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 DEGRADERSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to US Provisional Application No. 63 / 595,065, 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 naive 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. Over-expression 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 cocrystal 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, 77, 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, Z1, Z2, R1, R2, 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)-(VI) 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)-(VI) 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)-(VI) 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)-(VI) 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)-(VI) 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)-(VI) 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 DESCRIPTIONDefinitions

[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 -NH2 radical.

[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 =0 radical.

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

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

[0027] Oximo” refers to the =N-0H 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-C6 alkyl). 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., Ci- 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-C3 alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (e.g., C1-C2 alkyl). In other embodiments, an alkyl comprises one carbon atom (e.g., Ci 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-C8 alkyl). 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 (zz-propyl), 1 -methylethyl (z.w-propyl), 1 -butyl (zz-butyl),1 -methylpropyl (sec-butyl), 2-methylpropyl ( / .w-butyl), 1,1 -dimethylethyl (tert-butyl), and 1 -pentyl ( / / -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-C6 alkyl 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-l-enyl (i.e., allyl), but-l-enyl, pent-l-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, -0C(0)- 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, -0C(0)-Ra, -N(Ra)2, -C(0)Ra, -C(0)0Ra, -C(0)N(Ra)2, -N(Ra)C(0)0Ra, -OC(O)- N(Ra)2, -N(Ra)C(0)Ra, -N(Ra)S(0)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 a 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, fluorenely, indanyl, indenyl, tetralinyl, and naphthal enyl. 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 hsa 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, norbomyl (i.e., bicyclo[2.2.1]heptanyl), norbomenyl, 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-C3 haloalkyl). The halo radicals may be all the same, or the halo radicals may be different.

[0045] “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[l,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-lH-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, -RbOC(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 Raisindependently 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.

[0046] "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.

[0047] “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.

[0048] 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.

[0049] “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 is optionally substituted as defined above for alkyl. The heterocyclyl part of the heterocyclylalkylis optionally substituted as defined above for heterocyclyl.

[0050] “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.

[0051] “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 quatemized. 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[Z>][l,4]dioxepinyl, benzo[b][l,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodi oxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotri azolyl, benzo[4,6]imidazo[l,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[l,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-naphthyri dinonyl, 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-0Ra, -Rb-0C(0)-Ra, -Rb-0C(0)-0Ra, -Rb-0C(0)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(0)Ra, -Rb-C(0)0Ra, -Rb-C(0)N(Ra)2, -Rb-0-Rc-C(0)N(Ra)2, -Rb-N(Ra)C(0)0Ra, -Rb-N(Ra)C(0)Ra, -Rb-N(Ra)S(0)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.

[0052] "Nitrogen-containing heteroaryl” refers to a heteroaryl, as defined above, containing at least one nitrogen, e.g., N-heteroaryl, C-heteroaryl.

[0053] “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 of attachment to the rest of the molecule.

[0054] C-heteroaryl” refers to a heteroaryl 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.

[0055] “Heteroaryl alkyl” 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 heteroaryl alkyl is optionally substituted as defined above for heteroaryl.

[0056] “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 heteroaryl alkoxy is optionally substituted as defined above for alkyl. The heteroaryl part of the heteroaryl alkoxy is optionally substituted as defined above for heteroaryl.

[0057] 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).

[0058] 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 or base and an organic acid or base. Suitable pharmaceutically acceptable base addition salts of a compound include, but are not limited to, metallic salts made from, e.g., aluminum, calcium, lithium, magnesium, potassium, sodium and zinc, or organic salts made from, e.g., 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) or Remington: The Science and Practice of Pharmacy, 19theds., Mack Publishing, Easton PA (1995).

[0059] 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.

[0060] 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).

[0061] 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:

[0062] 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.

[0063] 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.

[0064] 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 used herein, “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.

[0065] The disclosure also includes “deuterated analogs” of compounds described herein inwhich 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.

[0066] 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.

[0067] 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.

[0068] “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.

[0069] “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.

[0070] 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.

[0071] 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.

[0072] 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

[0073] 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, phenyleneor is 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;Z1is C(R3) and Z2is N, or Z1is N and Z2is C(R3);R3is halo or cyano;L1is N(Rn), 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;Z3is C(H)2, C(H)(CH2CH2C(O)NRlbRlc), C(H)(OCH2C(O)NRlbRlc), N(CH2CH2C(O)NRlbRlc), and Z4is C(H)2; orZ3is C(H)2or C(H)(CH2CH2C(O)NRlbRlc), and Z4is O;Z5is C(H)2, C(F)2, or C(H)(F);Rlais hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 deuteroalkyl, C1-C6 haloalkyl, or -CH2CH2C(O)NRlbRlc;Rlbis hydrogen or C1-C6 alkyl;Rlcis Ci-C6alkyl;Rldis hydrogen or halo;Rleis -N(Rla)C(O)( C1-C6 alkyl), -N(Rla)C(O)NRlbRlc, -CH2C(O)NRlbRlc,5 to 6-membered heteroaryl, orZ6is C(H2), C(H)Rla, orN(Rla);Z7is O or S;R2is hydrogen or fluoro;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 X3andX4are 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; provided R1is not when R4is

[0074] In another aspect, provided herein is a compound of Formula (II):or a pharmaceutically acceptable salt thereof, wherein values for variables (e.g., Ring A, L2, R1, R2, R3, R4) are as described with respect to Formula (I) or elsewhere herein.

[0075] In yet another aspect, provided herein is a compound of Formula (III):or a pharmaceutically acceptable salt thereof, wherein values for variables (e.g., R1, R2, R3, R4, R10, R11, x) are as described with respect to Formula (I) or elsewhere herein.

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

[0077] In another aspect, provided herein is a compound of Formula (V):or a pharmaceutically acceptable salt thereof, wherein one of L1and L2is absent and R50ishydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 deuteroalkyl, or C1-C6 haloalkyl. Values for the remaining variables (e.g., Ring A, L1, L2, R2, R3) are as described with respect to Formula (I) or elsewhere herein. In some embodiments of Formula (V),, wherein values for variables R10, R11, x are as described with respect to Formula (I) or elsewhere herein. Values for the remaining variables are as described with respect to Formula (I) or elsewhere herein. In some embodiments of Formula (V), the compound is not 3-(6-(4-((5- chloro-4-((l-(3-hydroxy-3-methylbutyl)-2-oxoindolin-6-yl)amino)pyrimidin-2- yl)amino)piperidin-l-yl)-l-methyl-lH-indazol-3-yl)piperidine-2, 6-dione, 3-[6-[[l-[5-Chloro-4- [[l-(3-hydroxy-3-methyl-butyl)-2-oxo-indolin-6-yl]amino] pyrimidin-2-yl]-4-piperidyl]amino]- l-methyl-indazol-3-yl]piperidine-2, 6-dione, 3-(6-((l-(5-chloro-4-((l-(3-hydroxy-3- methylbutyl)-2-oxoindolin-6-yl)amino)pyrimidin-2-yl)piperidin-4-yl)(methyl)amino)-l -methyl- lH-indazol-3-yl)piperidine-2, 6-dione, 3-(6-(4-((5-chloro-4-((l-(3-hydroxy-3-methylbutyl)-2- oxoindolin-6-yl)amino)pyrimi din-2 -yl)(methyl)amino)piperidin-l-yl)-l-m ethyl-lH-indazol-3 - yl)piperidine-2, 6-dione, 3-(6-(((3R,4R)-l-(5-chloro-4-((l-methyl-2-oxoindolin-6- yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-l-methyl-lH-indazol-3-yl)piperidine- 2, 6-dione, or 3-(6-(((3R,4R)-l-(5-chloro-4-((l-(3-hydroxy-3-methylbutyl)-2-oxoindolin-6- yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-l-methyl-lH-indazol-3-yl)piperidine- 2, 6-dione, or a salt thereof.

[0078] In another aspect, provided herein is a compound of Formula (VI):or a pharmaceutically acceptable salt thereof, wherein R51is hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 deuteroalkyl, or C1-C6 haloalkyl (e.g., in some embodiments, C1-C6 alkyl, such as methyl); R52is hydrogen or C1-C6 alkyl (e.g., in some embodiments, hydrogen or methyl); and R53is hydrogen, halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, or C1-C6 haloalkyl (e.g., in some embodiments, hydrogen, C1-C6 alkyl, or C1-C6 alkoxy, such as hydrogen, methyl, or methoxy). Values for the remaining variables (e.g., R2, R3, R13) are as described with respect to Formula (I) or elsewhere herein.

[0079] 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 tenmembered spirocyclic nitrogen-containing heterocyclylene, substituted with (R10)x.

[0080] In some embodiments, Ring A is a five to twelve-membered carbocyclylene or phenylene.

[0081] 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-lH-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, orsubstituted 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.

[0082] In alternative embodiments, Ring A is absent.

[0083] 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, 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, 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.

[0084] 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.

[0085] In some embodiments, L1is N(Rn). In some embodiments, L1is absent.

[0086] 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.

[0087] 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 more particular 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)-.

[0088] In alternative embodiments, L2is absent.

[0089] In some embodiments, each R12is independently hydrogen or C1-C6 alkyl. 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. In some embodiments, each R12is independently hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, or C1-C6 deuteroalkyl. In a particular embodiment, each R12is independently hydrogen, methyl, hydroxy ethyl, or -CD3.

[0090] In some embodiments, y is 0. In some embodiments, y is 1.

[0091] 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.

[0092] In some embodiments, R1is:

[0093] In some embodiments, Z3is C(H)2, C(H)(CH2CH2C(O)N(H)CH3), or N(CH2CH2C(O)N(H)CH3), and Z4is C(H)2. In some embodiments, Z3is C(H)2or C(H)(CH2CH2C(O)N(H)CH3), and Z4is O.

[0094] In some embodiments, Z5is C(H)2.

[0095] In some embodiments, Rlais hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 deuteroalkyl, or -CH2CH2C(O)NRlbRlc. In some embodiments, Rlais hydrogen, methyl, -CD3, hydroxymethyl, hydroxypentyl, or -CH2CH2C(O)N(H)CH3. In some embodiments, Rlais hydrogen or methyl.

[0096] In some embodiments, Rlbis hydrogen or methyl. In a particular embodiment, Rlbis hydrogen. In another particular embodiment, Rlbis methyl.

[0097] In some embodiments, Rlcis methyl.

[0098] In some embodiments, Rldis hydrogen or fluoro.

[0099] In some embodiments, Rleis -N(Rla)C(O)CH3, -N(Rla)C(O)NRlbRlc,-CH2C(O)NRlbRlc, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, or

[0100] In some embodiments, Z6is C(H)2. In some embodiments, Z6is C(H)RlaorN(Rla).

[0101] In some embodiments, Z7is O. In some embodiments, Z7is S.

[0102] In some embodiments, R2is hydrogen.

[0103] In some embodiments, R3is chloro or cyano. In a particular embodiment, R3is chloro. In another particular embodiment, R3is cyano.

[0104] In some embodiments, R4is:embodiment,embodiment,In another particular embodiment,

[0105] In some embodiments, R4is:

[0106] 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.

[0107] In some embodiments, R13is hydrogen or methyl. In a particular embodiment, R13is hydrogen.

[0108] In some embodiments, R14is fluoro.

[0109] In some embodiments, R50is hydrogen, C1-C6 alkyl, or C1-C6 hydroxyalkyl. In a particular embodiment, R50is hydrogen, methyl, or hydroxypentyl.

[0110] In some embodiments, R51is C1-C6 alkyl. In a particular embodiment, R51is methyl.

[0111] In some embodiments, R52is hydrogen or methyl. In a particular embodiment, R52is hydrogen. In another particular embodiment, R52is methyl.

[0112] In some embodiments, R53is hydrogen, C1-C6 alkyl, or C1-C6 alkoxy. In a particular embodiment, R53is hydrogen, methyl or methoxy.

[0113] In some embodiments, p is 0 or 1. In a particular embodiment, p is 0. In another particular embodiment, p is 1.

[0114] In another aspect, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is phenylene. Values for the remaining variables are as described with respect to Formula (I) or elsewhere herein.

[0115] 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, Z3, Z4, Z5, Z6, R1, Rla, Rib RIC Rid Rle R2 R4 R10 R11 R12 R13

[0116] 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), (V), and are equally described, the same as if each and every description, variation, embodiment, or aspect were separately and individually listed for all formulae.

[0117] 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.Table 1.or a pharmaceutically acceptable salt thereof.

[0118] In some embodiments, provided is a compound selected from:or a pharmaceutically acceptable salt thereof.

[0119] 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.

[0120] 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.Scheme 1.wherein Rla, Rle, R2and R3are as described for Formula (I); X" is C and R and R' are as described for Rldand Rleof Formula (I), or X" is C or N and R and R' are taken together with the intervening atoms to form a monocyclic or multi cyclic (e.g., bicyclic) ring, such as in R1of Formula (I); LG2 and LG3 are independently a leaving group, such as F or Cl.herein x, R10, R11, and R12are as described for Formula (I); LG4 is a leaving group, such as Br or Cl; Y is H, C1-C6 alkyl, 6- or 7 membered eterocyclyl, or Boc, wherein the heterocyclyl contains 1-3 heteroatoms selected from N, O, and S; PG is a protecting group, such as Boc; X is CH, H2, N, NH, or NBoc; X' is CH, CH2, N, or NH; is as described for Ring A of Formula (I), such as a five- or six-membered heterocyclylene;nd Bn is benzyl.wherein R12is as described for Formula (I); PG1is a protecting group, such as Fmoc or Boc;LG4 is a leaving group, such as Br or Cl; and Y is H, C1-C6 alkyl, 6- or 7 membered heterocyclyl, or Boc, wherein the heterocyclyl contains 1-3 heteroatoms selected from N, O, and S.wherein R2, R3, R10, R11, and R13are as defined for Formula (I); LG3 is a leaving group, such as OTs, OMs, F, Cl, or I; A is C or N; E is N, C(=O), or C(H); G is N, N(H), N(CH3), C(H), C(H)2, C(CH3), C(H)(CH3), or C(=O); and X", R, and R' are as described in Scheme 1.

[0121] As outlined in Scheme 1, compounds of Formula (i-1) can be synthesized by coupling compounds e, such as compounds e-1 to e-16, and compounds f to form compounds of Formula (i-1).

[0122] Scheme 2 provides two routes for synthesizing compounds j' or m'. Indazole derivatives g can be coupled to compounds h to afford compounds i. Deprotection and further reduction of compounds i forms compounds j, which are optionally subjected to deprotection to form compounds j'. Alternatively, indazole derivatives g can be coupled to compounds k to afford compounds 1. Deprotection and further reduction of compounds 1 forms compounds m, which are optionally subjected to deprotection of the amine to form compounds m'.

[0123] Scheme 3 provides a synthesis of compounds p'. Indazole derivatives n can be coupled to compounds h to afford compounds 0, which are deprotected to form compounds pand optionally subsequently deprotected to form compounds p'.

[0124] Scheme 4 provides syntheses for various compounds of Formula (I) (e.g., Formula (I-a), Formula (I-b), etc.}. Compounds of Formula (i-1) can be coupled to various compounds of Formula (i-2), such as compounds of Formulas (i-2a) to (i-21), to afford compounds of Formula (I).Methods of Use

[0125] 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).

[0126] 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.

[0127] 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%.

[0128] 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.

[0129] 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.

[0130] 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%.

[0131] 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).

[0132] 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.

[0133] 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.

[0134] 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.

[0135] 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.

[0136] 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, providedherein is a method of enhancing the effect of another medication used to treat a cancer in a subject, the method comprising administering an effective amount of a compound provided herein to the subj ect.

[0137] 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.

[0138] 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).

[0139] 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-Barre 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-Barre 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, Sjogren's syndrome, stiff person syndrome, temporal arteritis, ulcerative colitis, vasculitis, vitiligo, and Wegener's granulomatosis.

[0140] 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).

[0141] 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.

[0142] 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.

[0143] 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

[0144] 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, hydroxypropyl starch, 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 pyrrolidone 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.

[0145] 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.

[0146] 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.

[0147] 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.

[0148] 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.

[0149] 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.

[0150] 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.

[0151] 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.

[0152] 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, com 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.

[0153] 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.

[0154] 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.

[0155] 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

[0156] 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,or is 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;Z1is C(R3) and Z2is N, or Z1is N and Z2is C(R3);R3is halo or cyano;L1is N(Rn), 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;Z3is C(H)2, C(H)(CH2CH2C(O)NRlbRlc), C(H)(OCH2C(O)NRlbRlc), N(CH2CH2C(O)NRlbRlc), and Z4is C(H)2; orZ3is C(H)2or C(H)(CH2CH2C(O)NRlbRlc), and Z4is O;Z5is C(H)2, C(F)2, or C(H)(F);Rlais hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 deuteroalkyl, C1-C6 haloalkyl, or -CH2CH2C(O)NRlbRlc;Rlbis hydrogen or C1-C6 alkyl;Rlcis Ci-C6alkyl;Rldis hydrogen or halo;Rleis -N(Rla)C(O)(Ci-C6alkyl), -N(Rla)C(O)NRlbRlc, -CH2C(O)NRlbRlc,5 to 6-membered heteroaryl, orZ6is C(H2), C(H)Rla, orN(Rla);Z7is O or S;R2is hydrogen or fluoro;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 X3andX4are 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;

[0157] Embodiment 2. The compound of embodiment 1, wherein Ring A is a four to twelve-membered nitrogen-containing heterocyclylene.

[0158] Embodiment 3. The compound of embodiment 2, wherein Ring A is a four to six -membered monocyclic nitrogen-containing heterocyclylene or eight to ten-membered spirocyclic nitrogen-containing heterocyclylene.

[0159] Embodiment 4. The compound of embodiment 1, wherein Ring A is piperidinylene, piperazinylene,2,8-diazaspiro[4.5]decanylene, phenylene, or, substituted with (R10)x.

[0160] Embodiment 5. The compound of embodiment 4, wherein Ring A is piperidinylene substituted with (R10)x.

[0161] Embodiment 6. The compound of embodiment 1, wherein Ring A is absent.

[0162] Embodiment 7. The compound of any one of embodiments 1-5, wherein R10is halo, C1-C6 alkyl, or C1-C6 alkoxy.

[0163] Embodiment 8. The compound of embodiment 7, wherein R10is fluoro, methyl, or methoxy.

[0164] Embodiment 9. The compound of any one of embodiments 1-8, wherein x is 0 or 1.

[0165] Embodiment 10. The compound of any one of embodiments 1-9, wherein L1is N(Rn).

[0166] Embodiment 11. The compound of any one of embodiments 1-10, wherein R11is hydrogen or C1-C6 alkyl.

[0167] Embodiment 12. The compound of embodiment 11, wherein R11is hydrogen or methyl.

[0168] Embodiment 13. The compound of any one of embodiments 1-9, wherein L1is absent.

[0169] Embodiment 14. The compound of any one of embodiments 1-13, wherein L2is -(CH2)yN(R12)-, -O(CH2)y-, -N(R12)C(O)-, or -(CH2)ZC(O)N(R12)-.

[0170] Embodiment 15. The compound of embodiment 14, wherein L2is (CH2)yN(R12) or -O(CH2)y-.

[0171] Embodiment 16. The compound of any one of embodiments 1-15, wherein each R12is independently hydrogen or C1-C6 alkyl.

[0172] Embodiment 17. The compound of embodiment 16, wherein each R12is independently hydrogen or methyl.

[0173] Embodiment 18. The compound of any one of embodiments 1-17, wherein y is 0.

[0174] Embodiment 19. The compound of any one of embodiments 1-17, wherein y is 1.

[0175] Embodiment 20. The compound of any one of embodiments 1-18, wherein z is 1,2, or 3.

[0176] Embodiment 21. The compound of any one of embodiments 1-13, wherein L2is -N(H)-, -N(CH3)-, -CH2N(H)-, -O-, -N(H)C(O)-, or -CH2C(O)N(H)-.

[0177] Embodiment 22. The compound of any one of embodiments 1-13, wherein L2isabsent.

[0178] Embodiment 23. The compound of any one of embodiments 1-22, wherein R1is:

[0179] Embodiment 24. The compound of any one of embodiments 1-23, wherein Z3is C(H)2, C(H)(CH2CH2C(O)N(H)CH3), or N(CH2CH2C(O)N(H)CH3), and Z4is C(H)2.

[0180] Embodiment 25. The compound of any one of embodiments 1-23, wherein Z3is C(H)2or C(H)(CH2CH2C(O)N(H)CH3), and Z4is O.

[0181] Embodiment 26. The compound of any one of embodiments 1-25, wherein Z5is C(H)2.

[0182] Embodiment 27. The compound of any one of embodiments 1-26, wherein Rlais hydrogen, methyl, -CD3, hydroxymethyl, hydroxypentyl, or -CH2CH2C(O)N(H)CH3.

[0183] Embodiment 28. The compound of any one of embodiments 1-27, wherein Rlbis hydrogen or methyl.

[0184] Embodiment 29. The compound of any one of embodiments 1-28, wherein Rlcis methyl.

[0185] Embodiment 30. The compound of any one of embodiments 1-29, wherein Rldis hydrogen or fluoro.

[0186] Embodiment 31. The compound of any one of embodiments 1-30, wherein Rleis -N(Rla)C(O)CH3, -N(Rla)C(O)NRlbRlc, -CH2C(O)NRlbRlc, imidazolyl, pyrazolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, or

[0187] Embodiment 32. The compound of any one of embodiments 1-23, wherein R1is:

[0188] Embodiment 33. The compound of any one of embodiments 1-32, wherein R2is hydrogen.

[0189] Embodiment 34. The compound of any one of embodiments 1-33, wherein R3is chloro or cyano.

[0190] Embodiment 35. The compound of any one of embodiments 1-34, wherein R4is:

[0191] Embodiment 36. The compound of embodiment 35, wherein R4is:

[0192] Embodiment 37. The compound of any one of embodiments 1-36, wherein X2, X3and X4are C(H).

[0193] Embodiment 38. The compound of any one of embodiments 1-37, wherein R13is hydrogen or methyl.

[0194] Embodiment 39. The compound of embodiment 38, wherein R13is hydrogen.

[0195] Embodiment 40. The compound of any one of embodiments 1-39, wherein R14is fluoro.

[0196] Embodiment 41. The compound of any one of embodiments 1-40, wherein R52is hydrogen or methyl.

[0197] Embodiment 42. The compound of any one of embodiments 1-41, wherein p is 0 or 1.

[0198] Embodiment 43. The compound of any one of embodiments 1-5, 7-9, and 14-42, of Formula (II):or a pharmaceutically acceptable salt thereof.

[0199] Embodiment 44. The compound of any one of embodiments 1, 7-12, and 23-42, of Formula (III):or a pharmaceutically acceptable salt thereof.

[0200] Embodiment 45. The compound of any one of embodiments 1-9 and 23-42, of Formula (IV):or a pharmaceutically acceptable salt thereof.

[0201] Embodiment 46. The compound of any one of embodiments 1, 33, 34, 38, 39, and 41, of Formula (VI):or a pharmaceutically acceptable salt thereof, wherein:R51is hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 deuteroalkyl, or C1-C6 haloalkyl;R52is hydrogen or C1-C6 alkyl; andR53is hydrogen, halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, or C1-C6 haloalkyl.

[0202] Embodiment 47. The compound of embodiment 46, wherein R51is C1-C6 alkyl.

[0203] Embodiment 48. The compound of embodiment 47, wherein R51is methyl.

[0204] Embodiment 49. The compound of any one of embodiments 46-48, wherein R53is hydrogen, C1-C6 alkyl, or C1-C6 alkoxy.

[0205] Embodiment 50. The compound of embodiment 49, wherein R53is hydrogen, methyl, or methoxy.

[0206] Embodiment 51. A compound of Table 1, or a pharmaceutically acceptable salt thereof.

[0207] Embodiment 52. The compound of embodiment 51, selected from:or a pharmaceutically acceptable salt thereof.

[0208] Embodiment 53. A pharmaceutical composition comprising a compound of any of embodiments 1-52, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0209] Embodiment 54. 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 1-52, or a pharmaceutically acceptable salt thereof, or pharmaceutical composition of embodiment 53.

[0210] Embodiment 55. 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 embodiments 1-52, or a pharmaceutically acceptable salt thereof, or pharmaceutical composition of embodiment 53.EXAMPLES

[0211] 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.

[0212] Salts of the compounds described herein can be prepared by standard methods, such as inclusion of an acid (for example TFA, formic acid, or HC1) in the mobile phases during chromatography purification, or stirring of the products after chromatography purification, with a solution of an acid (for example, aqueous HC1).

[0213] The following abbreviations may be relevant for the application.AbbreviationsACN, MeCN acetonitrile AcOH acetic acid anh anhydrous atm atmospheric pressureBF3OEt2 boron trifluoride etherateBINAP 2,2'-bis(diphenylphosphino)-l, 1 '-binaphthylBOC tert-butyl oxy carb ony 1CBM Cereblon Binding MoietyCbz-Cl benzyl chloroformateCDI 1 , 1 '-carbonyldiimidazoleCPhos 2'-(dicyclohexylphosphanyl)-N2,N2,N6,N6-tetramethyl[l,r- biphenyl]-2,6-diamineDBU l,8-diazabicyclo[5.4.0]undec-7-eneDCE 1.2-di chloroethaneDCM dichloromethaneDIPEA N,N-dii sopropy 1 ethyl ami neDMA N,N-dimethylacetamideDMAP 4-dimethylaminopyridineDMEDA 1.2-dimethylethylenediamineDMF dimethylformamideDMSO dimethyl sulfoxideDPM Dess-Martin periodinaneEDC ethylene di chloride eq or equiv equivalentsESI electrospray ionizationEt3N triethylamineEt2O diethyl etherEtO Ac or EA ethyl acetateEtOH ethanolFA formic acid h or hrs hourHATU N-[(Dimethylamino)-lH-l,2,3-triazolo-[4,5-b]pyridin-l- ylmethylene]-N-methylmethanaminium hexafluorophosphate N- oxide hex hexanesHPLC high pressure liquid chromatography iPrOH isopropanolJosiphos Pd G3 {(7?)-l-[(Sp)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert- butylphosphine } [2-(2 '-amino- 1 , 1 '-biphenyl)]pall adium(II) methanesulfonateLCMS liquid chromatography mass spectrometryLHDMS lithium bis(trimethylsilyl)amideLiHMDS lithium hexamethyldisilazideM molarity mCPBA meta-chloroperoxybenzoic acidMeCN acetonitrileMeOH methanolMeTHF 2-methyltetrahydrofuran min minute MS mass spectrometry N normalityNaOtBu sodium tert-butoxideNBS N-bromosuccinimideNIS N-iodosuccinimideNMP N-methyl-2-pyrrolidone oMe mesylate oTs tosylatePd2dba3 tris(dibenzylideneacetone)dipalladium(0)Pd-Ruphos-G3 (2-dicyclohexylphosphino-2',6'-diisopropoxy-l,l'-biphenyl)(2-(2'- amino-1, l'-biphenyl))palladium(II) methanesulfonatePE, pet ether petroleum ether quant. quantitativeRBF round bottom flask rt or RT room temperatureRt retention timeSFC supercritical fluid chromatographySM starting materialSNAr nucleophilic aromatic substitutionTBAB tetrabutylammonium bromide tBuOH tert-butanolTEA trimethylamineTFA trifluoroacetic acidTHF tetrahydrofuranTLC thin layer chromatography xantphosXPhos Pd G3Synthetic ExamplesGeneral Procedure 1: First SNAr onto pyrimidine.

[0214] To a -40 °C mixture of 5-amino-l-methylindolin-2-one (1 eq) in dry tetrahydrofuran [0.4M] was added DIPEA (1.1 eq). A solution of 5-chloro-2,4-difluoropyrimidine (1 eq) in dry tetrahydrofuran [1.5M] was slowly added to the above mixture and allowed to slowly warm to rt. The reaction mixture was stirred at rt for 16 h. After this time, the reaction mixture was filtered and washed with acetonitrile. The solid was dried under vacuum to afford title compound.General Procedure 2: Buchwald Coupling of Amine to Indazole CBM.

[0215] A mixture of 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-l-methyl-indazole la (1.1 eq), amine (1.0 eq), Ruphos-Pd-G3 (0.20 equiv.) and NaOtBu (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 EtOAc. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel using a gradient of 0-100% EtOAc in hexanes to afford title compound.General Procedure 3: Methylation of amine

[0216] To a solution of amine (1.0 eq, 14.2 mmol) in DMF [0.15M] was added NaH (4.4 eq), and stirred at 0 °C for 1 h. To the mixture was added iodomethane (2.8 eq) at 0 °C. The resulting reaction mixture was stirred at room temperature for 16hr. The reaction mixture was then quenched with water, and extracted with EA. 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 PEZEA (15: 1) to obtain title compound.General Procedure 4: Reduction of CBM with Hydrogen.

[0217] A mixture of indazole intermediate (1.0 equiv.) and Pd / C (10 wt. % palladium; 40% by weight) in EtOH:THF (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 through Celite. The filter cake was washed sequentially with EtOH and THF. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel using a gradient of 0-100% EtOAc in hexanes to afford title compound.General Procedure 5: BOC Deprotection with HCI or TFA.

[0218] To a solution of BOC protected amine (1.0 eq) in 1,4-dioxane [0.3 M] was added 4N HC1 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 title compound (quant.) as a solid, which was used in the next step without further purification.General Procedure 6: SNAr of Decorated TBM with CBM.

[0219] 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 hr. 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 compound.Intermediate i-1

[0220] Step i-1.1: Synthesis of 5-((5-chloro-2-fluoropyrimidin-4-yl)amino)-l-methylindolin-2-one. To a solution of 5-amino-l-methylindolin-2-one (2.0 g, 12.3 mmol) in tetrahydrofuran (32 mL) was added DIPEA (2.37 ml, 13.6 mmol) at -40 °C. A solution of 5- chloro-2,4-difluoropyrimidine (1.86 g, 12.3 mmol) in dry tetrahydrofuran (8 mL) was slowly added to the above mixture and allowed to slowly warm to rt. The reaction mixture was stirred at rt for 16 h. After this time, the reaction mixture was filtered and washed with acetonitrile (~50 mL). The solid was dried under vacuum to afford the title compound as a tan solid. MS (ESI) [M+H]+293.1.Intermediate i-2.

[0221] Step i-2.1: Synthesis of 6-bromo-3-iodo-l-methyl-indazole. To a solution of 6- bromo-l-methyl-indazole (8.00 g, 37.9 mmol) in DMF (100 mL) was added NIS (25.58 g, 113.7 mmol). The reaction mixture was heated to 150 °C for on 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+H]+ 336.90.

[0222] Step i-2.2: Synthesis of 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-l-methyl- indazole. To a solution of 6-bromo-3-iodo-l-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 (3x 40 mL), washed with brine(2x 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 ptroleum ether) to the title compound (2.1 g, 4.20 mmol, 71% yield) as a pale yellow solid. MS (ES)[M+H]+ 500.3. 'HNMR (400 MHz, DMSO-d6) 5 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).

[0223] Step i-2.3: Synthesis of tert-butyl 4-[[3-(2,6-dibenzyloxy-3-pyridyl)-l-methyl-indazol-6-yl]amino]piperidine-l-carboxylate. A mixture of 6-bromo-3-(2,6-dibenzyloxy-3- pyridyl)-l-methyl-indazole (4.0 g, 7.99 mmol), tert-butyl 4-aminopiperidine-l -carboxylate (1.92 g, 9.59 mmol), XPhos-Pd-G3 (1.35 g, 1.6 mmol)and CS2CO3 (5.2 g, 15.99 mmol) inl,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 EtOAc (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)- l-methyl-indazol-6-yl]amino]piperidine-l-carboxylate (2.81 g, 4.53 mmol, 57% yield)as a solid. MS (ESI) [M+H]+: 620.4; 1H NMR (500 MHz, CDCI3) 8 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).

[0224] Step i-2.4: Synthesis of tert-butyl 4-[[3-(2,6-dioxo-3-piperidyl)-l-methyl-indazol- 6-yl]amino]piperidine-l-carboxylate. A mixture of tert-butyl 4-[[3-(2,6-dibenzyloxy-3- pyridyl)-l-methyl-indazol-6-yl]amino]piperidine-l -carboxylate (600 mg, 0.970 mmol) and Pearlman's Catalyst (167 mg, 0.240 mmol) in THF (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 MeOH:MeCN (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)-l-methyl-indazol-6- yl]amino]piperidine-l-carboxylate (495 mg, 0.9496 mmol, 98.085% yield) as a solid. MS (ESI) [M+H]+: 442.4; *HNMR (400 MHz, DMSO-d6) 5 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).

[0225] Step i-2.5: Synthesis of 3-[l-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)-l- methyl-indazol-6-yl]amino]piperidine-l -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]+. 'H NMR (400 MHz, DMSO-d6) 5 ppm 10.85 (s, 1 H), 9.01 (br d, J=2.45 Hz, 1 H), 8.76 - 8.95 (m, 1H), 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, 3 H), 1.72 (br s, 2 H).Intermediate i-3.

[0226] Step i-3.1: Synthesis of 6-bromo-3-iodo-l-methyl-indazole. To a solution of 6- bromo-l-methyl-indazole (8.00 g, 37.9 mmol) in DMF (100 mL) was added NIS (25.58 g, 113.7 mmol). The reaction mixture was heated to 150 °C for on 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+H]+336.90.

[0227] Step i-3.2: Synthesis of 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-l-methyl- indazole. To a solution of 6-bromo-3-iodo-l-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, 17.8 mmol) and [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(ii) (0.43 g, 0.590 mmol) under N2, then the mixture was stirred at 80 °C for 17 hrs under N2. The reaction was then cooled to room temperature and filtered. The filtrate was extracted with ethyl acetate (3x 40 mL), washed with brine (2x 40 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude material was purified by column chromatography (silica, gradient: 0-30% ethyl acetate in petroleum ether) to afford the title compound (2.1 g, 4.20 mmol, 71% yield) as a pale yellow solid. MS (ES) [M+H]+500.3; 'H NMR (400 MHz, DMSO-d6) 5 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).

[0228] Step i-3.3: Synthesis of tert-Butyl (3R,4R)-4-[[3-(2,6-dibenzyloxy-3-pyridyl)-l- methyl-indazol-6-yl]amino]-3-methyl-piperidine-l-carboxylate. A mixture of 6-bromo-3- (2,6-dibenzyloxy-3-pyridyl)-l-methyl-indazole (1.92 g, 3.84 mmol), tert-butyl (3R,4R)-4- amino-3-methyl-piperidine-l -carboxylate (685 mg, 3.20 mmol), 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 EtOAc (4 x 30 mL). Thefiltrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel using a gradient of 0-40% EtOAc in hexanes to afford title compound (1.37 g, 68%) as a solid. MS (ESI) [M+H]+634.1; 'HNMR (400 MHz, DMSO-d6) 5 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).

[0229] Step i-3.4: Synthesis of tert-Butyl (3R,4R)-4-[[3-(2,6-dioxo-3-piperidyl)-l- methyl-indazol-6-yl]amino]-3-methyl-piperidine-l-carboxylate. A mixture of tert-butyl (3R,4R)-4-[[3-(2,6-dibenzyloxy-3-pyridyl)-l-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; 'HNMR (400 MHz, DMSO-d6) 5 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).

[0230] Step i-3.5: Synthesis of 3-(l-methyl-6-(((3R,4R)-3-methylpiperidin-4-yl)amino)- lH-indazol-3-yl)piperidine-2, 6-dione hydrochloride. To a solution of tert-butyl (3R,4R)-4- [[3-(2,6-dioxo-3-piperidyl)-l-methyl-indazol-6-yl]amino]-3-methyl-piperidine-l-carboxylate (8.0 g, 17.6 mmol) in DCM (35 mL) was added 4M HC1 in dioxane (35 mL) at 25 °C. After addition, the reaction mixture was stirred at 25 °C for 16 hrs. The reaction mixture was filtered to offer the title compound (8.0 g, 100% yield) as an off-white solid. MS (ESI) [M+H]+ 356.2. 400 MHz MeOD 5: 8.04 (s, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.11 (d, J = 8.8 Hz, 1H), 4.59-4.55 (m, 1H), 4.11 (s, 3H), 3.75-7.71 (m, 1H), 3.49-3.46 (m,2 H), 3.20-3.15 (m, 1H), 3.03 (s, 2H), 2.93-2.89 (m, 1H), 2.83-2.81 (m, 2H), 2.52-2.48 (m, 1H), 2.40-2.35 (m, 1H), 2.30-2.26 (m, 1H), 2.20-2.15 (m, 1H), 2.02 (s, 1H), 1.80-1.75 (m, 1H), 1.24-1.22 (m, 3H).Example 15-(((l-((l-(5-chloro-4-((l-methyl-2-oxoindolin-5-yl)amino)pyrimidin-2-yl)piperi din-4- yl)methyl)piperidin-4-yl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-l,3-dione

[0231] Step 1.1 : Synthesis of 2-(2, 6-dioxopiperidin-3-yl)-5-((piperidin-4- ylmethyl)amino)isoindoline-l, 3-dione hydrochloride. To a solution of 5-amino-2-(2,6- dioxopiperidin-3-yl)isoindoline-l, 3-dione (546 mg, 2.00 mmol), tert-butyl 4-formylpiperidine- 1-carboxylate (853 mg, 4.00 mmol) in DMSO (10 mL) and 1,4-dioxane (10 mL) was added decaborane (14) (244 mg, 2.000 mmol). The reaction mixture was stirred at 25 °C for 15 h. The mixture was filtered and purified on reverse-phase HPLC (10 to 100 % acetonitrile in water with 0.1% formic acid additive) to afford the title compound (550 mg, 59%); LCMS m / z 371.2 [M+H]+; 'H NMR (500 MHz, DMSO-d6) 5 ppm 6.79 (br d, J=8.44 Hz, 1 H), 6.23 (s, 1 H), 6.10 (br d, J=8.44 Hz, 1 H), 4.26 (br dd, J=12.29, 4.83 Hz, 1 H), 2.85 - 2.89 (m, 2 H), 2.64 (br d, J=12.47 Hz, 1 H), 2.55 - 2.59 (m, 1 H), 2.42 (br d, J=6.36 Hz, 2 H), 2.21 (br t, J=12.47 Hz, 2 H), 2.00 - 2.12 (m, 1 H), 1.85 - 1.99 (m, 2 H), 1.16 - 1.34 (m, 4 H), 0.62 - 0.74 (m, 2H).

[0232] Step 1.2: Synthesis of tert-butyl 4-((4-(((2-(2,6-dioxopiperidin-3-yl)-l,3- dioxoisoindolin-5-yl)amino)methyl)piperidin-l-yl)methyl)piperidine-l-carboxylate. To a solution of 2-(2,6-dioxopiperidin-3-yl)-5-((piperidin-4-ylmethyl)amino)isoindoline-l, 3-dione hydrochloride (203 mg, 0.5 mmol), tert-butyl 4-formylpiperidine-l -carboxylate (213 mg, 1.0 mmol), and DIPEA (78 mg, 0.6 mmol) in DMSO (2mL) and DCM (1 mL) was added sodium triacetoxyborohydride (212 mg, 1.0 mmol) at room temperature for 1 hr. The crude material was purified on reverse-phase HPLC (10 to 100 % acetonitrile in water with 0.1% formic acid additive) to afford the title compound (226 mg, 79% yield); LCMS m / z 568.2 [M+H]+;1H NMR (500 MHz, DMSO-d6) 5 ppm 11.05 (s, 1 H), 8.16 (s, 1 H), 7.55 (d, J=8.44 Hz, 1 H), 7.16 (t, J=5.56 Hz, 1 H), 6.96 (s, 1 H), 6.87 (dd, J=8.38, 1.90 Hz, 1 H), 5.02 (dd, J=12.90, 5.32 Hz, 1 H), 3.90 (br d, J=12.10 Hz, 2 H), 3.32 (br s, 1 H), 3.06 (br t, J=6.05 Hz, 2 H), 2.78 - 2.95 (m, 3 H), 2.54 - 2.76 (m, 3 H), 2.12 (br d, J=6.60 Hz, 2 H), 1.94 - 2.04 (m, 1 H), 1.86 (br t, J=10.64 Hz, 2 H), 1.59 - 1.77 (m, 5 H), 1.48 - 1.59 (m, 1 H), 1.38 (s, 9 H), 1.14 - 1.30 (m, 2 H), 0.83 - 1.00 (m, 2 H).

[0233] Step 1.3: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-(((l -(piperidin-4- ylmethyl)piperidin-4-yl)methyl)amino)isoindoline-l, 3-dione hydrochloride. The title compound was synthesized according to General Procedure 4 using tert-butyl 4-((4-(((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-5-yl)amino)methyl)piperidin-l-yl)methyl)piperidine-l- carboxylate as the starting material.

[0234] Step 1.4: Synthesis of 5-(((l-((l-(5-chloro-4-((l-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)amino)-2-(2,6- dioxopiperi din-3 -yl)isoindoline- 1 ,3 -di one

[0235] The title compound was synthesized according to General Procedure 6 using 5- ((5-chloro-2-fluoropyrimidin-4-yl)amino)-l-methylindolin-2-one (8.7 mg, 0.030 mmol) and 2- (2,6-dioxopiperidin-3-yl)-5-(((l-(piperidin-4-ylmethyl)piperidin-4-yl)methyl)amino)isoindoline- 1,3-dione hydrochloride (15 mg, 0.030 mmol) as the starting materials. The crude material was purified on reverse-phase HPLC (10 to 100 % acetonitrile in water with 0.1% TFA additive) to afford the title compound (3.5 mg, 16%); LCMS C38H42CIN9O5 requires 739.3, found 740.2 [M+H]+; 'HNMR (500 MHz, DMSO-d6) 5 ppm 11.06 (s, 1 H), 8.61 - 8.86 (m, 2 H), 8.01 (s, 1 H), 7.58 (d, J=8.44 Hz, 1 H), 7.52 (s, 1 H), 7.48 (dd, J=8.31, 1.96 Hz, 1 H), 7.17 - 7.30 (m, 1 H), 6.98 - 7.04 (m, 1 H), 6.88 - 6.96 (m, 2 H), 4.98 - 5.08 (m, 1 H), 4.40 - 4.48 (m, 2 H), 3.54 (s, 4 H), 3.19 - 3.29 (m, 1 H), 3.14 (br s, 2 H), 2.78 - 2.97 (m, 7 H), 2.52 - 2.63 (m, 2 H), 1.89 - 2.15 (m, 4 H), 1.78 - 1.88 (m, 1 H), 1.73 (br d, J=10.27 Hz, 2 H), 1.38 - 1.55 (m, 2 H), 1.00 - 1.20 (m, 2 H).3-(6-(((3R,4R)-l-(4-([l,2,4]triazolo[l,5-a]pyridin-6-ylamino)-5-chloropyrimidin-2-yl)-3- methylpiperidin-4-yl)amino)-l -methyl- lH-indazol-3-yl)piperidine-2, 6-dione

[0236] Step 2.1 : Synthesis of N-(5-chloro-2-fluoropyrimidin-4-yl)-[l,2,4]triazolo[l,5- a]pyridin-6-amine. A mixture of [l,2,4]triazolo[l,5-a]pyridin-6-amine (111 mg, 0.830 mmol and 5-chl oro-2, 4-difluoropyrimi dine (100 mg, 0.664 mmol) were dissolved in NMP (2 mL) and treated with DIPEA (0.232 mL, 1.33 mmol). The vial was sealed and heated at 65 °C for 16h. The reaction was cooled to rt and treated with water (~10 mL) and stirred until the product crashed out. The solids were filtered, washed with water and dried to give the title compound (150 mg, 85% yield).

[0237] Step 2.2: Synthesis of 3-(6-(((3R,4R)-l-(4-([l,2,4]triazolo[l,5-a]pyridin-6- ylamino)-5-chloropyrimidin-2-yl)-3-methylpiperi din-4-yl)amino)-l -methyl- lH-indazol-3- yl)piperidine-2, 6-dione. The title compound was synthesized according to General Procedure 6using N-(5-chloro-2-fluoropyrimidin-4-yl)-[l,2,4]triazolo[l,5-a]pyridin-6-amine (25 mg, 0.094 mmol) and 3-(l-methyl-6-(((3R,4R)-3-methylpiperidin-4-yl)amino)-lH-indazol-3-yl)piperidine- 2,6-dione HC1 (37 mg, 0.094 mmol) as the starting materials. The crude material was purified on reverse-phase HPLC (10 to 100 % acetonitrile in water with 0.1% TFA additive) to afford the title compound (3.5 mg, 16%); LCMS C29H30CIN11O2 requires 599.2, found 601.2 [M+H]+; 'HNMR (500 MHz, DMSO-d6) 5 ppm 10.82 (s, IH), 9.36 (br s, IH), 9.10 (s, IH), 8.44 (s,lH), 8.14 (s, IH), 7.96 (dd, IH, 7=2.0, 9.5 Hz), 7.84 (d, IH, J=9.5 Hz), 7.31 (d, 1H,7=8.8 Hz), 6.51 (dd, IH, 7=1.6, 8.8 Hz), 6.45 (s, IH), 5.71 (d, IH, 7=8.9 Hz), 4.49 (brs, 2H), 4.18 (dd, IH, 7=5.1, 8.7 Hz), 3.82 (s, 3H), 3.0-3.3 (m, IH), 2.7-2.8 (m, IH), 2.5-2.6 (m, 2H), 2.1-2.3 (m, 4H), 1.6-1.7 (m, IH), 1.1-1.3 (m, IH), 1.01 (d, 3H, 7=6.4 Hz).3-(6-(((3R,4R)-l-(5-chloro-4-((4-methoxyimidazo[l,2-a]quinolin-7-yl)amino)pyrimidin-2-yl)-3- methylpiperidin-4-yl)amino)-l -methyl- lH-indazol-3-yl)piperidine-2, 6-dione

[0238] Step 3.1 : Synthesis of 3-methoxy-6-nitroquinolin-2(lH)-one. To a solution containing 5 -nitroindoline-2, 3-dione (1 g, 5.20 mmol) in DMF (10 mL) was added ethanol (10 mL) followed by slow addition of TMS-diazomethane (7.81 mL, 15.6 mmol) over 10 min. The reaction was stirred for lOh. An additional 0.5 eq. of TMS-diazomethane was added with stirring further for an additional 4h. The reaction was then poured onto water / ice (~50 mL) and stirred for 30 min to give a fine solid that was filtered and washed with water and dried to give the title compound (670 mg, 3.04 mmol, 58.5 % yield), m / z (221, M+H).

[0239] Step 3.2: Synthesis of 2-chl oro-3 -methoxy-6-nitroquinoline. To a solution containing 3-methoxy-6-nitroquinolin-2(lH)-one (1.3 g, 5.90 mmol) in DMF (10 mL) was added POCI3 (2.75 mL, 29.5 mmol) in small portion as to not increase reaction temperature above 30 C. The reaction was stirred for Ih and poured onto ice / water (~50 mL) and stirred for 30 min and the solids were filtered, rinsed and dried to give the title compound (900 mg, 3.77 mmol, 63.9 % yield), m / z (239, M+H).

[0240] Step 3.3: Synthesis of 3-methoxy-6-nitroquinolin-2-amine. To a suspension containing 2-chloro-3-methoxy-6-nitroquinoline (750 mg, 3.14 mmol) in 2-Propanol (10 mL) was added ammonium hydroxide (10 mL, 64.2 mmol). The vessel was sealed and heated at 75 °C for 20h. The reaction was cooled to rt and most of the solvent evaporated under a stream of nitrogenand the solids filtered and rinsed with water and dried to give the title compound (500 mg, 2.281 mmol, 72.6 % yield), m / z (220, M+H).

[0241] Step 3.4: Synthesis of 4-methoxy-7-nitroimidazo[l,2-a]quinoline. To a suspension of 3-methoxy-6-nitroquinolin-2-amine (250 mg, 1.14 mmol) in 2-Propanol (2.5 mL) was added CHLORO ACETALDEHYDE SOLUTION in water (0.358 mL, 2.28 mmol) followed by sodium bicarbonate (383 mg, 4.56 mmol). The vial was sealed and heated at 55 °C for 14h. The reaction was cooled and the solids were filtered and washed with water and drie to give impure title compound (160 mg, 0.658 mmol, 57.7 % yield), m / z (244, M+H). that was used without further purification.

[0242] Step 3.5: Synthesis of 4-methoxyimidazo[l,2-a]quinolin-7-amine. A solution containing 4-methoxy-7-nitroimidazo[l,2-a]quinoline (175 mg, 0.720 mmol) in MeOH:THF (10 mL) was purged with nitrogen gas and pearlman's catalyst (101 mg, 0.072 mmol) was added. The reaction was purged with hydrogen gas and fitted with a balloon containing hydrogen gas and stirred for 12h. The reaction was purged with nitrogen gas and filtered through celite and the pad rinsed with DCM. The filtrate was concentrated to give the title compound (74 mg, 0.347 mmol, 48 % yield), m / z (214, M+H).

[0243] Step 3.6: Synthesis of N-(5-chloro-2-fluoropyrimidin-4-yl)-4- methoxyimidazo[l,2-a]quinolin-7-amine. The title compound was synthesized according to General Procedure 1 using 4-methoxyimidazo[l,2-a]quinolin-7-amine (50 mg, 0.234 mmol) and 5-chloro-2,4-difluoropyrimidine (35 mg, 0.234 mmol) as the starting materials, reacting at 70 °C for 16h. Water was added to the mixture and the title compound was isolated by filtration of the resulting solids (70 mg, 87 % yield).

[0244] Step 3.7: Synthesis of 3-(6-(((3R,4R)-l-(5-chloro-4-((4-methoxyimidazo[l,2- a]quinolin-7-yl)amino)pyrimi din-2 -yl)-3-methylpiperidin-4-yl)amino)-l -m ethyl-lH-indazol-3 - yl)piperidine-2, 6-dione. The title compound was synthesized according to General Procedure 6 using N-(5-chloro-2-fluoropyrimidin-4-yl)-4-methoxyimidazo[l,2-a]quinolin-7-amine (70 mg, 0.204 mmol) and 3-(l-methyl-6-(((3R,4R)-3-methylpiperidin-4-yl)amino)-lH-indazol-3- yl)piperidine-2, 6-dione HC1 (96 mg, 0.244 mmol) as the starting materials. The crude material was purified on reverse-phase HPLC (10 to 100 % acetonitrile in water with 0.1% TFA additive) to afford the title compound (16.5 mg, 12%); LCMS C35H35CIN10O3 requires 678.3, found 680.0 [M+H]+; ‘H NMR (500 MHz, DMSO-d6) 5 ppm 10.82 (s, 1H), 8.98 (s, 1H), 8.58 (s, 1H), 8.1-8.2 (m, 3H), 7.80 (dd, 1H, J=2.3, 9.0 Hz), 7.53 (d, 1H, J=l.l Hz), 7.31 (d, 1H, J=8.8 Hz), 6.89 (s, 1H), 6.51 (dd, 1H, J=1.6, 8.8 Hz), 6.45 (s, 1H), 5.70 (d, 1H, J=8.9 Hz), 4.52 (br d, 1H, J=12.2 Hz), 4.0- 4.2 (m, 2H), 3.93 (s, 3H), 3.81 (s, 3H), 3.17 (d, 1H, J=4.5 Hz), 3.06 (br t, 1H, J=11.7 Hz), 2.7-2.8(m, 1H), 2.5-2.7 (m, 2H), 2.1-2.3 (m, 2H), 1.6-1.7 (m, 1H), 1.1-1.3 (m, 1H), 0.99 (d, 3H, J=6.5 Hz).3 -(5-(((3R,4R)- 1 -(5 -chloro-4-(( 1 -methyl-2-oxoindolin-5-yl)amino)pyrimidin-2-yl)-3 - methylpiperidin-4-yl)amino)-lH-indazol-l-yl)piperidine-2, 6-dione

[0245] Step 4.1: Synthesis of 3-(5-bromo-lH-indazol-l-yl)piperidine-2, 6-dione. To a solution of 5-bromo-lH-indazole (5g, 25.4 mmol) in DMF (80 mL) were added 3- bromopiperidine-2, 6-dione (7.31 g, 38.1 mmol) and sodium hydride (1.52 g, 38.1 mmol) at 0 °C. The mixture was stirred at room temperature over night, then diluted with water (100 mL) and extracted with EtOAc (2x 50 mL). The combined organics were washed with brine, dred over sodium sulfate, and concentratee before purification by silica gel chromatography 0-100% EtOAc in hexanes. The title compound (1.04 g, 13%) elutes first followed by the undesired regioisomer.

[0246] Step 4.2: Synthesis of tert-butyl (3R,4R)-4-((l-(2,6-dioxopiperidin-3-yl)-lH- indazol-5-yl)amino)-3-methylpiperidine-l-carboxylate. A mixture of 3-(5-bromo-lH-indazol-l- yl)piperidine-2, 6-dione (300 mg, 0.974 mmol), tert-butyl (3R,4R)-4-amino-3-methylpiperidine- 1-carboxylate (417 mg, 1.95 mmol), 3A molecular sieves (lx by wt), RuPhos Pd G2 (151 mg, 0.195 mmol), LiHMDS (5.84 mL, 5.84 mmol) in Toluene (5mL)) was stirred at 80 °C for 2 hrs under N2 atmosphere. On completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo. This was purified via reverse phase prep HPLC with a gradient of 0-100% MeCN in water. Fractions containing the desired product were combined and concentrated to give the title compound (114 mg, 26%).

[0247] Step 4.3: Synthesis of 3-(5-(((3R,4R)-3-methylpiperidin-4-yl)amino)-lH- indazol-l-yl)piperidine-2, 6-dione HC1. The title compound was synthesized according to General Procedure 5 using tert-butyl (3R,4R)-4-((l-(2,6-dioxopiperidin-3-yl)-lH-indazol-5- yl)amino)-3 -methylpiperidine- 1 -carboxylate (116 mg, 0.263 mmol) as the starting material.

[0248] Step 4.4: Synthesis of 3-(5-(((3R,4R)-l-(5-chloro-4-((l-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-lH-indazol-l-yl)piperidine-2, 6-dione. The title compound was synthesized according to General Procedure 6 using 5-((5-chloro-2- fluoropyrimidin-4-yl)amino)-l-methylindolin-2-one (70 mg, 0.238 mmol) and 3-(5-(((3R,4R)-3-methylpiperidin-4-yl)amino)-lH-indazol-l-yl)piperidine-2, 6-dione, HC1 (90 mg, 0.238 mmol) as the starting materials. The crude material was purified on reverse-phase HPLC (10 to 100 % acetonitrile in water with 10 mM ammonium acetate additive) to afford the title compound (25.7 mg, 17%); LCMS C31H32CIN9O3 requires 613.2, found 614.7 [M+H]+; 'H NMR (500 MHz, DMSO-d6) 5 ppm 8.65 (s, 1 H) 8.02 (s, 1 H) 7.79 (s, 1 H) 7.44 - 7.67 (m, 2 H) 7.33 (d, 7=9.06 Hz, 1 H) 6.90 - 6.98 (m, 1 H) 6.87 (br d, 7=8.94 Hz, 1 H) 6.74 (s, 1 H) 5.67 (dd, 7=11.74, 4.95 Hz, 1 H) 5.15 (br d, 7=8.82 Hz, 1 H) 4.45 (br d, 7=11.09 Hz, 2 H) 3.54 (s, 3 H) 3.14 - 3.25 (m, 2 H) 3.11 (s, 3 H) 3.01 (br t, 7=11.80 Hz, 1 H) 2.75 - 2.90 (m, 1 H) 2.63 - 2.75 (m, 3 H) 2.14 - 2.37 (m, 1 H) 2.03 - 2.11 (m, 2 H) 1.87 (s, 2 H) 1.53 - 1.67 (m, 1 H) 1.04 - 1.32 (m, 2 H) 1.00 (br d, 7=6.20 Hz, 3 H).2-((3R,4R)-4-((l-(2,6-dioxopiperidin-3-yl)-lH-indazol-5-yl)amino)-3-methylpiperidin-l-yl)-4- ((l-methyl-2-oxoindolin-5-yl)amino)pyrimidine-5-carbonitrile

[0249] Step 5.1 : Synthesis of 2-Chloro-4-[(l-methyl-2-oxo-indolin-5- yl)amino]pyrimidine-5-carbonitrile. The title compound was synthesize according to General Procedure 1 using 2,4-dichloropyrimidine-5-carbonitrile as the starting material.

[0250] Step 5.2: Synthesis of 2-((3R,4R)-4-((l-(2,6-dioxopiperidin-3-yl)-lH-indazol-5- yl)amino)-3-methylpiperidin-l-yl)-4-((l-methyl-2-oxoindolin-5-yl)amino)pyrimidine-5- carbonitrile. The title compound was synthesized according to General Procedure 6 using 2- chloro-4-((l-methyl-2-oxoindolin-5-yl)amino)pyrimidine-5-carbonitrile (10.5 mg, 0.035 mmol) and 3-(5-(((3R,4R)-3-methylpiperidin-4-yl)amino)-lH-indazol-l-yl)piperidine-2, 6-dione, HC1 (12 mg, 0.035 mmol) as the starting materials. The crude material was purified on reverse-phase HPLC (10 to 100 % acetonitrile in water with 10 mM ammonium acetate additive) to afford the title compound (25.7 mg, 17%); LCMS C32H32N10O3 requires 604.3, found 605.2 [M+H]+; 'H NMR (500 MHz, CDCI3) 8 ppm 8.30 (s, 1H), 7.98 (s, 1H), 7.89 (s, 1H), 7.41 (br s, 1H), 7.2-7.3 (m, 2H), 6.8-6.9 (m, 2H), 5.08 (t, 1H, J=2.7 Hz), 3.8-3.8 (m, 2H), 3.7-3.8 (m, 3H), 3.6-3.7 (m, 2H), 3.5-3.6 (m, 2H), 3.0-3.2 (m, 2H), 2.8-2.9 (m, 2H), 2.48 (br dd, 1H, J=3.5, 12.9 Hz), 1.2-1.5 (m, 3H), 1.13 (br s, 3H).3-(5-((l-(5-chloro-4-((l-methyl-2-oxoindolin-5-yl)amino)pyrimidin-2-yl)piperidin-4-yl)amino)- 3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2, 6-dione

[0251] Step 6.1: Synthesis of tert-butyl 4-[[l-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo- benzimidazol-5-yl]amino]piperidine-l-carboxylate. To a solution of tert-butyl 4-Oxo-l- piperidinecarboxylate (160 mg, 0.800 mmol), 3-(5-amino-3-methyl-2-oxo-benzimidazol-l- yl)piperidine-2,6-dione;hydrochloride (250 mg, 0.800 mmol), Decaborane(14) (45.11 mg, 0.4000 mmol) in 1,4-Dioxane (2 mL) and DMSO (2 mL) was added N,N-Diisopropylethylamine (104 mg, 0.800 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then filtered and purified using reverse-phase semi-preparative HPLC to afford the title compound (185 mg, 50 % yield).

[0252] Step 6.2: Synthesis of 3-[3-methyl-2-oxo-5-(4-piperidylamino)benzimidazol-l- yl]piperidine-2, 6-dione hydrochloride. The title compound was synthesized according to General Procedure 5 using tert-butyl 4-[[l-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo- benzimidazol-5-yl]amino]piperidine-l -carboxylate (180 mg, 0.39 mmol) as the starting material.

[0253] Step 6.3: Synthesis of 3-(5-((l-(5-chloro-4-((l-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)piperidin-4-yl)amino)-3-methyl-2-oxo-2,3-dihydro-lH- benzo[d]imidazol-l-yl)piperidine-2, 6-dione. The title compound was synthesized according to General Procedure 6 using 5-((5-chloro-2-fluoropyrimidin-4-yl)amino)-l-methylindolin-2-one (15 mg, 0.051 mmol) and 3-[3-methyl-2-oxo-5-(4-piperidylamino)benzimidazol-l-yl]piperidine- 2, 6-dione hydrochloride (20 mg, 0.051 mmol) as the starting materials. The crude material was purified on reverse-phase HPLC (10 to 100 % acetonitrile in water with 0.1% formic acid additive) to afford the title compound (17 mg, 52%); LCMS C31H32CIN9O4 requires 629.2, found 630.2 [M+H]+; 'HNMR (500 MHz, DMSO-d6) 5 ppm 11.04 (s, 1 H), 8.64 (s, 1 H), 8.01 (s, 1 H), 7.47 - 7.56 (m, 2 H), 6.90 - 6.98 (m, 1 H), 6.80 (d, J=8.44 Hz, 1 H), 6.46 (d, J=1.96 Hz, 1 H), 6.32 (dd, J=8.50, 2.02 Hz, 1 H), 5.07 - 5.29 (m, 2 H), 4.35 (br d, J=12.84 Hz, 2 H), 3.54 (s, 2 H), 3.26 (s, 3 H), 3.10 (s, 3 H), 3.02 - 3.08 (m, 2 H), 2.83 - 2.94 (m, 1 H), 2.72 - 2.73 (m, 1 H), 2.55 - 2.72 (m, 1 H), 1.87 - 2.03 (m, 3 H), 1.20 - 1.32 (m, 2 H).3-(6-((l-(5-chloro-4-((l-methyl-2-oxo-l,2,3,4-tetrahydroquinolin-6-yl)amino)pyrimidin-2- yl)piperidin-4-yl)amino)-l -methyl- lH-indazol-3-yl)piperidine-2, 6-dione

[0254] Step 7.1: Synthesis of 6-[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]-l-methyl-3,4- dihydroquinolin-2-one. The title compound was synthesized according to General Procedure 1 using 6-Amino-3,4-dihydro-l-methyl-2(lH)-quinolinone as the starting material.

[0255] Step 7.2: Synthesis of 3-(6-((l-(5-chloro-4-((l-methyl-2-oxo-l,2,3,4- tetrahydroquinolin-6-yl)amino)pyrimidin-2-yl)piperidin-4-yl)amino)-l -methyl- lH-indazol-3- yl)piperidine-2, 6-dione. The title compound was synthesized according to General Procedure 6 using 6-[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]-l-methyl-3,4-dihydroquinolin-2-one (30 mg, 0.099 mmol) and 3 -[l-methyl-6-(4-piperidylamino)indazol-3-yl]piperidine-2, 6-dione hydrochloride (40 mg, 0.118 mmol) as the starting materials. The crude material was purified on reverse-phase HPLC (10 to 100 % acetonitrile in water with 0.1% formic acid additive) to afford the title compound (40 mg, 63%); LCMS C32H34CIN9O3 requires 627.2, found 628.0 [M+H]+; 'HNMR (400 MHz, DMSO-d6) 5 ppm 10.76 (s, 1H), 8.92 (br s, 1H), 8.03 (s, 1H), 7.5-7.5 (m, 1H), 7.47 (d, 1H, J=8.8 Hz), 7.30 (d, 1H, J=8.4 Hz), 7.00 (d, 1H, J=8.7 Hz), 6.49 (br d, 2H, J=9.0 Hz), 4.2-4.3 (m, 3H), 4.1-4.2 (m, 2H), 3.77 (s, 4H), 3.61 (br s, 1H), 3.1-3.2 (m, 5H), 2.76 (t, 2H, J=7.4 Hz), 2.5-2.6 (m, 2H), 2.5-2.5 (m, 1H), 2.1-2.2 (m, 1H), 1.9-2.1 (m, 4H), 1.3-1.4 (m, 2H).3-(6-(((R)-l-(5-chloro-4-((l-methyl-2-oxoindolin-5-yl)amino)pyrimidin-2-yl)piperidin-3- yl)oxy)-l-methyl-lH-indazol-3-yl)piperidine-2, 6-dione

[0256] Step 8.1: Synthesis of tert-butyl-(3R)-3-[3-(2,6-dibenzyloxy-3-pyridyl)-l-methyl- indazol-6-yl]oxypiperidine-l -carboxylate. 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-l-methyl-indazole (250.2 mg, 0.500 mmol), Quinuclidine (61.15 mg, 0.550 mmol), 4,4'-DI-TERT- BUTYL-2,2'-DIPYRIDYL (6.71 mg, 0.020 mmol), Nickel(II) chloride ethylene glycol dimethyl ether complex (5.49 mg, 0.020 mmol), and 200 uL of acetonitrile were added to a 2 dram vial equipped with a stir bar. In a separate 1 dram vial, (4,4'-Di-tert-butyl-2,2'-bipyridine)bis[3,5- difluoro-2-[5-trifluoromethyl-2-pyridinyl-KN)phenyl-KC]iridium(III) hexafluorophosphate (5.61 mg, 0.005 mmol), and 200 uL of MeCN were added. The solution was sonicated and added to the reaction vial. (R)-l-BOC-3 -HYDROXYPIPERIDINE (301 mg, 1.50 mmol) was added and argon was bubbled through the reaction for 10 minutes. The reaction vial was sealed with parafilm and irradiated with blue lights for 4 days hours without fan cooling (reaction temp ~55 °C). The reaction was stirred at a rate of 1000 RPMs. The reaction stirred for 3 days at RT. LCMS indicated significant product formation. The reaction was concentrated and loaded onto a SNAP 25G cartridge and purified with 0-30% EA / / hexanes to give the title compound.

[0257] Step 8.2: Synthesis of 3-[l-methyl-6-[[(3R)-3-piperidyl]oxy]indazol-3- yl]piperidine-2,6-dione;hydrochloride. The title compound was synthesized according to General Procedures 4 and 5 using tert-butyl-(3R)-3-[3-(2,6-dibenzyloxy-3-pyridyl)-l-methyl- indazol-6-yl]oxypiperidine-l-carboxylate as the starting material.

[0258] Step 8.3: Synthesis of 3-(6-(((R)-l-(5-chloro-4-((l-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)piperi din-3 -yl)oxy)-l -methyl- lH-indazol-3-yl)piperidine-2, 6-dione. The title compound was synthesized according to General Procedure 6 using 5-[(5-chloro-2- fluoro-pyrimidin-4-yl)amino]-l-methyl-indolin-2-one (20 mg, 0.068 mmol) and 3-[l-methyl-6- [[rac-(3S)-3-piperidyl]oxy]indazol-3-yl]piperidine-2,6-dione;hydrochloride (31 mg, 0.081 mmol) as the starting materials. The crude material was purified on reverse-phase HPLC (10 to 100 % acetonitrile in water with 0.1% formic acid additive) to afford the title compound (21 mg, 47%); LCMS C31H31CIN8O4 requires 614.2, found 615.0 [M+H]+; *HNMR (400 MHz, DMSO- d6) 5 ppm 10.7-11.0 (m, 1H), 8.5-8.8 (m, 1H), 8.02 (d, 1H, J=0.9 Hz), 7.3-7.6 (m, 3H), 7.0-7.2 (m, 1H), 6.6-6.8 (m, 1H), 4.4-4.6 (m, 1H), 4.2-4.4 (m, 2H), 3.9-4.1 (m, 1H), 3.7-3.9 (m, 3H), 3.3-3.4 (m, 2H), 3.32 (s, 5H), 2.9-3.0 (m, 2H), 2.6-2.7 (m, 2H), 2.3-2.4 (m, 1H), 2.1-2.2 (m, 2H), 1.7-1.9 (m, 2H), 1.5-1.6 (m, 1H).3-(6-((l-(5-chloro-4-((l-methyl-2-oxo-4-((2-(pyrimidin-2-yl)propan-2-yl)amino)-l,2- dihydroquinazolin-6-yl)amino)pyrimidin-2-yl)piperidin-4-yl)amino)-l-methyl-lH-indazol-3- yl)piperidine-2, 6-dione

[0259] Step 9.1: Synthesis of 6-nitro-lH-quinazoline-2, 4-dione. To a solution of 1H- quinazoline-2, 4-dione (20.0 g, 123 mmol) in concentrated sulfuric acid (330.0 mL, 6.19 mol) at 0 °C, was added concentrated nitric acid (9.5 mL, 159 mmol). The reaction mixture was slowly warmed to rt, stirred for 2 h and then poured into ice cold water (500 mL). After stirring for 30 min, the resulting precipitate was filtered, then dried in a vacuum oven at 55 °C for 12 h to afford the title compound (23.1 g, 90%) as a solid.

[0260] Step 9.2: Synthesis of 2,4-dichloro-6-nitro-quinazoline. A solution of 6-nitro- lH-quinazoline-2, 4-dione (10.0 g, 48.3 mmol) in POCI3 (60.0 mL, 642.0 mmol) was refluxed for 72 h and then cooled to rt. The mixture was poured into ice cold water, and after stirring for 1 h, the resulting precipitate was filtered, dried in a vacuum oven at 55 °C for 12 h to afford the title compound (9.77 g, 83%) as a solid. *H NMR (500 MHz, DMSO) 5 8.74 (d, J = 2.4 Hz, 1H), 8.56 (dd, J = 8.9, 2.7 Hz, 1H), 7.81 (d, J = 9.0 Hz, 1H).

[0261] Step 9.3: Synthesis of 2-chloro-N-(l-methyl-l-pyrimidin-2-yl-ethyl)-6-nitro- quinazolin-4-amine. To a solution of 2,4-dichloro-6-nitro-quinazoline (4.0 g, 16.4 mmol) in DMF (35.0 mL) at rt, were sequentially added 2-pyrimidin-2-ylpropan-2-amine (2.47 g, 18.0 mmol) and TEA (9.6 mL, 68.8 mmol). The reaction mixture was heated to 80 °C for 2 h and then cooled to rt. The volatiles were evaporated under reduced pressure and water was added. The resulting precipitate was collected by filtration, then dried under vacuum, to afford the title compound (5.48 g, 97%) as a solid. *H NMR (500 MHz, DMSO) 5 9.72 (d, J = 2.3 Hz, 1H), 9.48 (s, 1H), 8.72 (d, J = 4.8 Hz, 2H), 8.51 (d, J = 9.0 Hz, 1H), 7.73 (d, J = 9.3 Hz, 1H), 7.32 (t, J = 4.9 Hz, 1H), 1.85 (s, 6H), DMF and TEA present. MS (ESI) [M+H]+345.2.

[0262] Step 9.4: Synthesis of 4-[(l-methyl-l-pyrimidin-2-yl-ethyl)amino]-6-nitro-lH- quinazolin-2-one. A solution of 2-chloro-N-(l -methyl- l-pyrimidin-2-yl-ethyl)-6-nitro- quinazolin-4-amine (5.50 g, 16.0 mmol) in acetic acid (143 mL) was heated to 70 °C for 2 h and then cooled to rt. The volatiles were evaporated under reduced pressure and then saturated aqueous NaHCOs (100 mL) was slowly added. After stirring for 10 min, the resulting precipitate was collected by filtration, washed with diethyl ether (10.0 mL) and dried under vacuum to afford the title compound (3.93 g, 76 %) as a solid. 'H NMR (400 MHz, DMSO) 5 11.14 (bs, 1H), 9.42 (d, J = 2.5 Hz, 1H), 8.74 (bs, 1H), 8.70 (d, J = 4.8 Hz, 2H), 8.37 (dd, J = 9.1, 2.3 Hz, 1H), 7.28 (t, J = 4.9 Hz, 1H), 7.20 (d, J = 9.1 Hz, 1H), 1.81 (s, 6H). MS (ESI) [M+H]+327.2.

[0263] Step 9.5: Synthesis of l-methyl-4-[(l-methyl-l-pyrimidin-2-yl-ethyl)amino]-6-nitro-quinazolin-2-one. To a solution of 4-[(l-methyl-l-pyrimidin-2-yl-ethyl)amino]-6-nitro- lH-quinazolin-2-one (2.0 g, 6.13 mmol) in DMF (48.0 mL) was added NaH (60% dispersion in mineral oil, 235.0 mg, 6.13 mmol). After stirring for 10 min, iodomethane (0.38 mL, 6.13 mmol) was added and the reaction mixture was stirred at rt for 1 h. Water (500 mL) and ethyl acetate (500 mL) were added and, the layers were separated. The organic layer was washed with brine (500.0 mL), dried (ISfeSCL), filtered and concentrated under reduced pressure to afford the title compound (1.98 g, 95 %) as a solid, which was used in the next step without further purification. 'H NMR (400 MHz, DMSO) 5 9.44 (d, J = 2.5 Hz, 1H), 8.81 (s, 1H), 8.70 (d, J = 4.8 Hz, 2H), 8.46 (dd, J = 9.4, 2.5 Hz, 1H), 7.48 (d, J = 9.4 Hz, 1H), 7.28 (t, J = 4.8 Hz, 1H), 3.40 (s, 3H), 1.81 (s, 6H).

[0264] Step 9.6: Synthesis of 6-amino-l-methyl-4-[(l-methyl-l-pyrimidin-2-yl- ethyl)amino]quinazolin-2-one. A mixture of l-methyl-4-[(l -methyl- l-pyrimidin-2-yl- ethyl)amino]-6-nitro-quinazolin-2-one (1.98 g, 5.82 mmol) and 10% Pd / C (619.0 mg, 5.82 mmol) in a mixture of DMF (33.0 mL) and isopropanol (66.0 mL) was hydrogenated under hydrogen atmosphere at rt for 7 h. The mixture was filtered through Celite and washed with acetonitrile. The filtrate was concentrated under reduced pressure to afford title compound (1.40 g, 78 %) as a solid, which was used in the next step without further purification. MS (ESI) [M+H]+311.3.

[0265] Step 9.7: Synthesis of 6-[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]-l-methyl-4- [(l-methyl-l-pyrimidin-2-yl-ethyl)amino]quinazolin-2-one. To a solution of 6-amino-l-methyl- 4-[(l-methyl-l-pyrimidin-2-yl-ethyl)amino]quinazolin-2-one (1.40 g, 4.51 mmol) in DMF (55.0 mL) cooled to -15 °C were sequentially added 5-chloro-2,4-difluoro-pyrimidine (0.52 mL, 5.41 mmol) and DIPEA (3.14 mL, 18.0 mmol). The reaction mixture was slowly warmed to rt and stirred for 3 h. The volatiles were evaporated under reduced pressure and water (20.0 mL) was added. The resulting precipitate was collected by filtration and purified by column chromatography on silica gel using a gradient of 0-10% MeOH in DCM to afford the title compound (704.0 mg, 35 %) as a solid. 'H NMR (500 MHz, DMSO) 5 9.81 (s, 1H), 8.73 (d, J = 4.8 Hz, 2H), 8.42 - 8.37 (m, 2H), 8.18 (s, 1H), 7.77 (dd, J = 9.0, 2.2 Hz, 1H), 7.37 (d, J = 9.1 Hz, 1H), 7.31 (t, J = 4.8 Hz, 1H), 3.38 (s, 3H), 1.81 (s, 6H). MS (ESI) [M+H]+441.2.

[0266] Step 9.8: Synthesis of 3-(6-((l-(5-chloro-4-((l-methyl-2-oxo-4-((2-(pyrimidin-2- yl)propan-2-yl)amino)-l,2-dihydroquinazolin-6-yl)amino)pyrimidin-2-yl)piperidin-4-yl)amino)- l-methyl-lH-indazol-3-yl)piperidine-2, 6-dione. The title compound was synthesized according to General Procedure 6 using 6-[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]-l-methyl-4-[(l-methyl- l-pyrimidin-2-yl-ethyl)amino]quinazolin-2-one (20 mg, 0.045 mmol) and 3-[l-methyl-6-(4- piperidylamino)indazol-3-yl]piperidine-2, 6-dione hydrochloride (17 mg, 0.050 mmol) as thestarting materials. The crude material was purified on reverse-phase HPLC (10 to 100 % acetonitrile in water with 0.1% formic acid additive) to afford the title compound (10 mg, 28%); LCMS C38H40CIN13O3 requires 761.3, found 762.2 [M+H]+; 'H NMR (400 MHz, DMSO-d6) 5 ppm 10.84 (s, 1 H), 8.93 (s, 1 H), 8.58 (d, J=4.77 Hz, 3 H), 8.05 - 8.15 (m, 2 H), 7.78 (dd, J=9.05, 2.20 Hz, 1 H), 7.30 (dd, J=8.99, 4.34 Hz, 2 H), 7.12 (t, J=4.89 Hz, 1 H), 6.50 (dd, J=8.74, 1.53 Hz, 1 H), 6.38 (d, J=1.10 Hz, 1 H), 5.74 (br s, 1 H), 4.39 (br d, J=12.47 Hz, 2 H), 4.19 (dd, J=8.68, 5.26 Hz, 1 H), 3.75 (s, 3 H), 3.56 - 3.58 (m, 1 H), 3.34 (s, 3 H), 3.13 (br t, J=11.13 Hz, 2 H), 2.58 - 2.65 (m, 2 H), 2.21 - 2.32 (m, 1 H), 2.11 - 2.21 (m, 1 H), 2.02 (br d, J=10.27 Hz, 2 H), 1.73 (s, 6 H), 1.27 - 1.40 (m, 2 H).3-(6-(((3S,4S)-l-(5-chloro-4-((l-methyl-2-oxo-4-((2-(pyrimidin-2-yl)propan-2-yl)amino)-l,2- dihydroquinazolin-6-yl)amino)pyrimidin-2-yl)-3-fluoropiperidin-4-yl)amino)-l -methyl- 1H- indazol-3-yl)piperidine-2, 6-dione

[0267] Step 10.1 : Synthesis of tert-butyl-(3S,4S)-4-[[3-(2,6-dibenzyloxy-3-pyridyl)-l- methyl-indazol-6-yl]amino]-3-fluoro-piperidine-l -carboxylate. The title compound was synthesized according to General Procedure 2 using 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-l- methyl-indazole (500 mg. 1.0 mmol), tert-butyl-(3S,4S)-4-amino-3-fluoro-piperidine-l- carboxylate (327 mg, 1.5 mmol), XPHOS Pd G3 (84.5 mg, 0.1 mmol), and cesium carbonate (651 mg, 2 mmol) the starting reagents. Crude material was purified on silica gel chromatography (0 to 50 % ethyl acetate in hexanes with 1% methanol additive to give the title compound (566 mg, 88%).

[0268] Step 10.2: Synthesis of 3-(6-(((3S,4S)-l-(5-chloro-4-((l-methyl-2-oxo-4-((2- (pyrimidin-2-yl)propan-2-yl)amino)-l,2-dihydroquinazolin-6-yl)amino)pyrimidin-2-yl)-3- fluoropiperidin-4-yl)amino)-l-methyl-lH-indazol-3-yl)piperidine-2, 6-dione. The title compound was synthesized according to General Procedures 4, 5, and 6 using tert-butyl-(3S,4S)-4-[[3-(2,6- dibenzyloxy-3-pyridyl)-l-methyl-indazol-6-yl]amino]-3-fluoro-piperidine-l-carboxylate as the starting material. The title compound (43 mg, 79% yield) was isolated after reverse phase HPLC purification. LCMS C38H39CIFN13O3 requires 779.3, found 780.0 [M+H]+; *H NMR (400 MHz,DMS0-d6) 5 ppm 10.7-10.9 (m, 1H), 9.0-9.2 (m, 1H), 8.5-8.6 (m, 3H), 8.1-8.2 (m, 2H), 7.7-7.8 (m, 1H), 7.2-7.4 (m, 2H), 7.1-7.2 (m, 1H), 6.5-6.6 (m, 1H), 6.4-6.5 (m, 1H), 4.6-4.6 (m, 1H), 4.5- 4.5 (m, 1H), 4.2-4.4 (m, 2H), 4.2-4.2 (m, 1H), 4.0-4.1 (m, 1H), 3.8-3.9 (m, 1H), 3.8-3.8 (m, 3H),3.6-3.6 (m, 1H), 3.4-3.5 (m, 1H), 3.35 (s, 3H), 2.6-2.6 (m, 2H), 2.2-2.3 (m, 1H), 2.1-2.2 (m, 2H),1.7-1.8 (m, 6H), 1.4-1.5 (m, 1H).l-(5-chloro-4-((l-(3-(methylamino)-3-oxopropyl)-lH-indol-6-yl)amino)pyrimidin-2-yl)-N-(3- (2,6-dioxopiperidin-3-yl)-l-methyl-lH-indazol-6-yl)piperidine-4-carboxamide

[0269] Step 11.1: Synthesis of 3-(6-bromoindol-l-yl)-N-methyl-propanamide. 6- Bromoindole (200. mg, 1.02 mmol) and sodium hydride (61.21 mg, 1.53 mmol) were added to a 2 dram vial equipped with a stir bar. DMF (4.1 mL) was added and the reaction was stirred for 1 hour at RT. 3-chloro-N-methyl-propanamide (136.43 mg, 1.12 mmol) was added and the mixture stirred ON at RT. LCMS indicated significant product formation. The reaction was quenched with water, extracted with ethyl acetate (3x), and the combined organic layers were washed with water (2x) and brine (lx). The organic layer was dried over magnesium sulfate, filtered, concentrated, and purified using silica gel chromatography (SNAP-25G, 20% EA in hexanes) to give the title compound (210 mg, 73% yield).

[0270] Step 11.2: Synthesis of tert-butyl N-[l-[3-(methylamino)-3-oxo-propyl]indol- 6-yl] carbamate. 3-(6-bromoindol-l-yl)-N-methyl-propanamide (279. mg, 0.990 mmol), tert- Butyl carbamate (140 mg, 1.19 mmol), XPHOS (42.58 mg, 0.0900 mmol), Cesium carbonate (485 mg, 1.49 mmol), tris(dibenzylideneacetone)dipalladium (0) (27 mg, 0.030 mmol), and 1,4- Dioxane (3.97 mL) were added to a 2 dram vial and purged with nitrogen. The vial was sealed and stirred at 80 °C overnight. LCMS indicated complete conversion to product. The reaction was diluted with DCM and water, and extracted with DCM (3x). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The residue was purified with a SNAP 25G silica cartridge with 0-100% 10%meoh in EA / hexanes to give the title compound (146 mg, 46 % yield).

[0271] Step 11.3: Synthesis of 3-(6-aminoindol-l-yl)-N-methyl-propanamide. tertbutyl N-[l-[3-(methylamino)-3-oxo-propyl]indol-6-yl]carbamate (100. mg, 0.3200 mmol) wasreacted with 4 M HC1 in dioxane (4 mL). After 1 hour, the reaction was concentrated and carried onto the next step directly.

[0272] Step 11.4: Synthesis of3-[6-[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]indol-l- yl]-N-methyl-propanamide. 3-(6-aminoindol-l-yl)-N-methyl-propanamide hydrochloride (183 mg, 0.720 mmol) and THF (7.2 mL) were added to a vial equipped with a stir bar and cooled to - 40 °C using a dry ice acetonitrile bath. N,N-Diisopropylethylamine (0.14 mL, 0.79 mmol) and 5- chloro-2,4-difluoro-pyrimidine (108 mg, 0.72 mmol) were added and the reaction was allowed to stir ON, slowly warming to RT. The reaction was concentrated and loaded onto a 25G SNAP silica column and purified with a 0-100% gradient of 10%MeOH / EA in hexanes. All fractions containing product were combined and concentrated to give the title compound (51 mg, 20 % yield).

[0273] Step 11.5: Synthesis of l-[5-chloro-4-[[l-[3-(methylamino)-3-oxo-propyl]indol-6- yl]amino]pyrimidin-2-yl]piperidine-4-carboxylic acid. 3-[6-[(5-chloro-2-fluoro-pyrimidin-4- yl)amino]indol-l-yl]-N-methyl-propanamide (75 mg, 0.22 mmol), DIPEA (33 mg, 0.26 mmol), isonipecotic acid (33 mg, 0.26 mmol), and DMSO (0.43 mL) were added to a 2 dram vial equipped with a stir bar. The mixture was heated to 85 °C and stirred for 6 hours. The crude material was purified using reverse phase HPLC to give the title compound (52 mg, 52 % yield).

[0274] Step 11.6: Synthesis of tert-butyl (3-(2,6-bis(benzyloxy)pyridin-3-yl)-l- methyl-lH-indazol-6-yl)carbamate. 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-l-methyl-lH- indazole (160g, 320 mmol) was taken in 1,4-Dioxane (1600 mL) in a 3000ml multineck RBF fitted with reflux condenser under N2 atm with mechanical stirring. Next, tert-butyl carbamate (56.2 g, 480 mmol) was added , followed by K2CO3 (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 filtered through a celite bed, washing with ethyl acetate. The filtrate obtained was evaporated to give crude product which was purified using ISCO in silica gel with PEZEtOAc as eluant to give the title compound (148 g, 275 mmol, 86 % yield) as white solid. MS (ESI) m / z 537.30 [M+H]+. 1H NMR (400 MHz, DMSO- d6) 5 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).

[0275] Step 11.7: Synthesis of tert-butyl (3-(2,6-dioxopiperidin-3-yl)-l-methyl-lH- indazol-6-yl)carbamate. To a flask was added tert-butyl (3-(2,6-bis(benzyloxy)pyridin-3-yl)-l- methyl-lH-indazol-6-yl)carbamate (25 g, 46.6 mmol) and THF (500 mL). This mixture was purged Nitrogen for 5 min and then palladium on carbon (24.79 g, 23.29 mmol) was added and then stirred under H2 atmosphere overnight at 55 °C. After this time, the reaction mixture wasfiltered through celite washing with THF (2L) 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]+; 'HNMR (400 MHz, DMSO-d6) 5 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).

[0276] Step 11.8: Synthesis of 3-(6-amino-l-methyl-lH-indazol-3-yl)piperidine-2,6- dione, HC1 salt, tert-butyl (3-(2,6-dioxopiperidin-3-yl)-l-methyl-lH-indazol-6-yl)carbamate (25 g, 69.8 mmol) was dissolved in 1,4-Dioxane (250 mL) in a 2L RBF under magnetic stirring. HC1 (4M 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]+. 'H NMR (400 MHz, DMSO-d6) 5 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).

[0277] Step 11.9: Synthesis of l-(5-chloro-4-((l-(3-(methylamino)-3-oxopropyl)-lH- indol-6-yl)amino)pyrimidin-2 -yl)-N-(3-(2,6-di oxopiperi din-3 -yl)-l -methyl- lH-indazol-6- yl)piperidine-4-carboxamide. l-[5-chloro-4-[[l-[3-(methylamino)-3-oxo-propyl]indol-6- yl]amino]pyrimidin-2-yl]piperidine-4-carboxylic acid (25 mg, 0.050 mmol), 3-(6-amino-l- methyl-indazol-3-yl)piperidine-2, 6-dione hydrochloride (18 mg, 0.060 mmol), HATU (26 mg, 0.070 mmol), N,N-Diisopropylethylamine (0.02 mL, 0.12 mmol), and DMF (0.51 mL) were added to a 1 dram vial equipped with a stir bar. The reaction was stirred at 55 °C ON. The crude material was purified on reverse phase HPLC to give the title compound (18 mg, 46 % yield); LCMS (ESI) m / z 697.2 [M+H]+. 'H NMR (400 MHz, DMSO-d6) 5 ppm 10.8-10.9 (m, 1H), 10.0-10.2 (m, 1H), 8.5-8.7 (m, 1H), 8.05 (s, 3H), 7.7-7.9 (m, 1H), 7.5-7.6 (m, 1H), 7.4-7.5 (m, 1H), 7.2-7.3 (m, 2H), 7.1-7.2 (m, 1H), 6.3-6.4 (m, 1H), 4.5-4.7 (m, 2H), 4.2-4.4 (m, 3H), 3.90 (s, 3H), 2.9-3.0 (m, 2H), 2.6-2.7 (m, 3H), 2.5-2.6 (m, 2H), 2.3-2.4 (m, 3H), 2.1-2.2 (m, 1H), 1.8-1.9 (m, 2H), 1.5-1.7 (m, 2H).3-(7-((5-chloro-2-(4-((3-(2,6-dioxopiperidin-3-yl)-l-methyl-lH-indazol-6-yl)amino)piperidin-l- yl)pyrimidin-4-yl)amino)-4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][l,4]oxazin-2-yl)-N-methylpropanamide

[0278] Step 12.1: Synthesis of (rac)-5-(benzyloxy)-2-bromo-5-oxopentanoic acid. To a suspension of 2-amino-5-(benzyloxy)-5-oxopentanoic acid (3.0 g, 12.6 mmol), sodium bromide (4.55 g, 44.2 mmol) in water (20 mL) was added aq 48% hydrobromic acid (2.86 mL, 25.3 mmol), the suspension became a clear solution. Reaction was cooled to -10 °C, and a solution of sodium nitrite (1.745 g, 25.3 mmol) in Water (3 mL) was added slowly over 30 min. The reaction was stirred at 0 °C for 2h, and the slowly to RT overnight.

[0279] Then the mixture was cooled to 0°C, cone, sulfuric acid (1.1 mL, 20.64 mmol) was added, and the mixture was extracted with Et2O (2x). The combined organics were washed with brine, dried over MgSCh, and concentrated. The residue was purified by silica column (40 g, EtOAc / hexane=0-50%) to give the title compound (2.45 g, 8.14 mmol, 64.3 % yield) as colorless oil. ‘H NMR (499 MHz, CHLOROFORM-d) 5 7.47 - 7.33 (m, 5H), 5.16 (s, 2H), 4.44 (dd, J=8.5, 5.7 Hz, 1H), 2.69 - 2.56 (m, 2H), 2.52 - 2.42 (m, 1H), 2.40 - 2.29 (m, 1H).

[0280] Step 12.2: Synthesis of benzyl (rac)-4-bromo-5-chloro-5-oxopentanoate. To a solution of (S)-5-(benzyloxy)-2-bromo-5-oxopentanoic acid (2.45 g, 8.14 mmol) in DCM (30 mL) cooled at 0 °C was added oxalyl chloride (1.42 mL, 16.3 mmol) and a couple drops of DMF, the mixture was then stirred at RT for Ih. Concentrated with some toluene, the residue was reevaporated with toluene again. The compound was then used in the next step without further purification.

[0281] Step 12.3: Synthesis of benzyl-3-(7-nitro-3-oxo-3,4-dihydro-2H- benzo[b][l,4]oxazin-2-yl)propanoate. A mixture of 2-amino-5-nitrophenol (1.25 g, 8.14 mmol) and K2CO3 (3.37 g, 24.4 mmol) in NMP (12 mL) was stirred for 30 min, cooled to 0 °C, and a solution of benzyl (rac)-4-bromo-5-chloro-5-oxopentanoate (2.60 g, 8.14 mmol) in NMP (5 mL) was added dropwise, the reaction mixture was stirred at RT for the weekend. The reaction was cooled to 0 °C, water was added, extracted with EtOAc (2x), the combined organics were washed with brine, dried over MgSCh, and concentrated. The residue was purified by silica gel chromatography (80 g, EtOAc / hexane=0-60%) to give benzyl (rac)-3-(7-nitro-3-oxo-3,4-dihydro- 2H-benzo[b][l,4]oxazin-2-yl)propanoate (1.92 g, 5.39 mmol, 66.2 % yield). *H NMR (500 MHz, CDCI3) 8 8.37 (br s, IH), 7.93 (dd, J=8.6, 2.4 Hz, IH), 7.86 (d, .7=2,4 Hz, IH), 7.45 - 7.32 (m, 5H), 6.90 (d, .7=8.6 Hz, IH), 5.17 (s, 2H), 4.75 (dd, .7=8.4, 4.6 Hz, IH), 2.69 (t, J=7.3 Hz, 2H), 2.45 (dtd, .7=14.8, 7.6, 4.6 Hz, IH), 2.36 - 2.22 (m, IH).

[0282] Step 12.4: Synthesis of benzyl (rac)-3-(4-methyl-7-nitro-3-oxo-3,4-dihydro- 2H-benzo[b][l,4]oxazin-2-yl)propanoate. To a solution of benzyl (rac)-3-(7-nitro-3-oxo-3,4- dihydro-2H-benzo[b][l,4]oxazin-2-yl)propanoate (320 mg, 0.898 mmol) in DMF (6 mL) wasadded K2CO3 (248 mg, 1.796 mmol) and Mel (0.084 mL, 1.347 mmol). The mixture was stirred at RT for 3h before being purified on reverse phase HPLC to give the title compound (298 mg, 90 % yield).

[0283] Step 12.5: Synthesis of (rac)-3-(7-amino-4-methyl-3-oxo-3,4-dihydro-2H- benzo[b][l,4]oxazin-2-yl)propanoic acid. A mixture of benzyl (rac)-3-(4-methyl-7-nitro-3-oxo-3.4-dihydro-2H-benzo[b][l,4]oxazin-2-yl)propanoate (298 mg, 0.805 mmol) and 10% Pd-C (50 mg, 0.047 mmol) in EtOH (5mL) / Ethyl acetate (5 mL) was purged with H2 and then stirred under H2 balloon for 2h. After this time, the reaction was purged with nitrogen gas and catalyst was filtered off, the filtrate was concentrated to give the title compound (200 mg, 0.799 mmol, 99 % yield).

[0284] Step 12.6: Synthesis of 3-(7-amino-4-methyl-3-oxo-3,4-dihydro-2H- benzo[b][l,4]oxazin-2-yl)-N-methylpropanamide. A mixture of 3-(7-amino-4-methyl-3-oxo-3.4-dihydro-2H-benzo[b][l,4]oxazin-2-yl)propanoic acid (10 mg, 0.040 mmol), methylamine HC1 (13 mg, 0.2 mmol), HATU (30.4 mg, 0.080 mmol) and TEA (0.017 mL, 0.12 mmol) in DMSO (1 mL) was stirred at RT for 30 min. The crude material was purified on reverse phase HPLC to give the title compound (10.5 mg, 95 % yield).

[0285] Step 12.7: Synthesis of 3-[7-[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]-4- methyl-3-oxo-l,4-benzoxazin-2-yl]-N-methyl-propanamide. To a solution of 3-(7-amino-4- methyl-3-oxo-l,4-benzoxazin-2-yl)-N-methyl-propanamide (810 mg, 3.08 mmol) in a mixture of THF (30 mL) and DMF (10 mL) at -40 °C, were sequentially added DIEA (580 pL, 3.39 mmol) and 5-chloro-2,4-difluoro-pyrimidine (312 pL, 3.23 mmol) dropwise. 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, diethyl ether, then dried under vacuum to provide title compound (1.07 g, 88%) as a solid. 'H NMR (500 MHz, DMSO) 5 9.55 (s, 1H), 8.38 (d, J = 1.3 Hz, 1H), 7.79 (bs, 1H), 7.34 - 7.29 (m, 2H), 7.17 (d, J = 9.4 Hz, 1H), 4.64 (dd, J = 8.4, 4.5 Hz, 1H), 3.29 (s, 3H), 2.55 (d, J = 4.6 Hz, 3H), 2.27 (t, J = 7.7 Hz, 2H), 2.12 - 2.03 (m, 1H), 1.96 - 1.87 (m, 1H). MS (ESI) [M+H]+394.2.

[0286] Step 12.8: Synthesis of 3-(7-((5-chloro-2-(4-((3-(2,6-dioxopiperidin-3-yl)-l- methyl-lH-indazol-6-yl)amino)piperidin-l-yl)pyrimidin-4-yl)amino)-4-methyl-3-oxo-3,4- dihydro-2H-benzo[b][l,4]oxazin-2-yl)-N-methylpropanamide. The title compound was synthesized according to General Procedure 6 using 3-[7-[(5-chloro-2-fluoro-pyrimidin-4- yl)amino]-4-methyl-3-oxo-l,4-benzoxazin-2-yl]-N-methyl-propanamide (30 mg, 0.076 mmol) and 3-[l-methyl-6-(4-piperidylamino)indazol-3-yl]piperidine-2, 6-dione hydrochloride (35 mg, 0.091 mmol) as the starting materials. The crude material was purified on reverse-phase HPLC(10 to 100 % acetonitrile in water with 0.1% formic acid additive) to afford the title compound (40 mg, 70%); LCMS C35H39CIN10O5 requires 714.3, found 715.0 [M+H]+; 'HNMR (400 MHz, DMSO-d6) 5 ppm 10.7-10.9 (m, 1H), 8.6-8.8 (m, 1H), 8.06 (s, 1H), 7.7-7.8 (m, 1H), 7.4-7.5 (m, 2H), 7.3-7.3 (m, 1H), 7.1-7.1 (m, 1H), 6.5-6.6 (m, 1H), 6.4-6.5 (m, 1H), 5.7-5.8 (m, 1H), 4.6-4.7 (m, 1H), 4.3-4.5 (m, 2H), 4.1-4.2 (m, 1H), 3.83 (s, 3H), 3.6-3.7 (m, 1H), 3.2-3.3 (m, 3H), 3.1-3.2 (m, 2H), 2.9-3.0 (m, 1H), 2.6-2.6 (m, 2H), 2.4-2.5 (m, 1H), 2.2-2.3 (m, 3H), 2.1-2.2 (m, 1H), 2.0- 2.1 (m, 3H), 1.8-1.9 (m, 1H), 1.2-1.4 (m, 2H), 0.9-1.0 (m, 3H).3-(7-((5-chloro-2-(4-((3-(2,6-dioxopiperidin-3-yl)-l-methyl-lH-indazol-6-yl)amino)piperidin-l- yl)pyrimidin-4-yl)amino)-3-oxo-2,3-dihydro-4H-benzo[b][l,4]oxazin-4-yl)-N- methylpropanamide

[0287] Step 13.1: Synthesis of Methyl 3-(7-nitro-3-oxo-l,4-benzoxazin-4- yl)propanoate. To a solution of 7-nitro-4H-l,4-benzoxazin-3-one (500 mg, 2.58 mmol) in DMF (10 mL) were sequentially added K2CO3 (1.07 g, 7.73 mmol), methyl 3-bromopropanoate (473 mg, 2.83 mmol) and KI (85.6 mg, 0.52 mmol). The reaction mixture was stirred at rt overnight and, the volatiles were removed under reduced pressure. Water (20.0 mL) was slowly added and the resulting precipitate was collected by filtration, washed with diethyl ether (50 mL) and dried under vacuum to provide the title compound (600.0 mg, 83%) as a solid. 'H NMR (500 MHz, DMSO) 5 7.95 (dd, J = 9.0, 2.6 Hz, 1H), 7.81 (d, J = 2.6 Hz, 1H), 7.49 (d, J = 9.0 Hz, 1H), 4.79 (s, 2H), 4.28 - 4.11 (m, 2H), 3.59 (s, 3H), 2.72 - 2.58 (m, 2H).

[0288] Step 13.2: Synthesis of Methyl 3-(7-amino-3-oxo-l,4-benzoxazin-4- yl)propanoate. A mixture of methyl 3-(7-nitro-3-oxo-l,4-benzoxazin-4-yl)propanoate (500.0 mg, 1.78 mmol) and 10% Pd / C ( 190 mg, 0.18 mmol) in DMF (20.0 mL) was hydrogenated under hydrogen atmosphere at rt for 4 h. The mixture was filtered through Celite and the filtrate was concentrated under reduced pressure to provide the title compound (450.0 mg, 94%) as a solid, which was used in next step without further purification. 'H NMR (500 MHz, DMSO) 5 6.87 (d, J = 8.6 Hz, 1H), 6.26 (dd, J = 8.5, 2.4 Hz, 1H), 6.23 (d, J = 2.4 Hz, 1H), 5.02 (s, 2H), 4.47 (s, 2H), 4.14 - 3.97 (m, 2H), 3.58 (s, 3H), 2.60 - 2.52 (m, 2H). MS (ESI) [M+H]+251.1.

[0289] Step 13.3: Synthesis of 3-(7-amino-3-oxo-l,4-benzoxazin-4-yl)-N-methyl- propanamide. To a solution of MeNH2 (2.0 M in methanol, 3.44 mL, 6.87 mmol) was addedmethyl 3-(7-amino-3-oxo-l,4-benzoxazin-4-yl)propanoate (430.0 mg, 1.72 mmol). The reaction mixture was heated to 60 °C overnight and then cooled to rt. The resulting precipitate was collected by filtration, washed with MeOH (2 x 5.0 mL) and diethyl ether (20 mL), then dried under vacuum to provide the title compound (212.0 mg, 49%) as a solid.JH NMR (500 MHz, DMSO) 5 7.87 (s, 1H), 6.86 (d, J = 8.6 Hz, 1H), 6.26 (dd, J = 8.6, 2.4 Hz, 1H), 6.22 (d, J = 2.4 Hz, 1H), 5.00 (s, 2H), 4.47 (s, 2H), 4.09 - 3.87 (m, 2H), 2.55 (d, J = 4.6 Hz, 3H), 2.38 - 2.27 (m, 2H).

[0290] Step 13.4: Synthesis of 3-[7-[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]-3-oxo- l,4-benzoxazin-4-yl]-N-methyl-propanamide. To a solution of 3-(7-amino-3-oxo-l,4- benzoxazin-4-yl)-N-methyl-propanamide (2.10 g, 8.42 mmol) in a mixture of THF (40 mL) and DMF (10 mL) cooled to -40 °C were sequentially added 5-chloro-2,4-difluoro-pyrimidine (0.81 mL, 8.42 mmol) and DIPEA (1.59 mL, 9.27 mmol). The reaction mixture was slowly warmed to rt and stirred for 24 h. The volatiles were evaporated under reduced pressure. THF (50.0 mL) was slowly added and, the resulting precipitate was collected by filtration, washed with THF (50.0 mL) then dried under vacuum to provide the title compound (2.24 g, 75%) as a solid. 'H NMR (500 MHz, DMSO) 5 9.55 (s, 1H), 8.38 (d, J = 1.1 Hz, 1H), 7.93 (d, J = 4.1 Hz, 1H), 7.39 - 7.27 (m, 2H), 7.23 (d, J = 8.7 Hz, 1H), 4.66 (s, 2H), 4.17 - 3.98 (m, 2H), 2.57 (d, J = 4.6 Hz, 3H), 2.46 - 2.34 (m, 2H);. MS (ESI) [M+H]+380.1.

[0291] Step 13.5: Synthesis of 3-(7-((5-chloro-2-(4-((3-(2,6-dioxopiperidin-3-yl)-l- methyl-lH-indazol-6-yl)amino)piperidin-l-yl)pyrimidin-4-yl)amino)-3-oxo-2,3-dihydro-4H- benzo[b] [ 1 ,4]oxazin-4-yl)-N-methylpropanamide. 3 -[ 1 -methyl-6-(4-piperidylamino)indazol-3 - yl]piperidine-2,6-dione;hydrochloride (35.8 mg, 0.090 mmol), 3-[7-[(5-chloro-2-fluoro- pyrimidin-4-yl)amino]-3-oxo-l,4-benzoxazin-4-yl]-N-methyl-propanamide (30. mg, 0.0800 mmol), N,N-Diisopropylethylamine (0.03 mL, 0.1600 mmol), and DMSO (0.15 mL) were added to a 1 dram vial equipped with a stir bar and heated to 80 °C overnight.

[0292] The reaction was cooled to RT and water was added to crash out the product. The resulting solid was filtered on a buchner funnel and washed with water (3x) and MTBE (lx). The solid was dried under vacuum at 45 °C overnight to afford the title compound (45 mg, 0.061 mmol, 76% yield). LCMS m / z = 701 [M+H]+; 'H NMR (DMSO-d6, 400 MHz) 5 10.75 (s, 1H), 8.6-8.7 (m, 1H), 7.99 (s, 1H), 7.8-7.9 (m, 1H), 7.4-7.4 (m, 1H), 7.3-7.4 (m, 1H), 7.2-7.3 (m, 1H), 7.0-7.1 (m, 1H), 6.40 (s, 2H), 5.6-5.8 (m, 1H), 4.53 (s, 2H), 4.3-4.4 (m, 2H), 4.1-4.2 (m, 1H), 3.9-4.0 (m, 2H), 3.76 (s, 3H), 3.5-3.7 (m, 1H), 3.0-3.2 (m, 2H), 2.5-2.6 (m, 2H), 2.47 (d, 3H, .7=4,6 Hz), 2.3- 2.3 (m, 2H), 2.1-2.2 (m, 1H), 2.0-2.1 (m, 1H), 1.9-2.0 (m, 2H), 1.2-1.4 (m, 2H).2-(4-(5-chloro-4-((l-methyl-2-oxoindolin-5-yl)amino)pyrimidin-2-yl)piperazin-l-yl)-N-(3-(2,6- dioxopiperidin-3-yl)-l-methyl-lH-indazol-7-yl)acetamide

[0293] Step 14.1: Synthesis of 7-Bromo-3-iodo-lH-indazole. To a solution of 7-bromo- IH-indazole (20.0 g, 101 mmol, 1 eq), iodine (51.53 g, 203.0 mmol, 2 eq) in dimethyl formamide (500 mL) was added potassium hydroxide (11.39 g, 203.0 mmol, 2 eq) at 0 °C. The mixture was stirred at 16 °C for 12 h. The reaction mixture was quenched with water (1 L), and a saturated sodium sulfite aqueous solution (40 mL). The reaction mixture was filtered and the filter cake was diluted with ethyl acetate (600 mL), washed with sodium sulfite (20 mL x 3). The organic layer was dried with anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuum. The title compound was used directly into the next step without further purification.JH NMR (400 MHz, DMSO-t / 6) 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).

[0294] Step 14.2: Synthesis of Bromo-3-iodo-l-methyl-lH-indazole. To a solution of 7-bromo-3-iodo-lH-indazole (32.7 g, 101 mmol, 1 eq) in tetrahydrofuran (300 mL) was added potassium tert-butoxide (22.73 g, 202.5 mmol, 2 eq) at 0 °C, the reaction was stirred at 0 °C for 1 h. Then a solution of methyl iodide (28.75 g, 202.5 mmol, 2 eq) in tetrahydrofuran (50 mL) was added 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. 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) to give the title compound (21.24 g, 63.04 mmol, 62% yield) was obtained as white solid. 'H NMR (400 MHz, DMSO-t / 6) 8 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).

[0295] Step 14.3: Synthesis of 3-(2,6-Bis(benzyloxy)pyridin-3-yl)-7-bromo-l-methyl- IH-indazole. To a solution of 7-bromo-3-iodo-l-methyl-lH-indazole (5.00 g, 14.8 mmol, 1 eq) in dioxane (50 mL) and water (5 mL) was added 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyridine (6.19 g, 14.8 mmol, 1 eq) , (1,1'- bis(diphenylphosphino)ferrocene)palladium(II) dichloride (1.09 g, 1.48 mmol, 0.1 eq) and cesium carbonate (14.5 g, 44.5 mmol, 3 eq). The mixture was stirred at 100 °C for 12 h. The reactionmixture was concentrated in vacuum. The residue was purified by silica gel chromatography (0- 8.5% Ethyl acetate in petroleum ether) to give the title compound (4.24 g, 8.47 mmol, 57% yield) as a yellow solid. 'H NMR (400 MHz, DMSO-t / 6) 8 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).

[0296] Step 14.4: Synthesis of tert-butyl (3-(2,6-bis(benzyloxy)pyridin-3-yl)-l- methyl-lH-indazol-7-yl)carbamate. [2-(2-aminophenyl)phenyl]-chloro- palladium;dicyclohexyl-[3-(2,4,6-triisopropylphenyl)phenyl]phosphane (1.31 g, 1.67 mmol, 0.05 eq) was added to a solution of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-7-bromo-l-methyl-lH- indazole (74% purity, 16.7 g, 33.4 mmol, 1 eq), tert-butyl carbamate (3.91 g, 33.4 mmol, 1 eq) and cesium carbonate (21.75 g, 66.75 mmol, 2 eq) in dioxane (300 mL), the mixture solution was heated to 100 °C and stirred for 16 h. The solution was cooled to RT and filtered. The filtrate was concentrated to give a residue which was purified by silica gel chromatography (a solution of 1% to 12% ethyl acetate in petroleum ether) to give the title compound (6.60 g, 12.3 mmol, 37% yield) as a yellow oil. 'HNMR (400 MHz, CDC13) 6 = 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).

[0297] Step 14.5: Synthesis of tert-butyl (3-(2,6-dioxopiperidin-3-yl)-l-methyl-lH- indazol-7-yl)carbamate. Pd / C (1.00 g, 10% by weight) was added to a solution of tert-butyl (3- (2,6-bis(benzyloxy)pyridin-3-yl)-l-methyl-lH-indazol-7-yl)carbamate (8.00 g, 14.9 mmol, 1 eq) in THF (150 mL), the mixture was stirred under hydrogen (50 psi) at 25 °C for 24 h. The mixture was filtered and the filtrate was concentrated to give a residue which was purified by silica gel chromatography (a solution of 10% to 67% ethyl acetate in petroleum ether) to give the title compound (3.60 g, 10.0 mmol, 67% yield) as a yellow solid. 'H NMR (400 MHz, DMSO-de) 6 = 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).

[0298] Step 14.6: Synthesis of 3-(7-Amino-l-methyl-lH-indazol-3-yl)piperidine-2,6- dione. TerLbutyl (3-(2,6-dioxopiperidin-3-yl)-l-methyl-lH-indazol-7-yl)carbamate (3.50 g, 9.77 mmol, 1 eq) was added to hydrogen chloride aqueous solution (12 M, 50 mL, 61.4 eq) at 0 °C, the mixture solution was stirred at 25 °C for 2 h. A yellow clear solution was obtained. The solution was poured into cold water (500 mL) at 0 °C, then the solution was set for lyophilization to give the title compound that was used without further purification (2673 mg, 8.73 mmol, 89% yield, 96.2% purity, HC1 salt). 'H NMR (400 MHz, DMSO-d6) 6 = 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).

[0299] Step 14.7: Synthesis of tert-butyl 4-[2-[[3-(2,6-dioxo-3-piperidyl)-l-methyl- indazol-7-yl]amino]-2-oxo-ethyl]piperazine-l -carboxylate. To a solution of 3-(7-amino-l- methyl-indazol-3-yl)piperidine-2,6-dione;hydrochloride (300. mg, 1.02 mmol), and 2-(4-(tert- Butoxycarbonyl)piperazin-l-yl)acetic acid (273 mg, 1.12 mmol) in DMSO (2 mL) was added N,N-Diisopropylethylamine (0.39 mL, 2.24 mmol). The reaction mixture was stirred at 80 °C for 15 hours before purification using reverse phase HPLC to afford the title compound (164 mg, 33 % yield). *HNMR (400 MHz, DMSO-d6) 5 ppm 10.90 (s, 1 H), 9.87 (s, 1 H), 7.58 (d, J=8.07 Hz, 1 H), 7.29 (d, J=7.34 Hz, 1 H), 7.08 (t, J=7.64 Hz, 1 H), 4.38 (dd, J=10.21, 5.07 Hz, 1 H), 4.10 (s, 3 H), 3.41 (br s, 4 H), 3.23 (s, 2 H), 2.52 - 2.77 (m, 3 H), 2.29 - 2.45 (m, 2 H), 2.11 - 2.23 (m, 1 H).

[0300] Step 14.8: Synthesis of N-[3-(2,6-dioxo-3-piperidyl)-l-methyl-indazol-7-yl]-2- piperazin-l-yl-acetamide;hydrochloride. The title compound was synthesized according to General Procedure 5 using tert-butyl 4-[2-[[3-(2,6-dioxo-3-piperidyl)-l-methyl-indazol-7- yl]amino]-2-oxo-ethyl]piperazine-l-carboxylate as the starting material.

[0301] Step 14.9: Synthesis of 2-(4-(5-chloro-4-((l-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)piperazin-l-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-lH-indazol-7- yl)acetamide. The title compound was synthesized according to General Procedure 6 using 5-[(5- chloro-2-fluoro-pyrimidin-4-yl)amino]-l-methyl-indolin-2-one (14.5 mg, 0.050 mmol) and N-[3-(2,6-dioxo-3-piperidyl)-l-methyl-indazol-7-yl]-2-piperazin-l-yl-acetamide;hydrochloride (22 mg, 0.052 mmol) as the starting materials. The crude material was purified on reverse-phase HPLC (10 to 100 % acetonitrile in water with 0.1% formic acid additive) to afford the title compound (10 mg, 29%); LCMS C32H33CIN10O4 requires 656.2, found 657.0 [M+H]+; 'HNMR (400 MHz, DMSO-d6) 5 ppm 10.90 (s, 1 H), 9.91 (s, 1 H), 8.68 (s, 1 H), 8.02 (s, 1 H), 7.58 (d, J=7.82 Hz, 1 H), 7.53 (s, 1 H), 7.46 - 7.51 (m, 1 H), 7.33 (d, J=7.21 Hz, 1 H), 7.08 (t, J=7.70 Hz, 1 H), 6.94 (d, J=8.44 Hz, 1 H), 4.38 (dd, J=9.96, 5.07 Hz, 1 H), 4.13 (s, 3 H), 3.70 (br s, 4 H), 3.56 (s, 2 H), 3.24 (s, 2 H), 3.12 (s, 3 H), 2.68 - 2.74 (m, 1 H), 2.56 - 2.65 (m, 5 H), 2.33 - 2.42 (m, 1 H), 2.12 - 2.21 (m, 1 H).3-(7-((l-(5-chloro-4-((l-methyl-2-oxoindolin-5-yl)amino)pyrimidin-2-yl)piperi din-4- yl)(methyl)amino)-l -methyl- lH-indazol-3-yl)piperidine-2, 6-dione

[0302] Step 15.4: Synthesis of 3-(7-((l-(5-chloro-4-((l-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)piperidin-4-yl)(methyl)amino)-l -methyl- lH-indazol-3-yl)piperi dine-2, 6-dione. The title compound was synthesized according to General Procedure 6 using 5-[(5- chloro-2-fluoro-pyrimidin-4-yl)amino]-l-methyl-indolin-2-one (19 mg, 0.064 mmol) and 3- [l-methyl-7-[methyl(4-piperidyl)amino]indazol-3-yl]piperidine-2,6-dione;hydrochloride (25 mg, 0.064 mmol) as the starting materials. The crude material was purified on reverse-phase HPLC (10 to 100 % acetonitrile in water with 0.1% formic acid additive) to afford the title compound (40 mg, 70%); LCMS C32H34CIN9O3 requires 627.3, found 628.0 [M+H]+; 'H NMR (400 MHz, DMSO-d6) 5 ppm 10.88 (s, 1 H), 8.62 (s, 1 H), 7.98 (s, 1 H), 7.47 - 7.56 (m, 2 H), 7.42 (d, J=7.95 Hz, 1 H), 7.16 (d, J=7.09 Hz, 1 H), 7.04 (t, J=7.70 Hz, 1 H), 6.92 (d, J=9.05 Hz, 1 H), 4.38 - 4.51 (m, 2 H), 4.34 (dd, J=9.72, 5.07 Hz, 1 H), 4.22 (s, 3 H), 3.53 (s, 2 H), 3.20 - 3.29 (m, 1 H), 3.10 (s, 3 H), 2.77 - 2.95 (m, 2 H), 2.59 - 2.73 (m, 5 H), 2.29 - 2.40 (m, 1 H), 2.12 - 2.23 (m, 1 H), 1.72 - 1.86 (m, 2 H), 1.41 - 1.58 (m, 2 H).3 -(5 -(2-((5 -chloro-4-((2-oxoindolin-5 -yl)amino)pyrimidin-2-yl)amino)ethyl)- 1 -oxoi soindolin-2- yl)piperidine-2, 6-dione

[0303] Step 16.1: Synthesis of 5-aminoindolin-2-one. A mixture of 5-nitroindolin-2-one (2.67 g, 15.0 mmol), 10% Pd / C (798.0 mg, 0.75 mmol) in ethyl acetate (40.0 mL) and methanol (70.0 mL) was shaken at rt for 1 h in a Parr hydrogenation apparatus under a 50 psi atmosphere of H2. The reaction was filtered over Celite and washed with methanol (2 x 10.0 mL). The filtrate was concentrated under reduced pressure to provide title compound (2.20 g, 99%) as a solid, which was used in the next step without further purification. MS (ESI) [M+H]+148.8.

[0304] Step 16.2: Synthesis of 5-[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]indolin-2- one. To a solution of 5-aminoindolin-2-one (1.04 g, 7.00 mmol) in THF (70.0 mL) cooled to -40 °C were sequentially added DIEA (1.32 mL, 7.70 mmol) and 5-chloro-2,4-difluoro-pyrimidine (1.05 g, 7.0 mol) portion wise. After the addition was completed, the reaction was then stirred at rt for 2 h. The resulting precipitate was collected by filtration, washed with THF (2.0 mL) and dried under vacuum to provide title compound (1.25 g, 64%) as a solid. The filtrate was concentrated under reduced pressure and the material was triturated in acetonitrile (10.0 mL). A precipitate formed and was collected by filtration, washed with acetonitrile (2.0 mL), and dried under vacuum to provide additional title compound (350.0 mg, 18%) as a solid. 'H NMR (500 MHz, DMSO) 5 10.40 (s, 1H), 9.49 (s, 1H), 8.31 (d, J = 1.2 Hz, 1H), 7.35 (s, 1H), 7.27 (dd, J = 8.3, 2.1 Hz, 1H), 6.82 (d, J = 8.3 Hz, 1H), 3.51 (s, 2H). MS (ESI) [M+H]+279.0.

[0305] Step 16.3: Synthesis of 3-(5-allyl-l-oxo-isoindolin-2-yl)piperidine-2, 6-dione. To a solution of 3-(5-bromo-l-oxo-isoindolin-2-yl)piperidine-2, 6-dione (1.03 g, 3.19 mmol) in dry DMF (20.0 mL) were sequentially added allyltri-n-butyltin (990.0 pL, 3.19 mmol) and Pd(PPh3)2Cl2(112.0 mg, 0.16 mmol). The reaction mixture was degassed with nitrogen, sealed, heated to 90°C overnight and then cooled to rt. Ethyl acetate (20.0 mL) and water (20.0 mL) were added, and the layers were separated. The organic layer was washed with water (20.0 mL) and brine (2 x 20.0 mL), then dried (MgSCh), filtered and concentrated under reduced pressure. The material was purified by silica gel chromatography eluting with an ethyl acetate in hexane gradient (5 to 95%) to provide title compound (0.600 g, 66 %) as a solid.1H NMR (500 MHz, DMSO) 5 10.97 (s, 1H), 7.66 (d, J = 7.7 Hz, 1H), 7.43 (s, 1H), 7.34 (d, J = 7.2 Hz, 1H), 5.99 (ddt, J = 16.8, 10.0, 6.7 Hz, 1H), 5.16 - 5.06 (m, 3H), 4.43 (d, J = 17.2 Hz, 1H), 4.30 (d, J = 17.2 Hz, 1H), 3.49 (d, J = 6.8 Hz, 2H), 2.96 - 2.86 (m, 1H), 2.60 (d, J = 17.5 Hz, 1H), 2.39 (dd, J = 13.2, 4.5 Hz, 1H), 2.03 - 1.96 (m, 1H).

[0306] Step 16.4: Synthesis of 3-[5-(2,3-dihydroxypropyl)-l-oxo-isoindolin-2- yl]piperidine-2, 6-dione. To a solution of 3-(5-allyl-l-oxo-isoindolin-2-yl)piperidine-2, 6-dione (600.0 mg, 2.11 mmol) in THF (6.0 mL) and water (3.0 mL) were sequentially added NaHCOs (88.6 mg, 1.06 mmol), NMO (1.14 g, 8.44 mmol), 2,6-lutidine (0.49 mL, 4.22 mmol) and OsCL (21.5 mg, 0.08 mmol, 0.157 M in water) and the reaction mixture was stirred at rt for 8 h. Solid Na2SC>3 (2.39 g, 19.0 mmol) was added portion wise and then the mixture was stirred for an additional 30 min. The volatiles were removed under reduced pressure, the material was freeze dried, dissolved in acetone and then filtered to remove insoluble material. The filtrate was concentrated under reduced pressure and the material was purified by reverse phase chromatography (C18) eluting with an acetonitrile / 0.1 % formic acid gradient (5-100%) toprovide the title compound (530.0 mg, 79%) as a solid. MS (ESI). [M+H]+319.

[0307] Step 16.5: Synthesis of 2-[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-5- yl] acetaldehyde. To a solution of 3-[5-(2,3-dihydroxypropyl)-l-oxo-isoindolin-2-yl]piperidine-2.6-dione (350.0 mg, 1.1 mmol) in a mixture of THF (7.0 mL) and water (7.0 mL) was added NaIO4 (470.0 mg, 2.2 mmol) and the reaction mixture was stirred at rt for 2 h. The mixture was extracted with DCM (3 x 20.0 mL), and the combined organic extracts were washed with brine (20.0 mL), dried (MgSCU), filtered and concentrated under reduced pressure to provide the title compound (220.0 mg, 70%) as a solid which was used in the next step without further purification (220 mg, 70%).1H NMR (500 MHz, DMSO) 5 11.04 (d, J = 9.4 Hz, 1H), 9.79 (t, J = 1.6 Hz, 1H), 7.77 (d, J = 7.8 Hz, 1H), 7.54 (s, 1H), 7.44 (t, J = 7.9 Hz, 1H), 5.18 (dd, J = 13.4, 5.2 Hz, 1H), 4.52 (d, J = 17.3 Hz, 1H), 4.38 (d, J = 17.3 Hz, 1H), 4.01 (d, J = 1.3 Hz, 2H), 3.02 - 2.93 (m, 1H), 2.68 - 2.64 (m, 1H), 2.46 (dd, J = 13.0, 4.5 Hz, 1H), 2.10 - 2.04 (m, 1H). MS (ESI) [M+H]+287.4

[0308] Step 16.6: Synthesis of 3-[5-(2-hydroxyethyl)-l-oxo-isoindolin-2- yl]piperidine-2, 6-dione. To a solution of 2-[2-(2,6-dioxo-3-piperidyl)-l-oxo-isoindolin-5- yl]acetaldehyde (440.0 mg, 1.54 mmol) in MeOH (5.0 mL) cooled to 0 °C was added NaBH4 (58.1 mg, 1.54 mmol) and the reaction mixture was stirred for 1 h. A saturated aqueous solution of NH4CI (0.5 mL) was slowly added and the mixture was then stirred for 15 min. The volatiles were removed under reduced pressure and the material was lyophilized to provide the title compound (400 mg, 90%) as a solid, which was used in the next step without further purification. MS (ESI) [M+H]+289.3.

[0309] Step 16.7: Synthesis of 3-[5-(2-chloroethyl)-l-oxo-isoindolin-2-yl]piperidine-2.6-dione. To a solution of 3 -[5-(2 -hydroxy ethyl)- l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (443.0 mg, 1.54 mmol) in DMF (10.0 mL) were sequentially added DIPEA (0.40 mL, 2.30 mmol) and methanesulfonyl chloride (0.13 mL, 1.69 mmol) and the reaction mixture was stirred overnight at rt for 1 day. Additional DIPEA (0.4 mL, 2.3 mmol) and methanesulfonyl chloride (0.13 mL, 1.69 mmol) were added and the reaction mixture was stirred for an additional day. Ethyl acetate (50.0 mL) and water (50.0 mL) were added, and the layers were separated. The aqueous layer was extracted with ethyl acetate (2 x 50.0 mL) and the combined organic layers were washed with brine (50.0 mL), then dried (MgSCU), filtered and concentrated under reduced pressure to provide title compound (440.0 mg, 93%), which was used in the next step without further purification. MS (ESI) [M+H]+307.3.

[0310] Step 16.8: Synthesis of 3-[5-(2-azidoethyl)-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione. To a solution of 3-[5-(2-chloroethyl)-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (250.0 mg, 0.82 mmol) in acetone (20.0 mL) was added Nal (1.2 g, 8.15 mmol). The reaction wasrefluxed for 8 h and then cooled to rt, filtered, and the filtrate was concentrated under reduced pressure. Ethyl acetate (10.0 mL) and water (10.0 mL) were added, and the layers were separated. The organic layer was washed with water (2 x 10.0 mL), then dried (MgSCU), filtered and concentrated under reduced pressure to provide 3-[5-(2-iodoethyl)-l-oxo-isoindolin-2- yl]piperidine-2, 6-dione which was used in the next step without further purification. To a solution of 3-[5-(2-iodoethyl)-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione in DMF (10.0 mL) was added NaNs (371.0 mg, 5.71 mmol). The reaction mixture was stirred for 18 h at rt. Ethyl acetate (20.0 mL) and water (30.0 mL) were added, the organic layer was separated, washed with water (30.0 mL), then dried (MgSCU), filtered and concentrated under reduced pressure to provide the title compound (230.0 mg, 90%) as a solid, which was used in the next step without further purification. MS (ESI) [M+H]+314.1

[0311] Step 16.9: Synthesis of 3-[5-(2-aminoethyl)-l-oxo-isoindolin-2-yl]piperidine- 2, 6-dione. To a solution of 3-[5-(2-azidoethyl)-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (100.0 mg, 0.32 mmol) in MeOH (10.0 mL) was added 10% Pd / C (85.0 mg, 0.079 mmol) and the reaction mixture was degassed with EE and then stirred under an atmosphere of EE for 1 hour. The mixture was filtered over Celite, washed with MeOH (2 x 10.0 mL). The filtrate was concentrated under reduced pressure to provide title compound Ih (90 mg, 98%) as a solid, which was used in the next step without further purification. MS (ESI) [M+H]+288.4.

[0312] Step 16.10: Synthesis of 3-(5-(2-((5-chloro-4-((2-oxoindolin-5- yl)amino)pyrimidin-2-yl)amino)ethyl)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione. To a solution of 3-[5-(2-aminoethyl)-l-oxo-isoindolin-2-yl]piperidine-2, 6-dione (26.0 mg, 0.09 mmol) in DMSO (1.0 mL) were sequentiaaly added 5-[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]indolin-2- one (25.2 mg, 0.09 mmol) and DIPEA (0.02 mL, 0.11 mmol). The reaction mixture was heated to 80 °C for 45 min and then cooled to rt. The mixture was directly purified by reverse-phase chromatography (Cis) eluting with an acetonitrile / 0.1% formic acid gradient (22-28%) to provide title compound (5.0 mg, 10% yield) as a solid. 'H NMR (500 MHz, DMSO) 5 10.97 (s, IH), 10.39 (s, IH), 7.95 (s, IH), 7.60 (s, IH), 7.46 (s, IH), 7.40 (d, J = 7.8 Hz, IH), 7.27 - 7.20 (bs, IH), 7.17 - 7.12 (m, IH), 6.77 (s, IH), 5.10 (dd, J = 13.3, 5.0 Hz, IH), 4.37 (d, J = 17.5 Hz, IH), 4.26 (d, J = 16.9 Hz, IH), 3.42 (s, 2H), 2.98 - 2.76 (m, 3H), 2.63 (d, J = 17.2 Hz, IH), 2.38 - 2.34 (m, 2H), 2.03 - 1.97 (m, IH); MS (ESI) [M+H]+546.2.3-(5-((l-(5-chloro-4-((l-methyl-2-oxoindolin-5-yl)amino)pyrimidin-2-yl)piperidin-4-yl)amino)- lH-benzo[d] [1,2,3 ]triazol- 1 -yl)piperidine-2, 6-dione

[0313] Step 17.1: Synthesis of tert-Butyl (4S)-5-amino-4-(4-bromo-2-nitro-anilino)-5- oxo-pentanoate. To a solution of 4-bromo-l-fluoro-2-nitro-benzene (19.0 g, 86.4 mmol) in DMF (400.0 mL) were sequentially added tert-butyl (4S)-4,5-diamino-5-oxo-pentanoate;hydrochloride (20.0 g, 83.8 mmol) and DIPEA (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 NH4CI (500.0 mL) and EtOAc (500.0 mL) were added and the layers were separated. The organic layer was washed with brine (200.0 mL), dried (Na2SC>4), 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.

[0314] Step 17.2: 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 THF (260.0 mL) cooled to 0 °C were sequentially added Zn dust (47.0 g, 718.0 mmol) and NH4CI (19.0 g, 355.0 mmol). Water (80.0 mL) was added slowly and the reaction mixture was stirred at 0 °C for 1 h. The mixture was filtered through Celite and washed with THF (200 mL). The filtrate was concentrated under reduced pressure. The material was purified by column chromatography on silica gel using a gradient of 10-20% MeOH in DCM to afford the title compound (28.1 g, 95%) as a solid. 'H NMR (400 MHz, DMSO) 5 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). MS (ESI) [M+H]+374.2.

[0315] Step 17.3: Synthesis of tert-butyl 5-amino-4-(5-bromobenzotriazol-l-yl)-5- oxo-pentanoate. To a solution of tert-butyl 5-amino-4-(2-amino-4-bromo-anilino)-5-oxo- pentanoate (5.97 g, 16.0 mmol) in MeCN (40.1 mL) were sequentially added tert-Butyl nitrite (4.31 mL, 32.6 mmol) and acetic acid (1.83 mL, 32.05 mmol). The reaction mixture was stirred at rt for 1.5 h. Water (20.0 mL) and diethyl ether (20.0 mL) were added and the layers were separated. The organic layer was dried QSfeSCU), filtered and concentrated under reduced pressure. The material was purified by column chromatography on silica gel using a gradient of0-100% ethyl acetate in hexane to afford the title compound (2.78 g, 44%) as a solid. 'H NMR (500 MHz, DMSO) 5 8.36 (s, 1H), 7.83 - 7.81 (m, 2H), 7.71 (d, J = 8.7 Hz, 1H), 7.52 (s, 1H), 5.62 - 5.60 (m, 1H), 2.21 - 2.15 (m, 1H), 2.10 - 2.04 (m, 1H), 1.33 (s, 9H). Note: two protons masked by DMSO signal. MS (ESI) [M+H]+383.1.

[0316] Step 17.4: Synthesis of tert-butyl N-[l-(2,6-dioxo-3-piperidyl)benzotriazol-5- yljcarbamate. A mixture of tert-butyl 5-amino-4-(5-bromobenzotriazol-l-yl)-5-oxo-pentanoate (1.31 g, 3.42 mmol), tert-butyl carbamate (600 mg, 5.13 mmol), tBuXPhos-Pd-G3 (554.1 mg, 0.68 mmol) and NaOtBu (821.2 mg, 8.55 mmol) in 1,4-dioxane (33.0 mL) was heated to 50 °C for 18 h and then cooled to rt. Acetic acid (0.98 mL, 17.1 mmol) was added and the mixture was stirred at rt for 30 min. The volatiles were evaporated under reduced pressure. Acetonitrile (50.0 mL) was added and the resulting precipitate was collected by filtration, then washed with acetonitrile (3 x 25.0 mL) and diethyl ether (3 x 25.0 mL). The material was purified by reverse phase chromatography (Cl 8), using a gradient of 0-100% acetonitrile and water (contains 0.1 formic acid) to afford title compound (331.0 mg, 28%) as a solid.1HNMR(400 MHz, DMSO) 5 9.58 (s, 1H), 8.16 (s, 1H), 7.70 - 7.68 (m, 1H), 7.56 (dd, J = 9.0, 1.7 Hz, 1H), 6.18 - 6.13 (m, 1H), 2.93 - 2.90 (m, 2H), 2.77 - 2.73 (m, 1H), 2.40 - 2.37 (m, 1H), 1.51 (s, 9H). Note: NH of glutarimide was not observed. MS (ESI) [M+H]+346.2.

[0317] Step 17.5: Synthesis of 3-(5-aminobenzotriazol-l-yl)piperidine-2,6- dione; hydrochloride. To a solution of tert-butyl N-[l-(2,6-dioxo-3-piperidyl)benzotriazol-5- yl]carbamate (110.0 mg, 0.32 mmol) in DCM (2.0 mL) was added 4N HC1 in 1,4-dioxane (0.8 mL, 3.19 mmol). The reaction mixture was stirred at rt for 4 h. The volatiles were evaporated under reduced pressure to afford the title compound (90.0 mg, 99% yield) as a solid, which was used in next step without further purification. 'H NMR (500 MHz, DMSO) 5 11.30 (s, 1H), 7.95 (s, 1H), 7.89 (d, J = 8.7 Hz, 1H), 7.48 (d, J = 7.8 Hz, 1H), 6.27 - 6.24 (m, 1H), 4.09 (bs, 3H), 2.98 - 2.90 (m, 2H), 2.80 - 2.76 (m, 1H), 2.50 - 2.42 (m, 1H). MS (ESI) [M+H]+246.2.

[0318] Step 17.6: Synthesis of tert-butyl 4-[[l-(2,6-dioxo-3-piperidyl)benzotriazol-5- yl] amino] piperidine-l-carboxylate. To a solution of 3-(5-aminobenzotriazol-l-yl)piperidine- 2,6-dione;hydrochloride (171 mg, 0.61 mmol) in DMSO (4.7 mL) were sequentially added tertbutyl 4-oxopiperidine-l -carboxylate (151 mg, 0.76 mmol) and acetic acid (0.95 mL), at rt. The reaction mixture was stirred for 30 min and then sodium triacetoxyborohydride (257 mg, 1.21 mmol) was added. The reaction mixture was stirred at rt overnight. Water was added and the resulting precipitate was collected by filtration, washed with diethyl ether (5.0 mL), then dried under vacuum to afford the title compound (201 mg, 69% yield) as a solid, which was used in the next step without further purification.1HNMR(500 MHz, DMSO) 5 11.23 (s, 1H), 7.48 (d, J = 8.8Hz, 1H), 6.98 (d, J = 8.9 Hz, 1H), 6.93 (s, 1H), 6.06 - 6.03 (m, 1H), 5.73 (d, J = 6.9 Hz, 1H), 3.88 (d, J = 10.9 Hz, 2H), 3.50 (s, 1H), 2.94 - 2.83 (m, 4H), 2.74 - 2.71 (m, 1H), 2.34 - 2.32 (m, 1H), 1.95 (d, J = 11.0 Hz, 2H), 1.41 (s, 9H), 1.28 -1.24 (m, 2H). MS (ESI) [M+H]+429.3.

[0319] Step 17.7: Synthesis of 3-[5-[methyl(4-piperidyl)amino]benzotriazol-l- yl]piperidine-2,6-dione;hydrochloride. To a solution of tert-butyl 4-[[l-(2,6-dioxo-3- piperidyl)benzotriazol-5-yl]-methyl-amino]piperidine-l-carboxylate (59.0 mg, 0.13 mmol), in 1,4-dioxane (0.80 mL) was added 4N HC1 in 1,4-dioxane (0.33 mL, 1.33 mmol). The reaction mixture was stirred at rt for 3 h. The volatiles were evaporated under reduced pressure to afford the title compound (50.0 mg, 98.9%) as a solid, which was used in next step without further purification. MS (ESI) [M+H]+343.3.

[0320] Step 17.8: Synthesis of 3-(5-((l-(5-chloro-4-((l-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)piperidin-4-yl)amino)-lH-benzo[d][l,2,3]triazol-l-yl)piperidine-2,6- dione. To a solution of 3-[5-(4-piperidylamino)benzotriazol-l-yl]piperidine-2,6- dione;hydrochloride (35.0 mg, 0.10 mmol) in DMSO (1.25 mL) were sequentially added 5-[(5- chloro-2-fluoro-pyrimidin-4-yl)amino]-l-methyl-indolin-2-one (22.5 mg, 0.08 mmol) and DIPEA (0.07 mL, 0.38 mmol), at rt. The reaction mixture was heated to 85 °C for 2 h and then cooled to rt. The material was purified by preparative HPLC (BEH, Cl 8) using a gradient of 36- 56% acetonitrile and 10 mM ammonium formate in water to afford the title compound (18.0 mg, 30%) as a solid. 'H NMR (500 MHz, DMSO) 8 11.08 (s, 1H), 8.64 (s, 1H), 8.01 (s, 1H), 7.55 - 7.50 (m, 2H), 7.47 (d, J = 8.9 Hz, 1H), 6.98 (dd, J = 9.0, 1.9 Hz, 1H), 6.96 - 6.91 (m, 2H), 6.04 (dd, J = 12.5, 5.1 Hz, 1H), 5.71 (d, J = 8.1 Hz, 1H), 4.44 - 4.30 (m, 2H), 3.67 - 3.56 (m, 1H), 3.55 (s, 2H), 3.17 - 3.11 (m, 2H), 3.10 (s, 3H), 2.95 - 2.81 (m, 2H), 2.76 - 2.70 (m, 1H), 2.38 - 2.30 (m, 1H), 2.05 - 1.95 (m, 2H), 1.36 - 1.26 (m, 2H); MS (ESI) [M+H]+601.4.3-(6-(4-((5-chloro-4-((l-methyl-2-oxoindolin-5-yl)amino)pyrimidin-2-yl)amino)piperidin-l-yl)- 1 -methyl- lH-indol-3-yl)piperidine-2, 6-dione

[0321] Step 18.1: Synthesis of 6-Bromo-3-iodo-l-methyl-indole. To a solution of 6- bromo-l-methyl-indole (4.20 g, 20.0 mmol) in DMF (80 mL) at 0 °C was added iodine (10.1 g,40.0 mmol), followed by powdered KOH (2.24 g, 40.0 mmol) portion-wise over 10 min. The reaction mixture was warmed to rt for 3 h and the reaction was diluted with water (100 mL), a saturated solution of Na2SOs (100 mL) and EtOAc (100 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (2 x 100 mL). The combined organic fractions were washed with a saturated solution of Na2SOs (100 mL), brine (100 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to afford title compound (6.51 g, 97%) as a solid. MS (ESI) [M+H]+334.8. 'H NMR (500 MHz, DMSO-t / 6) 8 7.77 (d, J= 1.6 Hz, 1H), 7.57 (s, 1H), 7.26 (dd, J= 8.4, 1.6 Hz, 1H), 7.22 (d, J= 8.4 Hz, 1H), 3.80 (s, 3H).

[0322] Step 18.2: Synthesis of 6-Bromo-3-(2,6-dibenzyloxy-3-pyridyl)-l-methyl- indole. To a degassed mixture of 6-bromo-3-iodo-l-methyl-indole (168 mg, 0.500 mmol), 2,6- dibenzyloxy-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (229 mg, 0.550 mmol, intermediate provided by Celgene), K3PO4 (530 mg, 2.50 mmol), water (1.5 mL) and 1,4-dioxane (3 mL) at rt was added Pd(PPhs)4 (57.8 mg, 0.0500 mmol). The reaction vessel was sealed and the reaction mixture was heated to 100 °C for 8 h, then cooled to rt. EtOAc (50 mL) was added, and the layers were separated. The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using 3% Et2O in hexanes to afford the title compound (111 mg, 44%) as a solid. MS (ESI) [M+H]+499.1. 'HNMR (500 MHz, DMSO-t / 6) 6 7.85 (d, J= 8.0 Hz, 1H), 7.73 (d, J= 1.7 Hz, 1H), 7.58 (s, 1H), 7.54 (d, J= 8.5 Hz, 1H), 7.46 - 7.42 (m, 2H), 7.42 - 7.36 (m, 4H), 7.36 - 7.31 (m, 3H), 7.30 - 7.25 (m, 1H), 7.14 (dd, J= 8.5, 1.8 Hz, 1H), 6.55 (d, J= 8.0 Hz, 1H), 5.43 (s, 2H), 5.37 (s, 2H), 3.80 (s, 3H).

[0323] Step 18.3: Synthesis of terCButyl-7V-[l-[3-(2,6-dibenzyloxy-3-pyridyl)-l- methyl-indol-6-yl]-4-piperidyl]carbamate. To a degassed mixture of 6-bromo-3-(2,6- dibenzyloxy-3 -pyridyl)- 1-methyl-indole (440 mg, 0.880 mmol), tert-butyl A-(4- piperidyl)carbamate (264 mg, 1.32 mmol) and / BuONa (127 mg, 1.32 mmol) in THF (4.4 mL) at rt was added ZBuXPhos-Pd-G3 (74.5 mg, 90 pmol). The reaction vessel was sealed, and the reaction mixture was heated to 80 °C for 18 h, then cooled to rt, diluted with EtOAc (20 mL) and filtered on Celite. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel using a gradient of 10-50% EtOAc in hexanes to afford the title compound (360 mg, 66%) as a solid. MS (ESI) [M+H]+618.6. 'H NMR (500 MHz, DMSO-ifc) 6 7.88 (d, J= 8.1 Hz, 1H), 7.48 (d, J= 8.8 Hz, 1H), 7.45 - 7.39 (m, 5H), 7.39 - 7.35 (m, 2H), 7.35 - 7.32 (m, 2H), 7.30 - 7.27 (m, 1H), 6.88 (d, J= 2.0 Hz, 1H), 6.86 (d, J= 7.5 Hz, 1H), 6.80 (dd, J= 8.9, 2.1 Hz, 1H), 6.53 (d, J= 8.0 Hz, 1H), 5.44 (s, 2H), 5.35 (s, 2H), 3.72 (s, 3H), 3.65 - 3.56 (m, 2H), 3.38 (br s, 1H), 2.72 (t, J= 10.9 Hz, 2H), 1.88 - 1.79 (m, 2H), 1.61- 1.49 (m, 2H), 1.40 (s, 9H).

[0324] Step 18.4: Synthesis of tert-Butyl-A-[l-[3-(2,6-dioxo-3-piperidyl)-l-methyl- indol-6-yl]-4-piperidyl]carbamate. A mixture of tert-butyl 7V-[l-[3-(2,6-dibenzyloxy-3- pyridyl)-l-methyl-indol-6-yl]-4-piperidyl] carbamate (360 mg, 0.580 mmol) and Pearlman's catalyst (93.9 mg, 0.130 mmol) in EtOH (6 mL) and THF (6 mL) was hydrogenated (1 atm) at 50 °C for 1 h. The reaction mixture was cooled to rt, filtered on Celite and rinsed with EtOH (2 x 10 mL). The filtrate was concentrated under reduced pressure to afford the title compound (250 mg, 97%) as a solid which was used in the next step without further purification. MS (ESI) [M+H]+441.2.

[0325] Step 18.5: Synthesis of 3-[6-(4-Amino-l-piperidyl)-l-methyl-indol-3- yl]piperidine-2, 6-dione hydrochloride. To a solution of 4N HC1 in 1,4-dioxane (7 mL, 28 mmol) at rt was added tert-butyl 7V-[l-[3-(2,6-dioxo-3-piperidyl)-l-methyl-indol-6-yl]-4- piperidyl]carbamate (250 mg, 0.570 mmol) and the reaction mixture was stirred at rt for 3 h. The mixture was concentrated under reduced pressure and the residue was triturated in Et2O (20 mL), filtered and dried under reduced pressure to afford the title compound (200 mg, 93%) as a solid which was used in the next step without further purification. MS (ESI) [M+H]+341.2.

[0326] Step 18.6: Synthesis of 3-(6-(4-((5-chloro-4-((l-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)amino)piperi din-1 -yl)- 1 -methyl- lH-indol-3-yl)piperidine-2, 6-dione. A mixture of 5-[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]-l-methyl-indolin-2-one (43.9 mg, 0.150 mmol), 3 -[6-(4-amino-l -piperidyl)- l-methyl-indol-3-yl]piperidine-2, 6-dione hydrochloride(62.1 mg, 0.170 mmol), DIEA (100 pL, 0.750 mmol) in DMSO (1 mL) was degassed by bubbling nitrogen for 10 min. The reaction vessel was sealed, and the reaction mixture was heated to 90 °C for 18 h, then cooled to rt. The crude reaction mixture was purified by reverse phase chromatography (Cl 8) using a gradient of 10-80% MeCN and 10 mM ammonium formate in water to afford the title compound (10.5 mg, 10%) as a solid. MS (ESI) [M+H]+613.3. 'H NMR (500 MHz, Acetic acid-tZ4) 5 8.12 (s, 1H), 7.78 (d, J= 2.1 Hz, 1H), 7.72 (d, J= 8.7 Hz, 1H), 7.67 (d, J= 2.1 Hz, 1H), 7.62 (dd, J= 8.4, 2.2 Hz, 1H), 7.38 (dd, J= 8.7, 2.1 Hz, 1H), 7.28 (s, 1H), 7.07 (d, J= 8.4 Hz, 1H), 4.23 - 4.16 (m, 2H), 3.99 - 3.90 (m, 2H), 3.83 (s, 3H), 3.75 - 3.67 (m, 2H), 3.26 (s, 3H), 2.85 - 2.78 (m, 2H), 2.52 - 2.45 (m, 2H), 2.45 - 2.38 (m, 1H), 2.38 - 2.32 (m, 1H), 2.32 - 2.24 (m, 2H), 1.43 - 1.37 (m, 2H). Note'. 3 exchangeable protons not visible.3-(6-(4-(5-chloro-4-((l-(methyl-d3)-2-oxo-4-((2-(pyrimidin-2-yl)propan-2-yl)amino)-l,2- dihydroquinazolin-6-yl)amino)pyrimidin-2-yl)piperazin-l-yl)-l -methyl- lH-indazol-3- yl)piperidine-2, 6-dione

[0327] Step 19.1 : Synthesis of 3-(l-methyl-6-piperazin-l-yl-indazol-3-yl)piperidine-2, 6- dione;hydrochloride. The title compound was synthesized according to General Procedures 2, 4, and 5 using 6-bromo-3 -(2, 6-dibenzyloxy-3 -pyridyl)- 1-methyl-indazole, 1-boc-piperazine, 25 mol % RuPhos-Pd-G3CS2CO3 (1.2 equiv), and 1,4-dioxane, reacting at 90 °C in the first step.

[0328] Step 19.2: Synthesis of 4-[(l-methyl-l-pyrimidin-2-yl-ethyl)amino]-6-nitro-l- (trideuteriomethyl)quinazolin-2-one. To a solution of 4-[(l-methyl-l-pyrimidin-2-yl- ethyl)amino]-6-nitro-lH-quinazolin-2-one (150.0 mg, 0.46 mmol) in DMF (5.0 mL) was added NaH (60% dispersion in mineral oil, 36.7 mg, 0.92 mmol), at rt. After stirring for 30 minutes, iodomethane-ds (66.6 mg, 0.46 mmol) was added. The reaction mixture was stirred at rt for 2 h. Water (10.0 mL) was added and the resulting precipitate was collected by filtration then dried under vacuum to afford title compound (148.0 mg, 93%) as a solid, which was used in the next step without further purification.JH NMR (500 MHz, DMSO) 5 9.44 (s, 1H), 8.81 (s, 1H), 8.70 (d, J = 4.5 Hz, 2H), 8.46 (d, J = 9.2 Hz, 1H), 7.47 (d, J = 9.3 Hz, 1H), 7.31 - 7.23 (m, 1H), 1.81 (s, 6H). MS (ESI) [M+H]+344.3.

[0329] Step 19.3: Synthesis of 6-amino-4-[(l-methyl-l-pyrimidin-2-yl-ethyl)amino]- l-(trideuteriomethyl)quinazolin-2-one. A mixture of 4-[(l-methyl-l-pyrimidin-2-yl- ethyl)amino]-6-nitro-l-(trideuteriomethyl)quinazolin-2-one (148.0 mg, 0.43 mmol) and 10% Pd / C (45.8 mg, 0.04 mmol) in a mixture of ethanol (14.0 mL) and THF (14.0 mL) was hydrogenated under hydrogen atmosphere at rt for 3 h. The reaction was filtered through Celite and washed with MeOH. The filtrate was concentrated under reduced pressure to afford the title compound (130 mg, 96%) as a solid, which was used in the next step without further purification. MS (ESI) [M+H]+314.3.

[0330] Step 19.4: Synthesis of 6-[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]-4-[(l-methyl-l-pyrimidin-2-yl-ethyl)amino]-l-(trideuteriomethyl)quinazolin-2-one. To a solution of 6- amino-4-[(l -methyl- l-pyrimidin-2-yl-ethyl)amino]-l -(trideuteri omethyl)quinazolin-2-one(130.0 mg, 0.41 mmol) in a mixture of THF (7.5 mL) and DMF (1.5 mL) cooled to -40 °C, were sequentially added DIPEA (0.090 mL, 0.50 mmol) and 5-chloro-2,4-difluoro-pyrimidine (62.4 mg, 0.41 mmol). The reaction was slowly warmed to rt and stirred for 18 h. The volatiles were evaporated under reduced pressure. THF was added and the resulting precipitate was collected by filtration, washed with THF then dried under vacuum to afford title compound (79.0 mg, 43%) as a solid, which was used in the next step without further purification.1H NMR (500 MHz, DMSO) 5 9.81 (s, 1H), 8.78 - 8.65 (m, 2H), 8.45 - 8.33 (m, 2H), 8.18 (s, 1H), 7.77 (d, J= 9.1 Hz, 1H), 7.37 (d, J= 9.0 Hz, 1H), 7.34 - 7.22 (m, 1H), 1.81 (s, 6H).

[0331] Step 19.5: Synthesis of 3-[6-[4-[5-chloro-4-[[4-[(l-methyl-l-pyrimidin-2-yl- ethyl)amino] -2-oxo- 1 -(trideuteri omethyl)quinazolin-6-yl]amino]pyrimidin-2-yl]piperazin- 1-yl]- l-methyl-indazol-3-yl]piperidine-2, 6-dione. To a solution of 6-[(5-chloro-2-fluoro-pyrimidin-4- yl)amino]-4-[( 1 -methyl- 1 -pyrimidin-2-yl-ethyl)amino]- 1 -(trideuteri omethyl)quinazolin-2-one (37.0 mg, 0.08 mmol) in DMSO (1.0 mL) were sequentially added 3-(l-methyl-6-piperazin-l-yl- indazol-3-yl)piperidine-2,6-dione;hydrochloride (30.3 mg, 0.08 mmol) and DIEA (0.06 mL, 0.33 mmol), at rt. The reaction mixture was heated to 80 °C for 2 h and then cooled to rt. Water was added and the resulting precipitate was collected by filtration, washed with diethyl ether (3 x 5.0 mL) and dried under vacuum to afford the title compound (16.8 mg, 26%) as a solid. 'H NMR (500 MHz, DMSO) 5 10.84 (s, 1H), 9.02 (s, 1H), 8.73 (d, J = 4.8 Hz, 2H), 8.66 (d, J = 1.4 Hz, 1H), 8.18 (s, 1H), 8.12 (s, 1H), 7.75 (dd, J = 9.1, 1.7 Hz, 1H), 7.47 (d, J = 8.9 Hz, 1H), 7.33 - 7.26 (m, 2H), 6.85 (dd, J = 9.0, 0.8 Hz, 1H), 6.76 (s, 1H), 4.25 (dd, J = 9.2, 5.1 Hz, 1H), 3.84 - 3.80 (m, 4H), 3.79 (s, 3H), 3.28 - 3.22 (m, 4H), 2.66 - 2.56 (m, 2H), 2.33 - 2.24 (m, 1H), 2.18 - 2.09 (m, 1H), 1.81 (s, 6H). MS (ESI) [M+H]+751.4.3-[7-[[5-Chloro-2-[4-[[3-(2,6-dioxo-3-piperidyl)-l-methyl-indazol-6-yl]amino]-l- piperidyl]pyrimidin-4-yl]amino]-3-oxo-4-(trideuteriomethyl)-l,4-benzoxazin-2-yl]-7V-methyl- propanamide

[0332] Step 20.1: Synthesis of (2S)-2-bromo-5-methoxy-5-oxo-pentanoic acid. To a solution of (2S)-2-amino-5-methoxy-5-oxo-pentanoic acid (3.75 g, 23.3 mmol) and NaBr (6.58 g,64.0 mmol) in 1.0 M HBr (140.0 mL), cooled to -5 °C, was added a solution of NaNCh (3.05 g, 44.2 mmol) in H2O (25.0 mL) dropwise over a period of 30 min. The reaction mixture was stirred for 10 h and then concentrated H2SO4 (2.50 mL) was added dropwise. After stirring for 5 min, diethyl ether (150.0 mL) was added and the layers were separated. The aqueous layer was extracted with diethyl ether (2 x 150.0 mL) and the combined organic extracts were washed with brine (100.0 mL), then dried (Na2SO4), filtered and concentrated under reduced pressure. The material was purified by column chromatography on silica gel eluting with an ethyl acetate / hexane gradient (0 - 70 %) to provide the title compound (750.0 mg, 14 %) as an oil.JH NMR (400 MHz, acetic acid) 5 4.49 (dd, J = 8.5, 5.8 Hz, 1H), 3.73 (s, 3H), 2.68 - 2.52 (m, 2H), 2.49 - 2.39 (m, 1H), 2.36 - 2.23 (m, 1H).

[0333] Step 20.2: Synthesis of Methyl 3-(7-nitro-3-oxo-4H-l,4-benzoxazin-2- yl)propanoate. To a solution of (2S)-2-bromo-5-methoxy-5-oxo-pentanoic acid (940.0 mg, 4.18 mmol) in THF cooled to 0 °C (15.0 ml) was added oxalyl chloride (707.0 pL, 8.35 mmol). The reaction mixture was stirred at 0 °C for 2 h. The volatiles were removed under reduced pressure to provide methyl (4S)-4-bromo-5-chloro-5-oxo-pentanoate. To a solution of methyl (4S)-4- bromo-5-chloro-5-oxo-pentanoate in NMP (15.0 mL) were sequentially added 2-amino-5-nitro- phenol (644 mg, 4.18 mmol) and K2CO3 (1.73 g, 12.5 mmol). The reaction mixture was heated to 80 °C for 2 h and then cooled to rt. Water (25.0 mL), 5% citric acid (25.0 mL) and ethyl acetate (25.0 mL) were added and after stirring for 5 min the layers were separated. The aqueous layer was extracted with ethyl acetate (2 x 25.0 mL) and the combined organic extracts were washed with brine (50.0 mL), then dried (Na2SO4), filtered and concentrated under reduced pressure. Ethyl acetate (10.0 mL) was added and the resulting precipitate was collected by filtration, dried under vacuum, to provide the title compound (650.0 mg, 56%) as a solid, which was used in the next step without further purification. 'H NMR (400 MHz, DMSO) 5 11.34 (s, 1H), 7.92 (dd, J = 8.7,2.5 Hz, 1H), 7.78 (d, J = 2.5 Hz, 1H), 7.07 (d, J = 8.7 Hz, 1H), 4.79 (dd, J = 8.6, 4.4 Hz, 1H), 3.60 (s, 3H), 2.55 (t, J = 7.4 Hz, 2H), 2.21 - 2.10 (m, 1H), 2.07 - 1.96 (m, 1H).

[0334] Step 20.3: Synthesis of Methyl 3-[7-nitro-3-oxo-4-(trideuteriomethyl)-l,4- benzoxazin-2-yl] propanoate. Iodomethane-t / 3 (240 pL, 3.85 mmol) was added to a mixture of methyl 3-(7-nitro-3-oxo-4J / -l,4-benzoxazin-2-yl) propanoate (900 mg, 3.21 mmol) and K2CO3 (1.33 g, 9.63 mmol) in MeCN (25 mL). The mixture was heated to 70 °C and stirred for 4 h. Water (50 mL) was added and the resulting precipitate was collected by filtration, washed with Et2O (3 x 10 mL), then dried under vacuum to afford the title compound (700 mg, 73%) as a solid, which was used as such without further purification. *HNMR (500 MHz, DMSO-de) 5 7.99 (dd, J= 8.9,2.6 Hz, 1H), 7.83 (d, J= 2.6 Hz, 1H), 7.37 (d, J= 8.9 Hz, 1H), 4.84 (dd, J= 8.7, 4.5 Hz, 1H), 3.60(s, 3H), 2.55 (t, J= 7.4 Hz, 2H), 2.21 - 2.10 (m, 1H), 2.07 - 1.97 (m, 1H).

[0335] Step 20.4: Synthesis of 3-[7-Amino-3-oxo-4-(trideuteriomethyl)-l,4- benzox:izin-2-yl|-\-inethyl-prop:in:iinide. A mixture of methyl 3-[7-nitro-3-oxo-4- (trideuteriomethyl)-l,4-benzoxazin-2-yl]propanoate (700 mg, 2.35 mmol) and 10% Pd / C (251 mg, 0.240 mmol) in MeOH (20 mL) was hydrogenated (1 atm) at rt for 2 h. The mixture was filtered on Celite and washed with MeOH (2 x 25 mL). The filtrate was concentrated under reduced pressure to afford a solid. To a solution of this crude intermediate in MeOH (15 mL) at rt was added methylamine (4.39 mL, 35.3 mmol, 33% wt. in EtOH) and the mixture was heated at 70 °C for 16 h, then cooled to rt. The volatiles were removed under reduced pressure and the residue was purified by reverse phase chromatography (Cl 8), using a gradient of 5-80% MeCN and 10 mM ammonium formate in water to afford a racemic mixture of title compound. Both enantiomers were separated using Chiral SFC (LuxCel2) eluting with isocratic 55% zPrOH and lOmM ammonium formate in water to afford the separated enantiomers. Each of these enantiomers was taken through the subsequent steps.

[0336] Step 20.5: Synthesis of 3-[7-[(5-Chloro-2-fluoro-pyrimidin-4-yl)amino]-3-oxo-4- (trideuteriomethyl)-l,4-benzoxazin-2-yl]-7V-methyl-propanamide. To a solution of 3-[7-amino-3- oxo-4-(trideuteriomethyl)-l,4-benzoxazin-2-yl]-7V-methyl-propanamide (139 mg, 0.520 mmol, first eluting isomer) and DIEA (109 pL, 0.630 mmol) in THF (5 mL) and DMF (1 mL) at -40 °C was added dropwise 5-chloro-2,4-difluoro-pyrimidine (78.6 mg, 0.520 mmol) and the mixture was warm to rt and stirred for 16 h. The volatiles were evaporated under reduced pressure. Water (10 mL) was added and the resulting precipitate was collected by filtration, washed with water (2 x 10 mL) and then dried under vacuum to afford the title compound (162 mg, 78%) as a solid, which was used as such without further purification. MS (ESI) [M-H] 395.3.

[0337] Step 20.6: Synthesis of 3-[7-[[5-Chloro-2-[4-[[3-(2,6-dioxo-3-piperidyl)-l- methyl-indazol-6-yl]amino]-l-piperidyl]pyrimidin-4-yl]amino]-3-oxo-4-(trideuteriomethyl)-l,4- benzoxazin-2-yl]-7V-methyl-propanamide. To a solution of 3-[7-[(5-chloro-2-fluoro-pyrimidin-4- yl) amino]-3-oxo-4-(trideuteriomethyl)-l,4-benzoxazin-2-yl]-7V-methyl-propanamide (65 mg, 0.160 mmol) in DMSO (2 mL) were added sequentially 3-[l-methyl-6-(4- piperidylamino)indazol-3-yl]piperidine-2, 6-dione dihydrochloride (55.9 mg, 0.160 mmol) and DIEA (114 pL, 0.66 mmol). The mixture was heated to 80 °C for 2 h and then cooled to rt. Water (10 mL) was added and the resulting precipitate was collected by filtration, washed with Et2O (3 x 5 mL) and dried under vacuum to afford diastereoisomers which were separated using Chiral SFC (AD) eluting with isocratic 55% zPrOH and lOmM ammonium formate in water to afford the title compounds as separated diastereomers:

[0338] 1stdiastereomer- MS (ESI) [M+H]+718.4. 'H NMR (500 MHz, DMSO-t / 6) 8 8.71 (s, 1H), 8.06 (s, 1H), 7.77 - 7.72 (m, 1H), 7.44 - 7.39 (m, 2H), 7.32 (d, J= 8.8 Hz, 1H), 7.10 (d, J= 9.0 Hz, 1H), 6.52 (dd, J= 8.8, 1.7 Hz, 1H), 6.46 (s, 1H), 5.78 (d, J= 7.9 Hz, 1H), 4.61 (dd, J = 8.9, 4.6 Hz, 1H), 4.46 - 4.36 (m, 2H), 4.18 (dd, J= 8.8, 5.2 Hz, 1H), 3.82 (s, 3H), 3.69 - 3.59 (m, 1H), 3.16 (t, J = 11.3 Hz, 2H), 2.63 - 2.55 (m, 2H), 2.52 - 2.51 (m, 3H), 2.30 - 2.20 (m, 3H), 2.18 - 2.10 (m, 1H), 2.05 - 1.95 (m, 3H), 1.92 - 1.81 (m, 1H), 1.39 - 1.28 (m, 2H). Note: glutarimide signal not visible.

[0339] 2nddiastereomer- MS (ESI) [M+H]+718.4. 'H NMR (500 MHz, DMSO-t / 6) 6 8.71 (s, 1H), 8.06 (s, 1H), 7.78 - 7.70 (m, 1H), 7.44 - 7.37 (m, 2H), 7.32 (d, J= 8.7 Hz, 1H), 7.11 (d, J= 8.9 Hz, 1H), 6.51 (d, J= 8.8 Hz, 1H), 6.46 (s, 1H), 5.78 (d, J= 8.5 Hz, 1H), 4.61 (dd, J= 8.8, 4.6 Hz, 1H), 4.41 (d, J = 12.1 Hz, 2H), 4.18 (dd, J = 8.8, 5.2 Hz, 1H), 3.82 (s, 3H), 3.69 - 3.60 (m, 1H), 3.16 (t, J = 11.3 Hz, 2H), 2.63 - 2.57 (m, 2H), 2.53 - 2.51 (m, 3H), 2.28 - 2.20 (m, 3H), 2.19 - 2.11 (m, 1H), 2.05 - 1.95 (m, 3H), 1.91 - 1.82 (m, 1H), 1.38 - 1.28 (m, 2H). Note: glutarimide signal not visible.

[0340] 3rddiastereomer - MS (ESI) [M+H]+718.4. 'H NMR (500 MHz, DMSO-t / 6) 8 10.81 (br s, 1H), 8.71 (s, 1H), 8.05 (s, 1H), 7.75 (d, J= 3.9 Hz, 1H), 7.45 - 7.37 (m, 2H), 7.32 (d,J= 8.8 Hz, 1H), 7.10 (d, J= 8.3 Hz, 1H), 6.52 (d, J= 8.6 Hz, 1H), 6.46 (s, 1H), 5.78 (d, J = 7.0 Hz, 1H), 4.61 (dd, J = 8.6, 4.6 Hz, 1H), 4.46 - 4.35 (m, 2H), 4.18 (dd, J= 8.5, 5.3 Hz, 1H), 3.82 (s, 3H), 3.69 - 3.61 (m, 1H), 3.16 (t, J= 11.5 Hz, 2H), 2.65 - 2.56 (m, 2H), 2.53 - 2.51 (m, 3H), 2.30 - 2.20 (m, 3H), 2.20 - 2.10 (m, 1H), 2.07 - 1.94 (m, 3H), 1.94 - 1.81 (m, 1H), 1.40 - 1.27 (m, 2H).

[0341] 4thdiastereomer - MS (ESI) [M+H]+718.4. 'HNMR (500 MHz, DMSO-t / 6) 8 8.71 (s, 1H), 8.05 (s, 1H), 7.78 - 7.71 (m, 1H), 7.44 - 7.38 (m, 2H), 7.32 (d, J= 8.8 Hz, 1H), 7.10 (d, J= 8.4 Hz, 1H), 6.52 (d, J= 8.6 Hz, 1H), 6.46 (s, 1H), 5.78 (d, J= 8.1 Hz, 1H), 4.61 (dd, J= 8.7, 4.5 Hz, 1H), 4.47 - 4.36 (m, 2H), 4.18 (dd, J= 8.6, 5.1 Hz, 1H), 3.82 (s, 3H), 3.68 - 3.61 (m, 1H), 3.16 (t, J= 11.2 Hz, 2H), 2.65 - 2.56 (m, 2H), 2.53 - 2.51 (m, 3H), 2.24 (t, J= 7.6 Hz, 3H), 2.19 - 2.09 (m, 1H), 2.06 - 1.94 (m, 3H), 1.92 - 1.81 (m, 1H), 1.41 - 1.26 (m, 2H). Note: glutarimide signal not visible.3-(5-(4-((5-chloro-4-((l-methyl-2-oxoindolin-5-yl)amino)pyrimidin-2- yl)(methyl)amino)piperidin-l-yl)-lH-benzo[d]imidazol-l-yl)piperidine-2, 6-dione

[0342] Step 21.1: 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 MeOH (200 mL) and the filtrate was concentrated under reduced pressure. EtOAc (500 mL) and a saturated aqueous solution of NaHCCL (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 the 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.

[0343] Step 21.2: Synthesis of 2,6-Dibenzyloxy-7V-(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-l- fluoro-2-nitro-benzene (2.8 mL, 22.9 mmol) in THF (163 mL) at 0 °C was added IM LiHMDS in THF (68.6 mL, 68.6 mmol) dropwise over 30 min. After the addition was completed, thereaction mixture was stirred at rt for 3 h and then cooled to 0 °C. A saturated aqueous solution of NH4CI (150 mL) and EtOAc (300 mL) were added and the layers were separated. The organic layer was washed with a saturated aqueous solution of NaHCCL (150 mL), water (150 mL), brine (150 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a gradient of 0-50% EtOAc in hexanes to afford the title compound (8.7 g, 53%). *H NMR (400 MHz, CDCI3) 8 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). MS (ESI) [M+H]+508.2.

[0344] Step 21.3: Synthesis of Bromo-\ l-(2.6-dibenzyloxy-3-pyridyl)benzene-1.2- diamine. To a solution of 2,6-dibenzyloxy-A-(4-bromo-2-nitro-phenyl)pyridin-3-amine (8.7 g, 17 mmol) and CaCL (3.8 g, 34 mmol) in EtOH (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 EtOAc (200 mL) and the filtrate was concentrated under reduced pressure. EtOAc (400 mL) and water (300 mL) were added and the 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.

[0345] Step 21.4: Synthesis of 5-Bromo-l-(2,6-dibenzyloxy-3-pyridyl)benzimidazole. To a solution of 4-bromo-Al-(2,6-dibenzyloxy-3-pyridyl)benzene-l,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 % EtOAc in hexanes to afford the title compound (5.4 g, 87%) as a semi-solid. *HNMR (500 MHz, DMSO) 5 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). MS (ESI) [M+H]+487.2.

[0346] Step 21.5: Synthesis of tert- Butyl \-|l-|l-(2.6-dibenzyloxy-3- pyridyl)benzimidazol-5-yl]-4-piperidyl]-A-methyl-carbamate. A mixture of 5-bromo-l-(2,6- dibenzyloxy-3-pyridyl)benzimidazole (500 mg, 1.03 mmol), tert-butyl A-methyl-A-(4- piperidyl)carbamate (440 mg, 2.1 mmol), NaO / Bu (296 mg, 3.1 mmol) and ZBuXPhos-Pd-G3 (82 mg, 0.10 mmol) in THF (12.5 mL) was heated to 70 °C for 18 h and then cooled to rt. The mixture was filtered through Celite, washed with MeOH (20 mL) and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using agradient of 0-100% EtOAc in hexanes to afford the title compound (284 mg, 45 % yield) as an oil. 'H NMR (500 MHz, DMSO) 5 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). MS (ESI) [M+H]+621.4.

[0347] Step 21.6: Synthesis of tc / 7-Butyl \ | l-| l-(2.6-dioxo-3- piperidyl)beiiziiiiid:izol-5-yl|-4-piperidyl|- \ -niethyl-c:irb:ini:ite. A mixture of tert-butyl N-[l- [l-(2,6-dibenzyloxy-3-pyridyl)benzimidazol-5-yl]-4-piperidyl]-N-methyl-carbamate (285 mg, 0.46 mmol) and 20% Pd(OH)2 / C (42 mg, 0.06 mmol) in THF (6 mL) and EtOH (6 mL) was subjected to hydrogenation at 1 atm and 50 °C for 5 h. The mixture was filtered through Celite and washed with MeOH (3 x 10 mL). The filtrate was concentrated under reduced pressure to afford title compound Id (192 mg) as a semi-solid which was used in the next step without further purification. MS (ESI) [M+H]+ 442.3.

[0348] Step 21.7: Synthesis of 3-[5-[4-(Methylamino)-l-piperidyl]benzimidazol-l- yl]piperidine-2, 6-dione dihydrochloride. To a solution of / c / 7-butyl A-[l-[l-(2,6-dioxo-3- piperidyl)benzimidazol-5-yl]-4-piperidyl]-A-methyl-carbamate (192 mg, 0.43 mmol) in 1,4- dioxane (10 mL) was added 4NHC1 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 the title compound (210 mg) as a solid which was used in the next step without further purification. MS (ESI) [M+H]+342.2.

[0349] Step 21.8: Synthesis of 3-[5-[4-[[5-Chloro-4-[(l-methyl-2-oxo-indolin-5- yl)amino]pyrimidin-2-yl]-methyl-amino]-l-piperidyl]benzimidazol-l-yl]piperidine-2, 6-dione.To a solution of 3-[5-[4-(methylamino)-l-piperidyl]benzimidazol-l-yl]piperidine-2, 6-dione hydrochloride (50 mg, 0.15 mmol) in DMSO (0.7 mL) were added sequentially 5-[(5-chloro-2- fluoro-pyrimidin-4-yl)amino]-l-methyl-indolin-2-one (21 mg, 0.07 mmol) and DIEA (0.1 mL, 0.59 mmol). The reaction mixture was heated to 80 °C for 18 h and then cooled to rt. The crude reaction mixture was purified by preparative HPLC (BEH column, Cl 8) using a gradient of 35- 45% MeCN and 10 mM ammonium formate in water to afford the title (4.8 mg, 10%) as a solid. MS (ESI) [M+H]+614.3. 'H NMR (500 MHz, DMSO-t / 6) 8 8.58 (s, 1H), 8.47 (s, 1H), 8.14 (s, 1H), 8.02 (s, 1H), 7.68 - 7.56 (m, 1H), 7.38 (d, J= 8.6 Hz, 1H), 7.18 (d, J= 2.3 Hz, 1H), 7.05 - 7.00 (m, 1H), 6.94 (d, J= 8.4 Hz, 1H), 5.61 (dd, J= 13.4, 5.3 Hz, 1H), 3.69 (d, J= 9.8 Hz, 2H), 3.54 (s, 2H), 3.30 - 3.26 (m, 3H), 3.09 (s, 3H), 2.93 (s, 3H), 2.89 - 2.65 (m, 3H), 2.23 - 2.19 (m, 1H), 1.95 - 1.87 (m, 2H), 1.71 - 1.65 (m, 2H). Note', one exchangeable proton not observed.3-(6-((5-chloro-2-(4-((3-(2,6-dioxopiperidin-3-yl)-l-methyl-lH-indazol-6-yl)amino)piperidin-l- yl)pyrimidin-4-yl)amino)- 1 -methyl-2-oxo- 1 ,4-dihydroquinazolin-3 (2H)-yl)-N- methylpropanamide

[0350] Step 22.1: Synthesis of 2-(aminomethyl)-4-bromo-N-methyl-aniline. To a solution of 5-bromo-2-(methylamino)benzonitrile (500 mg, 2.37 mmol) in THF (20.0 mL) cooled to 0 °C was added a 1.0 M solution of BH3 in THF (4.74 mL, 4.74 mmol) dropwise over a period of 10 minutes. After the addition was completed, the reaction mixture was stirred at rt overnight and then cooled to 0 °C. Aqueous HC1 (6.0 M, 10.0 mL) was added and the volatiles were evaporated under reduced pressure. The pH of the solution was adjusted to 10 using aqueous NaOH (1 M). DCM (100 mL) was added and the layers were separated. The aqueous layer was extracted with DCM (2 x 100 mL) and the combined organic extracts were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the title compound (400 mg, 78%) as a solid. 'HNMR (500 MHz, DMSO) 5 7.27 - 7.13 (m, 2H), 6.42 (d, J = 8.5 Hz, 1H), 5.82 (d, J = 4.1 Hz, 1H), 3.60 (s, 2H), 2.70 (d, J = 4.5 Hz, 3H), 1.83 (s, 2H).

[0351] Step 22.2: Synthesis of 6-bromo-l-methyl-3,4-dihydroquinazolin-2-one. To a solution of 2-(aminomethyl)-4-bromo-N-methyl-aniline (2.0 g, 9.30 mmol) in THF (30.0 mL) was added CDI (1.96 g, 12.1 mmol). The reaction mixture was refluxed for 18 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% MeOH in DCM to afford the title compound (2.10 g, 94%) as a solid. ’H NMR (500 MHz, DMSO) 5 7.40 (dd, J = 8.6, 2.4 Hz, 1H), 7.38 - 7.36 (m, 1H), 7.13 (s, 1H), 6.87 (d, J = 8.6 Hz, 1H), 4.36 - 4.19 (m, 2H), 3.12 (s, 3H). MS (ESI) [M+H]+243.1.

[0352] Step 22.3: Synthesis of 3-(6-bromo-l-methyl-2-oxo-4H-quinazolin-3-yl)-N- methyl-propanamide. To a solution of 6-bromo-l-methyl-3,4-dihydroquinazolin-2-one (450 mg, 1.87 mmol) in 1,4-dioxane (5.6 mL) cooled to 0 °C were sequentially added KOH (105.0 mg, 1.87 mmol) and methyl N-methylprop-2-enamide (238 mg, 2.80 mmol). The reaction mixture was stirred at rt overnight. Water (20 mL) and ethyl acetate (40 mL) were added and the layers were separated. The aqueous layer was extracted with ethyl acetate (2 x 40.0 mL) and the combined organic extracts were washed with brine (50 mL), dried over Na2SO4, filtered andconcentrated under reduced pressure. The material was purified by column chromatography on silica gel using a gradient of 0-20% MeOH in DCM to afford the title compound (400 mg, 66%) as a solid. 'HNMR (500 MHz, CDC13) 8 7.35 (dd, J = 8.6, 2.1 Hz, 1H), 7.18 (d, J = 1.7 Hz, 1H), 6.69 (d, J = 8.7 Hz, 1H), 6.14 (s, 1H), 4.40 (s, 2H), 3.70 (t, J = 6.4 Hz, 2H), 3.25 (s, 3H), 2.77 (d, J = 4.8 Hz, 3H), 2.53 (t, J = 6.4 Hz, 2H).

[0353] Step 22.4: Synthesis of tert-butyl N-[l-methyl-3-[3-(methylamino)-3-oxo- propyl]-2-oxo-4H-quinazolin-6-yl]carbamate. A suspension of 3-(6-bromo-l-methyl-2-oxo- 4H-quinazolin-3-yl)-N-methyl-propanamide (325.0 mg, 1.0 mmol), tert-butyl carbamate (175.0 mg, 1.49 mmol), CS2CO3 (649.0 mg, 1.99 mmol), Pd(OAc)2 (22.4 mg, 0.10 mmol) and X-Phos (86.4 mg, 0.20 mmol) in 1,4-dioxane (27.0 mL) was degassed with nitrogen, and the resulting mixture was heated to 90 °C for 24 h and then cooled to rt. The reaction was filtered through Celite, washed with DCM (30 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% MeOH in DCM to afford the title compound (320 mg, 89%) as a solid.1H NMR (500 MHz, CDCI3) 6 7.20 (s, 1H), 7.15 (d, J = 8.6 Hz, 1H), 6.74 (d, J = 8.7 Hz, 1H), 6.43 (s, 1H), 6.36 (s, 1H), 4.39 (s, 2H), 3.70 (t, J = 6.5 Hz, 2H), 3.26 (s, 3H), 2.77 (d, J = 4.8 Hz, 3H), 2.54 (t, J = 6.4 Hz, 2H), 1.51 (s, 9H). MS (ESI) [M+H]+363.3.

[0354] Step 22.5: Synthesis of [l-methyl-3-[3-(methylamino)-3-oxo-propyl]-2-oxo- 4H-quinazolin-6-yl]ammonium;2,2,2-trifluoroacetate. To a solution of tert-butyl N-[l-methyl- 3-[3-(methylamino)-3-oxo-propyl]-2-oxo-4H-quinazolin-6-yl]carbamate (320 mg, 0.88 mmol) in DCM (5.0 mL) cooled to 0 °C was added TFA (2.0 mL). The reaction mixture was stirred at rt for 4 h. The volatiles were evaporated under reduced pressure to afford the title compound (330 mg, 99%) as a solid, which was used in the next step without further purification.1H NMR (400 MHz, DMSO) 6 9.40 (bs, 3H), 7.84 (s, 1H), 7.18 (d, J = 8.6 Hz, 1H), 7.07 (s, 1H), 6.98 (d, J = 8.6 Hz, 1H), 4.41 (s, 2H), 3.52 (t, J = 6.4 Hz, 2H), 3.17 (s, 3H), 2.57 - 2.52 (m, 3H), 2.36 (t, J = 6.2 Hz, 2H). MS (ESI) [M+H]+263.2.

[0355] Step 22.6: Synthesis of 3-[6-[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]-l- methyl-2-oxo-4H-quinazolin-3-yl]-N-methyl-propanamide. To a solution of of [l-methyl-3- [3-(methylamino)-3-oxo-propyl]-2-oxo-4H-quinazolin-6-yl]ammonium;2,2,2-trifluoroacetate (126 mg, 0.33 mmol) in a mixture of THF (5.0 mL) and DMF (1.0 mL) cooled to -40 °C were sequentially added 5-chloro-2,4-difluoro-pyrimidine (35.5 pL, 0.37 mmol) and DIEA (140.0 pL, 0.84 mmol). The reaction mixture was slowly warmed to rt and stirred for 24 h. The volatiles were evaporated under reduced pressure. Diethyl ether (20.0 mL) was slowly added, a precipitate formed and was collected by filtration, washed with diethyl ether (10.0 mL) then dried undervacuum to afford the title compound (82.0 mg, 62%) as a solid, which was used in the next step without further purification. 'HNMR (500 MHz, DMSO) 5 9.54 (s, 1H), 8.35 (s, 1H), 7.85 (d, J = 4.2 Hz, 1H), 7.42 (dd, J = 8.7, 2.4 Hz, 1H), 7.32 (d, J = 2.1 Hz, 1H), 6.95 (d, J = 8.8 Hz, 1H), 4.40 (s, 2H), 3.54 (t, J = 7.1 Hz, 2H), 3.20 (s, 3H), 2.56 (d, J = 4.6 Hz, 3H), 2.38 (t, J = 7.1 Hz, 2H). MS (ESI) [M+H]+393.4.

[0356] Step 22.7: Synthesis of 3-(6-((5-chloro-2-(4-((3-(2,6-dioxopiperidin-3-yl)-l- m ethyl- lH-indazol-6-yl)amino)piperidin- 1 -yl)pyrimidin-4-yl)amino)- 1 -methyl-2-oxo- 1 ,4- dihydroquinazolin-3(2H)-yl)-N-methylpropanamide. To a solution of 3-[6-[(5-chloro-2-fluoro- pyrimidin-4-yl)amino]-l-methyl-2-oxo-4H-quinazolin-3-yl]-N-methyl-propanamide (30.0 mg, 76.0 pmol) in DMSO (1.0 mL) were sequentially added 3-[l-methyl-6-(4- piperidylamino)indazol-3-yl]piperidine-2,6-dione;hydrochloride (31.1 mg, 80.0 pmol) and DIEA (33.3 pL, 190.0 pmol). The reaction mixture was heated to 80 °C overnight and then cooled to rt. The reaction was directly purified by preparative HPLC (BEH, Cl 8) using a gradient of 36-66% acetonitrile and 10 mM ammonium formate in water to afford the title compound (29 mg, 53%) as a solid.1HNMR (500 MHz, DMSO) 5 10.79 (s, 1H), 8.66 (s, 1H), 8.03 (s, 1H), 7.86 - 7.73 (m, 1H), 7.53 (dd, J = 8.8, 2.4 Hz, 1H), 7.50 - 7.40 (m, 1H), 7.32 (d, J = 8.8 Hz, 1H), 6.88 (d, J = 8.9 Hz, 1H), 6.52 (dd, J = 8.8, 1.7 Hz, 1H), 6.46 (s, 1H), 5.78 (d, J = 8.1 Hz, 1H), 4.50 - 4.37 (m, 2H), 4.36 (s, 2H), 4.18 (dd, J = 8.8, 5.1 Hz, 1H), 3.82 (s, 3H), 3.72 - 3.58 (m, 1H), 3.55 - 3.48 (m, 2H), 3.16 (s, 3H), 3.16 - 3.08 (m, 2H), 2.65 - 2.57 (m, 2H), 2.52 - 2.51 (m, 3H, masked with DMSO), 2.35 (t, J = 7.1 Hz, 2H), 2.31 - 2.20 (m, 1H), 2.20 - 2.09 (m, 1H), 2.02 (d, J = 10.4 Hz, 2H), 1.40 - 1.27 (m, 2H). MS (ESI) [M+H]+714.4.3-(6-((l-(5-chloro-4-((l-methyl-2-oxo-4-((2-(pyrimidin-2-yl)propan-2-yl)amino)-l,2- dihydroquinazolin-6-yl)amino)pyrimidin-2-yl)piperidin-4-yl)(methyl)amino)-l-methyl-lH- indazol-3-yl)piperidine-2, 6-dione

[0357] Step 23.1: Synthesis of tert-Butyl 4-[[3-(2,6-dibenzyloxy-3-pyridyl)-l-methyl- indazol-6-yl]amino]piperidine-l-carboxylate. A mixture of 6-bromo-3-(2,6-dibenzyloxy-3- pyridyl)-l-methyl-indazole (500 mg, 1 mmol), tert-butyl 4-aminopiperidine-l -carboxylate (240 mg, 1.2 mmol), RuPhos-Pd-G3 (83 mg, 0.1000 mmol) and CS2CO3 (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 EtOAc (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% EtOAc in hexanes to afford the title compound (550 mg, 89%) as a solid.JH NMR (500 MHz, CDC13) 87.89 (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). MS (ESI) [M+H]+620.5.

[0358] Step 23.2: Synthesis of tert-Butyl 4-[[3-(2,6-dibenzyloxy-3-pyridyl)-l-methyl- indazol-6-yl]-methyl-amino]piperidine-l -carboxylate. To a solution of tert-butyl 4-[[3-(2,6- dibenzyloxy-3-pyridyl)-l-methyl-indazol-6-yl]amino] piperidine- 1 -carboxylate (550 mg, 0.89 mmol) in DMSO (3.6 mL) and acetic acid (0.9 mL) were sequentially added aqueous solution of formaldehyde (0.13 mL, 1.8 mmol) and NaBH(OAc)s (282 mg, 1.3 mmol). The reaction mixture was stirred at rt for 1 h. Water (10 mL) and EtOAc (25 mL) were added and the layers were separated. The organic layer was washed with a saturated aqueous solution of NaHCOs (5 mL), water (3 x 5 mL), brine (5 mL), dried on Na2SO4, filtered and concentrated under reduced pressure. The material was purified by column chromatography on silica gel using a gradient of 0-100% EtOAc in hexanes to afford the title compound (467 mg, 83% yield) as a solid. 'H NMR (400 MHz, CDCI3) 67.91 (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). MS (ESI) [M+H]+635.5.

[0359] Step 23.3: tert-Butyl 4-[[3-(2,6-dioxo-3-piperidyl)-l-methyl-indazol-6-yl]- methyl-amino] piperidine-l-carboxylate. A mixture of tert-butyl 4-[[3-(2,6-dibenzyloxy-3- pyridyl)-l-methyl-indazol-6-yl]-methyl-amino]piperidine-l -carboxylate (467 mg, 0.74 mmol) and 20% Pd(OH)2 / C (117 mg, 25 wt%) in THF (7 mL) and EtOH (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 MeCN and MeOH (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% MeOH in DCM to afford the title compound (258 mg, 77%) as a solid. 'H NMR (500 MHz, DMSO) 6 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). MS (ESI) [M+H]+456.3.

[0360] Step 23.4: Synthesis of 3-[l-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)-l-methyl-indazol-6-yl]-methyl-amino]piperidine-l-carboxylate (258 mg, 0.57 mmol) in 1,4-di oxane (10 mL) was added 4M HC1 in 1,4-di oxane (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. Et2O (5 x mL) was added and the resulting precipitate was collected by filtration, washed with 1,4-di oxane (3 x 1 mL) and Et2O (10 x 2 mL) then dried under vacuum to afford the title compound (217 mg, 92%) as a solid. 'H NMR (400 MHz, D2O) 5 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-di oxane. MS (ESI) [M+H]+356.2.

[0361] Step 23.5: Synthesis of 3-(6-((l-(5-chloro-4-((l-methyl-2-oxo-4-((2-(pyrimidin-2- yl)propan-2-yl)amino)-l,2-dihydroquinazolin-6-yl)amino)pyrimidin-2-yl)piperidin-4- yl)(methyl)amino)-l-methyl-lH-indazol-3-yl)piperidine-2, 6-dione. To a solution of 3-[l-methyl- 6-[methyl(4-piperidyl)amino]indazol-3-yl]piperidine-2, 6-dione (43.0 mg, 0.12 mmol) in DMSO (0.7 mL) were sequentially added 6-[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]-l-methyl-4-[(l- methyl-l-pyrimidin-2-yl-ethyl)amino]quinazolin-2-one (48.0 mg, 0.11 mmol) and DIPEA (0.08 mL, 0.48 mmol), at rt. The reaction mixture was heated to 80 °C for 12 h and then cooled to rt. The mixture was purified by preparative HPLC (BEH, C18) using a gradient of 41-51% acetonitrile and 10 mM ammonium formate in water to afford the title compound (30.5 mg, 32%) as a solid. 'H NMR (500 MHz, DMSO) 5 10.84 (s, 1H), 8.93 (s, 1H), 8.57 (d, J = 4.4 Hz, 3H), 8.11 (s, 1H), 8.07 (s, 1H), 7.75 (d, J = 9.0 Hz, 1H), 7.43 (d, J = 8.8 Hz, 1H), 7.29 (d, J = 8.5 Hz, 1H), 7.16 - 7.10 (m, 1H), 6.84 (d, J = 8.6 Hz, 1H), 6.61 (s, 1H), 4.66 - 4.62 (m, 2H), 4.28 - 4.21 (m, 1H), 4.03 - 3.97 (m, 1H), 3.82 (s, 3H), 3.30 (s, 3H, obscured by water), 2.92 (t, J = 11.1 Hz, 2H), 2.71 (s, 3H), 2.65 - 2.59 (m, 2H), 2.33 - 2.24 (m, 1H), 2.21 - 2.12 (m, 1H), 1.75 (s, 6H), 1.71 - 1.60 (m, 4H). MS (ESI) [M+H]+776.5.3-(6-(4-((5-chloro-4-((l-methyl-2-oxoindolin-5-yl)amino)pyrimidin-2- yl)(methyl)amino)phenyl)- 1 -methyl- lH-indazol-3 -yl)piperidine-2, 6-dione

[0362] Step 24.1: Synthesis of tert-Butyl 7V-[4-[3-(2,6-dibenzyloxy-3-pyridyl)-l- methyl-indazol-6-yl]phenyl]-7V-methyl-carbamate. A mixture of 6-bromo-3-(2,6-dibenzyloxy- 3 -pyridyl)- 1-methyl-indazole (2.63 g, 5.26 mmol), [4-[tert- butoxycarbonyl(methyl)amino]phenyl]boronic acid (1.10 g, 4.38 mmol), Pd(dppf)C12<DCM (0.18 g, 0.22 mmol) and K3PO4 (2.79 g, 13.1 mmol) in 1,4-dioxane (12 mL) and water (2 mL) 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 0-40% EtOAc in hexanes to afford the title compound (2.93 g, 89%) as a solid. MS (ESI) [M+H]+627.3.

[0363] Step 24.2: Synthesis of tert-Butyl 7V-[4-[3-(2,6-dioxo-3-piperidyl)-l-methyl- indazol-6-yl]phenyl]-7V-methyl-carbamate. A mixture of tert-butyl A-[4-[3-(2,6-dibenzyloxy- 3-pyridyl)-l-methyl-indazol-6-yl]phenyl]-A-methyl-carbamate (3.0 g, 4.79 mmol) and Pd / C (1.27 g, 1.20 mmol) in EtOH (100 mL) and THF (100 mL) was stirred under a hydrogen atmosphere (1 atm) at 50 °C for 8 h. The mixture was filtered on Celite and washed with THF (200 mL) and MeOH (200 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% EtOAc in hexanes to afford the title compound (1.47 g, 68%) as a solid. MS (ESI) [M+H]+448.8.

[0364] Step 24.3: Synthesis of 3-[l-Methyl-6-[4-(methylamino)phenyl]indazol-3- yl]piperidine-2, 6-dione hydrochloride. To a solution of tert-butyl A-[4-[3-(2,6-dioxo-3- piperidyl)-l-methyl-indazol-6-yl]phenyl]-A-methyl-carbamate (1.47 g, 3.28 mmol) in 1,4- dioxane (6 mL) was added 4N HC1 in 1,4-dioxane (4.10 mL, 16.4 mmol). The reaction mixture was stirred at rt for 16 h and the volatiles were evaporated under reduced pressure. Et2O (20 mL) was added and the resulting precipitate was collected by filtration, washed with Et2O (3 x 10 mL), then dried under vacuum to afford the title compound (1.29 g, quant.) as a solid. MS (ESI) [M+H]+349.3. 'H NMR (500 MHz, DMSO-tL) 8 10.90 (s, 1H), 7.89 (s, 1H), 7.89 (s, 1H), 7.87 (s, 1H),7.79 (d, J= 8.5 Hz, 1H), 7.53 (s, 1H), 7.52 (s, 1H), 7.44 (dd, J = 8.5, 1.4 Hz, 1H), 4.40 (dd, J = 9.9, 5.0 Hz, 1H), 4.05 (s, 3H), 2.92 (s, 3H), 2.74 - 2.58 (m, 2H), 2.44 - 2.34 (m, 1H), 2.20 (dq, J = 13.2, 5.3 Hz, 1H). Note', exchangeable proton not visible.

[0365] Step 24.4: Synthesis of 3-(6-(4-((5-chloro-4-((l-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)(methyl)amino)phenyl)-l -methyl- lH-indazol-3-yl)piperidine-2, 6- di one. A solution of 3 -[l-methyl-6-[4-(methylamino)phenyl]indazol-3-yl]piperidine-2, 6-dione hydrochloride (200 mg, 0.52 mmol) and 5-[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]-l-methyl- indolin-2-one (228 mg, 0.78 mmol) in NMP (2 mL) was purged under N2 and then placed in a preheated oil bath at 160 °C for 30 min. The crude reaction mixture was purified by reverse phase chromatography (C18) using a gradient of 5-70% MeCN and water containing 0.1% formic acid to afford the title compound (54.8 mg, 16%) as a solid. MS (ESI) [M+H]+622.2. 'H NMR (500 MHz, acetic acid-t / v) 8 8.19 (s, 1H), 7.98 (s, 1H), 7.96 (s, 1H), 7.95 (s, 1H), 7.88 (s, 1H), 7.68 (s, 1H), 7.63 (dd, J= 8.6, 1.2 Hz, 1H), 7.60 (s, 1H), 7.60 - 7.58 (m, 2H), 6.90 (d, J= 8.4 Hz, 1H), 4.67 (dd, J= 10.4, 5.2 Hz, 1H), 4.24 (s, 3H), 3.67 (s, 3H), 3.63 (s, 2H), 3.20 (s, 3H), 3.09 - 3.01 (m, 1H), 3.01 - 2.92 (m, 1H), 2.77 - 2.67 (m, 1H), 2.57 - 2.49 (m, 1H).3 -(6-(((3R,4R)- 1 -(5 -chloro-4-((3 -((S)-3 -(hy droxymethyl)-2-oxopyrrolidin- 1 - yl)phenyl)amino)pyrimidin-2-yl)-3-methylpiperi din-4-yl)amino)-l -methyl- lH-indazol-3- yl)piperidine-2, 6-dione

[0366] Step 25.1: Synthesis of l-(3-nitrophenyl)-2-oxopyrrolidine-3-carboxylic acid. To a stirred solution of 6, 6-dimethyl-5,7-dioxaspiro[2.5]octane-4, 8-dione (1, 1000 mg, 5.88 mmol) in ethanol (7.0 mL) in a microwave vial, 3 -nitroaniline (2, 2841 mg, 20.57 mmol) was added at 25 °C. The reaction mixture was irradiated in microwave at 100 °C for 10 min. The reaction mass was cooled to RT, volatiles were evaporated under vacuum. The crude residue was quenched with 10% NaOH solution (pH = 9-10) stirred for 30 min, washed with ethyl acetate (3 x 50 mL). The aqueous layer was then acidified using 1.5 N HC1, stirred for 15 min at RT. Solid precipitate was filtered, bed washed with excess water, dried under vacuum to afford the title compound (537.1 mg, 2.146 mmol, 36.5 % yield) as a yellow solid.

[0367] Step 25.2: Synthesis of methyl l-(3-nitrophenyl)-2-oxopyrrolidine-3- carboxylate. To a stirred solution of 1 -(3 -nitrophenyl)-2-oxopyrrolidine-3 -carboxylic acid (636mg, 2.54 mmol) in methanol (2.0 mL), thionyl chloride (0.371 mL, 5.08 mmol) was added dropwise at 25 °C. The reaction mass was heated to 80 °C and stirred for 4 h. The reaction mixture cooled to RT, quenched with 10% sodium bicarbonate solution, and extracted in di chloromethane (3 x 25 mL). The combined organic layer was dried over anhydrous sodium sulphate, filtered, and evaporated under reduced pressure to afford the title compound (470 mg, 1.581 mmol, 62.2 % yield) as a yellow solid.

[0368] Step 25.3: Synthesis of methyl l-(3-aminophenyl)-2-oxopyrrolidine-3- carboxylate. To a stirred solution of methyl 1 -(3 -nitrophenyl)-2-oxopyrrolidine-3 -carboxylate (470 mg, 1.581 mmol) in ethanol (2.0 mL) and THF (2.0 mL) was added 10% Pd / C (300 mg, 0.282 mmol) under nitrogen at 25 °C. The reaction mixture was stirred under hydrogen atmosphere for 24 h. The reaction mixture was filtered through celite and the celite pad was washed with ethanol (3 x 10 mL). The filtrate was evaporated under reduced pressure to obtain the title compound (400 mg, 1.537 mmol, 97 % yield). The crude product was used in the next step without further purification.

[0369] Step 25.4: Synthesis of methyl l-(3-((5-chloro-2-fluoropyrimidin-4- yl)amino)phenyl)-2-oxopyrrolidine-3-carboxylate. To a stirred solution of methyl l-(3- aminophenyl)-2-oxopyrrolidine-3-carboxylate (425 mg, 1.65 mmol) and 5-chloro-2,4- difhioropyrimidine (6, 297 mg, 1.975 mmol) in THF (10 mL) at -78 °C, DIPEA (1.15 mL, 6.58 mmol) was added dropwise under nitrogen atmosphere. The reaction mixture was slowly warmed to 25 °C and stirred for 16 h. The reaction mixture was evaporated under reduced pressure to obtain crude. The crude product was purified by flash column chromatography on silica gel with ethyl acetate as a eluent to afford the title compound (478 mg, 1.241 mmol, 75 % yield) as an off- white solid.

[0370] Step 25.5: Synthesis of l-(3-((5-chloro-2-fluoropyrimidin-4-yl)amino)phenyl)- 3-(hydroxymethyl)pyrrolidin-2-one. To a stirred solution of sodium borohydride (46.8 mg, 1.236 mmol) and calcium chloride (137 mg, 1.236 mmol) in Ethanol (15 ml), methyl l-(3-((5- chloro-2-fluoropyrimidin-4-yl)amino)phenyl)-2-oxopyrrolidine-3-carboxylate (238 mg, 0.618 mmol) was added at 0 °C. The reaction mass was stirred at 0 °C for 4 h. The reaction mass was quenched with water (5 mL) and evaporated under vacuum to remove ethanol. The concentrated reaction residue was extracted with ethyl acetate (20 mL x 3). Combined organic layers were washed with sat. brine solution, dried on anhydrous sodium sulfate, filtered, and evaporated to obtain crude product. The crude product was purified by flash column chromatography on silica gel with 70% ethyl acetate in pet. ether as an eluent to afford enantiomeric mixture of the title compound. The enantiomeric mixture was further purified by SFC column chromatography toafford chiral pure title compound (Peak 1 + Peak 2) (104 mg, 0.308 mmol, 48.0%). SFC HPLC method: Rt 6.64 and 8.98 min; Column: Chiralpak-IG (250 mm X 4.6 X 5u); 0.2% Ammonia in Methanol_40_4.1cd; Flow Rate: 4.0 mL / min.

[0371] Step 25.6: Synthesis of 3-(6-(((3R,4R)-l-(5-chloro-4-((3-((S)-3-(hydroxymethyl)- 2-oxopyrrolidin-l-yl)phenyl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-l -methyl- lH-indazol-3-yl)piperidine-2, 6-dione. To a stirred solution of l-(3-((5-chloro-2-fluoropyrimidin-4-yl)amino)phenyl)-3-(hydroxymethyl)pyrrolidin-2-one (peak 1, Step 25.5, 40 mg, 0.114 mmol) in DMSO (1.0 mL) was added 3-(l-methyl-6-(((3R,4R)-3-methylpiperidin-4-yl)amino)-lH- indazol-3-yl)piperidine-2, 6-dione hydrochloride (43.7 mg, 0.088 mmol) and DIPEA (0.062 mL, 0.353 mmol) at 25 °C. The reaction mixture was heated to 80 °C and stirred for 16 h. The reaction mixture was cooled to room temperature and purified by preparative HPLC to afford the title compound (20.31 mg, 0.030 mmol, 30.70% yield) as an pale pink solid. LCMS: 672.2 (M+H), Rt 2.140 min;XH NMR (400 MHz, DMSO-d6): 8 10.82 (s, 1H), 8.73 (s, 1H), 8.07 (s, 1H), 8.01 (s, 1H), 7.45-7.40 (m, 2H), 7.31 (d, J = 7.60 Hz, 2H), 6.51 (d, J = 8.80 Hz, 1H), 6.44 (s, 1H), 5.71 (d, J = 8.40 Hz, 1H), 4.80 (s, 1H), 4.52 (s, 2H), 4.19-4.16 (m, 1H), 4.00 (s, 1H), 3.81 (s, 3H), 3.79- 3.75 (m, 2H), 3.70-3.60 (m, 2H), 3.03 (t, J = 12.80 Hz, 1H), 2.69-2.67 (m, 2H), 2.60 (s, 2H), 2.33- 1.99 (m, 5H), 1.58 (s, 1H), 1.24-1.18 (m, 1H), 0.95 (d, J = 6.40 Hz, 3H).3-(6-(((3R,4R)-l-(5-chloro-4-((3-((R)-3-(hydroxymethyl)-2-oxopyrrolidin-l- yl)phenyl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-l-methyl-lH-indazol-3- yl)piperidine-2, 6-dione

[0372] Step 26.1 : Synthesis of 3-(6-(((3R,4R)-l-(5-chloro-4-((3-((R)-3-(hydroxymethyl)-2-oxopyrrolidin-l-yl)phenyl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-l -methyl- lH-indazol-3-yl)piperidine-2, 6-dione. To a stirred solution of l-(3-((5-chloro-2-fluoropyrimidin- 4-yl)amino)phenyl)-3-(hydroxymethyl)pyrrolidin-2-one (peak 2, Step 25.5, 40 mg, 114 mmol) in DMSO (1.0 mL) was added 3-(l-methyl-6-(((3R,4R)-3-methylpiperidin-4-yl)amino)-lH-indazol-3-yl)piperidine-2, 6-dione hydrochloride (56 mg, 0.114 mmol) and DIPEA (0.062 mL, 0.353 mmol) at 25 °C. The reaction mixture was heated to 80 °C and stirred for 16 h. The reaction mixture was cooled to room temperature and purified by preparative HPLC to afford the title compound (20.31 mg, 0.030 mmol, 30.70% yield) as an pale pink solid. LCMS: 672.2 (M+H), Rt2.140 min;XH NMR (400 MHz, DMSO-d6): 6 10.83 (s, 1H), 8.73 (s, 1H), 8.07 (s, 1H), 7.99 (s, 1H), 7.43 (t, J = 9.60 Hz, 2H), 7.31 (d, J = 8.00 Hz, 2H), 6.52 (d, J = 8.40 Hz, 1H), 6.44 (s, 1H), 5.71 (d, J = 8.40 Hz, 1H), 4.79 (s, 1H), 4.52 (s, 2H), 4.19-4.16 (m, 1H), 3.82 (s, 3H), 3.77 (t, J = 6.40 Hz, 2H), 3.65 (d, J = 18.00 Hz, 2H), 3.38-3.15 (m, 2H), 3.03 (t, J = 12.00 Hz, 1H), 2.73-2.61 (m, 3H), 2.33-2.01 (m, 5H), 1.59 (s, 1H), 1.24-1.18 (m, 1H), 0.96 (d, J = 6.00 Hz, 3H).3 -(5-(((3R,4R)- 1 -(5 -chloro-4-(( 1 -methyl-2-oxoindolin-5-yl)amino)pyrimidin-2-yl)-3 - methylpiperidin-4-yl)amino)-lH-indazol-l-yl)-3-methylpiperidine-2, 6-dione

[0373] Step 27.1: Synthesis of 2-(5-bromo-lH-indazol-l-yl)propanenitrile. To a stirred solution of 5-bromo-lH-indazole (1, 3.0 g, 15.23 mmol) in DMF (20 mL) was added 2- bromopropanenitrile (2, 3.06 g, 22.84 mmol) and K2CO3 (4.21 g, 30.5 mmol) at 25 °C under N2 atmosphere. The reaction mixture was heated to 70 °C and stirred for 16 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (150 mL) and washed with sat. brine solution. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to afford the crude compound. The crude compound was purified by flash column chromatography on silica with 5-10% ethyl acetate / pet ether to afford the title compound (2.4 g, 9.31 mmol, 61.1 % yield) as an off-white solid.

[0374] Step 27.2: Synthesis of tert-butyl 4-(5-bromo-lH-indazol-l-yl)-4- cyanopentanoate. To a stirred solution of 2-(5-bromo-lH-indazol-l-yl)propanenitrile (1.4 g, 5.60 mmol) in toluene (15 mL), were added tert-butyl acrylate 4 (0.717 g, 5.60 mmol), K2CO3 (0.928 g, 6.72 mmol), and benzyltriethylammonium chloride (0.127 g, 0.560 mmol) sequentially at RT. The reaction mixture was heated to 70 °C and stirred for 16 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (250 mL) and washed with sat. brine solution. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to afford the crude compound. The crude compound was purified by flash column chromatography on silica gel with 10-45% ethyl acetate / pet ether to afford the title compound (1.8 g, 4.38 mmol, 78 % yield) as an off-white solid.

[0375] Step 27.3: Synthesis of tert-butyl (3R,4R)-4-((l-(5-(tert-butoxy)-2-cyano-5- oxopentan-2-yl)-lH-indazol-5-yl)amino)-3 -methylpiperidine- 1 -carboxylate. A stirred solution oftert-butyl 4-(5-bromo-lH-indazol-l-yl)-4-cyanopentanoate (1 g, 2.64 mmol) and tert-butyl (3R,4R)-4-amino-3 -methylpiperidine- 1 -carboxylate 6 (0.567 g, 2.64 mmol) in toluene (10 mL) was degassed for 5 min. Then NaOtBu (0.508 g, 5.29 mmol), Pd2dba3 (0.242 g, 0.264 mmol)) and Cphos (0.346 g, 0.793 mmol) were added at 25 °C. The reaction mixture was heated to 100 °C and stirred for 12 h. The reaction mixture was quenched with water (100 mL) and diluted with ethyl acetate (50 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (2 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude product. The crude residue was purified by flash column chromatography on silica with 65% ethyl acetate / pet ether to afford the title compound (470 mg, 0.854 mmol, 32.3 % yield) as an off-white solid.

[0376] Step 27.4: Synthesis of 3-methyl-3-(5-(((3R,4R)-3-methylpiperidin-4- yl)amino)-lH-indazol-l-yl)piperidine-2, 6-dione. To a stirred solution of tert-butyl (3R,4R)-4- ((l-(5-(tert-butoxy)-2-cyano-5-oxopentan-2-yl)-lH-indazol-5-yl)amino)-3-methylpiperidine-l- carboxylate (470 mg, 0.854 mmol) in acetic acid (8 mL), sulphuric acid (0.046 mL, 0.854 mmol) was added. The reaction mixture was heated to 80 °C and stirred for 12 h. The reaction mixture was concentrated under reduced pressure and the resulting crude mixture was poured into ethyl acetate (50 mL) and washed with sat. brine solution (50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude title compound (220 mg, 0.390 mmol, 45.6 % yield) as an black sticky solid.

[0377] Step 27.5: Synthesis of 3-(5-(((3R,4R)-l-(5-chloro-4-((l-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-lH-indazol-l-yl)-3-methylpiperidine- 2, 6-dione. To a stirred solution of 3-methyl-3-(5-(((3R,4R)-3-methylpiperidin-4-yl)amino)-lH- indazol-l-yl)piperidine-2, 6-dione (150 mg, 0.270 mmol) in DMSO (4 mL) was added 5-((5- chloro-2-fluoropyrimidin-4-yl)amino)-l-methylindolin-2-one (84 mg, 0.270 mmol) and DIPEA (0.472 mL, 2.70 mmol) at 25 °C. The reaction mixture was heated to 80 °C and stirred for 8 h. The reaction mixture was cooled to room temperature and purified by preparative HPLC to afford the title compound (47 mg, 27%). LCMS: 628.2 (M+H)+, Rt 2.53 min; 'H NMR (400 MHz, DMSO-d6): 511.15 (s, 1H), 9.15 (s, 1H), 8.11 (s, 1H), 7.87 (s, 1H), 7.42-7.54 (m, 3H), 6.96 (d, J = 8.40 Hz, 2H), 4.34 (d, J = 12.40 Hz, 2H), 3.55 (s, 3H), 3.27 (d, J = 9.60 Hz, 1H), 3.11 (s, 3H), 3.04-3.08 (m, 1H), 2.75-2.81 (m, 2H), 2.67-2.70 (m, 1H), 2.25 (q, J = 15.60 Hz, 2H), 5 1.99 (d, J = 10.80 Hz, 1H), 1.87 (s, 3H), 1.68 (s, 1H), 1.21-1.24 (m, 1H), 1.02 (d, J = 6.00 Hz, 3H).3-(6-(((3R,4R)-l-(5-chloro-4-((l-(3-hydroxy-3-methylbutyl)-lH-indol-6-yl)amino)pyrimidin-2- yl)-3-methylpiperidin-4-yl)amino)-l-methyl-lH-indazol-3-yl)piperidine-2, 6-dione

[0378] Step 29.1: Synthesis of 2-methyl-4-(6-nitro-lH-indol-l-yl)butan-2-ol. To a stirred solution of 6-nitro-lH-indole (2.5 g, 15.42 mmol) in DMF (30 mL) was added compound3 -hydroxy-3 -methylbutyl 4-methylbenzenesulfonate (2, 5.97 g, 23.1 mmol) and cesium carbonate (15.07 g, 46.3 mmol) at 25 °C. The reaction mixture was heated to 120 °C for 16 h. The reaction mixture was cooled to room temperature and was quenched by ice cold water. Solid was precipitated out. Then solid was separated by filtration get to afford the title compound (3.42 g, 13.46 mmol, 87% yield) as a brown oily liquid.

[0379] Step 29.2: Synthesis of 4-(6-amino-lH-indol-l-yl)-2-methylbutan-2-ol. To a stirred solution of 2-methyl-4-(6-nitro-lH-indol-l-yl)butan-2-ol (3.42 g, 12.9 mmol) in ethanol (5 mL) and THF (5 mL) was added 10% Pd / C (1.648 g, 15.48 mmol) under nitrogen at 25 °C. The reaction mixture was stirred under hydrogen atmosphere for 6 h. The reaction mixture was filtered through celite and the celite pad was washed with 50% ethanol / THF (100 mL). The filtrate was concentrated under reduced pressure to obtain the title compound (2.38 g) as a green gummy solid. The crude product was used for the next step without further purification.

[0380] Step 29.3: Synthesis of 4-(6-((5-chloro-2-fluoropyrimidin-4-yl)amino)-lH- indol-l-yl)-2-methylbutan-2-ol. To a stirred solution of 4-(6-amino-lH-indol-l-yl)-2- methylbutan-2-ol (2.38 g, 10.9 mmol) in THF (10 mL), N2 gas was purged for 5 min. Then, 5- chloro-2,4-difhioropyrimidine (2.30 g, 15.3 mmol) and DIPEA (7.62 mL, 15.3 mmol) was added sequentially at -40 °C. The reaction mass slowly warmed to up to 25 °C and stirred for 12 h. Volatiles were evaporated to afford the crude product. The crude residue was purified by flash column chromatography on silica gel with 10 - 60% ethyl acetate / pet ether to afford the title compound (2.96 g, 53% yield) as a yellow solid.

[0381] Step 29.4: Synthesis of 3-(6-(((3R,4R)-l-(5-chloro-4-((l-(3-hydroxy-3- methylbutyl)-lH-indol-6-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-l -methyl- lH-indazol-3-yl)piperidine-2, 6-dione. To a stirred solution of 4-(6-((5-chloro-2-fluoropyrimidin-4-yl)amino)-lH-indol-l-yl)-2-methylbutan-2-ol (105 mg, 0.281 mmol) in DMSO (2.0 mL) was added 3-(l-methyl-6-(((3R,4R)-3-methylpiperidin-4-yl)amino)-lH-indazol-3-yl)piperidine-2,6-dione (150 mg, 0.316 mmol) and DIPEA (0.221 mL, 1.265 mmol) at 25 °C. The reaction mixture was heated to 80 °C and stirred for 3 h. The reaction mixture was cooled to room temperature and purified by preparative HPLC to afford the title compound (29 mg, 0.042 mmol, 13% yield) as an off-white solid. LCMS: 684.2 (M+H)+; 'H NMR (400 MHz, DMSO-d6): 5 10.82 (s, 1H), 8.67 (s, 1H), 8.03 (s,lH), 7.74 (s,lH), 7.48 (d, J = 16.4 Hz, 1H), 7.31 - 7.28 (m, 3H), 6.52 (dd, J = 1.6 Hz, 1H), 6.42 (s, 1H), 6.37 (d, J = 2.8 Hz, 1H), 5.7 (d, J = 9.2 Hz, 1H), 4.54 - 4.47 (m, 3H), 4.20 - 4.15 (m, 3H), 3.81 (s, 1H), 3.33 (s, 2H), 3.06 (t, J=12 Hz, 1H), 2.68 - 2.65 (m, 1H), 2.62 - 2.58 (m, 1H), 2.34 - 2.33 (m, 1H), 2.26 - 2.22 (m, 2H), 1.86 (t, J = 8.4 Hz, 2H), 1.58 - 1.57 (m, 1H), 1.15 (s, 6H), 0.95 (d, J= 6.4 Hz, 3H).3-(6-(((3R,4R)-l-(5-chloro-4-((l-(3-hydroxy-3-methylbutyl)-lH-indazol-6-yl)amino)pyrimidin-2-yl)-3-methylpiperi din-4-yl)amino)-l -methyl- lH-indazol-3-yl)piperidine-2, 6-dione

[0382] Step 30.1: Synthesis of 4-(6-((5-chloro-2-fluoropyrimidin-4-yl)amino)-lH- indazol-l-yl)-2-methylbutan-2-ol. The title compound was synthesized analogously to Example XX (above) Steps 1-3 using 6-nitro-lH-indazole as the starting material in Step 1.

[0383] Step 30.2: Synthesis of 3-(6-(((3R,4R)-l-(5-chloro-4-((l-(3-hydroxy-3- methylbutyl)-lH-indazol-6-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-l -methyl- lH-indazol-3-yl)piperidine-2, 6-dione. To a stirred solution of 4-(6-((5-chloro-2-fluoropyrimidin-4-yl)amino)-lH-indazol-l-yl)-2-methylbutan-2-ol (105 mg, 0.281 mmol) in DMSO (2.0 mL) was added 3-(l-methyl-6-(((3R,4R)-3-methylpiperidin-4-yl)amino)-lH-indazol-3-yl)piperidine-2,6- dione (100 mg, 0.281 mmol) and DIPEA (0.192 mL, 1.125 mmol) at 25 °C. The reaction mixture was heated to 80 °C and stirred for 3 h. The reaction mixture was cooled to room temperature and purified by preparative HPLC to afford the title compound (15 mg, 0.022 mmol, 7.7% yield) as an off-white solid. LCMS: 685.20 (M+H)+, ‘HNMR (400 MHz, DMSO-d6): 5 10.82 (s, 1H), 8.86 (s, 1H), 8.10 (s, 1H), 7.97 (s, J = 7.2 Hz, 2H), 7.68 (d, J = 8.8 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.32 (d, J = 8.8 Hz, 1H), 6.52 (dd, J = 1.6 Hz, 1H), 6.42 (s, 1H), 5.71 (d, J = 8.8 Hz, 1H), 4.56 (d, J = 12.4 Hz, 2H), 4.48 (s, 1H), 4.41 (t, J = 8 Hz, 1H), 3.8 (s, 3H), 3.32 (brs, 1H), 3.11 (t, J = 12.4Hz, 1H), 2.75 - 2.66 (m, 1H), 2.58 - 2.52 (m, 2H), 2.29 - 2.21 (m, 1H), 2.16 - 2.09 (m, 2H), 1.92 (t, J = 6.4 Hz, 2H), 1.59 (brs, 1H), 1.23 (d, J = 14 Hz, 1H), 1.14 (s, 6H), 0.97 (d, J = 6.4 Hz, 3H).3-(6-(((3R,4R)-l-(5-chloro-4-((l-(3-hydroxy-3-methylbutyl)-3-methyl-lH-indazol-6- yl)amino)pyrimidin-2-yl)-3-methylpiperi din-4-yl)amino)-l -methyl- lH-indazol-3-yl)piperidine- 2, 6-dione

[0384] Step 31.1: Synthesis of 4-(6-((5-chloro-2-fluoropyrimidin-4-yl)amino)-3- methyl-lH-indazol-l-yl)-2-methylbutan-2-ol. The title compound was synthesized analogously to Example XX (above) Steps 1-3 using 3-methyl-6-nitro-lH-indazole as the starting material in Step 1.

[0385] Step 31.2: Synthesis of 3-(6-(((3R,4R)-l-(5-chloro-4-((l-(3-hydroxy-3- methylbutyl)-3-methyl-lH-indazol-6-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)- l-methyl-lH-indazol-3-yl)piperidine-2, 6-dione. To a stirred solution of 4-(6-((5-chloro-2- fluoropyrimidin-4-yl)amino)-3-methyl-lH-indazol-l-yl)-2-methylbutan-2-ol (200 mg, 0.440 mmol) in DMSO (2.0 mL) was added 3-(l-methyl-6-(((3R,4R)-3-methylpiperidin-4-yl)amino)- lH-indazol-3-yl)piperidine-2, 6-dione (83 mg, 0.220 mmol) and DIPEA (0.192 mL, 1.099 mmol) at 25 °C. The reaction mixture was heated to 90 °C and stirred for 12 h. The reaction mixture was cooled to room temperature and purified by preparative HPLC to afford the title compound (64.14 mg, 0.0918 mmol, 39.7% yield) as an off-white solid. LCMS: 699.20 (M+H)+, 'H NMR (400 MHz, DMSO-de): 8 10.82 (s, 1H), 8.84 (s, 1H), 8.10 (s, 1H), 7.89 (s, 1H), 7.61 (d, J = 8.40 Hz, 1H), 7.41 (d, J = 1.20 Hz, 1H), 7.38 (d, J = 1.20 Hz, 1H), 7.31 (d, J = 8.80 Hz, 1H), 6.51 (dd, J = 1.60, 8.80 Hz, 1H), 6.43 (s, 1H), 5.68-5.70 (m, 1H), 4.54 (d, J = 12.00 Hz, 2H), 4.30 (t, J = 2.80 Hz, 3H), 4.18 (q, J = 5.20 Hz, 1H), 6 3.82 (s, 3H), 3.09 (t, J = Hz, 1H), 2.75 (t, J = 12.80 Hz, 1H), 2.61(t, J = 6.00 Hz, 1H), 2.44 (s, 3H), 2.23-2.27 (m, 1H), 2.10-2.17 (m, 2H), 1.87 (t, J = 8.00 Hz, 2H), 1.61-1.62 (m, 1H), 1.17-1.24 (m, 1H), 1.14 (s, 6H), 0.97 (d, J = 6.40 Hz, 3H).3-(6-(((3R,4R)-l-(5-chloro-4-((6-hydroxy-5-methylnaphthalen-2-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-l -methyl- lH-indazol-3-yl)piperidine-2, 6-dione

[0386] Step 32.1: Synthesis of 6-bromo-l-methylnaphthalen-2-ol. To a stirred solution of l-methylnaphthalen-2-ol (2.0 g, 12.64 mmol) in AcOH (6.0 mL) was cooled to 10 °C, added Bromine (0.651 mL, 12.64 mmol) in AcOH (4.00 mL) drop wise under nitrogen and stirred for the same temperature for 1 h. Then, the reaction mixture was treated with cold water (20 mL), the resulting solid was filtered and dried to give the crude title compound (3.5 g, 11.90 mmol, 94% yield) as a reddish powder.

[0387] Step 32.2: Synthesis of 6 -bromo-2-((4-methoxybenzyl)oxy)-l- methylnaphthalene. To a stirred solution of 6-bromo-l -methylnaphthal en-2-ol (200 mg, 680 mmol in DMF (2.0 mL) was cooled to 0 °C, added NaH (32.6 mg, 0.816 mmol) under nitrogen and stirred for 10 min. Then, (chi oromethyl)-4-m ethoxybenzene (160 mg, 1.020 mmol) was added to the reaction mixture and slowly warmed to 25 °C. The reaction mixture was stirred for 1 h, treated with cold water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude compound was purified by flash column chromatography on silica with 10 - 20% ethyl acetate / pet ether to afford the title compound (150 mg, 0.323 mmol, 47% yield) as an off-white solid.

[0388] Step 32.3: Synthesis of N-(6-((4-methoxybenzyl)oxy)-5-methylnaphthalen-2- yl)-l,l-diphenylmethanimine. To a stirred solution of 6 -bromo-2-((4-methoxybenzyl)oxy)-l- methylnaphthalene (550 mg, 1.386 mmol) and diphenylmethanimine (377 mg, 2.078 mmol) in toluene (20 mL). The reaction mixture was purged with nitrogen gas for 15 min. and later was added sodium tert-butoxide (399 mg, 4.16 mmol), BINAP (173 mg, 0.277 mmol) and Pd2(dba)s (127 mg, 0.139 mmol) The reaction mixture was stirred at 100 °C for 3 h. The reaction mixture was diluted with water and extracted with EtOAc (3 x 75 mL). The filtrate was concentrated under reduced pressure to obtain crude residue that was purified by flash column chromatography on silica with 5 - 10% ethyl acetate / pet ether to afford the title compound (490 mg, 1.03 mmol, 74% yield) as a yellow liquid.

[0389] Step 32.4: Synthesis of 6-((4-methoxybenzyl)oxy)-5-methylnaphthalen-2- amine. To a stirred solution of N-(6-((4-methoxybenzyl)oxy)-5-methylnaphthalen-2-yl)-l,l- diphenylmethanimine (490 mg, 1.028 mmol) in MeOH (15.0 mL). Then, sodium acetate (253 mg, 3.08 mmol) and hydroxylamine hydrochloride (214 mg, 3.08 mmol) were added sequentially at 25 °C. The reaction mass was stirred at 25 °C for 4 h. The reaction mixture was diluted with water and extracted with DCM (3 x 50 mL). Organic layers were evaporated to afford the crude compound 6 (300 mg, 68% yield). It was used next step without further purification.

[0390] Step 32.5: Synthesis of 5-chloro-2-fluoro-N-(6-((4-methoxybenzyl)oxy)-5- methylnaphthalen-2-yl)pyrimidin-4-amine. To a stirred solution of 6-((4-methoxybenzyl)oxy)-5- methylnaphthalen-2-amine (100 mg, 0.239 mmol) and 5-chloro-2,4-difluoropyrimidine (7, 46.7 mg, 0.310 mmol) in EtOH (4 mL) at -20 °C, DIPEA (0.125 mL, 0.716 mmol) was added dropwise under nitrogen atmosphere. The reaction mixture was slowly warmed to 25 °C and stirred for 16 h. The reaction mixture was evaporated under reduced pressure to obtain crude. The crude product was purified by flash column chromatography on silica with 10-20% ethyl acetate / pet ether as a eluent to afford the title compound (80 mg, 73% yield) as brown solid.

[0391] Step 32.6: Synthesis of 3-(6-(((3R,4R)-l-(5-chloro-4-((6-((4- methoxybenzyl)oxy)-5-methylnaphthalen-2-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4- yl)amino)-l-methyl-lH-indazol-3-yl)piperidine-2, 6-dione. To a stirred solution of 5-chloro-2- fluoro-N-(6-((4-methoxybenzyl)oxy)-5-methylnaphthalen-2-yl)pyrimidin-4-amine (80 mg, 0.176 mmol) in DMSO (1.0 mL) was added 3-(l-methyl-6-(((3R,4R)-3-methylpiperidin-4-yl)amino)- lH-indazol-3-yl)piperidine-2, 6-dione, TFA (82 mg, 0.176 mmol) and DIPEA (0.123 mL, 0.702 mmol) at 25 °C. The reaction mixture was heated to 85 °C and stirred for 4 h. The reaction mixture was cooled to room temperature and diluted with water and the obtained solid was filtered and dried to give the title compound (120 mg, 0.128 mmol, 73% yield) as an off-white solid.

[0392] Step 32.7: Synthesis of 3-(6-(((3R,4R)-l-(5-chloro-4-((6-hydroxy-5- methylnaphthalen-2-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-l-methyl-lH- indazol-3-yl)piperidine-2, 6-dione. To a stirred solution of 3-(6-(((3R,4R)-l-(5-chloro-4-((6-((4- methoxybenzyl)oxy)-5-methylnaphthalen-2-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4- yl)amino)-l-methyl-lH-indazol-3-yl)piperidine-2, 6-dione (80 mg, 0.085 mmol) in TFA (1.0 mL) was stirred at 70 °C for 2 h. The reaction mixture was then concentrated to give the crude compound which was purified by preparative HPLC method to afford the title compound (28 mg, 50% yield) as an off-white solid. LCMS: 639.2 (M+H)+, *HNMR (400 MHz, DMSO-d6): 8 10.84 (s, 1H), 9.39 (s, 1H), 8.90 (s, 1H), 8.13 (s, 1H), 8.09 (s, 1H), 7.81 (d, J = 9.20 Hz, 1H), 7.72 (dd, J = 2.00, 9.20 Hz, 1H), 7.49 (d, J = 8.80 Hz, 1H), 7.31 (d, J = 8.80 Hz, 1H), 7.14 (d, J = 8.80 Hz, 1H), 6.51 (dd, J = 1.60, 8.80 Hz, 1H), 6.45 (s, 1H), 5.73 (d, J = 7.60 Hz, 1H), 5 4.52 (d, J = 11.20 Hz, 2H), 4.18 (q, J = 5.20 Hz, 1H), 3.82 (s, 3H), 3.08 (t, J = 12.40 Hz, 1H), 2.68-2.77 (m, 1H), 2.59 (t, J = 5.60 Hz, 3H), 2.40 (s, 3H), 2.23-2.28 (m, 1H), 2.08-2.18 (m, 3H), 1.63 (t, J = 4.40 Hz, 1H), 1.22 (d, J = 15.20 Hz, 1H), 0.97 (d, J = 6.40 Hz, 3H).2-(5-((5-chloro-2-((3R,4R)-4-((3-(2,6-dioxopiperidin-3-yl)-l-methyl-lH-indazol-6-yl)amino)-3- methylpiperidin-l-yl)pyrimidin-4-yl)amino)-2-fluorophenyl)-N-methylacetamide

[0393] Step 33.1: Synthesis of 2-(2-fluoro-5-nitrophenyl)-N-methylacetamide. To a stirred solution of 2-(2-fluoro-5-nitrophenyl)acetic acid (100 mg, 0.502 mmol) and methylamine hydrochloride (37.3 mg, 0.552 mmol) in DMF (2 mL), DIPEA (0.351 mL, 2.009 mmol) and HATU (286 mg, 0.753 mmol) were added under nitrogen atmosphere. The reaction mixture was stirred 25 °C for 4 h. The reaction mixture quenched with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over anhydrous sodium sulphate, filtered, and evaporated under reduced pressure to afford the crude compound. The crude product was purified by flash column chromatography on silica gel with 10-30% ethyl acetate / pet. ether to afford the title compound (60 mg, 0.249 mmol, 50% yield) as an off-white solid.

[0394] Step 33.2: Synthesis of 2-(5-amino-2-fluorophenyl)-N-methylacetamide. To a stirred solution of 2-(2-fluoro-5-nitrophenyl)-N-methylacetamide (60 mg, 0.283 mmol) in ethanol (2 mL), was added Pd / C (30.1 mg, 0.283 mmol) under nitrogen at 25 °C. The reaction mixture was stirred under hydrogen atmosphere for 4 h. The reaction mixture was filtered through celite and the celite pad was washed with ethanol (3 x 5 mL). The filtrate was evaporated under reduced pressure to obtain compound 3 (38 mg, 0.158 mmol, 56% yield) as a brown liquid. The crude product was used for the next step without further purification.

[0395] Step 33.3: Synthesis of 2-(5-((5-chloro-2-((3R,4R)-4-((3-(2,6-dioxopiperidin-3- yl)-l-methyl-lH-indazol-6-yl)amino)-3-methylpiperidin-l-yl)pyrimidin-4-yl)amino)-2- fluorophenyl)-N-methylacetamide. The title compound was synthesized according to General Procedures 1 and 6 using 2-(5-amino-2-fluorophenyl)-N-methylacetamide (38 mg, 0.209 mmol) as the starting material. LCMS: 648.2 (M+H)+, 'HNMR (400 MHz, DMSO-d6): 8 10.82 (s, 1H), 9.16 (s, 1H), 8.13 (s, 1H), 7.96 (d, J = 4.40 Hz, 1H), 7.61-7.60 (m, 1H), 7.59-7.59 (m, 1H), 7.51- 7.50 (m, 1H), 7.48 (dd, J = 4.00, Hz, 1H), 7.33-7.23 (m, 1H), 7.17-7.10 (m, 1H), 6.54-6.45 (m, 2H), 4.38 (s, 2H), 4.20-4.16 (m, 1H), 4.00 (s, 8H), 3.37 (d, J = 45.20 Hz, 2H), 3.08-2.77 (m, 1H), 2.74-2.67 (m, 1H), 2.63-2.61 (m, 1H), 2.59-2.56 (m, 2H), 2.51 (s, 3H), 2.33 (s, 1H), 2.27-2.25 (m, 2H), 1.15-0.97 (m, 1H), 0.96 (d, J = Hz, 3H).3 -(3 -(((3R,4R)- 1 -(5 -chloro-4-(( 1 -methyl-2-oxoindolin-5-yl)amino)pyrimidin-2-yl)-3 - methylpiperidin-4-yl)amino)phenyl)piperidine-2, 6-dione

[0396] Step 34.1: Synthesis of 2,6-bis(benzyloxy)-3-(3-bromophenyl)pyridine. A stirred solution of l-bromo-3 -iodobenzene (1.0 g, 3.53 mmol) and (2,6-bis(benzyloxy)pyridin-3- yl)boronic acid (0.829 g, 2.474 mmol), potassium phosphate tribasic (2.25 g, 10.60 mmol) in 1,4- dioxane (30 mL) : water (1.5 mL). The reaction mass was degassed for 10 min. Then, PdC12(dppf)*dcm (0.144 g, 0.177 mmol) was added at 25 °C and stirred for 2 h. The reaction mass was filtered through celite bed, washed with ethyl acetate (50 mL). Combined filtrate was evaporated under reduced pressure to afford crude product. The crude residue was purified by flash column chromatography on silica with 25% ethyl acetate in pet ether as eluent to afford the title compound (600 mg, 0.914 mmol, 25.9 % yield) as a yellow solid.

[0397] Step 34.2: Synthesis of (3R,4R)-l-benzyl-N-(3-(2,6-bis(benzyloxy)pyridin-3- yl)phenyl)-3-methylpiperidin-4-amine. A stirred solution of compound 6 (600 mg, 1.344 mmol), (3R,4R)-l-benzyl-3-methylpiperidin-4-amine (302 mg, 1.479 mmol), CPhos (58.7 mg, 0.134 mmol) and sodium tert-butoxide (388 mg, 4.03 mmol) in toluene (12 mL). The reaction mass was degassed for 10 min. Then, Pd2(dba)s (61.5 mg, 0.067 mmol) at 25 °C. The reaction mixture was heated to 100 °C and stirred for 16 h. The reaction mass was filtered through celite bed, washing with ethyl acetate (50 mL). Combined filtrate was evaporated under reduced pressure to afford crude product. The crude residue was purified by flash column chromatography on silica with 25% ethyl acetate in pet ether as eluent to afford the title compound (500 mg, 0.668 mmol, 49.7 % yield) as a yellow solid.

[0398] Step 34.3: Synthesis of 3-(3-(((3R,4R)-3-methylpiperidin-4- yl)amino)phenyl)piperidine-2, 6-dione. To a stirred solution of (3R,4R)-l-benzyl-N-(3-(2,6- bis(benzyloxy)pyridin-3-yl)phenyl)-3-methylpiperidin-4-amine (500 mg, 0.878 mmol) in ethanol (2.0 mL) and THF (2.0 mL) mixture, were added TFA (0.068 mL, 0.878 mmol) and Pd(OH)2 (246 mg, 1.755 mmol) under nitrogen at 25 °C. The reaction mixture was stirred under 4 atm. hydrogen pressure for 4 h at 50 °C. The reaction mixture was filtered through celite and the celite pad was washed with ethanol (2 x 20 mL). The filtrate was evaporated under reduced pressure to obtainthe title compound (300 mg, 0.871 mmol, 99 % yield) as a black solid. The crude product was used for the next step without further purification.

[0399] Step 34.4: Synthesis of 3-(3-(((3R,4R)-l-(5-chloro-4-((l-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)phenyl)piperidine-2, 6-dione. To a stirred solution of 5-((5-chloro-2-fluoropyrimidin-4-yl)amino)-l-methylindolin-2-one (291 mg, 0.995 mmol) in DMSO (3 mL) was added 3-(3-(((3R,4R)-3-methylpiperidin-4- yl)amino)phenyl)piperidine-2, 6-dione (300 mg, 0.995 mmol) and DIPEA (0.522 mL, 2.99 mmol) at 25 °C. The reaction mixture was heated to 80 °C and stirred for 4 h. The reaction mixture was cooled to room temperature and purified by preparative HPLC to afford the title compound (78 mg, 0.111 mmol, 11.16 % yield) as an off-white solid. LCMS: 575.2 (M+H)+, 'HNMR (400 MHz, DMSO-de): 8 10.79 (s, 1H), 9.25 (s, 1H), 8.12 (s, 1H), 7.53-7.48 (m, 2H), 7.05-6.97 (m, 2H), 6.53- 0.47 (m, 2H), 6.37 (d, J = 7.20 Hz, 1H), 4.33-4.30 (m, 2H), 3.70-3.66 (m, 1H), 3.56 (s, 2H), 3.18- 3.06 (m, 5H), 2.77-2.74 (m, 1H), 2.68-2.61 (m, 1H), 2.52-2.50 (m, 2H), 2.13-2.09 (m, 3H), 2.02- 1.99 (m, 1H), 1.59-1.58 (m, 1H), 0.96 (d, J = 6.00 Hz, 3H).3-(6-(((3R,4R)-l-(5-chloro-4-((3-(3-methyl-2-thioxoimidazolidin-l-yl)phenyl)amino)pyrimidin- 2-yl)-3-methylpiperi din-4-yl)amino)-l -methyl- lH-indazol-3-yl)piperidine-2, 6-dione

[0400] Step 35.1: Synthesis of l-methyl-3-(3-nitrophenyl)imidazolidine-2-thione. To a stirred solution of l-isothiocyanato-3-nitrobenzene (1.0 g, 5.55 mmol) ) in THF (10 mL), was added 2-(methylamino)ethan-l-ol (0.417 g, 5.55 mmol) at 25 °C. The reaction mixture evaporated under reduced pressure to obtain crude compound, which was triturated with n-pentane to afford intermediate thiourea.

[0401] To a stirred solution of above crude thiourea in THF (5 mL), solution of NaOH (0.555 g, 13.87 mmol) in water was added at 25 °C and stirred for 15 min. Then, a solution of p- toluenesulfonyl chloride (1.058 g, 5.55 mmol) in THF was added. The reaction mixture was stirred at 25 °C for 3 h. reaction mixture quenched with water (25 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over anhydrous sodium sulphate, filtered, and evaporated under reduced pressure to afford the crude compound. The crude product was purified by flash column chromatography on silica gel with 10-20% ethyl acetate in pet. ether to afford the title compound (220 mg, 0.896 mmol, 16.15% yield) as a brown solid.

[0402] Step 35.2: Synthesis of l-(3-aminophenyl)-3-methylimidazolidine-2-thione. To a stirred solution of l-methyl-3-(3-nitrophenyl)imidazolidine-2-thione (120 mg, 0.489 mmol) in ethanol (3 mL), was added tin (II) chloride (278 mg, 1.467 mmol) at 25 °C. The reaction mixture was heated to 70 °C and maintained for 3 h. After reaction completion, cooled to RT, volatiles were evaporated under reduced pressure to obtain crude compound. The crude product was purified by flash column chromatography on silica gel with 20-30% ethyl acetate in pet. ether to afford the title compound (60 mg, 0.283 mmol, 57.9% yield) as a brown solid.

[0403] Step 35.3: Synthesis of 3-(6-(((3R,4R)-l-(5-chloro-4-((3-(3-methyl-2- thioxoimidazolidin- 1 -yl)phenyl)amino)pyrimidin-2-yl)-3 -methylpiperidin-4-yl)amino)- 1 - methyl-lH-indazol-3-yl)piperidine-2, 6-dione. The title compound was synthesized according to General Procedures 1 and 6 using l-(3-aminophenyl)-3-methylimidazolidine-2-thione (50 mg, 0.234 mmol) as the starting material. LCMS: 673.2 (M+H)+, 'H NMR (400 MHz, DMSO-d6): 8 10.84 (s, 1H), 8.78 (s, 1H), 8.08 (s, 1H), 7.95 (s, 1H), 7.51-7.48 (m, 1H), 7.34-7.28 (m, 1H), 6.53- 6.45 (m, 2H), 5.72 (d, J = 9.20 Hz, 2H), 4.51 (m, 2H), 4.20-4.16 (m, 1H), 4.00-3.82 (m, 2H), 3.69 (s, 3H), 3.66-3.36 (m, 2H), 3.00 (m, 4H), 2.73-2.70 (m, 1H), 2.68-2.63 (m, 2H), 2.50-2.24 (m, 1H), 2.17-2.12 (m, 1H), 2.08-1.60 (m, 1H), 1.24-1.20 (m, 1H), 0.94 (d, J = Hz, 3H).Example 363-(5-(((3R,4R)-l-(5-chloro-4-fluoro-6-((l-methyl-2-oxoindolin-5-yl)amino)pyrimidin-2-yl)-3- methylpiperidin-4-yl)amino)-lH-indazol-l-yl)piperidine-2, 6-dione

[0404] Step 36.1: Synthesis of 3-(5-bromo-lH-indazol-l-yl)piperidine-2, 6-dione. A stirred solution of 5-bromo-lH-indazole (100 mg, 0.508 mmol) in THF (0.5 mL), was added sodium hydride (60.9 mg, 1.52 mmol) portionwise at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. Then, 3 -bromopiperidine-2, 6-dione (195 mg, 1.01 mmol) was added at 0 °C. The reaction mixture was warmed to 25 °C and stirred for 16 h. The reaction mixture was quenched with water (5 mL) and diluted with ethyl acetate (5 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (2x 5 mL). The combined organic layer was dried over anhydrous sodium sulphate, filtered, and evaporated under reduced pressure to afford the crude product. The crude residue was purified by flash column chromatography on silica with 25% ethyl acetate in pet ether to afford the title compound (54 mg, 0.175 mmol, 34.5% yield) asa white solid.

[0405] Step 36.2: Synthesis of tert-butyl (3R,4R)-4-((l-(2,6-dioxopiperidin-3-yl)-lH- indazol-5-yl)amino)-3-methylpiperidine-l-carboxylate. A stirred solution of 3-(5-bromo-lH- indazol-l-yl)piperidine-2, 6-dione (200 mg, 0.649 mmol) and tert-butyl (3R,4R)-4-amino-3- methylpiperidine-1 -carboxylate (139 mg, 0.649 mmol) in 1,4-dioxane (5 mL), Molecular sieves 4A and LiHMDS (3.89 mL, 3.89 mmol) were added at 25 °C. The reaction mass was degassed for 10 min. Then, Ruphos Pd G4 (55.2 mg, 0.065 mmol) was added and again degassed for 2 min The reaction mixture was heated to 80 °C and stirred for 2 h. The reaction mass was cooled to 25 °C, quenched with acetic acid and volatiles were evaporated under reduced pressure to afford crude product. The crude residue was purified by flash column chromatography on silica with 5% methanol in DCM to afford the title compound (30 mg, 0.050 mmol, 7.64% yield) as a yellow solid.

[0406] Step 36.3: Synthesis of 3-(5-(((3R,4R)-3-methylpiperidin-4-yl)amino)-lHindazol- l-yl)piperidine-2, 6-dione TFA salt. The title compound was synthesized according to General Procedure 5 using tert-butyl (3R,4R)-4-((l-(2,6-dioxopiperidin-3-yl)-lH-indazol-5-yl)amino)-3- methylpiperidine-1 -carboxylate (90 mg, 0.204 mmol) as the starting material.

[0407] Step 36.4: Synthesis of 5-((5-chloro-2,6-difluoropyrimidin-4-yl)amino)-l- methylindolin-2-one. To a stirred solution of 5-amino-l-methylindolin-2-one (500 mg, 3.08 mmol) and 5-chloro-2,4,6-trifluoropyrimidine (519 mg, 3.08 mmol) in acetonitrile (25 mL) at 0 °C, DIPEA (0.538 mL, 3.08 mmol) was added dropwise under nitrogen atmosphere. The reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was quenched with water (10 mL) and diluted with DCM (3 x 25 mL). The combined organic layer was dried over anhydrous sodium sulphate, filtered, and evaporated under reduced pressure to afford compound 3 (550 mg, 1.593 mmol, 51.7% yield) as an off-white solid. The crude product was used for the next step without further purification

[0408] Step 36.5: Synthesis of 3-(5-(((3R,4R)-l-(5-chloro-4-fluoro-6-((l-methyl-2- oxoindolin-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-lH-indazol-l- yl)piperidine-2, 6-dione. To a stirred solution of 3-(5-(((3R,4R)-3-methylpiperidin-4-yl)amino)- lHindazol-l-yl)piperidine-2, 6-dione TFA salt (60 mg, 0.105 mmol) in DMSO (1.5 mL), was added 5-((5-chloro-2,6-difhioropyrimidin-4-yl)amino)-l-methylindolin-2-one (36.4 mg, 0.105 mmol) and DIPEA (0.092 mL, 0.527 mmol) at 0 °C. The reaction mixture was heated to 80 °C and stirred for 3 h. The reaction mixture was cooled to room temperature and purified by preparative HPLC to afford the title compound (10.5 mg, 0.016 mmol, 15% yield). LCMS: 632.3 (M+H)+, 'H NMR (400 MHz, DMSO-d6): 5 11.07 (s, 1H), 9.00 (s, 1H), 7.89 (br d, J= 4.0 Hz,1H), 7.58-7.26 (m, 3H), 6.97-6.93 (m, 1H), 5.72 (br d, J = 6.5 Hz, 1H), 4.38-4.27 (m, 2H), 3.54 (s, 2H), 3.31-3.22 (m, 1H), 3.14-3.07 (m, 3H), 3.02-2.95 (m, 1H), 2.87-2.82 (m, 1H), 2.75-2.63 (m, 3H), 2.28-2.19 (m, 1H), 2.07-1.93 (m, 1H), 1.71-1.59 (m, 1H), 1.26-1.15 (m, 1H), 1.09-0.97 (m, 3H).3 -(5-(((3R,4R)- 1 -(5 -chloro-4-(( 1 -methyl-2-oxoindolin-5-yl)amino)pyrimidin-2-yl)-3 - methylpiperidin-4-yl)amino)-3-methyl-lH-indazol-l-yl)piperidine-2, 6-dione

[0409] Step 37.1: Synthesis of 3-(5-bromo-3-methyl-lH-indazol-l-yl)piperidine-2,6- dione. A stirred solution of 5-bromo-3-methyl-lH-indazole (500 mg, 2.369 mmol) in THF (10 mL), was added sodium hydride (284 mg, 7.11 mmol) portionwise at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. Then, 3 -bromopiperidine-2, 6-dione (682 mg, 3.55 mmol) was added at 0 °C. The reaction mixture was warmed to 25 °C and stirred for 16 h. The reaction mixture was quenched with water (25 mL) and diluted with ethyl acetate (25 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (2x 25 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to afford the crude product. The crude residue was purified by flash column chromatography on silica with 25% ethyl acetate in pet ether to afford the title compound (420 mg, 1.269 mmol, 54% yield) as a white solid.

[0410] Step 37.2: Synthesis of tert-butyl (3R,4R)-4-((l-(2,6-dioxopiperidin-3-yl)-3- methyl-lH-indazol-5-yl)amino)-3-methylpiperidine-l-carboxylate. A stirred solution of 3-(5- bromo-3-methyl-lH-indazol-l-yl)piperidine-2, 6-dione (220 mg, 0.683 mmol) and tert-butyl (3R,4R)-4-amino-3 -methylpiperidine- 1 -carboxylate (146 mg, 0.683 mmol) in toluene (7 mL), molecular sieves 4A (451 mg, 1.02 mmol) and LiHMDS (4.10 mL, 4.10 mmol) were added at 25 °C. The reaction mass was degassed for 10 min. Then, Ruphos Pd G2 (53.0 mg, 0.068 mmol) was added and again degassed for 2 min. The reaction mixture was heated to 80 °C and stirred for 1 h. The reaction mass was cooled to 25 °C, quenched with acetic acid (5 equiv) and volatiles were evaporated under reduced pressure to afford crude product. The crude residue was purified by flash column chromatography on silica with 5% methanol in DCM to afford the title compound (220 mg, 0.303 mmol, 44% yield) as a yellow solid.

[0411] Step 37.3: Synthesis of 3-(3-methyl-5-(((3R,4R)-3-methylpiperidin-4- yl)amino)-lH-indazol-l-yl)piperidine-2, 6-dione TFA salt. To a stirred solution of tert-butyl (3R,4R)-4-((l-(2,6-dioxopiperidin-3-yl)-3-methyl-lH-indazol-5-yl)amino)-3-methylpiperidine- 1-carboxylate (260 mg, 0.360 mmol) in DCM (5 mL), TFA (0.554 mL, 7.19 mmol) was added dropwise at 0 °C under nitrogen atmosphere. The resulting solution was stirred at 25 °C for 3 h. Volatiles were evaporated under reduced pressure and triturated with diethyl ether to afford the title compound (20 mg, 0.186 mmol, 52 % yield) as a yellow solid. The crude product was used for the next step without further purification.

[0412] Step 37.4: Synthesis of 3-(5-(((3R,4R)-l-(5-chloro-4-((l-methyl-2-oxoindolin-5- yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-3-methyl-lH-indazol-l-yl)piperidine- 2, 6-dione. To a stirred solution of 3-(3-methyl-5-(((3R,4R)-3-methylpiperidin-4-yl)amino)-lH- indazol-l-yl)piperidine-2, 6-dione TFA salt (120 mg, 0.186 mmol) in DMSO (3.0 mL), were added 5-((5-chloro-2,6-difhioropyrimidin-4-yl)amino)-l-methylindolin-2-one (57.2 mg, 0.186 mmol) and DIPEA (0.162 mL, 0.928 mmol) at 25 °C. The reaction mixture was heated to 90 °C and stirred for 7 h. The reaction mixture was cooled to room temperature and purified by preparative HPLC to afford the title compound (86 mg, 0.135 mmol, 72.8 % yield) as an off-white solid. LCMS: 628.3 (M+H)+, 'HNMR (400 MHz, DMSO-d6): 511.05 (s, 1H), 9.16 (s, 1H), 8.10 (s, 1H), 7.53-7.47 (m, 3H), 7.22 (bs, 2H), 6.98-6.95 (m, 1H), 5.67-5.66 (m, 1H), 4.33 (d, J = 4.36 Hz, 2H), 3.51 (s, 2H), 3.39 (bs, 1H), 3.11 (s, 3H), 3.00-2.94 (m, 1H), 2.86-2.67 (m, 4H), 2.49 (s, 3H), 2.24- 2.20 (m, 1H), 1.96, (bs, 1H), 1.73 (bs, 1H), 1.35-1.20 (m, 1H), 1.09-1.07 (m, 3H).3 -(6-(((3R,4R)- 1 -(5 -chloro-4-((3 -hydroxyisoquinolin-7-yl)amino)pyrimidin-2-yl)-3 - methylpiperidin-4-yl)amino)-l -methyl- lH-indazol-3-yl)piperidine-2, 6-dione

[0413] Step 38.1: Synthesis of 7-bromo-3-((4-methoxybenzyl)oxy)isoquinoline. To a stirred solution of 7-bromoisoquinolin-3-ol (500 mg, 2.232 mmol in DMF (8.0 mL) was added CS2CO3 (873 mg, 2.68 mmol) at 0 °C under nitrogen and stirred for 10 min. 4-methoxybenzyl chloride (0.365 mL, 2.68 mmol) was added to the reaction mixture and slowly warmed to 25 °C. The reaction mixture was stirred for 4 h, treated with cold water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude title compound (550 mg,44% yield) as a yellow solid. It was used next step with out further purification.

[0414] Step 38.2: Synthesis of N-(3-((4-methoxybenzyl)oxy)isoquinolin-7-yl)-l,l- diphenylmethanimine. To a stirred solution of 7-bromo-3-((4-methoxybenzyl)oxy)isoquinoline (550 mg, 0.975mmol) and diphenylmethanimine (265 mg, 1.462 mmol) in toluene (10 mL). The reaction mixture was purged with nitrogen gas for 15 min. and later was added sodium tert- butoxide (281 mg, 2.92 mmol), BINAP (121 mg, 0.195 mmol) and Pd2(dba)s (89 mg, 0.097 mmol) The reaction mixture was stirred at 100 °C for 3 h. The reaction mixture was diluted with water and extracted with EtOAc (3 x 75 mL). The filtrate was concentrated under reduced pressure to obtain crude compound, which was purified by flash column chromatography on silica with 5 - 10% ethyl acetate / pet ether to afford the title compound (400 mg, 0.675 mmol, 69% yield) as a yellow liquid.

[0415] Step 38.3: Synthesis of 3-((4-methoxybenzyl)oxy)isoquinolin-7-amine. To a stirred solution of N-(3-((4-methoxybenzyl)oxy)isoquinolin-7-yl)-l,l-diphenylmethanimine (450 mg, 0.860 mmol)) in MeOH (10.0 mL). Then, sodium acetate (212 mg, 2.58 mmol) and hydroxylamine hydrochloride (179 mg, 2.58 mmol) was added sequentially at 25 °C. The reaction mass was stirred at 25 °C for 16 h. The reaction mixture was diluted with water and extracted with DCM (3 x 50 mL). Organic layers were evaporated to afford the crude title compound (360 mg, 74% yield). This was used in the next step without further purification.

[0416] Step 38.4: Synthesis of N-(5-chloro-2-fluoropyrimidin-4-yl)-3-((4- methoxybenzyl)oxy)isoquinolin-7-amine. To a stirred solution of 3 -((4- methoxybenzyl)oxy)isoquinolin-7-amine (100 mg, 0.350 mmol) and 5-chloro-2,4- difluoropyrimidine (79 mg, 0.524 mmol) in EtOH (4 mL) at -20 °C, DIPEA (0.183 mL, 1.049 mmol) was added dropwise under nitrogen atmosphere. The reaction mixture was slowly warmed to 25 °C and stirred for 16 h. The reaction mixture was evaporated under reduced pressure to obtain crude. The crude product was purified by flash column chromatography on silica with 30- 50% ethyl acetate / pet ether as eluent to afford the title compound (60 mg, 41% yield) as brown solid.

[0417] Step 38.5: Synthesis of 3-(6-(((3R,4R)-l-(5-chloro-4-((3-((4- methoxybenzyl)oxy)isoquinolin-7-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-l- methyl-lH-indazol-3-yl)piperidine-2, 6-dione. To a stirred solution of N-(5-chloro-2- fluoropyrimidin-4-yl)-3-((4-methoxybenzyl)oxy)isoquinolin-7-amine (60 mg, 0.143 mmol) in DMSO (1.0 mL) was added 3-(l-methyl-6-(((3R,4R)-3-methylpiperidin-4-yl)amino)-lH-indazol- 3-yl)piperidine-2, 6-dione, TFA (67.9 mg, 0.143 mmol) and DIPEA (0.100 mL, 0.572 mmol) at 25 °C. The reaction mixture was heated to 85 °C and stirred for 3 h. The reaction mixture was cooledto room temperature and diluted with water and the obtained solid was filtered and dried to give the title compound (105 mg, 0.136 mmol, 95% yield) as an off-white solid.

[0418] Step 38.6: Synthesis of 3-(6-(((3R,4R)-l-(5-chloro-4-((3-hydroxyisoquinolin-7- yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-l-methyl-lH-indazol-3-yl)piperidine- 2, 6-dione. To a stirred solution of 3-(6-(((3R,4R)-l-(5-chloro-4-((3-((4- methoxybenzyl)oxy)isoquinolin-7-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-l- methyl-lH-indazol-3-yl)piperidine-2, 6-dione (50 mg, 0.066 mmol) in TFA (1.0 mL) was stirred at 70 °C for 3 h. Then the reaction mixture was concentrated to yield the crude compound which was purified by trituration with diethyl ether (2x 15 mL). The ether layer was decanted and dried under reduced pressure to afford the title compound (46 mg, 90% yield) as pale-yellow solid. LCMS: 626.2 (M+H)+, 'H NMR (400 MHz, DMSO-d6): 8 10.84 (s, 1H), 9.25 (s, 1H), 8.85 (s, 1H), 8.23 (s, 1H), 8.15 (s, 1H), 7.88 (dd, J = 2.00, 9.00 Hz, 1H), 7.73 (d, J = 9.20 Hz, 1H), 7.32 (d, J = 8.80 Hz, 1H), 6.96 (s, 1H), 6.52 (d, J = 8.80 Hz, 1H), 6.46 (s, 1H), 4.45 (s, 2H), 4.18 (q, J = 5.20 Hz, 2H), 3.36 (q, J = 6.40 Hz, 2H), 3.10 (s, 1H), 2.71 (d, J = 22.00 Hz, 2H), 2.62 (d, J = 9.20 Hz, 2H), 2.34 (d, J = 1.60 Hz, 1H), 2.10-2.24 (m, 3H), 1.26-1.24 (m, 1H), 1.10-1.08 (m, 2H), 0.97 (d, J = 6.80 Hz, 3H).3-(6-(((3R,4R)-l-(5-chloro-4-((3-hydroxy-4-methylisoquinolin-7-yl)amino)pyrimidin-2-yl)-3- methylpiperidin-4-yl)amino)-l -methyl- lH-indazol-3-yl)piperidine-2, 6-dione

[0419] Step 39.1: Synthesis of (S)-N-(3-bromobenzyl)-2-hydroxypropanamide. In a sealed tube, was charged with 3 -brom ophenyl)m ethanamine (3.0 g, 16.12 mmol) and methyl (S)- 2-hydroxypropanoate (1.679 g, 16.12 mmol) at 25 °C. The reaction mixture was stirred at 130 °C for 2 h. The residue was azeotroped with toluene to dry to provide the title compound (4.0 g, 7.04 mmol, 43.7% yield) as a colorless oil.

[0420] Step 39.2: Synthesis of N-(3-bromobenzyl)-2-oxopropanamide. To a stirred solution of (S)-N-(3-bromobenzyl)-2-hydroxypropanamide (4.0 g, 7.04 mmol) in DCM (40 mL) was added cooled to 0 °C. Dess-martinperiodinane (2.99 g, 7.04 mmol) was added to the reaction mixture at 0 °C and stirred for 1 h. cold. The reaction mixture was quenched by saturated NaHCCL solution (30 mL) and extracted with DCM (3x 50 mL). The combined organic layers were driedover anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford the crude compound. The crude residue was purified by flash column chromatography on silica with 15 - 25% ethyl acetate / pet ether to afford the title compound (1.0 g, 21% yield) as a colorless oil.

[0421] Step 39.3: Synthesis of 7-bromo-4-methylisoquinolin-3(2H)-one. To a stirred solution of N-(3-bromobenzyl)-2-oxopropanamide (1.0 g, 1.469 mmol) in THF (10 mL) was added cooled to 0 °C. Sulfuric acid (0.078 ml, 1.47 mmol) was added to the reaction mixture at 0 °C and slowly warmed to room temperature and then stirred for 3 h. The reaction mixture was diluted with ice-cold water, and adjusted pH with dropwise addition of aqueous ammonium hydroxide. The resulting bright yellow precipitate was collected via filtration, washed with water, and then dried under vacuum to afford the title compound (0.8 g crude) as a yellow solid.

[0422] Step 39.4: Synthesis of 7-bromo-3-((4-methoxybenzyl)oxy)-4- methylisoquinoline. To a stirred solution of 7-bromo-4-methylisoquinolin-3(2H)-one (300 mg, 1.197mmol) in DMF (8.0 mL) was added CS2CO3 (468 mg, 1.436 mmol) at 0 °C under nitrogen and stirred for 10 min. 4-methoxybenzyl chloride (0.196 mL, 1.44 mmol) was added to the reaction mixture and slowly warmed to 25 °C. The reaction mixture was stirred for 4 h, treated with cold water (100 mL) and extracted with ethyl acetate (3x 75 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude compound. The crude was triturated by using diethyl ether to afford the title compound (300 mg, 21% yield) as a yellow solid.

[0423] Step 39.5: Synthesis of N-(3-((4-methoxybenzyl)oxy)-4-methylisoquinolin-7- yl)-l,l-diphenylmethanimine. To a stirred solution of 7-bromo-3-((4-methoxybenzyl)oxy)-4- methylisoquinoline (300 mg) and diphenylmethanimine (228 mg, 1.26 mmol) in toluene (10 mL). The reaction mixture was purged with nitrogen gas for 15 min. and later was added NaOtBu (241 mg, 2.51 mmol), BINAP (104 mg, 0.167 mmol) and Pd2(dba)s (77 mg, 0.084 mmol). The reaction mixture was stirred at 100 °C for 3 h. The reaction mixture was diluted with cold water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude compound, was purified by flash column chromatography on silica with 5 - 10% ethyl acetate / pet ether to afford the title compound (140 mg, 27%) as a pale yellow solid.

[0424] Step 39.6: Synthesis of 3-((4-methoxybenzyl)oxy)-4-methylisoquinolin-7- amine. To a stirred solution of N-(3-((4-methoxybenzyl)oxy)-4-methylisoquinolin-7-yl)-l,l- diphenylmethanimine (140 mg, 0.104 mmol)) in MeOH (5.0 mL). Then, sodium acetate (57.9 mg, 0.705 mmol) and hydroxylamine hydrochloride (49 mg, 0.705 mmol) was added sequentially at 25 °C. The reaction mass slowly warmed to up to 25 °C and stirred for 4 h. The reaction mixturewas diluted with water and extracted with DCM (3 x 50 mL). Organic layers were evaporated to afford the crude compound, was purified by flash column chromatography on silica with 50 - 60% ethyl acetate / pet ether to afford the title compound (50 mg, 61%) as a brown solid

[0425] Step 39.7: Synthesis of N-(5-chloro-2-fluoropyrimidin-4-yl)-3-((4- methoxybenzyl)oxy)-4-methylisoquinolin-7-amine. To a stirred solution of 3 -((4- methoxybenzyl)oxy)-4-methylisoquinolin-7-amine (50 mg, 0.144 mmol) and 5-chloro-2,4- difhioropyrimidine (21.7 mg, 0.144 mmol) in EtOH (2.0 mL) at -20 °C, DIPEA (0.025 mL, 0.144 mmol) was added dropwise under nitrogen atmosphere. The reaction mixture was slowly warmed to 25 °C and stirred for 16 h. The reaction mixture was evaporated under reduced pressure to obtain crude. The crude product was purified by flash column chromatography on silica gel with 40% ethyl acetate / PE as a eluent to afford the title compound (45 mg, 72% yield) as a yellow solid.

[0426] Step 39.8: Synthesis of 3-(6-(((3R,4R)-l-(5-chloro-4-((3-((4- methoxybenzyl)oxy)-4-methylisoquinolin-7-yl)amino)pyrimidin-2-yl)-3-methylpiperi din-4- yl)amino)-l-methyl-lH-indazol-3-yl)piperidine-2, 6-dione. To a stirred solution of N-(5-chloro-2- fluoropyrimidin-4-yl)-3-((4-methoxybenzyl)oxy)-4-methylisoquinolin-7-amine (45 mg, 0.104 mmol) and 3-(l-methyl-6-(((3R,4R)-3-methylpiperidin-4-yl)amino)-lH-indazol-3-yl)piperidine- 2,6-dione, TFA (12, 49.2 mg, 0.104 mmol) in DMSO (1.0 mL) at 23 °C, was added DIPEA (0.054 mL, 0.311 mmol) was added dropwise under nitrogen atmosphere. The reaction mixture was slowly warmed to 85 °C and stirred for 3 h. The reaction mixture was diluted with water, so obtained solid was filtered to obtain the title compound (55 mg, 67% yield) as an off-white solid.

[0427] Step 39.9: Synthesis of 3-(6-(((3R,4R)-l-(5-chloro-4-((3-hydroxy-4- methylisoquinolin-7-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-l-methyl-lH- indazol-3-yl)piperidine-2, 6-dione. To a stirred solution of compound 13 (55 mg, 0.070 mmol) in TFA (1.0 mL), reaction mixture was heated to 70 °C and stirred for 3 h. The reaction mixture was cooled to room temperature and concentrated, dried to afford crude compound. It was titurated with diethyl ether (2 x 15 mL), the ether layer was decanted and dried under reduced pressure to obtain the title compound (45 mg, 0.056 mmol, 80% yield) as a pale-yellow solid. LCMS: 640.2 (M+H)+, ‘H NMR (400 MHz, DMSO-d6): 8 10.84 (s, 1H), 9.24 (s, 1H), 8.64 (s, 1H), 8.23 (s, 1H), 8.15 (s, 1H), 7.82-7.90 (m, 2H), 7.32 (d, J = 8.80 Hz, 1H), 6.46-6.53 (m, 2H), 4.47 (d, J = 12.80 Hz, 2H), 4.18 (q, = 5.20 Hz, 1H), 3.82 (s, 3H), 2.99 (m, 1H), 2.73 (m, 2H), 2.59-2.67 (m, 2H), 2.37 (s, 1H), 2.12-2.23 (m, 3H), 1.65 (d, J = 4.80 Hz, 1H), 1.25 (q, J = 8.40 Hz, 1H), 0.97 (s, 3H).3-(6-(((3R,4R)-l-(5-chloro-4-((l-methyl-2,2-dioxido-l,3-dihydrobenzo[c]isothiazol-5- yl)amino)pyrimidin-2-yl)-3-methylpiperi din-4-yl)amino)-l -methyl- lH-indazol-3-yl)piperidine- 2, 6-dione

[0428] Step 40.1: Synthesis of l-methyl-l,3-dihydrobenzo[c]isothiazole 2,2-dioxide.To a stirred solution of l,3-dihydrobenzo[c]isothiazole 2,2-dioxide (200 mg, 1.18 mmol) in DMF (3.0 mL) was added K2CO3 (163 mg, 1.18 mmol) at 0 °C under nitrogen and stirred for 10 min. Methyl iodide (0.074 mL, 1.18 mmol) was added to the reaction mixture and slowly warmed to 25 °C. The reaction mixture was stirred for 4 h, then it was treated with cold water (100 mL) and extracted with ethyl acetate (3x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude compound. The crude was triturated with diethyl ether to afford the title compound (200 mg, 92% yield) as an off-white solid.

[0429] Step 40.2: Synthesis of 5-bromo-l-methyl-l,3-dihydrobenzo[c]isothiazole 2,2- dioxide. To a stirred solution of l-methyl-l,3-dihydrobenzo[c]isothiazole 2,2-dioxide (400 mg, 1.99 mmol) in DMF (5 mL) was added NBS (424 mg, 2.38 mmol) at 0 °C. The reaction mixture was slowly warmed to 25 °C for 1 h. The reaction mixture was quenched with ice cold water and extracted with EtOAc (3x 75 mL). Organic layers were combined and concentrated to afford the crude product. The crude residue was purified by flash column chromatography on silica gel with 10-20% ethyl acetate / pet ether to afford the title compound (250 mg, 46% yield) as an off-white solid.

[0430] Step 40.3: Synthesis of 5-((diphenylmethylene)amino)-l-methyl-l,3- dihydrobenzo[c]isothiazole 2,2-dioxide. To a stirred solution of 5-bromo-l-methyl-l,3- dihydrobenzo[c]isothiazole 2,2-dioxide (200 mg, 0.763 mmol) and diphenylmethanimine (207 mg, 1.14 mmol) in toulene (5 mL). The reaction mixture was purged with nitrogen gas for 15 min. and later was added K2CO3 (316 mg, 2.29 mmol), Pd2(dba)s (69.9 mg, 0.076 mmol) and xantphos (88 mg, 0.153 mmol). The reaction mixture was stirred at 100 °C for 8 h. The reaction mixture was filtered through celite and the celite pad was washed with EtOAc (100 mL). The filtrate was concentrated under reduced pressure to obtain the crude compound which was purified by flashcolumn chromatography on silica gel with 10 - 15% ethyl acetate / pet ether eluent to afford the title compound (90 mg, 21.8%) as a pale yellow solid.

[0431] Step 40.4: Synthesis of 5-amino-l-methyl-l,3-dihydrobenzo[c]isothiazole 2,2- dioxide. To a stirred solution of 5 -((diphenylmethylene)amino)-l -methyl- 1,3- dihydrobenzo[c]isothiazole 2,2-dioxide (90 mg, 0.174 mmol)) in MeOH (1.0 mL). Then sodium acetate (42.8 mg, 0.521 mmol) and hydroxylamine hydrochloride (36.2 mg, 0.521 mmol) were added sequentially at 25 °C. The reaction mass slowly warmed to up to 25 °C and stirred for 4 h. The reaction mixture was diluted with water and extracted with DCM (3 x 20 mL). Cmobined organic layers were evaporated to afford the title compound (75 mg, 35% yield) which was used next step without further purification.

[0432] Step 40.5: Synthesis of 5-((5-chloro-2-fluoropyrimidin-4-yl)amino)-l-methyl- 1,3- dihydrobenzo[c]isothiazole 2,2-dioxide. To a stirred solution of 5-amino-l-methyl-l,3- dihydrobenzo[c]isothiazole 2,2-dioxide (70 mg, 0.177 mmol) and 5-chloro-2,4- difhioropyrimidine (39.9 mg, 0.265 mmol) in EtOH (4 mL) at -40 °C, DIPEA (0.093 mL, 0.530 mmol) was added dropwise under nitrogen atmosphere. The reaction mixture was slowly warmed to 25 °C and stirred for 16 h. The reaction mixture was evaporated under reduced pressure to obtain crude material. The crude product was purified by flash column chromatography on silica with 35-45% ethyl acetate / pet ether as a eluent to afford the title compound (30 mg, 47% yield) as an off-white solid.

[0433] Step 40.6: Synthesis of 3-(6-(((3R,4R)-l-(5-chloro-4-((l-methyl-2,2-dioxido-l,3- dihydrobenzo[c]isothiazol-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-l -methyl- lH-indazol-3-yl)piperidine-2, 6-dione. To a stirred solution of 5-((5-chloro-2-fhioropyrimidin-4- yl)amino)-l -methyl- 1,3- dihydrobenzo[c]isothiazole 2,2-dioxide (30 mg, 0.084 mmol) in DMSO (1.0 mL) was added 3-(l-methyl-6-(((3R,4R)-3-methylpiperidin-4-yl)amino)-lH-indazol-3- yl)piperidine-2, 6-dione, TFA (47.8 mg, 0.101 mmol) and DIPEA (0.044 mL, 0.252 mmol) at 25 °C. The reaction mixture was heated to 85 °C and stirred for 4 h. The reaction mixture was cooled to room temperature and purified by preparative HPLC to afford the title compound (20 mg, 0.028 mmol, 33.5% yield) as an off-white solid. LCMS: 664.2 (M+H)+, 'H NMR (400 MHz, DMSO- d6): 8 10.82 (s, 1H), 8.75 (s, 1H), 8.04 (s, 1H), 7.62 (d, J = 7.20 Hz, 2H), 7.31 (d, J = 8.80 Hz, 1H), 6.93 (d, J = 9.20 Hz, 1H), 6.51 (dd, J = 1.20, 9.00 Hz, 1H), 6.44 (s, 1H), 5.69 (d, J = 9.20 Hz, 1H), 4.65 (s, 2H), 4.46 (d, J = 10.40 Hz, 2H), 4.18 (d, J = 5.20 Hz, 1H), 3.82 (s, 3H), 5 3.00 (s, 4H), 2.55-2.67 (m, 3H), 2.23-2.34 (m, 2H), 1.60 (s, 1H), 1.15 (s, 1H), 0.97 (d, J = 6.80 Hz, 3H).l-(5-((5-chloro-2-((3R,4R)-4-((3-(2,6-dioxopiperidin-3-yl)-l-methyl-lH-indazol-6-yl)amino)-3- methylpiperidin- 1 -yl)pyrimidin-4-yl)amino)-2-fluorophenyl)- 1 -(3 -hydroxy-3 -methylbutyl)-3 - methylurea

[0434] Step 42.1: Synthesis of 4-((2-fluoro-5-nitrophenyl)amino)-2-methylbutan-2-ol.To a stirred solution of 3 -methylbutane- 1,3 -diol (2.67 g, 25.6 mmol) in DCM (40 mL), DMP (21.73 g, 51.2 mmol) was added at 0 °C under N2 atmosphere. The reaction mixture was slowly warmed to 25 °C and stirred for 1 h. The reaction mixture was quenched with NaHCCh (5.0 g), stirred for 15 min, and then filtered through celite bed, washing with DCM (2x 50 mL). The filtrate was evaporated under vacuum at 25 °C. Then the crude residue was redissolved in diethyl ether (50 mL), filtered through celite bed, washing with diethyl ether (2x 30 mL) and the filtrate was evaporated under vacuum at 25 °C to afford crude aldehyde as an off-white semi solid.

[0435] To a stirred solution of above intermediate aldehyde and 2-fhioro-5 -nitroaniline (1, 2.0 g, 12.81 mmol) in Methanol (40 mL), acetic acid (0.073 mL, 1.281 mmol) was added. Then, sodium cyanoborohydride (1.61 g, 25.6 mmol) was added portion wise over 15 min at 25 °C. The reaction mixture was stirred for 16 h at 25 °C. The reaction mixture was filtered, and the filtrate was evaporated under vacuum to afford crude compound. The crude compound was purified by flash column chromatography on silica gel with 20-40% ethyl acetate in pet ether as the eluent to afford the title compound (1.80 g, 6.68 mmol, 52% yield) as a brown solid.

[0436] Step 42.2: Synthesis of 2-fluoro-N-(3-methyl-3-((2-(trimethylsilyl)ethoxy)methoxy)butyl)-5-nitroaniline. To a stirred solution of 4-((2-fluoro-5- nitrophenyl)amino)-2-methylbutan-2-ol (1.5 g, 4.77 mmol) in DCM (10 mL), were added DIPEA (3.33 mL, 19.1 mmol) and tetrabutylammonium iodide (3.87 g, 10.5 mmol) sequentially at 25 °C, and stirred for 15 min. Then, (2-(chloromethoxy)ethyl)trimethylsilane (1.59 g, 9.54 mmol) was added in one lot at 25 °C. The reaction mixture was heated to 50 °C and stirred for 16 h. The reaction mixture was then cooled to room temperature, quenched with water (25 mL) and extracted in DCM (3x 25 mL). Combined organic layers were washed with sat. brine solution, dried over anhydrous sodium sulfate, filtered, and evaporated under vacuum to afford the crude compound. The crude compound was purified by flash column chromatography on silica with 20-40% ethyl acetate in pet ether to afford the title compound (2.1 g, 4.83 mmol, 101% yield) as a yellow solid.

[0437] Step 42.3: Synthesis of l-(2-fluoro-5-nitrophenyl)-l-(3-hydroxy-3- methylbutyl)-3,3-dimethylurea.To a stirred solution of 2-fluoro-N-(3-methyl-3-((2- (trimethylsilyl)ethoxy)methoxy)butyl)-5-nitroaniline (200 mg, 0.537 mmol) in toluene (10 mL), triphosgene (191 mg, 0.644 mmol) was slowly added at 0 °C and stirred for 10 min. Then, TEA (0.225 mL, 1.611 mmol) was added and stirring was continued for another 10 min. Finally, methylamine hydrochloride (54.4 mg, 0.805 mmol) was added at 0 °C. The reaction mixture was slowly warmed to 25 °C and stirred for 16 h. After reaction completion, volatiles were evaporated, and crude mass was directly taken for next step without further purification.

[0438] To the stirred solution of above crude compound in DCM (5 mL), TFA (1 mL, 13 mmol) was added at 0 °C and stirred for 1 h. The reaction mixture was evaporated under vacuum and the crude mass was directly taken for next step without further purification.

[0439] To a stirred solution of above crude compound in DME (5 mL), 1,2- Dimethylethylenediamine (0.516 mL, 2.95 mmol) was added at 0 °C. The reaction mass was slowly warmed to 25 °C stirred for 30 min. The reaction mass was quenched with water (25 mL) and extracted in DCM (3 x 20 mL). Combined organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to afford the crude product. The crude residue was purified by flash column chromatography on silica with 20-40% ethyl acetate in pet ether to afford the title compound (130 mg, 0.526 mmol, 98% yield) as a yellow oil after 3 steps.

[0440] Step 42.4: Synthesis of l-(5-amino-2-fluorophenyl)-l-(3-hydroxy-3- methylbutyl)-3-methylurea. To a stirred solution of l-(2-fluoro-5-nitrophenyl)-l-(3-hydroxy-3- methylbutyl)-3, 3 -dimethylurea (130 mg, 0.434 mmol) in THF (2.5 mL) : Ethanol (2.5 mL) mixture, was added 10% Pd-C (100 mg, 0.940 mmol) under nitrogen at 25 °C. The reaction mixture was stirred under hydrogen atmosphere for 16 h. The reaction mixture was filtered through celite and the celite pad was washed with THF (3 x 10 mL). The combined filtrate was evaporated under reduced pressure to obtain the title compound (127 mg, 0.320 mmol, 34.0% yield) as a yellow oil. The crude product was used for the next step without further purification.

[0441] Step 42.5: Synthesis of l-(5-((5-chloro-2-fluoropyrimidin-4-yl)amino)-2- fluorophenyl)-l-(3-hydroxy-3-methylbutyl)-3-methylurea. To a stirred solution of l-(5- amino-2-fluorophenyl)-l -(3 -hydroxy-3 -methylbutyl)-3 -methylurea (120 mg, 0.446 mmol) and 5- chloro-2,4-difluoropyrimidine (80 mg, 0.535 mmol) in THF (2.0 mL) at -78 °C was added DIPEA (0.233 mL, 1.34 mmol) dropwise under nitrogen atmosphere. The reaction mixture was slowly warmed to 25 °C and stirred for 16 h. The reaction mixture was evaporated under reduced pressure to obtain crude. The crude product was purified by flash column chromatography on silica gel with 10% methanol / dichloromethane to afford the titel compound (110 mg, 0.139 mmol, 31%yield) as a brown gummy liquid.

[0442] Step 42.6: Synthesis of l-(5-((5-chloro-2-((3R,4R)-4-((3-(2,6-dioxopiperidin-3- yl)-l-methyl-lH-indazol-6-yl)amino)-3-methylpiperidin-l-yl)pyrimidin-4-yl)amino)-2- fluorophenyl)- 1 -(3 -hydroxy-3 -methylbutyl)-3 -methylurea. To a stirred solution of l-(5-((5- chloro-2-fluoropyrimidin-4-yl)amino)-2 -fluorophenyl)- 1 -(3 -hydroxy-3 -methylbutyl)-3- methylurea (80 mg, 0.20 mmol) in DMSO (2 mL) was added 3-(l-methyl-6-(((3R,4R)-3- methylpiperidin-4-yl)amino)-lH-indazol-3-yl)piperidine-2, 6-dione. TFA (109 mg, 0.220 mmol) and DIPEA (0.105 mL, 0.600 mmol) at 25 °C. The reaction mixture was heated to 80 °C and stirred for 4 h. The reaction mixture was cooled to room temperature and purified by preparative HPLC to afford the title compound (75 mg, 0.102 mmol, 50.9% yield) as an off-white solid. LCMS: 734.3 (M+H)+, 'H NMR (400 MHz, DMSO-d6): 6 10.81 (s, 1H), 8.79 (s, 1H), 8.08 (s, 1H), 7.79 (dd, J = 8.8, 2,8 Hz, 1H), 7.70-7.77 (m, 1H), 7.32-7.23 (m, 2H), 6.51 (dd, J = 8.8, 1.6 Hz, 1H), 6.44 (s, 1H), 5.78-5.70 (m, 2H), 4.51-4.48 (m, 2H), 4.22-4.16 (m, 2H), 3.81 (s, 3H), 3.59- 3.50 (m, 2H), 2.78-2.70 (m, 1H), 2.62-2.55 (m, 2H), 2.28-2.21( m, 1H), 2.16-2.07 (m, 2H), 1.61- 1.49 (m, 3H), 1.22-1.55 (m, 1H), 1.19 (s, 6H), 0.98 (d, J = 6.4 Hz, 3H).l-(3-((5-chloro-2-((3R,4R)-4-((3-(2,6-dioxopiperidin-3-yl)-l-methyl-lH-indazol-6-yl)amino)-3- methylpiperidin- 1 -yl)pyrimidin-4-yl)amino)phenyl)- 1 -(3 -hydroxy-3 -methylbutyl)-3 , 3 - dimethylurea

[0443] Step 43.1 : Synthesis of l-(3-((5-chloro-2-((3R,4R)-4-((3-(2,6-dioxopiperidin-3- yl)-l-methyl-lH-indazol-6-yl)amino)-3-methylpiperidin-l-yl)pyrimidin-4-yl)amino)phenyl)-l- (3 -hydroxy-3 -methylbutyl)-3, 3 -dimethylurea. The title compound was synthesized analogously to Example XX (above) using 3 -nitroaniline as the original starting material in Step 1. LCMS: 731.2 (M+H)+,JH NMR (400 MHz, DMSO-d6): 8 10.81 (s, 1H), 8.79 (s, 1H), 8.09 (s, 1H), 7.44 (d, J = 8.0 Hz, 2H), 7.32 - 7.26 (m, 2H), 6.75 - 6.77 (d, J = 6.40 Hz, 1H), 6.51 (dd, J = 8.40, 1.2 Hz, 2H), 6.48-6.44 (m, 2H), 5.71 (brs, 1H), 4.48-4.45 (m, 2H), 4.19-4.16 (m, 1H), 3.81 (s, 3H), 3.60-3.56 (m, 3H), 3.08-3.01 (m, 1H), 2.78-2.71 (m, 1H), 2.68-2.56 (m, 7H), 2.28-2.21 (m, 1H), 2.18-2.05 (m, 1H), 1.59 (t, J = 8.40 Hz, 2H), 1.22-1.15 (m, 1H), 1.04 (s, 6H), 0.97 (d, J = 6.40 Hz, 1H).

[0444] Examples in the table below have been made according to the general procedures outlined in the table beginning with their respective commercial starting materials and intermediates found within this document.Biological ExamplesExample Bl. BCL6_HiBiT degradation assay.

[0445] A DHL-4 cell line with HiBiT-tag knocked into endogenous BCL6 locus using CRISPR was generated. The DHL-4_BCL6_HiBiT cells were dispensed into 384-well plates (Corning no. 3570) that were pre-spotted with compounds. Compounds were dispensed by an acoustic despenser (ATS acoustic transfer system from EDC Biosystems) into a 384-well plate in a 10-point dose response curve using 3 -fold dilutions starting at 1-10 pM and going down to 0.0015-0.00015 pM. 25 pL of media (RPMI-1640 + 10% heat inactivated FBS + lxPen / Strep) containing 2500 of DHL-4 was dispensed per well. Assay plates were incubated at 37 °C with 5% CO2 for 2 hours. After incubation, 25 pL of the Nano-Gio HiBiT lytic detection working solution (Promega, catalogue no. N3040, Madison, WI) was added to each well and incubated at room temperature for 15-30 min, protected from light. After 30 min, luminescence was read on an Envision or PHERAstar luminescence reader. To determine the EC50 value (the halfmaximum effective concentration) and the level of the gradation (Yconstant) of a BCL6 degrader, luminescent signal normalized by DMSO control (Y) and compound concentration (x) was fitted using a four-para...

Claims

CLAIMS1. A compound of F ormula (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;Z1is C(R3) and Z2is N, or Z1is N and Z2is C(R3);R3is halo or cyano;L1is N(Rn), 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;Z3is C(H)2, C(H)(CH2CH2C(O)NRlbRlc), C(H)(OCH2C(O)NRlbRlc), N(CH2CH2C(O)NRlbRlc), and Z4is C(H)2; orZ3is C(H)2or C(H)(CH2CH2C(O)NRlbRlc), and Z4is O;Z5is C(H)2, C(F)2, or C(H)(F);Rlais hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 deuteroalkyl, C1-C6 haloalkyl, or -CH2CH2C(O)NRlbRlc;Rlbis hydrogen or C1-C6 alkyl;Rlcis Ci-C6alkyl;Rldis hydrogen or halo;Rleis -N(Rla)C(O)(Ci-C6alkyl), -N(Rla)C(O)NRlbRlc, -CH2C(O)NRlbRlc,5 to 6-membered heteroaryl,Z6is C(H2), C(H)Rla, orN(Rla);Z7is O or S;R2is hydrogen or fluoro;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; provided R1is notThe compound of claim 1, wherein Ring A is a four to six -membered monocyclic nitrogen-containing heterocyclylene or eight to ten-membered spirocyclic nitrogencontaining heterocyclylene.The compound of claim 1, wherein Ring A is piperidinylene, piperazinylene,2,8-diazaspiro[4.5]decanylene, phenylene, or, and Ring A is substituted with (R10)x.The compound of any one of claims 1-3, wherein R10is fluoro, methyl, or methoxy; and x is 0 or 1.The compound of any one of claims 1-4, wherein L1is N(Rn); and R11is hydrogen or Ci-C6alkyl.The compound of any one of claims 1-5, wherein L1is absent.The compound of any one of claims 1-6, wherein L2is -(CH2)yN(R12)-, -0(CH2)y-, -N(R12)C(O)-, or -(CH2)ZC(O)N(R12)-; and each R12is independently hydrogen or C1-C6 alkyl.The compound of any one of claims 1-7, wherein z is 1, 2, or 3.The compound of any one of claims 1-6, wherein L2is -N(H)-, -N(CH3)-, -CH2N(H)-, -O-, -N(H)C(O)-, or -CH2C(O)N(H)-, or L2is absent.The compound of any one of claims 1-9, wherein R1is:

11. The compound of any one of claims 1-10, wherein R2is hydrogen; and R3is chloro or cyano.

12. The compound of any one of claims 1-11, wherein R4is:X2, X3and X4are C(H);R13is hydrogen or methyl;R14is fluoro;R52is hydrogen or methyl; and p is 0 or 1.

13. The compound of any one of claims 1-4 and 7-12, of Formula (II):or a pharmaceutically acceptable salt thereof.

14. The compound of any one of claims 1, 4, 5, and 10-12, of Formula (III):or a pharmaceutically acceptable salt thereof.The compound of claim 1 or 11, of Formula (VI):or a pharmaceutically acceptable salt thereof, wherein:R51is hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 deuteroalkyl, or C1-C6 haloalkyl;R52is hydrogen or C1-C6 alkyl; andR53is hydrogen, halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, or C1-C6 haloalkyl.

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

17. The compound of claim 16, selected from: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.

0. 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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