “isotopologue” is an isotopically enriched compound. The term “isotopically enriched” refers to an atom having an isotopic composition other than the natural isotopic composition of that atom. “Isotopically enriched” may also refer to a compound containing at least one atom having an isotopic composition other than the natural isotopic composition of that atom. The term “isotopic composition” refers to the amount of each isotope present for a given atom. Radiolabeled and isotopically encriched compounds are useful as therapeutic agents, e.g., cancer therapeutic agents, research reagents, e.g., binding assay reagents, and diagnostic agents, e.g., in vivo imaging agents. All isotopic variations of the compounds as described herein, whether radioactive or not, are intended to be encompassed within the scope of the embodiments provided herein. In some embodiments, there are provided isotopologues of the compounds disclosed herein, for example, the isotopologues are deuterium, carbon-13, and / or nitrogen-15 enriched compounds. As usedherein, “deuterated”, means a compound wherein at least one hydrogen (H) has been replaced by deuterium (indicated by D or2H), that is, the compound is enriched in deuterium in at least one position.

[0066] The disclosure also includes “deuterated analogs” of compounds described herein in which from 1 to n hydrogens attached to a carbon atom is / are replaced by deuterium, in which n is the number of hydrogens in the molecule. When multiple deuterium atoms are present in a compound, the deuterium atoms may be on the same portion of the molecule (for example, on a single alkyl group or on a single ring) or on different portions of the molecule (for example, on separate alkyl groups or separate rings). Such compounds may exhibit increased resistance to metabolism and thus may be useful for increasing the half-life of any compound when administered to a mammal, particularly a human. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” Trends Pharmacol. Sci.5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogens have been replaced by deuterium.

[0067] It is understood that, independently of stereoisomerical or isotopic composition, each compound disclosed herein can be provided in the form of any of the pharmaceutically acceptable salts discussed herein. Equally, it is understood that the isotopic composition may vary independently from the stereoisomerical composition of each compound referred to herein. Further, the isotopic composition, while being restricted to those elements present in the respective compound or salt thereof disclosed herein, may otherwise vary independently from the selection of the pharmaceutically acceptable salt of the respective compound.

[0068] It should be noted that if there is a discrepancy between a depicted structure and a name for that structure, the depicted structure is to be accorded more weight.

[0069] “Treating” as used herein, means an alleviation, in whole or in part, of a disorder, disease or condition, or one or more of the symptoms associated with a disorder, disease, or condition, or slowing or halting of further progression or worsening of those symptoms, or alleviating or eradicating the cause(s) of the disorder, disease, or condition itself. In one embodiment, the disorder is a cancer, as described herein, or a symptom thereof.

[0070] “Preventing” as used herein, means a method of delaying and / or precluding the onset, recurrence or spread, in whole or in part, of a disorder, disease or condition; barring a subject from acquiring a disorder, disease, or condition; or reducing a subject’s risk of acquiring a disorder, disease, or condition. In one embodiment, the disorder is a cancer, as described herein, or symptoms thereof.

[0071] The term “effective amount” in connection with a compound disclosed herein means an amount capable of treating or preventing a disorder, disease or condition, or symptoms thereof, disclosed herein.

[0072] The term “subject” or “patient” as used herein include an animal, including, but not limited to, an animal such a cow, monkey, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit or guinea pig, in one embodiment a mammal, in another embodiment a human. In one embodiment, a subject is a human having or at risk for having a BCL6 mediated disease, or a symptom thereof.

[0073] Although various features of the technology described herein may be described in the context of a single embodiment, the features may also be provided separately or in any suitable combination. Conversely, although the technology may be described herein in the context of separate embodiments for clarity, the technology may also be implemented in a single embodiment. Compounds

[0074] In one aspect, provided herein is a compound of Formula (I):, or a pharmaceutically acceptable salt thereof, wherein: Ring A is a four to twelve-membered nitrogen-containing heterocyclylene, five to twelve-membered carbocyclylene, five to six-membered nitrogen-containing heteroarylene, phenylene,absent, wherein Ring A, when present, is substituted with (R10)x; each R10is independently halo, C1-C6alkyl, C1-C6alkoxy, C1-C6hydroxyalkyl, or C1-C6 haloalkyl, or two R10, taken together with a carbon atom to which they are both attached, form oxo; x is 0, 1, 2, 3, or 4; L1is N(R11) or N(R11)CH2C(O), or is absent; R11is hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, or C1-C6 haloalkyl; L2is -(CH2)yN(R12)-, -O(CH2)y-, -N(R12)C(O)-, -C(O)N(R12)(CH2)z-, -C(O)N(R12)(CH2)zN(R12)-, -C(O)N(R12)(CH2)zO-, -(CH2)zC(O)N(R12)-, or (CH2)z,or is absent; each R12is independently hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 deuteroalkyl, or C1-C6 haloalkyl; y is 0 or 1; z is 1, 2, 3, 4, or 5; R1is hydrogen or C1-C6 alkyl; R2is C1-C6alkyl; R3is halo or cyano; ,X1is C(R13) or N; X2, X3, and X4are C(H); or X2and X4are C(H), and X3is N; or X2is N and X3and X4are C(H); or X2and X3are C(H) and X4is N; R13is hydrogen or C1-C6alkyl;each R14is independently halo; R52is hydrogen or C1-C6 alkyl; and p is 0, 1, 2, or 3.

[0075] In another aspect, provided herein is a compound of Formula (II):, or a pharmaceutically acceptable salt thereof, wherein values for the variables (e.g., Ring A, L2, R1, R2, R3, R4) are as described with respect to a compound of Formula (I) or elsewhere herein.

[0076] In yet another aspect, provided herein is a compound of Formula (III):, or a pharmaceutically acceptable salt thereof, wherein values for the variables (e.g., R1, R2, R3, R4, R10, R11, x ) are as described with respect to a compound of Formula (I) or elsewhere herein.

[0077] In another aspect, provided herein is a compound of Formula (IV):, or a pharmaceutically acceptable salt thereof, wherein values for the variables (e.g., Ring A, R1, R2, R3, R4) are as described with respect to a compound of Formula (I) or elsewhere herein.

[0078] In some embodiments, Ring A is a four to twelve-membered nitrogen-containing heterocyclylene or five to six-membered nitrogen-containing heteroarylene, substituted with (R10)x. In some embodiments, Ring A is a four to twelve-membered nitrogen-containing heterocyclylene substituted with (R10)x. For example, in some embodiments, Ring A is a four to six-membered monocyclic nitrogen-containing heterocyclylene, eight to ten-membered spirocyclic nitrogen-containing heterocyclylene, or eight to ten-membered fused bicyclic nitrogen-containing heterocyclylene, substituted with (R10)x. In a particular embodiment, Ring A is a four to six-membered monocyclic nitrogen-containing heterocyclylene or eight to ten- membered spirocyclic nitrogen-containing heterocyclylene, substituted with (R10)x.

[0079] In some embodiments, Ring A is a five to twelve-membered carbocyclylene or phenylene.

[0080] In some embodiments, Ring A is piperidinylene, piperazinylene, azetidinylene, pyrrolindinylene, 2,6-diazaspiro[3.4]octanylene, 2,8-diazaspiro[4.5]decanylene, 8-azabicyclo[3.2.1]octanylene, octahydro-1H-pyrrolo[3,2-c]pyridinylene, cyclohexenylene, pyrazolylene, or, substituted with (R10)x. In some embodiments, Ring A is piperidinylene, piperazinylene, 2,8-diazaspiro[4.5]decanylene, phenylene, or, substituted with (R10)x. In a particular embodiment, Ring A is piperidinylene or piperazinylene, substituted with (R10)x. In a more particular embodiment, Ring A is piperidinylene substituted with (R10)x.

[0081] In alternative embodiments, Ring A is absent.

[0082] In some embodiments, each R10is independently halo, C1-C6 alkyl, or C1-C6 hydroxyalkyl, or two R10, taken together with a carbon atom to which they are both attached, form oxo. In a particular embodiment, each R10is independently fluoro, methyl, or hydroxymethyl, or two R10, taken together with a carbon atom to which they are both attached, form oxo. In some embodiments, each R10is independently halo, C1-C6 alkyl, or C1-C6 alkoxy. In a particular embodiment, each R10is independently fluoro, methyl, or methoxy. In some embodiments, each R10is independently halo, C1-C6 alkyl, C1-C6 hydroxyalkyl, or C1-C6 alkoxy, or two R10, taken together with a carbon atom to which they are both attached, form oxo. In a particular embodiment, each R10is independently fluoro, methyl, hydroxymethyl, or methoxy, or two R10, taken together with a carbon atom to which they are both attached, form oxo.

[0083] In some embodiments, x is 0, 1, or 2. In some embodiments, x is 0 or 1. In a particular embodiment, x is 0. In another particular embodiment, x is 1.

[0084] In some embodiments, L1is N(R11). In some embodiments, L1is absent.

[0085] In some embodiments, R11is hydrogen, C1-C6 alkyl, or C1-C6 hydroxyalkyl. In some embodiments, R11is hydrogen or C1-C6 alkyl. In a particular embodiment, R11is hydrogen or methyl. In a more particular embodiment, R11is hydrogen. In another embodiment, R11is methyl. In some embodiments, R11is C1-C6 alkyl, C1-C6 hydroxyalkyl, or C1-C6 haloalkyl.

[0086] In some embodiments, L2is -(CH2)yN(R12)-, -O(CH2)y-, -N(R12)C(O)-, -C(O)N(R12)(CH2)z-, -C(O)N(R12)(CH2)zN(R12)-, -(O)N(R12)(CH2)zO-, -(CH2)zC(O)N(R12)-, or (CH2)z. In some embodiments, L2is -(CH2)yN(R12)-, -O(CH2)y-, -N(R12)C(O)-, or -(CH2)zC(O)N(R12)- In a particular embodiment L2is (CH2)yN(R12) or -O(CH2)y- In a moreparticular embodiment, L2is -N(H)-, -N(CH3)-, -N(CH2CH2OH)-, -CH2N(H)-, -CH2N(CH3)-, -CH2N(CD3)-, -O-, -OCH2-, -N(H)C(O)-, -C(O)N(H)CH2-, -C(O)N(H)CH2CH2N(H)-, -C(O)N(H)CH2CH2CH2N(H)-, -C(O)N(H)CH2CH2O-, -CH2C(O)N(H)-, or -CH2-. In some embodiments, L2is -N(H)-, -N(CH3)-, -CH2N(H)-, -O-, -N(H)C(O)-, or -CH2C(O)N(H)-. In some embodiments, L2is -O- or -CH2-. In some embodiments, L2is -N(H)- or -N(CH3)-.

[0087] In alternative embodiments, L2is absent.

[0088] In some embodiments, each R12is independently hydrogen, C1-C6alkyl, C1-C6hydroxyalkyl, or C1-C6 deuteroalkyl. In a particular embodiment, each R12is independently hydrogen, methyl, hydroxyethyl, or -CD3. In some embodiments, each R12is independently hydrogen or C1-C6alkyl. In a particular embodiment, each R12is independently hydrogen or methyl. In a more particular embodiment, each R12is hydrogen. In another embodiment, each R12is methyl. In some embodiments, each R12is independently C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 deuteroalkyl, or C1-C6 haloalkyl.

[0089] In some embodiments, y is 0. In some embodiments, y is 1.

[0090] In some embodiments, z is 1, 2, 3, or 4. In some embodiments, z is 1, 2, or 3. In some embodiments, z is 1 or 2. In some embodiments, z is 1.

[0091] In some embodiments, R1is hydrogen or methyl. In a particular embodiment, R1is hydrogen or methyl and R2is methyl. In a more particular embodiment, R1is hydrogen and R2is methyl. In another embodiment, R1is methyl and R2is methyl.

[0092] In some embodiments, R2is methyl.

[0093] In some embodiments, R3is chloro or cyano. In a particular embodiment, R3is chloro. In another particular embodiment, R3is cyano.

[0094] In some embodiments, R4is: ,more particular embodiment,

[0095] In some embodiments, R4is:another particular embodiment,.

[0096] In some embodiments, X2, X3and X4are C(H). In some embodiments, one of X2,X3and X4is N, and the other two are C(H). In some embodiments, X2and X4are C(H), and X3is N. In some embodiments, X2is N and X3and X4are C(H). In some embodiments, X2and X3are C(H) and X4is N.

[0097] In some embodiments, R13is hydrogen or methyl. In a particular embodiment, R13is hydrogen.

[0098] In some embodiments, R14is fluoro.

[0099] In some embodiments, R52is hydrogen or methyl. In a particular embodiment, R52is hydrogen. In another particular embodiment, R52is methyl.

[0100] In some embodiments, p is 0 or 1. In a particular embodiment, p is 0. In another particular embodiment, p is 1.

[0101] It is understood that any of the compounds described herein can include replacement of one or more hydrogen atoms by deuterium. For example, any one or more of the substituents of Formula (I) can be deuterated, such as one or more of Ring A, L1, L2, R1, R2, R4, R10, R11, R12, R13.

[0102] In the descriptions herein, it is understood that all descriptions, variations, embodiments, or aspects of Formula (I), where applicable, apply equally to other formulae detailed herein, and are equally described, the same as if each and every description, variation, embodiment, or aspect were separately and individually listed. It is also understood that all descriptions, variations, embodiments, or aspects of Formula (I), where applicable, apply equally to other formulae detailed herein, and are equally described, the same as if each and every description, variation, embodiment, or aspect were separately and individually listed for all formulae. For example, all descriptions, variations, embodiments, or aspects of Formula (I), where applicable, apply equally to any of the formulae as detailed herein, such as Formulae (II), (III), (IV), and are equally described, the same as if each and every description, variation, embodiment, or aspect were separately and individually listed for all formulae.

[0103] In some embodiments, provided is a compound selected from the compounds in Table 1 or a pharmaceutically acceptable salt thereof. Although certain compounds described in the present disclosure, including in Table 1, are presented as specific stereoisomers and / or in a non-stereochemical form, it is understood that any or all stereochemical forms, including any enantiomeric or diastereomeric forms, and any tautomers or other forms of any of the compounds of the present disclosure, including in Table 1, are herein described.or a pharmaceutically acceptable salt thereof.

[0104] In some embodiments, the compound isacceptable salt thereof. In some embodiments, the compound ispharmaceutically acceptable salt thereof.

[0105] All compounds of Formula (I) that exist in free base or acid form can be converted to their pharmaceutically acceptable salts by treatment with the appropriate inorganic base or acid or organic base or acid by methods known to one skilled in the art. Salts (e.g., pharmaceutically acceptable salts) of the compounds of Formula (I) can be converted to their free base or free acid form by standard techniques.

[0106] The compounds described herein can be made using conventional organic syntheses and commercially available starting materials, or the methods provided herein. By way of example and not limitation, compounds of Formula (I) can be prepared as outlined in the Schemes and Examples set forth herein. It should be noted that one skilled in the art would know how to modify the procedures set forth herein to arrive at the desired products.wherein R1, R2, and R3 are as described for R1, R2, and R3, respectively, for compounds of Formula (I); and LG is a leaving group.T CP00-0500-77210.oNtekcoDyenrottA.2 e mehcST Cf-1 dPn00-0500-77210.oNtekcoDya oe,rcu nenN, so, Br attx) s;nAdnH(paCuB sorO g )221,i g2H RZ;niC 01, ) tOc (- R )=et;( o rI(Crrpo,lyal oeu , 1rahte mNro,)G,ly FH(Phtf Cdn eossdi a mG,n Y u;P H; ,eo -lpNr O- pm moo ) raxcH o,-ero (f C3ro,sH yiCf,lleX N vi ;- y,kltacH - HoepOl2as) e2N- hHsi6'C 4r, C -1X(-rM;C dno3a,Hr,l o,yO-lhr y2Xt,e o,l,kl3aoXyrhHrCeot tfeHuedem,N -d6biH ,2C- rsiH1cse21N-C, ds Rs 1G a,ei P-elpM;O 7ramao-lxm oyk6X,errlaob .)s6XfaCH(5,,)-1N XI( hcCrni a us,loerlu, yehmp krl Couo asi"FrgC6XT CP00-0500-77210.oNtekcoDyenrottA.3 e mehcSTrCo -6P C00-0500-77210.oNtekcoDy se i ,puolas6"nGro ;rtgC XtN - Ar g 1 do,niC,na;)3vaneG HelgC( a oP srdNrCi y,)Ghos C H(L; s)’i321i'C HR X1siC(;n;l, NB yXzelrsanepo, hbmaxN s,)cu isneroH(,sBp ;nf CuB ,) sI(i org O )22aZlu;)gnH OitC mro=(ce(- Cto rFf rrpo,oo, elysdN rahtnu,) 1e,opH(Gly CPhtmsdinaeocY Gm,rof ;P H,dN ;- ele rbo pir )O-rm csH(o,axedC -3erssiHofaX C r N,le;a )2-,-yklxH dnC(HaoNla -ah,Csi621ro 'C 0R)M - ;1C 1,H(HrR CsO o,1,i' -rlyXo,klniWer;) 3HaoreHehC(C HtuC NedT.CPpu00or-0g50gn0-itc7e7t2o10.oNtekcoDyenrottAN,)H(NNsiM;)I(alumroFfosdnuopm ocrofdebircsedsaeraxdn.041aeRm nieehrcehST CP00-0500-77210.oNtekcoDyenrottA.5 e mehcST CP00-0500-77210.oNtekcoDyenrottA.4- 1semehcS nidenifedsaeraselbairavehtrofseulavnierehTCPd0n0a-,0tn500-77210.oNtekcoDyenrottAmtrroaFpf so m sdronfudoephcmaotctar sofidXebhicrihcswedotsaneer gaortxidnneh2a t,1,tnR,es.061baseR im nie X e hrcenhehSTCPd0n0a-,0tn500-77210.oNtekcoDyenrottAalu fo mtrroaFpf so m sdronfudoephcmaotctar sofidXebhicrihcswedotsaneer gaortxidnneaht21, ,tnR,es.01ba7Rseim nie X e hrcenhehSTCP00-0500-77210.oNtekcoDyenrottA. 7dna,6,1semehcS nidenifedsaeraselbairavehtrofse .u8laevm nieehrcehS

[0107] As outlined in Scheme 1, compounds e can be synthesized by coupling compounds a and compounds b to form compounds c, which are then reduced to form compounds d, and coupled to form compounds e.

[0108] Scheme 2 provides routes for synthesizing compounds A, B, and C. Compounds g (such as any of compounds g-1 to g-8) can be coupled to compounds h to afford compounds i. Deprotection and further reduction of compounds i forms compounds j, which are optionally deprotected to form compounds A. Compounds i, wherein M’ is N(H), can be methylated to form compounds k. Deprotection and further reduction of compounds k forms compounds l, which are optionally deprotected to form compounds B. Alternatively, compounds g (such as any of compounds g-1 to g-8) can be coupled to compounds m to afford compounds n. Deprotection and further reduction of compounds n forms compounds o, which are optionally subjected to deprotection of the amine to form compounds C.

[0109] Scheme 3 provides the synthesis of compounds D, E, and F. Compounds p (such as any of compounds p-1 to p-5) can be coupled to compounds q to afford compounds r, which are optionally deprotected to form compounds D. Compounds r, wherein W’ is N(H), can be methylated to form compounds s. Optional deprotection of compounds s forms compounds E. Alternatively, compounds p (such as any of compounds p-1 to p-5) can be coupled to compounds t to form compounds u, which are optionally subsequently deprotected to form compounds F.

[0110] Scheme 4 provides routes for synthesizing compounds G and H. Compounds v can be coupled with compounds w to form compounds x, which are optionally subsequently deprotected to form compounds G. Alternatively, compounds v can be coupled with compounds y to form compounds z, which are optionally subsequently deprotected to form compounds H.

[0111] Scheme 5 provides routes for synthesizing compounds A’ to H’. Compounds A to H are coupled with compounds e to form compounds A’ to H’, respectively.

[0112] Schemes 6 and 7 provide routes for synthesizing compounds I, J, K, L, and M. In Scheme 6, compounds cc are coupled with compounds bb to form compounds aa, which are optionally deprotected to form compounds I. Alternatively, compounds cc are coupled with compounds dd to form compounds ee, which are optionally deprotected to form compounds J. Compounds ee, wherein R12is H, can be optionally methylated to form compounds ff, which are optionally deprotected to form compounds K. In Scheme 7, compounds gg are coupled with compounds hh to form compounds ii, which are optionally subsequently deprotected to form compounds L. Alternatively, compounds gg are coupled with compounds jj to form compounds kk, which are optionally subsequently deprotected to form compounds M.

[0113] Scheme 8 provides routes for synthesizing compounds J’ to M’. Compounds J to M are coupled with compounds e to form compounds J’ to M’, respectively. Methods of Use

[0114] Embodiments of the present disclosure provide a method for modulating BCL6 in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound provided herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof). Modulation (e.g., inhibition or activation) of BCL6 can be assessed and demonstrated by a wide variety of ways known in the art. Kits and commercially available assays can be utilized for determining whether and to what degree BCL6 has been modulated (e.g., inhibited or activated).

[0115] In one aspect, provided herein is a method of modulating BCL6 comprising contacting BCL6 with an effective amount of a compound provided herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof). In some embodiments, the compound inhibits BCL6. In some embodiments, the compound causes degradation of BCL6.

[0116] In some embodiments, the compound provided herein modulates the activity of BCL6 by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, the compound provided herein modulates the activity of BCL6 by about 1-100%, 5-100%, 10-100%, 15-100%, 20- 100%, 25-100%, 30-100%, 35-100%, 40-100%, 45-100%, 50-100%, 55-100%, 60-100%, 65- 100%, 70-100%, 75-100%, 80-100%, 85-100%, 90-100%, 95-100%, 5-95%, 5-90%, 5-85%, 5- 80%, 5-75%, 5-70%, 5-65%, 5-60%, 5-55%, 5-50%, 5-45%, 5-40%, 5-35%, 5-30%, 5-25%, 5- 20%, 5-15%, 5-10%, 10-90%, 20-80%, 30-70%, or 40-60%.

[0117] Also provided in certain embodiments of the present disclosure is a method for degrading BCL6 in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound provided herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof). Degradation of BCL6 can be assessed and demonstrated by a wide variety of ways known in the art. Kits and commercially available assays, including cell-based assays, can be utilized for determining whether and to what degree BCL6 has been degraded.

[0118] In one aspect, provided herein is a method of degrading BCL6 comprising contacting BCL6 with an effective amount of a compound provided herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof). In some embodiments, the compound partially degrades BCL6. In some embodiments, the compound fully degrades BCL6.

[0119] In some embodiments, a compound provided herein degrades BCL6 by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, a compound provided herein degrades BCL6 by about 1-100%, 5-100%, 10-100%, 15-100%, 20-100%, 25-100%, 30-100%, 35-100%, 40- 100%, 45-100%, 50-100%, 55-100%, 60-100%, 65-100%, 70-100%, 75-100%, 80-100%, 85- 100%, 90-100%, 95-100%, 5-95%, 5-90%, 5-85%, 5-80%, 5-75%, 5-70%, 5-65%, 5-60%, 5- 55%, 5-50%, 5-45%, 5-40%, 5-35%, 5-30%, 5-25%, 5-20%, 5-15%, 5-10%, 10-90%, 20-80%, 30-70%, or 40-60%.

[0120] In another aspect, provided herein is a method for treating a cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound provided herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof). In some embodiments, provided herein is a method for preventing a cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound provided herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof).

[0121] Non-limiting examples of a cancer include squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinomas, renal cell carcinomas, bladder cancer, bowel cancer, breast cancer, cervical cancer, colon cancer, esophageal cancer, cancer of the head, kidney cancer, liver cancer, lung cancer, neck cancer, ovarian cancer, pancreatic cancer, prostate cancer, stomach cancer, leukemia, benign lymphoma, malignant lymphoma, Burkitt's lymphoma, Non-Hodgkin's lymphoma (NHL), benign melanoma, malignant melanomas, myeloproliferative diseases, sarcomas, Ewing's sarcoma, hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas, peripheral neuroepithelioma, synovial sarcoma, gliomas, astrocytomas, oligodendrogliomas, ependymomas, gliobastomas, neuroblastomas, ganglioneuromas, gangliogliomas, medulloblastomas, pineal cell tumors, meningiomas, meningeal sarcomas, neurofibromas, and Schwannomas, prostate cancer, uterine cancer, testicular cancer, thyroid cancer, astrocytoma, stomach cancer, melanoma, carcinosarcoma, Hodgkin's disease, Wilms' tumor, teratocarcinomas, T-lineage Acute lymphoblastic Leukemia (T-ALL), T-lineage lymphoblastic Lymphoma (T-LL), Peripheral T- cell lymphoma, Adult T- cell Leukemia, Pre-B ALL, Pre-B Lymphomas, Diffuse Large B-cell Lymphoma, B-cell ALL, Philadelphia chromosome positive ALL, Philadelphia chromosome positive CML, follicular lymphoma, marginal zone lymphoma, mantle cell lymphoma, Waldenstroms Macroglobulinemia, Chronic Lymphocytic leukemia (CLL), Small Lymphocytic Lymphoma (SLL), intravascular large B-cell lymphoma, B-cell leukemia, chronic myeloid leukemia, and non-small cell lung cancer.

[0122] In some embodiments, administering a compound provided herein to a subject in need thereof diminishes the extent of the cancer (such as tumor size, tumor growth rate, metastasis) in the subject. In some embodiments, administering a compound provided herein to a subject in need thereof stabilizes the cancer (prevents or delays the worsening of the cancer). In some embodiments, administering a compound provided herein to a subject in need thereof delays the occurrence or recurrence of the cancer. In some embodiments, administering a compound provided herein to a subject in need thereof slows the progression of the cancer. In some embodiments, administering a compound provided herein to a subject in need thereof provides a partial remission of the cancer. In some embodiments, administering a compound provided herein to a subject in need thereof provides a total remission of the cancer. In some embodiments, administering a compound provided herein to a subject in need thereof decreases the dose of one or more other medications required to treat the cancer. In some embodiments, administering a compound provided herein to a subject in need thereof enhances the effect of another medication used to treat the cancer. In some embodiments, administering a compound provided herein to a subject in need thereof delays the progression of the cancer. In some embodiments, administering a compound provided herein to a subject in need thereof increases the quality of life of the subject having a cancer. In some embodiments, administering a compound provided herein to a subject in need thereof prolongs survival of a subject having a cancer.

[0123] In some aspects, provided herein is a method of slowing progression of a cancer in a subject, the method comprising administering an effective amount of a compound provided herein to the subject. In some embodiments, provided herein is a method of stabilizing a cancer in a subject, the method comprising administering an effective amount of a compound provided herein to the subject. In some embodiments, the method prevents the progression of the cancer. In some embodiments, the method delays the progression of the cancer. In some embodiments, the method provides a partial or total remission of the cancer.

[0124] In another aspect, provided herein is a method of delaying the occurrence or recurrence of a cancer in a subject, the method comprising administering an effective amount of a compound provided herein to the subject.

[0125] In further aspects, provided herein is a method of decreasing the dose of one or more other medications required to treat a cancer in a subject, the method comprising administering an effective amount of a compound provided herein to the subject. In some embodiments, provided herein is a method of enhancing the effect of another medication used to treat a cancer in asubject, the method comprising administering an effective amount of a compound provided herein to the subject.

[0126] Also provided here is a method of delaying the progression of a cancer in a subject, the method comprising administering an effective amount of a compound provided herein to the subject. In some embodiments, the method increases the quality of life of the subject having a cancer. In some embodiments, the method prolongs survival of the subject having a cancer.

[0127] In a further aspect, provided herein is a method for treating an autoimmune disease in a subject in need thereof, comprising administering to the subject an effective amount of a compound provided herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof). In some embodiments, provided herein is a method for preventing an autoimmune disease in a subject in need thereof, comprising administering to the subject an effective amount of a compound provided herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof).

[0128] Autoimmune diseases can be divided into two categories. Organ-specific autoimmune diseases occur when the immune system targets specific cells, tissues, or organs. Generalized autoimmune diseases occur when the immune system attacks the body without discriminating among different types of tissues or target cells. Examples of organ-specific autoimmune diseases include atopic dermatitis, asthma, insulin dependent diabetes, Hashimoto's thyroiditis, Grave's disease, Pernicious anemia, Myasthenia gravis, Pemphigus vulgaris, and Crohn's disease. Examples of generalized autoimmune diseases include Systemic lupus erythematosus (SLE), Rheumatoid arthritis, Scleroderma, Sarcoidosis, and Guillain-Barré Syndrome (GBS). The present disclosure encompasses treatment of all types of autoimmune disease, including organ-specific and general autoimmune diseases, including, but not limited to, lupus erythematosus, ankylosing spondylitis, Chagas disease, chronic obstructive pulmonary disease, Crohn's Disease, dermatomyositis, diabetes mellitus type 1, endometriosis, Goodpasture's syndrome, Graves' disease, Guillain-Barré syndrome (GBS), Hashimoto's disease, hidradenitis suppurativa, Kawasaki disease, IgA nephropathy, idiopathic thrombocytopenic purpura, interstitial cystitis, mixed connective tissue disease, morphea, multiple sclerosis, myasthenia gravis, narcolepsy, neuromyotonia, pemphigus vulgaris, pernicious anaemia, psoriasis, psoriatic arthritis, polymyositis, primary biliary cirrhosis, relapsing polychondritis, rheumatoid arthritis, sarcoidosis, schizophrenia, scleroderma, Sjögren's syndrome, stiff person syndrome, temporal arteritis, ulcerative colitis, vasculitis, vitiligo, and Wegener's granulomatosis.

[0129] In another aspect, provided herein is a method for treating a TH17-related condition, such as a TH17-related autoimmune condition, in a subject in need thereof, comprising administering to the subject an effective amount of a compound provided herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof).

[0130] In some embodiments, administering a compound provided herein to a subject in need thereof diminishes or reduces the symptoms of the autoimmune disease (such as inflammation, chronic fever, malaise, joint pains, myalgias, and fatigue) in the subject. In some embodiments, administering a compound provided herein to a subject in need thereof shortens or reduces the duration of a symptom of the autoimmune disease. In some embodiments, administering a compound provided herein to a subject in need thereof eliminates the symptoms of the autoimmune disease. In some embodiments, administering a compound provided herein to a subject in need thereof delays the occurrence or recurrence of the autoimmune disease. In some embodiments, administering a compound provided herein to a subject in need thereof slows the progression of the autoimmune disease. In some embodiments, administering a compound provided herein to a subject in need thereof decreases the dose of one or more other medications required to treat the autoimmune disease. In some embodiments, administering a compound provided herein to a subject in need thereof enhances the effect of another medication used to treat the autoimmune disease. In some embodiments, administering a compound provided herein to a subject in need thereof delays the progression of the autoimmune disease. In some embodiments, administering a compound provided herein to a subject in need thereof increases the quality of life of the subject having an autoimmune disease.

[0131] In some aspects, provided herein is a method of slowing progression of an autoimmune disease in a subject, the method comprising administering an effective amount of a compound provided herein to the subject. In some embodiments, provided herein is a method of stabilizing an autoimmune disease in a subject, the method comprising administering an effective amount of a compound provided hereinto the subject. In some embodiments, the method prevents the progression of the autoimmune disease. In some embodiments, the method delays the progression of the autoimmune disease. In some embodiments, the method increases the quality of life of the subject having an autoimmune disease.

[0132] In further aspects, provided herein is a method of decreasing the dose of one or more other medications required to treat an autoimmune disease in a subject, the method comprising administering an effective amount of a compound provided herein to the subject. In some embodiments, provided herein is a method of enhancing the effect of another medication used totreat an autoimmune disease in a subject, the method comprising administering an effective amount of a compound provided herein to the subject. Pharmaceutical Compositions and Routes of Administration

[0133] The compounds disclosed herein can be administered to a subject orally, topically or parenterally in the conventional form of preparations, such as capsules, microcapsules, tablets, granules, powder, troches, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions and emulsions. Suitable formulations can be prepared by methods commonly employed using conventional, organic or inorganic additives, such as an excipient (e.g., sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate or calcium carbonate), a binder (e.g., cellulose, methylcellulose, hydroxymethylcellulose, polypropylpyrrolidone, polyvinylpyrrolidone, gelatin, gum arabic, polyethyleneglycol, sucrose or starch), a disintegrator (e.g., starch, carboxymethylcellulose, hydroxypropylstarch, low substituted hydroxypropylcellulose, sodium bicarbonate, calcium phosphate or calcium citrate), a lubricant (e.g., magnesium stearate, light anhydrous silicic acid, talc or sodium lauryl sulfate), a flavoring agent (e.g., citric acid, menthol, glycine or orange powder), a preservative (e.g, sodium benzoate, sodium bisulfite, methylparaben or propylparaben), a stabilizer (e.g., citric acid, sodium citrate or acetic acid), a suspending agent (e.g., methylcellulose, polyvinyl pyrroliclone or aluminum stearate), a dispersing agent (e.g., hydroxypropylmethylcellulose), a diluent (e.g., water), and base wax (e.g., cocoa butter, white petrolatum or polyethylene glycol). The amount of the compound in the pharmaceutical formulation may be at a level that will produce a desired effect, e.g., an effective amount.

[0134] A compound provided herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be administered once, twice, three, four or more times daily. In general, the compounds disclosed herein are administered one to four times per day (e.g., one; two; three; four; or one to two times per day). In one embodiment, the compound is administered once per day. In another embodiment, the compound is administered twice per day. In yet another embodiment, the compound is administered once or twice per day. In a particular embodiment, doses of 100 mg or less are administered as a once daily dose and doses of more than 100 mg are administered twice daily in an amount equal to one half of the total daily dose.

[0135] A compound provided herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be administered orally. In one embodiment, when administered orally, the compound is administered with a meal and water. In anotherembodiment, the compound is dispersed in water or juice (e.g., apple juice or orange juice) or any other liquid, and administered orally as a solution or a suspension.

[0136] The compounds disclosed herein can also be administered intradermally, intramuscularly, intraperitoneally, percutaneously, intravenously, subcutaneously, intranasally, epidurally, sublingually, intracerebrally, intravaginally, transdermally, rectally, mucosally, by inhalation, or topically to the ears, nose, eyes, or skin. The mode of administration is left to the discretion of the healthcare practitioner, and can depend in part upon the site of the medical condition.

[0137] In one embodiment, provided herein are capsules containing a compound provided herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof) without an additional carrier, excipient or vehicle.

[0138] In another embodiment, provided herein are compositions comprising a compound provided herein (e.g., an effective amount of a compound provided herein, such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable carrier or vehicle, wherein a pharmaceutically acceptable carrier or vehicle can comprise an excipient, diluent, or a mixture thereof. In one embodiment, the composition is a pharmaceutical composition.

[0139] The compositions can be in the form of tablets (e.g., chewable tablets), capsules, solutions, parenteral solutions, troches, suppositories, suspensions and the like. Compositions can be formulated to contain a daily dose, or a convenient fraction of a daily dose, in a dosage unit, which may be a single tablet or capsule or convenient volume of a liquid. In one embodiment, the solutions are prepared from water-soluble salts, such as the hydrochloride salt. In general, all of the compositions are prepared according to known methods in pharmaceutical chemistry. Capsules can be prepared by mixing a compound with a suitable carrier or diluent and filling the proper amount of the mixture in capsules. The usual carriers and diluents include, but are not limited to, inert powdered substances such as starch of many different kinds, powdered cellulose, especially crystalline and microcrystalline cellulose, sugars such as fructose, mannitol and sucrose, grain flours and similar edible powders.

[0140] Tablets can be prepared by direct compression, by wet granulation, or by dry granulation. Their formulations usually incorporate diluents, binders, lubricants and disintegrators as well as the compound. Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride and powdered sugar. Powdered cellulose derivatives are also useful. Typical tablet binders are substances such as starch, gelatin and sugars such as lactose, fructose, glucose andthe like. Natural and synthetic gums are also convenient, including acacia, alginates, methylcellulose, polyvinylpyrrolidine and the like. Polyethylene glycol, ethylcellulose and waxes can also serve as binders.

[0141] A lubricant might be necessary in a tablet formulation to prevent the tablet and punches from sticking in the dye. The lubricant can be chosen from such slippery solids as talc, magnesium and calcium stearate, stearic acid and hydrogenated vegetable oils. Tablet disintegrators are substances that swell when wetted to break up the tablet and release the compound. They include starches, clays, celluloses, algins and gums. More particularly, corn and potato starches, methylcellulose, agar, bentonite, wood cellulose, powdered natural sponge, cation-exchange resins, alginic acid, guar gum, citrus pulp and carboxymethyl cellulose, for example, can be used as well as sodium lauryl sulfate. Tablets can be coated with sugar as a flavor and sealant, or with film-forming protecting agents to modify the dissolution properties of the tablet. The compositions can also be formulated as chewable tablets, for example, by using substances such as mannitol in the formulation.

[0142] When it is desired to administer a compound provided herein as a suppository, typical suppository bases can be used. Cocoa butter is a traditional suppository base, which can be modified by addition of waxes to raise its melting point slightly. Water-miscible suppository bases comprising, particularly, polyethylene glycols of various molecular weights are in wide use.

[0143] The effect of the compound can be delayed or prolonged by proper formulation. For example, a slowly soluble pellet of a compound can be prepared and incorporated in a tablet or capsule, or as a slow-release implantable device. The technique also includes making pellets of several different dissolution rates and filling capsules with a mixture of the pellets. Tablets or capsules can be coated with a film that resists dissolution for a predictable period of time. Even parenteral preparations can be made long-acting, by dissolving or suspending acompound in oily or emulsified vehicles that allow it to disperse slowly in the serum.

[0144] It is understood that the pharmaceutical compositions described herein may include a mixture of compounds described herein, including a racemic mixture of any of the compounds described herein. ENUMERATED EMBODIMENTS

[0145] Embodiment 1. A compound of Formula (I):,or a pharmaceutically acceptable salt thereof, wherein: Ring A is a four to twelve-membered nitrogen-containing heterocyclylene, five to twelve-membered carbocyclylene, five to six-membered nitrogen-containing heteroarylene, phenylene,absent, wherein Ring A, when present, is substituted with (R10)x; each R10is independently halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, or C1- C6haloalkyl, or two R10, taken together with a carbon atom to which they are both attached, form oxo; x is 0, 1, 2, 3, or 4; L1is N(R11) or N(R11)CH2C(O), or is absent; R11is hydrogen, C1-C6alkyl, C1-C6hydroxyalkyl, or C1-C6haloalkyl; L2is -(CH2)yN(R12)-, -O(CH2)y-, -N(R12)C(O)-, -C(O)N(R12)(CH2)z-, -C(O)N(R12)(CH2)zN(R12)-, -C(O)N(R12)(CH2)zO-, -(CH2)zC(O)N(R12)-, or (CH2)z, or is absent; each R12is independently hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 deuteroalkyl, or C1-C6 haloalkyl; y is 0 or 1; z is 1, 2, 3, 4, or 5; R1is hydrogen or C1-C6 alkyl; R2is C1-C6 alkyl; R3is halo or cyano;X1is C(R13) or N; X2, X3, and X4are C(H); or X2and X4are C(H), and X3is N; or X2is N and X3and X4are C(H); or X2and X3are C(H) and X4is N; R13is hydrogen or C1-C6 alkyl; each R14is independently halo; R52is hydrogen or C1-C6 alkyl; and p is 0, 1, 2, or 3.

[0146] Embodiment 2. The compound of embodiment 1, wherein Ring A is a four to twelve-membered nitrogen-containing heterocyclylene.

[0147] Embodiment 3. The compound of embodiment 2, wherein Ring A is a four to six-membered monocyclic nitrogen-containing heterocyclylene, eight to ten-membered spirocyclic nitrogen-containing heterocyclylene, or eight to ten-membered fused bicyclic nitrogen-containing heterocyclylene.

[0148] Embodiment 4. The compound of embodiment 1, wherein Ring A is piperidinylene, piperazinylene, azetidinylene, pyrrolindinylene, 2,6-diazaspiro[3.4]octanylene, 2,8-diazaspiro[4.5]decanylene, 8-azabicyclo[3.2.1]octanylene, octahydro-1H-pyrrolo[3,2-c]pyridinylene, cyclohexenylene, pyrazolylene, or, substituted with (R10)x.

[0149] Embodiment 5. The compound of embodiment 4, wherein Ring A is piperidinylene or piperazinylene, substituted with (R10)x.

[0150] Embodiment 6. The compound of embodiment 1, wherein Ring A is absent.

[0151] Embodiment 7. The compound of any one of embodiments 1-6, wherein each R10is independently halo, C1-C6 alkyl, or C1-C6 hydroxyalkyl, or two R10, taken together with a carbon atom to which they are both attached, form oxo.

[0152] Embodiment 8. The compound of embodiment 7, wherein each R10is independently fluoro, methyl, or hydroxymethyl, or two R10, taken together with a carbon atom to which they are both attached, form oxo.

[0153] Embodiment 9. The compound of any one of embodiments 1-8, wherein x is 0, 1, or 2.

[0154] Embodiment 10. The compound of any one of embodiments 1-9, wherein L1is N(R11).

[0155] Embodiment 11. The compound of embodiment 10, wherein R11is hydrogen, C1-C6 alkyl, or C1-C6 hydroxyalkyl.

[0156] Embodiment 12. The compound of embodiment 11, wherein R11is hydrogen or methyl.

[0157] Embodiment 13. The compound of any one of embodiments 1-9, wherein L1is absent.

[0158] Embodiment 14. The compound of any one of embodiments 1-13, wherein L2is -(CH2)yN(R12)-, -O(CH2)y-, -N(R12)C(O)-, -C(O)N(R12)(CH2)z-, -C(O)N(R12)(CH2)zN(R12)-, -C(O)N(R12)(CH2)zO-, -(CH2)zC(O)N(R12)-, or (CH2)z.

[0159] Embodiment 15. The compound of embodiment 14, wherein L2is (CH2)yN(R12) or -O(CH2)y-.

[0160] Embodiment 16. The compound of any one of embodiments 1-15, wherein each R12is independently hydrogen, C1-C6alkyl, C1-C6hydroxyalkyl, or C1-C6deuteroalkyl.

[0161] Embodiment 17. The compound of embodiment 16, wherein each R12is independently hydrogen, methyl, hydroxyethyl, or -CD3.

[0162] Embodiment 18. The compound of any one of embodiments 1-17, wherein y is 0.

[0163] Embodiment 19. The compound of any one of embodiments 1-17, wherein y is 1.

[0164] Embodiment 20. The compound of any one of embodiments 1-18, wherein z is 1, 2, or 3.

[0165] Embodiment 21. The compound of any one of embodiments 1-13, wherein L2is -N(H)-, -N(CH3)-, -N(CH2CH2OH)-, -CH2N(H)-, -CH2N(CH3)-, -CH2N(CD3)-, -O-, -OCH2-,-N(H)C(O)-, -C(O)N(H)CH2-, -C(O)N(H)CH2CH2N(H)-, -C(O)N(H)CH2CH2CH2N(H)-, -C(O)N(H)CH2CH2O-, -CH2C(O)N(H)-, or -CH2-.

[0166] Embodiment 22. The compound of any one of embodiments 1-13, wherein L2is absent.

[0167] Embodiment 23. The compound of any one of embodiments 1-22, wherein R1is hydrogen or methyl.

[0168] Embodiment 24. The compound of any one of embodiments 1-23, wherein R2is methyl.

[0169] Embodiment 25. The compound of any one of embodiments 1-24, wherein R3is chloro or cyano.

[0170] Embodiment 26. The compound of any one of embodiments 1-25, wherein R4is:

[0171] Embodiment 27. The compound of embodiment 26, wherein R4is:

[0172] Embodiment 28. The compound of embodiment 27, wherein R4is.

[0173] Embodiment 29. The compound of any one of embodiments 1-28, wherein X2, X3and X4are C(H).

[0174] Embodiment 30. The compound of embodiment 27, wherein R4is

[0175] Embodiment 31. The compound of embodiment 26, wherein R4is.

[0176] Embodiment 32. The compound of any one of embodiments 1-31, wherein R13is hydrogen or methyl.

[0177] Embodiment 33. The compound of embodiment 32, wherein R13is hydrogen.

[0178] Embodiment 34. The compound of any one of embodiments 1-33, wherein R14is fluoro.

[0179] Embodiment 35. The compound of any one of embodiments 1-25 and 32-34,wherein R52is hydrogen or methyl.

[0180] Embodiment 36. The compound of any one of embodiments 1-35, wherein p is 0 or 1.

[0181] Embodiment 37. The compound of any one of embodiments 1-9, 14-21 and 23- 36, of Formula (II):, or a pharmaceutically acceptable salt thereof.

[0182] Embodiment 38. The compound of any one of embodiments 1, 7-12, and 23-35, of Formula (III):, or a pharmaceutically acceptable salt thereof.

[0183] Embodiment 39. The compound of any one of embodiments 1-9 and 23-35, of Formula (IV):, or a pharmaceutically acceptable salt thereof.

[0184] Embodiment 40. A compound of Table 1, or a pharmaceutically acceptable salt thereof.

[0185] Embodiment 41. A pharmaceutical composition comprising a compound of any of embodiments 1-40, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0186] Embodiment 42. A method of degrading B-cell lymphoma 6 protein (BCL6), comprising contacting BCL6 with an effective amount of a compound of any one of embodiments 1-40, or a pharmaceutically acceptable salt thereof, or pharmaceutical composition of embodiment 41.

[0187] Embodiment 43. A method of treating a cancer or an autoimmune disease in a subject in need thereof, comprising administering to the subject an effective amount of acompound of any one of embodiments 1-40, or a pharmaceutically acceptable salt thereof, or pharmaceutical composition of embodiment 41. EXAMPLES

[0188] The following Examples are presented by way of illustration, not limitation. Compounds are named using the automatic name generating tool provided in ChemBiodraw Ultra (Cambridgesoft), which generates systematic names for chemical structures, with support for the Cahn-Ingold-Prelog rules for stereochemistry. One skilled in the art can modify the procedures set forth in the illustrative examples to arrive at the desired products.

[0189] Salts of the compounds described herein can be prepared by standard methods, such as inclusion of an acid (for example TFA, formic acid, or HCl) in the mobile phases during chromatography purification, or stirring of the products after chromatography purification, with a solution of an acid (for example, aqueous HCl).

[0190] The following abbreviations may be relevant for the application. Abbreviations ACN, MeCN acetonitrile AcOH acetic acid anh anhydrous atm atmospheric pressure BF3OEt2boron trifluoride etherate BINAP 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl BOC tert-butyloxycarbonyl CBM Cereblon Binding Moiety Cbz-Cl benzyl chloroformate CDI 1,1'-carbonyldiimidazole CPhos 2′-(dicyclohexylphosphanyl)-N2,N2,N6,N6-tetramethyl[1,1′- biphenyl]-2,6-diamine DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCE 1,2-dichloroethane DCM dichloromethane DIPEA N,N-diisopropylethylamine DMA N,N-dimethylacetamide DMAP 4-dimethylaminopyridine DMEDA 1,2-dimethylethylenediamine DMF dimethylformamide DMSO dimethyl sulfoxideDPM Dess-Martin periodinane EDC ethylene dichloride eq or equiv equivalents ESI electrospray ionization Et3N triethylamine Et2O diethyl ether EtOAc or EA ethyl acetate EtOH ethanol FA formic acid h or hrs hour HATU N-[(Dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1- ylmethylene]-N-methylmethanaminium hexafluorophosphate N- oxide hex hexanes HPLC high pressure liquid chromatography iPrOH isopropanol Josiphos Pd G3 {(R)-1-[(Sp)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert- butylphosphine}[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate LCMS liquid chromatography mass spectrometry LHDMS lithium bis(trimethylsilyl)amide LiHMDS lithium hexamethyldisilazide M molarity mCPBA meta-chloroperoxybenzoic acid MeCN acetonitrile MeOH methanol MeTHF 2-methyltetrahydrofuran min minute MS mass spectrometry N normality NaOtBu sodium tert-butoxide NBS N-bromosuccinimide NIS N-iodosuccinimide NMP N-methyl-2-pyrrolidone oMe mesylate oTs tosylate Pd2dba3tris(dibenzylideneacetone)dipalladium(0)Pd-Ruphos-G3 (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-(2'- amino-1,1'-biphenyl))palladium(II) methanesulfonate PE, pet ether petroleum ether quant. quantitative RBF round bottom flask rt or RT room temperature Rt retention time SFC supercritical fluid chromatography SM starting material SNAr nucleophilic aromatic substitution TBAB tetrabutylammonium bromide tBuOH tert-butanol TEA trimethylamine TFA trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography xantphos XPhos Pd G3 Synthetic Examples General Procedure 1: Buchwald Coupling of Amine to Indazole CBM.

[0191] A mixture of 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole (1.1 eq), amine (1.0 eq), Ruphos-Pd-G3 (0.20 equiv.) and sodium tert-butoxide (1.5 eq) in 1,4-dioxane [0.3M] was heated to 90 °C for 16 h and then cooled to rt. The mixture was filtered on celite and the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel using a gradient of 0–100% ethyl acetate in hexanes to afford title compound. General Procedure 2: Coupling of Alcohol to Generic CBM.wherein Z = C(H), N(CH3), N; Y = C(H), N; X = C, N

[0192] A solution of the 2,6-dibenzyloxy-3-pyridyl)-aryl bromide (1 eq), quinuclidine (1.1 eq), 4,4'-Di-tert-butyl-2,2'-dipyridyl (0.05 eq), nickel(II) chloride ethylene glycol dimethyl ether complex (0.05 eq), and acetonitrile (.25 M) were added to a 2 dram vial equipped with a stir bar. In a separate 1 dram vial, [4,42-Bis(1,1-dimethylethyl)-2,22-bipyridine-N1,N12]bis[3,5- difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C]Iridium(III) hexafluorophosphate (0.10 eq), and 200 ^L of acetonitrile were added. The solution was sonicated and added to the reaction vial. The alcohol (3 eq) was added and argon was bubbled through the reaction for 10 minutes. The reaction vial was sealed with parafilmed and irradiated with blue lights for 48 hours without fan cooling (reaction temp ~55 °C). The reaction was stirred at a rate of 1000 RPMs. After, the reaction was quenched after 16 hrs with ethyl acetate, filtered and concentrated. The crude material was purified with normal phase chromatography to give title compound. General Procedure 3: Buchwald Coupling of Amine to Isoindolinone CBM.

[0193] A mixture of amine (2 eq), 3-(bromo-1-oxo-isoindolin-2-yl)piperidine-2,6-dione (1 eq), cesium carbonate (4 eq), [2-(2-aminophenyl)phenyl]-[dicyclohexyl-[2-(2,6- diisobutoxyphenyl)phenyl]-λ^5-phosphanyl]palladium(1+);methanesulfonate (0.10 eq), and 1,4- dioxane (0.1 M) were added to a 2 dram vial, degassed, and stirred at 110 °C overnight. The reaction is diluted with water and 1 M hydrochloric acid and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified via column chromatography with 10% methanol in ethyl acetate / hexanes with a 0-100% gradient. Any fractions containing product were collected and concentrated to give title compound.General Procedure 4: Coupling of Alcohol to Isoindolinone CBM.

[0194] A solution of the 3-(5-bromo-1-oxo-isoindolin-2-yl)piperidine-2,6-dione (1 eq), quinuclidine (1.1 eq), 4,4'-di-tert-butyl-2,2'-dipyridyl (0.05 eq), nickel(II) chloride ethylene glycol dimethyl ether complex (0.05 eq), and acetonitrile (0.25 M) were added to a 2 dram vial equipped with a stir bar. In a separate 1 dram vial, [4,42-Bis(1,1-dimethylethyl)-2,22-bipyridine- N1,N12]bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C]Iridium(III) hexafluorophosphate (0.10 eq), and 200 ^L of acetonitrile were added. The solution was sonicated and added to the reaction vial. The alcohol (3 eq) was added and argon was bubbled through the reaction for 10 minutes. The reaction vial was sealed with parafilmed and irradiated with blue lights for 48 hours without fan cooling (reaction temp ~55 °C). The reaction was stirred at a rate of 1000 RPMs. After, the reaction was quenched after 16 hrs with ethyl acetate, filtered and concentrated. The crude material was purified with normal phase chromatography to give title compound. General Procedure 5: Amine Substitution of Benzimidazolone CBM.

[0195] 3-[5-(bromomethyl)-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (1 eq), amine (1.2 eq), N,N-diisopropylethylamine (3 eq), and N, N-dimethylformamide (0.5 M) were added to a flask equipped with a stir bar. The reaction stirred at rt for 24 hours. After, the reaction mixture was added to stirred ethyl acetate and the solid was collected by vacuum filtration, washed with diethyl ether and dried under high vac to afford title compound. If required, the product was purified with 0-100% ethyl acetate in hexanes to afford title compound. General Procedure 6: Amide Coupling

[0196] To a solution of amine (1.1 eq), 2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindoline-5- carboxylic acid (1.0 eq), and N,N-diisopropylethylamine (2.0 eq) in DMF (0.20 M) was treated with HATU (1.1 eq) and stirred at ambient temperature overnight. After, the reaction was diluted with water, extracted with ethyl acetate, and the organic layers were washed with brine, dried over sodium sulfate filtered and concentrated The crude product was absorbed on silicaand purified by flash chromatography. The pure fractions were combined and concentrated to give title compound. General Procedure 7: Reductive Amination with amine CBM to linker

[0197] To a solution of ketone (1 eq) in DMSO (0.1M) were sequentially added tert-butyl 4-oxopiperidine-1-carboxylate (1.1 eq), acetic acid (1 eq) and sodium triacetoxyborohydride (2 eq). The reaction mixture was stirred at rt for 18 h. The crude material was filtered through a syringe filter and The purified by reverse phase chromatography (C18), using a gradient of 5- 100 % acetonitrile and water (with 0.1 % formic acid) to afford title compound. General Procedure 8: Methylation of amine

[0198] To a solution of amine (1.0 eq) in N, N-dimethylformamide [0.15M] was added sodium hydride (4.4 eq), at 0 °C. After stirring for 1 h, iodomethane (2.8 eq) was added dropwise at 0 °C. The resulting reaction mixture was stirred at room temperature for 16 h. The reaction mixture was then quenched with water, and extracted with ethyl acetate. The extracts were combined and washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate to obtain title compound. General Procedure 9: Reduction of CBM with Hydrogen.

[0199] A mixture of indazole intermediate (1.0 eq) and palladium on carbon (10 wt. % palladium; 40% by weight) in ethanol:tetrahydrofuran (1:1.5; [0.05M]) was subjected to hydrogen (1 atm) at 50 °C for 4 h The mixture was degassed with nitrogen and filtered throughCelite. The filter cake was washed sequentially with ethanol and tetrahydrofuran. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel using a gradient of 0–100% ethyl acetate in hexanes to afford title compound. General Procedure 10: Boc Deprotection with HCl or TFA.

[0200] To a solution of Boc protected amine (1.0 eq) in 1,4-dioxane [0.3 M] was added 4N hydrochloric acid in 1,4-dioxane (14 eq), and the reaction mixture was stirred at rt for 12 h. The volatiles were evaporated under reduced pressure to afford the amine hydrochloride (quant.) as a solid, which was used in the next step without further purification. General Procedure 11: SNAr of Decorated TBM with CBM.

[0201] A solution of amine hydrochloride (1.0 eq), the chloro / fluoro pyrimidine (1.0 eq), N,N-diisopropylethylamine (3 to 5 eq) in DMSO [0.1-0.2 M] was stirred at 80 °C for 2 h. The reaction mixture was filtered and purified by reverse-phased semi-preparative HPLC (10-100% acetonitrile + 0.1% formic acid in water 0.1% formic acid, over 30 min). Fractions containing clean product were combined and lyophilized to afford title compounds. Synthesis of Intermediate i-1: 3-(6-amino-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione

[0202] Step i-1.1: Synthesis of tert-butyl (3-(2,6-bis(benzyloxy)pyridin-3-yl)-1- methyl-1H-indazol-6-yl)carbamate.3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-1-methyl-1H- indazole (160g, 320 mmol) was taken in 1,4-dioxane (1600 mL) in a 3000 mL multineck round bottom flask fitted with a reflux condenser under N2atm with mechanical stirring. Next, tert-butyl carbamate (56.2 g, 480 mmol) was added , followed by potassium carbonate (133 g, 959 mmol) and then purged for 5 minutes, followed by addition of XPhos Pd G2 (25.2 g, 32.0 mmol), purged again for 5 minutes and then refluxed at 110 °C for overnight The reaction mixture was filteredthrough a celite bed, washing with ethyl acetate. The filtrate obtained was evaporated to give crude product which was purified using normal phase column chromatography in silica gel with petroleum ether / ethyl acetate as eluent to give the title compound (148 g, 275 mmol, 86 % yield) as a white solid. MS (ESI) m / z 537.30 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ ppm 9.5 (s, 1H), 7.89 – 7.91 (m, 1H), 7.28 - 7.54 (m, 12 H), 6.94 (d, 1 H), 6.58 (d, 1 H), 5.41-5.45 (d, 4 H), 3.96 (s, 3 H), 1.50 (s, 9 H), 1.37 (s, 1H).

[0203] Step i-1.2: Synthesis of tert-butyl (3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H- indazol-6-yl)carbamate. To a flask was added tert-butyl (3-(2,6-bis(benzyloxy)pyridin-3-yl)-1- methyl-1H-indazol-6-yl)carbamate (25 g, 46.6 mmol) and tetrahydrofuran (500 mL). This mixture was purged with nitrogen for 5 min and then palladium on carbon (24.79 g, 23.29 mmol) was added and then stirred under H2atmosphere overnight at 55 °C. After this time, the reaction mixture was filtered through celite washing with tetrahydrofuran (2 L) and then the filtrate obtained was evaporated to give the title compound (15.69 g, 43.8 mmol, 94 % yield) as white solid. MS (ESI) m / z 359.1 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ ppm 10.90 (s, 1H), 9.54 (s, 1H), 7.82 (m, 1H), 7.55 - 7.57 (d, 1 H), 7.04 (d, 1 H), 4.30 (m, 1 H), 3.90 (s, 3 H), 2.30 – 2.70 (m, 2 H) 2.13 – 2.37 (m, 2 H), 1.36 (s, 9H).

[0204] Step i-1.3: Synthesis of 3-(6-amino-1-methyl-1H-indazol-3-yl)piperidine-2,6- dione, HCl salt. tert-butyl (3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)carbamate (25 g, 69.8 mmol) was dissolved in 1,4-dioxane (250 mL) in a 2 L round bottom flask under magnetic stirring. HCl (4 M in dioxane) (250 mL, 69.8 mmol) was added slowly and then the reaction was stirred at rt for 48 hours. After this time, the mixture was filtered and then the solids obtained were taken up in methanol and then stirred well for 20 minutes and then filtered again to give the title compound (18 g, 57.2 mmol, 82 % yield) as pale yellow solid. MS (ESI) m / z 259.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ ppm 7.80 - 7.82 (d, 1 H), 7.53 (s, 1 H), 7.08 - 7.11 (d 1 H), 4.39 - 4.43 (m, 1 H), 3.99 (s, 3 H), 2.50 – 2.73 (m, 2 H), 2.38 – 2.40 (m, 1 H), 2.18 - 2.36 (m, 1 H). Note: exchangeable protons not observed. Synthesis of Intermediate i-2: 3-(1-methyl-6-(piperidin-4-ylamino)-1H-indazol-3- yl)piperidine-2,6-dione hydrochloride

[0205] Step i-2.1: Synthesis of 6-bromo-3-iodo-1-methyl-indazole. To a solution of^6- bromo 1 methyl indazole (800 g 379 mmol) in^N N dimethylformamide (100 mL) was addedN-Iodosuccinimide (25.58 g, 113.7 mmol). The reaction mixture was heated to^150 °C for 16 h and then cooled to rt. The volatiles were evaporated under reduced pressure. The material was purified by column chromatography on silica gel using a gradient of 0-20% ethyl acetate in hexane to afford^the title compound (4.95 g, 14.7 mmol, 39% yield) as a solid. ^MS (ESI) m / z [M+H]+^336.90.

[0206] Step i-2.2: Synthesis of 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl- indazole. To a solution of^6-bromo-3-iodo-1-methyl-indazole (2. g, 5.94 mmol)^in 1,4-dioxane (30 mL)^and water (3 mL)^was added (2,6-dibenzyloxy-3-pyridyl)boronic acid (1.99 g, 5.94 mmol), potassium phosphate (3.78 g, 17.81 mmol)^and [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(ii) (0.43 g, 0.5900 mmol) under N2, then the mixture was stirred at^80 °C^for 17 hrs under N2. LCMS showed the reactant was consumed completely, and desired MS as main peak. The reaction was then cooled to room temperature and filtered. The filtrate was^extracted^with ethyl acetate (3 x 40 mL), washed with^brine(2 x 40 mL), dried over anhydrous Na2SO4^and concentrated under reduced pressure.^The crude was purified by column chromatography (silica, gradient: 0-30% ethyl acetate in petroleum ether) to the title compound (2.1 g, 4.20 mmol, 71% yield)^as a pale yellow solid. MS (ES) [M+H]+^500.3.1H NMR (400 MHz, DMSO-d6) δ 7.96 (s, 1H), 7.91 (d, J= 8.1 Hz, 1H), 7.62 (d, J= 8.7 Hz, 1H), 7.50 – 7.24 (m, 10H), 7.12 (dd, J= 8.7, 1.4 Hz, 1H), 6.60 (d, J= 8.1 Hz, 1H), 5.45 (s, 2H), 5.43 (s, 2H), 4.05 (s, 3H).

[0207] Step i-2.3: Synthesis of tert-butyl 4-[[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl- indazol-6-yl]amino]piperidine-1-carboxylate. A mixture of^6-bromo-3-(2,6-dibenzyloxy-3- pyridyl)-1-methyl-indazole (4.0 g, 7.99 mmol),^tert-butyl 4-aminopiperidine-1-carboxylate (1.92 g, 9.59 mmol), XPhos-Pd-G3 (1.35 g, 1.6 mmol) and^ cesium carbonate (5.2 g, 15.99 mmol) in 1,4-dioxane (53.292 mL) was heated to 110 °C for 28 h and then cooled to rt. The mixture was filtered through celite and washed with ethyl acetate (3 x 10 mL). The filtrate was concentrated under reduced pressure. The material was purified by column chromatography on silica gel using a gradient of 0-90% ethyl acetate in hexane to afford^tert-butyl 4-[[3-(2,6-dibenzyloxy-3-pyridyl)- 1-methyl-indazol-6-yl]amino]piperidine-1-carboxylate (2.81 g, 4.53 mmol, 57% yield)as a solid.^MS (ESI) [M+H]+:^620.4;^1H NMR (500 MHz, CDCl3) δ 7.89 (d, J = 8.1 Hz, 1H), 7.47 (d, J = 8.7 Hz, 1H), 7.45 – 7.42 (m, 2H), 7.39 – 7.27 (m, 7H), 7.25 – 7.22 (m, 1H), 6.49 (d, J = 8.1 Hz, 1H), 6.36 (dd, J = 8.8, 1.9 Hz, 1H), 6.31 (d, J = 1.7 Hz, 1H), 5.46 (s, 2H), 5.38 (s, 2H), 4.06 (br, 2H), 3.98 (s, 3H), 3.73 (br, 1H), 3.57 – 3.46 (m, 2H), 3.00 (t, J = 11.9 Hz, 2H), 2.10 (dd, J = 13.0, 2.8 Hz, 2H), 1.48 (s, 9H).

[0208] Step i-2.4: Synthesis of tert-butyl 4-[[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-6-yl]amino]piperidine-1-carboxylate. A mixture of tert-butyl 4-[[3-(2,6-dibenzyloxy- 3-pyridyl)-1-methyl-indazol-6-yl]amino]piperidine-1-carboxylate (600 mg, 0.970 mmol) and Pearlman’s catalyst (167 mg, 0.240 mmol) in tetrahydrofuran (5 mL) and ethanol (3 mL) was subjected to hydrogenation at 1 atm and 50 °C for 4 h. At this time, only the alkene product was observed. Additional^Pearlman’s Catalyst (33.4 mg, 0.0500 mmol) was added and the mixture was^subjected to hydrogenation at 1 atm and 50 °C for 24 h.^The mixture was filtered through celite and washed with methanol: acetonitrile (1:1 ratio, 3 x 50.0 mL). The filtrate was concentrated under reduced pressure to afford tert-butyl 4-[[3-(2,6-dioxo-3-piperidyl)-1-methyl- indazol-6-yl]amino]piperidine-1-carboxylate (495 mg, 0.9496 mmol, 98.085% yield) as a solid.^ MS (ESI) [M+H]+: 442.4;^1H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H), 7.33 (d, J = 8.7 Hz, 1H), 6.52 (dd, J = 8.8, 1.8 Hz, 1H), 6.43 (s, 1H), 5.79 (d, J = 8.2 Hz, 1H), 4.18 (dd, J = 8.7, 5.2 Hz, 1H), 3.93 – 3.86 (m, 2H), 3.81 (s, 3H), 2.96 (br, 2H), 2.60 (t, J = 7.0 Hz, 2H), 2.30 – 2.20 (m, 1H), 2.18 – 2.11 (m, 1H), 1.94 (d, J = 11.0 Hz, 2H), 1.41 (s, 9H), 1.30 – 1.19 (m, 3H).

[0209] Step i-2.5: Synthesis of 3-[1-Methyl-6-(4-piperidylamino)indazol-3- yl]piperidine-2,6-dione hydrochloride salt. To a solution of tert-butyl 4-[[3-(2,6-dioxo-3- piperidyl)-1-methyl-indazol-6-yl]amino]piperidine-1-carboxylate (1.22 g, 2.76 mmol) in 1,4- dioxane (20 mL) was added hydrogen chloride 4N in 1, 4 dioxane (3.45 mL, 13.8 mmol). The reaction mixture was stirred at 80 °C for 2 hours. The solid was collected by filtration to give title compound (1.0 g, 2.65 mmol, 96% yield) as white solid. MS (ESI) m / z 342.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ ppm 10.85 (s, 1 H), 9.01 (br d, J=2.45 Hz, 1 H), 8.76 - 8.95 (m, 1 H), 7.48 (br s, 1 H), 6.72 (br s, 3 H), 4.21 - 4.30 (m, 1 H), 3.87 (s, 3 H), 3.63 - 3.75 (m, 1 H), 3.32 (br d, J=12.59 Hz, 2 H), 2.99 (br d, J=10.39 Hz, 2 H), 2.55 - 2.69 (m, 2 H), 2.22 - 2.34 (m, 1 H), 2.07 - 2.22 (m, 2 H), 1.72 (br s, 2 H). Synthesis of Intermediate i-3: 3-(1-Methyl-6-(4-(methylamino)piperidin-1-yl)-1H-indazol- 3-yl)piperidine-2,6-dione hydrochloride

[0210] Step i-3.1: Synthesis of tert-Butyl (1-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1- methyl-1H-indazol-6-yl)piperidin-4-yl)(methyl)carbamate. 6-bromo-3-(2,6-dibenzyloxy-3- pyridyl)-1-methyl-indazole (300 mg, 0.6000 mmol), tert-butyl N-methyl-N-(piperidin-4- yl)carbamate (192.72 mg, 0.9000 mmol), cesium carbonate (390.68 mg, 1.2 mmol), and RuPhos- Pd-G3 (50.14 mg, 0.0600 mmol) were added to a 1 dram vial and purged with nitrogen for 1 min.After which, 1,4-dioxane (0.8 mL) was added and the reaction mixture was stirred at 100 °C for overnight. Product was purified from crude mixture using column chromatography (10 g SNAP cartridge, 0-7% methanol / dichloromethane 25 CV, 7% methanol / dichloromethane 10 CV) to give the title compound (106 mg, 0.1673 mmol, 27.8% yield) as a white solid. MS (ESI) m / z 634.0 [M+H]+;1H NMR (400 MHz, DMSO-d6 ) δ ppm 7.89 (d, J=8.19 Hz, 1 H), 7.26 - 7.51 (m, 11 H), 6.88 (d, J=1.59 Hz, 1 H), 6.82 (dd, J=9.17, 1.96 Hz, 1 H), 6.57 (d, J=8.19 Hz, 1 H), 5.44 (d, J=13.57 Hz, 4 H), 3.97 (s, 3 H), 3.87 (br d, J=12.59 Hz, 2 H), 2.77 (br t, J=11.55 Hz, 2 H), 2.70 (s, 3 H), 1.71 - 1.89 (m, 2 H), 1.61 - 1.70 (m, 2 H), 1.42 (s, 9 H).

[0211] Step i-3.2: Synthesis of tert-butyl (1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl- 1H-indazol-6-yl)piperidin-4-yl)(methyl)carbamate. Tert-butyl N-[1-[3-(2,6-dibenzyloxy-3- pyridyl)-1-methyl-indazol-6-yl]-4-piperidyl]-N-methyl-carbamate (106 mg, 0.1700 mmol) and ethanol (4.1813 mL) were dissolved in a 40 mL vial equipped with a sir bar. The mixture was purged with nitrogen and palladium on carbon (17.8 mg, 0.1700 mmol) was added. The mixture was purged again with nitrogen and then hydrogen. The reaction stirred under a balloon of hydrogen overnight. The slurry was filtered through celite and concentrated. The residue was loaded onto a SNAP25G column and purified with 0-50% ethyl acetate / hexanes with 2-5% methanol additive to give the title compound (50 mg, 0.110 mmol, 65.6% yield) as yellow oil.

[0212] Step i-3.3: Synthesis of 3-(1-Methyl-6-(4-(methylamino)piperidin-1-yl)-1H- indazol-3-yl)piperidine-2,6-dione hydrochloride. Tert-butyl N-[1-[3-(2,6-dioxo-3-piperidyl)- 1-methyl-indazol-6-yl]-4-piperidyl]-N-methyl-carbamate (50 mg, 0.1100 mmol) was added to a vial equipped with a stir bar and dichloromethane (1 mL) was added. HCl 4 N in 1,4-dioxane (0.4400 mmol) was then added to the mixture and stirred for 2 hours. The stir bar was removed and the solvent was removed in vacuo to give the title compound (42 mg, 0.107 mmol, 97.6% yield) as an off white solid. Synthesis of Intermediate i-4: 3-(1-methyl-6-(methyl(piperidin-4-yl)amino)-1H-indazol-3- yl)piperidine-2,6-dione hydrochloride

[0213] Step i-4.1: Synthesis of tert-Butyl 4-[[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl- indazol-6-yl]amino]piperidine-1-carboxylate. A mixture of 6-bromo-3-(2,6-dibenzyloxy-3- pyridyl)-1-methyl-indazole (500 mg, 1 mmol), tert-butyl 4-aminopiperidine-1-carboxylate (240 mg 12 mmol) RuPhos Pd G3 (83 mg 01000 mmol) and cesium carbonate (651 mg 2 mmol)in 1,4-dioxane (5 mL) was heated to 90 °C for 18 h and then cooled to rt. The mixture was filtered through celite and washed with ethyl acetate (3 x 10 mL). The filtrate was concentrated under reduced pressure. The material was purified by column chromatography on silica gel using a gradient of 0–100% Ethyl acetate in hexanes to afford the title compound (550 mg, 89%) as a solid. MS (ESI) [M+H]+620.5;1H NMR (500 MHz, CDCl3) δ 7.89 (d, J = 8.1 Hz, 1H), 7.47 (d, J = 8.7 Hz, 1H), 7.45 – 7.41 (m, 2H), 7.39 – 7.24 (m, 8H), 6.49 (d, J = 8.1 Hz, 1H), 6.36 (dd, J = 8.7, 1.9 Hz, 1H), 6.31 (d, J = 1.7 Hz, 1H), 5.46 (s, 2H), 5.38 (s, 2H), 4.13 – 4.03 (m, 2H), 3.98 (s, 3H), 3.73 (s, 1H), 3.57 – 3.50 (m, 1H), 3.00 (t, J = 12.1 Hz, 2H), 2.10 (d, J = 10.8 Hz, 2H), 1.48 (s, 9H), 1.43 – 1.35 (m, 2H).

[0214] Step i-4.2: Synthesis of tert-Butyl 4-[[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl- indazol-6-yl]-methyl-amino]piperidine-1-carboxylate. To a solution of tert-butyl 4-[[3-(2,6- dibenzyloxy-3-pyridyl)-1-methyl-indazol-6-yl]amino] piperidine-1-carboxylate (550 mg, 0.89 mmol) in dimethylsulfoxide (3.6 mL) and acetic acid (0.9 mL) were sequentially added aqueous solution of formaldehyde (0.13 mL, 1.8 mmol) and sodium triacetoxyborohydride (282 mg, 1.3 mmol). The reaction mixture was stirred at rt for 1 h. Water (10 mL) and ethyl acetate (25 mL) were added and the layers were separated. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate (5 mL), water (3 x 5 mL), brine (5 mL), dried on sodium sulfate, filtered and concentrated under reduced pressure. The material was purified by column chromatography on silica gel using a gradient of 0–100% ethyl acetate in hexanes to afford the title compound (467 mg, 83% yield) as a solid. MS (ESI) [M+H]+635.5;1H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 8.1 Hz, 1H), 7.56 (d, J = 9.0 Hz, 1H), 7.46 – 7.40 (m, 2H), 7.40 – 7.30 (m, 5H), 7.29 – 7.23 (m, 3H), 6.72 (dd, J = 9.3, 2.1 Hz, 1H), 6.50 (d, J = 8.1 Hz, 1H), 6.48 (d, J = 1.9 Hz, 1H), 5.47 (s, 2H), 5.38 (s, 2H), 4.25 (s, 2H), 4.01 (s, 3H), 3.80 (td, J = 10.8, 5.3 Hz, 1H), 2.84 (s, 3H), 2.83 – 2.74 (m, 2H), 1.81 – 1.64 (m, 4H), 1.49 (s, 9H).

[0215] Step i-4.3: tert-Butyl 4-[[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-6-yl]- methyl-amino] piperidine-1-carboxylate. A mixture of tert-butyl 4-[[3-(2,6-dibenzyloxy-3- pyridyl)-1-methyl-indazol-6-yl]-methyl-amino]piperidine-1-carboxylate (467 mg, 0.74 mmol) and 20% Pearlman’s catalyst (117 mg, 25 wt%) in tetrahydrofuran (7 mL) and ethanol (7 mL) was subjected to hydrogenation at 1 atm and 50 °C for 2 h. The mixture was filtered through celite, washed with a mixture of acetonitrile and methanol (1:1, 3 x 10 mL), and the filtrate was concentrated under reduced pressure. The material was purified by column chromatography on silica gel using a gradient of 0–20% methanol in dichloromethane to afford the title compound (258 mg, 77%) as a solid. MS (ESI) [M+H]+456.3;1H NMR (500 MHz, DMSO) δ 10.83 (s, 1H), 7.46 (d, J = 9.0 Hz, 1H), 6.87 (dd, J = 9.2, 2.0 Hz, 1H), 6.65 (d, J = 1.9 Hz, 1H), 4.23 (dd, J = 9.0,5.1 Hz, 1H), 4.09 – 3.99 (m, 2H), 3.98 – 3.91 (m, 1H), 3.87 (s, 3H), 2.86 (br s, 2H), 2.76 (s, 3H), 2.64 – 2.56 (m, 2H), 2.33 – 2.25 (m, 1H), 2.21 – 2.13 (m, 1H), 1.67 – 1.54 (m, 4H), 1.41 (s, 9H).

[0216] Step i-4.4: Synthesis of 3-[1-Methyl-6-[methyl(4-piperidyl)amino]indazol-3- yl]piperidine-2,6-dione;hydrochloride. To a solution of tert-butyl 4-[[3-(2,6-dioxo-3- piperidyl)-1-methyl-indazol-6-yl]-methyl-amino]piperidine-1-carboxylate (258 mg, 0.57 mmol) in 1,4-dioxane (10 mL) was added 4M HCl in 1,4-dioxane (1.42 mL, 5.66 mmol). The reaction mixture was heated to 100 °C for 3 h then cooled to rt. The volatiles were evaporated under reduced pressure. Diethyl ether (5 x mL) was added and the resulting precipitate was collected by filtration, washed with 1,4-dioxane (3 x 1 mL) and diethyl ether (10 x 2 mL) then dried under vacuum to afford the title compound (217 mg, 92%) as a solid. MS (ESI) [M+H]+356.2;1H NMR (400 MHz, D2O) δ 7.93 (d, J = 8.3 Hz, 1H), 7.65 (s, 1H), 7.31 (d, J = 8.0 Hz, 1H), 4.56 (dd, J = 10.8, 4.2 Hz, 1H), 4.18 – 4.09 (m, 1H), 4.07 (s, 3H), 3.61 (d, J = 12.6 Hz, 2H), 3.33 (s, 3H), 3.11 (t, J = 12.9 Hz, 2H), 2.91 – 2.79 (m, 2H), 2.61 – 2.48 (m, 1H), 2.44 – 2.35 (m, 1H), 2.28 (d, J = 12.0 Hz, 2H), 2.05 – 1.90 (m, 2H). Note: exchangeable protons not observed, contains < 1 wt% 1,4-dioxane. Synthesis of Intermediate i-5: 3-(1-methyl-6-(((3R,4R)-3-methylpiperidin-4-yl)amino)-1H- indazol-3-yl)piperidine-2,6-dione.

[0217] Step i-5.1: Synthesis of tert-butyl (3R,4R)-4-[[3-(2,6-dibenzyloxy-3-pyridyl)-1- methyl-indazol-6-yl]amino]-3-methyl-piperidine-1-carboxylate. A mixture of 6-bromo-3-(2,6- dibenzyloxy-3-pyridyl)-1-methyl-indazole (1.92 g, 3.84 mmol), tert-butyl (3R,4R)-4-amino-3- methyl-piperidine-1-carboxylate (685.23 mg, 3.20 mmol, J&W PharmLab #60R1019, lot JWY790-124B, 98.63% ee), RuPhos Pd G3 (668.6 mg, 0.80 mmol) and Cs2CO3(1.25 g, 3.84 mmol) in 1,4-dioxane (15 mL) was heated to 90 °C for 20 h. The mixture was cooled to rt, filtered through Celite and washed with Ethyl acetate (4 x 30 mL). The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel using a gradient of 0–40% Ethyl acetate in hexanes to afford title compound (1.37 g, 68%) as a solid. MS (ESI) [M+H]+634.1.1H NMR (400 MHz, DMSO-d6) δ 7.86 (d, J = 8.1 Hz, 1H), 7.50 – 7.46 (m, 1H), 7.46 – 7.25 (m, 10H), 6.54 (d, J = 8.1 Hz, 1H), 6.43 (d, J = 1.8 Hz, 1H), 6.41 (d, J = 2.2 Hz, 1H), 5.70 (d, J = 8.9 Hz, 1H), 5.44 (s, 2H), 5.40 (s, 2H), 3.97 – 3.89 (m, 2H), 3.88 (s, 3H), 3.24 –3.14 (m, 1H), 2.99 – 2.87 (m, 1H), 2.05 – 2.01 (m, 1H), 2.01 – 1.98 (m, 1H), 1.57 – 1.47 (m, 1H), 1.41 (s, 9H), 1.17 – 1.08 (m, 1H), 0.93 (d, J = 6.5 Hz, 3H).

[0218] Step i-5.2: Synthesis of tert-butyl (3R,4R)-4-[[3-(2,6-dioxo-3-piperidyl)-1-methyl- indazol-6-yl]amino]-3-methyl-piperidine-1-carboxylate. A mixture of tert-butyl (3R,4R)-4-[[3- (2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazol-6-yl]amino]-3-methyl-piperidine-1-carboxylate (1.40 g, 2.21 mmol) and Pd(OH)2 / C (1.18 g, 1.10 mmol) in MeOH (25 mL) and THF (75 mL) was hydrogenated under H2(1 atm) at 50 °C for 9 h. The mixture was filtered through Celite and washed with MeOH (2 x 50 mL) and THF (2 x 100 mL). The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel using a gradient of 0–5% MeOH in DCM to afford title compound (695 mg, 69%) as a solid. MS (ESI) [M+H]+456.3.1H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H), 7.31 (d, J = 8.8 Hz, 1H), 6.51 (dd, J = 8.8, 1.7 Hz, 1H), 6.40 (s, 1H), 5.72 (d, J = 8.9 Hz, 1H), 4.17 (dd, J = 8.7, 5.2 Hz, 1H), 3.98 – 3.88 (m, 2H), 3.80 (s, 3H), 3.26 – 3.14 (m, 1H), 3.00 – 2.86 (m, 1H), 2.65 – 2.56 (m, 3H), 2.34 – 2.20 (m, 1H), 2.18 – 2.09 (m, 1H), 2.05 – 1.94 (m, 1H), 1.60 – 1.46 (m, 1H), 1.41 (s, 9H), 1.22 – 1.05 (m, 1H), 0.92 (d, J = 6.5 Hz, 3H).

[0219] Step i-5.3: Synthesis of 3-(1-methyl-6-(((3R,4R)-3-methylpiperidin-4- yl)amino)-1H-indazol-3-yl)piperidine-2,6-dione. To a solution of tert-butyl (3R,4R)-4-[[3-(2,6- dioxo-3-piperidyl)-1-methyl-indazol-6-yl]amino]-3-methyl-piperidine-1-carboxylate (695.0 mg, 1.53 mmol) in 1,4-dioxane (5 mL) was added 4N HCl in dioxane (3.81 mL, 15.26 mmol). The reaction mixture was stirred at rt for 16 h and the volatiles were evaporated under reduced pressure. Et2O (10 mL) was added and the resulting precipitate was collected by filtration, washed with Et2O (3 x 10 mL) and dried under vacuum to afford title compound (673 mg, quant.) as a solid. MS (ESI) [M+H]+356.2.1H NMR (500 MHz, Acetic acid-d4) δ 7.93 (d, J = 8.6 Hz, 1H), 7.42 (d, J = 8.3 Hz, 1H), 4.59 (dd, J = 10.7, 5.1 Hz, 1H), 4.15 (s, 3H), 4.01 – 3.90 (m, 1H), 3.67 – 3.61 (m, 2H), 3.24 (t, J = 12.3 Hz, 1H), 3.07 (t, J = 12.6 Hz, 1H), 2.98 (dt, J = 17.7, 4.8 Hz, 1H), 2.91 (dd, J = 10.6, 5.3 Hz, 1H), 2.88 – 2.78 (m, 1H), 2.69 – 2.57 (m, 1H), 2.48 – 2.41 (m, 1H), 2.35 – 2.22 (m, 1H), 1.36 (d, J = 6.5 Hz, 3H). Note: exchangeable protons not visible; traces of diethyl ether (0.3%) dioxane (0.9%). Synthesis of Intermediate i-6: 3-[1-methyl-6-(4-piperidyloxy)indazol-3-yl]piperidine-2,6- dione; hydrochloride

[0220] Step i-6.1: Synthesis of tert-butyl 4-[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl- indazol-6-yl]oxypiperidine-1-carboxylate. 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl- indazole (250.2 mg, 0.5000 mmol), quinuclidine (61.15 mg, 0.5500 mmol), 4,4'-di-tert-butyl-2,2'- dipyridyl (6.71 mg, 0.0200 mmol), nickel(II) chloride ethylene glycol dimethyl ether complex (5.49 mg, 0.0200 mmol), and 200 uL of acetonitrile were added to a 2 dram vial equipped with a stir bar. In a separate 1 dram vial , [4,42-Bis(1,1-dimethylethyl)-2,22-bipyridine-N1,N12]bis[3,5- difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C] Iridium(III) hexafluorophosphate (5.61 mg, 0 mmol), and 200 uL of Acetonitrile were added. The solution was sonicated and added to the reaction vial. 1-Boc-4-hydroxypiperidine (301.89 mg, 1.5 mmol) was added and argon was bubbled through the reaction for 10 minutes. The reaction vial was sealed with parafilmed and irradiated with blue lights for 48 hours without fan cooling (reaction temp ~55 °C). The reaction was stirred at a rate of 1000 RPMs. After 16 hours, the reaction was quenched with ethyl acetate, filtered and concentrated. The crude residue was purified via a SNAP 25G column with hexanes / ethyl acetate to give title compound (279.3 mg, 0.450 mmol, 90%).

[0221] Step i-6.2: Synthesis of tert-butyl 4-[3-(2,6-dioxo-3-piperidyl)-1-methyl- indazol-6-yl]oxypiperidine-1-carboxylate. Tert-butyl 4-[3-(2,6-dibenzyloxy-3-pyridyl)-1- methyl-indazol-6-yl]oxypiperidine-1-carboxylate (510. mg, 0.8200 mmol) (contaminated with hydroxy piperidine) was added to a 30 mL vial and diluted with ethanol (20.54 mL). The mixture was stirred and purged with nitrogen. Palladium on carbon (87.42 mg, 0.8200 mmol) was then added and the mixture was again purged with nitrogen. A hydrogen balloon was added to the reaction vial and it was allowed to stir overnight at rt. After, the reaction vial was purged with nitrogen and filtered through celite. The filtrate was concentrated and purified on silica using 0- 50% ethyl acetate / hexanes with 5% methanol. Fractions containing product were collected and carried onto the next step.

[0222] Step i-6.3: Synthesis of 3-[1-methyl-6-(4-piperidyloxy)indazol-3-yl]piperidine- 2,6-dione;hydrochloride . Tert-butyl 4-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-6- yl]oxypiperidine-1-carboxylate (140. mg, 0.3200 mmol) was added to a vial equipped with a stir bar. HCl in dioxane (0.24 mL, 0.9500 mmol) was added and the mixture stirred for 2 hours. LCMS indicated deprotection was complete and the reaction was concentrated to give 3-[1-methyl-6-(4-piperidyloxy)indazol-3-yl]piperidine-2,6-dione;hydrochloride (123 mg, 0.3247 mmol, 102.62% yield) as a white solid. Synthesis of Intermediate i-7: 3-(7-Amino-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione

[0223] Step i-7.1. Synthesis of 7-Bromo-3-iodo-1H-indazole. To a solution of 7- bromo-1H-indazole (20.000 g, 101.51 mmol, 1 eq), iodine (51.530 g, 203.01 mmol, 2 eq) in dimethyl formamide (500 mL) was added potassium hydroxide (11.390 g, 203.01 mmol, 2 eq) at 0 °C. The mixture was stirred at 16 °C for 12 h. LCMS showed the reaction was completed. The reaction mixture was quenched with water (1 L), saturated sodium sulfite aqueous solution (40 mL). The reaction mixture was filtered and the filter cake was diluted with ethyl acetate (600 mL), extracted with sodium sulfite (20 mL × 3). The organic phase was dried with anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuum. It was used directly into the next step without further purification. 7-Bromo-3-iodo-1H-indazole (32.700 g, 101.26 mmol, 99.8% yield) was obtained as yellow solid. MS (ESI) m / z: 322.9 [M+1]+;1H NMR (400 MHz, DMSO-d6) δ 13.93 (s, 1 H), 7.64 - 7.79 (m, 1 H), 7.47 (d, J = 8.0 Hz, 1 H), 7.08 - 7.26 (m, 1 H).

[0224] Step i-7.2. Synthesis of 7-Bromo-3-iodo-1-methyl-1H-indazole. To a solution of 7-bromo-3-iodo-1H-indazole (32.700 g, 101.26 mmol, 1 eq) in tetrahydrofuran (300 mL) was added potassium tert-butoxide (22.730 g, 202.52 mmol, 2 eq) at 0 °C, the reaction was stirred at 0 °C for 1 h. Then a solution of methyl iodide (28.750 g, 202.52 mmol, 2 eq) in tetrahydrofuran (50 mL) was dropwise to the reaction mixture at 0 °C. Then the mixture was stirred at 17 °C for 12 h. The desired mass was detected by LCMS. TLC showed 7-bromo-3-iodo-1H-indazole was consumed completely and new spot was detected. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel chromatography (2-67% Ethyl acetate in Petroleum ether). Totally 28 g of desired product was obtained, 7-Bromo-3-iodo-1- methyl-1H-indazole (21.240 g, 63.04 mmol, 62.3% yield) was obtained as white solid. MS (ESI) m / z: 336.9 [M+1]+;1H NMR (400 MHz, DMSO-d6) δ 7.66 (d, J = 7.6 Hz, 1 H), 7.40 (d, J = 8.0 Hz, 1 H), 6.95 - 7.16 (m, 1 H), 4.31 (s, 3 H).

[0225] Step i-7.3. Synthesis of 3-(2,6-Bis(benzyloxy)pyridin-3-yl)-7-bromo-1-methyl- 1H-indazole. To a solution of 7-bromo-3-iodo-1-methyl-1H-indazole (5.000 g, 14.84 mmol, 1 eq) in dioxane (50 mL) and water (5 mL) was added 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (6.190 g, 14.84 mmol, 1 eq) , (1,1'- bis(diphenylphosphino)ferrocene)palladium(II) dichloride (1.090 g, 1.48 mmol, 0.1 eq) and cesium carbonate (14.500 g, 44.52 mmol, 3 eq). The mixture was stirred at 100 °C for 12 h. 7- Bromo-3-iodo-1-methyl-1H-indazole was consumed and desired mass was detected by LCMS. TLC showed 7-bromo-3-iodo-1-methyl-1H-indazole was remained and new spot was detected. The reaction mixture was concentrated in vacuum. The residue was purified by silica gel chromatography (0-8.5% Ethyl acetate in Petroleum ether) to give the desired product. 3-(2,6- Bis(benzyloxy)pyridin-3-yl)-7-bromo-1-methyl-1H-indazole (4.240 g, 8.47 mmol, 57.1% yield) was obtained as yellow solid. MS (ESI) m / z: 500.1 [M+1]+; 1H NMR (400 MHz, DMSO-d6) δ 7.86 (d, J = 8.0 Hz, 1 H), 7.57 - 7.69 (m, 2 H), 7.45 - 7.50 (m, 2 H), 7.25 - 7.43 (m, 8 H), 6.93 (t, J = 7.6 Hz, 1 H), 6.60 (d, J = 8.0 Hz, 1 H), 5.43 (s, 4 H), 4.36 (s, 3 H).

[0226] Step i-7.4. Synthesis of tert-butyl (3-(2,6-bis(benzyloxy)pyridin-3-yl)-1- methyl-1H-indazol-7-yl)carbamate. [2-(2-aminophenyl)phenyl]-chloro- palladium;dicyclohexyl-[3-(2,4,6-triisopropylphenyl)phenyl]phosphane (1.310 g, 1.67 mmol, 0.05 eq) was added to a solution of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-7-bromo-1-methyl-1H- indazole (74% purity, 16.700 g, 33.37 mmol, 1 eq), tert-butyl carbamate (3.910 g, 33.37 mmol, 1 eq) and cesium carbonate (21.750 g, 66.75 mmol, 2 eq) in dioxane (300 mL), the mixture solution was heated to 100 °C and stirred for 16 h. LCMS showed mass of desired product was detected. The solution was filtered and the filtrate was concentrated to give a residue. The residue was purified by silica gel chromatography (a solution of 1% to 12% ethyl acetate in petroleum ether). tert-butyl (3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazol-7- yl)carbamate (6.600 g, 12.30 mmol, 36.85% yield) was a yellow oil, detected by NMR MS (ESI) m / z: 537.0 [M+1]+;1H NMR (400 MHz, CDCl3) δ = 7.85 (d, J = 8.0 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.44-7.47 (m, 1H), 7.36-7.41 (m, 2H), 7.27-7.35 (m, 4H), 7.21-7.27 (m, 3H), 6.97 (t, J = 7.6 Hz, 1H), 6.52 (d, J = 8.0 Hz, 1H), 6.40 (s, 1H), 5.45 (s, 2H), 5.41 (s, 2H), 4.29 (s, 3H), 1.54 (s, 9H).

[0227] Step i-7.5. Synthesis of tert-butyl (3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H- indazol-7-yl)carbamate. Palladium on carbon (1.000 g, 10% purity) was added to a solution of tert-butyl (3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazol-7-yl)carbamate (8.000 g, 14.91 mmol, 1 eq) in tetrahydrofuran (150 mL), the mixture solution was stirred under hydrogen (50 psi) at 25 °C for 24 h. LCMS showed mass of desired product was detected. The solution was filtered and the filtrate was concentrated to give a residue. The residue was purified by silica gel chromatography (a solution of 10% to 67% ethyl acetate in petroleum ether). Tert- butyl (3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)carbamate (3.600 g, 10.04 mmol,67.38% yield) was a yellow solid, detected by HNMR. MS (ESI) m / z: 359.1 [M+1]+;1H NMR (400 MHz, DMSO-d6) δ = 10.91 (s, 1H), 9.10 (s, 1H), 7.57 (d, J = 7.2 Hz, 1H), 7.02-7.12 (m, 2H), 4.34-4.40 (m, 1H), 4.07 (s, 3H), 2.60-2.73 (m, 2H), 2.32-2.40 (m, 1H), 2.12-2.20 (m, 1H), 1.47 (s, 9H).

[0228] Step i-7.6. Synthesis of 3-(7-Amino-1-methyl-1H-indazol-3-yl)piperidine-2,6- dione . Tert-butyl (3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)carbamate (3.500 g, 9.77 mmol, 1 eq) was added to hydrogen chloride aqueous solution (12 M, 50 mL, 61.44 eq) at 0 °C, the mixture solution was stirred at 25 °C for 2 h. A yellow clear solution was obtained, LCMS showed mass of desired product was detected. The solution was poured into cold water (500 mL) at 0 °C, then the solution was set for lyophilization. The title compound was collected, 3-(7-Amino-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (2673.81 mg, 8.73 mmol, 89.36% yield, 96.2% purity, HCl salt) as a yellow solid,. MS (ESI) m / z: 259.2 [M+1]+;1H NMR (400 MHz, DMSO-d6) δ = 10.91 (s, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.50 (d, J = 7.2 Hz, 1H), 7.15 (t, J = 7.6 Hz, 1H), 4.39-4.45 (m, 1H), 4.32 (s, 3H), 2.57-2.75 (m, 2H), 2.32-2.45 (m, 1H), 2.13-2.21 (m, 1H). Note: exchangeable protons not visible Synthesis of Intermediate i-8: 1-(6-amino-1-methyl-indazol-3-yl) hexahydropyrimidine- 2,4-dione

[0229] Step i-8.1. Synthesis of 1-(1-methyl-6-nitro-indazol-3-yl) hexahydropyrimidine-2,4-dione. A mixture of 3-bromo-1-methyl-6-nitro-indazole (3.00 g, 11.72 mmol), hexahydropyrimidine-2,4-dione (1.60 g, 14.06 mmol), potassium phosphate tribasic (6.22 g, 29.29 mmol), tetramethyl tBuXPhos (281.0 mg, 0.58 mmol ) and Tris(dibenzylideneacetone)dipalladium(0) (268.0 mg, 0.29 mmol) in tert-butanol (125.0 mL) was degassed with nitrogen 3 times. The reaction mixture was heated to 100 °C for 24 h and then cooled to rt. Additional Tris(dibenzylideneacetone)dipalladium(0) (268.0 mg, 0.29 mmol) and tetramethyl tBuXPhos (281.0 mg, 0.58 mmol) were added. The reaction mixture was heated to 100 °C for an additional 16 h and then cooled to rt. The volatiles were evaporated under reduced pressure. Water (200.0 mL) was added and the resulting precipitate was collected by filtration (Buchner funnel), then washed with water (3 x 50.0 mL) and dried under vacuum. The material was triturated in diethyl ether (100.0 ml) and collected by filtration to afford title compound (2.64 g, 78%) as a solid, which was used in next step without further purification. MS (ESI) [M+H] +:290.2;1H NMR (500 MHz, DMSO) δ 10.67 (s, 1H), 8.70 (dd, J = 1.7, 0.7 Hz, 1H), 7.95 – 7.84 (m, 2H), 4.14 (s, 3H), 3.97 (t, J = 6.7 Hz, 2H), 2.77 (t, J = 6.7 Hz, 2H).

[0230] Step i-8.2. Synthesis of 1-(6-amino-1-methyl-indazol-3-yl) hexahydropyrimidine-2,4-dione. A mixture of 1-(1-methyl-6-nitro-indazol-3- yl)hexahydropyrimidine-2,4-dione (2.64 g, 9.13 mmol) and 10% palladium on carbon (0.97 g, 0.91 mmol) in methanol (250.0 mL) was hydrogenated under hydrogen atmosphere (1 atm) at rt for 6.5 h. The mixture was filtered through celite and washed with methanol (5 x 45.0 mL). The filtrate was concentrated under reduced pressure, the material was triturated in diethyl ether and collected by filtration to afford the title compound (1.92 g, 81%) as a solid. MS (ESI) [M+H] +: 260.1;1H NMR (400 MHz, DMSO) δ 10.45 (s, 1H), 7.27 (d, J = 8.7 Hz, 1H), 6.48 (dd, J = 8.7, 1.8 Hz, 1H), 6.39 (d, J = 1.3 Hz, 1H), 5.39 (s, 2H), 3.85 (t, J= 6.7 Hz, 2H), 3.76 (s, 3H), 2.71 (t, J= 6.7 Hz, 2H). Synthesis of Intermediate i-9: [3-(2,4-Dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6- yl]boronic acid.

[0231] Step i-9.1. Synthesis of 1-(6-Iodo-1-methyl-indazol-3- yl)hexahydropyrimidine-2,4-dione. To a solution of 1-(6-amino-1-methyl-indazol-3- yl)hexahydropyrimidine-2,4-dione, Intermediate 8 (2.1 g, 8.1 mmol) in acetic acid (21 mL) cooled to 0 °C was added sequentially a solution of sulfuric acid (1.11 mL, 20.3 mmol) in water (5 mL) and a solution of sodium nitrite (838 mg, 12.15 mmol) in water (5 mL), and the reaction mixture was stirred at 0 °C for 2 h. A solution of potassium iodide (4 g, 24 mmol) in water (5 mL) was added and the mixture was stirred at 0 °C for 2 h then warmed to rt. A 50% aqueous solution of sodium bicarbonate (50 mL) was added to the mixture and stirred for 18 h. The resulting precipitate was collected by filtration, washed with water (3 x 10 mL) and diethyl ether (3 x 10 mL) then dried under vacuum to afford the title compound (1.98 g, 66%) as a solid, which was used in the next step without further purification. MS (ESI) [M+H]+ 371.3.1H NMR (400 MHz, DMSO-d6) δ 10.58 (s, 1H), 8.12 (d, J = 0.6 Hz, 1H), 7.47 (d, J = 8.6 Hz, 1H), 7.39 (dd, J = 8.6, 1.3 Hz, 1H), 3.97 (s, 3H), 3.92 (t, J = 6.7 Hz, 2H), 2.75 (t, J = 6.7 Hz, 2H).

[0232] Step i-9.2. Synthesis of 1-[1-Methyl-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)indazol-3-yl]hexahydropyrimidine-2,4-dione. A mixture of 1-(6-iodo-1- methyl-indazol-3-yl)hexahydropyrimidine-2,4-dione (500 mg, 1.35 mmol),bis(pinacolato)diboron (412 mg, 1.62 mmol), palladium (II) acetate (30 mg, 0.14 mmol) and potassium acetate (398 mg, 4.05 mmol) in N, N-dimethylformamide (14 mL) was heated to 80 °C for 18 h and then cooled to rt. The mixture was filtered on celite and washed with ethyl acetate (5 x 15 mL). Water (50 mL) was added to the filtrate and the layers were separated. The organic layer was washed with water (5 x 25 mL), brine (25 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a gradient of 50-100% ethyl acetate in hexanes to afford the title compound (335 mg, 67%) as a solid. MS (ESI) [M+H]+ 371.2;1H NMR (400 MHz, DMSO-d6) δ 10.56 (s, 1H), 7.90 (s, 1H), 7.66 (dd, J = 8.2, 0.8 Hz, 1H), 7.38 (d, J = 8.7 Hz, 1H), 4.04 (s, 3H), 3.93 (t, J = 6.7 Hz, 2H), 2.77 (t, J = 6.7 Hz, 2H), 1.33 (s, 12H).

[0233] Step i-9.3. Synthesis of [3-(2,4-Dioxohexahydropyrimidin-1-yl)-1-methyl- indazol-6-yl]boronic acid. To a solution of 1-[1-methyl-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)indazol-3-yl]hexahydropyrimidine-2,4-dione (403 mg, 1.09 mmol) in tetrahydrofuran (5 mL) and water (5 mL) were added sequentially sodium periodate (698 mg, 3.27 mmol) and 1M aqueous HCl (2.2 mL, 2.2 mmol). The reaction mixture was stirred at rt for 18 h. The volatiles were evaporated under reduced pressure and the resulting precipitate was collected by filtration, washed with water (3 x 2 mL), and diethyl ether (3 x 1 mL), then dried under vacuum to afford title compound (240 mg, 76%) as a solid, which was used in the next step without further purification. MS (ESI) [M+H]+ 289.1;1H NMR (400 MHz, DMSO-d6) δ 10.54 (s, 1H), 8.16 (s, 2H), 8.01 (s, 1H), 7.59 (d, J = 8.2 Hz, 1H), 7.52 (d, J = 8.3 Hz, 1H), 4.00 (s, 3H), 3.92 (t, J = 6.7 Hz, 2H), 2.76 (t, J = 6.6 Hz, 2H). Synthesis of Intermediate i-10: 1-[6-(4-Amino-1-piperidyl)-1-methyl-indazol-3- yl]hexahydropyrimidine-2,4-dione hydrochloride.

[0234] Step i-10.1. Synthesis of tert-Butyl N-[1-[3-(2,4-dioxohexahydropyrimidin-1-yl)- 1-methyl-indazol-6-yl]-4-piperidyl]carbamate. A mixture of [3-(2,4-dioxohexahydropyrimidin-1- yl)-1-methyl-indazol-6-yl]boronic acid (240 mg, 0.83 mmol, Intermediate 9), tert-butyl N-(4- piperidyl)carbamate (334 mg, 1.67 mmol), copper (II) acetate (183 mg, 0.92 mmol), triethylamine (0.23 mL, 1.67 mmol) and 3Å MS (200 mg) in dichloroethane (12 mL) was heated to 50 °C for24 h. The mixture was filtered on celite and washed with a 1:1 mixture of acetonitrile and methanol (3 x 5 mL). The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel using a gradient of 0–100% ethyl acetate in hexanes to afford title compound (96 mg, 23%) as a solid. MS (ESI) [M+H]+ 443.2.

[0235] Step i-10.2. Synthesis of 1-[6-(4-Amino-1-piperidyl)-1-methyl-indazol-3- yl]hexahydropyrimidine-2,4-dione hydrochloride. To a solution of tert-butyl N-[1-[3-(2,4- dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]-4-piperidyl]carbamate (175 mg, 0.36 mmol) in 1,4-dioxane (5 mL) was added 4N HCl in 1,4-dioxane (0.44 mL, 1.78 mmol). The reaction mixture was heated to 100 °C for 2 h, then cooled to rt and the volatiles were evaporated under reduced pressure. Diethyl ether (5 mL) was added and the resulting precipitate was collected by filtration, washed with diethyl ether (3 x 2 mL), then dried under vacuum to afford the title compound (138 mg, quant.) as a solid, which was used in the next step without further purification. MS (ESI) [M+H]+ 343.2. Synthesis of Intermediate i-11: (R)-3-(7-Amino-1-methyl-1H-indazol-3-yl)-3- methylpiperidine-2,6-dione

[0236] Step i-11.1. Synthesis of 3-Iodo-7-nitro-1H-indazole. To the solution of 7-nitro- 1H-indazole (100.000 g, 613.00 mmol, 1 eq) in N,N-dimethyl formamide (2000 mL) was added diiodine (311.170 g, 1230.00 mmol, 2.00 eq), potassium hydroxide (68.790 g, 1230.00 mmol, 2 eq). The mixture was stirred at 15°C for 12 hr. 7-nitro-1H-indazole was consumed and desired mass was detected by LCMS. The reaction mixture was added into the ice water (2000 mL) with stirring. The precipitate was collected by filtration. The crude product was diluted with ethyl acetate (3000 mL), washed with Sat sodium sulfite (3 x 50 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The crude product was rinsed with ethyl acetate (20 mL) and filtered, dried under vacuum. 3-iodo-7-nitro-1H- indazole (168.000 g, 581.26 mmol, 94.8% yield) as a yellow solid was obtained. MS (ESI) m / z: 289.9 [M+1]+;1H NMR (400 MHz, DMSO-d6) δ 11.63 (s, 1H), 8.43 (d, J = 8.0 Hz, 2H), 7.93 (d, J = 8.0 Hz, 2H), 7.40 (t, J = 8.0 Hz, 2H).

[0237] Step i-11.2. Synthesis of 3-Iodo-1-methyl-7-nitro-1H-indazole. To a solution of 3-iodo-7-nitro-1H-indazole (197.000 g, 681.59 mmol, 1 eq) in tetrahydrofuran (1000 mL) was added methyl iodide (193.490 g, 1360.00 mmol, 85 mL, 2 eq) and cesium carbonate (333.110 g,1020.00 mmol, 1.5 eq) and the mixture was stirred at 50 °C for 12 hours. 3-iodo-7-nitro-1H- indazole was consumed and desired mass was detected by LCMS. The mixture was filtered and the filtrate was concentrated to give the brown solid. The filter was concentrated in vacuum to give residue. 3-iodo-7-nitro-1H-indazole was consumed and desired mass was detected by LCMS. The residue was purified by column chromatography on silica gel (2~100% Ethyl acetate in Petroleum ether). 3-iodo-1-methyl-7-nitro-indazole (2.65 g, 8.74 mmol, 1.28% yield) as a yellow solid was obtained. Another batch of 3-iodo-1-methyl-7-nitro-indazole (128 g, 282.98 mmol, 41.52% yield, 67 % purity) was obtained as a yellow solid. MS (ESI) m / z: 304.0 [M+1]+;1H NMR (400 MHz, DMSO-d6) δ 8.29 (dd, J= 0.8 Hz, 7.6 Hz, 1 H), 7.90 (d, J= 8.0 Hz, 1 H), 7.40 (t, J= 8.0 Hz, 1 H), 4.15 (s, 3 H).

[0238] Step i-11.3. Synthesis of 1-Methyl-7-nitro-3-(prop-1-en-2-yl)-1H-indazole. To a solution of 3-iodo-1-methyl-7-nitro-indazole (123.000 g, 271.93 mmol, 1 eq), 4,4,5,5- tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (68.540 g, 407.90 mmol, 1.5 eq), potassium phosphate (2 M, 1020 mL, 7.5 eq) in dioxane (3000 mL) was added tetrakis(triphenylphosphine)palladium (3.104 g, 2.72 mmol, 0.01 eq) and the reaction mixture was stirred for 12 h at 90°C under nitrogen atmosphere. 3-Iodo-1-methyl-7-nitro-indazole was consumed and desired product was detected by LCMS. The mixture was extracted with ethyl acetate (3x500 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (100% Petroleum ether). 1-Methyl-7-nitro-3-(prop-1-en-2-yl)-1H-indazole (56.000 g, 257.80 mmol, 94.8% yield) was obtained as yellow solid. MS (ESI) m / z: 218.1 [M+1]+;1H NMR (400 MHz, DMSO-d6) δ 8.41 (d, J = 8.0 Hz, 1 H), 8.17 (d, J = 8.0 Hz, 1 H), 7.35 (t, J = 8.0 Hz, 1 H), 5.80 (s, 1 H), , 5.48 (s, 1 H), 4.09 (s, 3 H), 2.24 (s, 3 H).

[0239] Step i-11.4. Synthesis of 2-(1-Methyl-7-nitro-1H-indazol-3-yl)propan-1-ol. To 1-Methyl-7-nitro-3-(prop-1-en-2-yl)-1H-indazole (56.000 g, 257.80 mmol, 1 eq) in tetrahydrofuran (1200 mL) was dropped borane dimethyl sulfide complex solution (10 M, 64.45 mL, 2.5 eq) at -5 °C under nitrogen atmosphere. The reaction mixture was warmed to 15 °C and stirred for 2 h. Then the mixture was added a solution of sodium perborate (63.260 g, 773.40 mmol, 3.0 eq) in water (300 mL) at -5 °C. The resulting mixture was stirred at 15 °C for 12 h. 1- Methyl-7-nitro-3-(prop-1-en-2-yl)-1H-indazole was consumed and desired mass was detected by LCMS. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in ethyl acetate (1000 mL) and the water layer was separated. The organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The crude product was rinsed with ethyl acetate (20mL) and the precipitate was collected by filtration. It gave the product 2-(1-methyl-7-nitro-1H-indazol-3-yl)propan-1-ol (60.000 g, 255.06 mmol, 98.9% yield) as a yellow solid. MS (ESI) m / z: 236.2 [M+1]+;1H NMR (400 MHz, DMSO-d6) δ 8.25 (d, J = 8.0 Hz, 1 H), 8.14 (dd, J= 0.8 Hz, 7.6 Hz, 1 H), 7.27 (t, J= 8.0 Hz, 1 H), 4.78 (t, J = 5.6 Hz, 1 H), 4.05 (s, 3 H), 3.72~3.63 (m, 1 H), 1.34 (d, J = 6.8 Hz, 3 H).

[0240] Step i-11.5. Synthesis of 2-(1-methyl-7-nitro-1H-indazol-3-yl)propanoic acid. To 2-(1-methyl-7-nitro-1H-indazol-3-yl)propan-1-ol (60.000 g, 255.06 mmol, 1 eq) in acetonitrile (2400 mL) and water (1200 mL) was dropped 2,2,6,6-tetramethyl-piperidin-1-oxyl (8.020 g, 51.01 mmol, 0.2 eq), sodium dihydrogen phosphate (192.180 g, 1.60 mol, 6.28 eq) and sodium chlorite (57.670 g, 510.12 mmol, 80% purity, 2 eq) and stirred at 15 °C. A solution of sodium hypochlorite (75.230 g, 53.56 mmol, 62.17 mL, 5.3% purity, 0.21 eq) in water (240 mL) was added dropwise and the mixture was stirred at 15 °C for 12 h. 2-(1-methyl-7-nitro-1H-indazol-3-yl)propan-1-ol was consumed and desired mass was detected by LCMS. The mixture was extracted with ethyl acetate (3x1000 mL). The organic layer was concentrated to give the residue. The residue was rinsed with ethyl acetate (100 mL). The precipitate was collected by filtration. It gave the product 2-(1-methyl-7-nitro-1H-indazol-3-yl)propanoic acid (62.000 g, 248.77 mmol, 97.5% yield) as a yellow solid. MS (ESI) m / z: 250.1 [M+1]+;1H NMR (400 MHz, DMSO-d6) δ 12.57 (s, 1H), 8.21 (d, J = 8.0 Hz, 1 H), 8.17 (d, J= 7.6 Hz, 1 H), 7.39~7.26 (m, 1 H), 4.28 (q, J = 7.2 Hz, 1 H), 4.08 (s, 3 H), 1.55 (d, J = 7.2 Hz, 3 H).

[0241] Step i-11.6. Synthesis of Methyl 2-(1-methyl-7-nitro-1H-indazol-3- yl)propanoate. To 2-(1-methyl-7-nitro-1H-indazol-3-yl)propanoic acid (62.000 g, 248.77 mmol, 1 eq) in methanol (500 mL) and toluene (500 mL) was dropped (diazomethyl)trimethylsilane (2 M, 248.77 mL, 2 eq) at 0 °C and the mixture was stirred at 15 °C for 2 h. 2-(1-methyl-7-nitro- 1H-indazol-3-yl)propanoic acid was consumed and desired mass was detected by LCMS. A new spot was formed by TLC and the mixture was concentrated to give the residue. The residue was purified by column chromatography on silica gel (10~50% Ethyl acetate in Petroleum ether). It gave the product methyl 2-(1-methyl-7-nitro-1H-indazol-3-yl)propanoate (61.000 g, 231.72 mmol, 93.1% yield) as a yellow solid. MS (ESI) m / z: 264.1 [M+1]+;1H NMR (400 MHz, DMSO-d6) δ 8.20~8.17 (m, 2 H), 7.40~7.31 (m, 1 H), 4.45~4.39 (m, 1 H), 4.13 (s, 3 H), 3.59 (s, 3 H), 1.57 (d, J = 7.2 Hz, 3 H).

[0242] Step i-11.7. Synthesis of methyl 4-cyano-2-methyl-2-(1-methyl-7-nitro-1H- indazol-3-yl)butanoate. To methyl 2-(1-methyl-7-nitro-1H-indazol-3-yl)propanoate (61.000 g, 231.72 mmol, 1 eq) and acrylonitrile (122.960 g, 2.32 mol, 10 eq) in acetonitrile (1500 mL) was added N-benzyl-N,N-diethylethanaminium hydroxide (19.380 g, 46.34 mmol, 40% purity, 0.2 eq) and the mixture was stirred at 80 °C for 12h. Methyl 2-(1-methyl-7-nitro-1H-indazol-3-yl)propanoate was consumed and desired mass was detected by LCMS. A new spot was detected by TLC and the mixture was concentrated. The residue was purified by column chromatography on silica gel (10~33% Ethyl acetate in Petroleum ether). It gave the product methyl 4-cyano-2- methyl-2-(1-methyl-7-nitro-1H-indazol-3-yl)butanoate (70.000 g, 221.30 mmol, 95.5% yield) as a yellow oil. MS (ESI) m / z: 317.1 [M+1]+;1H NMR (400 MHz, DMSO-d6) δ 8.18 (d, J= 7.6 Hz, 1 H), 8.03 (d, J= 8.0 Hz, 1 H), 7.33 (t, J= 8.0 Hz, 1 H), 4.09 (s, 3H), 3.63 (s, 3 H), 2.79~2.73 (m, 2 H), 2.61~2.46 (m, 2 H), 1.69 (s, 3 H).

[0243] Step i-11.8. Synthesis of 5-amino-2-methyl-2-(1-methyl-7-nitro-1H-indazol-3- yl)-5-oxopentanoic acid. To methyl 4-cyano-2-methyl-2-(1-methyl-7-nitro-1H-indazol-3- yl)butanoate (70.000 g, 221.30 mmol, 1 eq) in dimethylsulfoxide (200 mL) and methanol (200 mL) was added sodium hydroxide (1 M, 360.72 mL, 1.63 eq) and hydrogen peroxide (116.320 g, 1.03 mol, 98.58 mL, 30% purity, 4.64 eq) at 0°C and the mixture was stirred at 15 °C for 3 h. Methyl 4-cyano-2-methyl-2-(1-methyl-7-nitro-1H-indazol-3-yl)butanoate was consumed and desired mass was detected by LCMS. 100 mL of sat sodium sulfite was added into the mixture to quench excess hydrogen peroxide. The mixture was adjusted to pH=5.0 and extracted with ethyl acetate (3x200 mL). The organic layer was washed with water (3x50 mL). The organic layer was dried over anhydrous sodium sulfate. It was filtered and the filtrate was concentrated. It gave the product 5-amino-2-methyl-2-(1-methyl-7-nitro-1H-indazol-3-yl)-5-oxopentanoic acid (70.000 g, 218.55 mmol, 98.8% yield) as a yellow solid. MS (ESI) m / z:321.1 [M+1]+;1H NMR (400 MHz, DMSO-d6) δ 12.25 (s, 1H), 8.15 (dd, J= 5.2 Hz, 7.6 Hz, 1 H), 8.06 (d, J= 8.0 Hz, 1 H), 7.32~7.27 (m, 1 H), 7.13 (s, 1H), 4.08 (s, 3H), 2.43~2.39 (m, 1 H), 2.34~2.32 (m, 1 H), 2.09~2.06 (m, 1H), 1.91 (m, 1 H), 1.57 (s, 3H).

[0244] Step i-11.9. Synthesis of 3-methyl-3-(1-methyl-7-nitro-1H-indazol-3- yl)piperidine-2,6-dione. To 5-amino-2-methyl-2-(1-methyl-7-nitro-1H-indazol-3-yl)-5- oxopentanoic acid (70.000 g, 218.55 mmol, 1 eq) in tetrahydrofuran (500 mL) was added di(1H- imidazol-1-yl)methanone (42.520 g, 262.25 mmol, 1.2 eq) and N,N-dimethylpyridin-4-amine (2.670 g, 21.85 mmol, 0.1 eq) and the mixture was stirred at 70 °C for 12h. 5-amino-2-methyl-2- (1-methyl-7-nitro-1H-indazol-3-yl)-5-oxopentanoic acid was consumed and desired mass was detected by LCMS. A new spot was detected by TLC. The mixture was concentrated. The residue was purified by column chromatography on silica gel (10~33% Ethyl acetate in Petroleum ether). It gave the product 3-Methyl-3-(1-methyl-7-nitro-1H-indazol-3-yl)piperidine-2,6-dione (42.000 g, 138.94 mmol, 63.6% yield) as a yellow solid. MS (ESI) m / z: 303.1 [M+1]+;1H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.28 (d, J = 8.0 Hz, 1H), 8.16 (d, J = 7.2 Hz, 1H), 7.31 (t, J= 8.0 Hz, 1H), 4.07 (s, 3H), 2.65~2.59 (m, 2H), 2.47~2.46 (m, 1H), 2.15~2.11 (m, 1H), 1.70 (s,3H).

[0245] Step i-11.10. Synthesis of (R)-3-methyl-3-(1-methyl-7-nitro-1H-indazol-3- yl)piperidine-2,6-dione. 3-Methyl-3-(1-methyl-7-nitro-1H-indazol-3-yl)piperidine-2,6-dione (20.000 g, 66.16 mmol, 1 eq) was purified by SFC (column: DAICEL CHIRALPAK AD(250mm*30mm,10um);mobile phase: [Neu-methanol];B%: 55%-55%,5.3min;1050minmin) at 15 °C for 12 h. The two fractions were concentrated under pressure below 45°C. It gave the product (R)-3-Methyl-3-(1-methyl-7-nitro-1H-indazol-3-yl)piperidine-2,6-dione (P1, Rt= 1.80 min, 7.100 g, 23.21 mmol, 35.07% yield, 98.8% purity) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.28 (d, J = 8.0 Hz, 1H), 8.17 (d, J = 7.6 Hz, 1H), 7.32 (t, J = 8.0 Hz, 1H), 4.06 (s, 3H), 2.66~2.58 (m, 3H), 2.15~2.10 (m, 1 H), 1.70 (s, 3 H).

[0246] Step i-11.11. Synthesis of (R)-3-(7-Amino-1-methyl-1H-indazol-3-yl)-3- methylpiperidine-2,6-dione. To (R)-3-Methyl-3-(1-methyl-7-nitro-1H-indazol-3-yl)piperidine- 2,6-dione (7.100 g, 23.49 mmol, 1 eq) in ethanol (100 mL) and water (50 mL) was added iron powder (6.560 g, 117.44 mmol, 5 eq) and ammonium chloride (12.560 g, 234.88 mmol, 10 eq) and the mixture was stirred at 80 °C for 2h. (R)-3-Methyl-3-(1-methyl-7-nitro-1H-indazol-3- yl)piperidine-2,6-dione was consumed and desired mass was detected by LCMS. A new spot was detected by TLC and the mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (2~33% Ethyl acetate in Petroleum ether). It gave the product (R)-3-(7-Amino-1-methyl-1H-indazol-3-yl)-3-methylpiperidine-2,6-dione (6.000 g, 21.83 mmol, 92.9% yield, 99.1% purity) as a yellow solid. MS (ESI) m / z: 273.1 [M+1]+;1H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H), 7.01 (d, J = 8.0 Hz, 1H), 6.78 (t, J = 8.0 Hz, 1H), 6.55 (t, J = 7.2 Hz, 1H), 5.18 (s, 2H), 4.19 (s, 3H), 2.55~2.52 (m, 1H), 2.48~2.47 (m, 1H), 2.34~2.32 (m, 1 H), 2.07~2.05 (m, 1 H), 1.60 (s, 3 H). Synthesis of Intermediate i-12: (3R)-3-(6-amino-1-methyl-indazol-3-yl)-3-methyl- piperidine-2,6-dione

[0247] Step i-12.1: Synthesis of 3-Iodo-6-nitro-1H-indazole. To a solution of 6-nitro- 1H-indazole (60.000 g, 367.80 mmol, 1 eq) in N,N-dimethylformamide (1200 mL) was added potassium hydroxide (41.270 g, 735.59 mmol, 2 eq) and iodine (186.700 g, 735.59 mmol, 2 eq) at 0 °C. The mixture was stirred at 20 °C for 12 h. LCMS showed the reaction was completed. The mixture solution was poured to Sodium sulfite solution (4000 mL), filtrated and concentratedto give a residue. 3-Iodo-6-nitro-1H-indazole (200.000 g, crude) was obtained as yellow solid, detected by HNMR. MS (ESI) m / z: 289.9 [M+1]+.1H NMR (400MHz, DMSO-d6) δ 14.13 (s, 1H), 8.43 (d, J=1.6 Hz, 1H), 7.97 - 7.93 (m, 1H), 7.63 (d, J=8.8 Hz, 1H).

[0248] Step i-12.2: Synthesis of 3-iodo-1-methyl-6-nitro-1H-indazole. To a solution of 3-iodo-6-nitro-1H-indazole (100.000 g, 345.99 mmol, 1 eq) in N,N-dimethylformamide (1500 mL) was added cesium carbonate (169.090 g, 518.98 mmol, 1.5 eq) and iodomethane (54.020 g, 380.58 mmol, 1.1 eq). The mixture was stirred at 50 °C for 12 h. TLC and LCMS showed the reaction was completed. The mixture solution was poured to water (3000 mL), filtrated and concentrated to give a residue. The residue was purified by silica column chromatography on silica gel (a solution of 5% to 50% ethyl acetate in petroleum ether). 3-iodo-1-methyl-6-nitro- indazole (29.000 g, 95.69 mmol, 7.25% yield) was obtained as yellow solid. MS (ESI) m / z: 304.0 [M+1]+.

[0249] Step i-12.3: Synthesis of 1-methyl-6-nitro-3-(prop-1-en-2-yl)-1H-indazole. To a solution of 3-iodo-1-methyl-6-nitro-indazole (29.000 g, 95.69 mmol, 1 eq) in dioxane (435.0 mL) and water (145.0 mL) was added tetrakis(triphenylphosphine) palladium (1.110 g, 0.96 mmol, 0.01 eq), isopropenylboronic acid (9.860 g, 114.83 mmol, 1.2 eq) and potassium phosphate (2 M, 143.5 mL, 3 eq). The mixture was stirred at 90 °C for 12 h. LCMS showed the reaction was completed. The residue was diluted with water (200 mL) and extracted with ethyl acetate (200 mL × 3). The combined organic layers were washed with brine(200 mL × 3), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. 3-Isopropenyl- 1-methyl-6-nitro-indazole (22.000 g, crude) was obtained as yellow solid. MS (ESI) m / z: 218.1 [M+1]+.

[0250] Step i-12.4: Synthesis of 2-(1-methyl-6-nitro-1H-indazol-3-yl)propan-1-ol. To 3-isopropenyl-1-methyl-6-nitro-indazole (22.000 g, 101.28 mmol, 1 eq) in tetrahydrofuran (400 mL) was dropped Borane dimethyl sulfide complex solution (10 M, 25.3 mL, 2.5 eq) at -5 °C under nitrogen. The reaction mixture was warmed to 15 °C and stirred for 2 h. Then the mixture was added a solution of sodium perborate (24.850 g, 303.83 mmol, 3 eq) in water (100 mL) at -5 °C. The resulting mixture was stirred at 15 °C for 12 h. TLC and LCMS showed the reaction was completed. The mixture was filtered and concentrated. The residue was dissolved in ethyl acetate (300 mL) and the water layer was separated. The organic layer was dried over sodium sulfate, filtered and the filtrate was concentrated. The residue was purified by silica column chromatography on silica gel (a solution of 10% to 50% ethyl acetate in petroleum ether). 2-(1- Methyl-6-nitro-indazol-3-yl)propan-1-ol (20.000 g, 85.02 mmol, 83.95% yield) was obtained as yellow solid, detected by HNMR. MS (ESI) m / z: 236.1 [M+1]+.1H NMR (400MHz, DMSO-d6) δ 8.61 (d, J=1.6 Hz, 1H), 8.01 (d, J=8.8 Hz, 1H), 7.87 (dd, J=2.0, 8.8 Hz, 1H), 4.78 (t, J=5.6 Hz, 1H), 4.11 (s, 3H), 3.74 - 3.61 (m, 2H), 3.37 (s, 1H), 1.35 (d, J=7.2 Hz, 3H).

[0251] Step i-12.5: Synthesis of 2-(1-methyl-6-nitro-1H-indazol-3-yl)propanoic acid. To 2-(1-methyl-6-nitro-indazol-3-yl)propan-1-ol (18.000 g, 76.52 mmol, 1 eq) in acetonitrile (360.0 mL) and water (180.0 mL) was dropped 2,2,6,6-Tetramethyl-1-piperidinyloxy (2.410 g, 15.30 mmol, 0.2 eq), sodium dihydrogen phosphate (57.650 g, 480.53 mmol, 6.28 eq) and sodium chlorite (17.300 g, 153.04 mmol, 80% purity, 2 eq) and stirred at 0 °C. A solution of sodium hypochlorite (32.240 g, 22.96 mmol, 26.7 mL, 5.3% purity, 0.3 eq) in water (36 mL) was added dropwise and the mixture was stirred at 15 °C for 12 h. TLC and LCMS showed the reaction was completed. The mixture was extracted with ethyl acetate (3 × 200 mL). The organic layer was concentrated to give the residue. The residue was purified by silica column chromatography on silica gel (a solution of 10% to 50% ethyl acetate in petroleum ether). 2-(1-methyl-6-nitro- indazol-3-yl)propanoic acid (19.000 g, 76.24 mmol, 99.63% yield) was obtained as yellow solid. MS (ESI) m / z: 250.1 [M+1]+.

[0252] Step i-12.6: Synthesis of Methyl 2-(1-methyl-6-nitro-1H-indazol-3- yl)propanoate. To 2-(1-methyl-6-nitro-indazol-3-yl)propanoic acid (19.000 g, 76.24 mmol, 1 eq) in Methanol (150 mL) and toluene (150 mL) was dropped Trimethylsilane diazomethane (2 M, 114.4 mL, 3 eq) at 0 °C. And the mixture was stirred at 15 °C for 2 h. LCMS showed the reaction was completed. The mixture was concentrated to give a residue. Methyl 2-(1-methyl-6-nitro- indazol-3-yl)propanoate (20.000 g, crude) was obtained as gray solid. MS (ESI) m / z: 264.1 [M+1]+.

[0253] Step i-12.7: Synthesis of methyl 4-cyano-2-methyl-2-(1-methyl-6-nitro-1H- indazol-3-yl)butanoate. To a solution of methyl 2-(1-methyl-6-nitro-indazol-3-yl)propanoate (20.000 g, 75.97 mmol, 1 eq) in acetonitrile (300.0 mL) was added benzyltrimethylammonium hydroxide (6.350 g, 15.19 mmol, 40% purity, 0.2 eq) and prop-2-enenitrile (40.310 g, 759.74 mmol, 10 eq). The mixture was stirred at 80 °C for 12 hr. TLC and LCMS showed the reaction was completed. The mixture was concentrated to give a residue. The residue was purified by silica column chromatography on silica gel (a solution of 5% to 50% ethyl acetate in petroleum ether). Methyl 4-cyano-2-methyl-2-(1-methyl-6-nitro-indazol-3-yl)butanoate (20.000 g, 63.23 mmol, 83.22% yield) was obtained as yellow solid. MS (ESI) m / z: 317.1 [M+1]+.

[0254] Step i-12.8: Synthesis of 5-amino-2-methyl-2-(1-methyl-6-nitro-1H-indazol-3- yl)-5-oxopentanoic acid. To methyl 4-cyano-2-methyl-2-(1-methyl-6-nitro-indazol-3- yl)butanoate (20.000 g, 63.23 mmol, 1 eq) in DMSO (150 mL) and methyl alcohol (150 mL) was added sodium hydroxide (1 M, 63.2 mL, 1 eq) and hydrogen peroxide (73.750 g, 650.45 mmol,62.5 mL, 30% purity, 10.29 eq) at 0 °C and the mixture was stirred at 15 °C for 12 h. LCMS showed the reaction was completed. 100 mL saturated sodium sulfite was added into the mixture to quench excess hydrogen peroxide. The mixture was adjusted to pH = 5.0 (1 M hydrogen chloride) and extracted with ethyl acetate (3 × 300 mL). The organic layer was washed with water (3 × 200 mL). The organic layer was dried over sodium sulfate. It was filtered and the filtrate was concentrated. 5-amino-2-methyl-2-(1-methyl-6-nitro-indazol-3-yl)-5-oxo-pentanoic acid (15.000 g, crude) was obtained as yellow solid. MS (ESI) m / z: 321.1 [M+1]+.

[0255] Step i-12.9: Synthesis of 3-methyl-3-(1-methyl-6-nitro-1H-indazol-3- yl)piperidine-2,6-dione. To a solution of 5-amino-2-methyl-2-(1-methyl-6-nitro-indazol-3-yl)-5- oxo-pentanoic acid (15.000 g, 46.83 mmol, 1 eq) in tetrahydrofuran (300 mL) was added 1,1'- carbonyldiimidazole (18.980 g, 117.08 mmol, 2.5 eq) and dimethylaminopyridine (0.572 g, 4.68 mmol, 0.1 eq). The mixture was stirred at 70 °C for 12 h. LCMS, HPLC and TLC showed the reaction was completed. The mixture was concentrated to give a residue. he residue was purified by silica column chromatography on silica gel (a solution of 5% to 50% ethyl acetate in petroleum ether). 3-methyl-3-(1-methyl-6-nitro-indazol-3-yl)piperidine-2,6-dione (15.000 g, crude) was obtained as yellow solid. MS (ESI) m / z: 303.1 [M+1]+.

[0256] Step i-12.10: Synthesis of rel-(R)-3-methyl-3-(1-methyl-6-nitro-1H-indazol-3- yl)piperidine-2,6-dione. 3-Methyl-3-(1-methyl-6-nitro-indazol-3-yl)piperidine-2,6-dione (15.000 g, 49.62 mmol, 1 eq) was purified by prep-SFC(Column: Chiralcel OJ-350×4.6mm I.D., 3um Mobile phase: methanol (0.05% DEA) in CO2 from 5% to 40%).). (3R)-3-methyl-3-(1- methyl-6-nitro-indazol-3-yl)piperidine-2,6-dione (6.500 g, 21.37 mmol, 43.07% yield, 99.4% purity) was obtained as yellow solid, detected by HPLC and SFC.

[0257] Step i-12.11: Synthesis of (R)-3-(6-amino-1-methyl-1H-indazol-3-yl)-3- methylpiperidine-2,6-dione. To a solution of (3R)-3-methyl-3-(1-methyl-6-nitro-indazol-3- yl)piperidine-2,6-dione (6.500 g, 21.50 mmol, 1 eq) in ethyl alcohol (100 mL) and water (50 mL) was added iron (6.000 g, 107.51 mmol, 5 eq) and ammonia hydrochloride (11.500 g, 215.03 mmol, 10 eq). The mixture was stirred at 80 °C for 2 h. TLC showed the reaction was completed. The mixture was filtered and concentrated to give a residue. The residue was purified by silica column chromatography on silica gel (a solution of 1% to 5% methanol in dichloromethane). (3R)-3-(6- amino-1-methyl-indazol-3-yl)-3-methyl-piperidine-2,6-dione (4.600 g, 16.83 mmol, 92.74% yield, 99.5% purity) was obtained as brown solid, detected by HNMR, HPLC, SFC and QC- LCMS. MS (ESI) m / z:273.3 [M+1]+.1H NMR (400MHz, DMSO-d6) δ 10.77 (s, 1H), 7.43 (d, J=8.8 Hz, 1H), 6.47 (dd, J=1.6, 8.8 Hz, 1H), 6.41 (s, 1H), 5.36 (s, 2H), 3.75 (s, 3H), 2.49 - 2.29 (m, 3H), 2.13 - 2.01 (m, 1H), 1.58 (s, 3H).Synthesis of Intermediate i-13: 3-[5-[4-(Methylamino)-1-piperidyl]benzimidazol-1- yl]piperidine-2,6-dione dihydrochloride

[0258] Step i-13.1: Synthesis of 2,6-dibenzyloxypyridin-3-amine. To a solution of 2,6- dibenzyloxy-3-nitro-pyridine(10.0 g, 29.7 mmol) in acetic acid (297 mL) was added iron powder (8.3 g, 148 mmol). The reaction mixture was stirred at 80 °C for 2 h then cooled to rt for 12 h. The mixture was filtered through celite, washed with methanol (200 mL) and the filtrate was concentrated under reduced pressure. Ethyl acetate (500 mL) and a saturated aqueous solution of sodium bicarbonate (400 mL) were added and the layers were separated. The organic layer was washed with water (400 mL), brine (300 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford title compound (9.3 g, quant.) as an oil which was used in the next step without further purification. MS (ESI) [M+H]+ 307.2.

[0259] Step i-13.2: Synthesis of 2,6-dibenzyloxy-N-(4-bromo-2-nitro-phenyl)pyridin- 3-amine. To a solution of 2,6-dibenzyloxypyridin-3-amine (10.0 g, 32.6 mmol) and 4-bromo-1- fluoro-2-nitro-benzene (2.8 mL, 22.9 mmol) in tetrahydrofuran (163 mL) at 0 °C was added a solution of 1M lithium bis(trimethylsilyl)amide in tetrahydrofuran (68.6 mL, 68.6 mmol) dropwise over 30 min. After the addition was completed, the reaction mixture was stirred at rt for 3 h and then cooled to 0 °C. A saturated aqueous solution of ammonium chloride (150 mL) and ethyl acetate (300 mL) were added and the layers were separated. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate (150 mL), water (150 mL), brine (150 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a gradient of 0–50% ethyl acetate in hexanes to afford title compound (8.7 g, 53%). MS (ESI) [M+H]+ 508.2;1H NMR (400 MHz, CDCl3) δ 9.11 (s, 1H), 8.30 (d, J = 2.3 Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.42 – 7.26 (m, 8H), 7.26 – 7.24 (m, 2H), 7.23 (s, 1H), 6.70 (d, J = 9.1 Hz, 1H), 6.42 (d, J = 8.3 Hz, 1H), 5.35 (s, 2H), 5.33 (s, 2H).

[0260] Step i-13.3: Synthesis of 4-bromo-N1-(2,6-dibenzyloxy-3-pyridyl)benzene-1,2- diamine. To a solution of 2,6-dibenzyloxy-N-(4-bromo-2-nitro-phenyl)pyridin-3-amine (8.7 g, 17 mmol) and calcium chloride (3.8 g, 34 mmol) in ethanol (104 mL) and water (5.5 mL) was added iron powder (4.8 g, 86 mmol). The reaction mixture was refluxed for 12 h and then cooled to rt. The mixture was filtered through celite, washed with ethyl acetate (200 mL) and the filtrate was concentrated under reduced pressure. ethyl acetate (400 mL) and water (300 mL) were added andthe layers were separated. The organic layer was washed with brine (300 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound (7.1 g, 87%) as an oil which was used without further purification. MS (ESI) [M+H]+ 476.2.

[0261] Step i-13.4: Synthesis of 5-bromo-1-(2,6-dibenzyloxy-3- pyridyl)benzimidazole. To a solution of 4-bromo-N1-(2,6-dibenzyloxy-3-pyridyl)benzene-1,2- diamine (6.1 g, 12.8 mmol) in triethyl orthoformate (19.1 mL, 115 mmol) was added formic acid (9.7 mL, 256 mmol). The reaction mixture was stirred at 100 °C for 15 min and then cooled to rt. The volatiles were evaporated under reduce pressure. The residue was purified by column chromatography on silica gel using a gradient of 0–100 % ethyl acetate in hexanes to afford title compound (5.4 g, 87%) as a semi-solid. MS (ESI) [M+H]+ 487.2;1H NMR (500 MHz, DMSO) δ 8.41 (s, 1H), 8.13 (s, 1H), 7.95 (d, J = 8.3 Hz, 1H), 7.93 (d, J = 1.8 Hz, 1H), 7.49 – 7.46 (m, 2H), 7.42 – 7.35 (m, 4H), 7.28 – 7.24 (m, 4H), 7.24 – 7.21 (m, 1H), 6.67 (d, J = 8.3 Hz, 1H), 5.43 (s, 2H), 5.40 (s, 2H).

[0262] Step i-13.5: Synthesis of tert-butyl N-[1-[1-(2,6-dibenzyloxy-3- pyridyl)benzimidazol-5-yl]-4-piperidyl]-N-methyl-carbamate. A mixture of 5-bromo-1-(2,6- dibenzyloxy-3-pyridyl)benzimidazole (500 mg, 1.03 mmol), tert-butyl N-methyl-N-(4- piperidyl)carbamate (440 mg, 2.1 mmol), sodium tert-butoxide (296 mg, 3.1 mmol) and tBuXPhos-Pd-G3 (82 mg, 0.10 mmol) in tetrahydrofuran (12.5 mL) was heated to 70 °C for 18 h and then cooled to rt. The mixture was filtered through celite, washed with methanol (20 mL) and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a gradient of 0–100% ethyl acetate in hexanes to afford title compound (284 mg, 45 % yield) as an oil. MS (ESI) [M+H]+ 621.4;1H NMR (500 MHz, DMSO) δ 8.21 (s, 1H), 7.89 (d, J = 8.3 Hz, 1H), 7.49 – 7.46 (m, 2H), 7.42 – 7.38 (m, 2H), 7.37 – 7.33 (m, 1H), 7.30 – 7.27 (m, 5H), 7.20 (d, J = 2.2 Hz, 1H), 7.11 – 7.08 (m, 1H), 7.02 – 6.98 (m, 1H), 6.65 (d, J = 8.3 Hz, 1H), 5.42 (s, 2H), 5.40 (s, 2H), 3.66 (m, 2H), 3.30 – 3.27 (m, 1H), 2.73 – 2.68 (m, 2H), 2.71 (s, 3H), 1.88 – 1.79 (m, 2H), 1.67 – 1.59 (m, 2H), 1.41 (s, 9H).

[0263] Step i-13.6: Synthesis of tert-butyl N-[1-[1-(2,6-dioxo-3- piperidyl)benzimidazol-5-yl]-4-piperidyl]-N-methyl-carbamate. A mixture of tert-butyl N-[1- [1-(2,6-dibenzyloxy-3-pyridyl)benzimidazol-5-yl]-4-piperidyl]-N-methyl-carbamate (285 mg, 0.46 mmol) and 20% Pearlman’s catalyst (42 mg, 0.06 mmol) in tetrahydrofuran (6 mL) and ethanol (6 mL) was subjected to hydrogenation at 1 atm and 50 °C for 5 h. The mixture was filtered through celite and washed with methanol (3 x 10 mL). The filtrate was concentrated under reduced pressure to afford title compound (192 mg) as a semi-solid which was used in the next step without further purification. MS (ESI) [M+H]+ 442.3.

[0264] Step i-13.7: Synthesis of 3-[5-[4-(methylamino)-1-piperidyl]benzimidazol-1- yl]piperidine-2,6-dione dihydrochloride. To a solution of tert-butyl N-[1-[1-(2,6-dioxo-3- piperidyl)benzimidazol-5-yl]-4-piperidyl]-N-methyl-carbamate (192 mg, 0.43 mmol) in 1,4- dioxane (10 mL) was added 4N HCl in 1,4-dioxane (0.9 mL, 3.5 mmol). The reaction mixture was heated to 100 °C for 1 h, then cooled to rt. The volatiles were evaporated under reduced pressure to afford title compound (210 mg) as a solid which was used in the next step without further purification. MS (ESI) [M+H]+ 342.2. Synthesis of Intermediate i-14: 3-[5-(4-amino-1-piperidyl)benzimidazol-1-yl]piperidine-2,6- dione dihydrochloride

[0265] Step i-14.1: Synthesis of tert-Butyl N-[1-[1-(2-benzyloxy-6-phenoxy-3- pyridyl)benzimidazol-5-yl]-4-piperidyl]carbamate. Two batches of 5-bromo-1-(2,6- dibenzyloxy-3-pyridyl)benzimidazole (500 mg, 1.03 mmol, see above), tert-butyl N-(4- piperidyl)carbamate (412 mg, 2.06 mmol), sodium tert-butoxide (296 mg, 3.08 mmol) and tBuXPhos-Pd-G3 (82 mg, 0.10 mmol) in tetrahydrofuran (10 mL) were stirred at 25 °C for 2 h. The mixtures were combined, filtered on celite and washed with methanol (20 mL). The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel using a gradient of 0–100% ethyl acetate in hexanes, followed by a second purification on silica gel using a gradient of 0–20% methanol in dichloromethane to afford title compound (768 mg, 62%) as an oil. MS (ESI) [M+H]+ 608.4.

[0266] Step i-14.2: Synthesis of tert-Butyl N-[1-[1-(2,6-dioxo-3- piperidyl)benzimidazol-5-yl]-4-piperidyl]carbamate. A mixture of tert-butyl N-[1-[1-(2,6- dibenzyloxy-3-pyridyl)benzimidazol-5-yl]-4-piperidyl] carbamate (768 mg, 1.27 mmol) and Pearlman’s catalyst (116 mg, 0.16 mmol) in tetrahydrofuran (18 mL) and ethanol (18 mL) was subjected to hydrogenation at 1 atm and 50 °C for 10 h. The mixture was filtered through celite and washed with methanol (3 x 10 mL). The filtrate was concentrated under reduced pressure to afford title compound (419 mg, 77%) as a semi-solid. MS (ESI) [M+H]+ 428.6.1H NMR (400 MHz, DMSO-d6) δ 11.16 (s, 1H), 8.12 (s, 1H), 7.35 (d, J = 8.9 Hz, 1H), 7.13 (d, J = 2.0 Hz, 1H), 7.01 – 6.97 (m, 1H), 6.85 (d, J = 7.5 Hz, 1H), 5.60 (dd, J = 12.8, 5.1 Hz, 1H), 3.52 (d, J = 12.3Hz, 2H), 3.34 – 3.30 (m, 1H), 2.93 – 2.73 (m, 2H), 2.72 – 2.66 (m, 3H), 2.23 – 2.17 (m, 1H), 1.85 – 1.79 (m, 2H), 1.59 – 1.50 (m, 2H), 1.39 (s, 9H).

[0267] Step i-14.3: Synthesis of 3-[5-(4-amino-1-piperidyl)benzimidazol-1- yl]piperidine-2,6-dione dihydrochloride. To a solution of tert-butyl N-[1-[1-(2,6-dioxo-3- piperidyl)benzimidazol-5-yl]-4-piperidyl] carbamate (148 mg, 0.35 mmol) in 1,4-dioxane (10.0 mL) was added a 4N solution of HCl in 1,4-dioxane (1.0 mL, 4.2 mmol). The reaction mixture was heated to 100 °C for 2 h and then cooled to rt. The volatiles were evaporated under reduced pressure to afford the title compound (138 mg, 91%) as a solid, which was used directly in the next step without further purification. MS (ESI) [M+H]+ 328.2. Synthesis of Intermediate i-15: 3-[5-(2,8-Diazaspiro[4.5]decan-8-yl)benzimidazol-1- yl]piperidine-2,6-dione hydrochloride.

[0268] Step i-15.1: Synthesis of tert-Butyl 8-[1-(2,6-dibenzyloxy-3- pyridyl)benzimidazol-5-yl]-2,8-diazaspiro[4.5]decane-2-carboxylate. A mixture of 5-bromo- 1-(2,6-dibenzyloxy-3-pyridyl)benzimidazole (350 mg, 0.72 mmol), tert-butyl 2,8- diazaspiro[4.5]decane-2-carboxylate (346 mg, 0.72 mmol), sodium tert-butoxide (207 mg, 2.16 mmol) and tBuXPhos-Pd-G3 (57 mg, 80 µmol) in tetrahydrofuran (3 mL) was heated to 70 °C for 5 h and then cooled to rt. The mixture was filtered on celite and washed with methanol (20 mL). The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel using a gradient of 0–100% Ethyl acetate in hexanes to afford title compound (296 mg, 64%) as a solid. MS (ESI) [M+H]+646.0.1H NMR (400 MHz, CDCl3) δ 7.88 (s, 1H), 7.54 (d, J = 8.3 Hz, 1H), 7.42 – 7.25 (m, 6H), 7.24 – 7.14 (m, 5H), 7.05 (d, J = 8.7 Hz, 1H), 6.96 (d, J = 8.2 Hz, 1H), 6.46 (d, J = 8.3 Hz, 1H), 5.33 (s, 2H), 5.31 (s, 2H), 3.43 – 3.28 (m, 2H), 3.26 – 3.09 (m, 4H), 3.09 – 2.98 (m, 2H), 1.78 – 1.64 (m, 6H), 1.40 (s, 9H).

[0269] Step i-15.2: Synthesis of tert-Butyl 8-[1-(2,6-dioxo-3-piperidyl)benzimidazol- 5-yl]-2,8-diazaspiro[4.5]decane-2-carboxylate. A mixture of tert-butyl 8-[1-(2,6-dibenzyloxy- 3-pyridyl)benzimidazol-5-yl]-2,8-diazaspiro [4.5]decane-2-carboxylate (105 mg, 0.16 mmol) and Pearlman’s catalyst (22 mg, 30 µmol, STREM Escat 1951) in tetrahydrofuran (3 mL) and ethanol (3 mL) was hydrogenated (1 atm) at 50 °C for 3h. The mixture was filtered on Celiteand washed with ethanol (25 mL). The filtrate was concentrated under reduced pressure to afford title compound (75 mg, 98% yield) as a solid, which was used in the next step without further purification. MS (ESI) [M+H]+469.3.1H NMR (500 MHz, DMSO-d6) δ 11.15 (s, 1H), 8.12 (s, 1H), 7.36 (d, J = 8.9 Hz, 1H), 7.15 (d, J = 1.8 Hz, 1H), 7.01 (dd, J = 8.9, 2.1 Hz, 1H), 5.60 (dd, J = 13.0, 5.2 Hz, 1H), 3.30 (m, 1H) 3.18 – 2.98 (m, 5H), 3.13 (s, 2H), 2.91 – 2.85 (m, 1H), 2.80 – 2.67 (m, 2H), 2.22 – 2.18 (m, 1H), 1.76 – 1.73 (m, 2H), 1.68 – 1.61 (m, 4H), 1.40 (s, 9H).

[0270] Step i-15.3: Synthesis of 3-[5-(2,8-Diazaspiro[4.5]decan-8-yl)benzimidazol-1- yl]piperidine-2,6-dione hydrochloride. To a solution of tert-butyl 8-[1-(2,6-dioxo-3- piperidyl)benzimidazol-5-yl]-2,8-diazaspiro [4.5]decane-2-carboxylate (299 mg, 0.64 mmol) in 1,4-dioxane (6 mL) was added 4N HCl in 1,4-dioxane (0.23 mL, 0.92 mmol), and the reaction mixture was stirred at rt for 18 h. The volatiles were removed under reduced pressure to afford title compound (250 mg, 96%) as a solid, which was used in the next step without further purification. MS (ESI) [M+H]+368.2. Synthesis of Intermediate i-16: 3-(5-aminobenzimidazol-1-yl)piperidine-2,6- dione;hydrochloride

[0271] Step i-16.1: Synthesis of tert-butyl (4S)-5-amino-4-(4-bromo-2-nitro-anilino)- 5-oxo-pentanoate. To a solution of 4-bromo-1-fluoro-2-nitro-benzene (19.0 g, 86.4 mmol) in N, N-dimethylformamide (400.0 mL) were sequentially added tert-butyl (4S)-4,5-diamino-5-oxo- pentanoate;hydrochloride (20.0 g, 83.8 mmol) and N,N-diisopropylethylamine (50.0 mL). The reaction mixture was heated to 90 °C for 3 h and then cooled to rt. The volatiles were evaporated under reduced pressure. A saturated aqueous solution of ammonium chloride (500.0 mL) and ethyl acetate (500.0 mL) were added and the layers were separated. The organic layer was washed with brine (200.0 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound (32.3 g, 96 %) as a solid, which was used in next step without further purification. MS (ESI) [M-H]- 400.2.

[0272] Step i-16.2: Synthesis of tert-butyl 5-amino-4-(2-amino-4-bromo-anilino)-5- oxo-pentanoate. To a suspension of tert-butyl (4S)-5-amino-4-(4-bromo-2-nitro-anilino)-5-oxo- pentanoate (32.1 g, 79.8 mmol) in tetrahydrofuran (260.0 mL) cooled to 0 °C were sequentially added Zn dust (47.0 g, 718.0 mmol) and ammonium chloride (19.0 g, 355.0 mmol). Water (80.0mL) was added slowly and the reaction mixture was stirred at 0 °C for 1 h. The mixture was filtered through celite and washed with tetrahydrofuran (200.0 mL). The filtrate was concentrated under reduced pressure. The material was purified by column chromatography on silica gel using a gradient of 10-20% methanol in dichloromethane to afford the title compound (28.1 g, 95%) as a solid. MS (ESI) [M+H]+ 374.2;1H NMR (400 MHz, DMSO) δ 7.39 (bs, 1H), 7.06 (bs, 1H), 6.69 (d, J = 2.3 Hz, 1H), 6.55 (dd, J = 8.4, 2.3 Hz, 1H), 6.23 (d, J = 8.5 Hz, 1H), 4.93 (s, 2H), 4.63 (d, J = 8.1 Hz, 1H), 3.68 – 3.60 (m, 1H), 2.42 – 2.29 (m, 2H), 1.96 – 1.84 (m, 2H), 1.39 (s, 9H).

[0273] Step i-16.3: Synthesis of 2-(5-bromobenzimidazol-1-yl)-5-oxo- hexanamide;formate. To a solution of tert-butyl (4S)-5-amino-4-(2-amino-4-bromo-anilino)-5- oxo-pentanoate (10.0 g, 27.0 mmol) in triethyl orthoformate (40.0 mL, 241.0 mmol) was added formic acid (20.0 mL, 529.0 mmol). The reaction mixture was heated to 100 °C for 15 min and then cooled to rt. The volatiles were evaporated under reduced pressure. The material was purified by column chromatography on silica gel using a gradient of 0-20% methanol in dichloromethane to afford the title compound (10.2 g, 89%) as a solid. MS (ESI) [M+H]+ 384.2;1H NMR (500 MHz, DMSO) δ 8.33 (s, 1H), 8.14 (s, 1H), 7.86 (d, J = 1.8 Hz, 1H), 7.83 (s, 1H), 7.54 (d, J = 8.6 Hz, 1H), 7.44 – 7.40 (m, 2H), 5.09 (dd, J = 9.2, 6.3 Hz, 1H), 2.41 – 2.25 (m, 2H), 2.19 – 1.98 (m, 2H), 1.33 (s, 9H).

[0274] Step i-16.4: Synthesis of 3-(5-bromobenzimidazol-1-yl)piperidine-2,6- dione;trifluoroacetate. To a solution of tert-butyl 5-amino-4-(5-bromobenzimidazol-1-yl)-5- oxo-pentanoate (5.3 g, 13.9 mmol) in tetrahydrofuran (69.0 mL) cooled to 0 °C was added potassium tert-butoxide (1.9 g, 16.6 mmol). The reaction mixture was stirred at 0 °C for 15 min and at rt for 2 h. Acetic acid (0.95 mL, 17.0 mmol) was added and the mixture was stirred at rt for an additional 2 h. The resulting precipitate was collected by filtration, washed with water (10.0 mL), diethyl ether (20.0 mL), tetrahydrofuran (10.0 mL), acetonitrile (10.0 mL) and then dried under vacuum. The material was purified by reverse phase chromatography (C18) using a gradient of 5-100 % acetonitrile and water (contains 0.1 % TFA) to afford the title compound (3.9 g, 65%) as a solid. MS (ESI) [M+H]+ 308.1, 310.1;1H NMR (400 MHz, DMSO) δ 11.25 (s, 1H), 8.59 (s, 1H), 7.94 (d, J = 1.7 Hz, 1H), 7.63 (d, J = 8.7 Hz, 1H), 7.50 (dd, J = 8.7, 1.8 Hz, 1H), 5.77 (dd, J = 12.7, 5.0 Hz, 1H), 2.95 – 2.66 (m, 3H), 2.34 – 2.23 (m, 1H), three exchangeable protons missing; 19F NMR (376 MHz, DMSO) δ -74.87 (s).

[0275] Step i-16.5: Synthesis of tert-butyl N-[1-(2,6-dioxo-3-piperidyl)benzimidazol- 5-yl]carbamate. A mixture of 3-(5-bromobenzimidazol-1-yl)piperidine-2,6-dione;2,2,2- trifluoroacetate (425.0 mg, 1.01 mmol), tert-butyl carbamate (177.0 mg, 1.51 mmol), tBuXPhos- Pd-G3 (160.0 mg, 0.2 mmol) and sodium tert-butoxide (242.0 mg, 2.52 mmol) in 1,4-dioxane(13.0 mL) was heated to 50 °C for 18 h and then cooled to rt. Acetic acid (0.2 mL, 3.0 mmol) was added and the mixture was stirred at rt for 30 min. The volatiles were evaporated under reduced pressure. Acetonitrile (10.0 mL) was added and insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure. Diethyl ether (10.0 mL) was added and the resulting precipitate was collected by filtration, washed with diethyl ether (3 x 5.0 mL), then dried under vacuum to afford title compound (357.0 mg, 87%) as a solid, which was used in next step without further purification. MS (ESI) [M+H]+ 345.3;1H NMR (400 MHz, DMSO) δ 11.23 (bs, 1H), 9.30 (bs, 1H), 8.24 (s, 1H), 7.84 (bs, 1H), 7.45 (d, J = 8.7 Hz, 1H), 7.39 – 7.35 (m, 1H), 5.69 (dd, J = 12.9, 5.1 Hz, 1H), 2.90 – 2.75 (m, 3H), 2.31 – 2.24 (m, 1H), 1.55 (s, 9H).

[0276] Step i-16.6: Synthesis of 3-(5-aminobenzimidazol-1-yl)piperidine-2,6- dione;hydrochloride. To a solution of tert-butyl N-[1-(2,6-dioxo-3-piperidyl)benzimidazol-5- yl]carbamate (357.0 mg, 1.04 mmol) in 1,4-dioxane (4.0 mL) was added 4N HCl in 1,4-dioxane (2.6 mL, 10.4 mmol). The reaction mixture was stirred at rt for 1 h. The volatiles were evaporated under reduced pressure. The material was purified by reverse phase chromatography (C18), using a gradient of 5-100 % acetonitrile and water (contains 0.1 % formic acid) to afford the title compound (173.0 mg, 68% yield) as a solid. MS (ESI) [M+H]+ 245.2;1H NMR (400 MHz, DMSO) δ 11.33 (s, 1H), 9.09 (bs, 1H), 7.70 (d, J = 8.7 Hz, 1H), 7.36 (bs, 1H), 7.17 – 7.06 (m, 1H), 5.90 (d, J = 12.1 Hz, 1H), 2.94 – 2.73 (m, 3H), 2.37 – 2.31 (m, 1H). Note: two exchangeable protons not observed. Synthesis of Intermediate i-17: 3-(4-Amino-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-1-yl)piperidine-2,6-dione.

[0277] Step i-17.1: Synthesis of tert-butyl (2-fluoro-3-nitrophenyl)carbamate. To a solution of 1-bromo-2-fluoro-3-nitro-benzene (30.000 g, 136.37 mmol, 1.0 eq) in toluene (400 mL) was added 4,5-Bis(diphenylphospheno)-9,9-dimethyl (7.890 g, 13.64 mmol, 0.1 eq), tert- butyl carbamate (19.170 g, 163.64 mmol, 1.2 eq), cesium carbonate (53.320 g, 163.64 mmol, 1.2 eq) and tris(dibenzylidenacetone)dipalladium (6.240 g, 6.82 mmol, 0.05 eq). The mixture was stirred at 90 °C for 12 h. TLC and LCMS showed the reaction was completed. The mixture was concentrated to give a residue. The residue was purified by silica column chromatography on silica gel (petroleum ether). Tert-butyl N-(2-fluoro-3-nitro-phenyl)carbamate (32.000 g, crude) was obtained as yellow solid, detected by HNMR. MS (ESI) m / z: 279.9 [M+Na]+.1H NMR (400MHz, DMSO-d6) δ 9.49 (s, 1H), 8.01 (t, J=7.2 Hz, 1H), 7.83 - 7.80 (m, 1H), 7.37 - 7.31 (m,1H), 1.47 (s, 9H).

[0278] Step i-17.2: Synthesis of 2-fluoro-3-nitroaniline. To a solution of tert-butyl N- (2-fluoro-3-nitro-phenyl)carbamate (32.000 g, 124.89 mmol, 1.0 eq) was added in hydrogen chloride (12 M, 39 mL, 3.8 eq) at 0 °C. The mixture was stirred at 0 °C for 1 h. TLC and LCMS showed the reaction was completed. The mixture was diluted with water (300 mL), concentrated and lyophilized to give a residue. The residue was dissolve in acetonitrile (150 mL) and water(15 mL), sodium bicarbonate (15.000 g) was added. The mixture was stirred for 0.5 h, filtered and concentrated to give a residue. The residue was purified by silica column chromatography on silica gel (a solution of 1% to 10% ethyl acetate in petroleum ether). 2-Fluoro-3-nitro-aniline (15.300 g, 98.0 mmol, 78.47% yield) was obtained as yellow solid, detected by HNMR. MS (ESI) m / z: 157.1 [M+1]+.1H NMR (400MHz, DMSO-d6) δ 7.20 - 7.12 (m, 1H), 7.12 - 7.03 (m, 2H), 5.83 (s, 2H).

[0279] Step i-17.3: Synthesis of 2,6-bis(benzyloxy)-N-(2-fluoro-3- nitrophenyl)pyridin-3-amine. To a solution of 2-fluoro-3-nitro-aniline (15.000 g, 96.08 mmol, 1.0 eq) in dioxane (400 mL) was added potassium carbonate (39.840 g, 288.25 mmol, 3.0 eq), 2,6- dibenzyloxy-3-bromo-pyridine (42.690 g, 115.30 mmol, 1.2 eq) and [2-(2-aminophenyl)phenyl]- methylsulfonyloxy-palladium;dicyclohexyl-[3,6-dimethoxy-2-(2,4,6- triisopropylphenyl)phenyl]phosphane (6.530 g, 7.21 mmol, 0.075 eq). The mixture was stirred at 100 °C for 12 h. TLC and LCMS showed the reaction was completed. The mixture was filtered and concentrated to give a residue. The residue was purified by silica column chromatography on silica gel (a solution of 1% to 5% ethyl acetate in petroleum ether). 2,6-dibenzyloxy-N-(2-fluoro- 3-nitro-phenyl)pyridin-3-amine (20.000 g, crude) was obtained as brown oil, detected by HPLC. MS (ESI) m / z: 446.2 [M+1]+.

[0280] Step i-17.4: Synthesis of N1-(2,6-bis(benzyloxy)pyridin-3-yl)-N2-methyl-3- nitrobenzene-1,2-diamine. To a solution of 2,6-dibenzyloxy-N-(2-fluoro-3-nitro- phenyl)pyridin-3-amine (20.000 g, 37.72 mmol, 1.0 eq) was added methylamine (1 M, 50 mL, 1.3 eq) and triethylamine (11.450 g, 113.15 mmol, 15.8 mL, 3.0 eq). Then reaction mixture was stirred in a sealed vessel at 110 °C for 12 h. TLC and LCMS showed the reaction was completed. The mixture was concentrated to give a residue. Then the mixture was diluted with water (100 mL), extracted with ethyl acetate (150 mL × 3). The combined organic layer was washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate. The organic layer was filtrated and concentrated to give a residue. The residue was purified by silica column chromatography on silica gel (a solution of 1% to 10% ethyl acetate in petroleum ether). N1-(2,6-dibenzyloxy-3- pyridyl)-N2-methyl-3-nitro-benzene-1,2-diamine (16.500 g, crude) was obtained as brown oil.MS (ESI) m / z: 457.1 [M+1]+.

[0281] Step i-17.5: Synthesis of 1-(2,6-bis(benzyloxy)pyridin-3-yl)-3-methyl-4-nitro- 1H-benzo[d]imidazol-2(3H)-one. To a solution of N1-(2,6-dibenzyloxy-3-pyridyl)-N2-methyl- 3-nitro-benzene-1,2-diamine (16.500 g, 36.15 mmol, 1.0 eq) in Boc Anhydride (50 mL) was added dimethylaminopyridine (0.442 g, 3.61 mmol, 0.1 eq). The mixture was stirred at 60 °C for 2 h. TLC and LCMS showed the reaction was completed. The mixture was concentrated to give a residue. The residue was purified by silica column chromatography on silica gel (a solution of 2% to 20% ethyl acetate in petroleum ether). 1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-4-nitro- benzimidazol-2-one (15.500 g, 32.13 mmol, 88.88% yield) was obtained as yellow solid. MS (ESI) m / z: 483.2 [M+1]+.

[0282] Step i-17.6: Synthesis of 4-amino-1-(2,6-bis(benzyloxy)pyridin-3-yl)-3-methyl- 1H-benzo[d]imidazol-2(3H)-one. To a solution of 1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-4- nitro-benzimidazol-2-one (15.500 g, 32.13 mmol, 1.0 eq) in ethanol (100 mL) and water (50 mL) was added iron (8.970 g, 160.63 mmol, 5.0 eq) and ammonium chloride (17.180 g, 321.25 mmol, 10.0 eq). The mixture was stirred at 85 °C for 1 h. TLC and LCMS showed the reaction was completed. The reaction mixture was filtered and concentrated. The residue was diluted with water (150 mL) and extracted with ethyl acetate (200 mL × 3). The combined organic layers were washed with brine (200 mL × 3), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. 4-Amino-1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl- benzimidazol-2-one (17.000 g, crude) was obtained as yellow solid, detected by HPLC. MS (ESI) m / z: 453.0 [M+1]+.

[0283] Step i-17.7: Synthesis of tert-butyl (1-(2,6-bis(benzyloxy)pyridin-3-yl)-3-methyl- 2-oxo-2,3-dihydro-1H-benzo [d]imidazol-4-yl)carbamate. To a solution of 4-amino-1-(2,6- dibenzyloxy-3-pyridyl)-3-methyl-benzimidazol-2-one (17.000 g, 30.06 mmol, 1.0 eq) in tetrahydrofuran (80 mL) and water (80 mL) was added potassium carbonate (12.460 g, 90.17 mmol, 3.0 eq) and Boc anhydride (19.680 g, 90.17 mmol, 3.0 eq). The mixture was stirred at 20 °C for 12 h. TLC and LCMS showed the reaction was completed. The mixture solution was concentrated. Then water (150 mL) and ethyl acetate (150 mL × 3) was added. The combined organic layers were washed with brine (150 mL × 2), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica column chromatography on silica gel (a solution of 1% to 50% ethyl acetate in petroleum ether). Tert- butyl(1-(2,6-bis(benzyloxy)pyridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4- yl)carbamate (12.000 g, 21.71 mmol, 72.25% yield) was obtained as yellow solid, detected by HNMR. MS (ESI) m / z: 553.3 [M+1]+.1H NMR (400MHz, DMSO-d6) δ 8.94 (s, 1H), 7.80 (d,J=8.4 Hz, 1H), 7.46 - 7.42 (m, 2H), 7.41 - 7.33 (m, 3H), 7.27 (s, 5H), 6.96 - 6.89 (m, 1H), 6.89 - 6.81 (m, 1H), 6.61 (d, J=8.4 Hz, 1H), 6.54 (d, J=7.6 Hz, 1H), 5.45 - 5.34 (m, 4H), 3.50 (s, 3H), 1.47 (s, 9H).

[0284] Step i-17.8: Synthesis of tert-butyl (1-(2,6-dioxopiperidin-3-yl)-3-methyl-2- oxo-2,3-dihydro-1H-benzo[d] imidazol-4-yl)carbamate. To a solution of tert-butyl (1-(2,6- bis(benzyloxy)pyridin-3-yl)-3-methyl-2-oxo-2,3-dihydro -1H-benzo[d]imidazol-4-yl)carbamate (7.000 g, 12.67 mmol, 1.0 eq) in tetrahydrofuran (400 mL) was added palladium / carbon catalyst (14.000 g, 10% purity, 1.0 eq) under nitrogen. The suspension was degassed under vacuum and purged with hydrogen several times. The mixture was stirred under hydrogen (50 psi) at 20 °C for 12 h. TLC and LCMS showed the reaction was completed. The mixture was filtered and concentrated to give a residue. The residue was purified by silica column chromatography on silica gel (a solution of 1% to 5% methanol in dichloromethane). Tert-butyl(1-(2,6- dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3 -dihydro-1H-benzo[d]imidazol-4-yl)carbamate (7.500 g, 19.87 mmol, 74.40% yield, 99.2% purity) was obtained as white solid, detected by HNMR and HPLC. MS (ESI) m / z: 375.1 [M+1]+.1H NMR (400MHz, DMSO-d6) δ 11.09 (s, 1H), 8.90 (s, 1H), 7.05 - 6.94 (m, 2H), 6.82 (dd, J=1.2, 7.6 Hz, 1H), 5.37 (dd, J=5.2, 12.8 Hz, 1H), 3.45 (s, 3H), 2.96 - 2.83 (m, 1H), 2.77 - 2.59 (m, 2H), 2.09 - 1.99 (m, 1H), 1.46 (s, 9H).

[0285] Step i-17.9: Synthesis of 3-(4-amino-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-1-yl)piperidine-2,6-dione. To a solution of tert-butyl(1-(2,6-dioxopiperidin- 3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-4-yl)carbamate (4.000 g, 10.68 mmol, 1.0 eq) was added hydrogen chloride (12 M, 20 mL, 22.5 eq) at 0 °C. The mixture was stirred at 0 °C for 0.5 h. LCMS showed the reaction was completed. Water (100 mL) was added to the mixture solution. The mixture was lyophilized to give a residue. 3-(4-Amino-3-methyl-2-oxo- benzimidazol-1-yl)piperidine-2,6-dione (2.550 g, 9.20 mmol, 86.15% yield, 98.9% purity) was obtained as white solid, detected by HNMR and LCMS. MS (ESI) m / z: 275.2 [M+1]+.1H NMR (400MHz, DMSO-d6) δ 11.11 (s, 1H), 7.15 - 6.99 (m, 3H), 5.41 (dd, J=5.2, 12.8 Hz, 1H), 3.66 (s, 3H), 2.94 - 2.84 (m, 1H), 2.76 - 2.59 (m, 2H), 2.09 - 1.99 (m, 1H). Note: two exchangeable protons not observed Synthesis of Intermediate i-18: 3-(5-Amino-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0286] Step i-18.1: Synthesis of 2,6-bis(benzyloxy)-3-nitropyridine. To a solution of 2,6-difluoro-3-nitro-pyridine (20.000 g, 124.940 mmol, 1.00 eq) in acetonitrile (300 mL) was added cesium carbonate (120.000 g, 368.30 mmol, 2.95 eq) and phenylmethanol (29.120 g, 269.29 mmol, 28 mL, 2.16 eq) at 10 °C. The mixture was stirred at 80 °C for 12 hr. TLC showed the reaction was complete. The solid was filtered out and the filtrate was concentrated in vacuum to give product. 2,6-Dibenzyloxy-3-nitro-pyridine (40.000 g, 118.93 mmol, 95.2% yield) was obtained as a yellow solid. HNMR confirmed the product.1H NMR (400 MHz, DMSO-d6) δ ppm 8.44 (d, J = 8.8 Hz, 1 H), 7.26-7.52 (m, 10 H), 6.62 (d, J = 8.8 Hz, 1 H),5.57 (s, 2 H), 5.47 (s, 2 H).

[0287] Step i-18.2: Synthesis of 2,6-bis(benzyloxy)pyridin-3-amine. To a solution of 2,6-dibenzyloxy-3-nitro-pyridine (45.000 g, 133.79 mmol, 1.00 eq) in ethyl alcohol (500 mL) and water (50 mL) was added iron (37.360 g, 668.96 mmol, 5.00 eq) and ammonium chloride (71.570 g, 1340.00 mmol, 10.00 eq). The mixture was stirred at 80 °C for 2 hr. LCMS showed the reaction was complete. The solvent was removed in vacuum. The residue was purified by column chromatography (SiO2, ethyl acetate in petroleum ether =10% to 20%). 2,6-Dibenzyloxypyridin- 3-amine (33.000 g, 107.72 mmol, 80.5% yield) was obtained as a yellow solid. HNMR confirmed the product. MS (ESI) m / z: 307.2 [M+1]+;1H NMR (400 MHz, DMSO-d6) δ ppm 7.45 (d, J = 7.6 Hz, 2 H), 7.30-7.38 (m, 8 H), 6.99 (d, J = 8.0 Hz, 1 H), 6.24 (d, J = 8.0 Hz, 1 H), 5.35 (s, 2 H), 5.19 (s, 2 H), 4.39 (s, 2 H).

[0288] Step i-18.3: Synthesis of methyl 2-((2,6-bis(benzyloxy)pyridin-3-yl)amino)-5- nitrobenzoate. To a solution of 2,6-dibenzyloxypyridin-3-amine (30.000 g, 97.92 mmol, 1.00 eq) in dioxane (300 mL) was added chloro(2-dicyclohexylphosphino-2,4,6-tri-i-propyl-1,1- biphenyl)(2-amino-1,1-biphenyl-2-yl) palladium(II) (3.850 g, 4.90 mmol, 0.05 eq), methyl 2- bromo-5-nitro-benzoate (35.000 g, 134.59 mmol, 1.37 eq) and potassium carbonate (40.600 g, 293.77mmol, 3.00 eq). The mixture was stirred at 100 °C for 12 hr under nitrogen. Desired product was detected by LCMS. The solvent was removed in vacuum. The residue was purified by column chromatography (SiO2, ethyl acetate in petroleum ether 1% - 10%). Methyl 2-((2,6- bis(benzyloxy)pyridin-3-yl)amino)-5-nitrobenzoate (27.000 g, 55.61 mmol, 56.8% yield) was obtained as a yellow solid. HNMR confirmed the product. MS (ESI) m / z: 486.2 [M+1]+;1H NMR (400 MHz, DMSO-d6) δ ppm 9.72 (s, 1 H), 8.68 (d, J = 2.8 Hz, 1 H), 8.12 (dd, J = 9.6, 2.8 Hz, 1 H), 7.74 (d, J = 8.4 Hz, 1 H), 7.21-7.50 (m, 10 H), 6.74 (d, J = 9.6 Hz, 1 H), 6.55 (d, J = 8.4 Hz, 1 H), 5.38 (d, J = 18.4 Hz, 4 H), 3.91 (s, 3 H).

[0289] Step i-18.4: Synthesis of 2-((2,6-Bis(benzyloxy)pyridin-3-yl)amino)-5- nitrobenzoic acid. To a solution of methyl 2-((2,6-bis(benzyloxy)pyridin-3-yl)amino)-5-nitrobenzoate (22.000 g, 45.32 mmol, .001 eq) in tetrahydrofuran (100 mL) and water (100 mL) was added sodium hydroxide (9.060 g, 226.58 mmol, 5.00 eq). The mixture was stirred at 80 °C for 2 hr. LCMS showed the reaction was complete. The mixture was extracted with ethyl acetate (200 mL x 3), dried over sodium sulfate, filtered and concentrated. 2-((2,6- Bis(benzyloxy)pyridin-3-yl)amino)-5-nitrobenzoic acid (21.000 g, 44.54 mmol, 98.3% yield) was obtained as a yellow solid. MS (ESI) m / z: 472.2 [M+1]+

[0290] Step i-18.5: Synthesis of 1-(2,6-bis(benzyloxy)pyridin-3-yl)-5-nitro-1H- benzo[d]imidazol-2(3H)-one. To a solution of 2-((2,6-Bis(benzyloxy)pyridin-3-yl)amino)-5- nitrobenzoic acid (22.000 g, 46.66 mmol, 1.00 eq) in toluene (300 mL) was added diphenyl phosphoryl azide (16.690 g, 60.66 mmol, 1.30 eq) and triethylamine (12.300 g, 121.58 mmol, 2.61 eq) at 0 °C. The mixture was stirred at 100 °C for 12 hr under nitrogen. Desired product was detected by LCMS. The solvent was removed in vacuum to give residue. The residue was purified by prep-TLC (SiO2, ethyl acetate petroleum ether). 3-(2,6-dibenzyloxy-3-pyridyl)-6-nitro-1H- benzimidazol-2-one (20.500 g, 43.76 mmol, 93.8% yield) was obtained as a yellow solid. HNMR confirmed the product. MS (ESI) m / z: 469.2 [M+1]+;1H NMR (400 MHz, DMSO-d6) δ ppm 11.69 (s, 1 H), 7.76-7.99 (m, 3 H), 7.43-7.50 (m, 2 H), 7.32-7.41 (m, 3 H), 7.23-7.29 (m, 5 H), 6.85 (d, J = 8.8 Hz, 1 H), 6.65 (d, J = 8.4 Hz, 1 H), 5.30-5.48 (m, 4 H).

[0291] Step i-18.6: Synthesis of 1-(2,6-bis(benzyloxy)pyridin-3-yl)-3-methyl-5-nitro- 1H-benzo[d]imidazol-2(3H)-one. To a solution of 3-(2,6-dibenzyloxy-3-pyridyl)-6-nitro-1H- benzimidazol-2-one (12.000 g, 25.62 mmol, 1.00 eq) in tetrahydrofuran (120 mL) was added sodium hydride (2.050 g, 51.23 mmol, 60% purity, 2.00 eq) and methyl 4-methylbenzenesulfonate (6.000 g, 32.22 mmol, 1.26 eq). The mixture was stirred at 20 °C for 12 hr. LCMS showed the reaction was complete. The mixture was quenched by addition water (100mL), then the mixture was extracted with ethyl acetate (100mL x 3), organic layer was combined and dried over sodium sulfate, filtered and concentrated in vacuum to give product. 1-(2,6-Dibenzyloxy-3-pyridyl)-3- methyl-5-nitro-benzimidazol-2-one (10.500 g, 21.76 mmol, 84.9% yield) was obtained as a yellow solid. MS (ESI) m / z: 483.1[M+1]+

[0292] Step i-18.7: Synthesis of 5-amino-1-(2,6-bis(benzyloxy)pyridin-3-yl)-3-methyl- 1H-benzo[d]imidazol-2(3H)-one. To a solution of 1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-5- nitro-benzimidazol-2-one (10.500 g, 21.76 mmol, 1.00 eq) in ethyl alcohol (100 mL) and water (20 mL) was added ferrum (6.000 g, 107.44 mmol, 4.94 eq) and ammonium chloride (12.000 g, 224.34 mmol, 10.31 eq). The mixture was stirred at 80 °C for 2 hr. LCMS showed the reaction was complete. The mixture was filtered and the filtrate was extracted with ethyl acetate (100mL x 3), organic phase was dried over sodium sulfate, filtered and concentrated. 5-Amino-1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-benzimidazol-2-one (9.800 g, 21.66 mmol, 99.5% yield) was obtained as a yellow solid. MS (ESI) m / z: 453.2 [M+1]+

[0293] Step i-18.8: Synthesis of (1-(2,6-bis(benzyloxy)pyridin-3-yl)-3-methyl-2-oxo- 2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbamate. To a solution of 5-amino-1-(2,6- dibenzyloxy-3-pyridyl)-3-methyl-benzimidazol-2-one (9.800 g, 21.66 mmol, 1.00 eq) in tetrahydrofuran (100 mL) and water (100 mL) was added potassium carbonate (6.000 g, 43.41 mmol, 2.00 eq) and di-tert-butyl decarbonate ester (6.000 g, 27.49 mmol, 1.27 eq). The mixture was stirred at 20 °C for 12 hr. LCMS showed the reaction was complete. The mixture was extracted with ethyl acetate (100mL x 3), organic layer was combined and dried over sodium sulfate, filtered and concentrated in vacuum. tert-Butyl(1-(2,6-bis(benzyloxy)pyridin-3-yl)-3- methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbamate (11.500 g, 20.81 mmol, 96.0% yield) was obtained as a yellow solid. MS (ESI) m / z: 553.1 [M+1]+

[0294] Step i-18.9: Synthesis of (1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-5-yl)carbamate. To a solution of tert-butyl(1-(2,6- bis(benzyloxy)pyridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbamate (6.000 g, 10.86 mmol, 1.00 eq) in tetrahydrofuran (400 mL) was added palladium on carbon (6.000 g, 10% purity). The mixture was stirred at 25 °C for 12 hr under hydrogen (50 Psi). LCMS showed the reaction was complete. The mixture was filtered. The filtrate was concentrated in vacuum to give residue. The residue was stirred solvent (ethyl acetate in petroleum ether = 10:1) 150 mL for 1 h, the solid was collected by filtration. tert-Butyl(1-(2,6-dioxopiperidin-3-yl)-3- methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbamate (3.600 g, 9.62 mmol, 88.5% yield) was obtained as a white solid. HNMR confirmed the product. MS (ESI) m / z: 375.3 [M+1]+;1H NMR (400 MHz, DMSO-d6) δ ppm 11.07 (s, 1 H), 9.27 (s, 1 H), 7.41 (s, 1 H), 6.98 (s, 2 H), 5.31 (dd, J = 12.8, 5.26 Hz, 1 H), 3.29 (s, 3 H), 2.84-2.95 (m, 1 H), 2.59-2.74 (m, 2 H), 1.99-2.05 (m, 1 H), 1.48 (s, 9 H).

[0295] Step i-18.10: Synthesis of 3-(5-amino-3-methyl-2-oxo-benzimidazol-1-yl) piperidine-2,6-dione. The mixture of tert-Butyl(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo- 2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbamate (3.600 g, 9.62 mmol, 1 eq) and hydrogen chloride (12 M, 25 mL, 31.20 eq) was stirred at 0 °C for 2 hours. LCMS showed the reaction was complete. Water (100 mL) was added to the mixture and the mixture was lyophilized. The mixture was stirred in acetonitrile (200 mL) for 12 hours. The solid was collected by filtration. 3-(5-amino-3-methyl-2-oxo-benzimidazol-1-yl) piperidine-2,6-dione (2.754 g, 8.77 mmol, 91.2% yield, 99.0% purity, hydrogen chloride) was obtained as a yellow solid. HNMR confirmed the product. HPLC showed the purity was 95.8%, QC-LCMS showed the purity was 99.0%. MS(ESI) m / z: 275.0 [M+1]+;1H NMR (400 MHz, DMSO-d6) δ ppm 11.13 (s, 1 H), 10.49 (s, 2 H), 7.24 (d, J = 8.2 Hz, 1 H), 7.19 (d, J = 1.6 Hz, 1 H), 7.09 (dd, J = 8.2, 1.6 Hz, 1 H), 5.44 (dd, J = 12.8, 5.2 Hz, 1 H), 3.35 (s, 3 H), 2.85-3.00 (m, 1 H), 2.58-2.79 (m, 2 H), 1.96-2.12 (m, 1 H). Synthesis of Intermediate i-19: 5-Bromo-1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl- benzimidazol-2-one.

[0296] Step i-19.1: Synthesis of 2,6-dibenzyloxy-N-(4-bromo-2-nitro-phenyl)pyridin- 3-amine. To a solution of 2,6-dibenzyloxypyridin-3-amine (11 g, 35.9 mmol) in pyridine (100 mL) was added 4-bromo-1-fluoro-2-nitro-benzene (4.16 mL, 43.1 mmol), and the reaction mixture was heated to 55 °C for 48 h and then cooled to rt. The volatiles were evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using a gradient of 0–60% Ethyl acetate in hexanes to afford title compound (8.8 g, 48%) as a solid. MS (ESI) [M+H]+506.1.1H NMR (400 MHz, DMSO-d6) δ 9.22 (s, 1H), 8.21 (d, J = 2.4 Hz, 1H), 7.70 (d, J = 8.3 Hz, 1H), 7.55 (dd, J = 9.2, 2.4 Hz, 1H), 7.48 – 7.22 (m, 10H), 6.68 (d, J = 9.2 Hz, 1H), 6.55 (d, J = 8.2 Hz, 1H), 5.37 (s, 2H), 5.35 (s, 2H).

[0297] Step i-19.2: Synthesis of 4-bromo-N1-(2,6-dibenzyloxy-3-pyridyl)benzene-1,2- diamine. To a solution of 2,6-dibenzyloxy-N-(4-bromo-2-nitro-phenyl)pyridin-3-amine (8.8 g, 17.4 mmol) in tetrahydrofuran (52 mL) and water (17 mL) cooled to 0 °C were added sequentially solid zinc (4.55 g, 69.5 mmol) and ammonium chloride (3.72 g, 69.5 mmol), and the reaction mixture was stirred at rt for 16 h. The mixture was filtered on celite and washed with dichloromethane (2 x 50 mL). The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel using a gradient of 0–15% methanol in dichloromethane to afford title compound (6.5 g, 79%) as a solid. MS (ESI) [M+H]+476.1.

[0298] Step i-19.3: Synthesis of 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1H- benzimidazol-2-one. To a solution of 4-bromo-N1-(2,6-dibenzyloxy-3-pyridyl)benzene-1,2- diamine (6.5 g, 13.6 mmol) in tetrahydrofuran (136 mL) was added 1,1'-carbonyldiimidazole (4.43 g, 27.3 mmol), and the reaction mixture was stirred at 80 °C and then cooled to rt. The volatiles were evaporated under reduced pressure and the residue was purified by columnchromatography on silica gel using a gradient of 0–15% methanol in dichloromethane to afford title compound (4.2 g, 61%) as a solid. MS (ESI) [M+H]+504.0.

[0299] Step i-19.4: Synthesis of 5-bromo-1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl- benzimidazol-2-one. To a solution of 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1H-benzimidazol- 2-one (4.2 g, 8.36 mmol) in tetrahydrofuran (47 mL) were added sequentially at 0 °C a 60% dispersion of Sodium hydride in mineral oil (300 mg, 12.54 mmol) and iodomethane (0.78 mL, 12.54 mmol), and the reaction mixture was stirred at 0 °C for 15 min and then at rt for 48 h. The volatiles were evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using a gradient of 0–60% ethyl acetate in hexanes to afford title compound (3.4 g, 79%) as a solid. MS (ESI) [M+H]+516.1. Synthesis of Intermediate i-20: 3-[5-(bromomethyl) -1-oxo-isoindolin-2-yl]piperidine-2,6- dione

[0300] Step i-20.1: Synthesis of 3-[5-(hydroxymethyl)-1-oxo-isoindolin-2- yl]piperidine-2,6-dione. To a degassed solution of 3-(5-bromo-1-oxo-isoindolin-2-yl)piperidine- 2,6-dione (84 g, 260 mmol) in dry dioxane (1.8 L) was added tributylstannylmethanol (108 g, 338 mmol), palladium-tetrakis(triphenylphosphine (15 g, 13 mmol) at 20 °C. After addition, the reaction mixture was stirred at 100 °C for 16 hrs. TLC showed starting material was consumed completely. The reaction mixture was filtered through a pad of celite, and filtrate was concentrated. The residue was washed with ethyl acetate (500 mL) to offer 3-[5-(hydroxymethyl)- 1-oxo-isoindolin-2-yl]piperidine-2,6-dione (50 g, 70.1% yield) as an off-white solid.1H NMR (400 MHz CDCl3) δ: 10.98 (s, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.55 (s, 1H), 7.45 (d, J = 8.0 Hz, 1H), 5.39 (t, J = 7.6 Hz, 1H), 5.11 (dd, J = 4.8, 13.2 Hz, 1H), 4.62 (d, J = 6.0 Hz, 2H), 4.38 (dd, J = 17.2, 53.6 Hz, 2H), 2.93-2.88 (m, 1H), 2.62-2.58 (m, 1H), 2.41-2.38 (m, 1H), 2.02-1.99 (m, 1H)

[0301] Step i-20.2: Synthesis of 3-[5-(bromomethyl) -1-oxo-isoindolin-2- yl]piperidine-2,6-dione. To a mixture of 3-[5-(hydroxymethyl)-1-oxo-isoindolin-2- yl]piperidine-2,6-dione (38.0 g, 138 mmol) in anhydrous dichloromethane (160 mL) was added sulfurous dibromide (49.0 g, 236 mmol, 18.3 mL) dropwise at 0°C under N2. The mixture was stirred at 30°C for 16 hours. The combined organic layer was washed with dichloromethane (250 mL), filtered, the cake was washed with methanol (150 mL) and dried to give 3-[5-(bromomethyl) -1-oxo-isoindolin-2-yl]piperidine-2,6-dione (37.0 g, 79.2% yield) as a gray solid.1H NMR (400 MHz, DMSO-d6) δ 11.01 (s,1H), 7.73 (t, J = 8.0 Hz, 2H), 7.61 (d, J = 7.6 Hz, 1H), 5.15-5.11 (m, 1H), 4.84 (s, 2H), 4.51 (d, J = 17.6 Hz, 1H), 4.37 (d, J = 9.2 Hz, 1H), 2.97-2.88 (m, 1H), 2.64-2.39 (m, 2H), 2.05-2.01 (m, 1H). Synthesis of Intermediate i-21: [1-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]-4- piperidyl]-methyl-ammonium; benzenesulfonate.

[0302] Step i-21.1: Synthesis of tert-butyl (4S)-5-amino-4-[5-[4-[tert- butoxycarbonyl(methyl)amino]-1-piperidyl]-1-oxo-isoindolin-2-yl]-5-oxo-pentanoate. To a solution of tert-butyl (4S)-5-amino-4-(5-bromo-1-oxo-isoindolin-2-yl)-5-oxo-pentanoate (100.0 mg, 252.0 µmol) in N,N-dimethylformamide (2.0 mL) were sequentially added tert-butyl N- methyl-N-(4-piperidyl)carbamate (162.0 mg, 755.0 µmol), cesium carbonate (164.0 mg, 503.0 µmol) and XPhos Pd G3 (22.4 mg, 25.1 µmol) and the reaction vessel was sealed. The reaction mixture was heated to 100 °C under microwave irradiation for 1 h and then cooled to rt. The volatiles were evaporated under reduced pressure.1.0 N HCl (1.5 mL) and dichloromethane (50.0 mL) were added and the layers were separated. The aqueous layer was extracted with dichloromethane (2 x 25.0 mL), the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The material was purified by reverse phase chromatography (C18) using a gradient of 0-80% acetonitrile and water (contains 0.1 % formic acid) to afford title compound (15.0 mg, 10%) as a solid. MS (ESI) [M+H]+531.4;1H NMR (400 MHz, DMSO) δ 7.48 (d, J = 8.5 Hz, 2H), 7.17 – 6.98 (m, 3H), 4.67 (dd, J = 10.3, 4.3 Hz, 1H), 4.40 (AB q, J = 17.3 Hz, 2H), 3.97 -3.93 (m, 2H), 2.94 – 2.80 (m, 2H), 2.66 (s, 3H), 2.19 – 2.03 (m, 3H), 2.05 – 1.85 (m, 2H), 1.82 – 1.66 (m, 2H), 1.67 – 1.56 (m, 2H), 1.40 (s, 9H), 1.33 (s, 9H).

[0303] Step i-21.2: Synthesis of [1-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]-4- piperidyl]-methyl-ammonium; benzenesulfonate. To a solution of tert-butyl 5-amino-4-[5-[4- [tert-butoxycarbonyl(methyl)amino]-1-piperidyl]-1-oxo-isoindolin-2-yl]-5-oxo-pentanoate (40.0 mg, 75.4 µmol) in acetonitrile (3.0 mL) was added benzenesulfonic acid (18.0 mg, 113.0 µmol), at rt. The reaction mixture was heated to 75 °C for 18 h and then cooled to rt. The volatiles were removed under reduced pressure. The material was purified by reverse phase chromatography (C18) using a gradient of 0-80% acetonitrile and water (contains 0.1% formic acid) to afford title compound (22.0 mg, 57%) as a solid. MS (ESI) [M+H]+357.2 Synthesis of Intermediate i-22: 2-[[6-[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]-1-methyl-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide

[0304] Step i-22.1. Synthesis of 2-(methylamino)-5-nitro-benzaldehyde. A solution of methyl amine (3.0 mL, 5.91 mmol, 2 M in tetrahydrofuran) was added to a solution of 2-fluoro- 5-nitro-benzaldehyde (1.0 g, 5.91 mmol) in dimethyl sulfoxide (18 mL) at 0 °C under nitrogen. The mixture was stirred at rt for 4 h, and then diluted with water (5 mL). The aqueous phase was extracted with ethyl acetate (2 x 50 mL), and the combined organic phases were washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The material was purified by silica chromatography on silica gel (40 g cartridge) using a gradient of 0-20% of ethyl acetate in hexane as eluent to provide title compound (0.80 g, 75%) as a pale yellow solid. MS (ESI) [M+H]+181.1.1H NMR (500 MHz, CDCl3) δ 9.87 (d, J = 0.6 Hz, 1H), 9.01 (s, 1H), 8.47 (d, J = 2.7 Hz, 1H), 8.27 (ddd, J = 9.4, 2.7, 0.7 Hz, 1H), 6.72 (d, J = 9.4 Hz, 1H), 3.06 (d, J = 5.2 Hz, 3H).

[0305] Step i-22.2. Synthesis of 2-[(1-methyl-6-nitro-2-oxo-3-quinolyl)oxy]acetic acid. To a solution of 2-(methylamino)-5-nitro-benzaldehyde (400 mg, 2.22 mmol) in anhydrous N,N- dimethylformamide (7.00 mL), sodium hydride (222 mg, 5.55 mmol) was added at rt. The deep red colored reaction mixture was stirred for 30 min before the addition of 1,4-dioxane-2,6-dione (515 mg, 4.44 mmol) and the reaction mixture was stirred at 110 °C for 18 h. The mixture was diluted with dichloromethane (25 mL) and the resulting solid (sodium salt of the product) was filtered then was washed with dichloromethane (2 x 15 mL) and dried under reduced pressure. The solid (sodium salt) was dissolved in water (50 ml) and the aqueous layer was acidified with 1 N HCl until pH 2. The resulting solid was filtered and dried under reduced pressure to afford title compound (186 mg, 30%) as a dark brown solid. MS (ESI) [M+H]+ 280.1.

[0306] Step i-22.3. Synthesis of N-methyl-2-[(1-methyl-6-nitro-2-oxo-3- quinolyl)oxy]acetamide. To a solution of 2-[(1-methyl-6-nitro-2-oxo-3-quinolyl)oxy]acetic acid (185 mg, 0.665 mmol) in N,N-dimethylformamide (9 mL) were added, hydroxybenzotriazole (135 mg, 0.997 mmol), 1-Ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride (192 mg, 0.997 mmol) sequentially at 0 °C under nitrogen. The reaction mixture was stirred at 0 °C for 15 min, then added methylamine hydrochloride (49 mg, 0.73 mmol) and diisopropylethylamine (0.46 mL, 2.66 mmol) slowly and sequentially. The reaction mixture was warmed to rt and stirred for 18 h. The mixture was diluted with an aqueous solution of ammonium chloride (2.0 mL) and the aqueous phase was extracted with dichloromethane (3 x 10 mL). The combined organic layerswere washed with brine (3.0 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The material was purified by flash chromatography on silica gel (4 g cartridge) using a gradient 0-10% methanol in dichloromethane as eluent to provide title compound (145 mg, 76%) as a brown solid. MS (ESI) [M+H]+ 291.2;1H NMR (500 MHz, DMSO) δ 8.61 (d, J = 2.6 Hz, 1H), 8.27 (dd, J = 9.3, 2.7 Hz, 1H), 8.01 (s, 1H), 7.70 (d, J = 9.3 Hz, 1H), 7.54 (s, 1H), 4.60 (s, 2H), 3.73 (s, 3H), 2.66 (d, J = 4.6 Hz, 3H).

[0307] Step i-22.4. Synthesis of 2-[(6-amino-1-methyl-2-oxo-3-quinolyl)oxy]-N- methyl-acetamide. N-methyl-2-[(1-methyl-6-nitro-2-oxo-3-quinolyl)oxy]acetamide (50.0 mg, 0.172 mmol) was suspended in a mixture of ethanol (6.00 mL) and water (3.00 mL) and to the suspension ammonium chloride (55.1 mg, 1.03 mmol) and iron powder (28.8 mg, 0.52 mmol) were added sequentially at rt. The reaction mixture was heated to reflux for 2 h and then cooled to rt. The mixture was filtered over celite, filter cake was washed with methanol (2 x 5 mL) and the filtrate was then concentrated under reduced pressure. The material was purified by flash chromatography on silica gel (4 g cartridge) using a gradient of 0-10% methanol in dichloromethane as eluent to afford title compound (26 mg, 58%) as a white solid. MS (ESI) [M+H]+ 262.2;1H NMR (500 MHz, DMSO) δ 7.92 (s, 1H). 7.20 (d, J = 8.9 Hz, 1H), 7.05 (s, 1H), 6.80 (dd, J = 8.9, 2,5 Hz, 1H), 6,70 (d, J = 2.5 Hz, 1H), 5.05 (s, 2H), 4.51 (s, 2H), 3.58 (s, 3H), 2.66 (d, J= 4.7 Hz, 3H).

[0308] Step i-22.5. Synthesis of 2-[[6-[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]-1- methyl-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide. To a solution of 2-[(6-amino-1-methyl-2- oxo-3-quinolyl)oxy]-N-methyl-acetamide (1.40 g, 3.73 mmol) in a mixture of tetrahydrofuran / N, N-dimethylformamide (7:1, 40.0 mL) were sequentially added 5-chloro-2,4-difluoro-pyrimidine (431.0 µL, 4.48 mmol) and diisopropylethylamine (2.55 mL, 14.9 mmol) at -40 °C. The reaction mixture was slowly warmed to rt and stirred for 16 h. The resulting precipitate was collected by filtration and then dissolved in dimethylsulfoxide (30.0 mL). Water was slowly added, and the resulting precipitate was collected by filtration, washed with methanol (40.0 mL) and diethyl ether (40.0 mL) then dried under vacuum to provide title compound (950.0 mg, 65%) as a solid. MS (ESI) [M+H]+ 392.1;1H NMR (500 MHz, DMSO) δ 9.71 (s, 1H), 8.39 (s, 1H), 7.93 (bs, 1H), 7.79 (d, J = 2.1 Hz, 1H), 7.65 (dd, J = 9.0, 2.2 Hz, 1H), 7.53 (d, J = 9.1 Hz, 1H), 7.25 (s, 1H), 4.58 (s, 2H), 3.69 (s, 3H), 2.67 (d, J = 4.6 Hz, 3H). Synthesis of Intermediate i-23: 2-((6-((2-chloro-5-cyanopyrimidin-4-yl)amino)-1-methyl-2- oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide

[0309] Step i-23.1: Synthesis of 2-[(6-Bromo-1-methyl-2-oxo-3-quinolyl)oxy]-N- methyl-acetamide. To a solution of 6-bromo-3-hydroxy-1-methyl-quinolin-2-one (10 g, 39.36 mmol) in N, N-dimethylformamide (200 mL) were added sequentially 2-bromo-N-methyl- acetamide (11.96 g, 78.72 mmol) and cesium carbonate (19.24 g, 59.04 mmol), and the reaction mixture was stirred at rt for 24 h. Water (100 mL) was added and the resulting precipitate was collected by filtration, washed with water (3 x 20 mL), then dried under vacuum to afford title compound (11.0 g, 84%) as a solid. MS (ESI) [M+H]+ 325.1.

[0310] Step i-23.2: Synthesis of tert-butyl N-[1-methyl-3-[2-(methylamino)-2-oxo- ethoxy]-2-oxo-6-quinolyl]carbamate . A mixture of 2-[(6-bromo-1-methyl-2-oxo-3- quinolyl)oxy]-N-methyl-acetamide (2.16 g, 6.64 mmol), tert-butyl carbamate (1.17 g, 9.96 mmol), XPhos Pd G3 (1.41 g, 1.66 mmol) and cesium carbonate (2.60 g, 7.97 mmol) in 1,4- dioxane (5 mL) was heated to 100 °C for 16 h and then cooled to rt. The mixture was filtered on celite and washed with ethyl acetate (2 x 25 mL) and dichloromethane (2 x 25 mL). The filtrate was concentrated under reduced pressure and the residue was purified by reverse phase chromatography (C18) using a gradient of 5–50% acetonitrile and 10 mM ammonium formate in water to afford title compound (200 mg, 8%) as a solid. MS (ESI) [M+H]+ 362.2;1H NMR (400 MHz, DMSO-d6) δ 9.45 (s, 1H), 8.01 (d, J = 4.3 Hz, 1H), 7.79 (s, 1H), 7.46 (dd, J = 9.1, 2.4 Hz, 1H), 7.40 (d, J = 9.2 Hz, 1H), 7.21 (s, 1H), 4.55 (s, 2H), 3.63 (s, 3H), 2.66 (d, J = 4.7 Hz, 3H), 1.50 (s, 9H).

[0311] Step i-23.3: Synthesis of 2-[(6-Amino-1-methyl-2-oxo-3-quinolyl)oxy]-N- methyl-acetamide 2,2,2-trifluoroacetic acid. To a solution of tert-butyl N-[1-methyl-3-[2- (methylamino)-2-oxo-ethoxy]-2-oxo-6-quinolyl]carbamate (0.2 g, 0.55 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (1 mL, 13.07 mmol) and the reaction mixture was stirred at rt for 4 h. The volatiles were evaporated under reduced pressure. Diethyl ether (10 mL) was added, and the resulting precipitate was collected by filtration, washed with diethyl ether (10 mL), then dried under vacuum to afford title compound (0.21 g, 99%) as a solid, which was used in the next step without further purification. MS (ESI) [M+H]+ 262.1.

[0312] Step i-23.4: Synthesis of 2-[[6-[(2-Chloro-5-cyano-pyrimidin-4-yl) amino]-1- methyl-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide. To a solution of 2-[(6-amino-1-methyl-2- oxo-3-quinolyl)oxy]-N-methyl-acetamide (260 mg, 0.69 mmol) in tetrahydrofuran (2.5 mL) and N, N-dimethylformamide (0.5 mL) cooled to –40 °C was added sequentially 2,4-dichloropyrimidine-5-carbonitrile (133 mg, 0.76 mmol) and diisopropylethylamine (300 µL, 1.73 mmol). The mixture was stirred at –40 °C for 1 h and at rt for 16 h. The resulting precipitate was collected by filtration, washed with tetrahydrofuran (2 x 10 mL), then dried under vacuum to afford title compound (190 mg, 69%) as a solid, which was used in the next step without further purification. MS (ESI) [M+H]+ 399.1. Synthesis of Intermediate i-24: 2-[[6-[(2,5-dichloropyrimidin-4-yl)amino]-1-methyl-2-oxo- 3-quinolyl]oxy]-N-methyl-acetamide

[0313] Step i-24.1. Synthesis of 2-(methylamino)-5-nitro-benzaldehyde. A solution of methylamine (3.0 mL, 5.91 mmol, 2 M in tetrahydrofuran) was added to a solution of 2-fluoro-5- nitro-benzaldehyde (1.0 g, 5.91 mmol) in dimethylsulfoxide (18 mL) at 0 °C under nitrogen. The mixture was stirred at rt for 4 h, and then diluted with water (5 mL). The aqueous phase was extracted with ethyl acetate (2 x 50 mL), and the combined organic phases were washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The material was purified by silica chromatography on silica gel (40 g cartridge) using a gradient of 0-20% of ethyl acetate in hexane as eluent to provide title compound (0.80 g, 75%) as a pale yellow solid. MS (ESI) [M+H]+ [M+H]+ 181.1;1H NMR (500 MHz, CDCl3) δ 9.87 (d, J = 0.6 Hz, 1H), 9.01 (s, 1H), 8.47 (d, J = 2.7 Hz, 1H), 8.27 (ddd, J = 9.4, 2.7, 0.7 Hz, 1H), 6.72 (d, J = 9.4 Hz, 1H), 3.06 (d, J = 5.2 Hz, 3H).

[0314] Step i-24.2. Synthesis of 2-[(1-methyl-6-nitro-2-oxo-3-quinolyl)oxy]acetic acid. To a solution of 2-(methylamino)-5-nitro-benzaldehyde (400 mg, 2.22 mmol) in anhydrous N,N- dimethylformamide (7.00 mL), sodium hydride (222 mg, 5.55 mmol) was added at rt. The deep red colored reaction mixture was stirred for 30 min before the addition of 1,4-dioxane-2,6-dione (515 mg, 4.44 mmol) and the reaction mixture was stirred at 110 °C for 18 h. The mixture was diluted with dichloromethane (25 mL) and the resulting solid (sodium salt of the product) was filtered then was washed with dichloromethane (2 x 15 mL) and dried under reduced pressure. The solid (sodium salt) was dissolved in water (50 ml) and the aqueous layer was acidified with 1 N HCl until pH 2. The resulting solid was filtered and dried under reduced pressure to afford title compound (186 mg, 30%) as a dark brown solid. MS (ESI) [M+H]+ 280.1.

[0315] Step i-24.3. Synthesis of N-methyl-2-[(1-methyl-6-nitro-2-oxo-3- quinolyl)oxy]acetamide. To a solution of 2-[(1-methyl-6-nitro-2-oxo-3-quinolyl)oxy]acetic acid (185 mg, 0.665 mmol) in N,N-dimethylformamide (9 mL) were added, hydroxybenzotriazole (135mg, 0.997 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (192 mg, 0.997 mmol) sequentially at 0 °C under nitrogen. The reaction mixture was stirred at 0 °C for 15 min, then added methylamine hydrochloride (49 mg, 0.73 mmol) and N, N-Diisopropylethylamine (0.46 mL, 2.66 mmol) slowly and sequentially. The reaction mixture was warmed to rt and stirred for 18 h. The mixture was diluted with an aqueous solution of ammonium chloride (2.0 mL) and the aqueous phase was extracted with dichloromethane (3 x 10 mL). The combined organic layers were washed with brine (3.0 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The material was purified by flash chromatography on silica gel (4 g cartridge) using a gradient 0-10% methanol in dichloromethane as eluent to provide title compound (145 mg, 76%) as a brown solid. MS (ESI) [M+H]+ 291.2;1H NMR (500 MHz, DMSO) δ 8.61 (d, J = 2.6 Hz, 1H), 8.27 (dd, J = 9.3, 2.7 Hz, 1H), 8.01 (s, 1H), 7.70 (d, J = 9.3 Hz, 1H), 7.54 (s, 1H), 4.60 (s, 2H), 3.73 (s, 3H), 2.66 (d, J = 4.6 Hz, 3H).

[0316] Step i-24.4. Synthesis of 2-[(6-amino-1-methyl-2-oxo-3-quinolyl)oxy]-N- methyl-acetamide. N-methyl-2-[(1-methyl-6-nitro-2-oxo-3-quinolyl)oxy]acetamide (50.0 mg, 0.172 mmol) was suspended in a mixture of ethanol (6.00 mL) and water (3.00 mL) and to the suspension ammonium chloride (55.1 mg, 1.03 mmol) and iron powder (28.8 mg, 0.52 mmol) were added sequentially at rt. The reaction mixture was heated to reflux for 2 h and then cooled to rt. The mixture was filtered over celite, filter cake was washed with methanol (2 x 5 mL) and the filtrate was then concentrated under reduced pressure. The material was purified by flash chromatography on silica gel (4 g cartridge) using a gradient of 0-10% methanol in dichloromethane as eluent to afford title compound (26 mg, 58%) as a white solid. MS (ESI) [M+H]+ 262.2;1H NMR (500 MHz, DMSO) δ 7.92 (s, 1H). 7.20 (d, J = 8.9 Hz, 1H), 7.05 (s, 1H), 6.80 (dd, J = 8.9, 2,5 Hz, 1H), 6,70 (d, J = 2.5 Hz, 1H), 5.05 (s, 2H), 4.51 (s, 2H), 3.58 (s, 3H), 2.66 (d, J= 4.7 Hz, 3H).

[0317] Step i-24.5. Synthesis of 2-[[6-[(2,5-dichloropyrimidin-4-yl)amino]-1-methyl- 2-oxo-3-quinolyl]oxy]-N-methyl-acetamide. To a solution of 2-[(6-amino-1-methyl-2-oxo-3- quinolyl)oxy]-N-methyl-acetamide (23.0 mg, 0.09 mmol) in a mixture of ethanol and dichloromethane (1:1, 4.00 mL), 2,4,5-trichloropyrimidine (9.0 μL, 0.08 mmol) and sodium bicarbonate (23.3 mg, 0.22 mmol) were added sequentially at rt under nitrogen. The reaction mixture was stirred at the rt for 18 h and then the solvent was evaporated under reduced pressure. The material was purified by flash chromatography on silica gel (4 g cartridge) using a gradient of 0-10% methanol in dichloromethane as eluent to provide title compound (29 mg, 80%) as a white solid. MS (ESI) [M+H]+ 408.0;1H NMR (500 MHz, DMSO) δ 9.65 (s, 1H), 8.37 (s, 1H), 7.93 (s, 1H), 7.74 (s, 1H), 7.66 (d, J = 9.0 Hz, 1H), 7.53 (d, J = 9.1 Hz, 1H), 7.23 (s, 1H), 4.58 (s,2H), 3.69 (s, 3H), 2.67 (d, J = 3.8 Hz, 3H). Synthesis of Intermediate i-25: 2-((6-((5-chloro-2-fluoropyrimidin-4-yl)amino)-1-methyl-2- oxo-1,2-dihydroquinolin-3-yl)oxy)-N,N-dimethylacetamide.

[0318] Step i-25.1. Synthesis of 1-methyl-5-nitro-indoline-2,3-dione. To a solution of 5-bromoindoline-2,3-dione (30.0 g, 156.0 mmol) in N, N-dimethylformamide (250.0 mL) at 0 °C, was added sodium hydride (60% dispersion in mineral oil, 6.87 g, 172 mmol) portion wise and the mixture was stirred for 15 min. iodomethane (11.7 mL, 187.0 mmol) was added dropwise and the reaction mixture was stirred at 0 °C for 30 min. Water (400.0 mL) was added and the resulting precipitate was collected by filtration, washed with water and diethyl ether, dried under vacuum to afford title compound (27.8 g, 86%) as a solid, which was used in the next step without further purification.1H NMR (400 MHz) δ 8.55 (dd, J = 8.8, 2.4 Hz, 1H), 8.23 (d, J = 2.3 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H), 3.22 (s, 3H).

[0319] Step i-25.2. Synthesis of ethyl 3-hydroxy-1-methyl-6-nitro-2-oxo-quinoline-4- carboxylate. To a suspension of 1-methyl-5-nitro-indoline-2,3-dione (3.0 g, 14.6 mmol) in ethanol (50.0 mL), were sequentially added ethyl diazoacetate (15.0 % in toluene, 14.8 mL, 17.5 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.33 mL, 2.18 mmol). The mixture was stirred at rt for 3 h and then rhodium(II) acetate (106.0 mg, 240.0 µmol) was added. The reaction mixture was stirred at rt for an additional 3 h. The resulting precipitate was collected by filtration, washed with water (3 x 25.0 mL), diethyl ether (2 x 25.0 mL) and dried under vacuum to afford title compound (2.97 g, 70%) as a solid, which was used in the next step without further purification.1H NMR (400 MHz) δ 10.92 (s, 1H), 8.31 (d, J = 2.6 Hz, 1H), 8.26 (dd, J = 9.3, 2.6 Hz, 1H), 7.75 (d, J = 9.3 Hz, 1H), 4.45 (q, J = 7.1 Hz, 2H), 3.77 (s, 3H), 1.35 (t, J = 7.1 Hz, 3H).

[0320] Step i-25.3. Synthesis of 3-hydroxy-1-methyl-6-nitro-quinolin-2-one. To a suspension of ethyl 8-bromo-3-hydroxy-1-methyl-6-nitro-2-oxo-quinoline-4-carboxylate (11.9 g, 40.7 mmol) in a mixture of tetrahydrofuran and water (3:1, 585.0 mL), was added lithium hydroxide. Water (5.13 g, 122.0 mmol). The reaction mixture was heated to 80 °C 16 h and then cooled to rt. The volatiles were evaporated under reduced pressure and then the pH was adjusted to 2 using 2N aqueous HCl (65.0 mL). The solution was heated to 100 °C for 16 h and then cooled to rt. The resulting precipitate was collected by filtration, washed with water (50.0 mL), diethyl ether (50.0 mL) and dried under vacuum to afford title compound (6.82 g, 72%) as a solid, which was used in the next step without further purification. MS (ESI) [M+H]+ 221.2;1H NMR (400MHz) δ 10.06 (s, 1H), 8.54 (d, J = 2.7 Hz, 1H), 8.19 (dd, J = 9.3, 2.7 Hz, 1H), 7.65 (d, J = 9.3 Hz, 1H), 7.33 (s, 1H), 3.74 (s, 3H).

[0321] Step i-25.4. Synthesis of N,N-dimethyl-2-[(1-methyl-6-nitro-2-oxo-3- quinolyl)oxy]acetamide. To a solution of 3-hydroxy-1-methyl-6-nitro-quinolin-2-one (750.0 mg, 3.41 mmol) in N, N-dimethylformamide (15.0 mL) at rt, were sequentially added cesium carbonate (3.33 g, 10.2 mmol), potassium iodide (283.0 mg, 1.70 mmol) and 2-chloro-N,N-dimethyl- acetamide (0.42 mL, 4.09 mmol). The reaction mixture was stirred at rt for 2 h. Water was added, and the resulting precipitate was collected by filtration, washed with water (3 x 30.0 mL), ethyl acetate (30.0 mL), then dried under vacuum to afford title compound (1.02 g, 98%) as a solid.1H NMR (400 MHz, DMSO) δ 8.57 (d, J = 2.7 Hz, 1H), 8.25 (dd, J = 9.3, 2.7 Hz, 1H), 7.67 (d, J = 9.3 Hz, 1H), 7.43 (s, 1H), 4.93 (s, 2H), 3.72 (s, 3H), 3.03 (s, 3H).

[0322] Step i-25.5. Synthesis of 2-[(6-amino-1-methyl-2-oxo-3-quinolyl)oxy]-N,N- dimethyl-acetamide. A mixture of N,N-dimethyl-2-[(1-methyl-6-nitro-2-oxo-3- quinolyl)oxy]acetamide (650.0 mg, 2.13 mmol) and 10% palladium on carbon (227.0 mg, 0.21 mmol) in N, N-dimethylformamide (50.0 mL) was hydrogenated under hydrogen atmosphere at rt for 18 h. The mixture was filtered on celite and washed with methanol (10.0 mL). The filtrate was concentrated under reduced pressure to afford title compound (464.0 mg, 79%) as a solid, which was used in next step without further purification. MS (ESI) [M+H]+ 276.2.

[0323] Step i-25.6. Synthesis of 2-[[6-[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]-1- methyl-2-oxo-3-quinolyl]oxy]-N,N-dimethyl-acetamide. To a solution of 2-[(6-amino-1- methyl-2-oxo-3-quinolyl)oxy]-N,N-dimethyl-acetamide (464.0 mg, 1.69 mmol) in a mixture of tetrahydrofuran (10.0 mL) and N, N-dimethylformamide (5.0 mL) at -40 °C, were sequentially added diisopropylethylamine (317.0 µL, 1.85 mmol) and 5-chloro-2,4-difluoro-pyrimidine (279.0 mg, 1.85 mmol). The reaction mixture was slowly warmed to rt and stirred for 16 h. The volatiles were evaporated under reduced pressure. Water was added and the resulting precipitate was collected by filtration, washed with water (3 x 30.0 mL), ethyl acetate (30.0 mL), then dried under vacuum to afford title compound (395.0 mg, 58%) as a solid. MS (ESI) [M+H]+ 406.2.1H NMR (400 MHz, DMSO) δ 9.69 (s, 1H), 8.38 (d, J = 1.3 Hz, 1H), 7.77 (d, J = 2.3 Hz, 1H), 7.62 (dd, J = 9.0, 2.4 Hz, 1H), 7.51 (d, J = 9.1 Hz, 1H), 7.16 (s, 1H), 4.91 (s, 2H), 3.68 (s, 3H), 3.02 (s, 3H), 2.86 (s, 3H). Synthesis of Intermediate i-26: 1-(5-chloro-4-((1-methyl-3-(2-(methylamino)-2-oxoethoxy)- 2-oxo-1,2-dihydroquinolin-6-yl)amino)pyrimidin-2-yl)piperidine-4-carboxylic acid

[0324] Step i-26.1. Synthesis of 1-(5-chloro-4-((1-methyl-3-(2-(methylamino)-2- oxoethoxy)-2-oxo-1,2-dihydroquinolin-6-yl)amino)pyrimidin-2-yl)piperidine-4-carboxylic acid. To the solution of 2-[[6-[(2,5-dichloropyrimidin-4-yl)amino]-1-methyl-2-oxo-3-quinolyl]oxy]-N- methyl-acetamide (1.30 g, 3.32 mmol, Intermediate 24) in dimethylsulfoxide (40.0 mL), were sequentially added isonipecotic acid (643.0 mg, 4.98 mmol) and diisopropylethylamine (1.44 mL, 8.30 mmol). The reaction mixture was heated to 100 °C for 3 h and then cooled to rt. The solvent was removed by vacuum distillation. Water was added and the resulting precipitate was collected by filtration, washed with methanol, dried under vacuum to provide title compound (1.24 g, 75%) as a solid. MS (ESI) [M+H]+ 501.2.1H NMR (500 MHz, DMSO) δ 12.15 (s, 1H), 8.83 (s, 1H), 8.04 (s, 1H), 7.95 (d, J = 4.7 Hz, 1H), 7.90 (d, J = 2.4 Hz, 1H), 7.75 (dd, J = 9.1, 2.5 Hz, 1H), 7.48 (d, J = 9.1 Hz, 1H), 7.12 (s, 1H), 4.57 (s, 2H), 4.40 – 4.28 (m, 2H), 3.67 (s, 3H), 3.00 (ddd, J = 13.6, 11.4, 2.9 Hz, 2H), 2.66 (d, J = 4.6 Hz, 3H), 2.51 – 2.56 (m, 1H, partially obscured by DMSO peak), 1.84 (dd, J = 13.3, 3.8 Hz, 2H), 1.40 – 1.52 (m, 2H). Synthesis of Intermediate i-27: 4-[Benzyl(methyl)amino]piperidin-2-one.

[0325] Step i-27.1: Synthesis of 4-[Benzyl(methyl)amino]piperidin-2-one. To a solution of piperidine-2,4-dione (1.0 g, 8.8 mmol) in 1,2-dichloroethane (25 mL) were added sequentially N-methyl-1-phenyl-methanamine (1.1 mL, 8.8 mmol) and acetic acid (0.5 mL, 8.8 mmol), and the mixture was stirred for 2 h at rt. Sodium cyanoborohydride (833 mg, 13.3 mmol) was added to the reaction mixture and stirring was continued for 36 h. A saturated aqueous solution of sodium bicarbonate (100 mL) and dichloromethane (100 mL) were added, and the layers were separated. The organic layer was washed with water (100 mL), brine (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a gradient of 0–100% ethyl acetate in hexanes to afford title compound (790 mg, 41%) as a semi-solid. MS (ESI) [M+H]+ 219.2.1H NMR (400 MHz, DMSO-d6) δ 7.45 (br s, 1H), 7.35 – 7.28 (m, 4H), 7.27 – 7.19 (m, 1H), 3.54 (q, J = 13.5 Hz, 2H), 3.22 – 3.16 (m, 1H), 3.08 – 2.99 (m, 1H), 2.89 – 2.80 (m, 1H), 2.31 – 2.20 (m, 2H), 2.09 (s, 3H), 1.97 – 1.87 (m, 1H), 1.68– 1.54 (m, 1H).

[0326] Examples in the table below have been made according to general procedures outlined in the table beginning with their respective commercial starting materials and intermediates found within this document.Example 62. Synthesis of 2-((6-((5-chloro-2-((2-(4-((3-(2,6-dioxopiperidin-3-yl)-1-methyl- 1H-indazol-6-yl)amino)piperidin-1-yl)-2-oxoethyl)amino)pyrimidin-4-yl)amino)-1-methyl- 2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide

[0327] Step 62.1: Synthesis of tert-Butyl N-[2-[4-[[3-(2,6-dioxo-3-piperidyl)-1-methyl- indazol-6-yl]amino]-1-piperidyl]-2-oxo-ethyl]carbamate. To a solution of 2-(tert- butoxycarbonylamino)acetic acid (33.4 mg, 0.19 mmol) in N, N-dimethylformamide (2 mL) were added sequentially hydroxybenzotriazole(32.2 mg, 0.24 mmol), 1-Ethyl-3-[3- dimethylaminopropyl]carbodiimide hydrochloride (45.7 mg, 0.24 mmol), 3-[1-methyl-6-(4- piperidylamino)indazol-3-yl]piperidine-2,6-dione hydrochloride (60.0 mg, 0.16 mmol) and N,N- diisopropylethylamine (0.11 mL, 0.64 mmol). The reaction mixture was stirred at rt for 12 h. Water (2 mL) and ethyl acetate (75 mL) were added and the layers were separated. The organic layer was washed with brine (3 x 5 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a gradient of 0–100% ethyl acetate in hexanes to afford title compound (57 mg, 72%) as a solid. MS (ESI) [M–Boc+H]+ 399.2.

[0328] Step 62.2: Synthesis of 3-[6-[[1-(2-Aminoacetyl)-4-piperidyl]amino]-1-methyl- indazol-3-yl]piperidine-2,6-dione hydrochloride. To the solution of tert-butyl N-[2-[4-[[3-(2,6- dioxo-3-piperidyl)-1-methyl-indazol-6-yl]amino]-1-piperidyl]-2-oxo-ethyl]carbamate (55.0 mg,0.11 mmol) in 1,4-dioxane (2 mL) was added 4N HCl in dioxane (0.14 mL, 0.55 mmol) at rt and the reaction mixture was stirred for 18 h. The volatiles were removed under vacuum and the residue was triturated with diethyl ether (4 mL), filtered and dried under vacuum to afford title compound (42 mg) as a solid which was used in the next step without further purification.

[0329] Step 62.3: Synthesis of 2-[[6-[[5-Chloro-2-[[2-[4-[[3-(2,6-dioxo-3-piperidyl)-1- methyl-indazol-6-yl]amino]-1-piperidyl]-2-oxo-ethyl]amino]pyrimidin-4-yl]amino]-1- methyl-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide. To a solution of crude 3-[6-[[1-(2- aminoacetyl)-4-piperidyl]amino]-1-methyl-indazol-3-yl]piperidine-2,6-dione hydrochloride (42 mg, 0.11 mmol) in dimethylsulfoxide (0.60 mL) were added sequentially 2-[[6-[(5-chloro-2- fluoro-pyrimidin-4-yl)amino]-1-methyl-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide (30.3 mg, 80.0 µmol, Intermediate 22) and N,N-diisopropylethylamine (80.0 µL, 0.44 mmol). The reaction mixture was heated to 100 °C for 12 h and then cooled to rt. The crude reaction mixture was purified by preparative HPLC (BEH column, C18) using a gradient of 25–35% Acetonitrile and 10 mM ammonium formate in water to afford title compound (11.4 mg, 13%) as a solid. MS (ESI) [M+H]+ 770.3;1H NMR (400 MHz, DMSO d6) δ 10.82 (s, 1H), 8.75 (s, 1H), 8.36 – 8.08 (m, 1H), 8.00 (s, 1H), 7.94 (d, J = 3.8 Hz, 1H), 7.78 (d, J = 8.7 Hz, 1H), 7.43 (d, J = 7.9 Hz, 1H), 7.34 (d, J = 8.8 Hz, 1H), 7.30 (s, 1H), 6.81 (t, J = 5.6 Hz, 1H), 6.53 (dd, J = 8.8, 0.9 Hz, 1H), 6.43 (s, 1H), 5.81 (s, 1H), 4.57 (s, 2H), 4.23 – 4.15 (m, 2H), 4.14 – 4.07 (m, 2H), 3.83 (s, 3H), 3.71 – 3.68 (m, 1H), 3.69 (s, 3H), 2.95 – 2.83 (m, 1H), 2.66 (d, J = 4.5 Hz, 3H), 2.67 – 2.57 (m, 2H), 2.32 – 2.21 (m, 1H), 2.18 – 2.10 (m, 1H), 2.07 – 1.79 (m, 3H), 1.34 – 1.11 (m, 3H). Example 63. Synthesis of 2-[[6-[[5-Chloro-2-[[1-[3-(2,6-dioxo-3-piperidyl)-1-methyl- indazol-6-yl]-4-piperidyl]-(2-hydroxyethyl)amino]pyrimidin-4-yl]amino]-1-methyl-2-oxo-3- quinolyl]oxy]-N-methyl-acetamide

[0330] Step 63.1: Synthesis of tert-Butyl 4-[2-benzyloxyethyl-(2- nitrophenyl)sulfonyl-amino]piperidine-1-carboxylate. To a solution of tert-butyl 4-(2- benzyloxyethylamino)piperidine-1-carboxylate (502 mg, 1.5 mmol) and triethylamine (250 µL, 1.8 mmol) in dichloromethane (20 mL) at 0 °C was added 2-nitrobenzenesulfonyl chloride (366mg, 1.65 mmol). The mixture was stirred at rt for 18 h and diluted with dichloromethane (25 mL). The mixture was washed with a saturated solution of sodium bicarbonate (20 mL), water (20 mL) and brine (20 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a gradient of 15–60% Ethyl acetate in hexanes to afford title compound (530 mg, 68%) as a solid. MS (ESI) [M–Boc+H]+ 420.1.1H NMR (500 MHz, DMSO-d6) δ 8.08 (dd, J = 7.9, 1.4 Hz, 1H), 7.95 (dd, J = 8.0, 1.3 Hz, 1H), 7.87 (td, J = 7.7, 1.3 Hz, 1H), 7.79 (td, J = 7.7, 1.3 Hz, 1H), 7.38 – 7.31 (m, 2H), 7.31 – 7.26 (m, 3H), 4.45 (s, 2H), 3.95 (br s, 2H), 3.77 (tt, J = 11.8, 4.0 Hz, 1H), 3.52 (t, J = 6.3 Hz, 2H), 3.46 (t, J = 5.6 Hz, 2H), 2.70 (br s, 2H), 1.58 (qd, J = 12.2, 4.5 Hz, 2H), 1.52 – 1.46 (m, 2H), 1.38 (s, 9H).

[0331] Step 63.2: Synthesis of N-(2-Benzyloxyethyl)-2-nitro-N-(4-piperidyl) benzenesulfonamide. To a solution of TFA (5 mL, 65.3 mmol) in dichloromethane (10 mL) at rt was added tert-butyl 4-[2-benzyloxyethyl-(2-nitrophenyl)sulfonyl-amino]piperidine-1- carboxylate (530 mg, 1.02 mmol). The mixture was stirred at rt for 4 h and the volatiles were removed under reduced pressure. The residue was dissolved in methanol (5 mL) and the solution was filtered on two 500 mg SP-HCO3 SPE cartridges to afford title compound (332 mg, 77%) as a solid. MS (ESI) [M+H]+ 420.1.1H NMR (500 MHz, MeOD-d4) δ 8.09 (dd, J = 7.9, 1.3 Hz, 1H), 7.81 – 7.75 (m, 1H), 7.78 – 7.73 (m, 1H), 7.74 – 7.68 (m, 1H), 7.36 – 7.26 (m, 5H), 4.46 (s, 2H), 3.92 (tt, J = 11.9, 4.1 Hz, 1H), 3.63 – 3.57 (m, 2H), 3.57 – 3.51 (m, 2H), 3.25 – 3.20 (m, 1H), 3.23 – 3.18 (m, 1H), 2.81 (td, J = 12.8, 3.0 Hz, 2H), 1.85 (qd, J = 12.7, 4.2 Hz, 2H), 1.80 – 1.71 (m, 2H). Note: one exchangeable proton could not visible.

[0332] Step 63.3: Synthesis of N-(2-Benzyloxyethyl)-N-[1-[3-(2,6-dibenzyloxy-3- pyridyl)-1-methyl-indazol-6-yl]-4-piperidyl]-2-nitro-benzenesulfonamide. A mixture of N-(2- benzyloxyethyl)-2-nitro-N-(4-piperidyl)benzenesulfonamide (320 mg, 0.76 mmol), 6-bromo-3- (2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole (573 mg, 1.14 mmol), RuPhos Pd G3 (160 mg, 0.19 mmol), and cesium carbonate (373 mg, 1.14 mmol) in 1,4-dioxane (5 mL) was heated at 80 °C for 16 h and then cooled to rt. The mixture was filtered on celite, washed with dichloromethane (50 mL) and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a gradient of 0–50% ethyl acetate in hexanes to afford title compound (384 mg, 60%) as a solid. MS (ESI) [M+H]+ 839.3.

[0333] Step 63.4: Synthesis of N-(2-Benzyloxyethyl)-1-[3-(2,6-dibenzyloxy-3- pyridyl)-1-methyl-indazol-6-yl]piperidin-4-amine. To a solution of N-(2-benzyloxyethyl)-N- [1-[3-(2, 6-dibenzyloxy-3-pyridyl)-1-methyl-indazol-6-yl]-4-piperidyl]-2-nitro- benzenesulfonamide (360 mg, 0.43 mmol) in acetonitrile (2 mL) was added sequentially cesiumcarbonate (280 mg, 0.86 mmol) and thiophenol (47.3 mg, 0.43 mmol), and the mixture was stirred at rt for 3 h. Water (20 mL) and ethyl acetate (30 mL) were added and the layers were separated. The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a gradient of 0– 20% methanol in dichloromethane to afford title compound (230 mg, 82%). MS (ESI) [M+H]+ 654.3.1H NMR (400 MHz, DMSO-d6) δ 7.88 (d, J = 8.1 Hz, 1H), 7.51 – 7.24 (m, 15H), 6.83 (s, 1H), 6.80 (dd, J = 9.1, 1.9 Hz, 1H), 6.56 (d, J = 8.1 Hz, 1H), 5.44 (s, 2H), 5.41 (s, 2H), 4.49 (s, 2H), 3.95 (s, 3H), 3.72 (d, J = 12.6 Hz, 2H), 3.52 (t, J = 5.6 Hz, 2H), 3.17 (d, J = 4.9 Hz, 1H), 2.84 – 2.76 (m, 3H), 2.70 – 2.58 (m, 1H), 1.96 – 1.87 (m, 2H), 1.45 – 1.33 (m, 2H). Note: one exchangeable proton and one aromatic proton not visible.

[0334] Step 63.5: Synthesis of 3-[6-[4-(2-Hydroxyethylamino)-1-piperidyl]-1-methyl- indazol-3-yl]piperidine-2,6-dione. A mixture of N-(2-benzyloxyethyl)-1-[3-(2,6-dibenzyloxy-3- pyridyl)-1-methyl-indazol-6-yl] piperidin-4-amine (230 mg, 0.35 mmol) and Pearlman’s catalyst (187 mg, 0.180 mmol) in methanol (20 mL) and tetrahydrofuran (30 mL) was stirred under a hydrogen atmosphere (1 atm) at 50 °C for 9 h. The mixture was filtered on celite and washed with methanol (100 mL) and tetrahydrofuran (200 mL). The filtrate was concentrated under reduced pressure to afford title compound (130 mg, 96%) as an oil, which was used in the next step without further purification. MS (ESI) [M+H]+ 386.3.

[0335] Step 63.6: Synthesis of 2-[[6-[[5-Chloro-2-[[1-[3-(2,6-dioxo-3-piperidyl)-1- methyl-indazol-6-yl]-4-piperidyl]-(2-hydroxyethyl)amino]pyrimidin-4-yl]amino]-1-methyl- 2-oxo-3-quinolyl]oxy]-N-methyl-acetamide. To a solution of 3-[6-[4-(2-hydroxyethylamino)-1- piperidyl]-1-methyl-indazol-3-yl] piperidine-2,6-dione (34.0 mg, 90 µmol) in dimethylsulfoxide (0.5 mL) was added sequentially 2-[[6-[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]-1-methyl-2- oxo-3-quinolyl]oxy]-N-methyl-acetamide (34.6 mg, 90 µmol, Intermediate i-22) and diisopropylethylamine (60 µL, 0.35 mmol), and the mixture was heated to 120 °C for 20 h and then cooled to rt. The crude reaction mixture was purified by preparative HPLC (BEH column, C18) using a gradient of 31–41% acetonitrile and 10 mM ammonium formate in water to afford title compound (17 mg, 25%) as a solid. MS (ESI) [M+H]+ 757.3.1H NMR (500 MHz, DMSO- d6, 90 °C) δ 10.49 (s, 1H), 8.50 (s, 1H), 8.05 (s, 1H), 8.01 (s, 1H), 7.78 – 7.73 (m, 1H), 7.65 (s, 1H), 7.49 (d, J = 8.9 Hz, 1H), 7.44 (d, J = 9.1 Hz, 1H), 7.32 (s, 1H), 6.88 (d, J = 8.9 Hz, 1H), 6.79 (d, J = 7.4 Hz, 1H), 4.49 (s, 3H), 4.47 (s, 1H), 4.23 (dd, J = 8.4, 5.2 Hz, 1H), 4.07 – 4.05 (m, 1H), 3.89 (s, 3H), 3.88 – 3.85 (m, 1H), 3.63 (s, 2H), 3.62 – 3.61 (m, 1H), 3.57 (d, J = 5.7 Hz, 2H), 3.53 (d, J = 5.6 Hz, 2H), 2.80 – 2.73 (m, 2H), 2.69 (d, J = 4.7 Hz, 3H), 2.68 – 2.62 (m, 2H), 2.37 – 2.28 (m, 1H), 2.27 – 2.19 (m, 1H), 1.96 – 1.87 (m, 2H), 1.81 – 1.75 (m, 2H).

[0336] Example 64. 2-[[6-[[2-[Butyl-[1-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol- 6-yl]-4-piperidyl]amino]-5-chloro-pyrimidin-4-yl]amino]-1-methyl-2-oxo-3-quinolyl]oxy]- N-methyl-acetamide

[0337] Step 64.1: Synthesis of 1-[3-(2,6-Dihydroxy-3-pyridyl)-1-methyl-indazol-6- yl]piperidin-4-one. A mixture of 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole (6.0 g, 11.99 mmol), piperidin-4-one hydrochloride (2.44 g, 17.99 mmol), sodium tert-butoxide (3.0 g, 31.2 mmol), and tBuXPhos Pd G3 (952.5 mg, 1.2 mmol) in anhydrous tetrahydrofuran (120 mL) was heated to 70 °C for 2 h and then cooled to rt. The reaction mixture was filtered on celite and the rinsed with dichloromethane (3 x 100 mL). The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel using a gradient of 0–80% Ethyl acetate in hexanes to afford title compound (4.01 g, 65%) as a solid. MS (ESI) [M+H]+ 518.9.

[0338] Step 64.2: Synthesis of 3-[1-Methyl-6-(4-oxo-1-piperidyl)indazol-3- yl]piperidine-2,6-dione. A mixture of 1-[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazol-6- yl]piperidin-4-one (2.58 g, 4.97 mmol) and 20% Pearlman’s catalyst (0.87 g, 1.24 mmol) in tetrahydrofuran (25 mL) and Ethanol (25 mL) was subjected to hydrogenation (1 atm) at 50 °C for 18 h. The reaction mixture was cooled to rt, then a second portion of 20% Pearlman’s catalyst (0.87 g, 1.24 mmol) was subjected to hydrogenation (1 atm) at 50 °C for 22 h. The reaction mixture was cooled to rt and the reaction mixture was filtered on celite and rinsed with dichloromethane (3 x 300 mL) and with N, N-dimethylformamide (3 x 25 mL). The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel using a gradient of 0–10% methanol in dichloromethane to afford title compound (1.15 g, 64%) as a solid. MS (ESI) [M+H]+ 341.7.1H NMR (500 MHz, DMSO-d6) δ 10.85 (s, 1H), 7.54 (d, J = 8.9 Hz, 1H), 7.00 (dd, J = 9.0, 2.1 Hz, 1H), 6.97 (d, J = 1.7 Hz, 1H), 4.26 (dd, J = 9.3, 5.1 Hz, 1H), 3.90 (s, 3H), 3.69 (t, J = 6.0 Hz, 4H), 2.68 – 2.56 (m, 2H), 2.46 (t, J = 6.0 Hz, 4H), 2.35 – 2.26 (m, 1H), 2.20 – 2.12 (m, 1H).

[0339] Step 64.3: Synthesis of 3-[6-[4-(Butylamino)-1-piperidyl]-1-methyl-indazol-3- yl]piperidine-2,6-dione. To a solution of 3-[1-methyl-6-(4-oxo-1-piperidyl)indazol-3-yl]piperidine-2,6-dione (94 mg, 0.28 mmol), 3-[tert-butyl(dimethyl)silyl]oxypropan-1-amine (110 mg, 0.55 mmol) and sodium triacetoxyborohydride (117 mg, 0.55 mmol) in dimethylsulfoxide (2 mL) was added acetic acid (0.4 mL) followed by scandium (III) triflate (13.6 mg, 30 µmol), and the reaction mixture was stirred at rt for 1 h. The crude reaction mixture was purified by preparative HPLC (BEH column, C18) using a gradient of 55–65% acetonitrile and 10 mM ammonium bicarbonate in water to afford title compound (39.1 mg, 27%) as a solid.1H NMR (500 MHz, DMSO-d6) δ 10.85 (s, 1H), 7.47 (d, J = 9.0 Hz, 1H), 6.90 (dd, J = 9.0, 1.8 Hz, 1H), 6.82 (d, J = 1.7 Hz, 1H), 4.24 (dd, J = 9.2, 5.1 Hz, 1H), 3.88 (s, 3H), 3.71 (d, J = 12.5 Hz, 2H), 3.65 (t, J = 6.2 Hz, 2H), 2.80 (dd, J = 17.3, 6.7 Hz, 2H), 2.65 – 2.59 (m, 4H), 2.57 – 2.53 (m, 1H), 2.34 – 2.24 (m, 1H), 2.19 – 2.11 (m, 1H), 1.89 (d, J = 10.8 Hz, 2H), 1.63 – 1.55 (m, 2H), 1.42 – 1.30 (m, 2H), 0.87 (s, 9H), 0.03 (s, 6H). Note: one signal not visible, most likely due to exchange with solvent.

[0340] Step 64.4: Synthesis of 2-[[6-[[2-[Butyl-[1-[3-(2,6-dioxo-3-piperidyl)-1-methyl- indazol-6-yl]-4-piperidyl]amino]-5-chloro-pyrimidin-4-yl]amino]-1-methyl-2-oxo-3- quinolyl]oxy]-N-methyl-acetamide. To a solution of 3-[6-[4-[3-[tert- butyl(dimethyl)silyl]oxypropylamino]-1-piperidyl]-1-methyl-indazol-3-yl]piperidine-2,6-dione (20 mg, 40 mmol) in dimethylsulfoxide (0.4 mL) were added sequentially 2-[[6-[(5-chloro-2- fluoro-pyrimidin-4-yl)amino]-1-methyl-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide (30.5 mg, 80 µmol, Intermediate i-22) and diisopropylethylamine (30 µL, 0.16 mmol) at rt, and the reaction mixture was heated to 80 °C for 20 h, then cooled rt. A second portion of diisopropylethylamine (30 µL, 0.16 mmol) was added to the reaction mixture and was stirred at 90 °C for 64 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (BEH column, C18) using a gradient of 29–39% Acetonitrile and 10 mM ammonium formate in water to afford title compound the title compound as a solid. The desired product was detected. MS (ESI) [M+H]+ 771.4.1H NMR (500 MHz, DMSO-d6, 90 °C) δ 10.47 (s, 1H), 8.48 (s, 1H), 8.04 (s, 1H), 7.84 (d, J = 2.3 Hz, 1H), 7.77 (dd, J = 9.0, 2.4 Hz, 1H), 7.64 (br s, 1H), 7.49 (d, J = 8.9 Hz, 1H), 7.44 (d, J = 9.1 Hz, 1H), 7.25 (s, 1H), 6.87 (d, J = 9.1 Hz, 1H), 6.79 (s, 1H), 4.50 (s, 3H), 4.23 (dd, J = 8.4, 5.1 Hz, 1H), 4.13 (br s, 1H), 3.89 (s, 3H), 3.87 (s, 1H), 3.85 (s, 1H), 3.63 (s, 3H), 3.48 – 3.44 (m, 2H), 3.38 (s, 2H), 2.74 (t, J = 12.1 Hz, 2H), 2.69 (d, J = 4.7 Hz, 3H), 2.67 – 2.62 (m, 2H), 2.37 – 2.28 (m, 1H), 2.26 – 2.18 (m, 1H), 1.98 – 1.89 (m, 2H), 1.78 (d, J = 10.5 Hz, 2H), 1.75 – 1.68 (m, 2H).Example 65. Synthesis of 2-((6-((5-chloro-2-((2-(4-((3-(2,6-dioxopiperidin-3-yl)-1-methyl- 1H-indazol-6-yl)amino)piperidin-1-yl)-2-oxoethyl)amino)pyrimidin-4-yl)amino)-1-methyl- 2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide

[0341] Step 65.1: Synthesis of tert-butyl O5-ethyl 4-[[(1R)-1-phenylethyl]amino]-3,6- dihydro-2H-pyridine-1,5-dicarboxylate. To a solution of O1-tert-butyl O3-ethyl 4- oxopiperidine-1,3-dicarboxylate (22 g, 81 mmol) and (1R)-1-phenylethanamine (12.5 mL, 97.2 mmol) in toluene (400 mL) was added p-toluenesulfonic acid (1.39 g, 8.1 mmol) and the mixture was heated to reflux with a Dean-Stark trap for 18 h. The mixture was cooled to rt, washed with a saturated aqueous solution of sodium bicarbonate (2 x 200 mL) and brine (2 x 200 mL). The combined organic fractions were dried over magnesium sulfate, filtered and concentrated. The residue was filtered on a pad of silica, rinsed with dichloromethane (2 x 100 mL) and concentrated to afford title compound (30.2 g, 99%) as an oil, which was used in the next step without further purification. MS (ESI) [M+H]+375.2.1H NMR (400 MHz, CDCl3) δ 9.25 (d, J = 7.5 Hz, 1H), 7.36 – 7.28 (m, 2H), 7.26 – 7.18 (m, 3H), 4.66 – 4.54 (m, 1H), 4.24 – 4.14 (m, 2H), 4.07 (br s, 2H), 3.48 – 3.35 (m, 1H), 3.35 – 3.24 (m, 1H), 2.39 (dd, J = 13.0, 6.2 Hz, 1H), 2.09 – 2.00 (m, 1H), 1.50 (d, J = 6.8 Hz, 3H), 1.43 (s, 9H), 1.29 (t, J = 7.0 Hz, 3H).

[0342] Step 65.2: Synthesis of tert-butyl O3-ethyl (3S,4R)-4-[[(1R)-1- phenylethyl]amino]piperidine-1,3-dicarboxylate. To a solution of tert-butyl O5-ethyl 4-[[(1R)- 1-phenylethyl]amino]-3,6-dihydro-2H-pyridine-1,5-dicarboxylate (15 g, 40.1 mmol) in acetonitrile (200 mL) and acetic acid (100 mL) cooled to 0 °C was added portion-wise sodium triacetoxyborohydride (34 g, 160 mmol) over 2 h, and the reaction mixture was stirred at 0 °C for 2 h. The mixture was then cooled to –10 °C and slowly treated with a 1M aqueous solution of sodium hydroxide (100 mL), a 4M aqueous solution of sodium hydroxide (100 mL), a 6M aqueous solution of sodium hydroxide (100 mL), followed by a 50% aqueous solution of sodium hydroxide (50 mL). The mixture was warmed to rt and the layers were separated. The aqueous layer was extracted with dichloromethane (3 x 80 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a gradient of 0–50% ethyl acetate in hexanes to afford a 4:1 mixture of isomers (14.8 g, 98%) as an oil. A portion (7 g) of the 4:1 mixture was separated by SFC to afford title compound (3.7 g) as an oil. MS (ESI) [M+H]+377.2.1H NMR(400 MHz, DMSO-d6) δ 7.36 – 7.25 (m, 4H), 7.24 – 7.15 (m, 1H), 4.09 (q, J = 6.8 Hz, 2H), 3.82 – 3.66 (m, 2H), 3.60 – 3.46 (m, 1H), 3.24 – 3.11 (m, 1H), 3.07 – 2.86 (m, 1H), 2.82 – 2.75 (m, 1H), 2.73 –2.66 (m, 1H), 1.64 – 1.52 (m, 1H), 1.42 – 1.37 (m, 1H), 1.35 (s, 9H), 1.22 (t, J = 7.0 Hz, 3H), 1.17 (d, J = 6.6 Hz, 3H).

[0343] Step 65.3: Synthesis of tert-butyl (3S,4R)-3-(hydroxymethyl)-4-[[(1R)-1- phenylethyl]amino]piperidine-1-carboxylate. To a solution of tert-butyl O3-ethyl (3S,4R)-4- [[(1R)-1-phenylethyl]amino]piperidine-1,3-dicarboxylate (500 mg, 1.33 mmol) in tetrahydrofuran (3 mL) was added lithium borohydride (1.33 mL, 2.66 mmol), and the mixture was heated to reflux for 2 h, then cooled to rt. Ice-water (10 mL) was added and the mixture was concentrated under reduced pressure. The residue was extracted with ethyl acetate (3 x 30 mL). The combined organic fractions were dried over sodium sulfate, filtered, and concentrated to afford title compound (404 mg, 91%) as an oil, which was used in the next step without further purification. MS (ESI) [M+H]+335.3.

[0344] Step 65.4: Synthesis of tert-butyl (3S,4R)-3-[[tert- butyl (dimethyl)silyl]oxymethyl]-4-[[(1R)-1-phenylethyl]amino]piperidine-1-carboxylate. To a solution of tert-butyl (3S,4R)-3-(hydroxymethyl)-4-[[(1R)-1-phenylethyl]amino]piperidine- 1-carboxylate (404 mg, 1.21 mmol) in dichloromethane (5 mL) was added sequentially tert- butylchlorodimethylsilane (218 mg, 1.45 mmol) and imidazole (123 mg, 1.81 mmol), and the reaction mixture was stirred at rt for 3 h. Water (15 mL) and diethyl ether (20 mL) were added and the layers were separated. The aqueous layer was washed with diethyl ether (3 x 10 mL) and the combined organic fractions were dried over sodium sulfate filtered, and concentrated to afford title compound (540 mg, 99%) as an oil, which was used in the next step without further purification. Note: SFC analysis confirmed the presence of only one diastereomer. MS (ESI) [M+H]+449.4.1H NMR (400 MHz, DMSO-d6) δ 7.35 – 7.26 (m, 4H), 7.23 – 7.16 (m, 1H), 3.86 – 3.68 (m, 3H), 3.68 – 3.54 (m, 1H), 3.48 (t, J = 9.6 Hz, 1H), 2.89 – 2.68 (m, 1H), 2.81 (dd, J = 13.1, 3.2 Hz, 1H), 2.59 – 2.52 (m, 1H), 1.82 – 1.72 (m, 1H), 1.36 (s, 9H), 1.34 – 1.27 (m, 1H), 1.26 – 1.18 (m, 1H), 1.22 (d, J = 6.7 Hz, 3H), 0.90 (s, 9H), 0.07 (d, J = 3.1 Hz, 6H). Note: one exchangeable proton not visible.

[0345] Step 65.5: Synthesis of tert-butyl (3S,4R)-4-amino-3-[[tert- butyl(dimethyl)silyl]oxymethyl]piperidine-1-carboxylate. A mixture of tert-butyl (3S,4R)-3- [[tert-butyl(dimethyl)silyl]oxymethyl]-4-[[(1R)-1-phenylethyl]amino]piperidine-1-carboxylate (530 mg, 1.18 mmol), ammonium formate (596 mg, 9.45 mmol) and palladium on carbon (126 mg, 0.12 mmol) in ethanol (15 mL) was heated to 65 °C for 2 h. The mixture was filtered through celite and washed with methanol (3 x 15 mL). The filtrate was concentrated under reducedpressure to afford title compound (320 mg, 79%) as a solid, which was used in the next step without further purification. MS (ESI) [M+H]+345.3.1H NMR (400 MHz, DMSO-d6) δ 3.61 (dd, J = 10.2, 4.9 Hz, 1H), 3.49 – 3.41 (m, 2H), 3.39 – 3.24 (m, 3H), 3.23 – 3.08 (m, 1H), 3.06 – 2.98 (m, 1H), 1.71 – 1.55 (m, 2H), 1.55 – 1.44 (m, 1H), 1.40 – 1.33 (m, 1H), 1.38 (s, 9H), 0.89 – 0.84 (m, 9H), 0.06 – 0.01 (m, 6H).

[0346] Step 65.6: Synthesis of tert-butyl (3S, 4R)-3-[[tert-butyl(dimethyl) silyl] oxymethyl]-4-[[3-(2, 6-dibenzyloxy-3-pyridyl)-1-methyl-indazol-6-yl] amino] piperidine-1- carboxylate. A mixture of 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole (471 mg, 0.94 mmol), tert-butyl (3S,4R)-4-amino-3-[[tert-butyl(dimethyl)silyl] oxymethyl]piperidine-1- carboxylate (270 mg, 0.78 mmol), cesium carbonate (638 mg, 1.96 mmol) and RuPhos Pd G3 (98.3 mg, 0.12 mmol) in 1,4-dioxane (7 mL) was heated to 90 °C for 16 h and then cooled to rt. The residue was purified by column chromatography on silica gel using a gradient of 0–50% ethyl acetate in hexanes to afford title compound (458 mg, 67%) as a solid. Note: the reaction was repeated, and the crude residue combined before purification. MS (ESI) [M+H]+764.4.1H NMR (400 MHz, DMSO-d6) δ 7.87 (d, J = 8.1 Hz, 1H), 7.50 – 7.44 (m, 2H), 7.42 – 7.26 (m, 9H), 6.55 (d, J = 7.9 Hz, 1H), 6.52 (dd, J = 9.0, 1.9 Hz, 1H), 6.45 (d, J = 1.3 Hz, 1H), 5.78 (d, J = 8.6 Hz, 1H), 5.44 (s, 2H), 5.41 (s, 2H), 3.88 (s, 3H), 3.85 – 3.77 (m, 1H), 3.67 – 3.61 (m, 1H), 3.60 – 3.41 (m, 4H), 3.39 – 3.32 (m, 1H), 2.10 – 2.00 (m, 1H), 1.67 – 1.53 (m, 2H), 1.41 (s, 9H), 0.82 (s, 9H), –0.05 (d, J = 15.0 Hz, 6H).

[0347] Step 65.7: Synthesis of tert-butyl (3S,4R)-3-[[tert- butyl(dimethyl)silyl]oxymethyl]-4-[[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-6- yl]amino]piperidine-1-carboxylate. A mixture of tert-butyl (3S,4R)-3-[[tert- butyl(dimethyl)silyl]oxymethyl]-4-[[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazol-6- yl]amino]piperidine-1-carboxylate (458 mg, 0.60 mmol) and Pearlman's catalyst (210 mg, 0.15 mmol) in ethanol (10 mL) and tetrahydrofuran (10 mL) was subjected to hydrogenation (1 atm) at 50 °C for 2 h. The mixture was filtered on celite and washed with methanol (3 x 15 mL). The filtrate was concentrated under reduced pressure to afford title compound (350 mg, quant.) as a solid, which was used in the next step without further purification. MS (ESI) [M+H]+586.4.

[0348] Step 65.8: Synthesis of 3-[6-[[(3S,4R)-3-(hydroxymethyl)-4-piperidyl]amino]- 1-methyl-indazol-3-yl]piperidine-2,6-dione dihydrochloride. To a solution of tert- butyl (3S,4R)-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-[[3-(2,6-dioxo-3-piperidyl)-1-methyl- indazol-6-yl]amino]piperidine-1-carboxylate (350 mg, 0.60 mmol) in dichloromethane (2.5 mL) was added 4N HCl in 1,4-dioxane (1.5 mL, 6.0 mmol) and the mixture was stirred for 2 h at rt. The resulting precipitate was collected by filtration, washed with diethyl ether (3 x 5 mL) anddried under vacuum to afford title compound (250 mg, 77%) as a solid, which was used in the next step without further purification. MS (ESI) [M+H]+372.2.1H NMR (500 MHz, DMSO-d6) δ 10.82 (s, 1H), 8.89 – 8.68 (m, 2H), 7.35 (d, J = 8.8 Hz, 1H), 6.66 (dd, J = 8.8, 1.7 Hz, 1H), 6.51 (s, 1H), 4.18 (dd, J = 9.0, 5.1 Hz, 1H), 3.99 – 3.92 (m, 1H), 3.82 (s, 3H), 3.51 – 3.41 (m, 2H), 3.27 – 3.15 (m, 2H), 3.15 – 3.04 (m, 2H), 2.67 – 2.54 (m, 2H), 2.32 – 2.21 (m, 2H), 2.18 – 2.10 (m, 1H), 1.98 – 1.89 (m, 1H), 1.87 – 1.78 (m, 1H). Note: exchangeable signals not visible.

[0349] Step 65.9: Synthesis of 2-[[6-[[5-chloro-2-[(3S,4R)-4-[[3-(2,6-dioxo-3- piperidyl)-1-methyl-indazol-6-yl]amino]-3-(hydroxymethyl)-1-piperidyl]pyrimidin-4- yl]amino]-1-methyl-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide. To a mixture of 2-[[6-[(5- chloro-2-fluoro-pyrimidin-4-yl)amino]-1-methyl-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide (35 mg, 90 µmol, Intermediate 22) and diisopropylethylamine (80 µL, 0.45 mmol) in dimethylsulfoxide (1 mL) at rt was added 3-[6-[[(3S,4R)-3-(hydroxymethyl)-4-piperidyl]amino]- 1-methyl-indazol-3-yl]piperidine-2,6-dione dihydrochloride (58.2 mg, 0.11 mmol), and the reaction mixture was heated to 80 °C for 16 h. The crude reaction mixture was purified by preparative HPLC (BEH column, C18) with a gradient of 30−40% acetonitrile and 10 mM ammonium formate in water to afford title compound (46.9 mg, 71%) as a solid. MS (ESI) [M+H]+743.4.1H NMR (500 MHz, DMSO-d6) δ 8.80 (s, 1H), 8.35 (s, 1H), 8.06 (s, 1H), 7.93 – 7.88 (m, 1H), 7.82 (dd, J = 9.2, 2.0 Hz, 1H), 7.44 (d, J = 9.1 Hz, 1H), 7.33 (d, J = 8.8 Hz, 1H), 7.19 (br s, 1H), 6.65 (dd, J = 8.8, 1.7 Hz, 1H), 6.49 (s, 1H), 5.87 (d, J = 8.6 Hz, 1H), 4.54 (s, 2H), 4.18 (dd, J = 8.9, 5.1 Hz, 1H), 3.94 – 3.85 (m, 2H), 3.81 (s, 3H), 3.79 – 3.73 (m, 1H), 3.65 (s, 3H), 3.56 – 3.50 (m, 1H), 3.45 – 3.29 (m, 4H), 2.66 – 2.56 (m, 2H), 2.61 (d, J = 4.0 Hz, 3H), 2.31 – 2.22 (m, 1H), 2.20 – 2.07 (m, 2H), 1.79 – 1.70 (m, 1H), 1.70 – 1.60 (m, 1H). Note: glutarimide NH signal not visible. Example 66.2-[[6-[[5-Chloro-2-[(3R,4R)-4-[[3-(2,4-dioxohexahydropyrimidin-1-yl)-1- methyl-indazol-6-yl]amino]-3-methyl-1-piperidyl]pyrimidin-4-yl]amino]-1-methyl-2-oxo-3- quinolyl]oxy]-N-methyl-acetamide

[0350] Step 66.1: Synthesis of tert-Butyl (3R,4R)-4-[[3-(2,4- dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]amino]-3-methyl-piperidine-1- carboxylate. A mixture of [3-(2,4-dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]boronic acid (200 mg, 0.69 mmol, Intermediate 9), tert-butyl (3R,4R)-4-amino-3-methyl- piperidine-1-carboxylate (228 mg, 1.04 mmol), copper (II) acetate (152 mg, 0.76 mmol), triethylamine (190 µL, 1.39 mmol) and 3Å MS (100 mg) in 1,2-dichloroethane (12.6 mL) under O2(1 atm) was heated to 50 °C for 18 h. The mixture was filtered on celite and washed with a 1:1 mixture of acetonitrile and methanol (3 x 10 mL). The filtrate was concentrated under reduced pressure and the residue was purified by preparative HPLC (BEH column, C18) using a gradient of 10–80% acetonitrile and 10 mM ammonium formate in water to afford title compound (76 mg, 24%) as a solid. MS (ESI) [M+H]+ 457.3.

[0351] Step 66.2: Synthesis of 1-[1-Methyl-6-[[(3R,4R)-3-methyl-4- piperidyl]amino]indazol-3-yl]hexahydropyrimidine-2,4-dione hydrochloride. To a solution of tert-butyl (3R,4R)-4-[[3-(2,4-dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]amino]- 3-methyl-piperidine-1-carboxylate (76 mg, 0.166 mmol) in 1,4-dioxane (1.66 mL) was added a 4N solution of HCl in 1,4-dioxane (0.42 mL, 1.66 mmol) and the mixture was stirred at rt for 20 h. The volatiles were removed under reduced pressure and the residue was washed with diethyl ether (5 mL) and dried under vacuum to afford title compound (45 mg, 70%) as a solid, which was used in the next step without further purification. MS (ESI) [M+H]+ 357.3.

[0352] Step 66.3: Synthesis of 2-[[6-[[5-Chloro-2-[(3R,4R)-4-[[3-(2,4- dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]amino]-3-methyl-1- piperidyl]pyrimidin-4-yl]amino]-1-methyl-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide. To a mixture of 2-[[6-[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]-1-methyl-2-oxo-3-quinolyl]oxy]-N- methyl-acetamide (24 mg, 60 µmol, Intermediate 22) and 1-[1-methyl-6-[[(3R,4R)-3-methyl-4- piperidyl]amino]indazol-3-yl]hexahydropyrimidine-2,4-dione hydrochloride (22 mg, 60 µmol) in N, N-dimethylformamide (1.1 mL) was added diisopropylethylamine (40 µL, 0.17 mmol). The mixture was heated to 80°C for 1 h and then cooled to rt. The volatiles were removed under reduced pressure and the residue was purified by preparative HPLC (BEH column, C18) using a gradient of 39–49% acetonitrile and 10 mM ammonium formate in water to afford title compound (4.33 mg, 11%) as a solid. MS (ESI) [M+H]+ 728.4.1H NMR (400 MHz, DMSO-d6) δ 10.40 (br s, 1H), 8.90 (s, 1H), 8.07 (s, 1H), 7.96 (d, J = 4.8 Hz, 1H), 7.90 (s, 1H), 7.82 – 7.70 (m, 1H), 7.47 (d, J = 9.1 Hz, 1H), 7.25 (d, J = 8.9 Hz, 1H), 7.13 (s, 1H), 6.49 (d, J = 8.9 Hz, 1H), 6.42 (s, 1H), 5.77 (d, J = 8.8 Hz, 1H), 4.59 – 4.37 (m, 4H), 3.85 (t, J = 6.7 Hz, 2H), 3.80 (s, 3H), 3.66 (s, 3H), 3.04 (t, J = 12.1 Hz, 1H), 2.73 – 2.69 (m, 2H), 2.61 (d, J = 4.6 Hz, 3H), 2.08 (d, J = 10.3 Hz, 1H), 1.59 (br s, 1H), 1.27 – 1.08 (m, 2H), 0.95 (d, J = 6.4 Hz, 3H).Example 67.2-[[6-[[5-Chloro-2-[4-[3-(2,4-dioxohexahydropyrimidin-1-yl)-1-methyl- indazol-6-yl]-1-piperidyl]pyrimidin-4-yl]amino]-1-methyl-2-oxo-3-quinolyl]oxy]-N-methyl- acetamide.

[0353] Step 67.1: Synthesis of tert-butyl N-(6-bromo-1-methyl-indazol-3- yl)carbamate. To a solution of 6-bromo-1-methyl-indazol-3-amine (1.0 g, 4.42 mmol) in 1,4- dioxane (25 mL) was added Boc anhydride (1.16 g, 5.31 mmol), and the reaction mixture was heated to 100 °C for 16 h and then cooled to rt. The volatiles were evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using a gradient of 0–100% ethyl acetate in hexanes to afford title compound (1.18 g, 82%) as a solid. MS (ESI) [M– tBu]+ 271.0.1H NMR (400 MHz, DMSO-d6) δ 9.62 (s, 1H), 7.89 (s, 1H), 7.67 (dd, J = 8.6, 2.4 Hz, 1H), 7.20 (dd, J = 8.7, 1.6 Hz, 1H), 3.91 (s, 3H), 1.47 (s, 9H).

[0354] Step 67.2: Synthesis of tert-butyl N-(6-bromo-1-methyl-indazol-3-yl)-N-(2- cyanoethyl)carbamate. To a solution of tert-butyl N-(6-bromo-1-methyl-indazol-3-yl)carbamate (1.18 g, 3.61 mmol) in acetonitrile (15 mL) were added sequentially potassium fluoride (429.4 mg, 7.39 mmol), acrylonitrile (0.83 mL, 12.6 mmol) and aluminum(III) oxide (1.29 g, 12.6 mmol), and the reaction mixture was heated to reflux for 18 h and then cooled to rt. The mixture was filtered on celite and washed with acetonitrile (20 mL). The filtrate was concentrated under reduced pressure to afford title compound (1.0 g, 73%) as an oil, which was used in the next step without further purification. MS (ESI) [M–tBu]+ 324.6.

[0355] Step 67.3: Synthesis of tert-butyl N-(3-amino-3-oxo-propyl)-N-(6-bromo-1- methyl-indazol-3-yl)carbamate. To a solution of tert-butyl N-(6-bromo-1-methyl-indazol-3-yl)- N-(2-cyanoethyl)carbamate (12 g, 31.6 mmol) in methanol (90 mL) at 0 °C were added sequentially 30% hydrogen peroxide (128 mL, 1.23 mol) and ammonium hydroxide (118 mL, 0.92 mol), and the reaction mixture was warmed to rt and stirred for 6 h. Water (500 mL) and dichloromethane (500 mL) were added and the layers were separated. The organic layer was washed with a saturated aqueous solution of sodium sulfite (200 mL), dried over sodium sulfate,filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a gradient of 0–100% ethyl acetate in hexanes followed by a second purification using and 0–20% methanol in dichloromethane to afford title compound (10.6 g, 84%) as a solid. MS (ESI) [M+H]+ 397.1.

[0356] Step 67.4: Synthesis of 1-(6-bromo-1-methyl-indazol-3- yl)hexahydropyrimidine-2,4-dione. To a solution of tert-butyl N-(3-amino-3-oxo-propyl)-N-(6- bromo-1-methyl-indazol-3-yl)carbamate (10.6 g, 26.7 mmol) in tetrahydrofuran (125 mL) was added potassium tert-butoxide (6.0 g, 53.4 mmol), and the reaction mixture was stirred at 0 °C for 2 h. Ethyl acetate (100 mL) and 1N HCl (40 mL) were added and the layers were separated. The organic layer was washed with brine (40 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a gradient of 0–100% ethyl acetate in hexane to afford title compound (2.1 g, 24%) as a solid. MS (ESI) [M+H]+ 323.1.

[0357] Step 67.5: Synthesis of tert-butyl 4-[3-(2,4-dioxohexahydropyrimidin-1-yl)-1- methyl-indazol-6-yl]-3,6-dihydro-2H-pyridine-1-carboxylate. A mixture of 1-(6-bromo-1- methyl-indazol-3-yl)hexahydropyrimidine-2,4-dione (600 mg, 1.86 mmol), tert-butyl 4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (603 mg, 1.95 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (75.8 mg, 90 µmol) and potassium phosphate, tribasic (1.18 g, 5.57 mmol) in 1,4-dioxane (16 mL) and water (4 mL) was heated to 90 °C for 4 h and then cooled to rt. Volatiles were removed and the residue was purified by reverse phase chromatography (C18) with a gradient of 20–100% acetonitrile and 10 mM ammonium formate in water to afford title compound (200 mg, 25%) as a solid. MS (ESI) [M– H]– 424.3.1H NMR (500 MHz, DMSO-d6) δ 10.54 (s, 1H), 7.62 – 7.57 (m, 2H), 7.26 (dd, J = 8.6, 1.4 Hz, 1H), 6.29 (s, 1H), 4.07 – 4.02 (m, 2H), 3.99 (s, 3H), 3.92 (t, J = 6.7 Hz, 2H), 3.61 – 3.55 (m, 2H), 2.76 (t, J = 6.7 Hz, 2H), 2.61 – 2.55 (m, 2H), 1.44 (s, 9H).

[0358] Step 67.6: Synthesis of tert-butyl 4-[3-(2,4-dioxohexahydropyrimidin-1-yl)-1- methyl-indazol-6-yl]piperidine-1-carboxylate. A mixture of tert-butyl 4-[3-(2,4- dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (200 mg, 0.470 mmol) and 10% palladium on carbon (250 mg, 0.24 mmol) in methanol (15 mL) was hydrogenated (1 atm) at rt for 4 h. The mixture was filtered on celite and washed with methanol (3 x 10 mL). The filtrate was concentrated under reduced pressure to afford title compound (200 mg, quant.) as a solid which was used in the next step without further purification. MS (ESI) [M–H]– 426.3.

[0359] Step 67.7: Synthesis of 1-[1-methyl-6-(4-piperidyl)indazol-3-yl]hexahydropyrimidine-2,4-dione hydrochloride. To a solution of tert-butyl 4-[3-(2,4- dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl] piperidine-1-carboxylate (200 mg, 0.47 mmol) in dichloromethane (2.5 mL) was added 4N M HCl in 1,4-dioxane (2.5 mL, 10 mmol) and the mixture was stirred for 4 h at rt. The resulting precipitate was collected by filtration, washed with diethyl ether (2 x 10 mL) and dried under vacuum to afford title compound (163 mg, 96% over 2 steps) as a solid, which was used in the next step without further purification. MS (ESI) [M+H]+ 328.1;1H NMR (500 MHz, DMSO-d6) δ 10.54 (s, 1H), 7.61 (d, J = 8.5 Hz, 1H), 7.39 (s, 1H), 7.02 (dd, J = 8.6, 1.4 Hz, 1H), 3.98 (s, 3H), 3.91 (t, J = 6.6 Hz, 2H), 3.42 – 3.36 (m, 3H), 3.09 – 2.95 (m, 3H), 2.75 (t, J = 6.7 Hz, 2H), 2.04 – 1.95 (m, 3H), 1.97 – 1.87 (m, 2H).

[0360] Step 67.8: Synthesis of 2-[[6-[[5-chloro-2-[4-[3-(2,4- dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]-1-piperidyl]pyrimidin-4-yl]amino]- 1-methyl-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide. To a mixture of 2-[[6-[(5-chloro-2- fluoro-pyrimidin-4-yl)amino]-1-methyl-2-oxo-3-quinolyl] oxy]-N-methyl-acetamide (30 mg, 80 µmol, Intermediate 22) and diisopropylethylamine (50 µL, 0.310 mmol) in dimethylsulfoxide (1 mL) at rt was added 1-[1-methyl-6-(4-piperidyl)indazol-3-yl]hexahydropyrimidine-2,4-dione hydrochloride (27.9 mg, 80 µmol) and the reaction mixture was heated to 80 °C for 2 h. The crude reaction mixture was purified by preparative HPLC (BEH column, C18) with a gradient of 30– 50% acetonitrile and 10 mM ammonium formate in water to afford title compound (26.2 mg, 48%) as a solid. MS (ESI) [M+H]+ 699.3.1H NMR (500 MHz, DMSO-d6) δ 10.52 (s, 1H), 8.85 (s, 1H), 8.08 (s, 1H), 7.95 (d, J = 2.4 Hz, 1H), 7.93 – 7.88 (m, 1H), 7.78 (dd, J = 9.1, 2.4 Hz, 1H), 7.54 (d, J = 8.6 Hz, 1H), 7.47 (d, J = 9.2 Hz, 1H), 7.45 (s, 1H), 7.11 (s, 1H), 7.05 (dd, J = 8.6, 1.1 Hz, 1H), 4.76 – 4.65 (m, 2H), 4.55 (s, 2H), 3.95 (s, 3H), 3.90 (t, J = 6.7 Hz, 2H), 3.66 (s, 3H), 3.01 – 2.91 (m, 3H), 2.74 (t, J = 6.7 Hz, 2H), 2.61 (d, J = 4.7 Hz, 3H), 1.93 – 1.86 (m, 2H), 1.74 – 1.61 (m, 2H). Example 68.2-[[6-[[5-Chloro-2-[[4-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-6- yl]cyclohex-3-en-1-yl]-methyl-amino]pyrimidin-4-yl]amino]-1-methyl-2-oxo-3- quinolyl]oxy]-N-methyl-acetamide

[0361] Step 68.1: Synthesis of tert-butyl N-[4-[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazol-6-yl]-4-hydroxy-cyclohexyl]-N-methyl carbamate. To a solution of 6-bromo- 3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole (10 g, 20 mmol) in tetrahydrofuran (200 mL) cooled to –78 °C was added dropwise tert-butyl lithium (13.7 mL, 22 mmol) and the reaction mixture was stirred at –78 °C for 30 min. A solution of tert-butyl N-methyl-N-(4- oxocyclohexyl)carbamate (5.0 g, 22 mmol) in tetrahydrofuran (30 mL) was added dropwise to the reaction mixture at –78 °C. The mixture was stirred for 1 h at –78 °C, then warmed to rt and stirred for 18 h. A saturated aqueous solution of ammonium chloride (20 mL) and ethyl acetate (300 mL) were added and the layers were separated. The organic layer was washed with water (10 mL), brine (10 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a gradient of 0–100% ethyl acetate in hexanes to afford a diastereomeric mixture of title compound (5.4 g, 42%) as a solid. MS (ESI) [M+H]+ 649.5.

[0362] Step 68.2: Synthesis of tert-butyl N-[4-[3-(2,6-dioxo-3-piperidyl)-1-methyl- indazol-6-yl]-4-hydroxy-cyclohexyl]-N-methyl carbamate. A mixture of tert-butyl N-[4-[3- (2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazol-6-yl]-4-hydroxy-cyclohexyl]-N-methyl- carbamate (1.0 g, 1.54 mmol) and Pearlman's catalyst (250 mg, 25 wt% loading) in ethanol (12 mL) and tetrahydrofuran (12 mL) was subjected to hydrogenation (1 atm) at 50 °C for 3 h. The mixture was filtered through celite and washed with methanol(3 x 50 mL). The filtrate was concentrated under reduced pressure. Methanol (2 mL) and diethyl ether (200 mL) was added sequentially, and the resulting precipitate was collected by filtration, washed with diethyl ether (20 mL), then dried under vacuum to afford title compound (506 mg, 70%) as a solid. MS (ESI) [M+H]+ 471.3.1H NMR (400 MHz, DMSO-d6) δ 10.92 – 10.91 (m, 1H), 7.72 – 7.53 (m, 2H), 7.39 – 7.25 (m, 1H), 5.01 – 4.99 (m, 1H), 4.41 – 4.29 (m, 1H), 4.02 – 3.98 (m, 3H), 2.77 – 2.57 (m, 4H), 2.46 (s, 2H), 2.43 – 2.29 (m, 1H), 2.23 – 2.11 (m, 1H), 2.04 – 1.88 (m, 1H), 1.83 – 1.69 (m, 2H), 1.57 – 1.54 (m, 1H), 1.47 – 1.34 (m, 12H). Note: one exchangeable proton not visible.

[0363] Step 68.3: Synthesis of 3-[1-methyl-6-[4-(methylamino)cyclohexen-1- yl]indazol-3-yl]piperidine-2,6-dione 2,2,2-trifluoroacetic acid. To a solution of tert-butyl N- [4-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-6-yl]-4-hydroxy-cyclohexyl]-N-methyl carbamate (453 mg, 0.96 mmol) in 1,2-dichloroethane (10 mL) was added trifluoroacetic acid (1.84 mL, 24.1 mmol) at rt. The mixture was heated to 60 °C and stirred for 1 h, then the volatiles were evaporated under reduced pressure. Methanol (2 mL) and diethyl ether (150 mL) were added sequentially, and the resulting precipitate was collected by filtration, washed with diethyl ether (50 mL), then dried under vacuum to afford title compound(423 mg, 89%) as a solid. MS (ESI) [M+H]+ 353.3.1H NMR (500 MHz, DMSO-d6, 90 °C) δ 10.52 (s, 1H), 8.49 (s, 2H), 7.67 (d, J =8.5 Hz, 1H), 7.53 (s, 1H), 7.25 (dd, J = 8.6, 1.3 Hz, 1H), 6.18 – 6.17 (m, 1H), 4.34 (dd, J = 9.0, 5.2 Hz, 1H), 4.00 (s, 3H), 3.40 – 3.35 (m, 1H), 2.75 – 2.62 (m, 8H), 2.41 – 2.32 (m, 2H), 2.28 – 2.22 (m, 2H), 1.88 – 1.80 (m, 1H).

[0364] Step 68.4: Synthesis of 2-[[6-[[5-chloro-2-[[4-[3-(2,6-dioxo-3-piperidyl)-1- methyl-indazol-6-yl]cyclohex-3-en-1-yl]-methyl-amino]pyrimidin-4-yl]amino]-1-methyl-2- oxo-3-quinolyl]oxy]-N-methyl-acetamide. To a solution of 3-[1-methyl-6-[4- (methylamino)cyclohexen-1-yl] indazol-3-yl] piperidine-2, 6-dione; 2, 2, 2-trifluoroacetic acid (48.0 mg, 0.100 mmol, in dimethylsulfoxide (1.5 mL) was added 2-[[6-[(5-chloro-2-fluoro- pyrimidin-4-yl)amino]-1-methyl-2-oxo-3-quinolyl] oxy]-N-methyl-acetamide (35 mg, 90 µmol, Intermediate i-22) and diisopropylethylamine (80 µL, 0.450 mmol) at rt. The mixture was heated to 90 °C and stirred for 18 h. The residue was purified by preparative HPLC (BEH column, C18) using a gradient of 37–47% acetonitrile and 10 mM ammonium formate in water to afford title compound (42.1 mg, 63%) as a solid. MS (ESI) [M+H]+ 724.4.1H NMR (500 MHz, DMSO-d6, 90 °C) δ 8.51 (s, 1H), 8.34 (s, 1H), 8.04 (s, 1H), 7.92 (d, J = 2.3 Hz, 1H), 7.81 (dd, J = 9.0, 2.4 Hz, 1H), 7.63 (d, J = 8.5 Hz, 1H), 7.47 (s, 1H), 7.39 (d, J = 9.1 Hz, 1H), 7.21 – 7.18 (m, 2H), 6.24 – 6.22 (m, 1H), 4.81 – 4.74 (m, 1H), 4.43 (s, 2H), 4.33 (dd, J = 8.9, 5.2 Hz, 1H), 3.99 (s, 3H), 3.57 (s, 3H), 3.02 (s, 3H), 2.71 – 2.62 (m, 7H), 2.46 – 2.31 (m, 3H), 2.28 – 2.22 (m, 1H), 2.03 – 1.95 (m, 1H), 1.94 – 1.90 (m, 1H). Note: glutarimide NH signal not visible. Example 69.2-[[6-[[5-chloro-2-[8-[3-(2,4-dioxohexahydropyrimidin-1-yl)-1-methyl- indazol-6-yl]-2,8-diazaspiro[4.5]decan-2-yl]pyrimidin-4-yl]amino]-1-methyl-2-oxo-3- quinolyl]oxy]-N-methyl-acetamide

[0365] Step 69.1: Synthesis of tert-butyl 8-[3-(2,4-dioxohexahydropyrimidin-1-yl)-1- methyl-indazol-6-yl]-2,8-diazaspiro[4.5]decane-2-carboxylate. A mixture of [3-(2,4- dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]boronic acid (Intermediate i-9) (124 mg, 0.43 mmol), tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (207 mg, 0.86 mmol), copper (II) acetate (95 mg, 0.47 mmol), triethylamine (0.12 mL, 0.86 mmol) and 3Å MS (200 mg) in 1,2- dichloroethane (8 mL) under O2(1 atm) was heated to 50 °C for 24 h. The mixture was filtered on celite and washed with a 1:1 mixture of acetonitrile and methanol (3 x 5 mL). The filtrate was concentrated under reduced pressure and the residue was purified by reverse phase chromatography (C18) using a gradient of 10–70% acetonitrile and 10 mM ammonium formatein water to afford title compound (84 mg, 36%) as a solid. MS (ESI) [M+H]+ 484.3.1H NMR (400 MHz, DMSO-d6) δ 10.49 (s, 1H), 7.44 (d, J = 9.1 Hz, 1H), 6.91 (d, J = 9.1 Hz, 1H), 6.84 (s, 1H), 3.89 (t, J = 6.8 Hz, 2H), 3.88 (s, 3H), 3.30 – 3.17 (m, 6H), 3.14 (s, 2H), 2.73 (t, J = 6.7 Hz, 2H), 1.80 – 1.71 (m, 2H), 1.63 (br s, 4H), 1.40 (s, 9H).

[0366] Step 69.2: Synthesis of 1-[6-(2,8-Diazaspiro[4.5]decan-8-yl)-1-methyl-indazol- 3-yl]hexahydropyrimidine-2,4-dione hydrochloride. To a mixture of tert-butyl 8-[3-(2,4- dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]-2,8-diazaspiro[4.5]decane-2-carboxylate (84 mg, 0.16 mmol) in 1,4-dioxane (5 mL) was added a 4N solution of HCl in 1,4-dioxane (0.39 mL, 1.57 mmol). The reaction mixture was heated to 100 °C for 2 h and then cooled to rt. The volatiles were evaporated under reduced pressure to afford title compound (78 mg, quant.) as a solid, which was used in the next step without further purification. MS (ESI) [M+H]+ 384.2.

[0367] Step 69.3: Synthesis of 2-[[6-[[5-Chloro-2-[8-[3-(2,4- dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]-2,8-diazaspiro[4.5]decan-2- yl]pyrimidin-4-yl]amino]-1-methyl-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide. To a mixture of 2-[[6-[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]-1-methyl-2-oxo-3-quinolyl]oxy]-N-methyl- acetamide (15 mg, 40 µmol, Intermediate i-22) in dimethylsulfoxide (0.5 mL) were added sequentially 1-[6-(2,8-diazaspiro[4.5]decan-8-yl)-1-methyl-indazol-3-yl]hexahydropyrimidine- 2,4-dione hydrochloride (20 mg, 50 µmol) and diisopropylethylamine (80 µL, 0.48 mmol). The reaction mixture was heated to 100 °C for 18 h and then cooled to rt. The crude reaction mixture was purified by preparative HPLC (BEH column, C18) using a gradient of 34–44% acetonitrile and 10 mM ammonium formate in water to afford title compound (10.5 mg, 29%) as a solid. MS (ESI) [M+H]+ 754.4.1H NMR (500 MHz, DMSO-d6) δ 10.49 (s, 1H), 8.75 (s, 1H), 8.09 (s, 1H), 8.04 (s, 1H), 7.91 (d, J = 9.3 Hz, 2H), 7.44 (d, J = 9.0 Hz, 2H), 7.15 (s, 1H), 6.92 (d, J = 10.2 Hz, 1H), 6.84 (s, 1H), 4.62 – 4.45 (m, 3H), 3.96 – 3.82 (m, 2H), 3.88 (s, 3H), 3.67 (s, 3H), 3.56 (t, J = 6.9 Hz, 2H), 3.41 (s, 2H), 3.27 – 3.17 (m, 3H), 2.73 (t, J = 6.7 Hz, 2H), 2.66 (s, 3H), 1.89 (t, J = 7.1 Hz, 2H), 1.77 – 1.63 (m, 4H). Example 70.6-((5-chloro-2-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)-3,5- dimethyl-1H-pyrazol-1-yl)pyrimidin-4-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinolin-3- yl)oxy)-N-methylacetamide

[0368] Step 70.1: Synthesis of tert-butyl 4-[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazol-6-yl]-3,5-dimethyl-pyrazole-1-carboxylate. A mixture of 6-bromo-3-(2,6-dibenzyloxy- 3-pyridyl)-1-methyl-indazole (2.5 g, 5.0 mmol), (1-tert-butoxycarbonyl-3,5-dimethyl-pyrazol-4- yl) boronic acid (1.44 g, 6.0 mmol), [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.18 g, 0.22 mmol) and potassium phosphate, tribasic (2.65 g, 12.5 mmol) in 1,4-dioxane (15 mL) and water (2.5 mL) and was heated to 90 °C for 3 h and then cooled to rt. The mixture was filtered on celite and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a gradient of 0–50% ethyl acetate in hexanes to afford title compound (2.70 g, 88%) as a solid. MS (ESI) [M+H]+ 616.3.1H NMR (500 MHz, DMSO-d6) δ 7.93 (d, J = 8.1 Hz, 1H), 7.74 (d, J = 8.5 Hz, 1H), 7.51 (s, 1H), 7.50 – 7.25 (m, 10H), 6.91 (dd, J = 8.4, 1.3 Hz, 1H), 6.61 (d, J = 8.1 Hz, 1H), 5.46 (s, 2H), 5.44 (s, 2H), 4.08 (s, 3H), 2.43 (s, 3H), 2.18 (s, 3H), 1.60 (s, 9H).

[0369] Step 70.2: Synthesis of tert-butyl 4-[3-(2,6-dioxo-3-piperidyl)-1-methyl- indazol-6-yl]-3,5-dimethyl-pyrazole-1-carboxylate. A mixture of tert-butyl 4-[3-(2,6- dibenzyloxy-3-pyridyl)-1-methyl-indazol-6-yl]-3,5-dimethyl-pyrazole-1-carboxylate (2.64 g, 4.29 mmol) and Pearlman's catalyst (1.14 g, 1.07 mmol) in methanol (20 mL) and tetrahydrofuran (30 mL) was hydrogenated (1 atm) at 50 °C for 7 h. The mixture was cooled to rt, filtered on Celite and washed with methanol (3 x 50 mL) and tetrahydrofuran (3 x 50 mL). The filtrate was concentrated under reduced pressure to afford title compound (1.85 g, 98%) as a solid, which was used in the next step without further purification. MS (ESI) [M+H]+ 438.2.1H NMR (400 MHz, CDCl3) δ 7.99 (s, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.18 (s, 1H), 7.02 (d, J = 8.3 Hz, 1H), 4.34 (t, J = 5.9 Hz, 1H), 4.04 (s, 3H), 3.09 – 2.98 (m, 1H), 2.77 – 2.66 (m, 1H), 2.63 – 2.51 (m, 1H), 2.47 (s, 3H), 2.44 – 2.36 (m, 1H), 2.26 (s, 3H), 1.68 (s, 9H).

[0370] Step 70.3: Synthesis of 3-[6-(3,5-dimethyl-1H-pyrazol-4-yl)-1-methyl-indazol- 3-yl]piperidine-2,6-dione hydrochloride. To a solution of tert-butyl 4-[3-(2,6-dioxo-3- piperidyl)-1-methyl-indazol-6-yl]-3,5-dimethyl-pyrazole-1-carboxylate (1.8 g, 4.11 mmol) in 1,4- dioxane (10 mL) was added 4N HCl in 1,4-dioxane (5.14 mL, 20.6 mmol), and the mixture was stirred at rt for 16 h. The volatiles were evaporated under reduced pressure. Ethyl acetate (10 mL) was added and the resulting precipitate was collected by filtration, washed with ethyl acetate (3 x 10 mL), then dried under vacuum to afford title compound (1.45 g, quant.) as a solid, which was used in the next step without further purification. MS (ESI) [M+H]+ 338.2.1H NMR (500 MHz, DMSO-d6) δ 10.91 (s, 1H), 7.78 (dd, J = 8.3, 0.4 Hz, 1H), 7.57 (s, 1H), 7.11 (dd, J = 8.4, 1.3 Hz, 1H), 4.41 (dd, J = 10.0, 5.1 Hz, 1H), 4.02 (s, 3H), 2.75 – 2.59 (m, 2H), 2.44 – 2.36 (m, 1H), 2.36 (s, 6H), 2.24 – 2.16 (m, 1H). Note: exchangeable protons not visible.

[0371] Step 70.4: Synthesis of 2-[[6-[[5-chloro-2-[4-[[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-6-yl]methyl]piperazin-1-yl]pyrimidin-4-yl]amino]-1-methyl-2-oxo-3- quinolyl]oxy]-N-methyl-acetamide. To a mixture of 3-[6-(3,5-dimethyl-1H-pyrazol-4-yl)-1- methyl-indazol-3-yl]piperidine-2,6-dione hydrochloride (40 mg, 0.11 mmol) and 2-[[6-[(5- chloro-2-fluoro-pyrimidin-4-yl)amino]-1-methyl-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide (41.9 mg, 0.11 mmol, Intermediate 22) was added N-methyl-2-pyrrolidone (0.25 mL), and the mixture was heated to 160 °C for 1 h , then cooled to rt. The crude reaction mixture was purified by preparative HPLC (BEH column, C18) using a gradient of 28–38% acetonitrile and 10 mM ammonium formate in water to afford title compound (32.5 mg, 40%) as a solid. MS (ESI) [M+H]+ 709.3.1H NMR (500 MHz, DMSO-d6) δ 8.52 (s, 1H), 8.32 (s, 1H), 8.10 (d, J = 2.4 Hz, 1H), 7.92 (d, J = 4.4 Hz, 1H), 7.80 – 7.76 (m, 1H), 7.76 – 7.73 (m, 1H), 7.52 (s, 1H), 7.50 (s, 1H), 7.19 (s, 1H), 7.04 (dd, J = 8.2, 1.0 Hz, 1H), 4.56 (s, 2H), 4.39 (dd, J = 9.8, 5.0 Hz, 1H), 4.00 (s, 3H), 3.68 (s, 3H), 2.73 – 2.61 (m, 2H), 2.56 (d, J = 4.7 Hz, 3H), 2.44 – 2.38 (m, 1H), 2.36 (s, 3H), 2.24 (s, 3H), 2.22 – 2.16 (m, 1H). Note: exchangeable protons not visible. Example 71.2-[[6-[[5-Chloro-2-[4-[3-(2,4-dioxohexahydropyrimidin-1-yl)-1-methyl- indazol-6-yl]oxy-1-piperidyl]pyrimidin-4-yl]amino]-1-methyl-2-oxo-3-quinolyl]oxy]-N- methyl-acetamide.

[0372] Step 71.1: Synthesis of tert-butyl 4-[3-(2,4-dioxohexahydropyrimidin-1-yl)-1- methyl-indazol-6-yl]oxypiperidine-1-carboxylate. A mixture of [3-(2,4- dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]boronic acid (100 mg, 0.35 mmol, Intermediate 9), tert-butyl 4-hydroxypiperidine-1-carboxylate (140 mg, 0.69 mmol), copper (II) acetate (139 mg, 0.69 mmol), 4-dimethylaminopyridine (21 mg, 0.17 mmol) and 3Å MS (350 mg) in 1,2-dichloroethane (7 mL) under an O2atmosphere (1 atm) was heated to 50 °C for 24 h. The mixture was filtered on celite and washed with a 1:1 mixture of acetonitrile and methanol (3 x 5 mL). The filtrate was concentrated under reduced pressure and the residue was purified by reverse phase chromatography (C18) using a gradient of 10–100% acetonitrile and 10 mM ammonium formate in water to afford title compound (42 mg, 27%) as a solid. MS (ESI) [M+H]+ 444.3.1H NMR (400 MHz, DMSO-d6) δ 7.51 (d, J = 8.7 Hz, 1H), 7.13 (s, 1H), 6.76 (dd, J = 8.9, 1.7 Hz, 1H), 4.70 (s, 1H), 3.92 (s, 3H), 3.96 – 3.85 (m, 2H), 3.71 – 3.64 (m, 2H), 3.26 – 3.18 (m, 2H), 2.74 (t, J = 6.5 Hz, 2H), 2.01 – 1.90 (m, 2H), 1.62 – 1.51 (m, 2H), 1.41 (s, 9H). Note: oneexchangeable proton not visible.

[0373] Step 71.2: Synthesis of 1-[1-methyl-6-(4-piperidyloxy)indazol-3- yl]hexahydropyrimidine-2,4-dione hydrochloride. To a solution of tert-butyl 4-[3-(2,4- dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]oxypiperidine-1-carboxylate (42 mg, 0.09 mmol) in 1,4-dioxane (5 mL) was added a 4N solution of HCl in 1,4-dioxane (0.24 mL, 0.95 mmol). The reaction mixture was heated to 100 °C for 3 h and then cooled to rt. The volatiles were evaporated under reduced pressure to afford title compound (33 mg, 92%) as a solid, which was used in the next step without further purification. MS (ESI) [M+H]+ 344.2.

[0374] Step 71.3: Synthesis of 2-[[6-[[5-chloro-2-[4-[3-(2,4- dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]oxy-1-piperidyl]pyrimidin-4- yl]amino]-1-methyl-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide. To a mixture of 2-[[6-[(5- chloro-2-fluoro-pyrimidin-4-yl)amino]-1-methyl-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide (30 mg, 80 µmol, Intermediate i-22) in DMSO (1 mL) were added sequentially 1-[1-methyl-6- (4-piperidyloxy)indazol-3-yl]hexahydropyrimidine-2,4-dione (33 mg, 0.10 mmol) and diisopropylethylamine (0.17 mL, 0.96 mmol). The reaction mixture was heated to 100 °C for 18 h and then cooled to rt. The crude reaction mixture was purified by preparative HPLC (BEH column, C18) using a gradient of 41–51% acetonitrile and 10 mM ammonium formate in water to afford title compound (20.7 mg, 30%) as a solid. MS (ESI) [M+H]+ 715.3.1H NMR (400 MHz, DMSO-d6) δ 10.53 (s, 1H), 8.88 (s, 1H), 8.07 (s, 1H), 7.93 (d, J = 4.6 Hz, 1H), 7.90 (d, J = 2.3 Hz, 1H), 7.77 (dd, J = 9.1, 2.4 Hz, 1H), 7.51 (d, J = 8.9 Hz, 1H), 7.47 (d, J = 9.2 Hz, 1H), 7.15 (d, J = 1.7 Hz, 1H), 7.11 (s, 1H), 6.76 (dd, J = 8.9, 2.0 Hz, 1H), 4.84 – 4.74 (m, 1H), 4.56 (s, 2H), 4.13 – 4.03 (m, 2H), 3.92 (d, J = 2.0 Hz, 3H), 3.92 – 3.88 (m, 2H), 3.66 (s, 3H), 3.52 (t, J = 9.6 Hz, 2H), 2.74 (t, J = 6.7 Hz, 2H), 2.60 (d, J = 4.6 Hz, 3H), 2.08 – 1.98 (m, 2H), 1.70 – 1.60 (m, 2H). Example 72.2-[[6-[[5-Chloro-2-[4-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-7-yl]oxy-1- piperidyl]pyrimidin-4-yl]amino]-1-methyl-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide

[0375] Step 72.1: Synthesis of 7-bromo-3-iodo-1-methyl-indazole. To a solution of 7- bromo-1H-indazole (5 g, 25 mmol) in N, N-dimethylformamide (25 mL) at 0 ºC was added sequentially iodine (13 g, 51 mmol), and potassium hydroxide (2.8 g, 50.8 mmol). The reactionmixture was warmed to rt for 18 h then cooled to 0 °C. Water (50 mL) and a saturated solution of sodium sulfite (50 mL) were added and the resulting precipitate was collected by filtration, washed with water (3 x 10 mL), then dried under vacuum to afford title compound (7.8 g, 95%) as a solid which was used in the next step without further purification. MS (ESI) [M+H]+ 322.6.1H NMR (400 MHz, DMSO-d6) δ 13.94 (s, 1H), 7.70 (dd, J = 7.4, 0.7 Hz, 1H), 7.47 (dd, J = 8.1, 0.7 Hz, 1H), 7.15 (dd, J = 8.0, 7.5 Hz, 1H).

[0376] Step 72.2: Synthesis of 7-bromo-3-iodo-1H-indazole. To a solution of 7-bromo- 3-iodo-1H-indazole (7.8 g, 24 mmol) in N, N-dimethylformamide (25 mL) at 0 ºC was added sodium hydride (1.7 g, 43 mmol) and the reaction mixture was stirred for 30 min. iodomethane (1.6 mL, 26 mmol) was added and the mixture was warmed to rt for 2 h. The mixture was cooled to 0 ºC, water (100 mL) was added and the resulting precipitate was collected by filtration, washed with water (2 x 50 mL), then dried under vacuum. The residue was purified by column chromatography on silica gel using a gradient of 0–100% ethyl acetate in hexanes to afford title compound (6.1 g, 75%) as a solid. MS (ESI) [M+H]+ 336.9.1H NMR (400 MHz, DMSO-d6) δ 7.73 (dd, J = 7.4, 0.9 Hz, 1H), 7.46 (dd, J = 8.1, 0.9 Hz, 1H), 7.13 (dd, J = 8.1, 7.5 Hz, 1H), 4.35 (s, 3H).

[0377] Step 72.3: Synthesis of 7-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl- indazole. A mixture of 7-bromo-3-iodo-1-methyl-indazole (1.5 g, 4.5 mmol), 2,6-dibenzyloxy-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (2.8 g, 6.7 mmol), tetrakis(triphenylphosphine)palladium(0) (514 mg, 0.45 mmol) and potassium phosphate, tribasic (2.8 g, 13.4 mmol) in 1,4-dioxane (36 mL) and water (9 mL) was heated to 100 °C for 3 h and then cooled to rt. Water (20 mL) and ethyl acetate (50 mL) were added and the layers were separated. The organic layer was washed with a saturated aqueous solution of ammonium chloride (20 mL), brine (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a gradient of 5– 50% ethyl acetate in hexanes to afford title compound (1.1 g, 49%) as a solid. MS (ESI) [M+H]+ 501.2.1H NMR (400 MHz, DMSO-d6) δ 7.87 (d, J = 8.1 Hz, 1H), 7.66 (dd, J = 8.1, 0.8 Hz, 1H), 7.61 (dd, J = 7.4, 0.8 Hz, 1H), 7.50 – 7.45 (m, 2H), 7.43 – 7.38 (m, 2H), 7.37 – 7.30 (m, 4H), 7.30 – 7.26 (m, 2H), 6.93 (dd, J = 8.1, 7.5 Hz, 1H), 6.60 (d, J = 8.1 Hz, 1H), 5.44 (s, 2H), 5.43 (s, 2H), 4.36 (s, 3H).

[0378] Step 72.4: Synthesis of 3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazol-7-ol. A mixture of 7-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole (1.1 g, 2.2 mmol), tBuXPhos-Pd-G3 (93 mg, 0.11 mmol) and 1M potassium hydroxide (8.8 mL, 8.8 mmol) in 1,4- dioxane (20 mL) was heated to 100 °C for 1 h and then cooled to rt. Water (50 mL) and ethylacetate (100 mL) were added and the layers were separated. The organic layer was washed with a saturated aqueous solution of ammonium chloride(50 mL), brine (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a gradient of 0–100% ethyl acetate in hexanes to afford title compound (800 mg, 83%) as a semi-solid. MS (ESI) [M+H]+ 439.2.1H NMR (500 MHz, DMSO- d6) δ 10.12 (s, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.47 (d, J = 7.1 Hz, 2H), 7.43 – 7.37 (m, 2H), 7.37 – 7.32 (m, 3H), 7.31 – 7.23 (m, 3H), 7.04 (d, J = 8.1 Hz, 1H), 6.79 (app t, J = 7.8 Hz, 1H), 6.65 (d, J = 7.4 Hz, 1H), 6.57 (d, J = 8.0 Hz, 1H), 5.43 (s, 2H), 5.41 (s, 2H), 4.25 (s, 3H).

[0379] Step 72.5: Synthesis of tert-butyl 4-[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl- indazol-7-yl]oxypiperidine-1-carboxylate. To a solution of 3-(2,6-dibenzyloxy-3-pyridyl)-1- methyl-indazol-7-ol (800 mg, 1.8 mmol) in N, N-dimethylformamide (12 mL) were added sequentially tert-butyl 4-(p-tolylsulfonyloxy)piperidine-1-carboxylate (975 mg, 2.7 mmol) and cesium carbonate (1.2 g, 3.7 mmol). The reaction mixture was heated to 60 °C for 2 h and then cooled to rt. Water (10 mL) and ethyl acetate (20 mL) were added and the layers were separated. The organic layer was washed with a saturated aqueous solution of ammonium chloride (5 mL), water (3 x 5 mL), brine (5 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a gradient of 0– 100% ethyl acetate in hexanes to afford title compound (800 mg, 70%) as a solid. MS (ESI) [M+H]+ 622.7.1H NMR (400 MHz, DMSO-d6) δ 7.84 (d, J = 8.1 Hz, 1H), 7.47 (d, J = 7.0 Hz, 2H), 7.43 – 7.33 (m, 5H), 7.32 – 7.24 (m, 3H), 7.17 (dd, J = 7.0, 1.8 Hz, 1H), 6.94 – 6.84 (m, 2H), 6.58 (d, J = 8.1 Hz, 1H), 5.43 (s, 2H), 5.42 (s, 2H), 4.82 – 4.74 (m, 1H), 4.26 (s, 3H), 3.68 – 3.55 (m, 2H), 3.40 – 3.33 (m, 2H), 2.04 – 1.92 (m, 2H), 1.77 – 1.66 (m, 2H), 1.41 (s, 9H).

[0380] Step 72.6: Synthesis of tert-butyl 4-[3-(2,6-dioxo-3-piperidyl)-1-methyl- indazol-7-yl]oxypiperidine-1-carboxylate. A mixture of tert-butyl 4-[3-(2,6-dibenzyloxy-3- pyridyl)-1-methyl-indazol-7-yl]oxypiperidine-1-carboxylate (800 mg, 1.29 mmol) and Pearlman's catalyst (200 mg, 25 wt% loading) in a mixture of ethanol (13 mL) and tetrahydrofuran (13 mL) was subjected to hydrogenation at 1 atm and 50 °C for 3 h. The mixture was filtered through celite and washed with a mixture of acetonitrile and methanol (1:1, 3 x 20 mL). The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel using a gradient of 0–10% methanol in dichloromethane to afford title compound (405 mg, 71%) as a solid. MS (ESI) [M+H]+ 443.2.1H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 7.21 (dd, J = 8.0, 0.7 Hz, 1H), 6.98 (app t, J = 7.8 Hz, 1H), 6.91 (d, J = 7.4 Hz, 1H), 4.83 – 4.75 (m, 1H), 4.31 (dd, J = 9.8, 5.1 Hz, 1H), 4.18 (s, 3H), 3.66 – 3.56 (m, 2H), 3.40 – 3.33 (m, 2H), 2.73 – 2.55 (m, 2H), 2.38 – 2.27 (m, 1H), 2.21 – 2.11 (m, 1H), 2.03 – 1.92 (m, 2H), 1.77 – 1.65(m, 2H), 1.41 (s, 9H).

[0381] Step 72.7: Synthesis of 3-[1-methyl-7-(4-piperidyloxy)indazol-3-yl]piperidine- 2,6-dione hydrochloride. To a solution of tert-butyl 4-[3-(2,6-dioxo-3-piperidyl)-1-methyl- indazol-7-yl]oxypiperidine-1-carboxylate (405 mg, 0.92 mmol) in 1,4-dioxane (10 mL) was added 4N HCl in 1,4-dioxane (2.3 mL, 9.2 mmol). The reaction mixture was heated to 100 °C for 3 h and then cooled to rt. The volatiles were evaporated under reduced pressure. diethyl ether (10 mL) was added and the resulting precipitate was collected by filtration, washed with diethyl ether (3 x 5 mL), then dried under vacuum to afford title compound (340 mg, 96%) as a solid. MS (ESI) [M+H]+ 343.5.1H NMR (400 MHz, D2O) δ 7.28 (d, J = 7.8 Hz, 1H), 7.11 (app t, J = 7.5 Hz, 1H), 6.96 (d, J = 7.9 Hz, 1H), 4.92 (br s, 1H), 4.43 (dd, J = 11.6, 4.8 Hz, 1H), 4.26 (s, 3H), 3.52 – 3.39 (m, 2H), 3.38 – 3.24 (m, 2H), 2.89 – 2.72 (m, 2H), 2.53 – 2.40 (m, 1H), 2.35 – 2.16 (m, 5H).

[0382] Step 72.8: Synthesis of 2-[[6-[[5-chloro-2-[4-[3-(2,6-dioxo-3-piperidyl)-1- methyl-indazol-7-yl]oxy-1-piperidyl]pyrimidin-4-yl]amino]-1-methyl-2-oxo-3- quinolyl]oxy]-N-methyl-acetamide. To a suspension of 3-[1-methyl-7-(4-piperidyloxy)indazol- 3-yl]piperidine-2,6-dione hydrochloride (70 mg, 0.18 mmol) in dimethylsulfoxide (1 mL) were added sequentially 2-[[6-[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]-1-methyl-2-oxo-3- quinolyl]oxy]-N-methyl-acetamide (60 mg, 0.15 mmol, Intermediate 22) ) and diisopropylethylamine (0.11 mL, 610 µmol). The reaction mixture was heated to 85 °C for 1 h and then cooled to rt. The crude reaction mixture was purified by reverse phase chromatography (C18) using a gradient of 10–95% acetonitrile and 10 mM ammonium formate in water to afford title compound (19.5 mg, 18%) as a solid. MS (ESI) [M+H]+ 714.3.1H NMR (400 MHz, DMSO- d6) δ 10.87 (s, 1H), 8.88 (s, 1H), 8.07 (s, 1H), 7.95 – 7.90 (m, 1H), 7.89 (d, J = 2.3 Hz, 1H), 7.77 (dd, J = 9.1, 2.4 Hz, 1H), 7.47 (d, J = 9.2 Hz, 1H), 7.21 (d, J = 7.8 Hz, 1H), 7.12 (s, 1H), 7.03 – 6.90 (m, 2H), 4.91 – 4.84 (m, 1H), 4.55 (s, 2H), 4.31 (dd, J = 9.8, 5.1 Hz, 1H), 4.19 (s, 3H), 4.01 – 3.91 (m, 2H), 3.73 – 3.66 (m, 2H), 3.66 (s, 3H), 2.68 – 2.55 (m, 2H), 2.60 (d, J = 4.6 Hz, 3H), 2.36 – 2.28 (m, 1H), 2.19 – 2.12 (m, 1H), 2.09 – 1.99 (m, 2H), 1.85 – 1.74 (m, 2H). Example 73.2-[[6-[[5-Chloro-2-[4-[[3-(2,4-dioxohexahydropyrimidin-1-yl)-1-methyl- indazol-6-yl]amino]-3,3-difluoro-1-piperidyl]pyrimidin-4-yl]amino]-1-methyl-2-oxo-3- quinolyl]oxy]-N-methyl-acetamide

[0383] Step 73.1: Synthesis of tert-butyl 4-[[3-(2,4-dioxohexahydropyrimidin-1-yl)-1- methyl-indazol-6-yl]amino]-3,3-difluoro-piperidine-1-carboxylate. To a solution of 1-(6- amino-1-methyl-indazol-3-yl) hexahydropyrimidine-2,4-dione (900 mg, 3.47 mmol, Intermediate 8), tert-butyl 3,3-difluoro-4-oxo-piperidine-1-carboxylate (980 mg, 4.17 mmol) in acetic acid (5 mL) and dimethylsulfoxide (25 mL) was added decaborane(14) (195 mg, 1.74 mmol) and the mixture was stirred for 6 h at rt. Volatiles were removed and the residue was purified by reverse phase chromatography (C18) with a gradient of 20–100% acetonitrile and 10 mM ammonium formate in water to afford title compound (450 mg, 27%) as a solid. MS (ESI) [M–H]– 477.3.

[0384] Step 73.2: Synthesis of 1-[6-[(3,3-difluoro-4-piperidyl)amino]-1-methyl- indazol-3-yl]hexahydropyrimidine-2,4-dione hydrochloride. To a solution of tert-butyl 4-[[3- (2,4-dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]amino]-3,3-difluoro-piperidine-1- carboxylate (450 mg, 0.940 mmol) in dichloromethane (5 mL) was added 4N HCl in 1,4-dioxane (5.3 mL, 21.2 mmol) and the mixture was stirred for 4 h at rt. The resulting precipitate was collected by filtration, washed with diethyl ether (2 x 10 mL) and dried under vacuum. The residue was purified by reverse phase chromatography (C18) with a gradient of 5–50% acetonitrile and water to afford title compound (210 mg, 54%) as a solid, which was used in the next step without further purification. MS (ESI) [M+H]+ 379.2.1H NMR (400 MHz, DMSO-d6) δ 10.48 (s, 1H), 10.00 (br s, 1H), 9.40 (br s, 1H), 7.33 (d, J = 8.9 Hz, 1H), 6.66 (dd, J = 8.9, 1.9 Hz, 1H), 6.60 (d, J = 1.8 Hz, 1H), 6.35 – 6.23 (m, 1H), 4.49 – 4.28 (m, 1H), 3.87 (t, J = 6.7 Hz, 2H), 3.81 (s, 3H), 3.80 – 3.75 (m, 1H), 3.65 – 3.49 (m, 1H), 3.36 – 3.30 (m, 1H), 3.20 – 3.08 (m, 1H), 2.72 (t, J = 6.7 Hz, 2H), 2.18 – 2.08 (m, 1H), 1.95 – 1.83 (m, 1H).

[0385] Step 73.3: Synthesis of 2-[[6-[[5-chloro-2-[4-[[3-(2,4- dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]amino]-3,3-difluoro-1- piperidyl]pyrimidin-4-yl]amino]-1-methyl-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide. To a mixture of 1-[6-[(3,3-difluoro-4-piperidyl)amino]-1-methyl-indazol-3-yl] hexahydropyrimidine- 2,4-dione hydrochloride (31.8 mg, 80 µmol) and diisopropylethylamine (50 µL, 0.310 mmol) in dimethylsulfoxide (1 mL) at rt was added 2-[[6-[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]-1- methyl-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide (30 mg, 80 µmol, Intermediate 22) and the mixture was heated to 80 °C for 16 h. The crude reaction mixture was purified by preparative HPLC (BEH column, C18) with a gradient of 28–48% Acetonitrile and 10 mM ammonium formate in water to afford title compound (20.2 mg, 34%) as a solid. MS (ESI) [M+H]+ 750.2.1H NMR (500 MHz, DMSO-d6) δ 9.01 (s, 1H), 8.12 (s, 1H), 7.95 – 7.90 (m, 1H), 7.89 (d, J = 2.5 Hz, 1H), 7.76 (dd, J = 9.1, 2.4 Hz, 1H), 7.49 (d, J = 9.2 Hz, 1H), 7.31 (d, J = 8.8 Hz, 1H), 7.15 (s,1H), 6.66 (dd, J = 9.0, 1.9 Hz, 1H), 6.62 (d, J = 1.9 Hz, 1H), 6.05 (d, J = 9.1 Hz, 1H), 4.79 – 4.67 (m, 1H), 4.55 (s, 2H), 4.49 – 4.39 (m, 1H), 4.33 – 4.20 (m, 1H), 3.87 (t, J = 6.7 Hz, 2H), 3.82 (s, 3H), 3.68 (s, 3H), 3.61 – 3.52 (m, 1H), 3.32 – 3.25 (m, 1H), 2.73 (t, J = 6.7 Hz, 2H), 2.63 (d, J = 4.7 Hz, 3H), 2.06 – 1.98 (m, 1H), 1.72 – 1.62 (m, 1H). Note: one CH piperidine obstructed by water signal and dihydrouracil signal not visible. Example 74.2-[[6-[[5-Chloro-2-[[1-[3-(2,4-dioxohexahydropyrimidin-1-yl)-1-methyl- indazol-6-yl]-4-piperidyl]-methyl-amino]pyrimidin-4-yl]amino]-1-methyl-2-oxo-3- quinolyl]oxy]-N-methyl-acetamide

[0386] Step 74.1: Synthesis of tert-Butyl N-[1-[3-(2,4-dioxohexahydropyrimidin-1- yl)-1-methyl-indazol-6-yl]-4-piperidyl]-N-methyl carbamate. A mixture of [3-(2,4- dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]boronic acid (310 mg, 1.08 mmol, Intermediate 9), tert-butyl N-methyl-N-(4-piperidyl) carbamate (461 mg, 2.15 mmol), copper (II) acetate (258 mg, 1.29 mmol), triethylamine (300 µL, 2.15 mmol) in 1,2-dichloroethane (10 mL) was heated to 50 °C for 16 h. The mixture was filtered on celite and washed with a 1:1 mixture of acetonitrile and methanol (1:1, 3 x 5 mL). The filtrate was concentrated under reduced pressure and the residue was purified by reverse phase chromatography (C18) using a gradient of 5–70% acetonitrile and 10 mM ammonium formate in water to afford title compound (120 mg, 24%) as a solid. MS (ESI) [M+H]+ 457.3;1H NMR (500 MHz, DMSO-d6) δ 10.50 (br s, 1H), 7.44 (d, J = 9.0 Hz, 1H), 6.91 (dd, J = 9.1, 1.9 Hz, 1H), 6.85 (d, J = 1.6 Hz, 1H), 3.93 – 3.85 (m, 7H), 2.82 – 2.75 (m, 2H), 2.73 (t, J = 6.7 Hz, 2H), 2.69 (s, 3H), 2.68 – 2.64 (m, 1H), 1.85 – 1.74 (m, 2H), 1.67 – 1.59 (m, 2H), 1.41 (s, 9H).

[0387] Step 74.2: Synthesis of 1-[1-Methyl-6-[4-(methylamino)-1-piperidyl]indazol- 3-yl]hexahydropyrimidine-2,4-dione hydrochloride. To a solution of tert-butyl N-[1-[3-(2,4- dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]-4-piperidyl]-N-methyl-carbamate (120 mg, 0.26 mmol) in dichloromethane (2 mL) was added 4N HCl in 1,4-dioxane (2 mL, 8 mmol), and the mixture was stirred for 4 h at rt. The resulting precipitate was collected by filtration, washed with diethyl ether (2 x 5 mL), and dried under vacuum to afford title compound (100 mg, 82%) as a solid, which was used in the next step without further purification. MS (ESI) [M+H]+357.2.

[0388] Step 74.3: Synthesis of 2-[[6-[[5-Chloro-2-[[1-[3-(2,4- dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]-4-piperidyl]-methyl- amino]pyrimidin-4-yl]amino]-1-methyl-2-oxo-3-quinolyl]oxy]-N-methyl-acetamide. To a mixture of 2-[[6-[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]-1-methyl-2-oxo-3-quinolyl] oxy]-N- methyl-acetamide (25 mg, 60 µmol, Intermediate 22) and diisopropylethylamine (24.4 µL, 0.32 mmol) in dimethylsulfoxide(1 mL) at rt was added 1-[1-methyl-6-[4-(methylamino)-1- piperidyl]indazol-3-yl]hexahydropyrimidine-2,4-dione hydrochloride (27.6 mg, 70 µmol), and the mixture was heated to 80 °C for 16 h. The crude reaction mixture was purified by preparative HPLC (BEH column, C18), using a gradient of 31–41% acetonitrile and 10 mM ammonium formate in water to afford title compound (11.6 mg, 25%) as a solid. MS (ESI) [M+H]+ 728.3;1H NMR (500 MHz, DMSO-d6) δ 8.83 (s, 1H), 8.07 (s, 1H), 8.02 – 7.82 (m, 2H), 7.79 (br d, J = 8.9 Hz, 1H), 7.50 – 7.41 (m, 2H), 7.19 (s, 1H), 6.91 (br d, J = 7.7 Hz, 1H), 6.82 (br s, 1H), 4.50 (br s, 2H), 4.86 – 4.32 (m, 1H), 3.94 – 3.85 (m, 7H), 3.64 (s, 3H), 2.93 (br s, 3H), 2.83 – 2.69 (m, 1H), 2.74 (t, J = 6.5 Hz, 2H), 2.64 (d, J = 4.1 Hz, 3H), 1.92 – 1.80 (m, 2H), 1.75 – 1.65 (m, 2H). Note: dihydrouracil NH not visible and one CH obscured by water signal. Example 75.2-[[6-[[5-chloro-2-[4-[[3-(2,4-dioxohexahydropyrimidin-1-yl)-1-methyl- indazol-6-yl]amino]-1-piperidyl]pyrimidin-4-yl]amino]-1-methyl-2-oxo-3-quinolyl]oxy]- N,N-dimethyl-acetamide

[0389] Step 75.1: Synthesis of tert-butyl 4-[[3-(2,4-dioxohexahydropyrimidin-1-yl)-1- methyl-indazol-6-yl]amino]piperidine-1-carboxylate. A mixture of 1-(6-amino-1-methyl- indazol-3-yl)hexahydropyrimidine-2,4-dione Intermediate 8 (100. mg, 0.3900 mmol), tert-butyl 4-oxo-1-piperidinecarboxylate (84.54 mg, 0.4200 mmol), and decaborane(14) (21.63 mg, 0.1900 mmol) was stirred in dimethylsulfoxide (1 mL) and acetic acid (0.04 mL, 0.7700 mmol) at ambient temperature. After 1h, the reaction was complete according to LCMS. The reaction was diluted with methanol (1 mL) which resulted in bubbling. After 10 min, the bubbling subsided and the solution was diluted with ethyl acetate, washed with water and then brine, dried over sodium sulfate, filtered and concentrated. The resulting solid was triturated with diethyl ether to give 140 mg light yellow solid that was 90% pure by LCMS. The crude product was diluted withdichloromethane-10% methanol(10 mL) and treated with trifluoroacetic acid (2 mL). After 1 h, the reaction was treated with 1 mL 6N HCl in isopropanol and concentrated by rotary evaporation to give the title compound, 1-[1-methyl-6-(4-piperidylamino)indazol-3-yl]hexahydropyrimidine- 2,4-dione;hydrochloride (137 mg, 0.3396 mmol, 88.032% yield). MS (ESI) [M+H]+ 443.3

[0390] Step 75.2: Synthesis of 1-[1-methyl-6-[methyl(4-piperidyl)amino]indazol-3- yl]hexahydropyrimidine-2,4-dione;hydrochloride. To a stirred solution of tert-butyl 4-[[3-(2,4- dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]-methyl-amino]piperidine-1-carboxylate (105. mg, 0.2100 mmol) in dichloromethane (2 mL) (10% methanol) was added trifluoroacetic acid (0.02 mL, 0.2100 mmol) and the reaction stirred at rt overnight. The reaction was concentrated, triturated with ethyl acetate, and the maroon-colored solid collected by vacuum filtration to give the title compound, 1-[1-methyl-6-[methyl(4-piperidyl)amino]indazol-3- yl]hexahydropyrimidine-2,4-dione;hydrochloride (60 mg, 0.1436 mmol, 66.829% yield). MS (ESI) [M+H]+ 357.2

[0391] Step 75.3: Synthesis of 2-[[6-[[5-chloro-2-[4-[[3-(2,4- dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]amino]-1-piperidyl]pyrimidin-4- yl]amino]-1-methyl-2-oxo-3-quinolyl]oxy]-N,N-dimethyl-acetamide. To a stirred mixture of 2- [[6-[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]-1-methyl-2-oxo-3-quinolyl]oxy]-N,N-dimethyl- acetamide (30. mg, 0.0700 mmol, Intermediate 25) and 1-[1-methyl-6-(4- piperidylamino)indazol-3-yl]hexahydropyrimidine-2,4-dione;hydrochloride (30.81 mg, 0.0800 mmol) in dimethylsulfoxide (0.5000 mL) was added N,N-diisopropylethylamine (0.05 mL, 0.3000 mmol) and the reaction stirred at 80 °C for 3 h. Purified by prep-HPLC to give the title compound, 2-[[6-[[5-chloro-2-[4-[[3-(2,4-dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]amino]-1- piperidyl]pyrimidin-4-yl]amino]-1-methyl-2-oxo-3-quinolyl]oxy]-N,N-dimethyl-acetamide (8 mg, 0.0107 mmol, 14.46% yield). MS (ESI) [M+H]+ 728.2;1H NMR (500 MHz, DMSO-d6) δ ppm 10.46 (s, 1 H), 8.84 (s, 1 H), 8.08 (s, 1 H), 7.97 (d, J=2.21 Hz, 1 H), 7.74 (dd, J=9.14, 2.52 Hz, 1 H), 7.47 (d, J=9.14 Hz, 1 H), 7.29 (d, J=8.83 Hz, 1 H), 6.99 (s, 1 H), 6.51 - 6.54 (m, 1 H), 6.46 (d, J=1.26 Hz, 1 H), 5.83 (d, J=8.20 Hz, 1 H), 4.89 (s, 2 H), 4.42 (br d, J=12.93 Hz, 2 H), 3.87 (t, J=6.78 Hz, 2 H), 3.83 (s, 3 H), 3.68 - 3.72 (m, 1 H), 3.66 (s, 3 H), 3.16 (br t, J=11.35 Hz, 2 H), 2.93 (s, 3 H), 2.78 (s, 3 H), 2.73 (t, J=6.62 Hz, 2 H), 2.00 - 2.07 (m, 2 H), 1.32 - 1.42 (m, 2 H) Example 76.2-((6-((5-chloro-2-(4-((3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl- 1H-indazol-6-yl)(methyl)amino)piperidin-1-yl)pyrimidin-4-yl)amino)-1-methyl-2-oxo-1,2- dihydroquinolin-3-yl)oxy)-N-methylacetamide

[0392] Step 76.1: Synthesis of tert-butyl 4-[[3-(2,4-dioxohexahydropyrimidin-1-yl)-1- methyl-indazol-6-yl]-methyl-amino]piperidine-1-carboxylate. A solution of tert-butyl 4-[[3- (2,4-dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]amino]piperidine-1-carboxylate (100. mg, 0.2300 mmol, see above), acetic acid (0.03 mL, 0.4500 mmol), paraformaldehyde (0.09 mL, 1.13 mmol), and decaborane(14) (12.67 mg, 0.1100 mmol) in dimethylsulfoxide (1 mL) was stirred at rt. After 2 h, the reaction was complete according to LCMS. The reaction was diluted with ethyl acetate (10% hexanes), washed with water, dried over sodium sulfate, and concentrated to give the tile compound, tert-butyl 4-[[3-(2,4-dioxohexahydropyrimidin-1-yl)-1-methyl- indazol-6-yl]-methyl-amino]pipe...

Claims

CLAIMS 1. A compound of Formula (I):, or a pharmaceutically acceptable salt thereof, wherein: Ring A is a four to twelve-membered nitrogen-containing heterocyclylene, five to twelve-membered carbocyclylene, five to six-membered nitrogen-containing heteroarylene, phenylene,absent, wherein Ring A, when present, is substituted with (R10)x; each R10is independently halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, or C1- C6 haloalkyl, or two R10, taken together with a carbon atom to which they are both attached, form oxo; x is 0, 1, 2, 3, or 4; L1is N(R11) or N(R11)CH2C(O), or is absent; R11is hydrogen, C1-C6alkyl, C1-C6hydroxyalkyl, or C1-C6haloalkyl; L2is -(CH2)yN(R12)-, -O(CH2)y-, -N(R12)C(O)-, -C(O)N(R12)(CH2)z-, -C(O)N(R12)(CH2)zN(R12)-, -C(O)N(R12)(CH2)zO-, -(CH2)zC(O)N(R12)-, or (CH2)z, or is absent; each R12is independently hydrogen, C1-C6alkyl, C1-C6hydroxyalkyl, C1-C6deuteroalkyl, or C1-C6 haloalkyl; y is 0 or 1; z is 1, 2, 3, 4, or 5; R1is hydrogen or C1-C6alkyl; R2is C1-C6 alkyl; R3is halo or cyano;,X1is C(R13) or N; X2, X3, and X4are C(H); or X2and X4are C(H), and X3is N; or X2is N and X3and X4are C(H); or X2and X3are C(H) and X4is N; R13is hydrogen or C1-C6alkyl; each R14is independently halo; R52is hydrogen or C1-C6 alkyl; and p is 0, 1, 2, or 3.

2. The compound of claim 1, wherein Ring A is a four to six-membered monocyclic nitrogen-containing heterocyclylene, eight to ten-membered spirocyclic nitrogen- containing heterocyclylene, or eight to ten-membered fused bicyclic nitrogen-containing heterocyclylene.

3. The compound of claim 1, wherein Ring A is piperidinylene, piperazinylene, azetidinylene, pyrrolindinylene, 2,6-diazaspiro[3.4]octanylene, 2,8-diazaspiro[4.5]decanylene, 8-azabicyclo[3.2.1]octanylene,octahydro-1H-pyrrolo[3,2-c]pyridinylene, cyclohexenylene, pyrazolylene, or, substituted with (R10)x; or Ring A is absent.

4. The compound of any one of claims 1-3, wherein each R10is independently halo, C1-C6 alkyl, or C1-C6hydroxyalkyl, or two R10, taken together with a carbon atom to which they are both attached, form oxo; and x is 0, 1, or 2.

5. The compound of any one of claims 1-4, wherein L1is N(R11); and R11is hydrogen, C1- C6alkyl, or C1-C6hydroxyalkyl.

6. The compound of any one of claims 1-5, wherein L1is absent.

7. The compound of any one of claims 1-6, wherein L2is -(CH2)yN(R12)-, -O(CH2)y-, -N(R12)C(O)-, -C(O)N(R12)(CH2)z-, -C(O)N(R12)(CH2)zN(R12)-, -C(O)N(R12)(CH2)zO-, -(CH2)zC(O)N(R12)-, or (CH2)z; and each R12is independently hydrogen, C1-C6alkyl, C1- C6 hydroxyalkyl, or C1-C6 deuteroalkyl.

8. The compound of any one of claims 1-6, wherein L2is -N(H)-, -N(CH3)-, -N(CH2CH2OH)-, -CH2N(H)-, -CH2N(CH3)-, -CH2N(CD3)-, -O-, -OCH2-, -N(H)C(O)-, -C(O)N(H)CH2-, -C(O)N(H)CH2CH2N(H)-, -C(O)N(H)CH2CH2CH2N(H)-, -C(O)N(H)CH2CH2O-, -CH2C(O)N(H)-, or -CH2-, or is absent.

9. The compound of any one of claims 1-8, wherein R1is hydrogen or methyl; and R2is methyl.

10. The compound of any one of claims 1-9, wherein R4is:

11. The compound of any one of claims 1-10, wherein R13is hydrogen or methyl.

12. The compound of any one of claims 1-11, wherein R14is fluoro.

13. The compound of any one of claims 1-12, wherein p is 0 or 1.

14. The compound of any one of claims 1-4 and 7-13, of Formula (II):, or a pharmaceutically acceptable salt thereof.

15. The compound of any one of claims 1, 4, 5, and 9-12, of Formula (III):, or a pharmaceutically acceptable salt thereof.

16. The compound of any one of claims 1-4 and 9-12, of Formula (IV):, or a pharmaceutically acceptable salt thereof.

17. A compound of Table 1, or a pharmaceutically acceptable salt thereof.

18. A pharmaceutical composition comprising a compound of any of claims 1-17, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

19. A method of degrading B-cell lymphoma 6 protein (BCL6), comprising contacting BCL6 with an effective amount of a compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, or pharmaceutical composition of claim 18.

20. A method of treating a cancer or an autoimmune disease in a subject in need thereof, comprising administering to the subject an effective amount of a compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, or pharmaceutical composition of claim 18.

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