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.

Description

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

[0001] This application claims priority to US Provisional Application No. 63 / 595,081, filed on November 1, 2023, the disclosure of which is incorporated herein by reference in its entirety for any purpose. FIELD

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

[0003] BCL6 (B cell lymphoma 6) is a member of the BTB / POZ-zinc finger family that contains an N-terminal BTB / POZ domain and a zinc finger at the C-terminus. As a transcription factor for T follicular helper (Tfh) cells, BCL6 is required for germinal center (GC) formation of naïve B cells and hence antibody affinity maturation. BCL6 was initially discovered as an oncogene in diffuse large B-cell lymphomas (DLBCLs) and its role has been implicated in many types of diseases including B-acute lymphoblastic leukemia, chronic myeloid leukemia, breast cancer, and non-small lung cancer (NSCLC) (Cardenas et al., Clin Cancer Res 2017, 23, 885- 893). The N-terminal BTB / POZ domain binds to and recruits of 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 cellularhomeostasis. Selective identification and removal of damaged, misfolded, or excess proteins is achieved through the ubiquitin-proteasome pathway (UPP). The UPP is central to the regulation of almost all cellular processes. Ubiquitination of the protein is accomplished by an E3 ubiquitin ligase that binds to a protein and adds ubiquitin molecules to the protein, thus marking the protein for proteasome degradation.

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

[0007] Accordingly, in one aspect, provided herein are 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] Embodiment 1 is a compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein: R1is halo, -CN, C1-C6alkyl, or C1-C6haloalkyl; Ring A is 4- to 10-membered monocyclic or fused bicyclic heterocyclylene, 6- to 10-membered monocyclic or fused bicyclic arylene, 5- to 10-membered monocyclic or fused bicyclicheteroarylene, C4-C6cycloalkylene, or C4-C6cycloalkenylene, wherein the heterocyclylene and heteroarylene contain 1-3 heteroatoms selected from N and O; Ring B is a fused 5-membered heterocyclyl or 5-membered heteroaryl, wherein the heterocyclyl and heteroaryl contain 1-3 nitrogen atoms and are optionally substituted with 1-2 groups selected from C1-C6alkyl, halo, and oxo; each R2is independently C1-C6alkyl, halo, C1-C6haloalkyl, or C1-C6alkyl-OH, or 2 R2groups on the same carbon atom are taken together to form an oxo group, or 2 R2groups are taken together with the carbon atom to which they are attached to form a spiro C3-C6cycloalkyl, or 2 R2groups on different carbon atoms are taken together to form C1-C6alkylene or -(C1-C4alkylene)O(C1-C4alkylene)-; L1is a bond, O, C1-C6alkylene, -N(H)-, -N(C1-C6alkyl)-, or -N(C1-C6alkyl-OH)-; L2is a bond, -N(H)-, -N(C1-C6alkyl)-, -N(H)C(O)-, -N(H)C(O)(C1-C6alkylene)-, -(C1-C6alkylene)N(C1-C6alkyl)-, O, or C1-C6alkylene; Y1and Y2are independently CR4or N; R3is H, C1-C6alkyl, C1-C6alkyl-OH, -(C1-C6alkylene)O(C1-C6alkyl), -(C1-C6alkylene)NR3aR3b, or -(C1-C6alkylene)(4- to 6-membered heterocyclyl), wherein the heterocyclyl contains 1-3 heteroatoms selected from N and O, and wherein the heterocyclyl is optionally substituted by 1-5 groups selected from halo, -OH, C1-C6alkyl, and C1-C6haloalkyl; each R3aand R3bis independently H or C1-C6alkyl; each R4is independently H, halo, or C1-C6alkyl; each R5is independently halo, C1-C6alkyl, or C1-C6haloalkyl; W1is C or N; W2is C or N; Z is C or N; each R6is independently halo, C1-C6alkyl, or C1-C6haloalkyl; R7is C1-C6alkyl, C1-C6alkyl-OH, -(C1-C6alkylene)NR3aR3b, -(C1-C6alkylene)C(O)NR3aR3b, -(C1-C6alkylene)CO2(C1-C6alkyl), C3-C6cycloalkyl, -(C1-C6alkylene)(C3-C6cycloalkyl), 4- to 6-membered heterocyclyl, or -(C1-C6alkylene)(4- to 6-membered heterocyclyl), wherein the heterocyclyl contains 1-3 heteroatoms selected from N and O, and the cycloalkyl and heterocyclyl are optionally substituted by 1-5 groups selected from -OH, C1-C6alkoxy, C1-C6alkyl, halo, and C1-C6haloalkyl; m is 0-2;n is 0-5; z is 0-3; * indicates alternative points of attachment to L2; and is a single or double bond; wherein one or more hydrogen atoms in the compound are optionally replaced by deuterium.

[0011] Embodiment 2 is the compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein: R1is halo, -CN, C1-C3alkyl, or C1-C3haloalkyl.

[0012] Embodiment 3 is the compound of embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: R1is Cl, -CN, or F.

[0013] Embodiment 4 is the compound of any one of embodiments 1-3, or a pharmaceutically acceptable salt thereof, wherein: Ring A is 4- to 7-membered monocyclic heterocyclylene, 8- to 10-membered fused bicyclic heterocyclylene, phenylene, 5- to 6-membered monocyclic heteroarylene, 8- to 10- membered fused bicyclic heteroarylene, C5-C6cycloalkylene, or C5-C6cycloalkenylene, wherein the heterocyclylene and heteroarylene contain 1-3 heteroatoms selected from N and O; each R2is independently C1-C3alkyl, halo, C1-C3haloalkyl, or C1-C3alkyl-OH, or 2 R2groups on the same carbon atom are taken together to form an oxo group, or 2 R2groups are taken together with the carbon atom to which they are attached to for a spiro C3-C5 cycloalkyl, or 2 R2groups on different carbon atoms are taken together to form C1-C3alkylene or -(C1-C3alkylene)O(C1-C3alkylene)-; and n is 0-3.

[0014] Embodiment 5 is the compound of any one of embodiments 1-4, or a pharmaceutically acceptable salt thereof, wherein:.

[0015] Embodiment 6 is the compound of any one of embodiments 1-5, or a pharmaceutically acceptable salt thereof, wherein: L1is a bond, O, C1-C3alkylene, -N(H)-, -N(C1-C3alkyl)-, or -N(C1-C3alkyl-OH)-; and L2is a bond, -N(H)-, -N(C1-C3alkyl)-, -N(H)C(O)-, -N(H)C(O)(C1-C3alkylene)-, -(C1-C3alkylene)N(C1-C3alkyl)-, O, or C1-C3alkylene.

[0016] Embodiment 7 is the compound of any one of embodiments 1-6, or a pharmaceutically acceptable salt thereof, wherein: L1is a bond, O, -CH2-, -N(H)-, -N(CH3)-, or -N(CH2CH2OH)-; and L2is a bond, -N(H)-, -N(CH3)-, -N(H)C(O)-, -N(H)C(O)(CH2)-, -(CH2)N(CH3)-, O, or -CH2-.

[0017] Embodiment 8 is the compound of any one of embodiments 1-7, or a pharmaceutically acceptable salt thereof, wherein: (i) Y1and Y2are independently CR4; or (ii) Y1and Y2are each N; wherein each R4is independently H, halo, or C1-C3alkyl.

[0018] Embodiment 9 is the compound of any one of embodiments 1-8, or a pharmaceutically acceptable salt thereof, wherein:.

[0019] Embodiment 10 is the compound of any one of embodiments 1-9, or apharmaceutically acceptable salt thereof, wherein: R3is H, C1-C3alkyl, C1-C5alkyl-OH, -(C1-C3alkylene)O(C1-C3alkyl), -(C1-C3alkylene)NR3aR3b, or -(C1-C3alkylene)(4- to 6-membered heterocyclyl), wherein the heterocyclyl contains 1-2 heteroatoms selected from N and O, and wherein the heterocyclyl is optionally substituted by 1-3 groups selected from halo, -OH, C1-C3alkyl, and C1-C3haloalkyl; R7is C1-C3alkyl, C4-C6alkyl-OH, -(C4-C6alkylene)NR3aR3b, -(C1-C3alkylene)C(O)NR3aR3b, -(C1-C3alkylene)CO2(C4-C6alkyl), C4-C6cycloalkyl, -(C1-C3alkylene)(C4-C6cycloalkyl), 4- to 6-membered heterocyclyl, or -(C1-C3alkylene)(4- to 6-membered heterocyclyl), wherein the heterocyclyl contains 1-2 heteroatoms selected from N and O, and the cycloalkyl and heterocyclyl are optionally substituted by 1-3 groups selected from -OH, C1-C3alkoxy, C1-C3alkyl, halo, and C1-C3haloalkyl; and each R3aand R3bis independently H or C1-C3alkyl.

[0020] Embodiment 11 is the compound of any one of embodiments 1-10, or a pharmaceutically acceptable salt thereof, wherein: R3is H, -CH3, -CD3, -CH2CH3, -CH(CH3)2, -CH2CH(CH3)OH, -CH2C(CH3)2OH, -CH2CH2OCH3, -CH2CH2N(CH3)2, -CH2CH2CH2N(CH3)2, -CH2CH2N(H)(CH3),.

[0021] Embodiment 12 is the compound of any one of embodiments 1-11, or a pharmaceutically acceptable salt thereof, wherein: each R5is independently halo, C1-C3alkyl, or C1-C3haloalkyl; and z is 0 or 1.

[0022] Embodiment 13 is the compound of any one of embodiments 1-12, or a pharmaceutically acceptable salt thereof, wherein: each R6is independently halo, C1-C3alkyl, or C1-C3haloalkyl; and m is 0 or 1.

[0023] Embodiment 14 is the compound of any one of embodiments 1-13, or a pharmaceutically acceptable salt thereof, wherein:.

[0024] Embodiment 15 is the compound of any one of embodiments 1-14, or a pharmaceutically acceptable salt thereof, wherein: Ring B is a fused 5-membered heterocyclyl or 5-membered heteroaryl, wherein the heterocyclyl and heteroaryl contain 1-3 nitrogen atoms and are optionally substituted with 1-2 groups selected from C1-C3alkyl, halo, and oxo.

[0025] Embodiment 16 is the compound of any one of embodiments 1-15, or a pharmaceutically acceptable salt thereof, wherein:.

[0026] Embodiment 17 is the compound of any one of embodiments 1-16, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (II), (III), (IV), (Va), or (Vb):

[0027] Embodiment 18 is a compound selected from the compounds of Table 1 and pharmaceutically acceptable salts thereof.

[0028] Embodiment 19 is a pharmaceutical composition comprising the compound of any one of embodiments 1-18, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0029] Embodiment 20 is a method of (i) degrading B-cell lymphoma 6 protein (BCL6) comprising contacting BCL6 with an effective amount of the compound of any one of embodiments 1-18, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of embodiment 19, or (ii) treating a cancer or an autoimmune disease in a subject in need thereof, comprising administering to the subject an effective amount of the compound of any one of embodiments 1-18, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of embodiment 19. DETAILED DESCRIPTION Definitions

[0030] 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 of the invention.

[0031] 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.

[0032] 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.

[0033] 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.

[0034] “Amino” refers to the -NH2 radical.

[0035] “Cyano” refers to the -CN radical.

[0036] “Nitro” refers to the -NO2radical.

[0037] “Oxa” refers to the -O- radical.

[0038] “Oxo” refers to the =O radical.

[0039] “Thioxo” refers to the =S radical.

[0040] “Imino” refers to the =N-H radical.

[0041] “Oximo” refers to the =N-OH radical.

[0042] “Hydrazino” refers to the =N-NH2radical.

[0043] “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-C15alkyl). In certain embodiments, an alkyl comprises one to thirteen carbon atoms (e.g., C1-C13alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (e.g., C1-C8alkyl). In other embodiments, an alkyl comprises one to six carbon atoms (e.g., C1-C6alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (e.g., C1-C5alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (e.g., C1-C4alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (e.g., C1-C3alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (e.g., C1-C2alkyl). In other embodiments, an alkyl comprises one carbon atom (e.g., C1alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (e.g., C5-C15alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (e.g., C5-C8alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (e.g., C2-C5alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (e.g., C3-C5alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), and1-pentyl (n-pentyl). The alkyl is attached to the rest of the molecule by a single bond. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)- N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2(where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0044] “Alkyl-OH” refers to an unbranched or branched alkyl group as defined above, wherein one or more hydrogen atoms are replaced by -OH. For example, “C1-C6alkyl-OH” refers to a C1-C6alkyl which is substituted by one or more -OH groups. An alkyl-OH may contain multiple hydroxy groups that are attached to the same carbon atom or to multiple carbon atoms. Examples of alkyl-OH include, e.g., -CH2OH, -CH2CH2OH, and -CH2CH2C(CH3)2OH.

[0045] “Alkoxy” refers to a radical bonded through an oxygen atom of the formula -O-alkyl, where alkyl is an alkyl chain as defined above.

[0046] “Alkenyl” refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. In certain embodiments, an alkenyl comprises two to eight carbon atoms. In other embodiments, an alkenyl comprises two to four carbon atoms. The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)- N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2 (where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, ortrifluoromethyl), 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).

[0047] “Alkynyl” refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, having from two to twelve carbon atoms. In certain embodiments, an alkynyl comprises two to eight carbon atoms. In other embodiments, an alkynyl has two to four carbon atoms. The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)- N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2(where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0048] “Alkylene” or “alkylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation and having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, n-butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. Thepoints of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through one carbon in the alkylene chain or through any two carbons within the chain. In certain embodiments, an alkylene comprises one to eight carbon atoms (e.g., C1-C8alkylene). In other embodiments, an alkylene comprises one to six carbon atoms (e.g., C1-C6alkylene). In other embodiments, an alkylene comprises one to five carbon atoms (e.g., C1-C5alkylene). In other embodiments, an alkylene comprises one to four carbon atoms (e.g., C1-C4alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (e.g., C1-C3alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (e.g., C1-C2alkylene). In other embodiments, an alkylene comprises one carbon atom (e.g., C1alkylene). In other embodiments, an alkylene comprises five to eight carbon atoms (e.g., C5-C8alkylene). In other embodiments, an alkylene comprises two to five carbon atoms (e.g., C2-C5alkylene). In other embodiments, an alkylene comprises three to five carbon atoms (e.g., C3-C5alkylene). Unless stated otherwise specifically in the specification, an alkylene chain 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).

[0049] “Aryl” refers to a radical derived from an aromatic monocyclic or multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon from five to eighteen carbon atoms, where at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) ^ –electron system in accordance with the Hückel theory. Aryl includes, but is not limited to, phenyl, fluorenyl, indanyl, indenyl, tetralinyl and naphthalenyl. Unless stated otherwise specifically in the specification, the term “aryl” or the prefix “ar” (such as in “aralkyl”) is meant to include aryl radicals optionallysubstituted 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.

[0050] “Aralkyl” refers to a radical of the formula -Rc-aryl where Rcis an alkylene chain as defined above, for example, methylene, ethylene, and the like. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.

[0051] “Aralkenyl” refers to a radical of the formula -Rd-aryl where Rdis an alkenylene chain as defined above. The aryl part of the aralkenyl radical is optionally substituted as described above for an aryl group. The alkenylene chain part of the aralkenyl radical is optionally substituted as defined above for an alkenylene group.

[0052] “Aralkynyl” refers to a radical of the formula -Re-aryl, where Reis an alkynylene chain as defined above. The aryl part of the aralkynyl radical is optionally substituted as described above for an aryl group. The alkynylene chain part of the aralkynyl radical is optionally substituted as defined above for an alkynylene chain.

[0053] “Carbocyclyl” refers to a stable non aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ringsystems, 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 comprises three to ten carbon atoms. In other embodiments, a carbocyclyl comprises five to seven carbon atoms. 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 double bonds or triple bonds.) A fully saturated carbocyclyl radical is also referred to as “carbocyclyl” or “cycloalkyl”. In some embodiments, a cycloalkyl comprises three to six carbon atoms (e.g., C3-C6cycloalkyl) or four to six carbon atoms (e.g., C4-C6cycloalkyl). Examples of monocyclic carbocyclyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. An unsaturated carbocyclyl is also referred to as “cycloalkenyl”. In some embodiments, a cycloalkenyl comprises three to six carbon atoms (e.g., C3-C6cycloalkenyl) or four to six carbon atoms (e.g., C4-C6cycloalkenyl). Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7 dimethyl bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically in the specification, the term "carbocyclyl" is meant to include carbocyclyl radicals that are optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -OC(O)- N(Ra)2, -N(Ra)C(O)Ra, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2) and -S(O)tN(Ra)2 (where t is 1 or 2) where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each Rb is independently a direct bond or a straight or branched alkylene oralkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

[0054] “Carbocyclylalkyl” refers to a radical of the formula -Rc-carbocyclyl where Rcis an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above.

[0055] “Carbonyl” refers to a radical of the formula -C(O)R10R20, wherein R10and R20is 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).

[0056] “Halo” or “halogen” refers to bromo, chloro, fluoro or iodo substituents.

[0057] “Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. In some embodiments, the haloalkyl group has one to six carbon atoms and is substituted by one or more halo radicals (C1-C6haloalkyl), or the haloalkyl group has one to five carbon atoms and is substituted by one or more halo radicals (C1-C5haloalkyl), or the haloalkyl group has one to three carbon atoms and is substituted by one or more halo radicals (C1-C3haloalkyl). The halo radicals may be all the same or the halo radicals may be different. Unless specifically stated otherwise, a haloalkyl group is optionally substituted.

[0058] “Fluoroalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. The alkyl part of the fluoroalkyl radical may be optionally substituted as defined above for an alkyl group.

[0059] “Heterocyclyl” refers to a stable 3 to 18 membered non-aromatic ring radical thatcomprises 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 or bridged 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 such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2 oxopiperazinyl, 2 oxopiperidinyl, 2 oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4 piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1 oxo thiomorpholinyl, and 1,1 dioxo thiomorpholinyl. Unless stated otherwise specifically in the specification, the term "heterocyclyl" is meant to include heterocyclyl radicals as defined above that are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 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.

[0060] “N-heterocyclyl” or “N-attached heterocyclyl” refers to a heterocyclyl radical as defined above containing at least one nitrogen and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical. An N-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such N-heterocyclyl radicals include, but are not limited to, 1- morpholinyl, 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl.

[0061] “C-heterocyclyl” or “C-attached heterocyclyl” refers to a heterocyclyl radical as defined above containing at least one heteroatom and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a carbon atom in the heterocyclyl radical. A C-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such C-heterocyclyl radicals include, but are not limited to, 2- morpholinyl, 2- or 3- or 4-piperidinyl, 2-piperazinyl, 2- or 3-pyrrolidinyl, and the like.

[0062] “Heterocyclylalkyl” refers to a radical of the formula -Rc-heterocyclyl where Rcis an alkylene chain as defined above. If the heterocyclyl is a nitrogen containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkyl radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl part of the heterocyclylalkyl radical is optionally substituted as defined above for a heterocyclyl group.

[0063] “Heterocyclylalkoxy” refers to a radical bonded through an oxygen atom of the formula -O-Rcheterocyclyl where Rcis an alkylene chain as defined above. If the heterocyclyl is a nitrogen containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl part of the heterocyclylalkoxy radical is optionally substituted as defined above for a heterocyclyl group.

[0064] “Heteroaryl” refers to a radical derived from a 3 to 18 membered aromatic ring radical that comprises two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. As used herein, the heteroaryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) ^–electron system in accordance with the Hückel theory. Heteroaryl includes fused or bridged ring systems. The heteroatom(s) in the heteroaryl radical is optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl is attached to the rest of the molecule through any atom of the ring(s). Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl,benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H- benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e. thienyl). Unless stated otherwise specifically in the specification, the term “heteroaryl” is meant to include heteroaryl radicals as defined above which are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N(Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2 (where t is 1 or 2), where each Rais independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy,methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each Rbis independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rcis a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

[0065] “N-heteroaryl” refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. An N-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0066] “C-heteroaryl” refers to a heteroaryl radical as defined above and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a carbon atom in the heteroaryl radical. A C-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0067] “Heteroarylalkyl” refers to a radical of the formula -Rc-heteroaryl, where Rcis an alkylene chain as defined above. If the heteroaryl is a nitrogen containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkyl radical is optionally substituted as defined above for a heteroaryl group.

[0068] “Heteroarylalkoxy” refers to a radical bonded through an oxygen atom of the formula -O-Rcheteroaryl, where Rcis an alkylene chain as defined above. If the heteroaryl is a nitrogen containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkoxy radical is optionally substituted as defined above for a heteroaryl group.

[0069] Certain commonly used alternative chemical names may be used. For example, a divalent group such as a divalent “alkyl” group, a divalent “cycloalkyl” group, a divalent “phenyl” group, a divalent “heteroaryl” group, a divalent “heterocyclyl” group etc., may also be referred to as an “alkylene” group, a cycloalkylene, a “phenylene” group, a “heteroarylene” group, or a “heterocyclylene” group, respectively.

[0070] Embodiments of the disclosure are meant to encompass pharmaceutically acceptable salts, tautomers, isotopologues, and stereoisomers of the compounds provided herein, such as the compounds of Formula (I).

[0071] As used herein, the term “pharmaceutically acceptable salt(s)” refers to a salt prepared from a pharmaceutically acceptable non-toxic acid or base including an inorganic acid and base and an organic acid and base. Suitable pharmaceutically acceptable base addition salts of the compounds of formula (I) include, but are not limited to metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, N,N’-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methyl-glucamine) and procaine. Suitable non-toxic acids include, but are not limited to, inorganic and organic acids such as acetic, alginic, anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, formic, fumaric, furoic, galacturonic, gluconic, glucuronic, glutamic, glycolic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phenylacetic, phosphoric, propionic, salicylic, stearic, succinic, sulfanilic, sulfuric, tartaric acid, and p-toluenesulfonic acid. Specific non-toxic acids include hydrochloric, hydrobromic, maleic, phosphoric, sulfuric, and methanesulfonic acids. Examples of specific salts thus include hydrochloride, formic, and mesylate salts. Others are well-known in the art, see for example, Remington’s Pharmaceutical Sciences, 18theds., Mack Publishing, Easton PA (1990) or Remington: The Science and Practice of Pharmacy, 19theds., Mack Publishing, Easton PA (1995).

[0072] 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 suchisomeric forms are included within the embodiments disclosed herein, including mixtures thereof.

[0073] 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).

[0074] “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:.

[0075] 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.

[0076] 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.

[0077] 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.

[0078] The disclosure also includes “deuterated analogs” of compounds described herein in which from 1 to n hydrogens attached to a carbon atom is / are replaced by deuterium, in which n is the number of hydrogens in the molecule. When multiple deuterium atoms are present in a compound, the deuterium atoms may be on the same portion of the molecule (for example, on a single alkyl group or on a single ring) or on different portions of the molecule (for example, on separate alkyl groups or separate rings). Such compounds may exhibit increased resistance to metabolism and thus may be useful for increasing the half-life of any compound when administered to a mammal, particularly a human. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” Trends Pharmacol. Sci.5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogens have been replaced by deuterium.

[0079] 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 therespective compound or salt thereof disclosed herein, may otherwise vary independently from the selection of the pharmaceutically acceptable salt of the respective compound.

[0080] 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.

[0081] “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.

[0082] “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.

[0083] 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.

[0084] 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.

[0085] Although various features of the invention 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 invention may be described herein in the context of separate embodiments for clarity, the invention may also be implemented in a single embodiment. Compounds

[0086] In one aspect, provided herein is a compound of Formula (I):(I)or a pharmaceutically acceptable salt thereof, wherein: R1is halo, -CN, C1-C6alkyl, or C1-C6haloalkyl; Ring A is 4- to 10-membered monocyclic or fused bicyclic heterocyclylene, 6- to 10- membered monocyclic or fused bicyclic arylene, 5- to 10-membered monocyclic or fused bicyclic heteroarylene, C4-C6cycloalkylene, or C4-C6cycloalkenylene, wherein the heterocyclylene and heteroarylene contain 1-3 heteroatoms selected from N and O; Ring B is a fused 5-membered heterocyclyl or 5-membered heteroaryl, wherein the heterocyclyl and heteroaryl contain 1-3 nitrogen atoms and are optionally substituted with 1-2 groups selected from C1-C6alkyl, halo, and oxo; each R2is independently C1-C6alkyl, halo, C1-C6haloalkyl, or C1-C6alkyl-OH, or 2 R2groups on the same carbon atom are taken together to form an oxo group, or 2 R2groups are taken together with the carbon atom to which they are attached to form a spiro C3- C6cycloalkyl, or 2 R2groups on different carbon atoms are taken together to form C1-C6alkylene or -(C1-C4alkylene)O(C1-C4alkylene)-; L1is a bond, O, C1-C6alkylene, -N(H)-, -N(C1-C6alkyl)-, or -N(C1-C6alkyl-OH)-; L2is a bond, -N(H)-, -N(C1-C6alkyl)-, -N(H)C(O)-, -N(H)C(O)(C1-C6alkylene)-, -(C1-C6alkylene)N(C1-C6alkyl)-, O, or C1-C6alkylene; Y1and Y2are independently CR4or N; R3is H, C1-C6alkyl, C1-C6alkyl-OH, -(C1-C6alkylene)O(C1-C6alkyl), -(C1-C6alkylene)NR3aR3b, or -(C1-C6alkylene)(4- to 6-membered heterocyclyl), wherein the heterocyclyl contains 1-3 heteroatoms selected from N and O, and wherein the heterocyclyl is optionally substituted by 1-5 groups selected from halo, -OH, C1-C6alkyl, and C1-C6haloalkyl; each R3aand R3bis independently H or C1-C6alkyl; each R4is independently H, halo, or C1-C6alkyl; each R5is independently halo, C1-C6alkyl, or C1-C6haloalkyl; W1is C or N; W2is C or N; Z is C or N;each R6is independently halo, C1-C6alkyl, or C1-C6haloalkyl; R7is C1-C6alkyl, C1-C6alkyl-OH, -(C1-C6alkylene)NR3aR3b, -(C1-C6alkylene)C(O)NR3aR3b, -(C1-C6alkylene)CO2(C1-C6alkyl), C3-C6cycloalkyl, -(C1-C6alkylene)(C3-C6cycloalkyl), 4- to 6-membered heterocyclyl, or -(C1-C6alkylene)(4- to 6-membered heterocyclyl), wherein the heterocyclyl contains 1-3 heteroatoms selected from N and O, and the cycloalkyl and heterocyclyl are optionally substituted by 1-5 groups selected from -OH, C1-C6alkoxy, C1-C6alkyl, halo, and C1-C6haloalkyl; m is 0-2; n is 0-5; z is 0-3; * indicates alternative points of attachment to L2; and is a single or double bond; wherein one or more hydrogen atoms in the compound are optionally replaced by deuterium.

[0087] In some embodiments, R1is halo, -CN, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments, R1is halo, -CN, C1-C3alkyl, or C1-C3haloalkyl. In some embodiments, R1is Cl, -CN, or F.

[0088] In some embodiments, R1is halo. In some embodiments, R1is F, Cl, Br, or I. In some embodiments, R1is F. In some embodiments, R1is Cl.

[0089] In some embodiments, R1is -CN.

[0090] In some embodiments, R1is C1-C6alkyl. In some embodiments, R1is C1-C3alkyl. In some embodiments, R1is methyl, ethyl, or propyl. In some embodiments, R1is methyl.

[0091] In some embodiments, R1is C1-C6haloalkyl. In some embodiments, R1is C1-C6haloalkyl containing 1-13 halogen atoms. In some embodiments, R1is C1-C3haloalkyl. In some embodiments, R1is C1-C3haloalkyl containing 1-7 halogen atoms. In some embodiments, R1is -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CF2Cl, -CFCl2, -CH2CF3, -CH2CHF2, or -CH2CCl3. In some embodiments, R1is -CF3.

[0092] In some embodiments, Ring A is 4- to 10-membered monocyclic or fused bicyclic heterocyclylene, 6- to 10-membered monocyclic or fused bicyclic arylene, 5- to 10-membered monocyclic or fused bicyclic heteroarylene, C4-C6cycloalkylene, or C4-C6cycloalkenylene, wherein the heterocyclylene and heteroarylene contain 1-3 heteroatoms selected from N and O. In some embodiments, Ring A is 4- to 7-membered monocyclic heterocyclylene, 8- to 10- membered fused bicyclic heterocyclylene, phenylene, 5- to 6-membered monocyclic heteroarylene, 8- to 10-membered fused bicyclic heteroarylene, C5-C6cycloalkylene, or C5-C6cycloalkenylene, wherein the heterocyclylene and heteroarylene contain 1-3 heteroatoms selected from N and O.

[0093] In some embodiments, Ring A is 4- to 10-membered monocyclic or fused bicyclic heterocyclylene containing 1-3 heteroatoms selected from N and O

[0094] In some embodiments, Ring A is 4- to 7-membered monocyclic heterocyclylene containing 1-3 heteroatoms selected from N and O. In some embodiments, Ring A is 4- to 7- membered monocyclic heterocyclylene containing 1-2 heteroatoms selected from N and O. In some embodiments, Ring A is 4- to 7-membered monocyclic heterocyclylene containing 1-2 nitrogen atoms. In some embodiments, Ring A is 4- to 7-membered monocyclic heterocyclylene containing 2 nitrogen atoms. In some embodiments, Ring A is 4- to 7-membered monocyclic heterocyclylene containing one nitrogen atom. In some embodiments, Ring A is azetidinylene, pyrrolidinylene, piperidinylene, piperazinylene, or azepanylene.

[0095] In some embodiments, Ring A is 8- to 10-membered fused bicyclic heterocyclylene containing 1-3 heteroatoms selected from N and O. In some embodiments, Ring A is 8- to 9- membered fused bicyclic heterocyclylene containing 1-3 heteroatoms selected from N and O. In some embodiments, Ring A is 8- to 9-membered fused bicyclic heterocyclylene containing 1- 3 nitrogen atoms. In some embodiments, Ring A is 8- to 9-membered fused bicyclic heterocyclylene containing 2-3 nitrogen atoms. In some embodiments, Ring A is 8- membered fused bicyclic heterocyclylene containing 3 nitrogen atoms. In some embodiments, Ring A is 9- membered fused bicyclic heterocyclylene containing 2 nitrogen atoms. In some embodiments, the fused bicyclic heterocyclylene is a saturated heterocyclic ring fused to another saturated heterocyclic ring. In some embodiments, the fused bicyclic heterocyclylene is a saturated heterocyclic ring fused to an unsaturated heterocyclic ring. In some embodiments, the fused bicyclic heterocyclylene is a saturated heterocyclic ring fused to a heteroaryl ring.

[0096] In some embodiments, Ring A is 6- to 10-membered monocyclic or fused bicyclic arylene. In some embodiments, Ring A is 6-membered monocyclic arylene. In some embodiments, Ring A is 10-membered fused bicyclic arylene. In some embodiments, Ring A is phenylene. In some embodiments, Ring A is naphthalene.

[0097] In some embodiments, Ring A is 5- to 10-membered monocyclic or fused bicyclic heteroarylene containing 1-3 heteroatoms selected from N and O.

[0098] In some embodiments, Ring A is 5- to 6-membered monocyclic heteroarylene containing 1-3 heteroatoms selected from N and O. In some embodiments, Ring A is 5- to 6- membered monocyclic heteroarylene containing 1-2 heteroatoms selected from N and O. In some embodiments, Ring A is 5- to 6-membered monocyclic heteroarylene containing 1-2 nitrogen atoms. In some embodiments, Ring A is 5-membered monocyclic heteroarylenecontaining 1-2 nitrogen atoms. In some embodiments, Ring A is 5-membered monocyclic heteroarylene containing 2 nitrogen atoms. In some embodiments, Ring A is 5-membered monocyclic heteroarylene containing one nitrogen atom. In some embodiments, Ring A is 6- membered monocyclic heteroarylene containing 1-2 nitrogen atoms. In some embodiments, Ring A is 6-membered monocyclic heteroarylene containing 2 nitrogen atoms. In some embodiments, Ring A is 6-membered monocyclic heteroarylene containing one nitrogen atom. In some embodiments, Ring A is pyrrolylene, imidazolylene, pyrazolylene, pyridinylene, pyrazinylene, pyrimidinylene, pyridazinylene, triazinylene, or oxazolylene,

[0099] In some embodiments, Ring A is 8- to 10-membered fused bicyclic heteroarylene containing 1-3 heteroatoms selected from N and O. In some embodiments, Ring A is 8- to 10- membered fused bicyclic heteroarylene containing 1-2 heteroatoms selected from N and O. In some embodiments, Ring A is 8-membered fused bicyclic heteroarylene containing 1-3 heteroatoms selected from N and O. In some embodiments, Ring A is 8-membered fused bicyclic heteroarylene containing 1-2 nitrogen atoms. In some embodiments, Ring A is 9- membered fused bicyclic heteroarylene containing 1-3 heteroatoms selected from N and O. In some embodiments, Ring A is 9-membered fused bicyclic heteroarylene containing 1-2 nitrogen atoms. In some embodiments, Ring A is 10-membered fused bicyclic heteroarylene containing 1-3 heteroatoms selected from N and O. In some embodiments, Ring A is 10-membered fused bicyclic heteroarylene containing 1-2 nitrogen atoms. In some embodiments, Ring A is quinolinylene or quinazolinylene.

[0100] In some embodiments, Ring A is C4-C6cycloalkylene. In some embodiments, Ring A C5-C6cycloalkylene. In some embodiments, Ring A is cyclobutylene, cyclopentylene, or cyclohexylene. In some embodiments, Ring A is cyclobutylene. In some embodiments, Ring A is cyclopentylene. In some embodiments, Ring A is cyclohexylene.

[0101] In some embodiments, Ring A is C4-C6cycloalkenylene. In some embodiments, Ring A is C4-C6cycloalkenylene containing a single double bond. In some embodiments, Ring A is C4-C6cycloalkenylene containing two double bonds. In some embodiments, Ring A is C5- C6 cycloalkenylene. In some embodiments, Ring A is C5-C6 cycloalkenylene containing a single double bond. In some embodiments, Ring A is C5-C6cycloalkenylene containing two double bonds. In some embodiments, Ring A is C4cycloalkenylene. In some embodiments, Ring A is C5 cycloalkenylene. In some embodiments, Ring A is C6 cycloalkenylene.

[0102] In some embodiments, Ring A is:.

[0103] In some embodiments, each R2is independently C1-C6alkyl, halo, C1-C6haloalkyl, or C1-C6alkyl-OH. In some embodiments, each R2is independently C1-C3alkyl, halo, C1-C3haloalkyl, or C1-C3alkyl-OH. In some embodiments, each R2is independently -CH3, F, or -CH2OH.

[0104] In some embodiments, R2is C1-C6alkyl. In some embodiments, R2is C1-C3alkyl. In some embodiments, R2is methyl, ethyl, or propyl. In some embodiments, R2is methyl. In some embodiments, R2is ethyl.

[0105] In some embodiments, R2is halo. In some embodiments, R2is F, Cl, Br, or I. In some embodiments, R2is F. In some embodiments, R2is Cl.

[0106] In some embodiments, R2is C1-C6haloalkyl. In some embodiments, R2is C1-C6haloalkyl containing 1-13 halogen atoms. In some embodiments, R2is C1-C3haloalkyl. In some embodiments, R2is C1-C3haloalkyl containing 1-7 halogen atoms. In some embodiments, R2is -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CF2Cl, -CFCl2, -CH2CF3, -CH2CHF2, or -CH2CCl3. In some embodiments, R2is -CF3.

[0107] In some embodiments, R2is C1-C6alkyl-OH. In some embodiments, R2is C1-C3alkyl-OH. In some embodiments, R2is -CH2OH, -CH2CH2OH, or -CH2CH2CH2OH. In some embodiments, R2is -CH2OH.

[0108] In some embodiments, 2 R2groups on the same carbon atom are taken together to form an oxo group, or 2 R2groups are taken together with the carbon atom to which they are attached to form a spiro C3-C6cycloalkyl. In some embodiments, 2 R2groups on the same carbon atom are taken together to form an oxo group, or 2 R2groups are taken together with the carbon atom to which they are attached to for a spiro C3-C5cycloalkyl. In some embodiments, 2 R2groups on the same carbon atom are taken together to form an oxo group, or 2 R2groups are taken together with the carbon atom to which they are attached to for a spiro cycloalkyl or spiro cyclobutyl.

[0109] In some embodiments, 2 R2groups on the same carbon atom are taken together to form an oxo group.

[0110] In some embodiments, 2 R2groups are taken together with the carbon atom to which they are attached to form a spiro C3-C6cycloalkyl. In some embodiments, 2 R2groups are taken together with the carbon atom to which they are attached to form a spiro C3-C5 cycloalkyl. In some embodiments, 2 R2groups are taken together with the carbon atom to which they areattached to form a spiro cyclopropyl. In some embodiments, 2 R2groups are taken together with the carbon atom to which they are attached to form a spiro cyclobutyl. In some embodiments, 2 R2groups are taken together with the carbon atom to which they are attached to form a spiro cyclopentyl. In some embodiments, 2 R2groups are taken together with the carbon atom to which they are attached to form a spiro cyclohexyl.

[0111] In some embodiments, 2 R2groups on different carbon atoms are taken together to form C1-C6alkylene or -(C1-C4alkylene)O(C1-C4alkylene)-. In some embodiments, 2 R2groups on different carbon atoms are taken together to form C1-C3alkylene or -(C1-C3alkylene)O(C1-C3alkylene)-. In some embodiments, 2 R2groups on different carbon atoms are taken together to form -CH2OCH2- or -CH2CH2CH2-.

[0112] In some embodiments, 2 R2groups on different carbon atoms are taken together to form C1-C6alkylene. In some embodiments, 2 R2groups on different carbon atoms are taken together to form C1-C3alkylene. In some embodiments, 2 R2groups on different carbon atoms are taken together to form -CH2-. In some embodiments, 2 R2groups on different carbon atoms are taken together to form -CH2CH2-. In some embodiments, 2 R2groups on different carbon atoms are taken together to form -CH2CH2CH2-.

[0113] In some embodiments, 2 R2groups on different carbon atoms are taken together to form -(C1-C4alkylene)O(C1-C4alkylene)-. In some embodiments, 2 R2groups on different carbon atoms are taken together to form -(C1-C3alkylene)O(C1-C3alkylene)-. In some embodiments, 2 R2groups on different carbon atoms are taken together to form -CH2OCH2-, -CH2CH2OCH2-, -CH2OCH2CH2-, or -CH2CH2OCH2CH2-. In some embodiments, 2 R2groups on different carbon atoms are taken together to form -CH2OCH2-.

[0114] In some embodiments, n is 0-5. In some embodiments, n is 0-3. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5..

[0116] In some embodiments, L1is a bond, C1-C6alkylene, O, -N(H)-, -N(C1-C6alkyl)-, or -N(C1-C6alkyl-OH)-. In some embodiments, L1is a bond, O, C1-C3alkylene, -N(H)-, -N(C1-C3alkyl)-, or -N(C1-C3alkyl-OH)-. In some embodiments, L1is a bond, O, -CH2-, -N(H)-, -N(CH3)-, or -N(CH2CH2OH)-.

[0117] In some embodiments, L1is a bond.

[0118] In some embodiments, L1is O.

[0119] In some embodiments, L1is C1-C6alkylene. In some embodiments, L1is C1-C3alkylene. In some embodiments, L1is -CH2-, -CH2CH2-, or -CH2CH2CH2-. In some embodiments, L1is -CH2-.

[0120] In some embodiments, L1is -N(H)-.

[0121] In some embodiments, L1is -N(C1-C6alkyl)-. In some embodiments, L1is -N(C1-C3alkyl)-. In some embodiments, L1is -N(CH3)-, -N(CH2CH3)-, or -N(CH2CH2CH3)-. In some embodiments, L1is -N(CH3)-. In some embodiments, L1is -N(CH2CH3)-.

[0122] In some embodiments, L1is -N(C1-C6alkyl-OH)-. In some embodiments, L1is -N(C1-C3alkyl-OH)-. In some embodiments, L1is -N(CH2OH)-, -N(CH2CH2OH)-, or -N(CH2CH2CH2OH)-. In some embodiments, L1is -N(CH2OH)-. In some embodiments, L1is -N(CH2CH2OH)-.

[0123] In some embodiments, L2is a bond, -N(H)-, -N(C1-C6alkyl)-, -N(H)C(O)-, -N(H)C(O)(C1-C6alkylene)-, -(C1-C6alkylene)N(C1-C6alkyl)-, O, or C1-C6alkylene. In some embodiments, L2is a bond, -N(H)-, -N(C1-C3alkyl)-, -N(H)C(O)-, -N(H)C(O)(C1-C3alkylene)-, -(C1-C3alkylene)N(C1-C3alkyl)-, O, or C1-C3alkylene. In some embodiments, L2is a bond, -N(H)-, -N(CH3)-, -N(H)C(O)-, -N(H)C(O)(CH2)-, -(CH2)N(CH3)-, O, or -CH2-.

[0124] In some embodiments, L2is a bond.

[0125] In some embodiments, L2is -N(H)-.

[0126] In some embodiments, L2is -N(C1-C6alkyl)-. In some embodiments, L2is -N(C1-C3alkyl)-. In some embodiments, L2is -N(CH3)-, -N(CH2CH3)-, or -N(CH2CH2CH3)-. In some embodiments, L2is -N(CH3)-. In some embodiments, L2is -N(CH2CH3)-.

[0127] In some embodiments, L2is -N(H)C(O)-.

[0128] In some embodiments, L2is -N(H)C(O)(C1-C6alkylene)-. In some embodiments, L2is -N(H)C(O)(C1-C3alkylene)-. In some embodiments, L2is -N(H)C(O)(CH2)-, -N(H)C(O)(CH2CH2)-, or -N(H)C(O)(CH2CH2CH2)-. In some embodiments, L2is -N(H)C(O)(CH2)-.

[0129] In some embodiments, L2is -(C1-C6alkylene)N(C1-C6alkyl)-. In some embodiments, L2is -(C1-C3alkylene)N(C1-C3alkyl)-. In some embodiments, L2is -CH2N(CH3)-, -CH2N(CH2CH3)-, or -CH2N(CH2CH2CH3)-. In some embodiments, L2is -CH2N(CH3)-. In some embodiments, L2is -(CH2CH2)N(CH3)-, -(CH2CH2CH2)N(CH3)-, -(CH2CH2)N(CH2CH3)-, -(CH2CH2CH2)N(CH2CH3)-, or -(CH2CH2CH2)N(CH2CH2CH3)-.

[0130] In some embodiments, L2is O.

[0131] In some embodiments, L2is C1-C6alkylene. In some embodiments, L2is C1-C3alkylene. In some embodiments, L2is -CH2-, CH2CH2-, or -CH2CH2CH2-. In some embodiments, L2is -CH2-..

[0133] In some embodiments, Y1and Y2are independently CR4or N. In some embodiments, Y1and Y2are each N. In some embodiments, Y1and Y2are independently CR4. In some embodiments, Y1is N and Y2is CR4. In some embodiments, Y2is N and Y1is CR4. In some variations, each R4is independently H or halo (such as F).

[0134] In some embodiments, each R4is independently H, halo, or C1-C6alkyl. In some embodiments, each R4is independently H, halo, or C1-C3alkyl. In some embodiments, each R4is independently H or F.

[0135] In some embodiments, R4is H.

[0136] In some embodiments, R4is halo. In some embodiments, R4is F, Cl, Br, or I. In some embodiments, R4is F. In some embodiments, R4is Cl.

[0137] In some embodiments, R4is C1-C6alkyl. In some embodiments, R4is C1-C3alkyl. In some embodiments, R4is methyl, ethyl, or propyl. In some embodiments, R4is methyl. In some embodiments, R4is ethyl..

[0139] In some embodiments, R3is H, C1-C6alkyl, C1-C6alkyl-OH, -(C1-C6alkylene)O(C1- C6alkyl), -(C1-C6alkylene)NR3aR3b, or -(C1-C6alkylene)(4- to 6-membered heterocyclyl), wherein the heterocyclyl contains 1-3 heteroatoms selected from N and O, and wherein the heterocyclyl is optionally substituted by 1-5 groups selected from halo, -OH, C1-C6alkyl, and C1-C6haloalkyl; and each R3aand R3bis independently H or C1-C6alkyl. In some embodiments, R3is H, C1-C3alkyl, C1-C5alkyl-OH, -(C1-C3alkylene)O(C1-C3alkyl), -(C1-C3alkylene)NR3aR3b, or -(C1-C3alkylene)(4- to 6-membered heterocyclyl), wherein the heterocyclyl contains 1-2 heteroatoms selected from N and O, and wherein the heterocyclyl is optionally substituted by 1-3 groups selected from halo, -OH, C1-C3alkyl, and C1-C3haloalkyl; and each R3aand R3bis independently H or C1-C3alkyl.

[0140] In some embodiments, R3is H.

[0141] In some embodiments, R3is C1-C6alkyl. In some embodiments, R3is C1-C3alkyl. In some embodiments, R3is methyl, ethyl, n-propyl, or isopropyl. In some embodiments, R3is -CH3. In some embodiments, R3is -CD3. In some embodiments, R3is -CH2CH3. In some embodiments, R3is -CH(CH3)2.

[0142] In some embodiments, R3is C1-C6alkyl-OH. In some embodiments, R3is C1-C5alkyl-OH. In some embodiments, R3is C1-C4alkyl-OH. In some embodiments, R3is C3-C4 alkyl-OH. In some embodiments, R3is C1-C3alkyl-OH. In some embodiments, R3is -CH2OH, -(CH2CH2)OH, -(CH2CH2CH2)OH, -CH2CH(CH3)OH, -CH(CH3)CH2OH, -CH2C(CH3)2OH, -C(CH3)2CH2OH, or -CH(CH3)CH(CH3)OH. In some embodiments, R3is -CH2CH(CH3)OH or -CH2C(CH3)2OH. In some embodiments, R3is -CH2CH(CH3)OH. In some embodiments, R3is -CH2C(CH3)2OH.

[0143] In some embodiments, R3is -(C1-C6alkylene)O(C1-C6alkyl). In some embodiments, R3is -(C1-C3alkylene)O(C1-C3alkyl). In some embodiments, R3is -CH2OCH3, -CH2CH2OCH3, -CH2OCH2CH3, or -CH2CH2OCH2CH3. In some embodiments, R3is -CH2OCH3. In some embodiments, R3is -CH2CH2OCH3.

[0144] In some embodiments, R3is -(C1-C6alkylene)NR3aR3b, wherein R3aand R3bare independently H or C1-C6alkyl. In some embodiments, R3is -(C1-C3alkylene)NR3aR3b, wherein R3aand R3bare independently H or C1-C3alkyl. In some embodiments, R3is -CH2NH2, -CH2NH(CH3), -CH2N(CH3)2, -CH2CH2NH2, -CH2CH2N(H)(CH3), -CH2CH2N(CH3)2, -CH2CH2CH2NH2, -CH2CH2CH2N(H)(CH3), or -CH2CH2CH2N(CH3)2. In some embodiments, R3is -CH2CH2N(CH3)2, -CH2CH2CH2N(CH3)2, or -CH2CH2N(H)(CH3). In some embodiments, R3is -CH2CH2N(CH3)2. In some embodiments, R3is -CH2CH2CH2N(CH3)2. In some embodiments, R3is -CH2CH2N(H)(CH3).

[0145] In some embodiments, R3is -(C1-C6alkylene)(4- to 6-membered heterocyclyl), wherein the heterocyclyl contains 1-3 heteroatoms selected from N and O, and wherein the heterocyclyl is optionally substituted by 1-5 groups selected from halo, -OH, C1-C6alkyl, and C1-C6haloalkyl. In some embodiments, R3is -(C1-C3alkylene)(4- to 6-membered heterocyclyl), wherein the heterocyclyl contains 1-2 heteroatoms selected from N and O, and wherein the heterocyclyl is optionally substituted by 1-3 groups selected from halo, -OH, C1-C3alkyl, and C1-C3haloalkyl. In some embodiments, R3is -(C1-C3alkylene)(4-membered heterocyclyl), wherein the heterocyclyl contains 1-2 heteroatoms selected from N and O, and wherein the heterocyclyl is optionally substituted by 1-3 groups selected from halo, -OH, C1-C3alkyl, and C1-C3haloalkyl. In some embodiments, R3is -(C1-C3alkylene)(4-membered heterocyclyl), wherein the heterocyclyl contains one nitrogen atom, and wherein the heterocyclyl is optionallysubstituted by 1-2 groups selected from halo, -OH, C1-C3alkyl, and C1-C3haloalkyl. In some embodiments, R3is -(C1-C3alkylene)(5-membered heterocyclyl), wherein the heterocyclyl contains 1-2 heteroatoms selected from N and O, and wherein the heterocyclyl is optionally substituted by 1-3 groups selected from halo, -OH, C1-C3alkyl, and C1-C3haloalkyl. In some embodiments, R3is -(C1-C3alkylene)(5-membered heterocyclyl), wherein the heterocyclyl contains one nitrogen atoms, and wherein the heterocyclyl is optionally substituted by 1-2 groups selected from halo, -OH, C1-C3alkyl, and C1-C3haloalkyl. In some embodiments, R3is -(C1-C3alkylene)(6-membered heterocyclyl), wherein the heterocyclyl contains 1-2 heteroatoms selected from N and O, and wherein the heterocyclyl is optionally substituted by 1-3 groups selected from halo, -OH, C1-C3alkyl, and C1-C3haloalkyl. In some embodiments, R3is -(C1-C3alkylene)(6-membered heterocyclyl), wherein the heterocyclyl contains 2 heteroatoms selected from N and O, and wherein the heterocyclyl is optionally substituted by 1-2 groups selected from halo, -OH, C1-C3alkyl, and C1-C3haloalkyl. In some embodiments, the heterocyclyl is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl.

[0146] In some embodiments, R3is H, -CH3, -CD3, -CH2CH3, -CH(CH3)2, -CH2CH(CH3)OH, -CH2C(CH3)2OH, -CH2CH2OCH3, -CH2CH2N(CH3)2, -CH2CH2CH2N(CH3)2,

[0147] In some embodiments, each R5is independently halo, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments, each R5is independently halo, C1-C3alkyl, or C1-C3haloalkyl. In some embodiments, each R5is Cl.

[0148] In some embodiments, R5is halo. In some embodiments, R5is F, Cl, Br, or I. In some embodiments, R5is F. In some embodiments, R5is Cl.

[0149] In some embodiments, R5is C1-C6alkyl. In some embodiments, R5is C1-C3alkyl. In some embodiments, R5is methyl, ethyl, or propyl. In some embodiments, R5is methyl. In some embodiments, R5is ethyl.

[0150] In some embodiments, R5is C1-C6haloalkyl. In some embodiments, R5is C1-C6haloalkyl containing 1-13 halogen atoms. In some embodiments, R5is C1-C3haloalkyl. In some embodiments, R5is C1-C3haloalkyl containing 1-7 halogen atoms. In some embodiments, R5is -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CF2Cl, -CFCl2, -CH2CF3, -CH2CHF2, or -CH2CCl3. In some embodiments, R5is -CF3.

[0151] In some embodiments, z is 0-3. In some embodiments, z is 0-1. In some embodiments, z is 0. In some embodiments, z is 1. In some embodiments, z is 2. In some embodiments, z is 3.

[0152] In some embodiments, each R6is independently halo, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments, each R6is independently halo, C1-C3alkyl, or C1-C3haloalkyl. In some embodiments, each R6is F.

[0153] In some embodiments, R6is halo. In some embodiments, R6is F, Cl, Br, or I. In some embodiments, R6is F. In some embodiments, R6is Cl.

[0154] In some embodiments, R6is C1-C6alkyl. In some embodiments, R6is C1-C3alkyl. In some embodiments, R6is methyl, ethyl, or propyl. In some embodiments, R6is methyl. In some embodiments, R6is ethyl.

[0155] In some embodiments, R6is C1-C6haloalkyl. In some embodiments, R6is C1-C6haloalkyl containing 1-13 halogen atoms. In some embodiments, R6is C1-C3haloalkyl. In some embodiments, R6is C1-C3haloalkyl containing 1-7 halogen atoms. In some embodiments, R6is -CF3, -CHF2, -CH2F, -CCl3, -CHCl2, -CH2Cl, -CF2Cl, -CFCl2, -CH2CF3, -CH2CHF2, or -CH2CCl3. In some embodiments, R6is -CF3.

[0156] In some embodiments, m is 0-2. In some embodiments, m is 0-1. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2.

[0157] In some embodiments, Z is C or N. In some embodiments, Z is C. In some embodiments, Z is N.

[0158] In some embodiments, is a single or double bond. In some embodiments, is a single bond. In some embodiments, is a double bond..

[0160] In some embodiments, R7is C1-C6alkyl, C1-C6alkyl-OH, -(C1-C6alkylene)NR3aR3b, -(C1-C6alkylene)C(O)NR3aR3b, -(C1-C6alkylene)CO2(C1-C6alkyl), C3-C6cycloalkyl, -(C1-C6alkylene)(C3-C6cycloalkyl), 4- to 6-membered heterocyclyl, or -(C1-C6alkylene)(4- to 6- membered heterocyclyl), wherein the heterocyclyl contains 1-3 heteroatoms selected from N and O, and the cycloalkyl and heterocyclyl are optionally substituted by 1-5 groups selected from -OH, C1-C6alkoxy, C1-C6alkyl, halo, and C1-C6haloalkyl; wherein R3aand R3bare independently H or C1-C6alkyl. In some embodiments, R7is C1-C3alkyl, C4-C6alkyl-OH, -(C4- C6alkylene)NR3aR3b, -(C1-C3alkylene)C(O)NR3aR3b, -(C1-C3alkylene)CO2(C4-C6alkyl), C4-C6cycloalkyl, -(C1-C3alkylene)(C4-C6cycloalkyl), 4- to 6-membered heterocyclyl, or -(C1-C3alkylene)(4- to 6-membered heterocyclyl), wherein the heterocyclyl contains 1-2 heteroatoms selected from N and O, and the cycloalkyl and heterocyclyl are optionally substituted by 1-3groups selected from -OH, C1-C3alkoxy, C1-C3alkyl, halo, and C1-C3haloalkyl; wherein R3aand R3bare independently H or C1-C3alkyl.

[0161] In some embodiments, R7is C1-C6alkyl. In some embodiments, R7is C1-C3alkyl. In some embodiments, R7is methyl, ethyl, or propyl. In some embodiments, R7is methyl. In some embodiments, R7is ethyl.

[0162] In some embodiments, R7is C1-C6alkyl-OH. In some embodiments, R7is C1-C3alkyl-OH. In some embodiments, R7is C3-C6alkyl-OH. In some embodiments, R7is C4-C6alkyl-OH. In some embodiments, R7is -CH2CH2C(CH3)2OH, -CH2CH2CH2OH, -CH2CH2CH(CH3)OH, -CH2CH2CH2CH2OH, -CH2CH2CH2CH(CH3)OH, -CH2CH2CH2C(CH3)2OH, or -CH2CH2CH(CH3)OH. In some embodiments, R7is methyl, ethyl, n- propyl, or isopropyl. In some embodiments, R7is -CH2CH2C(CH3)2OH, -CH2CH2CH2C(CH3)2OH, or -CH2CH2CH(CH3)OH.

[0163] In some embodiments, R7is -(C1-C6alkylene)NR3aR3b, wherein R3aand R3bare independently H or C1-C6alkyl. In some embodiments, R7is -(C1-C3alkylene)NR3aR3b, wherein R3aand R3bare independently H or C1-C3alkyl. In some embodiments, R7is -(C4-C6alkylene)NR3aR3b, wherein R3aand R3bare independently H or C1-C3alkyl. In some embodiments, R7is -CH2NH2, -CH2N(H)(CH3), -CH2N(CH3)2, -CH2CH2NH2, -CH2CH2N(H)(CH3), or -CH2CH2N(CH3)2. In some embodiments, R7is -CH2CH2CH2NH2, -CH2CH2CH(CH3)NH2, -CH2CH2C(CH3)2NH2, -CH2CH2CH2NH(CH3), -CH2CH2CH(CH3)NH(CH3), -CH2CH2C(CH3)2NH(CH3), -CH2CH2CH2N(CH3)2, -CH2CH2CH(CH3)N(CH3)2, or -CH2CH2C(CH3)2N(CH3)2. In some embodiments, R7is -CH2CH2C(CH3)2NH2.

[0164] In some embodiments, R7is -(C1-C6alkylene)C(O)NR3aR3b, wherein R3aand R3bare independently H or C1-C6alkyl. In some embodiments, R7is -(C1-C3alkylene)C(O)NR3aR3b, wherein R3aand R3bare independently H or C1-C3alkyl. In some embodiments, R7is -CH2C(O)NH2, -CH2C(O)NH(CH3), -CH2C(O)N(CH3)2, -CH2CH2C(O)NH2, -CH2CH2C(O)NH(CH3), or -CH2CH2C(O)N(CH3)2. In some embodiments, R7is -CH2CH2C(O)N(H)CH3.

[0165] In some embodiments, R7is -(C1-C6alkylene)CO2(C1-C6alkyl). In some embodiments, R7is -(C1-C3alkylene)CO2(C1-C3alkyl). In some embodiments, R7is -(C1-C3alkylene)CO2(C4-C6alkyl). In some embodiments, R7is -CH2CO2CH3, -CH2CO2CH2CH3, -CH2CO2CH2CH2CH3, -CH2CO2C(CH3)3, -CH2CH2CO2CH3, -CH2CH2CO2CH2CH3, -CH2CH2CO2CH2CH2CH3, or -CH2CH2CO2C(CH3)3. In some embodiments, R7is -CH2CH2CO2C(CH3)3.

[0166] In some embodiments, R7is C3-C6cycloalkyl optionally substituted by 1-5 groupsselected from -OH, C1-C6alkoxy, C1-C6alkyl, halo, and C1-C6haloalkyl. In some embodiments, R7is C4-C6cycloalkyl optionally substituted by 1-3 groups selected from -OH, C1-C3alkoxy, C1-C3alkyl, halo, and C1-C3haloalkyl. In some embodiments, R7is C4-C6cycloalkyl optionally substituted by 1-3 groups selected from -OH, -OCH3, -CH3, F, Cl, and -CF3. In some embodiments, R7is cyclobutyl optionally substituted by 1-2 groups selected from -OH, -OCH3, and -CH3. In some embodiments, R7is cyclopentyl optionally substituted by 1-2 groups selected from -OH, -OCH3, and -CH3. In some embodiments, R7is cyclohexyl optionally substituted by 1-2 groups selected from -OH, -OCH3, and -CH3. In some embodiments, R7is:.

[0167] In some embodiments, R7is -(C1-C6alkylene)(C3-C6cycloalkyl), wherein the cycloalkyl is optionally substituted by 1-5 groups selected from -OH, C1-C6alkoxy, C1-C6alkyl, halo, and C1-C6haloalkyl. In some embodiments, R7is -(C1-C3alkylene)(C4-C6cycloalkyl), wherein the cycloalkyl is optionally substituted by 1-3 groups selected from -OH, C1-C3alkoxy, C1-C3alkyl, halo, and C1-C3haloalkyl. In some embodiments, R7is -(CH2)(C4-C6cycloalkyl) or -(CH2CH2)(C4-C6cycloalkyl), wherein the cycloalkyl is optionally substituted by 1-3 groups selected from -OH, C1-C3alkoxy, C1-C3alkyl, halo, and C1-C3haloalkyl. In some embodiments, R7is -(CH2)(C4-C6cycloalkyl) or -(CH2CH2)(C4-C6cycloalkyl), wherein the cycloalkyl is optionally substituted by 1-3 groups selected from -OH, -OCH3, -CH3, F, Cl, and -CF3. In some embodiments, R7is -(CH2)(cyclobutyl) or -(CH2CH2)(cyclobutyl), wherein the cyclobutyl is optionally substituted by 1-2 groups selected from -OH, -OCH3, and -CH3. In some embodiments, R7is -(CH2)(cyclopentyl) or -(CH2CH2)(cyclopentyl), wherein the cyclopentyl is optionally substituted by 1-2 groups selected from -OH, -OCH3, and -CH3. In some embodiments, R7is -(CH2)(cyclohexyl) or -(CH2CH2)(cyclohexyl), wherein the cyclohexyl is optionally substituted by 1-2 groups selected from -OH, -OCH3, and -CH3. In some embodiments, R7is:.

[0168] In some embodiments, R7is 4- to 6-membered heterocyclyl containing 1-3 heteroatoms selected from N and O, and optionally substituted by 1-5 groups selected from -OH, C1-C6alkoxy, C1-C6alkyl, halo, and C1-C6haloalkyl. In some embodiments, R7is 4- to 6- membered heterocyclyl containing 1-2 heteroatoms selected from N and O, and optionally substituted by 1-3 groups selected from -OH, C1-C3alkoxy, C1-C3alkyl, halo, and C1-C3haloalkyl. In some embodiments, R7is oxetanyl, tetrahydrofuranyl, dioxanyl, morpholinyl, azetidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionally substituted by 1- 2 groups selected from -OH, -CH3, and -OCH3.

[0169] In some embodiments, R7-(C1-C6alkylene)(4- to 6-membered heterocyclyl), wherein the heterocyclyl contains 1-3 heteroatoms selected from N and O, and the heterocyclyl is optionally substituted by 1-5 groups selected from -OH, C1-C6alkoxy, C1-C6alkyl, halo, and C1- C6 haloalkyl. In some embodiments, R7is -(C1-C3alkylene)(4- to 6-membered heterocyclyl), wherein the heterocyclyl contains 1-2 heteroatoms selected from N and O, and the heterocyclyl is optionally substituted by 1-3 groups selected from -OH, C1-C3alkoxy, C1-C3alkyl, halo, and C1-C3haloalkyl. In some embodiments, the heterocyclyl is oxetanyl, tetrahydrofuranyl, dioxanyl, morpholinyl, azetidinyl, pyrrolidinyl, piperidinyl, or piperazinyl, each of which is optionally substituted by 1-2 groups selected from -OH, -CH3, and -OCH3. In some embodiments, R7is:.

[0170] In some embodiments, R7is -CH3, -CH2CH2C(CH3)2OH, -CH2CH2CH2C(CH3)2OH, -CH2CH2CH(CH3)OH, -CH2CH2C(CH3)2NH2, -CH2CH2C(O)N(H)CH3, -CH2CH2CO2C(CH3)3,.

[0171] In some embodiments, each R3aand R3bis independently H or C1-C6alkyl. In some embodiments, each R3aand R3bis independently H or C1-C3alkyl.

[0172] In some embodiments, R3ais H.

[0173] In some embodiments, R3ais C1-C6alkyl. In some embodiments, R3ais C1-C3alkyl. In some embodiments, R3ais methyl, ethyl, or propyl. In some embodiments, R3ais methyl. In some embodiments, R3ais ethyl.

[0174] In some embodiments, R3bis H.

[0175] In some embodiments, R3bis C1-C6alkyl. In some embodiments, R3bis C1-C3alkyl. In some embodiments, R3bis methyl, ethyl, or propyl. In some embodiments, R3bis methyl. In some embodiments, R3bis ethyl.

[0176] In some embodiments, R3aand R3bare each H. In some embodiments, R3aand R3bare each C1-C6alkyl, such as C1-C3alkyl, for example, methyl or ethyl. In some embodiments, R3aand R3bare each methyl. In some embodiments, R3ais H and R3bis C1-C6alkyl, such as C1- C3 alkyl, for example, methyl or ethyl. In some embodiments, R3ais H and R3bis methyl. In some embodiments, R3bis H and R3ais C1-C6alkyl, such as C1-C3alkyl, for example, methyl or ethyl. In some embodiments, R3bis H and R3ais methyl.

[0177] In some embodiments, Ring B is a fused 5-membered heterocyclyl or 5-membered heteroaryl, wherein the heterocyclyl and heteroaryl contain 1-3 nitrogen atoms and are optionally substituted with 1-2 groups selected from C1-C6alkyl, halo, and oxo. In some embodiments, Ring B is a fused 5-membered heterocyclyl or 5-membered heteroaryl, wherein the heterocyclyl and heteroaryl contain 1-3 nitrogen atoms and are optionally substituted with 1- 2 groups selected from C1-C3alkyl, halo, and oxo..

[0179] In some embodiments, W1is C or N. In some embodiments, W1is C. In some embodiments, W1is N.

[0180] In some embodiments, W2is C or N. In some embodiments, W2is C. In some embodiments, W2is N.

[0181] In some embodiments,.

[0182] In some embodiments, the compound of Formula (I) is a compound of Formula (II):wherein R1, R2, R3, R4, R5, R6, R7, L2, Ring B, Z, W1, W2, Y1, Y2, m, n, z, *, and are as described for Formula (I).

[0183] In some embodiments, the compound of Formula (I) is a compound of Formula (IIa), (IIb), or (IIc):wherein R1, R2, R3, R4, R5, R6, R7, Z, Y1, Y2, m, n, and z are as described for Formula (I).

[0184] In some embodiments, the compound of Formula (I) is a compound of Formula (III):wherein R1, R2, R3, R4, R5, R6, R7, L1, Ring B, Z, W1, W2, Y1, Y2, m, n, z, *, and are as described for Formula (I).

[0185] In some embodiments, the compound of Formula (I) is a compound of Formula (IIIa), (IIIb), (IIIc), (IIId), or (IIIe):wherein Rais H, C1-C6alkyl, or C1-C6alkyl-OH; and R1, R2, R3, R4, R5, R6, R7, Z, Y1, Y2, m, n, z, and are as described for Formula (I).

[0186] In some embodiments, the compound of Formula (I) is a compound of Formula (IV):wherein R1, R2, R3, R4, R5, R6, R7, L2, Ring B, Z, W1, W2, Y1, Y2, m, n, z, *, and are as described for Formula (I).

[0187] In some embodiments, the compound of Formula (I) is a compound of Formula (IVa) or (IVb):wherein R1, R2, R3, R4, R5, R6, R7, Z, Y1, Y2, m, n, z, and are as described for Formula (I).

[0188] In some embodiments, the compound of Formula (I) is a compound of Formula (Va) or (Vb):wherein R2, R3, R7, L1, L2, Ring A, and n are as described for Formula (I).

[0189] In some embodiments, the compound of Formula (I) is a compound of Formula (VIa), (VIb), (VIc), (VId), (VIe), (VIf), and (VIg):wherein Rais H, C1-C6alkyl, or C1-C6alkyl-OH;is monocyclic 4- to 7-membered heterocyclylene or 5- to 6-membered heteroarylene;is fused bicyclic 8- to 10- membered heterocyclylene or heteroarylene;is monocyclic 4- to 7-membered heterocyclylene or 5- to 6-membered heteroarylene; and R1, R2, R3, R4, R5, R6, R7, Ring B, Z, W1, W2, Y1, Y2, m, n, z, *, and are as described for Formula (I).

[0190] It is understood that any of the compounds described herein can include replacement of one or more hydrogen atoms by deuterium. Any one or more of the substituents of Formula (I) can be deuterated, such as one or more of R1, R2, R3, R3a, R3b, R4, R5, R6, R7, L1, L2, Y1, Y2,Ring A, and Ring B. For example, in some embodiments, R3is a deuterated group, such as -CD3.

[0191] 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), (IIa), (IIb), (IIc), (III), (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IV), (IVa), (IVb), (Va), (Vb), (VIa), (VIb), (VIc), (VId), (VIe), (VIf), and (VIg), and are equally described, the same as if each and every description, variation, embodiment, or aspect were separately and individually listed for all formulae.

[0192] 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.

[0193] 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 or organic base or acid by methods known to one skilled in the art. Salts of the compounds of Formula (I) can be converted to their free base or acid form by standard techniques.Methods of Synthesis

[0194] 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-a) through Formula (I-d) can be prepared as outlined in Schemes 1-5, as well as in the Examples set forth herein. It should be noted that one skilled in the art would know how to modify the procedures set forth in the illustrative schemes and Examples to arrive at the desired products.

[0195] As outlinedx in Scheme 1, compounds of Formula (i-1) can be synthesized from coupling derivatives a with intermediate compounds b to form intermediate compounds c, which are then cyclized to form intermediate compounds d. Derivatization with R7affords intermediate compounds e, which are then reduced to intermediates f, followed by coupling to intermediate f-1 to form compounds of Formula (i-1).

[0196] Scheme 2 provides routes for synthesizing intermediates j or j’, and m or m’. compounds of Formula (i-2) that contain a glutarimide motif. Intermediate compounds g are coupled with amine h, followed by hydrogenation to afford intermediates j, which can be optionally deprotected to afford intermediates j’. Alternatively, intermeidates g can be coupled with derivatives k to form intermediates l, which are then hydrogenated to intermediate compounds m, and optionally deprotected to afford intermediate compounds m’.

[0197] Scheme 3 provides the synthesis of intermediate compounds p or p’. Intermediates n can be coupled with amines h to afford intermediates o, which are then deprotected to intermediates p’ and optionally further deprotected to intermediates p’.

[0198] Scheme 4 provides the synthesis of intermediate compounds s or s’ and t or t’. Intermediates q can be coupled with derivatives r to afford intermediates s, which are then deprotected to intermediates s’. Optionally, intermediates s can be alkylated to afford intermediates t, which can be deported to form intermediates t’.

[0199] Scheme 5 provides multiple routes for synthesizing various compounds of Formula (I-a), (I-b), (I-c), and (I-d) using intermediate i-1. Methods of Use

[0200] 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 of Formula (I). 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).

[0201] In one aspect, provided herein is a method of modulating BCL6 comprising contacting BCL6 with an effective amount of a compound of Formula (I) or any embodiment or variation thereof. In some embodiments, the compound of Formula (I) inhibits BCL6. In some embodiments, the compound of Formula (I) causes degradation of BCL6.

[0202] In some embodiments, a compound of Formula (I) 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, a compound of Formula (I)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%.

[0203] 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 of Formula (I). 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.

[0204] In one aspect, provided herein is a method of degrading BCL6 comprising contacting BCL6 with an effective amount of a compound of Formula (I) or any embodiment or variation thereof. In some embodiments, the compound of Formula (I) partially degrades BCL6. In some embodiments, the compound of Formula (I) fully degrades BCL6.

[0205] In some embodiments, a compound of Formula (I) 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 of Formula (I) 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%.

[0206] 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 of Formula (I). 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 of Formula (I). 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.

[0207] In some embodiments, administering a compound of Formula (I) 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 of Formula (I) to a subject in need thereof stabilizes the cancer (prevents or delays the worsening of the cancer). In some embodiments, administering a compound of Formula (I) to a subject in need thereof delays the occurrence or recurrence of the cancer. In some embodiments, administering a compound of Formula (I) to a subject in need thereof slows the progression of the cancer. In some embodiments, administering a compound of Formula (I) to a subject in need thereof provides a partial remission of the cancer. In some embodiments, administering a compound of Formula (I) to a subject in need thereof provides a total remission of the cancer. In some embodiments, administering a compound of Formula (I) 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 of Formula (I) to a subject in need thereof enhances the effect of another medication used to treat the cancer. In some embodiments, administering a compound of Formula (I) to a subject in need thereof delays the progression of the cancer. In some embodiments, administering a compound of Formula (I) to a subject in need thereof increases the quality of life of the subject having a cancer. In some embodiments, administering a compound of Formula (I) to a subject in need thereof prolongs survival of a subject having a cancer.

[0208] In some aspects, provided herein is a method of slowing progression of a cancer in a subject, the method comprising administering a compound of Formula (I) to the subject. In some embodiments, provided herein is a method of stabilizing a cancer in a subject, the method comprising administering a compound of Formula (I) to the subject. In some embodiments, the method prevents the progression of the cancer. In some embodiments, the method delays theprogression of the cancer. In some embodiments, the method provides a partial or total remission of the cancer.

[0209] In another aspect, provided herein is a method of delaying the occurrence or recurrence of a cancer in a subject, the method comprising administering a compound of Formula (I) to the subject.

[0210] 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 a compound of Formula (I) to the subject. In some embodiments, provided herein is a method of enhancing the effect of another medication used to treat a cancer in a subject, the method comprising administering a compound of Formula (I) to the subject.

[0211] Also provided here is a method of delaying the progression of a cancer in a subject, the method comprising administering a compound of Formula (I) 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.

[0212] 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 of Formula (I). 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 of Formula (I). 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. Exemplary 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. Exemplary generalized autoimmune diseases include Systemic lupus erythematosus (SLE), Rheumatoid arthritis, Scleroderma, Sarcoidosis, and Guillain-Barré Syndrome (GBS). The present disclosure encompasses treatment of all types of autoimmune disease, including organ-specific and general autoimmune diseases, including, but not limited to, lupus erythematosus, ankylosing spondylitis, Chagas disease, chronic obstructive pulmonary disease, Crohn's Disease, dermatomyositis, diabetes mellitus type 1, endometriosis, Goodpasture's syndrome, Graves' disease, Guillain-Barré syndrome (GBS), Hashimoto's disease, hidradenitis suppurativa, Kawasaki disease, IgA nephropathy, idiopathic thrombocytopenic purpura, interstitial cystitis, mixed connective tissue disease, morphea, multiple sclerosis, myasthenia gravis, narcolepsy, neuromyotonia, pemphigus vulgaris, pernicious anaemia, psoriasis, psoriatic arthritis, polymyositis, primary biliary cirrhosis,relapsing polychondritis, rheumatoid arthritis, sarcoidosis, schizophrenia, scleroderma, Sjögren's syndrome, stiff person syndrome, temporal arteritis, ulcerative colitis, vasculitis, vitiligo, and Wegener's granulomatosis.

[0213] 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 of Formula (I).

[0214] In some embodiments, administering a compound of Formula (I) 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 of Formula (I) to a subject in need thereof shortens or reduces the duration of a symptom of the autoimmune disease. In some embodiments, administering a compound of Formula (I) to a subject in need thereof eliminates the symptoms of the autoimmune disease. In some embodiments, administering a compound of Formula (I) to a subject in need thereof delays the occurrence or recurrence of the autoimmune disease. In some embodiments, administering a compound of Formula (I) to a subject in need thereof slows the progression of the autoimmune disease. In some embodiments, administering a compound of Formula (I) 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 of Formula (I) to a subject in need thereof enhances the effect of another medication used to treat the autoimmune disease. In some embodiments, administering a compound of Formula (I) to a subject in need thereof delays the progression of the autoimmune disease. In some embodiments, administering a compound of Formula (I) to a subject in need thereof increases the quality of life of the subject having an autoimmune disease.

[0215] In some aspects, provided herein is a method of slowing progression of an autoimmune disease in a subject, the method comprising administering a compound of Formula (I) to the subject. In some embodiments, provided herein is a method of stabilizing an autoimmune disease in a subject, the method comprising administering a compound of Formula (I) to 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.

[0216] 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 a compound of Formula (I) to the subject. In some embodiments, provided hereinis a method of enhancing the effect of another medication used to treat an autoimmune disease in a subject, the method comprising administering a compound of Formula (I) to the subject. Pharmaceutical Compositions and Routes of Administration

[0217] The compounds provided 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.

[0218] The compounds disclosed herein can be administered to a subject orally, topically or parenterally in the conventional form of preparations, such as capsules, microcapsules, tablets, granules, powder, troches, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions and emulsions. Suitable formulations can be prepared by methods commonly employed using conventional, organic or inorganic additives, such as an excipient (e.g., sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate or calcium carbonate), a binder (e.g., cellulose, methylcellulose, hydroxymethylcellulose, polypropylpyrrolidone, polyvinylpyrrolidone, gelatin, gum arabic, polyethyleneglycol, sucrose or starch), a disintegrator (e.g., starch, carboxymethylcellulose, hydroxypropylstarch, low substituted hydroxypropylcellulose, sodium bicarbonate, calcium phosphate or calcium citrate), a lubricant (e.g., magnesium stearate, light anhydrous silicic acid, talc or sodium lauryl sulfate), a flavoring agent (e.g., citric acid, menthol, glycine or orange powder), a preservative (e.g, sodium benzoate, sodium bisulfite, methylparaben or propylparaben), a stabilizer (e.g., citric acid, sodium citrate or acetic acid), a suspending agent (e.g., methylcellulose, polyvinyl pyrroliclone or aluminum stearate), a dispersing agent (e.g., hydroxypropylmethylcellulose), a diluent (e.g., water), and base wax (e.g., cocoa butter, white petrolatum or polyethylene glycol). The effective amount of the compounds of Formula (I) in the pharmaceutical composition may be at a level that will exercise the desired effect.

[0219] A compound of Formula (I) can be administered orally for reasons of convenience. In one embodiment, when administered orally, a compound of Formula (I) is administered with a meal and water. In another embodiment, the compound of Formula (I) 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.

[0220] 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 thediscretion of the health-care practitioner, and can depend in-part upon the site of the medical condition.

[0221] In one embodiment, provided herein are capsules containing a compound of Formula (I) without an additional carrier, excipient or vehicle.

[0222] In another embodiment, provided herein are compositions comprising an effective amount of a compound of Formula (I) 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.

[0223] The compositions can be in the form of tablets, chewable tablets, capsules, solutions, parenteral solutions, troches, suppositories and 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 of Formula (I) 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.

[0224] 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 and the 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.

[0225] A lubricant might be necessary in a tablet formulation to prevent the tablet and punches from sticking in the dye. The lubricant can be chosen from such slippery solids as talc, magnesium and calcium stearate, stearic acid and hydrogenated vegetable oils. Tablet disintegrators are substances that swell when wetted to break up the tablet and release the compound. They include starches, clays, celluloses, algins and gums. More particularly, corn and potato starches, methylcellulose, agar, bentonite, wood cellulose, powdered natural sponge, cation-exchange resins, alginic acid, guar gum, citrus pulp and carboxymethyl cellulose, forexample, 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.

[0226] When it is desired to administer a compound of Formula (I) as a suppository, typical 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.

[0227] The effect of the compound of Formula (I) can be delayed or prolonged by proper formulation. For example, a slowly soluble pellet of the compound of Formula (I) 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 the parenteral preparations can be made long- acting, by dissolving or suspending the compound of Formula (I) in oily or emulsified vehicles that allow it to disperse slowly in the serum.

[0228] It is understood that the pharmaceutical compositions described herein may include a mixture of compounds of Formula (I), including a racemic mixture of any of the compounds described herein. Exemplary Embodiments

[0229] The present disclosure is further described by the following embodiments.

[0230] Embodiment P1. A compound of Formula (I)or a pharmaceutically acceptable salt thereof, wherein: R1is halo, -CN, C1-C6alkyl, or C1-C6haloalkyl; Ring A is 4- to 10-membered monocyclic or fused bicyclic heterocyclylene, 6- to 10-membered monocyclic or fused bicyclic arylene, 5- to 10-membered monocyclic or fused bicyclic heteroarylene, C4-C6cycloalkylene, or C4-C6cycloalkenylene, wherein the heterocyclylene and heteroarylene contain 1-3 heteroatoms selected from N and O;Ring B is a fused 5-membered heterocyclyl or 5-membered heteroaryl, wherein the heterocyclyl and heteroaryl contain 1-3 nitrogen atoms and are optionally substituted with 1-2 groups selected from C1-C6alkyl, halo, and oxo; each R2is independently C1-C6alkyl, halo, C1-C6haloalkyl, or C1-C6alkyl-OH, or 2 R2groups on the same carbon atom are taken together to form an oxo group, or 2 R2groups are taken together with the carbon atom to which they are attached to form a spiro C3-C6cycloalkyl, or 2 R2groups on different carbon atoms are taken together to form C1-C6alkylene or -(C1-C4alkylene)O(C1-C4alkylene)-; L1is a bond, O, C1-C6alkylene, -N(H)-, -N(C1-C6alkyl)-, or -N(C1-C6alkyl-OH)-; L2is a bond, -N(H)-, -N(C1-C6alkyl)-, -N(H)C(O)-, -N(H)C(O)(C1-C6alkylene)-, -(C1-C6alkylene)N(C1-C6alkyl)-, O, or C1-C6alkylene; Y1and Y2are independently CR4or N; R3is H, C1-C6alkyl, C1-C6alkyl-OH, -(C1-C6alkylene)O(C1-C6alkyl), -(C1-C6alkylene)NR3aR3b, or -(C1-C6alkylene)(4- to 6-membered heterocyclyl), wherein the heterocyclyl contains 1-3 heteroatoms selected from N and O, and wherein the heterocyclyl is optionally substituted by 1-5 groups selected from halo, -OH, C1-C6alkyl, and C1-C6haloalkyl; each R3aand R3bis independently H or C1-C6alkyl; each R4is independently H, halo, or C1-C6alkyl; each R5is independently halo, C1-C6alkyl, or C1-C6haloalkyl; W1is C or N; W2is C or N; Z is C or N; each R6is independently halo, C1-C6alkyl, or C1-C6haloalkyl; R7is C1-C6alkyl, C1-C6alkyl-OH, -(C1-C6alkylene)NR3aR3b, -(C1-C6alkylene)C(O)NR3aR3b, -(C1-C6alkylene)CO2(C1-C6alkyl), C3-C6cycloalkyl, -(C1-C6alkylene)(C3-C6cycloalkyl), 4- to 6-membered heterocyclyl, or -(C1-C6alkylene)(4- to 6-membered heterocyclyl), wherein the heterocyclyl contains 1-3 heteroatoms selected from N and O, and the cycloalkyl and heterocyclyl are optionally substituted by 1-5 groups selected from -OH, C1-C6alkoxy, C1-C6alkyl, halo, and C1-C6haloalkyl; m is 0-2; n is 0-5; z is 0-3; * indicates alternative points of attachment to L2; andis a single or double bond; wherein one or more hydrogen atoms in the compound are optionally replaced by deuterium.

[0231] Embodiment P2. The compound of embodiment P1, or a pharmaceutically acceptable salt thereof, wherein: R1is halo, -CN, C1-C3alkyl, or C1-C3haloalkyl.

[0232] Embodiment P3. The compound of embodiment P1 or P2, or a pharmaceutically acceptable salt thereof, wherein: R1is Cl, -CN, or F.

[0233] Embodiment P4. The compound of any one of embodiments P1-P3, or a pharmaceutically acceptable salt thereof, wherein: Ring A is 4- to 7-membered monocyclic heterocyclylene, 8- to 10-membered fused bicyclic heterocyclylene, phenylene, 5- to 6-membered monocyclic heteroarylene, 8- to 10- membered fused bicyclic heteroarylene, C5-C6cycloalkylene, or C5-C6cycloalkenylene, wherein the heterocyclylene and heteroarylene contain 1-3 heteroatoms selected from N and O.

[0234] Embodiment P5. The compound of embodiment P4, or a pharmaceutically acceptable salt thereof, wherein: Ring A is.

[0235] Embodiment P6. The compound of any one of embodiments P1-P5, or a pharmaceutically acceptable salt thereof, wherein: each R2is independently C1-C3alkyl, halo, C1-C3haloalkyl, or C1-C3alkyl-OH, or 2 R2groups on the same carbon atom are taken together to form an oxo group, or 2 R2groups are taken together with the carbon atom to which they are attached to for a spiro C3-C5 cycloalkyl, or 2 R2groups on different carbon atoms are taken together to form C1-C3alkylene or -(C1-C3alkylene)O(C1-C3alkylene)-.

[0236] Embodiment P7. The compound of embodiment P6, or a pharmaceutically acceptable salt thereof, wherein: each R2is independently -CH3, F, or -CH2OH,or 2 R2groups on the same carbon atom are taken together to form an oxo group, or 2 R2groups are taken together with the carbon atom to which they are attached to for a spiro cycloalkyl or spiro cyclobutyl, or 2 R2groups on different carbon atoms are taken together to form -CH2OCH2- or -CH2CH2CH2-.

[0237] Embodiment P8. The compound of any one of embodiments P1-P7, or a pharmaceutically acceptable salt thereof, wherein: n is 0-3.

[0238] Embodiment P9. The compound of any one of embodiments P1-P8, or a pharmaceutically acceptable salt thereof, wherein:.

[0239] Embodiment P10. The compound of any one of embodiments P1-P9, or a pharmaceutically acceptable salt thereof, wherein: L1is a bond, O, C1-C3alkylene, -N(H)-, -N(C1-C3alkyl)-, or -N(C1-C3alkyl-OH)-.

[0240] Embodiment P11. The compound of embodiment P10, or a pharmaceutically acceptable salt thereof, wherein: L1is a bond, O, -CH2-, -N(H)-, -N(CH3)-, or -N(CH2CH2OH)-.

[0241] Embodiment P12. The compound of any one of embodiments P1-P11, or a pharmaceutically acceptable salt thereof, wherein:L2is a bond, -N(H)-, -N(C1-C3alkyl)-, -N(H)C(O)-, -N(H)C(O)(C1-C3alkylene)-, -(C1-C3alkylene)N(C1-C3alkyl)-, O, or C1-C3alkylene.

[0242] Embodiment P13. The compound of embodiment P12, or a pharmaceutically acceptable salt thereof, wherein: L2is a bond, -N(H)-, -N(CH3)-, -N(H)C(O)-, -N(H)C(O)(CH2)-, -(CH2)N(CH3)-, O, or -CH2-.

[0243] Embodiment P14. The compound of any one of embodiments P1-P13, or a pharmaceutically acceptable salt thereof, wherein:.

[0244] Embodiment P15. The compound of any one of embodiments P1-P14, or a pharmaceutically acceptable salt thereof, wherein: Y1and Y2are independently CR4.

[0245] Embodiment P16. The compound of any one of embodiments P1-P15, or a pharmaceutically acceptable salt thereof, wherein: each R4is independently H, halo, or C1-C3alkyl.

[0246] Embodiment P17. The compound of any one of embodiments P1-P16, or a pharmaceutically acceptable salt thereof, wherein: each R4is independently H or F.

[0247] Embodiment P18. The compound of any one of embodiments P1-P14, or a pharmaceutically acceptable salt thereof, wherein: Y1and Y2are each N.

[0248] Embodiment P19. The compound of any one of embodiments P1-P18, or a pharmaceutically acceptable salt thereof, wherein:.

[0249] Embodiment P20. The compound of any one of embodiments P1-P19, or a pharmaceutically acceptable salt thereof, wherein: R3is H, C1-C3alkyl, C1-C5alkyl-OH, -(C1-C3alkylene)O(C1-C3alkyl), -(C1-C3alkylene)NR3aR3b, or -(C1-C3alkylene)(4- to 6-membered heterocyclyl), wherein the heterocyclyl contains 1-2 heteroatoms selected from N and O, and wherein the heterocyclyl is optionally substituted by 1-3 groups selected from halo, -OH, C1-C3alkyl, and C1-C3haloalkyl; and each R3aand R3bis independently H or C1-C3alkyl.

[0250] Embodiment P21. The compound of embodiment P20, or a pharmaceutically acceptable salt thereof, wherein: R3is H, -CH3, -CD3, -CH2CH3, -CH(CH3)2, -CH2CH(CH3)OH, -CH2C(CH3)2OH, -CH2CH2OCH3, -CH2CH2N(CH3)2, -CH2CH2CH2N(CH3)2, -CH2CH2N(H)(CH3),.

[0251] Embodiment P22. The compound of any one of embodiments P1-P21, or a pharmaceutically acceptable salt thereof, wherein: each R5is independently halo, C1-C3alkyl, or C1-C3haloalkyl.

[0252] Embodiment P23. The compound of embodiment P22, or a pharmaceutically acceptable salt thereof, wherein:each R5is Cl.

[0253] Embodiment P24. The compound of any one of embodiments P1-P23, or a pharmaceutically acceptable salt thereof, wherein: z is 1.

[0254] Embodiment P25. The compound of any one of embodiments P1-P21, or a pharmaceutically acceptable salt thereof, wherein: z is 0.

[0255] Embodiment P26. The compound of any one of embodiments P1-P25, or a pharmaceutically acceptable salt thereof, wherein: each R6is independently halo, C1-C3alkyl, or C1-C3haloalkyl.

[0256] Embodiment P27. The compound of embodiment P26, or a pharmaceutically acceptable salt thereof, wherein: each R6is F.

[0257] Embodiment P28. The compound of any one of embodiments P1-P27, or a pharmaceutically acceptable salt thereof, wherein: m is 1.

[0258] Embodiment P29. The compound of any one of embodiments P1-P25, or a pharmaceutically acceptable salt thereof, wherein: m is 0.

[0259] Embodiment P30. The compound of any one of embodiments P1-P29, or a pharmaceutically acceptable salt thereof, wherein: Z is C.

[0260] Embodiment P31. The compound of any one of embodiments P1-P29, or a pharmaceutically acceptable salt thereof, wherein: Z is N.

[0261] Embodiment P32. The compound of any one of embodiments P1-P31, or a pharmaceutically acceptable salt thereof, wherein:.

[0262] Embodiment P33. The compound of any one of embodiments P1-P32, or a pharmaceutically acceptable salt thereof, wherein: R7is C1-C3alkyl, C4-C6alkyl-OH, -(C4-C6alkylene)NR3aR3b, -(C1-C3alkylene)C(O)NR3aR3b, -(C1-C3alkylene)CO2(C4-C6alkyl), C4-C6cycloalkyl, -(C1-C3alkylene)(C4-C6cycloalkyl), 4- to 6-membered heterocyclyl, or -(C1-C3alkylene)(4- to6-membered heterocyclyl), wherein the heterocyclyl contains 1-2 heteroatoms selected from N and O, and the cycloalkyl and heterocyclyl are optionally substituted by 1-3 groups selected from -OH, C1-C3alkoxy, C1-C3alkyl, halo, and C1-C3haloalkyl; and R3aand R3bare independently H or C1-C3alkyl.

[0263] Embodiment P34. The compound of embodiment P33, or a pharmaceutically acceptable salt thereof, wherein: R7is -CH3, -CH2CH2C(CH3)2OH, -CH2CH2CH2C(CH3)2OH, -CH2CH2CH(CH3)OH, -CH2CH2C(CH3)2NH2, -CH2CH2C(O)N(H)CH3, -CH2CH2CO2C(CH3)3,.

[0264] Embodiment P35. The compound of any one of embodiments P1-P34, or a pharmaceutically acceptable salt thereof, wherein: Ring B is a fused 5-membered heterocyclyl or 5-membered heteroaryl, wherein the heterocyclyl and heteroaryl contain 1-3 nitrogen atoms and are optionally substituted with 1-2 groups selected from C1-C3alkyl, halo, and oxo.

[0265] Embodiment P36. The compound of any one of embodiments P1-P35, or a pharmaceutically acceptable salt thereof, wherein:.

[0266] Embodiment P37. The compound of any one of embodiments P1-P36, or a pharmaceutically acceptable salt thereof, wherein: W1is C.

[0267] Embodiment P38. The compound of any one of embodiments P1-P36, or apharmaceutically acceptable salt thereof, wherein: W1is N.

[0268] Embodiment P39. The compound of any one of embodiments P1-P38, or a pharmaceutically acceptable salt thereof, wherein: W2is C.

[0269] Embodiment P40. The compound of any one of embodiments P1-P38, or a pharmaceutically acceptable salt thereof, wherein: W2is N.

[0270] Embodiment P41. The compound of any one of embodiments P1-P40, or a pharmaceutically acceptable salt thereof, wherein:.

[0271] Embodiment P42. The compound of any one of embodiments P1-P41, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (II), (III), or (IV):.

[0272] Embodiment P43. The compound of any one of embodiments P1-P41, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (Va) or (Vb):.

[0273] Embodiment P44. A compound selected from the compounds of Table 1 and pharmaceutically acceptable salts thereof.

[0274] Embodiment P45. A pharmaceutical composition comprising the compound of any one of embodiments P1-P44, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0275] Embodiment P46. A method of degrading B-cell lymphoma 6 protein (BCL6) comprising contacting BCL6 with an effective amount of the compound of any one of embodiments P1-P44, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of embodiment P45.

[0276] Embodiment P47. 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 the compound of any one of embodiments P1-P44, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of embodiment P45. EXAMPLES

[0277] 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.

[0278] Salts of the compounds described herein can be prepared by standard methods, such as inclusion of an acid (for example TFA, formic acid, or HCl) in the mobile phases during chromatography purification, or stirring of the products after chromatography purification, with a solution of an acid (for example, aqueous HCl).

[0279] The following abbreviations may be relevant for the application. AbbreviationsSynthetic Examples General Procedures Example G-1. SNAr for diamino-nitrophenyl precursors (General Procedure 1)wherein R3, Y1, and Y2are as defined for Formula (I).

[0280] A mixture of the aryl fluoride (1.0 eq), cesium carbonate (1.8 eq) and amine (1.2 eq) in DMF [0.4M] was heated to 90 °C for 16 h and then cooled to rt. The mixture was filtered through a Celite pad with EtOAc, then concentrated under reduced pressure. The followingcrude material was purified by column chromatography on silica gel using a gradient of 0-30% MeOH in DCM to afford the title compounds. Example G-2. Cyclization benzyimidazolone using DSC or CDI (General Procedure 2)wherein R3, Y1, and Y2are as defined for Formula (I).

[0281] To a stirred solution of the respective 4-nitrobenzene-1,2-diamine (1.0 eq) in MeCN [0.3 M] under nitrogen was added DSC (1.2 eq) at RT. The reaction mixture was stirred at 25 °C for 18 h. The mixture was concentrated to evaporate the solvent, then quenched with water and extracted with EtOAc. The organic layers were washed with brine, then dried and concentrated. The crude material was purified by column chromatography on silica gel using a gradient of 0- 20% MeOH in DCM to afford the title compounds. Example G-3. N-Alkylation 5-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one (General Procedure 3)wherein R3, R7, Y1, and Y2are as defined for Formula (I).

[0282] To a solution of amine (1.0 eq) in acetonitrile [0.3 M] was added cesium carbonate (2.5 eq), followed by a solution of the tosylate reagent (1.5 eq) in acetonitrile dropwise at 25 °C. The reaction mixture was headed to 85 °C for 18 h. Upon completion, the mixture was evaporated under reduced pressure to remove acetonitrile and water was added. The pH was adjusted by adding 1.5 N HCl, then extracted with EtOAc. The organic layers were dried using magnesium sulfate, filtered and concentrated under reduced pressure to provide the title compounds. Example G-4. Reduction of the aryl nitro (General Procedure 4)wherein R3, R7, Y1, and Y2are as defined for Formula (I).

[0283] A solution of the respective aryl nitro compound in methanol [0.4 M] was purged with nitrogen and then Pd-C (0.1 eq) was added. After addition, the reaction mixture was degassed with vacuum and the resulting reaction mixture was stirred under hydrogen bladder atrt overnight. The reaction mass was filtered through a Celite bed, washed with MeOH, and then concentrated. The solid was triturated with ether and stirred for 30 mins, then dried under vacuum to give the title compounds. Example G-5. SNAr onto pyrimidine (General Procedure 5)wherein R1, R3, R7, Y1, and Y2are as defined for Formula (I), and each X is independently Cl or F.

[0284] To a -40 °C mixture of 5-amino-1-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 [1.5 M] 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 the title compound as a tan solid. Example G-6. Buchwald Coupling of Amine to Indazole CBM (General Procedure 6)wherein Z, W1, and W2are as defined for Formula (I), and R and R’ are independently H or C1- C6alkyl.

[0285] A mixture of 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole (1.1 eq), amine (1.0 eq), Ruphos-Pd-G3 (0.20 equiv.) and NaOtBu (1.5 eq) in 1,4-dioxane [0.3 M] was heated to 90 °C for 16 h and then cooled to rt. The mixture was filtered through 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 the title compound. Example G-7. Methylation of amine (General Procedure 7) wherein R and R’ are independently H or C1-C6alkyl.

[0286] To a solution of amine (1.0 eq, 14.2 mmol) in DMF [0.15M] was added NaH (4.4eq), and the reaction mixture was 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 16 hr. 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 a gradient of 0–100% ethyl acetate in hexanes to obtain the title compound. Example G-8. Reduction of CBM with Hydrogen (General Procedure 8)wherein Z, W1, and W2are as defined for Formula (I), and R and R’ are independently H or C1- C6alkyl.

[0287] A mixture of indazole intermediate (1.0 equiv.) and Pd / C (10 wt. % palladium; 40% by weight) or Pd(OH)2 / C 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% ethyl acetate in hexanes to afford the title compound. Example G-9. Boc Deprotection with HCl or TFA (General Procedure 9)wherein R and R’ are independently H or C1-C6alkyl.

[0288] To a solution of Boc protected amine (1.0 eq) in 1,4-dioxane [0.3 M] was added 4N HCl in 1,4-dioxane (14 eq.), and the reaction mixture was stirred at rt for 12 h. The volatiles were evaporated under reduced pressure to afford the title compound (quant.) as a solid, which was used in the next step without further purification. Example G-10. SNAr of amine with halo-pyrimidine (General Procedure 10)wherein R1, R3, R7, Y1, and Y2are as defined for Formula (I), R and R’ are independently H orC1-C6alkyl, and X is F or Cl.

[0289] 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-phase 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 the title compounds. Example G-11. Mitsunobu with 1-methyl-5-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one (General Procedure 11)wherein Y1and Y2are as defined for Formula (I), and -CH2R corresponds to substitutent R7of Formula (I).

[0290] To a stirred solution of triphenylphosphine (1.10 equiv) in THF (0.5M) at 0 °C, DIAD (1.10 equiv) was added dropwise. Stirring was continued for 30 min at 0 °C, followed by the addition of primary alcohol (1.10 equiv). The reaction mixture was stirred for another 30 min at the same temperature, after which 1-methyl-5-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one (1.0 equiv) was added. The mixture was allowed to warm up to 25 °C and stirred for 16 h. The reaction mixture was directly concentrated under reduced pressure to afford the crude compound. The crude residue was purified by flash column chromatography on silica with 45 - 50% ethyl acetate / pet ether to afford the title compound. Synthesis of Intermediates Example I-1.3-(1-Methyl-6-(4-(methylamino)piperidin-1-yl)-1H-indazol-3-yl)piperidine- 2,6-dione hydrochloride (Intermediate 1)

[0291] Step 1: Synthesis of tert-Butyl (1-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl- 1H-indazol-6-yl)piperidin-4-yl)(methyl)carbamate. 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)- 1-methyl-indazole (300 mg, 0.600 mmol), tert-butyl N-methyl-N-(piperidin-4-yl)carbamate (192.72 mg, 0.9000 mmol), cesium carbonate (390.68 mg, 1.2 mmol), and RuPhos-Pd-G3 (50.14 mg, 0.0600 mmol) were added to a 1 dram vial and purged with nitrogen for 1 min. Next, 1,4-dioxane (0.8 mL) was added and the reaction mixture was stirred at 100 °C for 16 h.The reaction mixture was purified using column chromatography (10 g SNAP cartridge, 0-7% Methanol / DCM 25 CV, 7% methanol / DCM 10 CV) to give the title compound (106 mg, 0.1673 mmol, 27.8% yield) as a white solid. MS (ESI) m / z 634.0 [M+H]+;1H NMR (400 MHz, DMSO-d6 ) δ ppm 7.89 (d, J=8.19 Hz, 1 H), 7.26 - 7.51 (m, 11 H), 6.88 (d, J=1.59 Hz, 1 H), 6.82 (dd, J=9.17, 1.96 Hz, 1 H), 6.57 (d, J=8.19 Hz, 1 H), 5.44 (d, J=13.57 Hz, 4 H), 3.97 (s, 3 H), 3.87 (br d, J=12.59 Hz, 2 H), 2.77 (br t, J=11.55 Hz, 2 H), 2.70 (s, 3 H), 1.71 - 1.89 (m, 2 H), 1.61 - 1.70 (m, 2 H), 1.42 (s, 9 H).

[0292] Step 2: Synthesis of tert-butyl (1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H- indazol-6-yl)piperidin-4-yl)(methyl)carbamate. Tert-butyl N-[1-[3-(2,6-dibenzyloxy-3- pyridyl)-1-methyl-indazol-6-yl]-4-piperidyl]-N-methyl-carbamate (106 mg, 0.1700 mmol) and ethanol (4.1813 mL) were dissolved in a 40 mL vial equipped with a sir bar. The mixture was purged with nitrogen, and palladium on carbon (17.8 mg, 0.1700 mmol) was added. The mixture was purged again with nitrogen and then hydrogen. The reaction was stirred under a balloon of hydrogen overnight. The slurry was filtered through Celite and concentrated. The residue was loaded onto a SNAP 25G column and purified with 0-50% EtOAc / hex with 2-5% MeOH additive to give the title compound (50 mg, 0.110 mmol, 65.6% yield) as a yellow oil.

[0293] Step 3: Synthesis of 3-(1-Methyl-6-(4-(methylamino)piperidin-1-yl)-1H-indazol- 3-yl)piperidine-2,6-dione hydrochloride. Tert-butyl N-[1-[3-(2,6-dioxo-3-piperidyl)-1- methyl-indazol-6-yl]-4-piperidyl]-N-methyl-carbamate (50 mg, 0.1100 mmol) was added to a vial equipped with a stir bar, and dichloromethane (1 mL) was added. HCl (4 N in 1,4-dioxane, 0.4400 mmol) was then added to the mixture and stirred for 2 hours. The stir bar was removed and the solvent was removed in vacuo to give the title compound (42 mg, 0.107 mmol, 97.6% yield) as an off-white solid. Example I-2.3-(1-methyl-6-(piperidin-4-ylamino)-1H-indazol-3-yl)piperidine-2,6-dione hydrochloride (Intermediate 2)

[0294] Step 1: Synthesis of 6-bromo-3-iodo-1-methyl-indazole. To a solution of^6-bromo- 1-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 (4.95g, 14.7 mmol, 39% yield) as a solid. MS (ESI) [M+H]+^336.90.

[0295] Step 2: Synthesis of 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole. To a solution of^6-bromo-3-iodo-1-methyl-indazole (2. g, 5.94 mmol)^in 1,4-dioxane (30 mL)^and water (3 mL)was added (2,6-dibenzyloxy-3-pyridyl)boronic acid (1.99 g, 5.94 mmol), potassium phosphate (3.78 g, 17.81 mmol)^and [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(ii) (0.43 g, 0.5900 mmol) under N2, then the mixture was stirred at80 °Cfor 17 hr under N2. LCMS showed the reactant was consumed completely, and the desired MS as the 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 petroleum ether) to give the title compound (2.1 g, 4.20 mmol, 71% yield)^as a pale yellow solid. MS (ES) [M+H]+500.3;1H NMR (400 MHz, DMSO-d6) δ 7.96 (s, 1H), 7.91 (d, J= 8.1 Hz, 1H), 7.62 (d, J= 8.7 Hz, 1H), 7.50 – 7.24 (m, 10H), 7.12 (dd, J= 8.7, 1.4 Hz, 1H), 6.60 (d, J= 8.1 Hz, 1H), 5.45 (s, 2H), 5.43 (s, 2H), 4.05 (s, 3H).

[0296] Step 3: Synthesis of tert-butyl 4-[[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl- indazol-6-yl]amino]piperidine-1-carboxylate. A mixture of^6-bromo-3-(2,6-dibenzyloxy-3- pyridyl)-1-methyl-indazole (4.0 g, 7.99 mmol),^tert-butyl 4-aminopiperidine-1-carboxylate (1.92 g, 9.59 mmol), XPhos-Pd-G3 (1.35 g, 1.6 mmol) andCs2CO3(5.2 g, 15.99 mmol) in 1,4- dioxane (53.292 mL) was heated to 110 °C for 28 h and then cooled to rt. The mixture was filtered through Celite and washed with 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)- 1-methyl-indazol-6-yl]amino]piperidine-1-carboxylate (2.81 g, 4.53 mmol, 57% yield) as a solid.MS (ESI) [M+H]+:620.4;1H NMR (500 MHz, CDCl3) δ 7.89 (d, J = 8.1 Hz, 1H), 7.47 (d, J = 8.7 Hz, 1H), 7.45 – 7.42 (m, 2H), 7.39 – 7.27 (m, 7H), 7.25 – 7.22 (m, 1H), 6.49 (d, J = 8.1 Hz, 1H), 6.36 (dd, J = 8.8, 1.9 Hz, 1H), 6.31 (d, J = 1.7 Hz, 1H), 5.46 (s, 2H), 5.38 (s, 2H), 4.06 (br, 2H), 3.98 (s, 3H), 3.73 (br, 1H), 3.57 – 3.46 (m, 2H), 3.00 (t, J = 11.9 Hz, 2H), 2.10 (dd, J = 13.0, 2.8 Hz, 2H), 1.48 (s, 9H).

[0297] Step 4: Synthesis of tert-butyl 4-[[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-6- yl]amino]piperidine-1-carboxylate. A mixture of tert-butyl 4-[[3-(2,6-dibenzyloxy-3-pyridyl)- 1-methyl-indazol-6-yl]amino]piperidine-1-carboxylate (600 mg, 0.970 mmol) and Pearlman's Catalyst (167 mg, 0.240 mmol) in 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 mixturewassubjected 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)-1-methyl-indazol-6- yl]amino]piperidine-1-carboxylate (495 mg, 0.9496 mmol, 98.085% yield) as a solid.^ MS (ESI) [M+H]+: 442.4;1H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H), 7.33 (d, J = 8.7 Hz, 1H), 6.52 (dd, J = 8.8, 1.8 Hz, 1H), 6.43 (s, 1H), 5.79 (d, J = 8.2 Hz, 1H), 4.18 (dd, J = 8.7, 5.2 Hz, 1H), 3.93 – 3.86 (m, 2H), 3.81 (s, 3H), 2.96 (br, 2H), 2.60 (t, J = 7.0 Hz, 2H), 2.30 – 2.20 (m, 1H), 2.18 – 2.11 (m, 1H), 1.94 (d, J = 11.0 Hz, 2H), 1.41 (s, 9H), 1.30 – 1.19 (m, 3H).

[0298] Step 5: Synthesis of 3-[1-Methyl-6-(4-piperidylamino)indazol-3-yl]piperidine- 2,6-dione hydrochloride salt. To a solution of tert-butyl 4-[[3-(2,6-dioxo-3-piperidyl)-1- methyl-indazol-6-yl]amino]piperidine-1-carboxylate (1.22 g, 2.76 mmol) in 1,4-dioxane (20 mL) was added hydrogen chloride 4 N 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 the title compound (1.0 g, 2.65 mmol, 96% yield) as a white solid. MS (ESI) m / z 342.2 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ ppm 10.85 (s, 1 H), 9.01 (br d, J=2.45 Hz, 1 H), 8.76 - 8.95 (m, 1 H), 7.48 (br s, 1 H), 6.72 (br s, 3 H), 4.21 - 4.30 (m, 1 H), 3.87 (s, 3 H), 3.63 - 3.75 (m, 1 H), 3.32 (br d, J=12.59 Hz, 2 H), 2.99 (br d, J=10.39 Hz, 2 H), 2.55 - 2.69 (m, 2 H), 2.22 - 2.34 (m, 1 H), 2.07 - 2.22 (m, 3 H), 1.72 (br s, 2 H). Example I-3.3-(1-methyl-6-(4-(methylamino)-2-oxopiperidin-1-yl)-1H-indazol-3- yl)piperidine-2,6-dione (Intermediate 3)

[0299] Step 1: Synthesis of 4-(benzyl(methyl)amino)piperidin-2-one. To a solution of piperidine-2,4-dione (5.0 g, 44.2 mmol)) in DCE (80 mL) were added sequentially N-methyl-1- phenylmethanamine (5.36 g, 44.2 mmol) and acetic acid (2.53 mL, 44.2 mmol), and the reaction mixture was stirred for 2 h at rt. Sodium cyanoborohydride (4.17 g, 66.3 mmol) was added to the reaction mixture and stirring was continued for 16 h. The reaction mixture was monitored by LCMS and TLC. After completion of the reaction, the reaction mixture was quenched with satd aq sodium bicarbonate ( 50 mL) and extracted with DCM (2*100 mL). The organic layer was separated, dried over anhydrous sodium sulphate, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography on silica gel using up to 100%ethyl acetate and followed by up to 10% methanol in DCM as eluent to afford an oil compound, which was solidified at ambient temperature as an off-white solid. MS (ES): m / z = 219.2 [M+H]+.

[0300] Step 2: Synthesis of 4-(benzyl(methyl)amino)-1-(3-(2,6-bis(benzyloxy)pyridin-3- yl)-1-methyl-1H-indazol-6-yl)piperidin-2-one. A solution of 4- (benzyl(methyl)amino)piperidin-2-one (1.5 g, 5.98 mmol) and 3-(2,6-bis(benzyloxy)pyridin-3- yl)-6-bromo-1-methyl-1H-indazole (2.99 g, 5.98 mmol) in dioxane (50.0 mL) was degassed with nitrogen for 5 min, then Pd2(dba)3 (0.547 g, 0.598 mmol), xantphos (0.692 g, 1.196 mmol) and Cs2CO3(2.92 g, 8.97 mmol) were added at ambient temperature. The reaction mixture was heated to 100 °C for 18 h. TLC and LCMS showed completion of the reaction. The reaction mixture was filtered through a pad of Celite and washed with ethyl acetate. The filtrate was washed with water ( 100 mL) and extracted with ethyl acetate (2*100 mL). The organic layer was separated, dried over anhydrous sodium sulphate, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography on silica gel using up to 100% ethyl acetate followed by up to 10% methanol in DCM as eluent to afford 4- (benzyl(methyl)amino)-1-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazol-6- yl)piperidin-2-one (2.5 g with 96% purity by UPLC) as a gummy solid. The obtained product was subjected to SFC purification (SFC method development: Flow Rate: 5 mL / min, Column Name: YMC Cellulose SC, Co-Solvent: 40%, Co-Solvent Name: 0.1% IPAm in IPA:ACN(1:1), Injected Volume: 15 μl, Outlet Pressure: 100 bar, Temperature: 35 °C). After concentration of each individual isomer, isomer 1 (0.8 g, 1.2 mmol, 20% yield) and isomer 2 (0.8 g, 1.5 mmol, 25% yield) were obtained.

[0301] Step 3: Synthesis of 3-(1-methyl-6-(4-(methylamino)-2-oxopiperidin-1-yl)-1H- indazol-3-yl)piperidine-2,6-dione, 2 TFA. To a stirred solution of 4-(benzyl(methyl)amino)-1- (3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazol-6-yl)piperidin-2-one (800 mg, 1.25 mmol) in ethanol (20 mL) and THF (20 mL) was added TFA (0.097 mL, 1.25 mmol), followed by palladium hydroxide on carbon (440 mg, 0.627 mmol) under nitrogen. The reaction mixture was stirred under hydrogen pressure (4 atm) at 50 °C for 5 h. The reaction mixture was filtered through a pad of Celite and washed with a (1:1) mixture of DCM and MeOH (150 mL). The filtrate was concentrated completely under vacuum to afford an off-white solid. The obtained solid was triturated with diethyl ether (30 mL). The ether layer was decanted and the solid was dried under vacuum. The racemic mixture (500 mg) was separated by prep-HPLC (0.2% NH3 in MeOH: ACN, 70:30) to afford peak-1 (150 mg, 99% pure by HPLC) and peak-2 (157 mg, 99% pure by HPLC). Example I-4.3-(1-methyl-6-(((3R,4R)-3-methylpiperidin-4-yl)amino)-1H-indazol-3-yl)piperidine-2,6-dione hydrochloride (Intermediate 4)

[0302] Step 1: Synthesis of tert-Butyl (3R,4R)-4-[[3-(2,6-dibenzyloxy-3-pyridyl)-1- methyl-indazol-6-yl]amino]-3-methyl-piperidine-1-carboxylate. A mixture of 6-bromo-3- (2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole (1.92 g, 3.84 mmol), tert-butyl (3R,4R)-4- amino-3-methyl-piperidine-1-carboxylate (685 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). The filtrate 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 the title compound (1.37 g, 68%) as a solid. MS (ESI) [M+H]+634.1;1H NMR (400 MHz, DMSO-d6) δ 7.86 (d, J = 8.1 Hz, 1H), 7.50 – 7.46 (m, 1H), 7.46 – 7.25 (m, 10H), 6.54 (d, J = 8.1 Hz, 1H), 6.43 (d, J = 1.8 Hz, 1H), 6.41 (d, J = 2.2 Hz, 1H), 5.70 (d, J = 8.9 Hz, 1H), 5.44 (s, 2H), 5.40 (s, 2H), 3.97 – 3.89 (m, 2H), 3.88 (s, 3H), 3.24 – 3.14 (m, 1H), 2.99 – 2.87 (m, 1H), 2.05 – 2.01 (m, 1H), 2.01 – 1.98 (m, 1H), 1.57 – 1.47 (m, 1H), 1.41 (s, 9H), 1.17 – 1.08 (m, 1H), 0.93 (d, J = 6.5 Hz, 3H).

[0303] Step 2: Synthesis of tert-Butyl (3R,4R)-4-[[3-(2,6-dioxo-3-piperidyl)-1-methyl- indazol-6-yl]amino]-3-methyl-piperidine-1-carboxylate. A mixture of tert-butyl (3R,4R)-4- [[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazol-6-yl]amino]-3-methyl-piperidine-1- carboxylate (1.40 g, 2.21 mmol) and Pd(OH)2 / C (1.18 g, 1.10 mmol) in MeOH (25 mL) and THF (75 mL) was hydrogenated under H2 (1 atm) at 50 °C for 9 h. The mixture was filtered through Celite and washed with MeOH (2 x 50 mL) and THF (2 x 100 mL). The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel using a gradient of 0–5% MeOH in DCM to afford the title compound (695 mg, 69%) as a solid. MS (ESI) [M+H]+456.3;1H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H), 7.31 (d, J = 8.8 Hz, 1H), 6.51 (dd, J = 8.8, 1.7 Hz, 1H), 6.40 (s, 1H), 5.72 (d, J = 8.9 Hz, 1H), 4.17 (dd, J = 8.7, 5.2 Hz, 1H), 3.98 – 3.88 (m, 2H), 3.80 (s, 3H), 3.26 – 3.14 (m, 1H), 3.00 – 2.86 (m, 1H), 2.65 – 2.56 (m, 3H), 2.34 – 2.20 (m, 1H), 2.18 – 2.09 (m, 1H), 2.05 – 1.94 (m, 1H), 1.60 – 1.46 (m, 1H), 1.41 (s, 9H), 1.22 – 1.05 (m, 1H), 0.92 (d, J = 6.5 Hz, 3H).

[0304] Step 3: Synthesis of 3-(1-methyl-6-(((3R,4R)-3-methylpiperidin-4-yl)amino)-1H- indazol-3-yl)piperidine-2,6-dione hydrochloride. To a solution of tert-butyl (3R,4R)-4-[[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-6-yl]amino]-3-methyl-piperidine-1-carboxylate (8 g, 17.6 mmol) in ethyl acetate (35 mL) was added 4 M HCl in ethyl acetate (35 mL) at 25 °C. After completion of the addition, the reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was filtered to offer the title compound (8 g, 100% yield) as an off-white solid. MS (ESI) [M+H]+356.2;1H NMR (400 MHz MeOD) δ: 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 I-5.3-(1-methyl-6-(((3R,4S)-3-methylpiperidin-4-yl)amino)-1H-indazol-3- yl)piperidine-2,6-dione hydrochloride (Intermediate 5)

[0305] Synthesis of 3-(1-methyl-6-(((3R,4S)-3-methylpiperidin-4-yl)amino)-1H-indazol- 3-yl)piperidine-2,6-dione hydrochloride. The title compound was synthesized according to General Procedure 6 using tert-butyl (3R,4S)-4-amino-3-methyl-piperidine-1-carboxylate. The product of this reaction was then subjected to General Procedures 8 and 9 to give the title compound. Example I-6.3-(6-amino-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (Intermediate 6)

[0306] Step 1: Synthesis of tert-butyl (3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H- indazol-6-yl)carbamate. 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-1-methyl-1H-indazole (160g, 320 mmol) was taken in 1,4-dioxane (1600 mL) in a 3000 mL multi-neck RBF fitted with a reflux condenser under N2atm with mechanical stirring. Next, tert-butyl carbamate (56.2 g, 480 mmol) was added, followed by K2CO3 (133 g, 959 mmol), and the reaction mixture was 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 overnight. The reaction mixture was filtered through a Celite bed, washing with ethyl acetate. The filtrate obtained was evaporated to give crudeproduct, which was purified using ISCO in silica gel with PE / EtOAc as eluant to give the title compound (148 g, 275 mmol, 86 % yield) as a white solid. MS (ESI) m / z 537.30 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ ppm 9.5 (s, 1H), 7.89 – 7.91 (m, 1H), 7.28 - 7.54 (m, 12 H), 6.94 (d, 1 H), 6.58 (d, 1 H), 5.41-5.45 (d, 4 H), 3.96 (s, 3 H), 1.50 (s, 9 H), 1.37 (s, 1H).

[0307] Step 2: Synthesis of tert-butyl (3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol- 6-yl)carbamate. To a flask was added tert-butyl (3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl- 1H-indazol-6-yl)carbamate (25 g, 46.6 mmol) and THF (500 mL). This mixture was purged with nitrogen for 5 min, and then palladium on carbon (24.79 g, 23.29 mmol) was added and stirred under H2atmosphere overnight at 55 °C. Next, the reaction mixture was filtered through Celite, washing with THF (2 L), and then the filtrate was evaporated to give the title compound (15.69 g, 43.8 mmol, 94 % yield) as a white solid. MS (ESI) m / z 359.1 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ ppm 10.90 (s, 1H), 9.54 (s, 1H), 7.82 (m, 1H), 7.55 - 7.57 (d, 1 H), 7.04 (d, 1 H), 4.30 (m, 1 H), 3.90 (s, 3 H), 2.30 – 2.70 (m, 2 H) 2.13 – 2.37 (m, 2 H), 1.36 (s, 9H).

[0308] Step 3: Synthesis of 3-(6-amino-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione, HCl salt. Tert-butyl (3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)carbamate (25 g, 69.8 mmol) was dissolved in 1,4-dioxane (250 mL) in a 2 L RBF under magnetic stirring. HCl (4 M in dioxane, 250 mL, 69.8 mmol) was added slowly and then the reaction was stirred at RT for 48 hours. After this time, the mixture was filtered and then the obtained solids were taken up in methanol, stirred well for 20 minutes, and then filtered again to give the title compound (18 g, 57.2 mmol, 82 % yield) as a pale yellow solid. MS (ESI) m / z 259.1 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ ppm 7.80 - 7.82 (d, 1 H), 7.53 (s, 1 H), 7.08 - 7.11 (d 1 H), 4.39 - 4.43 (m, 1 H), 3.99 (s, 3 H), 2.50 – 2.73 (m, 2 H), 2.38 – 2.40 (m, 1 H), 2.18 - 2.36 (m, 1 H). Example I-7.5-((5-chloro-2-fluoropyrimidin-4-yl)amino)-3-(3-hydroxy-3-methylbutyl)-1- methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (Intermediate 7)

[0309] Step 1: Synthesis of 3-methyl-6-nitro-1H-benzimidazol-2-one. To a stirred solution of N1-methyl-4-nitrobenzene-1,2-diamine (50 g, 299 mmol) in THF (750 mL) under nitrogen was added CDI (72.7 g, 449 mmol) at 25 °C. The reaction mixture was heated to 65 °C for 18 h. Upon completion, the mixture was cooled to 0 °C for 1 hr. The resulting precipitate was collected by filtration, washed with a small amount of cold THF (150ml), and dried under vacuum to afford the title compound (55 g, 94% yield) as a brown solid. MS (ESI) [M-H]-192.02.

[0310] Step 2: Synthesis of 3-(3-hydroxy-3-methyl-butyl)-1-methyl-5-nitro- benzimidazol-2-one. To a solution of 3-methyl-6-nitro-1H-benzimidazol-2-one (4.83 g, 25.0 mmol) in acetonitrile (50.0 mL) were sequentially added Cs2CO3(22.0 g, 67.6 mmol) and a solution of (3-hydroxy-3-methyl-butyl) 4-methylbenzenesulfonate (11.3 g, 43.8 mmol) in MeCN (10.0 mL) dropwise at rt. The reaction mixture was heated to 85 °C for 18 h and then cooled to rt. The volatiles were evaporated under reduced pressure. Water (100.0 mL) was added and the pH was adjusted to 3 by adding 2.0 M aqueous HCl. Ethyl acetate was added, and the layers were separated. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to afford the title compound (4.38 g, 62%), which was used in the next step without further purification.1H NMR (500 MHz, DMSO) δ 8.06 (dd, J = 8.7, 2.2 Hz, 1H), 8.00 (d, J = 2.1 Hz, 1H), 7.36 (d, J = 8.7 Hz, 1H), 4.51 (s, 1H), 3.99 (dd, J = 9.3, 6.9 Hz, 2H), 3.40 (s, 3H), 1.76 – 1.70 (m, 2H), 1.17 (s, 6H).

[0311] Step 3: Synthesis of 5-amino-3-(3-hydroxy-3-methylbutyl)-1-methyl-1,3- dihydro-2H-benzo[d]imidazol-2-one. A mixture of 3-(3-hydroxy-3-methyl-butyl)-1-methyl-5- nitro-benzimidazol-2-one (5.34 g, 19.1 mmol) and 10% Pd / C (1.02 g, 0.956 mmol) in MeOH (190 mL) was shaken in a Parr flask at 50 psi hydrogen atmosphere at rt for 4 h. The mixture was filtered through Celite and washed with MeOH. The filtrate was concentrated under reduced pressure to afford the title compound (4.75 g, 99%) as a solid, which was used in the next step without further purification.1H NMR (500 MHz, DMSO) δ 6.78 (d, J = 8.2 Hz, 1H), 6.37 (d, J = 1.9 Hz, 1H), 6.30 (dd, J = 8.2, 2.0 Hz, 1H), 4.78 (br, 2H), 4.44 (s, 1H), 3.80 – 3.74 (m, 2H), 3.21 (s, 3H), 1.69 – 1.62 (m, 2H), 1.16 (s, 6H).

[0312] Step 4: Synthesis of 5-((5-chloro-2-fluoropyrimidin-4-yl)amino)-3-(3-hydroxy-3- methylbutyl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one. To a solution of 5-amino-3- (3-hydroxy-3-methyl-butyl)-1-methyl-benzimidazol-2-one (3.0 g, 12.0 mmol) in a mixture of DMF (25.0 mL) and THF (125.0 mL) cooled to - 40 °C were sequentially added DIPEA (2.27 mL, 13.2 mmol) and 5-chloro-2,4-difluoro-pyrimidine (1.90 g, 12.6 mmol). The reaction mixture was slowly warmed to rt and stirred for 18 h. The volatiles were evaporated under reduced pressure. DCM was added and the resulting precipitate was collected by filtration, washed with DCM, and dried under vacuum to afford the title compound (3.23 g, 70%) as a solid.1H NMR (500 MHz, DMSO) δ 9.61 (s, 1H), 8.34 (d, J = 0.9 Hz, 1H), 7.33 (d, J = 1.6 Hz, 1H), 7.21 (dd, J = 8.3, 1.7 Hz, 1H), 7.15 (d, J = 8.4 Hz, 1H), 4.44 (s, 1H), 3.93 – 3.83 (m, 2H), 3.33 (s, 3H), 1.76 – 1.66 (m, 2H), 1.17 (s, 6H). MS (ESI) [M - OH]+362.1. Example I-8.5-Bromo-1-(2,6-dibenzyloxy-3-pyridyl)benzimidazole (Intermediate 8)Step 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 NaHCO3 (400 mL) were added and the layers were separated. The organic layer was washed with water (400 mL), brine (300 mL), dried (Na2SO4), 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.

[0313] Step 2: Synthesis of 2,6-Dibenzyloxy-N-(4-bromo-2-nitro-phenyl)pyridin-3- amine. To a solution of 2,6-dibenzyloxypyridin-3-amine (10.0 g, 32.6 mmol) and 4-bromo-1- fluoro-2-nitro-benzene (2.8 mL, 22.9 mmol) in THF (163 mL) at 0 °C was added 1M LiHMDS in THF (68.6 mL, 68.6 mmol) dropwise over 30 min. After the addition was completed, the reaction mixture was stirred at rt for 3 h and then cooled to 0 °C. A saturated aqueous solution of NH4Cl (150 mL) and EtOAc (300 mL) were added and the layers were separated. The organic layer was washed with a saturated aqueous solution of NaHCO3(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%).1H NMR (400 MHz, CDCl3) δ 9.11 (s, 1H), 8.30 (d, J = 2.3 Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.42 – 7.26 (m, 8H), 7.26 – 7.24 (m, 2H), 7.23 (s, 1H), 6.70 (d, J = 9.1 Hz, 1H), 6.42 (d, J = 8.3 Hz, 1H), 5.35 (s, 2H), 5.33 (s, 2H); MS (ESI) [M+H]+508.2.

[0314] Step 3: Synthesis of 4-Bromo-N1-(2,6-dibenzyloxy-3-pyridyl)benzene-1,2- diamine. To a solution of 2,6-dibenzyloxy-N-(4-bromo-2-nitro-phenyl)pyridin-3-amine (8.7 g, 17 mmol) and CaCl2 (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 (Na2SO4), filtered and concentrated under reduced pressure to afford the title compound (7.1 g, 87%) as anoil, which was used without further purification. MS (ESI) [M+H]+476.2.

[0315] Step 4: Synthesis of 5-Bromo-1-(2,6-dibenzyloxy-3-pyridyl)benzimidazole. To a solution of 4-bromo-N1-(2,6-dibenzyloxy-3-pyridyl)benzene-1,2-diamine (6.1 g, 12.8 mmol) in triethyl orthoformate (19.1 mL, 115 mmol) was added formic acid (9.7 mL, 256 mmol). The reaction mixture was stirred at 100 °C for 15 min and then cooled to rt. The volatiles were evaporated under reduced 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.1H NMR (500 MHz, DMSO) δ 8.41 (s, 1H), 8.13 (s, 1H), 7.95 (d, J = 8.3 Hz, 1H), 7.93 (d, J = 1.8 Hz, 1H), 7.49 – 7.46 (m, 2H), 7.42 – 7.35 (m, 4H), 7.28 – 7.24 (m, 4H), 7.24 – 7.21 (m, 1H), 6.67 (d, J = 8.3 Hz, 1H), 5.43 (s, 2H), 5.40 (s, 2H). Example I-9.1-(1-methyl-6-(((3R,4R)-3-methylpiperidin-4-yl)amino)-1H-indazol-3- yl)dihydropyrimidine-2,4(1H,3H)-dione (Intermediate 9)

[0316] Step 1: Synthesis of 1-(1-methyl-6-nitro-indazol-3-yl) hexahydropyrimidine-2,4- dione. A mixture of 3-bromo-1-methyl-6-nitro-indazole (3.00 g, 11.7 mmol), hexahydropyrimidine-2,4-dione (1.60 g, 14.1 mmol), potassium phosphate tribasic (6.22 g, 29.3 mmol), tetramethyl tBuXPhos (281 mg, 0.58 mmol), and Pd2(dba)3(268 mg, 0.29 mmol) in tert- butanol (125 mL) was degassed with nitrogen 3 times. The reaction mixture was heated to 100 °C for 24 h with stirring and then cooled to rt. Additional Pd2(dba)3 (268 mg, 0.29 mmol) and tetramethyl tBuXPhos (281 mg, 0.58 mmol) were added. The reaction mixture was heated to 100 °C for an additional 16 h and then cooled to rt. The volatiles were evaporated under reduced pressure. Water (200 mL) was added and the resulting precipitate was collected by filtration on a Buchner funnel. The solid was then washed with water (3 x 50 mL) and dried under vacuum. The material was triturated in diethyl ether (100 mL) and collected by filtration to afford the title compound (2.64 g, 78%) as a solid, which was used in the next step without further purification. LCMS C12H11N5O4 requires 289.1, found 290.2 [M+H]+;1H NMR (500 MHz, DMSO) δ 10.67 (s, 1H), 8.70 (dd, J = 1.7, 0.7 Hz, 1H), 7.95 – 7.84 (m, 2H), 4.14 (s, 3H), 3.97 (t, J = 6.7 Hz, 2H), 2.77 (t, J = 6.7 Hz, 2H).

[0317] Step 2: Synthesis of 1-(6-amino-1-methyl-indazol-3-yl)hexahydropyrimidine-2,4- dione. A mixture of 1-(1-methyl-6-nitro-indazol-3-yl)hexahydropyrimidine-2,4-dione (2.64 g, 9.13 mmol) and 10% Pd / C (0.97 g, 0.91 mmol) in methanol (250 mL) was hydrogenated underhydrogen atmosphere (1 atm) at rt for 6.5 h. The mixture was filtered through Celite and washed with MeOH (5x 45 mL). The filtrate was concentrated under reduced pressure, the material was triturated in diethyl ether and collected by filtration to afford the title compound (1.92 g, 81%) as a solid.

[0318] Step 3: Synthesis of 1-(6-Iodo-1-methyl-indazol-3-yl)hexahydropyrimidine-2,4- dione. To a solution of 1-(6-amino-1-methyl-indazol-3-yl)hexahydropyrimidine-2,4-dione (2.1 g, 8.1 mmol) in acetic acid (21 mL) cooled to 0 °C was added sequentially a solution of H2SO4 (1.11 mL, 20.3 mmol) in water (5 mL), followed by a solution of sodium nitrite (838 mg, 12.15 mmol) in water (5 mL). The reaction mixture was stirred at 0 °C for 2 h. At this time, a solution of KI (4.0 g, 24 mmol) in water (5 mL) was added and the mixture was stirred at 0 °C for 2 h, then warmed to rt. A 50% aqueous solution of NaHSO3 (50 mL) was added to the mixture and stirred for 18 h. The resulting precipitate was collected by filtration, washed with water (3 x 10 mL) and Et2O (3 x 10 mL), then dried under vacuum to afford the title compound (1.98 g, 66%) as a solid, which was used in the next step without further purification. LCMS C12H11IN4O2 requires 370.0, found 371.3 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 10.58 (s, 1H), 8.12 (d, J = 0.6 Hz, 1H), 7.47 (d, J = 8.6 Hz, 1H), 7.39 (dd, J = 8.6, 1.3 Hz, 1H), 3.97 (s, 3H), 3.92 (t, J = 6.7 Hz, 2H), 2.75 (t, J = 6.7 Hz, 2H).

[0319] Step 4: Synthesis of 1-[1-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)indazol-3-yl]hexahydropyrimidine-2,4-dione. A mixture of 1-(6-iodo-1-methyl-indazol-3- yl)hexahydropyrimidine-2,4-dione (500 mg, 1.35 mmol), B2pin2(412 mg, 1.62 mmol), Pd(OAc)2 (30 mg, 0.14 mmol) and KOAc (398 mg, 4.05 mmol) in DMF (14 mL) was heated to 80 °C for 18 h and then cooled to rt. The mixture was filtered through celite and washed with EtOAc (5 x 15 mL). Water (50 mL) was added to the filtrate and the layers were separated. The organic layer was washed with water (5 x 25 mL), brine (25 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a gradient of 50-100% EtOAc in hexanes to afford the title compound (335 mg, 67%) as a solid. LCMS C18H23BN4O4 requires 372.2, found 371.2 [M+H]+.

[0320] Step 5: Synthesis of [3-(2,4-Dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6- yl]boronic acid. To a solution of 1-[1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)indazol-3-yl]hexahydropyrimidine-2,4-dione (403 mg, 1.09 mmol) in THF (5 mL) and water (5 mL) were added sequentially NaIO4 (698 mg, 3.27 mmol) and 1 M aqueous HCl (2.2 mL, 2.2 mmol). The reaction mixture was stirred at rt for 18 h. The volatiles were evaporated under reduced pressure and the resulting precipitate was collected by filtration, washed with water (3 x 2 mL) and Et2O (3 x 1 mL), then dried under vacuum to afford the title compound (240 mg, 76%) as a solid, which was used in the next step without further purification. LCMSC12H13BN4O4requires 288.1, found 289.1[M+H]+;1H NMR (400 MHz, DMSO-d6) δ 10.54 (s, 1H), 8.16 (s, 2H), 8.01 (s, 1H), 7.59 (d, J = 8.2 Hz, 1H), 7.52 (d, J = 8.3 Hz, 1H), 4.00 (s, 3H), 3.92 (t, J = 6.7 Hz, 2H), 2.76 (t, J = 6.6 Hz, 2H).

[0321] Step 6: Synthesis of tert-Butyl (3R,4R)-4-[[3-(2,4-dioxohexahydropyrimidin-1- yl)-1-methyl-indazol-6-yl]amino]-3-methyl-piperidine-1-carboxylate. A mixture of [3-(2,4- dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]boronic acid (200 mg, 0.69 mmol), tert- butyl (3R,4R)-4-amino-3-methyl-piperidine-1-carboxylate (228 mg, 1.04 mmol), Cu(OAc)2 (152 mg, 0.76 mmol), Et3N (190 µL, 1.39 mmol) and 3Å MS (100 mg) in DCE (12.6 mL) under O2 (1 atm) was heated to 50 °C for 18 h. The mixture was filtered through celite and washed with a 1:1 mixture of MeCN and MeOH (3 x 10 mL). The filtrate was concentrated under reduced pressure and the residue was purified by preparative HPLC (BEH column, C18) using a gradient of 10–80% MeCN and 10 mM ammonium formate in water to afford the title compound (76 mg, 24%) as a solid. LCMS C23H32N6O4requires 456.3, found 457.3, 487.2. Example I-10.1-(6-amino-1-methyl-indazol-3-yl)hexahydropyrimidine-2,4-dione (Intermediate 10)

[0322] Step 1: Synthesis of 1-(1-methyl-6-nitro-indazol-3-yl)hexahydropyrimidine-2,4- dione. A mixture of 3-bromo-1-methyl-6-nitro-indazole (3.00 g, 11.72 mmol), hexahydropyrimidine-2,4-dione (1.60 g, 14.06 mmol), potassium phosphate tribasic (6.22 g, 29.29 mmol), tetramethyl tBuXPhos (281.0 mg, 0.58 mmol ) and Pd2(dba)3(268.0 mg, 0.29 mmol) in tert-butanol (125.0 mL) was degassed with nitrogen 3 times. The reaction mixture was heated to 100 °C for 24 h and then cooled to rt. Additional Pd2(dba)3 (268.0 mg, 0.29 mmol) and tetramethyl tBuXPhos (281.0 mg, 0.58 mmol) were added. The reaction mixture was heated to 100 °C for an additional 16 h and then cooled to rt. The volatiles were evaporated under reduced pressure. Water (200.0 mL) was added and the resulting precipitate was collected by filtration (Buchner funnel), then washed with water (3 x 50.0 mL) and dried under vacuum. The material was triturated in diethyl ether (100.0 ml) and collected by filtration to afford the title compound (2.64 g, 78%) as a solid, which was used in the next step without further purification.1H NMR (500 MHz, DMSO) δ 10.67 (s, 1H), 8.70 (dd, J = 1.7, 0.7 Hz, 1H), 7.95 – 7.84 (m, 2H), 4.14 (s, 3H), 3.97 (t, J = 6.7 Hz, 2H), 2.77 (t, J = 6.7 Hz, 2H); MS (ESI) [M+H]+: 290.2.

[0323] Step 2: Synthesis of 1-(6-amino-1-methyl-indazol-3-yl)hexahydropyrimidine-2,4- dione. A mixture of 1-(1-methyl-6-nitro-indazol-3-yl)hexahydropyrimidine-2,4-dione (2.64 g,9.13 mmol) and 10% Pd / C (0.97 g, 0.91 mmol) in methanol (250.0 mL) was hydrogenated under hydrogen atmosphere (1 atm) at rt for 6.5 h. The mixture was filtered through Celite and washed with MeOH (5 x 45.0 mL). The filtrate was concentrated under reduced pressure, the material was triturated in diethyl ether and collected by filtration to afford the title compound (1.92 g, 81%) as a solid.1H NMR (400 MHz, DMSO) δ 10.45 (s, 1H), 7.27 (d, J = 8.7 Hz, 1H), 6.48 (dd, J = 8.7, 1.8 Hz, 1H), 6.39 (d, J = 1.3 Hz, 1H), 5.39 (s, 2H), 3.85 (t, J= 6.7 Hz, 2H), 3.76 (s, 3H), 2.71 (t, J= 6.7 Hz, 2H); MS (ESI) [M+H]+: 260.1. Example I-11.6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indole (Intermediate 11)

[0324] Step 1: Synthesis of 6-bromo-3-iodo-1-methyl-indole. To a solution of 6-bromo-1- 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 Na2SO3 (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 Na2SO3(100 mL), brine (100 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to afford the title compound (6.51 g, 97%) as a solid. MS (ESI) [M+H]+334.8;1H NMR (500 MHz, DMSO-d6) δ 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).

[0325] Step 2: Synthesis of 6-Bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indole. To a degassed mixture of 6-bromo-3-iodo-1-methyl-indole (168 mg, 0.500 mmol), 2,6-dibenzyloxy- 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (229 mg, 0.550 mmol), K3PO4(530 mg, 2.50 mmol), water (1.5 mL) and 1,4-dioxane (3 mL) at rt was added Pd(PPh3)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;1H NMR (500 MHz, DMSO-d6) δ 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).Final Compound Synthesis Example S1.3-(6-(4-((5-chloro-4-((3-(3-hydroxy-3-methylbutyl)-1-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-5-yl)amino)pyrimidin-2-yl)(methyl)amino)-3-methyl-2- oxopiperidin-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (Compound 1)

[0326] Step 1: Synthesis of 4-(benzyl(methyl)amino)-1-(3-(2,6-bis(benzyloxy)pyridine-3- yl)-1-methyl-1H-indazol-6-yl)-3-methylpiperidin-2-one. To a stirred solution of 4- (benzyl(methyl)amino)-1-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazol-6- yl)piperidin-2-one, isomer 1 (250 mg, 0.392 mmol) in THF (8 mL) in a 50 mL round bottom flask was added LHMDS (0.784 mL, 0.784 mmol) dropwise at -78 °C under nitrogen and stirred for 45 min. Then methyl iodide (0.049 mL, 0.784 mmol) was added, and the mixture was slowly warmed to 25 °C and stirred for 1 h. The reaction mixture was quenched with aq. Ammonium chloride solution (30 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over anhydrous sodium sulphate, filtered, concentrated under rotary evaporator to afford the crude compound. The crude was purified by flash column chromatography by using 50-70% ethyl acetate in pet-ether, the product containing fractions were collected and concentrated to afford 4-(benzyl(methyl)amino)-1-(3-(2,6-bis(benzyloxy)130midazol-3-yl)-1- methyl-1H-indazol-6-yl)-3-methylpiperidin-2-one (180 mg, 0.271 mmol, 69 % yield) as an off- white solid. MS (ES) m / z= 652.3 [M+H]+.

[0327] Step 2: Synthesis of 3-(1-methyl-6-(3-methyl-4-(methylamino)-2-oxopiperidin-1- yl)-1H-indazol-3-yl)piperidine-2,6-dione. A solution of 4-(benzyl(methyl)amino)-1-(3-(2,6- bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazol-6-yl)-3-methylpiperidin-2-one (120 mg, 0.180 mmol) in THF (2.5 mL), ethanol (2.5 mL), TFA (0.014 mL, 0.180 mmol), and Pd(OH)2(60 mg, 0.427 mmol) was stirred at 50 °C for 16 h. The reaction mixture was monitored by LCMS. The reaction mixture was cooled to room temperature, filtered on a Celite pad, washed with THF and ethanol, and concentrated under pressure to give 3-(1-methyl-6-(3-methyl-4-(methylamino)-2- oxopiperidin-1-yl)-1H-indazol-3-yl)piperidine-2,6-dione (70 mg, 0.172 mmol, 96 % yield) as a gummy liquid compound. LCMS: 383.45 (M+H)+.

[0328] Step 3: Synthesis of 3-(6-(4-((5-chloro-4-((3-(3-hydroxy-3-methylbutyl)-1- methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-yl)amino)pyrimidin-2- yl)(methyl)amino)-3-methyl-2-oxopiperidin-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6- dione. The title compound was synthesized according to General Procedure 10 using 3-(1- methyl-6-(3-methyl-4-(methylamino)-2-oxopiperidin-1-yl)-1H-indazol-3-yl)piperidine-2,6- dione, TFA (90 mg, 0.163 mmol) and 5-((5-chloro-2-fluoropyrimidin-4-yl)amino)-3-(3- hydroxy-3-methylbutyl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (61.8 mg, 0.163 mmol) to afford the title compound (13 mg, 0.017 mmol, 11 % yield) as an off-white solid. LCMS MS (ES) m / z = 743.4 [M-H]+;1H NMR (400 MHz, DMSO-d6): δ 10.59 (br s, 1H), 8.45 (s, 1H), 8.03 (s, 1H), 7.69 (d, J = 8.6 Hz, 1H), 7.44 (br s, 2H), 7.34 (dd, J = 1.8, 8.3 Hz, 1H), 7.09 (d, J = 8.4 Hz, 1H), 6.95 (br d, J = 8.6 Hz, 1H), 4.88 – 4.76 (m, 1H), 4.37 (dd, J = 5.2, 9.2 Hz, 1H), 4.15 (s, 1H), 3.99 (s, 3H), 3.94 – 3.88 (m, 2H), 3.70 – 3.62 (m, 2H), 3.31 (s, 3H), 3.02 – 3.00 (m, 4H), 2.91 – 2.85 (m, 1H), 2.72 – 2.66 (m, 2H), 2.42 – 2.37 (m, 1H), 2.29 – 2.19 (m, 2H), 2.01 – 1.94 (m, 1H), 1.80 – 1.73 (m, 2H), 1.20 – 1.18 (m, 6H), 1.09 – 1.05 (m, 3H). Example S2.1-(6-((2S,4R)-4-((5-chloro-4-((3-(3-hydroxy-3-methylbutyl)-1-methyl-2-oxo- 2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)pyrimidin-2-yl)(methyl)amino)-2- methylpiperidin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound 2)

[0329] Step 1: Synthesis of tert-Butyl N-[(2S,4R)-1,2-dimethyl-4-piperidyl]carbamate. To a solution of tert-butyl N-[(2S,4R)-2-methyl-4-piperidyl]carbamate hydrochloride (1.50 g, 5.98 mmol, 99.07% ee) in THF (46 mL) were added sequentially K2CO3 (2.48 g, 17.9 mmol) in water (13.8 mL) and benzyl chloroformate (0.94 mL, 6.58 mmol), and the reaction mixture was stirred at rt for 3 h. Water (50 mL) and EtOAc (50 mL) were added, and the layers were separated. The aqueous layer was extracted with EtOAc (3 x 50 mL), and the combined organic layer was washed with water (25 mL), brine (25 mL), dried (MgSO4), filtered and concentrated under reduced pressure to afford the title compound (2.0 g, 96%) as a solid, which was used inthe next step without further purification. MS (ESI) [M–Boc+H]+249.2.

[0330] Step 2: Synthesis of Benzyl (2S,4R)-4-[tert-butoxycarbonyl(methyl)amino]-2- methyl-piperidine-1-carboxylate. The title compound was synthesized according to General Procedure 7 using tert-butyl N-[(2S,4R)-1,2-dimethyl-4-piperidyl]carbamate (2.0 g, 5.95 mmol) to afford the title compound (2.10 g, 97%) as an oil. MS (ESI) [M–Boc+H]+264.2.

[0331] Step 3: Synthesis of tert-Butyl N-methyl-N-[(2S,4R)-2-methyl-4- piperidyl]carbamate. A mixture of benzyl (2S,4R)-4-[tert-butoxycarbonyl(methyl)amino]-2- methyl-piperidine-1-carboxylate (2.10 g, 5.79 mmol) and Pd / C (620 mg, 0.58 mmol) in MeOH (40 mL) was subjected to hydrogenation (1 atm) at rt for 1 h. The mixture was filtered on Celite and washed with a 1:1 mixture of MeOH and EtOAc (2 x 50 mL). The filtrate was concentrated under reduced pressure to afford the title compound (945 mg, 97%) as a solid, which was used in the next step without further purification. MS (ESI) [M–tBu+H]+173.2;1H NMR (400 MHz, DMSO-d6) δ 4.10 (br s, 1H), 3.32 – 3.21 (m, 1H), 2.86 – 2.68 (m, 2H), 2.64 (s, 3H), 1.66 (td, J = 12.2, 5.3 Hz, 1H), 1.49 – 1.42 (m, 2H), 1.39 (s, 9H), 1.31 (d, J = 12.4 Hz, 1H), 1.10 (d, J = 7.0 Hz, 3H).

[0332] Step 4: Synthesis of tert-Butyl N-[(2S,4R)-1-[3-(2,4-dioxohexahydropyrimidin-1- yl)-1-methyl-indazol-6-yl]-2-methyl-4-piperidyl]-N-methyl-carbamate. A mixture of [3- (2,4-dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]boronic acid (165 mg, 0.570 mmol), tert-butyl N-methyl-N-[(2S,4R)-2-methyl-4-piperidyl]carbamate (262 mg, 1.15 mmol), Cu(OAc)2(114 mg, 0.57 mmol), boric acid (70.8 mg, 1.15 mmol) and 3Å MS (100 mg) in DCE (4 mL) was placed under oxygen (1 atm) via balloon and heated to 40 °C for 18 h. The mixture was filtered on Celite, washed with a 1:1 mixture of MeCN and MeOH (3 x 25 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a gradient of 20–100% EtOAc in hexanes to afford the title compound (72.3 mg, 19%) as a solid. MS (ESI) [M+H]+471.3.

[0333] Step 5: Synthesis of 1-[1-Methyl-6-[(2S,4R)-2-methyl-4-(methylamino)-1- piperidyl]indazol-3-yl]hexahydropyrimidine-2,4-dione hydrochloride. The title compound was synthesized according to General Procedure 9 using tert-butyl N-[(2S,4R)-1-[3-(2,4- dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]-2-methyl-4-piperidyl]-N-methyl- carbamate to afford the title compound (31.1 mg, 50%) as a solid. MS (ESI) [M+H]+371.3.

[0334] Step 6.1-[6-[(2S,4R)-4-[[5-Chloro-4-[[3-(3-hydroxy-3-methyl-butyl)-1-methyl-2- oxo-benzimidazol-5-yl]amino]pyrimidin-2-yl]-methyl-amino]-2-methyl-1-piperidyl]-1- methyl-indazol-3-yl]hexahydropyrimidine-2,4-dione. The title compound was synthesized according to General Procedure 10 with 5-[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]-3-(3- hydroxy-3-methyl-butyl)-1-methyl-benzimidazol-2-one (26 mg, 70 µmol) and 1-[1-methyl-6-[(2S,4R)-2-methyl-4-(methylamino)-1-piperidyl]indazol-3-yl]hexahydropyrimidine-2,4-dione hydrochloride (31 mg, 80 µmol) as starting material, and DMF (0.7 mL) as the solvent to afford the title compound (12.3 mg, 24%) as a solid. MS (ESI) [M+H]+730.4;1H NMR (400 MHz, MeOD-d4) δ 7.93 (s, 1H), 7.49 (d, J = 9.1 Hz, 1H), 7.37 (dd, J = 8.4, 1.8 Hz, 2H), 7.11 (d, J = 8.6 Hz, 1H), 6.94 (d, J = 9.2 Hz, 1H), 6.67 (s, 1H), 4.41 (s, 1H), 4.06 – 3.98 (m, 4H), 3.94 (s, 3H), 3.51 (d, J = 14.6 Hz, 1H), 3.35 (s, 3H), 3.05 (br s, 1H), 2.96 (s, 3H), 2.86 (t, J = 6.7 Hz, 2H), 2.13 (td, J = 12.8, 5.1 Hz, 1H), 1.91 – 1.82 (m, 3H), 1.76 (d, J = 12.2 Hz, 1H), 1.58 (d, J = 10.6 Hz, 1H), 1.30 – 1.28 (m, 7H), 0.84 (s, 3H). Note: exchangeable protons not visible. Example S3.1-(6-(((3R,4R)-1-(5-chloro-4-((3-(3-hydroxy-3-methylbutyl)-1-methyl-2-oxo- 2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4- yl)amino)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound 3)

[0335] Step 1: Synthesis of tert-Butyl (3R,4R)-4-[[3-(2,4-dioxohexahydropyrimidin-1- yl)-1-methyl-indazol-6-yl]amino]-3-methyl-piperidine-1-carboxylate. A mixture of [3-(2,4- dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]boronic acid (200 mg, 0.69 mmol), tert- butyl (3R,4R)-4-amino-3-methyl-piperidine-1-carboxylate (228 mg, 1.04 mmol, 98.6% ee), Cu(OAc)2(152 mg, 0.76 mmol), Et3N (190 µL, 1.39 mmol) and 3Å MS (100 mg) in DCE (12.6 mL) under O2(1 atm) was heated to 50 °C for 18 h. The mixture was filtered on Celite and washed with a 1:1 mixture of MeCN and MeOH (3 x 10 mL). The filtrate was concentrated under reduced pressure and the residue was purified by preparative HPLC (BEH column, C18) using a gradient of 10–80% MeCN and 10 mM ammonium formate in water to afford the title compound (76 mg, 24%) as a solid. MS (ESI) [M+H]+457.3.

[0336] Step 2: Synthesis of 1-[1-Methyl-6-[[(3R,4R)-3-methyl-4- piperidyl]amino]indazol-3-yl]hexahydropyrimidine-2,4-dione hydrochloride. The title compound was synthesized according to General Procedure 9 with tert-butyl (3R,4R)-4-[[3- (2,4-dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]amino]-3-methyl-piperidine-1- carboxylate (76 mg, 0.166 mmol) to afford the title compound (45 mg, 70%) as a solid, which was used in the next step without further purification. MS (ESI) [M+H]+357.3.

[0337] Step 3.1-[6-[[(3R,4R)-1-[5-Chloro-4-[[3-(3-hydroxy-3-methyl-butyl)-1-methyl-2- oxo-benzimidazol-5-yl]amino]pyrimidin-2-yl]-3-methyl-4-piperidyl]amino]-1-methyl-indazol-3-yl]hexahydropyrimidine-2,4-dione. The title compound was synthesized according to General Procedure 10 using 5-[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]-3-(3-hydroxy-3- methyl-butyl)-1-methyl-benzimidazol-2-one (23 mg, 60 µmol) and 1-[1-methyl-6-[[(3R,4R)-3- methyl-4-piperidyl]amino]indazol-3-yl]hexahydropyrimidine-2,4-dione hydro-chloride (22 mg, 60 µmol) to afford the title (7.0 mg, 17%) as a solid. MS (ESI) [M+H]+716.5;1H NMR (400 MHz, DMSO-d6) δ 10.48 (br s, 1H), 8.73 (s, 1H), 8.03 (s, 1H), 7.41 (d, J = 1.7 Hz, 1H), 7.34 (d, J = 8.3 Hz, 1H), 7.25 (d, J = 8.8 Hz, 1H), 7.10 (d, J = 8.5 Hz, 1H), 6.49 (dd, J = 8.9, 1.6 Hz, 1H), 6.40 (s, 1H), 5.75 (d, J = 8.9 Hz, 1H), 4.49 (d, J = 11.0 Hz, 2H), 3.89 – 3.82 (m, 4H), 3.80 (s, 3H), 3.30 (s, 3H), 3.01 (t, J = 12.0 Hz, 1H), 2.77 – 2.62 (m, 3H), 2.10 – 2.01 (m, 1H), 1.73 – 1.65 (m, 2H), 1.62 – 1.50 (m, 1H), 1.25 – 1.11 (m, 8H), 0.94 (d, J = 6.5 Hz, 3H). Note: one exchangeable proton not visible. Example S4.2-((3R,4R)-4-((3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)amino)-3- methylpiperidin-1-yl)-4-((3-(3-hydroxy-3-methylbutyl)-1-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-5-yl)amino)pyrimidine-5-carbonitrile (Compound 4)

[0338] Step 1.2-Chloro-4-[[3-(3-hydroxy-3-methyl-butyl)-1-methyl-2-oxo- benzimidazol-5-yl]amino]pyrimidine-5-carbonitrile. The title compound was synthesized according to General Procedure 1 using 5-amino-3-(3-hydroxy-3-methyl-butyl)-1-methyl- benzimidazol-2-one (60 mg, 0.24 mmol) and sequentially 2,4-dichloropyrimidine-5-carbonitrile (42 mg, 0.24 mmol) and DIEA (50 µL, 0.26 mmol) to afford the title compound (101 mg, quant.) as a solid, which was used in the next step without further purification. MS (ESI) [M+H]+387.2.

[0339] Step 2.2-[(3R,4R)-4-[[3-(2,6-Dioxo-3-piperidyl)-1-methyl-indazol-6-yl]amino]-3- methyl-1-piperidyl]-4-[[3-(3-hydroxy-3-methyl-butyl)-1-methyl-2-oxo-benzimidazol-5- yl]amino]pyrimidine-5-carbonitrile. The title compound was synthesized according to General Procedure 10 using 2-chloro-4-[[3-(3-hydroxy-3-methyl-butyl)-1-methyl-2-oxo- benzimidazol-5-yl]amino]pyrimidine-5-carbonitrile (55 mg, 0.14 mmol) and 3-[1-methyl-6- [[(3R,4R)-3-methyl-4-piperidyl]amino]indazol-3-yl]piperidine-2,6-dione (50 mg, 0.14 mmol) to afford the title compound (16.2 mg, 16%) as a solid. MS (ESI) [M+H]+706.5;1H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H), 9.32 (s, 1H), 8.41 (s, 1H), 7.35 – 7.22 (m, 3H), 7.10 (d, J = 7.8Hz, 1H), 6.51 (dd, J = 8.9, 1.6 Hz, 1H), 6.42 (s, 1H), 5.68 (s, 1H), 4.77 – 4.61 (m, 1H), 4.56 – 4.35 (m, 2H), 4.17 (dd, J = 8.7, 5.2 Hz, 1H), 3.92 – 3.82 (m, 2H), 3.81 (s, 3H), 3.29 (s, 3H), 3.21 – 3.04 (m, 1H), 2.85 – 2.73 (m, 1H), 2.64 – 2.56 (m, 2H), 2.30 – 2.19 (m, 1H), 2.18 – 2.07 (m, 2H), 1.74 – 1.64 (m, 2H), 1.63 – 1.53 (m, 1H), 1.15 (s, 6H), 0.95 (d, J = 21.5 Hz, 3H). Note: one exchangeable proton not visible and one aliphatic proton obscured by water signal. Example S5.1-(6-((3R,4S)-4-((5-chloro-4-((3-(3-hydroxy-3-methylbutyl)-1-methyl-2-oxo- 2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)pyrimidin-2-yl)(methyl)amino)-3- fluoropiperidin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound 5)

[0340] Step 1: Synthesis of Benzyl (3R,4S)-4-(tert-butoxycarbonylamino)-3-fluoro- piperidine-1-carboxylate. To a solution of tert-butyl N-[(3R,4S)-3-fluoro-4- piperidyl]carbamate (800 mg, 3.67 mmol, 99.4% ee) in THF (28.2 mL) were added sequentially K2CO3(1.52 g, 11.0 mmol) in water (8.46 mL) and benzyl chloroformate (0.58 mL, 4.03 mmol). The reaction mixture was stirred at rt for 1 h. Water (50 mL) and EtOAc (50 mL) were added and the layers were separated. The aqueous layer was extracted with EtOAc (3 x 50 mL), and the combined organic layer was washed with water (25 mL), brine (25 mL), dried (MgSO4), filtered, and concentrated under reduced pressure to afford the title compound (945 mg, 97%) as a solid, which was used in the next step without further purification. MS (ESI) [M+H–Boc]+253.4;1H NMR (400 MHz, DMSO-d6) δ 7.42 – 7.23 (m, 5H), 7.03 (d, J = 7.7 Hz, 1H), 5.16 – 4.98 (m, 2H), 4.68 (d, J = 50.1 Hz, 1H), 4.22 (t, J = 13.0 Hz, 1H), 4.07 – 3.92 (m, 1H), 3.77 – 3.47 (m, 1H), 3.26 – 2.81 (m, 2H), 1.70 – 1.47 (m, 2H), 1.39 (s, 9H).

[0341] Step 2: Synthesis of Benzyl (3R,4S)-4-[tert-butoxycarbonyl(methyl)amino]-3- fluoro-piperidine-1-carboxylate. To a solution of benzyl (3R,4S)-4-(tert- butoxycarbonylamino)-3-fluoro-piperidine-1-carboxylate (945 mg, 3.56 mmol) in DMF (20 mL) cooled to 0 °C was added 60% NaH dispersion in mineral oil (367 mg, 9.16 mmol), and the mixture was stirred at 0 °C for 15 min. MeI (0.57 mL, 9.16 mmol) was added and the mixturewas stirred at rt for 2 h. Water (100 mL) and EtOAc (100 mL) were added and the layers were separated. The aqueous layer was extracted with EtOAc (3 x 100 mL), and the combined organic layer was washed with water (3 x 100 mL), brine (100 mL), dried (MgSO4), filtered and concentrated under reduced pressure. The material was purified by column chromatography on silica gel using a gradient of 0–50% EtOAc in hexanes to afford the title compound (1.07 g, 80%) as an oil. MS (ESI) [M+H–Boc]+267.2.

[0342] Step 3: Synthesis of tert-Butyl N-[(3R,4S)-3-fluoro-4-piperidyl]-N-methyl- carbamate. A mixture of benzyl (3R,4S)-4-[tert-butoxycarbonyl(methyl)amino]-3-fluoro- piperidine-1-carboxylate (1.07 g, 2.92 mmol) and Pd / C (622 mg, 0.58 mmol) in MeOH (19.5 mL) was subjected to hydrogenation (1 atm) at rt °C for 1 h. The mixture was filtered on Celite and washed with a 1:1 mixture of MeOH and EtOAc (150 mL). The filtrate was concentrated under reduced pressure to afford the title compound (671 mg, 99%) as an oil, which was used in the next step without further purification. MS (ESI) [M+H–tBu]+177.1;1H NMR (400 MHz, DMSO-d6) δ 4.60 (d, J = 51.4 Hz, 1H), 3.95 (br s, 1H), 3.31 (s, 1H), 3.14 – 2.93 (m, 2H), 2.77 (d, J = 1.5 Hz, 3H), 2.75 – 2.51 (m, 2H), 2.05 (br s, 1H), 1.86 (qd, J = 12.4, 4.2 Hz, 1H), 1.40 (s, 9H).

[0343] Step 4: Synthesis of tert-Butyl N-[(3R,4S)-1-[3-(2,4-dioxohexahydropyrimidin-1- yl)-1-methyl-indazol-6-yl]-3-fluoro-4-piperidyl]-N-methyl-carbamate. A mixture of [3-(2,4- dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]boronic acid (400 mg, 1.39 mmol), tert- butyl N-[(3R,4S)-3-fluoro-4-piperidyl]-N-methyl-carbamate (452 mg, 1.94 mmol), Cu(OAc)2(305 mg, 1.53 mmol), Et3N (0.58 mL, 4.17 mmol) and 3Å MS (250 mg) in DCE (28 mL) was placed under oxygen (1 atm) via balloon and heated to 50 °C for 18 h. The mixture was filtered on Celite and washed with a 1:1 mixture of MeCN and MeOH (3 x 25 mL). The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel using a gradient of 20–100% EtOAc in hexanes to afford the title compound (199 mg, 30%) as a solid. MS (ESI) [M+H]+475.3;1H NMR (400 MHz, DMSO-d6) δ 10.50 (s, 1H), 7.45 (d, J = 9.1 Hz, 1H), 6.90 (d, J = 9.2 Hz, 1H), 6.86 (s, 1H), 4.89 (d, J = 50.5 Hz, 1H), 4.00 – 3.95 (m, 1H), 3.92 – 3.85 (m, 5H), 3.15 – 2.87 (m, 2H), 2.81 (d, J = 1.3 Hz, 3H), 2.73 (t, J = 6.7 Hz, 3H), 2.38 – 2.13 (m, 1H), 1.47 – 1.39 (m, 11H).

[0344] Step 5: Synthesis of 1-[6-[(3R,4S)-3-Fluoro-4-(methylamino)-1-piperidyl]-1- methyl-indazol-3-yl]hexahydropyrimidine-2,4-dione hydrochloride. The title compound was synthesized according to General Procedure 9 with tert-butyl N-[(3R,4S)-1-[3-(2,4- dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]-3-fluoro-4-piperidyl]-N-methyl- carbamate (199 mg, 0.42 mmol) to afford the title compound (170 mg, quant.) as a solid, which was used in the next step without further purification. MS (ESI) [M+H]+375.3.

[0345] Step 6: Synthesis of 1-[6-[(3R,4S)-4-[[5-Chloro-4-[[3-(3-hydroxy-3-methyl- butyl)-1-methyl-2-oxo-benzimidazol-5-yl]amino]pyrimidin-2-yl]-methyl-amino]-3-fluoro-1- piperidyl]-1-methyl-indazol-3-yl]hexahydropyrimidine-2,4-dione. The title compound was synthesized according to General Procedure 10 using 5-[(5-chloro-2-fluoro-pyrimidin-4- yl)amino]-3-(3-hydroxy-3-methyl-butyl)-1-methyl-benzimidazol-2-one (45 mg, 0.12 mmol) and 1-[6-[(3R,4S)-3-fluoro-4-(methylamino)-1-piperidyl]-1-methyl-indazol-3- yl]hexahydropyrimidine-2,4-dione hydrochloride (58 mg, 0.14 mmol) to afford the title compound (27.9 mg, 32%) as a solid. MS (ESI) [M+H]+734.5;1H NMR (500 MHz, MeOD-d4) δ 7.96 (s, 1H), 7.52 (d, J = 9.0 Hz, 1H), 7.49 – 7.22 (m, 2H), 7.12 (d, J = 8.5 Hz, 1H), 6.94 (d, J = 9.1 Hz, 1H), 6.75 (s, 1H), 4.85 (d, J = 50.0 Hz, 1H), 4.58 (br s, 1H), 4.06 – 3.97 (m, 6H), 3.96 (s, 3H), 3.33 (s, 3H), 3.11 (d, J = 1.0 Hz, 3H), 2.86 (t, J = 6.7 Hz, 3H), 2.48 (q, J = 12.6 Hz, 1H), 1.85 (dd, J = 8.4, 4.1 Hz, 2H), 1.74 (d, J = 9.7 Hz, 1H), 1.29 (s, 1H), 1.27 (s, 6H). Example S6.2-((3R,4R)-4-((3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H- indazol-6-yl)amino)-3-methylpiperidin-1-yl)-4-((3-(3-hydroxy-3-methylbutyl)-1-methyl-2- oxo-2,3-dihydro-1H-benzo[d]imidazole-5-yl)amino)pyrimidine-5-carbonitrile (Compound 6)

[0346] The title compound was synthesized according to General Procedure 10 using 2- chloro-4-[[3-(3-hydroxy-3-methyl-butyl)-1-methyl-2-oxo-benzimidazol-5-yl]amino]pyrimidine- 5-carbonitrile (55 mg, 0.14 mmol) and 3-[1-methyl-6-[[(3R,4R)-3-methyl-4- piperidyl]amino]indazol-3-yl]piperidine-2,6-dione (50 mg, 0.14 mmol) to give the title compound (16.2 mg, 16%) as a solid. MS (ESI) [M+H]+706.5;1H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H), 9.32 (s, 1H), 8.41 (s, 1H), 7.35 – 7.22 (m, 3H), 7.10 (d, J = 7.8 Hz, 1H), 6.51 (dd, J = 8.9, 1.6 Hz, 1H), 6.42 (s, 1H), 5.68 (s, 1H), 4.77 – 4.61 (m, 1H), 4.56 – 4.35 (m, 2H), 4.17 (dd, J = 8.7, 5.2 Hz, 1H), 3.92 – 3.82 (m, 2H), 3.81 (s, 3H), 3.29 (s, 3H), 3.21 – 3.04 (m, 1H), 2.85 – 2.73 (m, 1H), 2.64 – 2.56 (m, 2H), 2.30 – 2.19 (m, 1H), 2.18 – 2.07 (m, 2H), 1.74 – 1.64 (m, 2H), 1.63 – 1.53 (m, 1H), 1.15 (s, 6H), 0.95 (d, J = 21.5 Hz, 3H). Note: one exchangeable proton not visible and one aliphatic proton obscured by water signal. Example S7.3-(6-(4-((5-chloro-4-((3-(3-hydroxy-3-methylbutyl)-1-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-5-yl)amino)pyrimidin-2-yl)(methyl)amino)piperidin-1-yl)-1-methyl-1H-pyrazolo[4,3-c]pyridin-3-yl)piperidine-2,6-dione (Compound 7)

[0347] Step 1: Synthesis of 6-Bromo-3-iodo-1H-pyrazolo[4,3-c]pyridine. To a solution of 6-bromo-1H-pyrazolo[4,3-c]pyridine (3.5 g, 17.7 mmol) in MeCN (177 mL) was added NIS (7.95 g, 35.4 mmol). The reaction mixture was heated to 85 °C for 18 h and then cooled to rt. Water (50 mL) was added and the resulting precipitate was collected by filtration, washed with water (50 mL), DCM (50 mL), and dried under vacuum to afford the title compound (6.21 g, quant.) as a solid. MS (ESI) [M+H]+325.8;1H NMR (400 MHz, DMSO-d6) δ 8.44 (s, 1H), 7.57 (s, 1H).

[0348] Step 2: Synthesis of 6-Bromo-3-iodo-1-methyl-pyrazolo[4,3-c]pyridine. The title compound was synthesized according to General Procedure 7 using 6-bromo-3-iodo-1H- pyrazolo[4,3-c]pyridine (100 mg, 0.31 mmol) to afford the title compound (46 mg, 44%) as a solid.1H NMR (400 MHz, DMSO-d6) δ 8.58 (d, J = 1.0 Hz, 1H), 8.09 (d, J = 1.0 Hz, 1H), 4.05 (s, 3H).

[0349] Step 3: Synthesis of 6-Bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl- pyrazolo[4,3-c]pyridine. A mixture of 6-bromo-3-iodo-1-methyl-pyrazolo[4,3-c]pyridine (100 mg, 0.30 mmol), (2,6-dibenzyloxy-3-pyridyl)boronic acid (595 mg, 0.89 mmol), Pd(PPh3)2Cl2 (41.5 mg, 60 µmol) and a 2 M aqueous solution of Na2CO3 (300 µL, 0.59 mmol) in 1,4-dioxane (1.5 mL) was heated to 80 °C for 16 h and then cooled to rt. Water (40 mL) and EtOAc (40 mL) were added and the layers were separated. The aqueous layer was extracted with EtOAc (2 x 20 mL). The combined organic fractions were washed with brine (40 mL), dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a gradient of 0–15% EtOAc in hexanes to afford the title compound (99.0 mg, 67%) as a solid.1H NMR (400 MHz, DMSO-d6) δ 8.87 (d, J = 1.0 Hz, 1H), 8.09 – 7.96 (m, 2H), 7.49 – 7.44 (m, 2H), 7.43 – 7.39 (m, 2H), 7.38 – 7.33 (m, 3H), 7.33 – 7.24 (m, 3H), 6.63 (d, J = 8.2 Hz, 1H), 5.52 (s, 2H), 5.44 (s, 2H), 4.06 (s, 3H).

[0350] Step 4: Synthesis of tert-Butyl N-[1-[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl- pyrazolo[4,3-c]pyridin-6-yl]-4-piperidyl]-N-methyl-carbamate. The title compound wassynthesized according to General Procedure 6 using 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1- methyl-pyrazolo[4,3-c]pyridine (1.44 g, 2.87 mmol) and tert-butyl N-methyl-N-(4- piperidyl)carbamate (677 mg, 3.16 mmol) to afford the title compound (1.08 g, 59%) as a solid.1H NMR (400 MHz, DMSO-d6) δ 8.71 (d, J = 1.0 Hz, 1H), 7.97 (d, J = 8.1 Hz, 1H), 7.51 – 7.43 (m, 2H), 7.43 – 7.33 (m, 5H), 7.33 – 7.23 (m, 3H), 6.72 (d, J = 1.1 Hz, 1H), 6.58 (d, J = 8.1 Hz, 1H), 5.51 (s, 2H), 5.40 (s, 2H), 4.47 (d, J = 12.6 Hz, 2H), 3.93 (s, 3H), 2.82 (t, J = 12.5 Hz, 2H), 2.72 – 2.66 (m, 1H), 2.64 (s, 3H), 1.80 – 1.52 (m, 4H), 1.40 (s, 9H).

[0351] Step 5: Synthesis of tert-Butyl N-[1-[3-(2,6-dioxo-3-piperidyl)-1-methyl- pyrazolo[4,3-c]pyridin-6-yl]-4-piperidyl]-N-methyl-carbamate. The title compound was synthesized according to General Procedure 8 using tert-butyl N-[1-[3-(2,6-dibenzyloxy-3- pyridyl)-1-methyl-pyrazolo[4,3-c]pyridin-6-yl]-4-piperidyl]-N-methyl-carbamate (1.59 g, 1.88 mmol) and Pd(OH)2 / C (200 mg, 0.38 mmol) as the palladium catalyst to afford the title compound (927 mg, quant.) as a solid. MS (ESI) [M+H]+457.4.

[0352] Step 6: Synthesis of 3-[1-Methyl-6-[4-(methylamino)-1-piperidyl]pyrazolo[4,3- c]pyridin-3-yl]piperidine-2,6-dione hydrochloride. The title compound was synthesized according to General Procedure 9 using tert-butyl N-[1-[3-(2,6-dioxo-3-piperidyl)-1-methyl- pyrazolo[4,3-c]pyridin-6-yl]-4-piperidyl]-N-methyl-carbamate (927 mg, 2.03 mmol), which afforded title compound (688 mg, 86%) as a solid, which was used in the next step without further purification. MS (ESI) [M+H]+357.3;1H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 9.06 (s, 2H), 8.91 (s, 1H), 7.17 (s, 1H), 4.51 (dd, J = 10.9, 4.9 Hz, 1H), 4.33 (d, J = 13.3 Hz, 2H), 3.97 (s, 3H), 3.36 – 3.17 (m, 1H), 3.07 (t, J = 12.6 Hz, 2H), 2.77 – 2.60 (m, 2H), 2.56 (t, J = 5.4 Hz, 3H), 2.48 – 2.38 (m, 1H), 2.25 – 2.15 (m, 1H), 2.14 (d, J = 13.4 Hz, 2H), 1.75 – 1.57 (m, 2H).

[0353] Step 7: Synthesis of 3-[6-[4-[[5-Chloro-4-[[3-(3-hydroxy-3-methyl-butyl)-1- methyl-2-oxo-benzimidazol-5-yl]amino]pyrimidin-2-yl]-methyl-amino]-1-piperidyl]-1- methyl-pyrazolo[4,3-c]pyridin-3-yl]piperidine-2,6-dione. The title compound was synthesized according to General Procedure 10 using 3-[1-methyl-6-[4-(methylamino)-1- piperidyl]pyrazolo[4,3-c]pyridin-3-yl]piperidine-2,6-dione hydrochloride (29.6 mg, 80 µmol) and 5-[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]-3-(3-hydroxy-3-methyl-butyl)-1-methyl- benzimidazol-2-one (26 mg, 70 µmol) reacting at 100 °C to give the title compound (19.9 mg, 40%) as a solid. MS (ESI) [M+H]+716.4;1H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 8.81 – 8.53 (m, 2H), 8.03 (s, 1H), 7.40 (s, 2H), 7.10 (d, J = 8.5 Hz, 1H), 6.71 (s, 1H), 4.50 (d, J = 12.8 Hz, 2H), 4.43 (s, 1H), 4.33 (dd, J = 10.0, 4.9 Hz, 1H), 3.86 (s, 4H), 3.28 (s, 4H), 2.86 (s, 3H), 2.65 – 2.56 (m, 3H), 2.42 – 2.33 (m, 2H), 2.22 – 2.13 (m, 1H), 1.79 – 1.50 (m, 6H), 1.32 – 1.01 (m, 6H). Note: one exchangeable proton not visible.Example S8.3-(6-(4-((5-chloro-4-((3-(3-hydroxy-3-methylbutyl)-1-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-5-yl)amino)pyrimidin-2-yl)(methyl)amino)piperidin-1-yl)-1- methyl-1H-pyrazolo[4,3-b]pyridin-3-yl)piperidine-2,6-dione (Compound 8)

[0354] Step 1.6-Bromo-3-iodo-1-methyl-pyrazolo[4,3-b]pyridine. To a solution of 6- bromo-1H-pyrazolo[4,3-b]pyridine (3.75 g, 18.9 mmol) in MeCN (90 mL) was added NIS (5.11 g, 22.7 mmol). The reaction mixture was heated to 85 °C for 18 h and then cooled to rt. The volatiles were evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using a gradient of 0–15% EtOAc in hexanes to afford the title compound (6.05 g, 98%) as a solid. MS (ESI) [M+H]+324.0.

[0355] Step 2.6-Bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-pyrazolo[4,3- b]pyridine. The title compound was synthesized according to General Procedure 7 with 6- bromo-3-iodo-1H-pyrazolo[4,3-b]pyridine (3.5 g, 10.8 mmol) and 0-30% EtOAc in hexanes gradient for flash column purification to give the title compound (2.10 g, 58%) as a solid. MS (ESI) [M+H]+338.0.

[0356] Step 3.6-Bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-pyrazolo[4,3- b]pyridine. A mixture of 6-bromo-3-iodo-1-methyl-pyrazolo[4,3-b]pyridine (900 mg, 2.66 mmol), (2,6-dibenzyloxy-3-pyridyl)boronic acid (5.36 g, 7.99 mmol), Pd(PPh3)2Cl2(374 mg, 0.53 mmol) and a 2 M aqueous solution of Na2CO3 (2.66 mL, 5.33 mmol) in 1,4-dioxane (18 mL) was heated to 80 °C for 16 h and then cooled to rt. The volatiles were evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using a gradient of 0–20% EtOAc in hexanes to afford the title compound (835 mg, 62%) as a solid. MS (ESI) [M+H]+502.2.

[0357] Step 4. Tert-Butyl N-[1-[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-pyrazolo[4,3- b]pyridin-6-yl]-4-piperidyl]-N-methyl-carbamate. The title compound was synthesized according to General Procedure 6 using 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl- pyrazolo[4,3-b]pyridine (100 mg, 0.20 mmol), tert-butyl N-methyl-N-(4-piperidyl)carbamate (51.3 mg, 0.24 mmol), Xphos-Pd-G3 (33.8 mg, 40 µmol) as the catalyst, NaOtBu (28.8 mg, 0.30mmol) as the base and toluene (1.5 mL) as the solvent at 80 °C to give the title compound (70 mg, 55%) as a solid. MS (ESI) [M+H]+635.0.

[0358] Step 5. Tert-Butyl N-[1-[3-(2,6-dioxo-3-piperidyl )-1-methyl-pyrazolo[4,3- b]pyridin-6-yl]-4- piperidyl]-N-methyl-carbamate. The title compound was synthesized according to General Procedure 8 with tert-butyl N-[1-[3-(2,6-dibenzyloxy-3-pyridyl)-1- methyl-pyrazolo[4,3-b]141yridine-6-yl]-4-piperidyl]-N-methyl-carbamate (144 mg, 0.23 mmol) at rt to give the title compound (120 mg, 93%). MS (ESI) [M+H]+457.1.

[0359] Step 6.3-[1-Methyl-6-[4-(methylamino)-1-piperidyl]pyrazolo[4,3-b]141yridine- 3-yl]piperidine-2,6-dione. The title compound was synthesized according to general procedure 9 with tert-butyl N-[1-[3-(2,6-dioxo-3-piperidyl)-1-methyl-pyrazolo[4,3- b]141yridine-6-yl]-4-piperidyl]-N-methyl-carbamate to afford the title compound (12 mg, 4%) as a solid, which was used in the next step without purification as the HCl salt. MS (ESI) [M+H]+357.2;1H NMR (500 MHz, DMSO-d6) δ 10.86 (s, 1H), 8.38 (d, J = 2.4 Hz, 1H), 8.33 (s, 1H), 7.35 (d, J = 2.4 Hz, 1H), 4.27 (dd, J = 9.8, 5.2 Hz, 1H), 3.93 (s, 3H), 3.84 (d, J = 12.8 Hz, 1H), 2.92 – 2.78 (m, 4H), 2.73 – 2.64 (m, 1H), 2.58 – 2.54 (m, 1H), 2.43 – 2.42 (m, 4H), 2.18 – 2.11 (m, 1H), 2.03 – 1.98 (m, 2H), 1.57 – 1.49 (m, 2H).

[0360] Step 7.3-[6-[4-[[5-Chloro-4-[[3-(3-hydroxy-3-methyl-butyl)-1-methyl-2-oxo- benzimidazol-5-yl]amino]pyrimidin-2-yl]-methyl-amino]-1-piperidyl]-1-methyl- pyrazolo[4,3-b]141yridine-3-yl]piperidine-2,6-dione. The title compound was synthesized according to general procedure 10 with 3-[1-methyl-6-[4-(methylamino)-1- piperidyl]pyrazolo[4,3-b]141yridine-3-yl]piperidine-2,6-dione;hydrochloride (28 mg, 70 µmol) and 5-[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]-3-(3-hydroxy-3-methyl-butyl)-1-methyl- benzimidazol-2-one (27.1 mg, 70 µmol) at 100 °C and purified by preparative HPLC (BEH column, C18) using a gradient of 41–51% MeCN and 10 mM ammonium formate in water to give the title compound (18.2 mg, 35%) as a solid. MS (ESI) [M+H]+716.3;1H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 8.67 (s, 1H), 8.40 (s, 1H), 8.03 (s, 1H), 7.44 – 7.37 (m, 1H), 7.34 (s, 1H), 7.11 (d, J = 8.3 Hz, 1H), 4.45 (s, 1H), 4.27 (dd, J = 10.0 Hz, 1H), 3.98 – 3.84 (m, 7H), 3.29 (s, 3H), 2.92 (s, 3H), 2.23 – 2.05 (m, 2H), 1.94 – 1.82 (m, 2H), 1.73 – 1.66 (m, 4H), 1.16 (s, 6H). Example S9.3-(6-(4-((5-chloro-4-((3-(3-hydroxy-3-methylbutyl)-1-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-5-yl)amino)pyrimidin-2-yl)(methyl)amino)piperidin-1-yl)-1- methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)piperidine-2,6-dione (Compound 9)

[0361] Step 1: Synthesis of 6-Bromo-1H-pyrazolo[3,4-b]pyridine. To a solution of 6- bromo-2-fluoro-pyridine-3-carbaldehyde (3.00 g, 14.7 mmol) in DMSO (30 mL) were added sequentially hydrazine monohydrate (5.63 mL, 73.5 mmol), AcOH (2.5 mL, 44 mmol) and Et3N (4 mL, 29.4 mmol), and the reaction mixture was stirred at 40 °C for 16 h. The volatiles were evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using a gradient of 0–60% EtOAc in hexanes to afford the title compound (1.78 g, 61%) as an oil.1H NMR (500 MHz, DMSO-d6) δ 13.84 (s, 1H), 8.20 (d, J = 8.3 Hz, 2H), 7.37 (d, J = 8.3 Hz, 1H).

[0362] Step 2: Synthesis of 6-Bromo-3-iodo-1H-pyrazolo[3,4-b]pyridine. To a solution of 6-bromo-1H-pyrazolo[3,4-b]pyridine (2.45 g, 12.4 mmol) in MeCN (72 mL) was added NIS (5.57 g, 24.7 mmol). The reaction mixture was heated to 85 °C for 18 h and then cooled to rt. The volatiles were evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using a gradient of 0–35% EtOAc in hexanes to afford the title compound (3.76 g, 94%) as a solid.1H NMR (400 MHz, DMSO-d6) δ 7.89 (dd, J = 8.4, 0.7 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H). Note: NH signal was not visible.

[0363] Step 3: Synthesis of 6-Bromo-3-iodo-1-methyl-pyrazolo[3,4-b]pyridine. The title compound was synthesized according to general procedure 7 using 6-bromo-3-iodo-1H- pyrazolo[3,4-b]pyridine (1.5 g, 4.63 mmol) to afford the title compound (845 mg, 54%) as a solid. MS (ESI) [M+H]+338.0.

[0364] Step 4: Synthesis of 6-Bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl- pyrazolo[3,4-b]pyridine. A mixture of 6-bromo-3-iodo-1-methyl-pyrazolo[3,4-b]pyridine (2.39 g, 7.06 mmol), 2,6-dibenzyloxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (7.36 g, 10.6 mmol), Pd(PPh3)2Cl2 (248 mg, 0.35 mmol) and a 2 M aqueous solution of Na2CO3 (7.06 mL, 14.1 mmol) in 1,4-dioxane (37 mL) was heated to 80 °C for 16 h and then cooled to rt. The volatiles were evaporated under reduced pressure. Water (100 mL) and DCM (100 mL) were added, and the layers were separated. The organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography onsilica gel using a gradient of 0–10% EtOAc in hexanes to afford the title compound (1.71 g, 41%) as a solid.1H NMR (500 MHz, DMSO-d6) δ 8.14 (d, J = 8.4 Hz, 1H), 8.02 (d, J = 8.2 Hz, 1H), 7.50 – 7.44 (m, 2H), 7.43 – 7.29 (m, 8H), 7.22 (d, J = 8.4 Hz, 1H), 6.62 (d, J = 8.1 Hz, 1H), 5.48 (s, 2H), 5.44 (s, 2H), 4.04 (s, 3H).

[0365] Step 5: Synthesis of tert-Butyl N-[1-[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl- pyrazolo[3,4-b]pyridin-6-yl]-4-piperidyl]-N-methyl-carbamate. The title compound was synthesized according to General Procedure 6 using 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1- methyl-pyrazolo[3,4-b]pyridine (1.99 g, 3.37 mmol) and tert-butyl N-methyl-N-(4- piperidyl)carbamate (795 mg, 3.71 mmol) as starting materials and Cs2CO3(1.65 g, 5.06 mmol) as base to afford the title compound (997 mg, 47%) as a solid.1H NMR (500 MHz, DMSO-d6) δ 7.97 (d, J = 8.1 Hz, 1H), 7.86 (d, J = 9.1 Hz, 1H), 7.50 – 7.43 (m, 2H), 7.43 – 7.36 (m, 4H), 7.36 – 7.23 (m, 4H), 6.67 (d, J = 9.2 Hz, 1H), 6.57 (d, J = 8.1 Hz, 1H), 5.48 (s, 2H), 5.41 (s, 2H), 4.56 (d, J = 12.6 Hz, 2H), 3.88 (s, 3H), 2.97 – 2.82 (m, 2H), 2.64 (s, 3H), 1.63 (s, 4H), 1.40 (s, 9H). Note: one signal obscured by solvent signal.

[0366] Step 6: Synthesis of tert-Butyl N-[1-[3-(2,6-dioxo-3-piperidyl)-1-methyl- pyrazolo[3,4-b]pyridin-6-yl]-4-piperidyl]-N-methyl-carbamate. The title compound was synthesized according to General Procedure 8 using tert-butyl N-[1-[3-(2,6-dibenzyloxy-3- pyridyl)-1-methyl-pyrazolo[3,4-b]143midazol-6-yl]-4-piperidyl]-N-methyl-carbamate (245 mg, 0.39 mmol) as starting material to afford the title compound (128 mg, 73%) as an oil.1H NMR (500 MHz, DMSO-d6) δ 10.85 (s, 1H), 7.83 (d, J = 9.0 Hz, 1H), 6.80 (d, J = 9.2 Hz, 1H), 4.58 (d, J = 13.3 Hz, 2H), 4.19 (dd, J = 9.5, 5.1 Hz, 1H), 3.81 (s, 3H), 3.02 – 2.77 (m, 2H), 2.69 – 2.57 (m, 5H), 2.34 – 2.26 (m, 1H), 2.20 – 2.10 (m, 1H), 1.63 (br s, 5H), 1.40 (s, 9H).

[0367] Step 7: Synthesis of 3-[1-Methyl-6-[4-(methylamino)-1-piperidyl]pyrazolo[3,4- b]pyridin-3-yl]piperidine-2,6-dione. The title compound was synthesized according to General Procedure 9 using tert-butyl N-[1-[3-(2,6-dioxo-3-piperidyl)-1-methyl-pyrazolo[3,4- b]pyridin-6-yl]-4-piperidyl]-N-methyl-carbamate (128 mg, 0.28 mmol) to afford the title compound as a solid.1H NMR (500 MHz, DMSO-d6) δ 7.83 (d, J = 9.0 Hz, 1H), 6.79 (d, J = 9.1 Hz, 1H), 4.41 (d, J = 12.5 Hz, 2H), 4.20 (dd, J = 9.6, 5.1 Hz, 1H), 3.81 (s, 3H), 3.36 (br s, 1H), 3.01 (t, J = 11.9 Hz, 2H), 2.71 – 2.55 (m, 2H), 2.35 – 2.26 (m, 1H), 2.20 – 2.06 (m, 1H), 1.95 (br s, 1H), 1.32 (d, J = 10.4 Hz, 1H). Note: glutarimide and NH signals not visible; the methyl signal peak and two hydrogens obscured by solvent.

[0368] Step 8: Synthesis of 3-[6-[4-[[5-Chloro-4-[[3-(3-hydroxy-3-methyl-butyl)-1- methyl-2-oxo-benzimidazol-5-yl]amino]pyrimidin-2-yl]-methyl-amino]-1-piperidyl]-1- methyl-pyrazolo[3,4-b]pyridin-3-yl]piperidine-2,6-dione. The title compound was synthesized according to General Procedure 10 using 3-[1-methyl-6-[4-(methylamino)-1-piperidyl]pyrazolo[3,4-b]pyridin-3-yl]piperidine-2,6-dione hydrochloride (32 mg, 80 µmol) and 5-[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]-3-(3-hydroxy-3-methyl-butyl)-1-methyl- benzimidazol-2-one (31 mg, 80 µmol) at 100 °C for 18 h to afford the title compound after purification (24.7 mg, 42%) as a solid. MS (ESI) [M+H]+716.3;1H NMR (500 MHz, DMSO- d6) δ 10.85 (s, 1H), 8.64 (s, 1H), 8.03 (s, 1H), 7.83 (d, J = 9.0 Hz, 1H), 7.39 (br s, 2H), 7.10 (d, J = 8.2 Hz, 1H), 6.80 (d, J = 9.2 Hz, 1H), 4.61 (d, J = 12.0 Hz, 2H), 4.43 (s, 1H), 4.20 (dd, J = 9.7, 4.9 Hz, 1H), 3.85 (d, J = 8.2 Hz, 2H), 3.81 (s, 3H), 3.28 – 3.22 (m, 5H), 2.86 (s, 3H), 2.61 (m, J = 12.3, 7.6 Hz, 2H), 2.32 (d, J = 8.6 Hz, 1H), 2.20 – 2.09 (m, 1H), 1.70 (m, J = 16.8 Hz, 6H), 1.16 (s, 6H). Note: one signal not visible. Example S10.1-(5-chloro-4-((1-(3-hydroxy-3-methylbutyl)-3-methyl-2-oxo-2,3-dihydro- 1H-benzo[d]imidazol-5-yl)amino)pyrimidin-2-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl- 1H-indazol-6-yl)piperidine-4-carboxamide (Compound 10)

[0369] Step 1: Synthesis of 1-(5-chloro-4-((3-(3-hydroxy-3-methylbutyl)-1-methyl-2- oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)pyrimidin-2-yl)piperidine-4-carboxylic acid. To a solution of 5-[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]-3-(3-hydroxy-3-methyl- butyl)-1-methyl-benzimidazol-2-one (760.0 mg, 2.0 mmol) in DMF (16.0 mL) were sequentially added piperidine-4-carboxylic acid (258.0 mg, 2.0 mmol) and DIEA (719.0 µL, 4.2 mmol) at rt. The reaction vessel was sealed. The reaction mixture was heated to 110 °C for 2 h and then cooled to rt. The mixture was directly purified by reverse phase chromatography (C18) using a gradient of 5-100% acetonitrile and water (ammonium formate buffer pH 4) to afford the title compound (570.0 mg, 58%) as a solid.1H NMR (500 MHz, DMSO) δ 8.66 (s, 1H), 8.00 (s, 1H), 7.42 (d, J = 1.7 Hz, 1H), 7.28 (dd, J = 8.4, 1.8 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 4.39 – 4.28 (m, 2H), 3.90 – 3.82 (m, 2H), 3.31 (s, 3H), 2.95 (t, J = 11.1 Hz, 2H), 2.46 – 2.37 (m, 1H), 1.85 – 1.75 (m, 2H), 1.75 – 1.66 (m, 2H), 1.50 – 1.37 (m, 2H), 1.16 (s, 6H). Note: 2 exchangeable protons could not be seen. MS (ESI) [M+H]+489.2.

[0370] Step 2: Synthesis of 1-[5-chloro-4-[[1-(3-hydroxy-3-methyl-butyl)-3-methyl-2- oxo-benzimidazol-5-yl]amino]pyrimidin-2-yl]-N-[3-(2,6-dioxo-3-piperidyl)-1-methyl- indazol-6-yl]piperidine-4-carboxamide. A solution of 3-(6-amino-1-methyl-indazol-3-yl)piperidine-2,6-dione;hydrochloride (21.7 mg, 0.070 mmol), 1-[5-chloro-4-[[1-(3-hydroxy-3- methyl-butyl)-3-methyl-2-oxo-benzimidazol-5-yl]amino]pyrimidin-2-yl]piperidine-4-carboxylic acid (30.0 mg, 0.060 mmol), and N,N-diisopropylethylamine (0.04 mL, 0.2500 mmol) in DMF (1 mL) was treated with HATU (25.7 mg, 0.070 mmol) and stirred at ambient temperature overnight. The crude reaction mixture was purified by preparative HPLC (C18) using a gradient of 5-95% 0.1% TFA in MeCN in water to afford the title compound 1-[5-chloro-4-[[1-(3- hydroxy-3-methyl-butyl)-3-methyl-2-oxo-benzimidazol-5-yl]amino]pyrimidin-2-yl]-N-[3-(2,6- dioxo-3-piperidyl)-1-methyl-indazol-6-yl]piperidine-4-carboxamide (24 mg, 0.0314 mmol, 51.175% yield). MS (ESI) [M+H]+729.4;1H NMR (500 MHz, DMSO-d6 ) δ ppm 10.14 (s, 1 H), 8.85 – 9.03 (m, 1 H), 8.09 (s, 2 H), 7.60 – 7.68 (m, 2 H), 7.27 (dd, J=8.20, 1.89 Hz, 1 H), 7.09 – 7.14 (m, 2 H), 4.55 (br dd, J=11.51, 3.31 Hz, 2 H), 4.32 (dd, J=9.46, 5.04 Hz, 1 H), 3.91 (s, 3 H), 3.88 – 3.90 (m, 2 H), 3.30 (s, 3 H), 2.94 – 3.03 (m, 2 H), 2.68 – 2.73 (m, 1 H), 2.47 (br dd, J=3.78, 1.89 Hz, 4 H), 2.28 – 2.36 (m, 1 H), 2.15 (s, 1 H), 1.85 – 1.93 (m, 2 H), 1.70 – 1.74 (m, 2 H), 1.58 – 1.69 (m, 2 H), 1.17 (s, 5 H), 1.14 – 1.15 (m, 1 H). Example S11.3-(6-((1-(5-chloro-4-((3-(3-hydroxy-3-methylbutyl)-1-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-5-yl)amino)pyrimidin-2-yl)piperidin-4-yl)oxy)-1-methyl-1H- indazol-3-yl)piperidine-2,6-dione (Compound 11)

[0371] Step 1: Synthesis of tert-Butyl 4-[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl- indazol-6-yl]oxypiperidine-1-carboxylate. To a solution of 6-bromo-3-(2,6-dibenzyloxy-3- pyridyl)-1-methyl-indazole (250 mg, 0.50 mmol), [Ir(dF(CF3)ppy)2(dtbbpy)]PF6(5.61 mg, 5.0 µmol), quinuclidine (61.1 mg, 0.55 mmol) in MeCN (2.0 mL) at rt were sequentially added 4,4- di-tert-butyl-2,2-dipyridyl (67.05 mg, 0.25 mmol) and NiCl2 ethylene glycol dimethyl ether complex (54.9 mg, 0.25 mmol). Tert-Butyl 4-hydroxypiperidine-1-carboxylate (301.65 mg, 1.5 mmol) was added to the reaction mixture and irradiated with 3 Kessil lamps (36 W, 454 nm blue LED) while stirring at rt for 120 h. Water (20 mL), a saturated solution of NH4Cl (10 mL), and EtOAc (15 mL) were added and the layers were separated. The aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a gradient of 0–60% EtOAc in hexanes. The material was purified by reverse phase chromatography (C18) using a gradient of 10–100% MeCN and water(+ 0.1% formic acid) to afford the title compound tert-butyl 4-[3-(2,6-dibenzyloxy-3-pyridyl)-1- methyl-indazol-6-yl]oxypiperidine-1-carboxylate (67.2 mg, 26%) as a solid.1H NMR (500 MHz, CDCl3) δ 7.90 (d, J = 8.1 Hz, 1H), 7.59 (d, J = 8.8 Hz, 1H), 7.46 – 7.42 (m, 2H), 7.40 – 7.35 (m, 2H), 7.35 – 7.30 (m, 3H), 7.29 – 7.22 (m, 3H), 6.73 (d, J = 1.9 Hz, 1H), 6.68 (dd, J = 8.9, 2.1 Hz, 1H), 6.51 (d, J = 8.1 Hz, 1H), 5.47 (s, 2H), 5.40 (s, 2H), 4.59 – 4.53 (m, 1H), 4.02 (s, 3H), 3.76 – 3.65 (m, 2H), 3.43 – 3.35 (m, 2H), 2.00 – 1.91 (m, 2H), 1.86 – 1.76 (m, 2H), 1.48 (s, 9H); MS (ESI) [M+H]+620.9.

[0372] Step 2: Synthesis of tert-Butyl 4-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-6- yl]oxypiperidine-1-carboxylate. Following General Procedure 8 with tert-butyl 4-[3-(2,6- dibenzyloxy-3-pyridyl)-1-methyl-indazol-6-yl]oxypiperidine-1-carboxylate afforded the title compound (189 mg, 71%) as a solid.1H NMR (500 MHz, DMSO) δ 10.85 (s, 1H), 7.57 (d, J = 8.8 Hz, 1H), 7.13 (d, J = 1.9 Hz, 1H), 6.77 (dd, J = 8.8, 2.0 Hz, 1H), 4.72 – 4.65 (m, 1H), 4.29 (dd, J = 9.5, 5.1 Hz, 1H), 3.92 (s, 3H), 3.71 – 3.64 (m, 2H), 3.26 – 3.18 (m, 2H), 2.67 – 2.58 (m, 2H), 2.37 – 2.28 (m, 1H), 2.19 – 2.12 (m, 1H), 1.99 – 1.92 (m, 2H), 1.62 – 1.52 (m, 2H), 1.41 (s, 9H); MS (ESI) [M+H]+443.3.

[0373] Step 3: Synthesis of 3-[1-Methyl-6-(4-piperidyloxy)indazol-3-yl]piperidine-2,6- dione hydrochloride. Following General Procedure 9 with tert-butyl 4-[3-(2,6-dioxo-3- piperidyl)-1-methyl-indazol-6-yl]oxypiperidine-1-carboxylate afforded the title compound 3-[1- methyl-6-(4-piperidyloxy)indazol-3-yl]piperidine-2,6-dione hydrochloride (160 mg, 98%) as a solid, which was used in the next step without further purification. MS (ESI) [M+H]+343.3.

[0374] Step 4: Synthesis of 3-[6-[[1-[5-Chloro-4-[[3-(3-hydroxy-3-methyl-butyl)-1- methyl-2-oxo-benzimidazol-5-yl]amino]pyrimidin-2-yl]-4-piperidyl]oxy]-1-methyl-indazol- 3-yl]piperidine-2,6-dione. Following General Procedure 10 with 3-[1-methyl-6-(4- piperidyloxy)indazol-3-yl]piperidine-2,6-dione hydrochloride and 5-[(5-chloro-2-fluoro- pyrimidin-4-yl)amino]-3-(3-hydroxy-3-methyl-butyl)-1-methyl-benzimidazol-2-one afforded the title compound 3-[6-[[1-[5-chloro-4-[[3-(3-hydroxy-3-methyl-butyl)-1-methyl-2-oxo- benzimidazol-5-yl]amino]pyrimidin-2-yl]-4-piperidyl]oxy]-1-methyl-indazol-3-yl]piperidine- 2,6-dione (26 mg, 24%) as a solid.1H NMR (500 MHz, DMSO) δ 8.70 (s, 1H), 8.03 (s, 1H), 7.56 (d, J = 8.8 Hz, 1H), 7.42 (d, J = 1.9 Hz, 1H), 7.30 (dd, J = 8.4, 1.9 Hz, 1H), 7.12 (d, J = 1.9 Hz, 1H), 7.09 (d, J = 8.5 Hz, 1H), 6.76 (dd, J = 8.8, 2.0 Hz, 1H), 4.77 – 4.71 (m, 1H), 4.29 (dd, J = 9.5, 5.1 Hz, 1H), 4.12 – 4.04 (m, 2H), 3.92 (s, 3H), 3.88 – 3.82 (m, 2H), 3.52 – 3.44 (m, 2H), 3.30 (s, 3H), 2.67 – 2.57 (m, 2H), 2.36 – 2.27 (m, 1H), 2.20 – 2.12 (m, 1H), 2.04 – 1.97 (m, 2H), 1.73 – 1.67 (m, 2H), 1.67 – 1.58 (m, 2H), 1.14 (s, 6H). Note: 2 exchangeable protons not visible. MS (ESI) [M+H]+702.4. Example S12.3-(6-((5-chloro-2-(4-((3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)amino)piperidin-1-yl)pyrimidin-4-yl)amino)-3-methyl-2-oxo-2,3-dihydro-1H- benzo[d]imidazol-1-yl)-N-methylpropanamide (Compound 12)

[0375] Step 1: Synthesis of Methyl 3-(3-methyl-6-nitro-2-oxo-benzimidazol-1- yl)propanoate. To a suspension of 3-methyl-6-nitro-1H-benzimidazol-2-one (966.0 mg, 5.0 mmol) in DMF (3.6 mL) were sequentially added methyl prop-2-enoate (498.0 µL, 5.50 mmol) and triton B (40.0 %, 418.0 mg, 1.0 mmol), and the reaction mixture was stirred at rt for 48 h. The volatiles were evaporated under reduced pressure and the material was purified by column chromatography on silica gel eluting with an ethyl acetate / hexane gradient (10-100%) to provide the title compound (810.0 mg, 58%) as a solid.1H NMR (500 MHz, DMSO) δ 8.19 (d, J = 2.2 Hz, 1H), 8.06 (dd, J = 8.7, 2.2 Hz, 1H), 7.36 (d, J = 8.7 Hz, 1H), 4.18 (t, J = 6.9 Hz, 2H), 3.56 (s, 3H), 3.40 (s, 3H), 2.76 (t, J = 6.9 Hz, 2H); MS (ESI) [M+H]+280.0.

[0376] Step 2: Synthesis of N-Methyl-3-(3-methyl-6-nitro-2-oxo-benzimidazol-1- yl)propanamide. To a solution of methylamine in methanol (33.0 %, 65.0 g, 691 mmol) was added methyl 3-(3-methyl-6-nitro-2-oxo-benzimidazol-1-yl)propanoate (4.11 g, 14.7 mmol), and the reaction vessel was sealed. The reaction mixture was heated to 75 °C for 2 h and then cooled to rt. The volatiles were evaporated under reduced pressure and ethanol was added. The resulting precipitate was collected by filtration, washed with a small amount of ethanol, and dried under vacuum to provide the title compound (3.20 g, 78%) as a solid, which was used in the next step without further purification.1H NMR (500 MHz, DMSO) δ 8.10 (d, J = 2.2 Hz, 1H), 8.05 (dd, J = 8.7, 2.2 Hz, 1H), 7.92 – 7.86 (m, 1H), 7.35 (d, J = 8.7 Hz, 1H), 4.12 (t, J = 6.8 Hz, 2H), 3.40 (s, 3H), 2.49 (s, 3H), 2.49 – 2.47 (m, 2H); MS (ESI) [M+H]+279.3.

[0377] Step 3: Synthesis of 3-(6-Amino-3-methyl-2-oxo-benzimidazol-1-yl)-N-methyl- propanamide. A mixture of N-methyl-3-(3-methyl-6-nitro-2-oxo-benzimidazol-1- yl)propanamide (3.14 g, 11.3 mmol) and Pd / C (10.0 %, 1.20 g, 1.13 mmol) in methanol (110.0 mL) was shaken under 50 psi hydrogen atmosphere for 4 h at rt. The reaction was filtered through Celite and washed with methanol. The filtrate was concentrated under reduced pressure to provide the title compound (2.75 g, 98%) as a solid, which was used in the next step without further purification.1H NMR (500 MHz, DMSO) δ 7.91 – 7.83 (m, 1H), 6.77 (d, J = 8.2 Hz, 1H), 6.41 (d, J = 1.9 Hz, 1H), 6.30 (dd, J = 8.2, 2.0 Hz, 1H), 4.76 (br, 2H), 3.93 – 3.85 (m, 2H),3.21 (s, 3H), 2.54 (d, J = 4.6 Hz, 3H), 2.41 (t, J = 7.3 Hz, 1H).

[0378] Step 4: Synthesis of 3-(6-((5-chloro-2-fluoropyrimidin-4-yl)amino)-3-methyl-2- oxo-2,3-dihydro-1H-benzo[d]imidazole-1-yl)-N-methylpropanamide. To a solution of 3-(6- amino-3-methyl-2-oxo-benzimidazol-1-yl)-N-methyl-propanamide (745.0 mg, 3.0 mmol) in a mixture of THF (31.0 mL) and DMF (6.0 mL) cooled to -40 °C were sequentially added DIEA (0.56 mL, 3.30 mmol) and 5-chloro-2,4-difluoro-pyrimidine (474.0 mg, 3.15 mmol). The reaction mixture was slowly warmed to rt and stirred for 18 h. The volatiles were evaporated under reduced pressure. The material was purified by column chromatography on silica gel using 3.75% of MeOH and 7.50% of acetone in DCM (isocratic) to afford the title compound, (700.0 mg, 61%) as a solid.1H NMR (500 MHz, DMSO) δ 9.62 (s, 1H), 8.34 (d, J = 1.4 Hz, 1H), 7.89 – 7.84 (m, 1H), 7.30 (d, J = 1.8 Hz, 1H), 7.19 (dd, J = 8.3, 1.9 Hz, 1H), 7.15 (d, J = 8.3 Hz, 1H), 4.00 (t, J = 7.2 Hz, 2H), 3.33 (s, 3H), 2.51 (d, J = 4.7 Hz, 3H), 2.46 (t, J = 7.2 Hz, 2H); MS (ESI) [M+H]+379.1.

[0379] Step 5: Synthesis of 3-(6-{[5-chloro-2-(4-{[3-(2,6-dioxopiperidin-3-yl)-1-methyl- 1H-indazol-6-yl]amino}piperidin-1-yl)pyrimidin-4-yl]amino}-3-methyl-2-oxo-2,3-dihydro- 1H-1,3-benzodiazol-1-yl)-N-methylpropanamide. The title compound was synthesized according to General Procedure 10 using 3-(6-((5-chloro-2-fluoropyrimidin-4-yl)amino)-3- methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-N-methylpropanamide (11.38 mg, 0.020 mmol) and 3-(1-methyl-6-(piperidin-4-ylamino)-1H-indazol-3-yl)piperidine-2,6-dione (6.8mg, 0.020 mmol) as starting materials to afford the title compound (4.8 mg, 0.0068 mmol) as a white solid. MS (ESI) m / z 700.2 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ ppm 10.81 (s, 1 H), 8.66 (s, 1 H), 8.03 (s, 1 H), 7.81 – 7.92 (m, 1 H), 7.61 (d, J=1.83 Hz, 1 H), 7.25 – 7.36 (m, 2 H), 7.09 (d, J=8.44 Hz, 1 H), 6.52 (dd, J=8.74, 1.65 Hz, 1 H), 6.45 (s, 1 H), 5.77 (d, J=7.95 Hz, 1 H), 4.41 (br d, J=12.84 Hz, 2 H), 4.18 (dd, J=8.80, 5.14 Hz, 1 H), 3.97 (br t, J=7.40 Hz, 2 H), 3.82 (s, 3 H), 3.54 – 3.68 (m, 1 H), 3.30 (s, 3 H), 3.13 (br t, J=11.19 Hz, 2 H), 2.57 – 2.63 (m, 2 H), 2.52 (br s, 3 H), 2.42 – 2.47 (m, 2 H), 2.20 – 2.29 (m, 1 H), 2.10 – 2.19 (m, 1 H), 1.92 – 2.05 (m, 2 H), 1.27 - 1.42 (m, 2 H). Example S13.3-[6-[[1-[5-chloro-4-[[3-[2-(1-hydroxycyclobutyl)ethyl]-1-methyl-2-oxo- benzimidazol-5-yl]amino]pyrimidin-2-yl]-4-piperidyl]amino]-1-methyl-indazol-3- yl]piperidine-2,6-dione (Compound 13)

[0380] Step 1: Synthesis of 3-[2-(1-hydroxycyclobutyl)ethyl]-1-methyl-5-nitro- benzimidazol-2-one. To a suspension of 3-methyl-6-nitro-1H-benzimidazol-2-one (283.19 mg, 1.47 mmol) and 1-(2-bromoethyl)cyclobutanol (250. Mg, 1.4 mmol) in DMF (2 mL) was added sodium carbonate (295.98 mg, 2.79 mmol). The reaction mixture was stirred at 80 °C for 15 hours. The reaction mixture was quenched with saturated aqueous sodium chloride (25 mL) and then washed with ethyl acetate (3 X 25 mL). The organic phases were combined and washed with saturated aqueous sodium chloride (1 X 25 mL). The organic layer was dried (anhydrous sodium sulfate), filtered, and concentrated. The crude product was purified using reverse-phase semi-preparative HPLC (5-100 % CAN in water with 1% formic acid). Concentration of the desired fractions under reduced pressure afforded 3-[2-(1-hydroxycyclobutyl)ethyl]-1-methyl-5- nitro-benzimidazol-2-one (110 mg, 0.3602 mmol, 25.801% yield) as a yellow solid. MS (ESI) m / z 292.0 [M+H]+;1H NMR (500 MHz, DMSO-d6) δ ppm 8.23 (d, J=2.21 Hz, 1 H), 8.10 (dd, J=8.83, 2.21 Hz, 1 H), 7.40 (d, J=8.51 Hz, 1 H), 4.40 (t, J=6.78 Hz, 2 H), 3.61 (t, J=6.78 Hz, 2 H), 3.42 (s, 3 H), 3.10 (s, 3 H).

[0381] Step 2: Synthesis of 5-amino-3-[2-(1-hydroxycyclobutyl)ethyl]-1-methyl- benzimidazol-2-one. To a suspension of 3-[2-(1-hydroxycyclobutyl)ethyl]-1-methyl-5-nitro- benzimidazol-2-one (102. Mg, 0.3500 mmol) in methanol (10 mL) was added palladium on carbon 10% w / w (0.020 g, 0.019 mmol). The reaction mixture was stirred under hydrogen 1 atm at 50 °C for 15 h. The reaction mixture was filtered over Celite, and the solvent was removed under reduced pressure to give 5-amino-3-[2-(1-hydroxycyclobutyl)ethyl]-1-methyl- benzimidazol-2-one (90 mg, 0.3444 mmol, 98.358% yield) as a yellow solid. MS (ESI) m / z 262.0 [M+H]+.

[0382] Step 3: Synthesis of 5-[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]-3-[2-(1- hydroxycyclobutyl)ethyl]-1-methyl-benzimidazol-2-one.5-amino-3-[2-(1- hydroxycyclobutyl)ethyl]-1-methyl-benzimidazol-2-one (90. Mg, 0.34 mmol), 5-chloro-2,4- difluoro-pyrimidine (57.0 mg, 0.38 mmol), and N,N-diisopropylethylamine (0.18 mL, 1.03 mmol) in ethanol (2 mL) was stirred at -20 °C for 0.5 h. The reaction was allowed to warm to room temperature over 1 hour, and the mixture was stirred for another 2 hours. The reaction mixture was concentrated. The crude was purified by silica gel column chromatography (0-100% ethyl acetate in hexane). Concentration of the desired fractions under reduced pressure afforded the title compound as white solid. MS (ESI) m / z 392.0 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ ppm 9.61 (s, 1 H), 8.34 (d, J=1.47 Hz, 1 H), 7.36 (d, J=1.71 Hz, 1 H), 7.19 – 7.23 (m, 1 H), 7.14 – 7.19 (m, 1 H), 5.10 (s, 1 H), 3.81 – 3.90 (m, 2 H), 3.34 (s, 3 H), 1.93 – 2.02 (m, 4 H), 1.81 – 1.91 (m, 2 H), 1.64 (br s, 1 H), 1.41 – 1.53 (m, 1 H)

[0383] Step 4: Synthesis of 3-[6-[[1-[5-chloro-4-[[3-[2-(1-hydroxycyclobutyl)ethyl]-1- methyl-2-oxo-benzimidazol-5-yl]amino]pyrimidin-2-yl]-4-piperidyl]amino]-1-methyl- indazol-3-yl]piperidine-2,6-dione. The title compound was synthesized according to General Procedure 10 using 1-chloro-5-[(2-fluoro-5-methyl-pyrimidin-4-yl)amino]-3-[2-(1- hydroxycyclobutyl)ethyl]150enzimidazole-2-one (27.1 mg, 0.07 mmol) and 3-[1-methyl-6-(4- piperidylamino)indazol-3-yl]piperidine-2,6-dione;hydrochloride (28.6 mg, 0.0800 mmol) as starting materials to afford the title compound (16 mg, 0.022 mmol, 31% yield) as a white solid. MS (ESI) m / z 713.2 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ ppm 10.82 (s, 1 H), 8.69 (s, 1 H), 8.03 (s, 1 H), 7.47 (d, J=1.83 Hz, 1 H), 7.32 – 7.35 (m, 1 H), 7.31 (s, 1 H), 7.10 (d, J=8.56 Hz, 1 H), 6.51 (dd, J=8.80, 1.59 Hz, 1 H), 6.43 (s, 1 H), 5.75 (d, J=8.19 Hz, 1 H), 5.10 (s, 1 H), 4.41 (br d, J=12.96 Hz, 2 H), 4.18 (dd, J=8.74, 5.20 Hz, 1 H), 3.79 – 3.86 (m, 5 H), 3.52 – 3.66 (m, 1 H), 3.31 (s, 3 H), 3.11 (br s, 2 H), 2.57 – 2.64 (m, 2 H), 2.20 – 2.31 (m, 1 H), 2.09 – 2.19 (m, 1 H), 1.91 – 2.03 (m, 6 H), 1.79 – 1.90 (m, 2 H), 1.57 – 1.69 (m, 1 H), 1.40 – 1.52 (m, 1 H), 1.21 - 1.38 (m, 2 H). Example S14.3-[6-[[1-[5-fluoro-4-[[3-(3-hydroxy-3-methyl-butyl)-1-methyl-2-oxo- benzimidazol-5-yl]amino]pyrimidin-2-yl]-4-piperidyl]amino]-1-methyl-indazol-3- yl]piperidine-2,6-dione (Compound 14)

[0384] Step 1: Synthesis of 5-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]-3-(3-hydroxy- 3-methyl-butyl)-1-methyl-benzimidazol-2-one. To a suspension of 2,4-dichloro-5- fluoropyrimidine (0.37 g, 2.2 mmol) and 5-amino-3-(3-hydroxy-3-methyl-butyl)-1-methyl- benzimidazol-2-one;hydrochloride (0.63 g, 2.2 mmol) in ethanol (10 mL) was added N,N- diisopropylethylamine (1.15 mL, 6.59 mmol). The reaction mixture was stirred at 25 °C 16 hours. The crude was concentrated and purified by silica gel column chromatography (0-100 % ethyl acetate in hexane). Concentration of the desired fractions under reduced pressure afforded 5-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]-3-(3-hydroxy-3-methyl-butyl)-1-methyl-benzimidazol-2-one (200 mg, 0.5266 mmol, 23.954% yield) as a white solid. MS (ESI) m / z 380.2 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ ppm 8.28 (d, J=3.55 Hz, 1 H), 7.77 (s, 1 H), 7.52 (d, J=1.96 Hz, 1 H), 7.30 (dd, J=8.31, 1.96 Hz, 1 H), 7.15 (d, J=8.44 Hz, 1 H), 4.44 (s, 1 H), 3.83 - 3.96 (m, 2 H), 3.33 (s, 3 H), 1.68 - 1.81 (m, 2 H), 1.19 (s, 6 H).

[0385] Step 2: Synthesis of 3-[6-[[1-[5-fluoro-4-[[3-(3-hydroxy-3-methyl-butyl)-1- methyl-2-oxo-benzimidazol-5-yl]amino]pyrimidin-2-yl]-4-piperidyl]amino]-1-methyl- indazol-3-yl]piperidine-2,6-dione. Following General Procedure 10 using 5-[(2-chloro-5- fluoro-pyrimidin-4-yl)amino]-3-(3-hydroxy-3-methyl-butyl)-1-methyl-benzimidazol-2-one (44 mg, 0.12 mmol) and 3-[1-methyl-6-(4-piperidylamino)indazol-3-yl]piperidine-2,6-dione hydrochloride (0.05 g, 0.12 mmol) afforded the title compound (19.5 mg, 0.0261 mmol, 22% yield) as a yellow solid. MS (ESI) m / z 685.2 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ ppm 10.82 (s, 1 H), 9.20 (s, 1 H), 7.99 (d, J=3.67 Hz, 1 H), 7.55 (d, J=1.83 Hz, 1 H), 7.39 (dd, J=8.50, 1.90 Hz, 1 H), 7.32 (d, J=8.68 Hz, 1 H), 7.09 (d, J=8.56 Hz, 1 H), 6.51 (dd, J=8.74, 1.65 Hz, 1 H), 6.44 (d, J=1.22 Hz, 1 H), 5.77 (d, J=8.07 Hz, 1 H), 4.38 - 4.49 (m, 3 H), 4.18 (dd, J=8.74, 5.20 Hz, 1 H), 3.78 - 3.91 (m, 5 H), 3.53 - 3.67 (m, 1 H), 3.30 (s, 3 H), 3.11 (br t, J=11.37 Hz, 2 H), 2.57 - 2.64 (m, 2 H), 2.20 - 2.31 (m, 1 H), 2.09 - 2.19 (m, 1 H), 1.95 - 2.06 (m, 2 H), 1.65 - 1.75 (m, 2 H), 1.27 - 1.42 (m, 2 H), 1.15 (s, 6 H). Example S15.3-[6-[[1-[5-chloro-4-[(1,3-dimethyl-2-oxo-benzimidazol-5- yl)amino]pyrimidin-2-yl]-4-piperidyl]amino]-1-methyl-indazol-3-yl]piperidine-2,6-dione (Compound 15)

[0386] Step 1: Synthesis of 5-[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]-1,3-dimethyl- benzimidazol-2-one. Following General Procedure 5 with 5-amino-1,3-dimethyl- benzimidazol-2-one (107.9 mg, 0.61 mmol) afforded the title compound (130.0 mg, 69%) as a solid, which was used in the next step without further purification. MS (ESI) [M+H]+308.2.

[0387] Step 2: Synthesis of 3-[6-[[1-[5-chloro-4-[(1,3-dimethyl-2-oxo-benzimidazol-5- yl)amino]pyrimidin-2-yl]-4-piperidyl]amino]-1-methyl-indazol-3-yl]piperidine-2,6-dione. The title compound was synthesized according to General Procedure 10 with 5-[(5-chloro-2- fluoro-pyrimidin-4-yl)amino]-1,3-dimethyl-benzimidazol-2-one (32.6 mg, 0.11 mmol) and 3-[1-methyl-6-(4-piperidylamino)indazol-3-yl]piperidine-2,6-dione hydrochloride (40.0 mg, 0.11 mmol) as starting materials. The material 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 (31.2 mg, 47%) as a solid.1H NMR (400 MHz, DMSO) δ 10.81 (s, 1H), 8.68 (s, 1H), 8.03 (s, 1H), 7.59 (d, J = 1.6 Hz, 1H), 7.32 (d, J = 8.7 Hz, 1H), 7.28 (dd, J = 8.5, 1.9 Hz, 1H), 7.10 (d, J = 8.5 Hz, 1H), 6.52 (dd, J = 8.6, 1.5 Hz, 1H), 6.45 (s, 1H), 5.78 (d, J = 7.6 Hz, 1H), 4.46 – 4.38 (m, 2H), 4.18 (dd, J = 8.8, 5.1 Hz, 1H), 3.82 (s, 3H), 3.67 – 3.59 (m, 1H), 3.31 (s, 3H, masked with H2O signal.), 3.28 (s, 3H), 3.13 (t, J = 11.3 Hz, 2H), 2.60 (t, J = 6.7 Hz, 2H), 2.29 – 2.22 (m, 1H), 2.17 – 2.11 (m, 1H), 2.04 – 1.97 (m, 2H), 1.40 – 1.30 (m, 2H); MS (ES) [M+H]+629.5. Example S16. tert-butyl 3-[6-[[5-chloro-2-[4-[[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol- 6-yl]amino]-1-piperidyl]pyrimidin-4-yl]amino]-3-methyl-2-oxo-benzimidazol-1- yl]propanoate (Compound 16)

[0388] Step 1: Synthesis of tert-butyl 3-(3-methyl-6-nitro-2-oxo-benzimidazol-1- yl)propanoate. A solution of tert-butyl 3-bromopropionate (600 mg, 2.87 mmol), 3-methyl-6- nitro-1H-benzimidazol-2-one (554.31 mg, 2.87 mmol), and potassium carbonate (793.25 mg, 5.74 mmol) in DMF (5 mL) was stirred at 80 °C for 15 hours. The reaction mixture was quenched with saturated aqueous sodium chloride (25 mL) and then washed with ethyl acetate (3 X 25 mL). The organic phase was combined and washed with saturated aqueous sodium chloride (1 X 25 mL). The organic layer was dried (anhydrous sodium sulfate), filtered, and concentrated. The crude was purified by silica gel column chromatography (0-80 % ethyl acetate in hexane). Concentration of the desired fractions under reduced pressure afforded tert-butyl 3- (3-methyl-6-nitro-2-oxo-benzimidazol-1-yl)propanoate (900 mg, 2.8009 mmol, 97.601% yield) as a yellow oil. MS (ESI) m / z 322.0 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ ppm 8.19 (d, J=2.20 Hz, 1 H), 8.08 (dd, J=8.68, 2.20 Hz, 1 H), 7.38 (d, J=8.68 Hz, 1 H), 4.16 (t, J=6.79 Hz, 2 H), 3.41 (s, 3 H), 2.66 (t, J=6.79 Hz, 2 H), 1.30 (s, 9 H).

[0389] Step 2: Synthesis of tert-butyl 3-(6-amino-3-methyl-2-oxo-benzimidazol-1- yl)propanoate. Following General Procedure 2 with tert-butyl 3-(3-methyl-6-nitro-2-oxo- benzimidazol-1-yl)propanoate (900. Mg, 2.8 mmol) afforded the title compound as a white solid. MS (ESI) m / z 292.0 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ ppm 6.79 (d, J=8.19 Hz, 1 H), 6.43 (d, J=1.96 Hz, 1 H), 6.31 (dd, J=8.19, 2.08 Hz, 1 H), 4.82 (br s, 2 H), 3.91 (t, J=7.09 Hz, 2 H), 3.21 (s, 3 H), 2.57 (t, J=7.09 Hz, 2 H), 1.35 – 1.39 (m, 1 H), 1.33 (s, 8 H).

[0390] Step 3: Synthesis of tert-butyl 3-[6-[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]-3- methyl-2-oxo-benzimidazol-1-yl]propanoate. Following General Procedure 5 using tert- butyl 3-(6-amino-3-methyl-2-oxo-benzimidazol-1-yl)propanoate (500. Mg, 1.72 mmol) and 5- chloro-2,4-difluoro-pyrimidine (271.21 mg, 1.8 mmol) afforded the title compound (520 mg, 1.23 mmol, 71% yield) as a white solid. MS (ESI) m / z 378.0 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ ppm 9.61 (s, 1 H), 8.34 (d, J=1.47 Hz, 1 H), 7.38 (d, J=1.83 Hz, 1 H), 7.19 – 7.23 (m, 1 H), 7.14 – 7.19 (m, 1 H), 4.02 (t, J=7.03 Hz, 2 H), 3.33 (s, 3 H), 2.63 (t, J=7.09 Hz, 2 H), 1.32 (s, 9 H).

[0391] Step 4: Synthesis of tert-butyl 3-[6-[[5-chloro-2-[4-[[3-(2,6-dioxo-3-piperidyl)-1- methyl-indazol-6-yl]amino]-1-piperidyl]pyrimidin-4-yl]amino]-3-methyl-2-oxo- benzimidazol-1-yl]propanoate. Following General Procedure 10 with tert-butyl 3-[6-[(5- chloro-2-fluoro-pyrimidin-4-yl)amino]-3-methyl-2-oxo-benzimidazol-1-yl]propanoate (231 mg, 0.55 mmol) and 3-[1-methyl-6-(4-piperidylamino)indazol-3-yl]piperidine-2,6-dione hydrochloride (228 mg, 0.60 mmol) afforded the title compound (10 mg, 0.0132 mmol, 2% yield) as a pink solid. MS (ESI) m / z 743.2 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ ppm 10.81 (s, 1 H), 8.66 (s, 1 H), 8.03 (s, 1 H), 7.59 (d, J=1.83 Hz, 1 H), 7.28 – 7.37 (m, 2 H), 7.10 (d, J=8.56 Hz, 1 H), 6.51 (dd, J=8.80, 1.71 Hz, 1 H), 6.44 (d, J=1.34 Hz, 1 H), 5.77 (d, J=8.07 Hz, 1 H), 4.42 (br d, J=13.08 Hz, 2 H), 4.18 (dd, J=8.86, 5.20 Hz, 1 H), 3.94 – 4.05 (m, 2 H), 3.82 (s, 3 H), 3.54 – 3.68 (m, 1 H), 3.30 (s, 3 H), 3.05 – 3.19 (m, 2 H), 2.57 – 2.64 (m, 4 H), 2.20 – 2.30 (m, 1 H), 2.09 – 2.19 (m, 1 H), 1.96 – 2.05 (m, 2 H), 1.24 - 1.40 (m, 12 H). Example S17.3-[6-[[1-[5-chloro-4-[[3-(3-hydroxy-3-methyl-butyl)-2-oxo-1H-benzimidazol- 5-yl]amino]pyrimidin-2-yl]-4-piperidyl]amino]-1-methyl-indazol-3-yl]piperidine-2,6-dione (Compound 17)

[0392] Step 1: Synthesis of methyl 2-[(3-hydroxy-3-methyl-butyl)amino]-4-nitro- benzoate. To a solution of methyl 2-fluoro-4-nitro-benzoate (1.85 g, 9.29 mmol) in DMF (50.0 mL) were sequentially added K2CO3(2.57 g, 18.5 mmol) and 4-amino-2-methyl-butan-2-ol (1.01 g, 9.75 mmol) at rt. The reaction mixture was heated to 60 °C for 4 h and then cooled to rt. The volatiles were evaporated under reduced pressure. Water (50.0 mL) was added and the pH was adjusted to 4 by adding a 1.0 M aqueous HCl. Ethyl acetate was added, and the layers were separated. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with water, brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The material was purified by column chromatography on silica gel using a gradient of 20-50% ethyl acetate in hexane to afford the title compound (1.91 g, 72%) as a solid.1H NMR (500 MHz, DMSO) δ 8.03 – 7.98 (m, 2H), 7.47 (d, J= 2.3 Hz, 1H), 7.31 (dd, J= 8.7, 2.3 Hz, 1H), 4.50 (s, 1H), 3.84 (s, 3H), 3.37 – 3.31 (m, 2H), 1.75 – 1.70 (m, 2H), 1.18 (s, 6H); MS (ESI) [M- H]- 281.2.

[0393] Step 2: Synthesis of 2-[(3-hydroxy-3-methyl-butyl)amino]-4-nitro-benzoic acid. To a solution of methyl 2-[(3-hydroxy-3-methyl-butyl)amino]-4-nitro-benzoate (1.91 g, 6.77 mmol) in a mixture of THF (20.0 mL), methanol (20.0 mL) and water (20.0 mL) was added an aqueous solution of KOH (3.2 M, 4.22 mL, 13.4 mmol) at rt. The reaction mixture was stirred at rt for 3 h. The volatiles were evaporated under reduced pressure. Water (20.0 mL), aqueous HCl (2.0 M, 6.2 mL) and ethyl acetate (50.0 mL) were added and the layers were separated. The aqueous layer was extracted with ethyl acetate (3 x 50.0 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to afford the title compound (1.58 g, 95%) as a solid, which was used in the next step without further purification.1H NMR (500 MHz, DMSO) δ 7.99 (d, J= 8.7 Hz, 1H), 7.44 (d, J= 2.3 Hz, 1H), 7.29 (dd, J= 8.7, 2.3 Hz, 1H), 4.44 (br, 1H), 3.35 – 3.28 (m, 2H), 1.75 – 1.67 (m, 2H), 1.17 (s, 6H).

[0394] Step 3: Synthesis of 3-(3-hydroxy-3-methyl-butyl)-5-nitro-1H-benzimidazol-2- one. To a solution of 2-[(3-hydroxy-3-methyl-butyl)amino]-4-nitro-benzoic acid (201.0 mg, 0.75 mmol) in tert-butanol (3.75 mL) were sequentially added DIPEA (0.39 mL, 2.25 mmol)and diphenylphosphoryl azide (0.19 mL, 0.90 mmol) dropwise at rt. The reaction mixture was heated to 90 °C 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 50-100% ethyl acetate in hexane to afford the title compound (180.0 mg, 90%) as a solid.1H NMR (500 MHz, DMSO) δ 11.62 (s, 1H), 7.97 (dd, J= 8.6, 2.2 Hz, 1H), 7.94 (d, J= 2.2 Hz, 1H), 7.14 (d, J= 8.6 Hz, 1H), 4.51 (s, 1H), 3.97 – 3.90 (m, 2H), 1.75 – 1.68 (m, 2H), 1.17 (s, 6H); MS (ESI) [M+H]+248.1.

[0395] Step 4: Synthesis of 5-amino-3-(3-hydroxy-3-methyl-butyl)-1H-benzimidazol-2- one. A mixture of 10% Pd / C (280.0 mg, 0.26 mmol) and 3-(3-hydroxy-3-methyl-butyl)-5-nitro- 1H-benzimidazol-2-one (1.40 g, 5.28 mmol) in MeOH (55.0 mL) was shaken in a Parr flask at 50 psi hydrogen atmosphere at rt for 1 h. The reaction was filtered through Celite and washed with MeOH. The filtrate was concentrated under reduced pressure to afford the title compound (1.13 g, 91%) as a solid, which was used in the next step without further purification.1H NMR (500 MHz, DMSO) δ 10.24 (s, 1H), 6.63 (d, J= 8.1 Hz, 1H), 6.32 (d, J= 1.9 Hz, 1H), 6.22 (dd, J= 8.2, 2.0 Hz, 1H), 4.70 (s, 2H), 4.42 (s, 1H), 3.77 – 3.69 (m, 2H), 1.68 – 1.61 (m, 2H), 1.16 (s, 6H).

[0396] Step 5: Synthesis of 5-[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]-3-(3-hydroxy- 3-methyl-butyl)-1H-benzimidazol-2-one. Following General Procedure 5 with 5-amino-3- (3-hydroxy-3-methyl-butyl)-1H-benzimidazol-2-one (176.0 mg, 0.75 mmol) afforded the title compound (234.0 mg, 85%) as a solid, which was used in the next step without further purification.1H NMR (500 MHz, DMSO) δ 10.85 (s, 1H), 9.57 (s, 1H), 8.33 (s, 1H), 7.26 (s, 1H), 7.12 (dd, J= 8.3, 1.7 Hz, 1H), 6.98 (d, J= 8.3 Hz, 1H), 4.42 (s, 1H), 3.87 – 3.78 (m, 2H), 1.75 – 1.65 (m, 2H), 1.17 (s, 6H).

[0397] Step 6: Synthesis of 3-[6-[[1-[5-chloro-4-[[3-(3-hydroxy-3-methyl-butyl)-2-oxo- 1H-benzimidazol-5-yl]amino]pyrimidin-2-yl]-4-piperidyl]amino]-1-methyl-indazol-3- yl]piperidine-2,6-dione. Following General Procedure 10 using 5-[(5-chloro-2-fluoro- pyrimidin-4-yl)amino]-3-(3-hydroxy-3-methyl-butyl)-1H-benzimidazol-2-one (73.1 mg, 0.20 mmol) and 3-[1-methyl-6-(4-piperidylamino)indazol-3-yl]piperidine-2,6-dione dihydrochloride (82.8 mg, 0.20 mmol) as starting materials at 70 °C for 3 h afforded the title compound after purification (70.0 mg, 50%) as a solid.1H NMR (500 MHz, DMSO) δ 8.64 (s, 1H), 8.34 (s, 1H), 8.01 (s, 1H), 7.38 (d, J= 1.8 Hz, 1H), 7.32 (d, J= 8.7 Hz, 1H), 7.20 (dd, J= 8.4, 1.9 Hz, 1H), 6.92 (d, J= 8.3 Hz, 1H), 6.51 (dd, J= 8.8, 1.6 Hz, 1H), 6.43 (s, 1H), 5.81 – 5.71 (m, 1H), 4.45 – 4.36 (m, 2H), 4.18 (dd, J= 8.7, 5.2 Hz, 1H), 3.85 – 3.76 (m, 5H), 3.59 (br, 1H), 3.10 (t, J= 11.3 Hz, 2H), 2.64 – 2.56 (m, 2H), 2.30 – 2.20 (m, 1H), 2.19 – 2.09 (m, 1H), 2.04 – 1.94 (m, 2H), 1.73 – 1.66 (m, 2H), 1.38 – 1.27 (m, 2H), 1.15 (s, 6H). Note: 2 exchangeable protons could not be seen.MS (ESI) [M+H]+687.4. Example S18.1-[5-chloro-4-[[3-[3-(methylamino)-3-oxo-propyl]-2-oxo-1H-benzimidazol-5- yl]amino]pyrimidin-2-yl]-N-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-6-yl]piperidine-4- carboxamide (Compound 18)

[0398] Step 1: Synthesis of methyl 2-[[3-(methylamino)-3-oxo-propyl]amino]-4-nitro- benzoate. Methyl 2-fluoro-4-nitro-benzoate (1000 mg, 5.02 mmol), N-methyl-3- aminopropionamide (666.78 mg, 6.53 mmol), potassium carbonate (1388.07 mg, 10.04 mmol), and DMF (10.043 mL) were added to a 2 dram vial equipped with a stir bar at RT. The vial was then sealed and heated to 70 °C and stirred overnight. LCMS indicated significant product formation. The reaction was cooled to 0 °C on ice and water was added. A bright orange solid formed. The mixture was poured onto a filter and rinsed with water. The bright orange solid was dried under vacuum at 45 °C ON. MS (ESI) [M+H]+282.0.

[0399] Step 2: Synthesis of N-methyl-3-(6-nitro-2-oxo-3H-benzimidazol-1- yl)propanamide. 2-[[3-(methylamino)-3-oxo-propyl]amino]-4-nitro-benzoic acid (488. mg, 1.83 mmol), triethylamine (0.32 mL, 2.19 mmol), and toluene (22.826 mL) were added to a 100 mL RBF equipped with a stir bar. Then diphenylphosphoryl azide (0.47 mL, 2.19 mmol) was added and the mixture was stirred at RT for 30 mins. The solution was then heated to 80 °C for 2 hours. A yellow precipitate formed during the reaction. After 2 hours, the reaction was cooled to RT, filtered, and washed with water. An orange solid was collected and a foamy / cloudy yellow mother liquor remained. The solid was dried under vacuum at 45 °C. MS (ESI) [M+H]+265.0.

[0400] Step 3: Synthesis of 3-(6-amino-2-oxo-3H-benzimidazol-1-yl)-N-methyl- propanamide. The title compound was prepared following General Procedure 2 using N- methyl-3-(6-nitro-2-oxo-3H-benzimidazol-1-yl)propanamide (288. mg, 1.09 mmol) and palladium on carbon (54.5 mg, 0.5400 mmol). The reaction was purged with nitrogen and filtered through Celite. The cake was washed with 500 mL of hot methanol. The solution was concentrated to yield the title compound. MS (ESI) [M+H]+235.2.

[0401] Step 4: Synthesis of 3-[6-[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]-2-oxo-3H- benzimidazol-1-yl]-N-methyl-propanamide. Following General Procedure 5 using 3-(6-amino-2-oxo-3H-benzimidazol-1-yl)-N-methyl-propanamide (100 mg, 0.43 mmol) and 5- chloro-2,4-difluoro-pyrimidine (64.25 mg, 0.43 mmol) afforded the title compound, which was used in the next step without further purification.1H NMR (DMSO-d6, 400 MHz) δ 10.90 (s, 1H), 9.59 (s, 1H), 8.34 (d, 1H, J=1.5 Hz), 7.89 (br d, 1H, J=4.5 Hz), 7.24 (d, 1H, J=1.8 Hz), 7.12 (dd, 1H, J=1.9, 8.4 Hz), 6.98 (d, 1H, J=8.3 Hz), 3.95 (t, 3H, J=7.3 Hz), 3.08 (s, 1H), 2.5- 2.6 (m, 2H), 2.4-2.5 (m, 3H), 2.1-2.4 (m, 1H), 1.24 (br s, 3H), 1.0-1.2 (m, 2H), 0.96 (br s, 3H); MS (ESI) [M+H]+365.0.

[0402] Step 5: Synthesis of 1-[5-chloro-4-[[3-[3-(methylamino)-3-oxo-propyl]-2-oxo-1H- benzimidazol-5-yl]amino]pyrimidin-2-yl]piperidine-4-carboxylic acid. To a solution of 3- [6-[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]-2-oxo-3H-benzimidazol-1-yl]-N-methyl- propanamide (728.0 mg, 2.0 mmol) in DMF (16.0 mL) were sequentially added piperidine-4- carboxylic acid (258.0 mg, 2.0 mmol) and DIEA (719.0 µL, 4.2 mmol) at rt. The reaction vessel was sealed. The reaction mixture was heated to 110 °C for 2 h and then cooled to rt. The mixture was directly purified by reverse phase chromatography (C18) using a gradient of 5-100% acetonitrile and water (ammonium formate buffer pH 4) to afford the title compound as a solid.

[0403] Step 6: Synthesis of 1-[5-chloro-4-[[3-[3-(methylamino)-3-oxo-propyl]-2-oxo-1H- benzimidazol-5-yl]amino]pyrimidin-2-yl]-N-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-6- yl]piperidine-4-carboxamide. 1-[5-chloro-4-[[3-[3-(methylamino)-3-oxo-propyl]-2-oxo-1H- benzimidazol-5-yl]amino]pyrimidin-2-yl]piperidine-4-carboxylic acid (24 mg, 0.05 mmol), 3- (6-amino-1-methyl-indazol-3-yl)piperidine-2,6-dione;hydrochloride (16.4 mg, 0.06 mmol), HATU (24 mg, 0.06 mmol), N,N-diisopropylethylamine (0.02 mL, 0.11 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 overnight. The reaction was cooled to RT, diluted in DMSO and formic acid, and purified by semi-preparative HPLC to give the title compound (8 mg, 0.011 mmol, 21% yield) as an off-white powder.1H NMR (DMSO-d6, 400 MHz) δ 10.8-10.9 (m, 1H), 10.8-10.8 (m, 1H), 10.0-10.2 (m, 1H), 8.7-9.1 (m, 1H), 8.0-8.1 (m, 2H), 7.8-7.9 (m, 1H), 7.6-7.6 (m, 1H), 7.5-7.6 (m, 1H), 7.1-7.2 (m, 1H), 7.1-7.1 (m, 1H), 6.9-7.0 (m, 1H), 4.5-4.6 (m, 3H), 4.3-4.3 (m, 2H), 3.9-4.0 (m, 5H), 2.9-3.0 (m, 2H), 2.5-2.7 (m, 2H), 2.4-2.5 (m, 3H), 2.3-2.5 (m, 6H), 2.1-2.2 (m, 1H), 1.8-1.9 (m, 2H), 1.5-1.7 (m, 2H); m / z = 714 [M+H]+. Example S19.1-(5-chloro-4-((1-methyl-3-(3-(methylamino)-3-oxopropyl)-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-5-yl)amino)pyrimidin-2-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1- methyl-1H-indazol-6-yl)piperidine-4-carboxamide (Compound 19)

[0404] Step 1: Synthesis of 1-(5-chloro-4-((1-methyl-3-(3-(methylamino)-3-oxopropyl)- 2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)pyrimidin-2-yl)piperidine-4-carboxylic acid. To a solution of 3-(6-((5-chloro-2-fluoropyrimidin-4-yl)amino)-3-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-1-yl)-N-methylpropanamide (756.0 mg, 2.0 mmol) in DMF (16.0 mL) were sequentially added piperidine-4-carboxylic acid (258.0 mg, 2.0 mmol) and DIEA (719.0 µL, 4.2 mmol) at rt. The reaction vessel was sealed. The reaction mixture was heated to 110 °C for 2 h and then cooled to rt. The mixture was directly purified by reverse phase chromatography (C18) using a gradient of 5-100% acetonitrile and water (ammonium formate buffer pH 4) to afford the title compound as a solid.

[0405] Step 2: Synthesis of 1-[5-chloro-4-[[1-methyl-3-[3-(methylamino)-3-oxo-propyl]- 2-oxo-benzimidazol-5-yl]amino]pyrimidin-2-yl]-N-[3-(2,6-dioxo-3-piperidyl)-1-methyl- indazol-6-yl]piperidine-4-carboxamide. A solution of 1-(5-chloro-4-((1-methyl-3-(3- (methylamino)-3-oxopropyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)amino)pyrimidin-2- yl)piperidine-4-carboxylic acid (24 mg, 0.05 mmol), 3-(6-amino-1-methyl-1H-indazol-3- yl)piperidine-2,6-dione hydrochloride (16.4 mg, 0.06 mmol), HATU (24 mg, 0.06 mmol), N,N- diisopropylethylamine (0.02 mL, 0.11 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 overnight. The mixture was directly purified by preparative HPLC (BEH, C18) using a gradient of 31-51% acetonitrile and 10 mM ammonium formate in water to afford the title compound (15.0 mg, 41%) as a solid.1H NMR (500 MHz, DMSO) δ 10.86 (s, 1H), 10.12 (s, 1H), 8.67 (s, 1H), 8.09 (s, 1H), 8.04 (s, 1H), 7.90 – 7.83 (m, 1H), 7.66 (s, 1H), 7.61 (d, J = 8.6 Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H), 7.10 (d, J = 8.5 Hz, 2H), 4.63 – 4.54 (m, 2H), 4.31 (dd, J = 9.5, 5.1 Hz, 1H), 3.97 (t, J = 7.3 Hz, 2H), 3.90 (s, 3H), 3.31 (s, 3H), 2.90 (t, J = 12.2 Hz, 2H), 2.69 – 2.57 (m, 3H), 2.49 (s, 3H), 2.49 – 2.42 (m, 2H), 2.38 – 2.28 (m, 1H), 2.21 – 2.14 (m, 1H), 1.88 – 1.79 (m, 2H), 1.65 – 1.54 (m, 2H); MS (ESI) [M+H]+728.4. Example S20.1-[6-[[1-[5-chloro-4-[(1,3-dimethyl-2-oxo-benzimidazol-5- yl)amino]pyrimidin-2-yl]-4-piperidyl]amino]-1-methyl-indazol-3-yl]hexahydropyrimidine- 2,4-dione (Compound 20)

[0406] Step 1: Synthesis of tert-Butyl 4-[[3-(2,4-dioxohexahydropyrimidin-1-yl)-1- methyl-indazol-6-yl]amino] piperidine-1-carboxylate. To a solution of 1-(6-amino-1-methyl- indazol-3-yl)hexahydropyrimidine-2,4-dione (1.27 g, 4.90 mmol), tert-butyl 4-oxopiperidine-1- carboxylate (1.02 g, 5.14 mmol) and scandium triflate (0.240 g, 0.490 mmol) in acetic acid (3.60 mL) and DMSO (14.5 mL) was added sodium triacetoxyborohydride (2.08 g, 9.80 mmol). The reaction mixture was stirred for 7 h at rt. Water was added and the resulting solid was collected by filtration, washed with water (10 mL) and Et2O (2 x 10 mL), and then dried under vacuum to afford the title compound (1.31 g, 60%) as a solid.1H NMR (400 MHz, DMSO) δ 10.46 (s, 1H), 7.28 (d, J = 8.8 Hz, 1H), 6.51 (dd, J = 8.9, 1.6 Hz, 1H), 6.41 (s, 1H), 5.84 (d, J = 8.2 Hz, 1H), 3.93 – 3.86 (m, 2H), 3.85 (t, J = 6.7 Hz, 2H), 3.81 (s, 3H), 3.56 – 3.51 (m, 1H), 2.99 – 2.88 (m, 2H), 2.72 (t, J = 6.7 Hz, 2H), 1.95 (d, J = 10.3 Hz, 2H), 1.41 (s, 9H), 1.31 – 1.17 (m, 2H); MS (ESI) [M+H]+443.4.

[0407] Step 2: Synthesis of 1-[1-methyl-6-(4-piperidylamino)indazol-3- yl]hexahydropyrimidine-2,4-dione. Following General Procedure 9 using tert-butyl 4-[[3- (2,4-dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]amino]piperidine-1-carboxylate (710 mg, 1.6 mmol) afforded the title compound (623 mg, quant.) as a solid, which was used in the next step without further purification. A small portion was purified by preparative HPLC (BEH column, C18) using a gradient of 7–17% MeCN and 10 mM ammonium formate in water for characterization.1H NMR (500 MHz, DMSO) δ 10.48 (s, 1H), 9.02 (dd, J = 8.2, 3.7 Hz, 1H), 8.89 (m, 1H), 7.37 (d, J = 8.4 Hz, 1H), 6.64 (d, J = 7.8 Hz, 2H), 3.87 (t, J = 6.7 Hz, 2H), 3.85 (s, 3H), 3.70 – 3.61 (m, 1H), 3.35 – 3.25 (m, 2H), 3.00 (td, J = 11.3, 2.7 Hz, 2H), 2.72 (t, J = 6.7 Hz, 2H), 2.11 (dd, J = 13.7, 2.6 Hz, 2H), 1.75 – 1.62 (m, 2H); MS (ESI) [M+H]+343.4.

[0408] Step 3: Synthesis of 1-[6-[[1-[5-chloro-4-[(1,3-dimethyl-2-oxo-benzimidazol-5- yl)amino]pyrimidin-2-yl]-4-piperidyl]amino]-1-methyl-indazol-3-yl]hexahydropyrimidine- 2,4-dione. Following General Procedure 10 using 5-[(5-chloro-2-fluoro-pyrimidin-4- yl)amino]-1,3-dimethyl-benzimidazol-2-one (30.0 mg, 0.10 mmol) and 1-[1-methyl-6-(4- piperidylamino)indazol-3-yl]hexahydropyrimidine-2,4-dione hydrochloride (38.78 mg, 0.10 mmol) afforded the title compound (41.4 mg, 65.4%) as a solid.1H NMR (500 MHz, DMSO) δ 10.45 (s, 1H), 8.69 (s, 1H), 8.03 (s, 1H), 7.59 (d, J = 1.9 Hz, 1H), 7.30 – 7.25 (m, 2H), 7.10 (d, J= 8.4 Hz, 1H), 6.51 (dd, J = 8.9, 1.8 Hz, 1H), 6.44 (d, J = 1.4 Hz, 1H), 5.83 (d, J = 8.2 Hz, 1H), 4.46 – 4.38 (m, 2H), 3.86 (t, J = 6.7 Hz, 2H), 3.82 (s, 3H), 3.67 – 3.59 (m, 1H), 3.31 (s, 3H), 3.28 (s, 3H), 3.16 – 3.09 (m, 2H), 2.72 (t, J = 6.7 Hz, 2H), 2.03 – 1.97 (m, 2H), 1.39 – 1.30 (m, 2H). Formic acid (~0.5 eq). MS (ESI) [M+H]+630.4. Example S21.2-[4-[[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-6-yl]amino]-1-piperidyl]-4- [[3-(3-hydroxy-3-methyl-butyl)-1-methyl-2-oxo-benzimidazol-5-yl]amino]pyrimidine-5- carbonitrile (Compound 21)

[0409] Step 1: Synthesis of 2-chloro-4-[[3-(3-hydroxy-3-methyl-butyl)-1-methyl-2-oxo- benzimidazol-5-yl]amino]pyrimidine-5-carbonitrile. Following General Procedure 5 with 5-amino-3-(3-hydroxy-3-methyl-butyl)-1-methyl-benzimidazol-2-one (100.0 mg, 0.40 mmol) and 2,4-dichloropyrimidine-5-carbonitrile (69.8 mg, 0.40 mmol) afforded the title compound (93.0 mg, 60%) as a solid, which was used in the next step without further purification.1H NMR (500 MHz, Acetic acid-d4) δ 8.58 (s, 1H), 7.52 (s, 1H), 7.34 (d, J = 8.1 Hz, 1H), 7.19 (d, J = 8.5 Hz, 1H), 4.13 – 4.06 (m, 2H), 3.47 (s, 3H), 2.01 – 1.94 (m, 2H), 1.35 (s, 6H). Note: Exchangeable protons were not observed. MS (ESI) [M-H]- 385.3.

[0410] Step 2: Synthesis of 2-[4-[[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-6- yl]amino]-1-piperidyl]-4-[[3-(3-hydroxy-3-methyl-butyl)-1-methyl-2-oxo-benzimidazol-5- yl]amino]pyrimidine-5-carbonitrile. Following General Procedure 10 with 2-chloro-4-[[3- (3-hydroxy-3-methyl-butyl)-1-methyl-2-oxo-benzimidazol-5-yl]amino]pyrimidine-5-carbonitrile (35.0 mg, 0.09 mmol) and 3-[1-methyl-6-(4-piperidylamino)indazol-3-yl]piperidine-2,6- dione;dihydrochloride (39.4 mg, 0.10 mmol) afforded the title compound (10.3 mg, 16%) as a solid.1H NMR (500 MHz, Acetic acid-d4) δ 8.41 (s, 1H), 7.56 (d, J = 1.8 Hz, 1H), 7.54 (d, J = 8.8 Hz, 1H), 7.39 (dd, J = 8.5, 1.9 Hz, 1H), 7.12 (d, J = 8.5 Hz, 1H), 6.80 (d, J = 8.8 Hz, 1H), 4.73 – 4.62 (m, 2H), 4.44 (dd, J = 10.7, 5.1 Hz, 1H), 4.12 – 4.02 (m, 2H), 3.96 (s, 3H), 3.85 – 3.76 (m, 1H), 3.44 (s, 3H), 3.28 – 3.15 (m, 2H), 2.93 – 2.78 (m, 2H), 2.57 – 2.46 (m, 1H), 2.39 – 2.31 (m, 1H), 2.24 – 2.15 (m, 2H), 1.97 – 1.91 (m, 2H), 1.64 – 1.53 (m, 2H), 1.31 (s, 6H). Note: Exchangeable protons were not observed. One aromatic proton was missing in acetic acid butwas visible in DMSO; better resolution in acetic acid.1H NMR (500 MHz, DMSO) δ 10.82 (bs, 1H), 9.31 (s, 1H), 8.42 (s, 1H), 7.36 (d, J = 1.7 Hz, 1H), 7.33 (d, J = 8.8 Hz, 1H), 7.25 (dd, J = 8.4, 1.8 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 6.52 (dd, J = 8.8, 1.6 Hz, 1H), 6.45 (d, J = 1.0 Hz, 1H), 5.78 (d, J = 8.0 Hz, 1H), 4.59 (bs, 1H), 4.51 – 4.31 (m, 2H), 4.18 (dd, J = 8.8, 5.2 Hz, 1H), 3.90 – 3.84 (m, 2H), 3.83 (s, 3H), 3.69 – 3.61 (m, 1H), 3.31 (s, 3H), 2.64 – 2.58 (m, 2H), 2.30 – 2.22 (m, 1H), 2.18 – 2.11 (m, 1H), 2.08 – 1.99 (m, 2H), 1.73 – 1.68 (m, 2H), 1.38 – 1.30 (m, 2H), 1.16 (s, 6H). Note: One piperidine CH2was obstructed by water signal (3.31 ppm). MS (ESI) [M+H]+692.4. Example S22.3-(6-((1-(5-chloro-4-((3-(3-hydroxy-3-methylbutyl)-1-(methyl-d3)-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-5-yl)amino)pyrimidin-2-yl)piperidin-4-yl)amino)-1-methyl- 1H-indazol-3-yl)piperidine-2,6-dione (Compound 22)

[0411] Step 1: Synthesis of 3-(3-hydroxy-3-methyl-butyl)-5-nitro-1- (trideuteriomethyl)benzimidazol-2-one. To a solution of 3-(3-hydroxy-3-methyl-butyl)-5- nitro-1H-benzimidazol-2-one (137.0 mg, 0.52 mmol) in THF (15.0 mL) was added NaH (60% dispersion in mineral oil, 24.8 mg, 0.62 mmol) at rt. After stirring for 30 minutes, iodomethane- d3 (374.0 mg, 2.58 mmol) was added. The reaction vessel was sealed. The reaction mixture was heated to 50 ^C for 2 h and then cooled to rt. The volatiles were evaporated under reduced pressure. Water and ethyl acetate were added, and the layers were separated. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure to afford the title compound (130.0 mg, 90%) as a solid, which was used in the next step without further purification.1H NMR (500 MHz, DMSO) δ 8.07 (dd, J = 8.7, 2.2 Hz, 1H), 8.01 (d, J = 2.2 Hz, 1H), 7.36 (d, J= 8.7 Hz, 1H), 4.02 – 3.95 (m, 2H), 1.76 – 1.69 (m, 2H), 1.17 (s, 6H).

[0412] Step 2: Synthesis of 5-amino-3-(3-hydroxy-3-methyl-butyl)-1- (trideuteriomethyl)benzimidazol-2-one. Following General Procedure 2 with 3-(3-hydroxy- 3-methyl-butyl)-5-nitro-1-(trideuteriomethyl)benzimidazol-2-one (131.0 mg, 0.47 mmol) afforded the title compound (115.0 mg, 97%) as a solid, which was used in next step withoutfurther purification. MS (ESI) [M-OH]+252.2.

[0413] Step 3: Synthesis of 5-[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]-3-(3-hydroxy- 3-methyl-butyl)-1-(trideuteriomethyl)benzimidazol-2-one. Following General Procedure 5 with 5-amino-3-(3-hydroxy-3-methyl-butyl)-1-(trideuteriomethyl)benzimidazol-2-one (116.0 mg, 0.46 mmol) afforded the title compound (170.0 mg, 96%) as a solid, which was used in the next step without further purification. MS (ESI) [M-OH]+365.3.

[0414] Step 4: Synthesis of 3-[6-[[1-[5-chloro-4-[[3-(3-hydroxy-3-methyl-butyl)-2-oxo-1- (trideuteriomethyl)benzimidazol-5-yl]amino]pyrimidin-2-yl]-4-piperidyl]amino]-1-methyl- indazol-3-yl]piperidine-2,6-dione. Following General Procedure 10 with 5-[(5-chloro-2- fluoro-pyrimidin-4-yl)amino]-3-(3-hydroxy-3-methyl-butyl)-1-(trideuteriomethyl)benzimidazol- 2-one (100.0 mg, 0.26 mmol) and 3-[1-methyl-6-(4-piperidylamino)indazol-3-yl]piperidine-2,6- dione dihydrochloride (108.0 mg, 0.26 mmol) afforded the title compound (38.6 mg, 20%) as a solid.1H NMR (500 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.32 (s, 1H), 8.02 (s, 1H), 7.43 (d, J= 1.8 Hz, 1H), 7.35 – 7.27 (m, 2H), 7.09 (d, J= 8.4 Hz, 1H), 6.51 (dd, J= 8.8, 1.7 Hz, 1H), 6.43 (s, 1H), 5.79 – 5.70 (m, 1H), 4.44 – 4.36 (m, 2H), 4.18 (dd, J= 8.8, 5.2 Hz, 1H), 3.89 – 3.83 (m, 2H), 3.82 (s, 3H), 3.60 (br, 1H), 3.11 (t, J= 11.1 Hz, 2H), 2.63 – 2.57 (m, 2H), 2.29 – 2.21 (m, 1H), 2.17 – 2.09 (m, 1H), 2.04 – 1.95 (m, 2H), 1.73 – 1.67 (m, 2H), 1.37 – 1.27 (m, 2H), 1.15 (s, 6H). Note: The glutarimide NH could not be seen. MS (ESI) [M+H]+704.4. Example S23.2-Chloro-4-[[3-(3-hydroxy-3-methyl-butyl)-1-methyl-2-oxo-benzimidazol-5- yl]amino]pyrimidine-5-carbonitrile (Compound 23)

[0415] Step 1: Synthesis of N2-Methyl-4-nitro-benzene-1,2-diamine. To a solution of 4- nitrobenzene-1,2-diamine (15.3 g, 100.0 mmol) in DMF (115.0 mL) were sequentially added iodomethane (4.98 mL, 80.0 mmol) and a saturated aqueous solution of sodium carbonate (23.0 mL) over a period of 5 min, and the reaction mixture was stirred at rt for 18 h. The mixture was filtered and the filtrate was concentrated under reduced pressure. The material was purified by column chromatography on silica gel eluting with a DCM / hexane gradient (0-100%) to providethe title compound (11.0 g, 65%) as a solid.1H NMR (500 MHz, DMSO) δ 7.49 (dd, J = 8.7, 2.6 Hz, 1H), 7.10 (d, J = 2.5 Hz, 1H), 6.56 (d, J = 8.7 Hz, 1H), 6.11 (s, 2H), 5.24 – 5.16 (m, 1H), 2.78 (d, J = 4.9 Hz, 3H); MS (ESI) [M+H]+168.2.

[0416] Step 2: Synthesis of 3-Methyl-5-nitro-1H-benzimidazol-2-one. To a solution of N2-methyl-4-nitro-benzene-1,2-diamine (11.0 g, 65.8 mmol) in THF (175.0 mL) was added CDI (10.7 g, 65.8 mmol) and the reaction mixture was heated to 65 ^C for 18 h and then cooled to 0 ^C. The resulting precipitate was collected by filtration, washed with cold THF, then dried under vacuum to provide the title compound (9.06 g, 71%) as a solid, which was used in the next step without further purification.1H NMR (500 MHz, DMSO) δ 11.60 (br, 1H), 7.99 (d, J = 2.1 Hz, 1H), 7.97 (dd, J = 8.5, 2.3 Hz, 1H), 7.13 (d, J = 8.5 Hz, 1H), 3.36 (s, 3H); MS (ESI) [M-H]- 192.2.

[0417] Step 3: Synthesis of (3-Hydroxy-3-methyl-butyl) 4-methylbenzenesulfonate. To a solution of 3-methylbutane-1,3-diol (18.7 g, 180 mmol) in pyridine (180.0 mL) at 0 ^C was added 4-methylbenzenesulfonyl chloride (51.5 g, 270 mmol), and the reaction mixture was stirred at 0 ^C for 2 h. The mixture was poured into a cold aqueous solution of HCl (2 M, 450.0 mL). Ethyl acetate (200.0 mL) was added and the layers were separated. The aqueous layer was extracted with ethyl acetate (3 x 200.0 mL) and the combined organic layers were washed with an aqueous solution of HCl (2 M, 4 x 450.0 mL) and brine, dried (MgSO4), filtered, and concentrated under reduced pressure. The material was purified by column chromatography on silica gel eluting with an ethyl acetate / hexane gradient (30-100 %) to provide the title compound (41.4 g, 89%) as an oil.1H NMR (500 MHz, CDCl3) δ 7.80 (d, J = 8.3 Hz, 2H), 7.35 (dd, J = 8.6, 0.6 Hz, 2H), 4.21 (t, J = 6.8 Hz, 2H), 2.45 (s, 3H), 1.86 (t, J = 6.8 Hz, 2H), 1.37 (s, 1H), 1.22 (s, 6H).

[0418] Step 4: Synthesis of (3-Hydroxy-3-methyl-butyl) 4-methylbenzenesulfonate. To a solution of 3-methyl-5-nitro-1H-benzimidazol-2-one (9.00 g, 46.6 mmol) in acetonitrile (110.0 mL) were sequentially added Cs2CO3(41.0 g, 126 mmol) and (3-hydroxy-3-methyl-butyl) 4- methylbenzenesulfonate (21.2 g, 82.2 mmol). The reaction mixture was heated to 85 ^C for 18 h and then cooled to rt. The mixture was filtered and the filtrate was concentrated under reduced pressure. DCM was added and the resulting precipitate was collected by filtration and dried under vacuum to provide the title compound (6.29 g, 48%) as a solid, which was used in the next step without further purification.1H NMR (500 MHz, DMSO) δ 8.09 – 8.03 (m, 1H), 7.32 (d, J = 9.3 Hz, 1H), 4.48 (s, 1H), 4.00 – 3.93 (m, 2H), 3.42 (s, 3H), 1.75 – 1.67 (m, 2H), 1.16 (s, 6H).

[0419] Step 5: Synthesis of 5-Amino-1-(3-hydroxy-3-methyl-butyl)-3-methyl- benzimidazol-2-one. A mixture of 1-(3-hydroxy-3-methyl-butyl)-3-methyl-5-nitro- benzimidazol-2-one (1.40 g, 5.0 mmol) and Pd / C (10.0 %, 266.0 mg, 0.250 mmol) in MeOH(50.0 mL) was shaken under 50 psi hydrogen atmosphere for 4 h. The mixture was filtered through Celite and washed with MeOH. The filtrate was concentrated under reduced pressure to provide the title compound (1.25 g, 99%) as a solid, which was used in the next step without further purification.1H NMR (500 MHz, DMSO) δ 6.77 (d, J = 8.2 Hz, 1H), 6.35 (d, J = 1.9 Hz, 1H), 6.31 (dd, J = 8.2, 2.0 Hz, 1H), 4.77 (s, 2H), 4.40 (s, 1H), 3.82 – 3.75 (m, 2H), 3.20 (s, 3H), 1.68 – 1.62 (m, 2H), 1.14 (s, 6H); MS (ESI) [M+H]+250.2.

[0420] Step 6: Synthesis of 2-chloro-4-[[3-(3-hydroxy-3-methyl-butyl)-1-methyl-2-oxo- benzimidazol-5-yl]amino]pyrimidine-5-carbonitrile. Following General Procedure 1 with 5-amino-3-(3-hydroxy-3-methyl-butyl)-1-methyl-benzimidazol-2-one (100.0 mg, 0.40 mmol) and 2,4-dichloropyrimidine-5-carbonitrile (69.8 mg, 0.40 mmol) afforded the title compound (93.0 mg, 60%) as a solid, which was used in the next step without further purification.1H NMR (500 MHz, Acetic acid-d4) δ 8.58 (s, 1H), 7.52 (s, 1H), 7.34 (d, J = 8.1 Hz, 1H), 7.19 (d, J = 8.5 Hz, 1H), 4.13 – 4.06 (m, 2H), 3.47 (s, 3H), 2.01 – 1.94 (m, 2H), 1.35 (s, 6H). Note: Exchangeable protons were not observed. MS (ESI) [M-H]- 385.3.

[0421] Step 7: Synthesis of 2-[[1-[3-(2,6-Dioxo-3-piperidyl)-1-methyl-indazol-6-yl]-4- piperidyl]-methyl-amino]-4-[[3-(3-hydroxy-3-methyl-butyl)-1-methyl-2-oxo-benzimidazol- 5-yl]amino]pyrimidine-5-carbonitrile. The title compound was synthesized following General Procedure 10 with 2-chloro-4-[[3-(3-hydroxy-3-methyl-butyl)-1-methyl-2-oxo- benzimidazol-5-yl]amino]pyrimidine-5-carbonitrile (46 mg, 0.12 mmol), 3-[1-methyl-6-[4- (methylamino)-1-piperidyl]indazol-3-yl]piperidine-2,6-dione hydrochloride (70 mg, 0.18 mmol), and DIEA (0.2 mL, 1.2 mmol). The reaction mixture was heated to 100 °C for 120 h and then cooled to rt. The crude reaction mixture was purified by preparative HPLC (BEH column, C18) using a gradient of 39–49% MeCN and 10 mM ammonium formate in water to afford the title compound (21.2 mg, 25%) as a solid. MS (ESI) [M+H]+706.4;1H NMR (500 MHz, DMSO-d6) δ 8.93 (br s, 1H), 8.37 (s, 1H), 7.51 (d, J = 8.9 Hz, 1H), 7.32 (br s, 1H), 7.30 (dd, J = 8.4, 1.6 Hz, 1H), 7.07 (d, J = 8.4 Hz, 1H), 6.89 (d, J = 9.1 Hz, 1H), 6.81 (s, 1H), 4.24 (dd, J = 8.5, 5.2 Hz, 1H), 3.92 – 3.87 (m, 3H), 3.90 (s, 3H), 3.86 (br s, 1H), 3.28 (s, 3H), 3.01 (s, 3H), 2.74 (br s, 1H), 2.69 – 2.58 (m, 2H), 2.37 – 2.28 (m, 1H), 2.26 – 2.18 (m, 1H), 1.96 – 1.85 (m, 2H), 1.81 – 1.75 (m, 2H), 1.75 – 1.69 (m, 2H), 1.19 (s, 6H). Note: two exchangeable protons and two protons not visible. Example S24.3-(5-((1-(5-chloro-4-((3-(3-hydroxy-3-methylbutyl)-1-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-5-yl)amino)pyrimidin-2-yl)piperidin-4-yl)amino)-1H- benzo[d][1,2,3]triazol-1-yl)piperidine-2,6-dione (Compound 24)

[0422] Step 1: Synthesis of tert-butyl 5-amino-4-(5-bromobenzotriazol-1-yl)-5-oxo- pentanoate. To a solution of tert-butyl 5-amino-4-(2-amino-4-bromo-anilino)-5-oxo-pentanoate (5.97 g, 16.03 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 (Na2SO4), filtered, and concentrated under reduced pressure. The material was purified by column chromatography on silica gel using a gradient of 0-100% ethyl acetate in hexane to afford the title compound (2.78 g, 44%) as a solid.1H NMR (500 MHz, DMSO) δ 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.

[0423] Step 2: Synthesis of tert-butyl N-[1-(2,6-dioxo-3-piperidyl)benzotriazol-5- yl]carbamate. A mixture of tert-butyl 5-amino-4-(5-bromobenzotriazol-1-yl)-5-oxo-pentanoate (1.31 g, 3.42 mmol), tert-butyl carbamate (600.0 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 (C18) using a gradient of 0-100% acetonitrile and water (contains 0.1 formic acid) to afford the title compound (331.0 mg, 28%) as a solid.1H NMR(400 MHz, DMSO) δ 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.

[0424] Step 3: Synthesis of 3-(5-aminobenzotriazol-1-yl)piperidine-2,6-dione hydrochloride. To a solution of tert-butyl N-[1-(2,6-dioxo-3-piperidyl)benzotriazol-5- yl]carbamate (110.0 mg, 0.32 mmol) in DCM (2.0 mL) was added 4N HCl in 1,4-dioxane (0.8 mL, 3.19 mmol). The reaction mixture was stirred at rt for 4 h. The volatiles were evaporatedunder reduced pressure to afford the title compound (90.0 mg, 99% yield) as a solid, which was used in the next step without further purification.1H NMR (500 MHz, DMSO) δ 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.

[0425] Step 4: Synthesis of Tert-butyl 4-[[1-(2,6-dioxo-3-piperidyl)benzotriazol-5- yl]amino]piperidine-1-carboxylate. To a solution of 3-(5-aminobenzotriazol-1-yl)piperidine- 2,6-dione hydrochloride (171 mg, 0.61 mmol) in DMSO (4.7 mL) were sequentially added tert- butyl 4-oxopiperidine-1-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.1H NMR(500 MHz, DMSO) δ 11.23 (s, 1H), 7.48 (d, J = 8.8 Hz, 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.

[0426] Step 5: Synthesis of 3-[5-[methyl(4-piperidyl)amino]benzotriazol-1- yl]piperidine-2,6-dione hydrochloride. Following General Procedure 9 with tert-butyl 4-[[1- (2,6-dioxo-3-piperidyl)benzotriazol-5-yl]-methyl-amino]piperidine-1-carboxylate (59.0 mg, 0.13 mmol) afforded the title compound (50.0 mg, 98.9%) as a solid, which was used in the next step without further purification. MS (ESI) [M+H]+343.3.

[0427] Step 6: Synthesis of 3-[5-[[1-[5-chloro-4-[[3-(3-hydroxy-3-methyl-butyl)-1- methyl-2-oxo-benzimidazol-5-yl]amino]pyrimidin-2-yl]-4-piperidyl]amino]benzotriazol-1- yl]piperidine-2,6-dione. Following General Procedure 10 using 3-[5-(4- piperidylamino)benzotriazol-1-yl]piperidine-2,6-dione;hydrochloride (39.0 mg, 0.11 mmol) and 5-[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]-3-(3-hydroxy-3-methyl-butyl)-1-methyl- benzimidazol-2-one (42.0 mg, 0.07 mmol) afforded the title compound (34.0 mg, 46%) as a solid.1H NMR (500 MHz, DMSO) δ 11.11 (s, 1H), 8.68 (s, 1H), 8.02 (s, 1H), 7.47 (d, J = 8.9 Hz, 1H), 7.43 (s, 1H), 7.32 (dd, J = 8.4, 1.1 Hz, 1H), 7.10 (d, J = 8.5 Hz, 1H), 6.97 (d, J = 9.0 Hz, 1H), 6.94 (s, 1H), 6.04 (dd, J = 12.4, 5.0 Hz, 1H), 5.69 (d, J = 7.5 Hz, 1H), 4.40 – 4.38 (m, 2H), 3.87 – 3.84 (m, 2H), 3.59 – 3.57 (m, 2H), 3.30 (s, 3H), 3.13 (t, J = 11.6 Hz, 2H), 2.94 – 2.80 (m, 2H), 2.74 – 2.71 (m, 1H), 2.35 – 2.31 (m, 1H), 2.01 – 1.99 (m, 2H), 1.72 – 1.68 (m, 2H), 1.34 – 1.28 (m, 2H), 1.15 (s, 6H); LCMS m / z: (ESI) [M+H]+: 688.3. Example S25.3-[5-[[1-[5-chloro-4-[[3-(3-hydroxy-3-methyl-butyl)-1-methyl-2-oxo-benzimidazol-5-yl]amino]pyrimidin-2-yl]-4-piperidyl]-methyl-amino]benzotriazol-1- yl]piperidine-2,6-dione (Compound 25)

[0428] Step 1: Synthesis of tert-butyl 4-[[1-(2,6-dioxo-3-piperidyl)benzotriazol-5-yl]- methyl-amino]piperidine-1-carboxylate. To a solution of tert-butyl 4-[[1-(2,6-dioxo-3- piperidyl)benzotriazol-5-yl]amino]piperidine-1-carboxylate (200.0 mg, 0.47 mmol) in a mixture of DMSO (2.0 mL) and acetic acid (1.0 mL) were sequentially added NaBH(OAc)3 (262.0 mg, 1.24 mmol), formaldehyde (37% aqueous solution, 0.09 mL, 1.24 mmol) and Sc(Otf)3 (30.5 mg, 0.06 mmol). The reaction mixture was stirred at rt overnight. Water was added and the resulting precipitate was collected by filtration and washed with diethyl ether (5.0 mL). The material was purified by preparative HPLC (BEH, C18) using a gradient of 5-80% acetonitrile and 10 mM ammonium formate in water to afford the title compound (65.0 mg, 31%) as a solid. MS (ESI) [(M-tBu)+H]+387.3.

[0429] Step 2: Synthesis of 3-[5-[methyl(4-piperidyl)amino]benzotriazol-1- yl]piperidine-2,6-dione hydrochloride. Following General Procedure 9 using tert-butyl 4- [[1-(2,6-dioxo-3-piperidyl)benzotriazol-5-yl]-methyl-amino]piperidine-1-carboxylate (59.0 mg, 0.13 mmol) afforded the title compound (50.0 mg, 100%) as a solid. MS (ESI) [M+H]+343.3.

[0430] Step 3: Synthesis of 3-[5-[[1-[5-chloro-4-[[3-(3-hydroxy-3-methyl-butyl)-1- methyl-2-oxo-benzimidazol-5-yl]amino]pyrimidin-2-yl]-4-piperidyl]-methyl- amino]benzotriazol-1-yl]piperidine-2,6-dione. Following General Procedure 10 using 3-[5- [methyl(4-piperidyl)amino]benzotriazol-1-yl]piperidine-2,6-dione hydrochloride (25.0 mg, 70.0 µmol) and 5-[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]-3-(3-hydroxy-3-methyl-butyl)-1- methyl-benzimidazol-2-one (17.5 mg, 50.0 µmol) reacting at 100 °C overnight afforded the title compound (15.1 mg, 32%) as a solid.1H NMR (500 MHz, DMSO) δ 11.21 (br s, 1H), 8.69 (s, 1H), 8.01 (s, 1H), 7.60 (d, J = 9.2 Hz, 1H), 7.45 (d, J = 1.8 Hz, 1H), 7.36 (dd, J = 9.3, 2.0 Hz, 1H), 7.28 (dd, J = 8.4, 1.8 Hz, 1H), 7.20 (d, J = 1.7 Hz, 1H), 7.09 (d, J = 8.5 Hz, 1H), 6.10 (dd, J = 12.6, 5.0 Hz, 1H), 4.64 (d, J = 11.7 Hz, 2H), 4.43 (s, 1H), 4.00 – 3.94 (m, 1H), 3.87 – 3.83 (m, 2H), 2.95 – 2.89 (m, 4H), 2.75 (d, J = 5.0 Hz, 1H), 2.73 (s, 3H), 2.37 – 2.34 (m, 1H), 1.71– 1.61 (m, 6H), 1.15 (s, 6H); MS (ESI) [M+H]+702.4.Example S26.3-[6-[[1-[5-chloro-4-[[3-(3-hydroxy-3-methyl-butyl)-1-methyl-2-oxo- benzimidazol-5-yl]amino]pyrimidin-2-yl]-4-piperidyl]-methyl-amino]-1-methyl-indol-3- yl]piperidine-2,6-dione (Compound 26)

[0431] Step 1: Synthesis of 3-bromo-6-nitro-1H-indole. To a solution of^6-nitro-1H- indole (7.0 g, 43.2 mmol) in THF (196.0 mL) was added N-bromosuccinimide (8.3 g, 46.6 mmol). The reaction mixture was stirred at rt overnight. A saturated aqueous solution of Na2S2O3 (200.0 mL) and EtOAc (200.0 mL) were added and the layers were separated. The organic layer was washed with a saturated aqueous solution of NaHSO4(150.0 mL), a saturated aqueous solution of NaHCO3(150.0 mL), water (150.0 mL) and brine (150.0 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The material was recrystallized from DCM^and hexanes to afford the title compound (9.60 g,^92 %) as a solid.^1H NMR (400 MHz, CDCl3) δ 8.74 (s, 1H), 8.39 (d, J = 1.9 Hz, 1H), 8.11 (dd, J = 8.8, 2.0 Hz, 1H), 7.66 (d, J = 8.8 Hz, 1H), 7.53 (d, J = 2.7 Hz, 1H).

[0432] Step 2: Synthesis of 3-bromo-1-methyl-6-nitro-1H-indole. To a solution of^3- bromo-6-nitro-1H-indole 1b (9.60 g, 39.8 mmol) in DMF (196.0 mL) cooled to 0 °C were sequentially added LiHMDS (1.0 M solution in THF, 59.7 mL, 59.7 mmol) and methyl iodide (4.96 mL, 79.7 mmol). The reaction mixture was stirred at rt overnight and then cooled to 0 °C. A saturated aqueous solution of NH4Cl (150.0 mL) and EtOAc (200.0 mL) were added and the layers were separated. The organic layer was washed with 10% aqueous solution of LiCl (75.0 mL), saturated aqueous solution of NaHCO3 (75.0 mL), water (2 x 75.0 mL), and brine (75.0 mL). The organic layer was^dried over Na2SO4, filtered and concentrated under reduced pressure. The material was purified by column chromatography on silica gel using a gradient of 0-50% DCM in hexanes to afford the title compound (9.10 g, 90%) as a solid.1H NMR (500 MHz, CDCl3) δ 8.32 (d, J = 1.9 Hz, 1H), 8.08 (dd, J = 8.8, 2.0 Hz, 1H), 7.62 (d, J = 8.8 Hz, 1H), 7.36 (s, 1H), 3.90 (s, 3H).

[0433] Step 3: Synthesis of 3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-6-nitro-indole. A mixture of 2,6-dibenzyloxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (400.0 mg, 0.96 mmol),^3-bromo-1-methyl-6-nitro-indole (257.0 mg, 1.01 mmol),^Pd(dppf)Cl2·DCM (39.1 mg, 0.05 mmol) and K3PO4(617.0 mg, 2.91 mmol)^in 1,4-dioxane / water (4:1, 5.0 mL)^wasdegassed with nitrogen for 5 minutes. The reaction mixture was heated to 100 °C overnight^and then cooled to rt.^DCM (15.0 mL) was added, then the mixture was filtered through Celite and washed with ethyl acetate (3 x 10.0 mL). The filtrate was concentrated under reduced pressure and the material was purified by column chromatography on silica gel using a gradient of 0-40% ethyl acetate in hexane to afford the title compound (312.0 mg, 46%) as a solid.1H NMR (500 MHz, CDCl3) δ 8.33 (s, 1H), 7.99 (d, J = 9.0 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.73 (d, J = 8.8 Hz, 1H), 7.60 (s, 1H), 7.50 – 7.43 (m, 2H), 7.41 – 7.35 (m, 4H), 7.35 – 7.27 (m, 4H), 6.53 (d, J = 8.0 Hz, 1H), 5.47 (s, 2H), 5.40 (s, 2H), 3.90 (s, 3H); MS (ESI) [M+H]+466.1.^

[0434] Step 4: Synthesis of 3-(6-amino-1-methyl-indol-3-yl)piperidine-2,6-dione. A suspension of^3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-6-nitro-indole (5.80 g, 12.5 mmol)^and 10% Pd / C (2.43 g, 1.25 mmol)^in a mixture of THF / isopropanol (2:1, 60.0 mL) was shaken in a Parr flask at 20 psi hydrogen atmosphere at rt overnight. The reaction mixture was filtered through Celite and washed with a mixture of^THF / isopropanol^(1:1, 60.0 mL). The filtrate was concentrated under reduced pressure^to afford the title compound (2.7 g, 82 %) as a solid, which was used in the next step without further purification.1H NMR (500 MHz, DMSO) δ 10.72 (s, 1H), 7.19 – 7.09 (m, 1H), 6.81 (s, 1H), 6.47 (d, J = 1.6 Hz, 1H), 6.40 (dd, J = 8.4, 1.9 Hz, 1H), 3.94 (dd, J = 9.4, 5.0 Hz, 1H), 3.56 (s, 3H), 2.66 – 2.56 (m, 1H), 2.49 – 2.42 (m, 1H), 2.21 – 2.02 (m, 2H). Note: 2 exchangeable protons were not seen. MS (ESI) [M+H]+258.1.

[0435] Step 5: Synthesis of tert-butyl 4-[[3-(2,6-dioxo-3-piperidyl)-1-methyl-indol-6-yl]- methyl- amino]piperidine-1-carboxylate. To a solution of^3-(6-amino-1-methyl-indol-3- yl)piperidine-2,6-dione (350.0 mg, 1.36 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (285.0 mg, 1.43 mmol)^in a mixture of^1,4-dioxane (2.0 mL) and^DMSO (2.0 mL) was added decaborane (83.1 mg, 0.68 mmol). The reaction mixture was stirred at rt for 4 h. Aqueous formaldehyde (37% w / w, 1.65 g, 20.4 mmol) and decaborane (83.1 mg, 0.68 mmol) were added and the reaction mixture was stirred at rt for an additional 4 h. The volatiles were evaporated under reduced pressure and the material was purified by reverse phase chromatography (C18), using a gradient of 5-60% acetonitrile and water (contains 0.1% formic acid) to afford the title compound (450.0 mg, 69%) as a solid.1H NMR (500 MHz, DMSO) δ 10.74 (s, 1H), 7.30 (d, J = 8.7 Hz, 1H), 6.94 (s, 1H), 6.76 (dd, J = 8.8, 2.1 Hz, 1H), 6.74 – 6.71 (m, 1H), 4.10 – 3.94 (m, 3H), 3.84 – 3.71 (m, 1H), 3.66 (s, 3H), 2.84 (s, 2H), 2.71 (s, 3H), 2.68 – 2.58 (m, 1H), 2.56 – 2.50 (m, 1H), 2.22 – 2.14 (m, 1H), 2.14 – 2.05 (m, 1H), 1.69 – 1.58 (m, 2H), 1.57 – 1.45 (m, 2H), 1.40 (s, 9H);^MS (ES) [M+H]+^455.3.

[0436] Step 6: Synthesis of 3-[1-methyl-6-[methyl(4-piperidyl)amino]indol-3- yl]piperidine-2,6-dione dihydrochloride. To a solution of tert-butyl 4-[[3-(2,6-dioxo-3- piperidyl)-1-methyl-indol-6-yl]-methyl-amino]piperidine-1-carboxylate (357. mg, 0.79 mmol)^in1,4-dioxane (10.0 mL)^cooled to 0 °C was^added 4 N HCl in 1,4-dioxane (1.15 mL, 31.4 mmol). The reaction mixture was refluxed^for 4 h and then cooled to rt. The volatiles were evaporated^under reduced pressure to afford the title compound (315.0 mg, 94%) as a solid.

[0437] Step 7: Synthesis of 3-[6-[[1-[5-chloro-4-[[3-(3-hydroxy-3-methyl-butyl)-1- methyl-2-oxo-benzimidazol-5-yl]amino]pyrimidin-2-yl]-4-piperidyl]-methyl-amino]-1- methyl-indol-3-yl]piperidine-2,6-dione. Following General Procedure 10 with 5-[(5-chloro- 2-fluoro-pyrimidin-4-yl)amino]-3-(3-hydroxy-3-methyl-butyl)-1-methyl-benzimidazol-2-one (30.0 mg, 0.08 mmol) and 3-(1-methyl-6-(methyl(piperidin-4-yl)amino)-1H-indol-3- yl)piperidine-2,6-dione dihydrochloride (37.1 mg, 0.09 mmol) afforded the title compound (18.0 mg, 32%) as a solid.1H NMR (500 MHz, DMSO) δ 10.75 (s, 1H), 8.68 (s, 1H), 8.02 (s, 1H), 7.45 (d, J = 1.8 Hz, 1H), 7.37 – 7.21 (m, 2H), 7.10 (d, J = 8.4 Hz, 1H), 6.95 (s, 1H), 6.77 (dd, J = 8.9, 2.0 Hz, 1H), 6.73 (d, J = 1.9 Hz, 1H), 4.63 (d, J = 12.1 Hz, 2H), 4.43 (s, 1H), 4.00 (dd, J = 9.6, 5.0 Hz, 1H), 3.90 – 3.78 (m, 3H), 3.66 (s, 3H), 3.31 (s, 3H), 2.90 (t, J = 11.7 Hz, 2H), 2.69 (s, 3H), 2.68 – 2.60 (m, 1H), 2.24 – 2.15 (m, 1H), 2.15 – 2.06 (m, 1H), 1.74 – 1.65 (m, 4H), 1.64 – 1.53 (m, 2H), 1.16 (s, 6H), 0.98 (d, J = 6.5 Hz, 1H); LCMS (ESI) [M+H]+714.4. Example S27.3-(6-((1-(5-chloro-4-((3-(3-hydroxy-3-methylbutyl)-1-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-5-yl)amino)pyrimidin-2-yl)piperidin-4-yl)amino)-1-methyl- 1H-indol-3-yl)piperidine-2,6-dione (Compound 27)

[0438] Step 1: Synthesis of 3-(1-methyl-6-(piperidin-4-ylamino)-1H-indol-3- yl)piperidine-2,6-dione. The title compound was synthesized according to the procedures outlined in Example S26, omitting the formaldehyde portion of Step 5.

[0439] Step 2: Synthesis of 3-[6-[[1-[5-chloro-4-[[3-(3-hydroxy-3-methyl-butyl)-1- methyl-2-oxo-benzimidazol-5-yl]amino]pyrimidin-2-yl]-4-piperidyl]amino]-1-methyl-indol- 3-yl]piperidine-2,6-dione. Following General Procedure 10 with 5-[(5-chloro-2-fluoro- pyrimidin-4-yl)amino]-3-(3-hydroxy-3-methyl-butyl)-1-methyl-benzimidazol-2-one (30.0 mg, 0.079 mmol) and 3-(1-methyl-6-(piperidin-4-ylamino)-1H-indol-3-yl)piperidine-2,6-dione dihydrochloride (32.7 mg, 0.08 mmol) afforded the title compound (26.0 mg, 47%) as a solid.1H NMR (500 MHz, DMSO) δ 10.73 (s, 1H), 8.67 (s, 1H), 8.02 (s, 1H), 7.43 (s, 1H), 7.31 (d, J = 8.5 Hz, 1H), 7.16 (d, J = 8.3 Hz, 1H), 7.10 (d, J = 8.0 Hz, 1H), 6.83 (s, 1H), 6.48 (s, 1H), 6.44(d, J = 8.6 Hz, 1H), 5.13 (s, 1H), 4.44 (s, 1H), 4.39 (d, J = 12.3 Hz, 2H), 3.94 (dd, J = 9.3, 4.7 Hz, 1H), 3.89 – 3.81 (m, 2H), 3.60 (s, 3H), 3.59 – 3.53 (m, 1H), 3.30 (s, 3H), 3.10 (t, J = 12.0 Hz, 2H), 2.67 – 2.57 (m, 1H), 2.22 – 2.04 (m, 2H), 1.98 (d, J = 11.4 Hz, 2H), 1.77 – 1.61 (m, 2H), 1.37 – 1.21 (m, 2H), 1.15 (s, 6H), 1.02 – 0.88 (m, 1H); MS (ESI) [M+H]+700.4. Example S28.2-(4-(5-chloro-4-((3-(3-hydroxy-3-methylbutyl)-1-methyl-2-oxo-2,3-dihydro- 1H-benzo[d]imidazol-5-yl)amino)pyrimidin-2-yl)piperazin-1-yl)-N-(3-(2,6-dioxopiperidin- 3-yl)-1-methyl-1H-indazol-7-yl)acetamide (Compound 28)

[0440] Step 1: Synthesis of 7-Bromo-3-iodo-1H-indazole. To a solution of 7-bromo-1H- indazole (20.0 g, 101.5 mmol, 1 eq) and iodine (51.53 g, 203 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. LCMS showed the reaction was completed. The reaction mixture was quenched with water (1 L) and saturated sodium sulfite aqueous solution (40 mL). The reaction mixture was filtered and the filter cake was diluted with ethyl acetate (600 mL), then extracted with sodium sulfite (20 mL × 3). The organic phase was dried with anhydrous sodium sulfate and filtered, and the filtrate was concentrated under vacuum to afford the title compound, which was used directly in the next step without further purification.7-Bromo-3- iodo-1H-indazole (32.7 g, 101.3 mmol, 99.8% yield) was obtained as yellow solid. MS (ESI) m / z: 322.9 [M+1]+;1H NMR (400 MHz, DMSO-d6) δ 13.93 (s, 1 H), 7.64 - 7.79 (m, 1 H), 7.47 (d, J = 8.0 Hz, 1 H), 7.08 - 7.26 (m, 1 H).

[0441] Step 2: Synthesis of 7-Bromo-3-iodo-1-methyl-1H-indazole. To a solution of 7- bromo-3-iodo-1H-indazole (32.7 g, 101.3 mmol, 1 eq) in tetrahydrofuran (300 mL) was added potassium tert-butoxide (22.73 g, 202.5 mmol, 2 eq) at 0 °C, and 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 dropwise to the reaction mixture at 0 °C. Next, the mixture was stirred at 17 °C for 12 h. 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 afford the titlecompound (ESI) m / z: 336.9 [M+1]+;1H NMR (400 MHz, DMSO-d6) δ 7.66 (d, J = 7.6 Hz, 1 H), 7.40 (d, J = 8.0 Hz, 1 H), 6.95 - 7.16 (m, 1 H), 4.31 (s, 3 H).

[0442] Step 3: Synthesis of 3-(2,6-Bis(benzyloxy)pyridin-3-yl)-7-bromo-1-methyl-1H- indazole. To a solution of 7-bromo-3-iodo-1-methyl-1H-indazole (5.00 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-1,3,2- 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 reaction mixture was concentrated under vacuum and the crude 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 yellow solid. MS (ESI) m / z: 500.1 [M+1]+;1H NMR (400 MHz, DMSO-d6) δ 7.86 (d, J = 8.0 Hz, 1 H), 7.57 - 7.69 (m, 2 H), 7.45 - 7.50 (m, 2 H), 7.25 - 7.43 (m, 8 H), 6.93 (t, J = 7.6 Hz, 1 H), 6.60 (d, J = 8.0 Hz, 1 H), 5.43 (s, 4 H), 4.36 (s, 3 H).

[0443] Step 4: Synthesis of tert-butyl (3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H- indazol-7-yl)carbamate. [2-(2-aminophenyl)phenyl]-chloro-palladium;dicyclohexyl-[3-(2,4,6- triisopropylphenyl)phenyl]phosphane (1.31 g, 1.67 mmol, 0.05 eq) was added to a solution of 3- (2,6-bis(benzyloxy)pyridin-3-yl)-7-bromo-1-methyl-1H-indazole (74% purity, 16.7 g, 33.3 mmol, 1 eq), tert-butyl carbamate (3.910 g, 33.37 mmol, 1 eq) and cesium carbonate (21.75 g, 66.8 mmol, 2 eq) in dioxane (300 mL), and the mixture solution was heated to 100 °C and stirred for 16 h. The solution was filtered and the filtrate was concentrated. The resulting residue was purified by silica gel chromatography (a solution of 1% to 12% ethyl acetate in petroleum ether) to give the title compound (6.6 g, 12.3 mmol, 36% yield) as a yellow oil, detected by1H NMR. MS (ESI) m / z: 537.0 [M+1]+;1H NMR (400 MHz, CDCl3) δ = 7.85 (d, J = 8.0 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.44-7.47 (m, 1H), 7.36-7.41 (m, 2H), 7.27-7.35 (m, 4H), 7.21-7.27 (m, 3H), 6.97 (t, J = 7.6 Hz, 1H), 6.52 (d, J = 8.0 Hz, 1H), 6.40 (s, 1H), 5.45 (s, 2H), 5.41 (s, 2H), 4.29 (s, 3H), 1.54 (s, 9H).

[0444] Step 5: Synthesis of Tert-butyl (3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H- indazol-7-yl)carbamate. Pd / C (1.00 g, 10% purity) was added to a solution of tert-butyl (3- (2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazol-7-yl)carbamate (8.00 g, 14.9 mmol, 1 eq) in THF (150 mL), and the mixture was stirred under hydrogen (50 psi) at 25 °C for 24 h. The reaction was filtered through Celite 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 afford the title compound (3.60 g, 10.0 mmol, 67% yield) as a yellow solid. MS (ESI) m / z: 359.1 [M+1]+;1H NMR (400 MHz, DMSO-d6) δ = 10.91 (s, 1H), 9.10 (s, 1H), 7.57 (d, J = 7.2 Hz, 1H), 7.02-7.12 (m, 2H), 4.34-4.40 (m, 1H), 4.07 (s, 3H), 2.60-2.73 (m, 2H), 2.32-2.40(m, 1H), 2.12-2.20 (m, 1H), 1.47 (s, 9H).

[0445] Step 6: Synthesis of 3-(7-Amino-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione. Tert-butyl (3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)carbamate (3.50 g, 9.77 mmol, 1 eq) was added to hydrogen chloride aqueous solution (12 M, 50 mL, 61.44 eq) at 0 °C, and the mixture solution was stirred at 25 °C for 2 h. A yellow clear solution was obtained, and LCMS showed the mass of the desired product. The solution was poured into cold water (500 mL) at 0 °C, then the solution was lyophilized to give the title compound (2.67 g, 8.73 mmol, 89% yield, HCl salt) as a yellow solid. MS (ESI) m / z: 259.1 [M+1]+;1H NMR (400 MHz, DMSO-d6) δ = 10.91 (s, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.50 (d, J = 7.2 Hz, 1H), 7.15 (t, J = 7.6 Hz, 1H), 4.39-4.45 (m, 1H), 4.32 (s, 3H), 2.57-2.75 (m, 2H), 2.32-2.45 (m, 1H), 2.13-2.21 (m, 1H).

[0446] Step 7: Synthesis of tert-butyl 4-[2-[[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol- 7-yl]amino]-2-oxo-ethyl]piperazine-1-carboxylate. To a solution of 3-(7-amino-1-methyl- indazol-3-yl)piperidine-2,6-dione hydrochloride (300. mg, 1.02 mmol) and 2-(4-(tert- butoxycarbonyl)piperazin-1-yl)acetic acid (273.5 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. The reaction mixture was filtered and purified using reverse-phase semi-preparative HPLC (10-100% acetonitrile in water 0.1% formic acid) over 30 min to afford the title compound (164 mg, 0.3381 mmol, 33.219% yield) as a white solid. MS (ESI) m / z 485.2 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 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).

[0447] Step 8: Synthesis of N-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-7-yl]-2- piperazin-1-yl-acetamide hydrochloride. To a solution of tert-butyl 4-[2-[[3-(2,6-dioxo-3- piperidyl)-1-methyl-indazol-7-yl]amino]-2-oxo-ethyl]piperazine-1-carboxylate (164 mg, 0.34 mmol) in 1,4-dioxane (2 mL) was added hydrogen chloride 4 N in 1,4-dioxane (1.69 mL, 6.77 mmol). The solution was stirred at 80 °C for 2 hours. The solid was collected by filtration to give N-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-7-yl]-2-piperazin-1-yl- acetamide;hydrochloride (100 mg, 0.2376 mmol, 70.198% yield) as a yellow solid. MS (ESI) m / z 385.2 [M+H]+.

[0448] Step 9: Synthesis of 2-[4-[5-chloro-4-[[3-(3-hydroxy-3-methyl-butyl)-1-methyl-2- oxo-benzimidazol-5-yl]amino]pyrimidin-2-yl]piperazin-1-yl]-N-[3-(2,6-dioxo-3-piperidyl)- 1-methyl-indazol-7-yl]acetamide. Following General Procedure 10 using 5-[(5-chloro-2- fluoro-pyrimidin-4-yl)amino]-3-(3-hydroxy-3-methyl-butyl)-1-methyl-benzimidazol-2-one (20.mg, 0.0500 mmol) and N-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-7-yl]-2-piperazin-1-yl- acetamide (22.27 mg, 0.0600 mmol) afforded the title compound (12 mg, 0.014 mmol, 27% yield). LCMS [M+H] = 744.4;1H NMR (500 MHz, DMSO-d6) δ ppm 1.16 (s, 6 H) 1.69 - 1.74 (m, 2 H) 2.18 (br dd, J=13.40, 5.20 Hz, 1 H) 2.37 (dt, J=3.78, 1.89 Hz, 1 H) 2.60 - 2.64 (m, 4 H) 3.24 (s, 2 H) 3.33 (s, 3 H) 3.42 - 3.48 (m, 1 H) 3.73 (br s, 4 H) 3.85 - 3.91 (m, 2 H) 4.13 (s, 3 H) 4.30 - 4.37 (m, 1 H) 4.39 (dd, J=10.09, 5.04 Hz, 1 H) 4.43 (s, 1 H) 7.08 (d, J=7.88 Hz, 1 H) 7.11 (d, J=8.51 Hz, 1 H) 7.30 (dd, J=8.51, 1.89 Hz, 1 H) 7.34 (d, J=7.25 Hz, 1 H) 7.44 (d, J=1.58 Hz, 1 H) 7.59 (d, J=7.88 Hz, 1 H) 8.04 (s, 1 H) 8.72 (s, 1 H) 9.90 (s, 1 H) 10.89 (s, 1 H). Example S29.3-(5-((1-(5-chloro-4-((3-(3-hydroxy-3-methylbutyl)-1-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-5-yl)amino)pyrimidin-2-yl)piperidin-4-yl)(methyl)amino)-3- methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (Compound 29)

[0449] Step 1: Synthesis of tert-butyl 4-[[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo- benzimidazol-5-yl]-methyl-amino]piperidine-1-carboxylate. To a solution of tert-butyl 4- oxo-1-piperidinecarboxylate (160.3 mg, 0.80 mmol), 3-(5-amino-3-methyl-2-oxo-benzimidazol- 1-yl)piperidine-2,6-dione hydrochloride (250. mg, 0.80 mmol), and decaborane (45.1 mg, 0.40 mmol) in 1,4-dioxane (2 mL) and DMSO (2 mL) was added N,N-diisopropylethylamine (103.98 mg, 0.8000 mmol). The reaction mixture was stirred at room temperature for 2 hours. Then, paraformaldehyde 37% w / w (979 mg, 12.1 mmol) was added, followed by another portion of decaborane(14) (45.1 mg, 0.40 mmol). The resulting solution was stirred for another 4 hours. The reaction mixture was filtered and purified using reverse-phase semi-preparative HPLC (0- 95% MeCN 0.1% formic acid in water). Fractions containing clean product were concentrated under reduced pressure to about 5 mL, and the solid was collected by filtration to afford tert- butyl 4-[[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-methyl- amino]piperidine-1-carboxylate (200 mg, 0.4237 mmol, 52.665% yield) as a white solid. MS (ESI) m / z 472.2 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ ppm 11.05 (br d, J=1.71 Hz, 1 H), 6.91 (d, J=8.56 Hz, 1 H), 6.73 (d, J=2.20 Hz, 1 H), 6.56 (dd, J=8.74, 2.26 Hz, 1 H), 5.27 (dd, J=12.90, 5.32 Hz, 1 H), 4.02 (br d, J=10.76 Hz, 2 H), 3.64 - 3.80 (m, 1 H), 3.31 (s, 3 H), 2.74 - 3.03 (m, 3 H), 2.57 - 2.73 (m, 4 H), 1.92 - 2.05 (m, 1 H), 1.57 - 1.68 (m, 2 H), 1.44 - 1.57 (m, 2 H), 1.40 (s, 9 H)

[0450] Step 2: Synthesis of 3-[3-methyl-5-[methyl(4-piperidyl)amino]-2-oxo- benzimidazol-1-yl]piperidine-2,6-dione;hydrochloride. To a 80 °C solution of tert-butyl 4- [[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-methyl-amino]piperidine-1- carboxylate (184.59 mg, 0.3900 mmol) in 1,4-dioxane (4 mL) was added hydrogen chloride in 1,4 dioxane 4N (0.97 mL, 3.89 mmol). The reaction mixture was stirred at 80 °C for 1 hour. The solid was collected by filtration to give 3-[3-methyl-5-[methyl(4-piperidyl)amino]-2-oxo- benzimidazol-1-yl]piperidine-2,6-dione;hydrochloride (120 mg, 0.2651 mmol, 67.714% yield) as a white solid. MS (ESI) m / z 372.2 [M+H]+;1H NMR (400 MHz, methanol-d4) δ ppm 7.66 (d, J=1.83 Hz, 1 H), 7.47 (dd, J=8.50, 1.77 Hz, 1 H), 7.35 (d, J=8.44 Hz, 1 H), 5.44 (dd, J=12.53, 5.32 Hz, 1 H), 4.15 (br t, J=11.43 Hz, 1 H), 3.54 - 3.64 (m, 2 H), 3.52 (s, 3 H), 3.40 (s, 3 H), 3.05 - 3.18 (m, 2 H), 2.76 - 3.03 (m, 3 H), 1.93 - 2.56 (m, 5 H).

[0451] Step 3: Synthesis of 3-[5-[[1-[5-chloro-4-[[3-(3-hydroxy-3-methyl-butyl)-1- methyl-2-oxo-benzimidazol-5-yl]amino]pyrimidin-2-yl]-4-piperidyl]-methyl-amino]-3- methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione. Following General Procedure 10 using 5-[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]-3-(3-hydroxy-3-methyl-butyl)-1-methyl- benzimidazol-2-one (16.5 mg, 0.04 mmol) and 3-[3-methyl-5-[methyl(4-piperidyl)amino]-2- oxo-benzimidazol-1-yl]piperidine-2,6-dione hydrochloride (17.7 mg, 0.04 mmol) afforded the title compound (19.2 mg, 0.026 mmol, 59% yield) as a white solid. MS (ESI) m / z 731.4 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ ppm 11.05 (s, 1 H), 8.69 (s, 1 H), 8.01 (s, 1 H), 7.44 (d, J=1.83 Hz, 1 H), 7.28 (dd, J=8.44, 1.83 Hz, 1 H), 7.09 (d, J=8.44 Hz, 1 H), 6.90 (d, J=8.56 Hz, 1 H), 6.73 (d, J=2.20 Hz, 1 H), 6.56 (dd, J=8.74, 2.26 Hz, 1 H), 5.27 (dd, J=12.78, 5.32 Hz, 1 H), 4.62 (br d, J=12.35 Hz, 2 H), 4.42 (s, 1 H), 3.82 - 3.91 (m, 2 H), 3.72 - 3.82 (m, 1 H), 3.30 (s, 6 H), 2.80 - 2.98 (m, 3 H), 2.56 - 2.75 (m, 4 H), 1.92 - 2.06 (m, 1 H), 1.62 - 1.75 (m, 4 H), 1.56 (qd, J=11.88, 3.85 Hz, 2 H), 1.15 (s, 6 H). Example S30.3-(5-(4-((5-chloro-4-((3-(3-hydroxy-3-methylbutyl)-1-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-5-yl)amino)pyrimidin-2-yl)(methyl)amino)piperidin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 30)

[0452] Step 1: Synthesis of 5-bromo-2-[(4-methoxyphenyl)methyl]isoindolin-1-one. To a solution of 5-bromoisoindolin-1-one (4.11 g, 18.4 mmol) in MeCN (90.0 mL) weresequentially added Cs2CO3(18.0 g, 55.3 mmol), KI (1.53 g, 9.21 mmol) and 1-(chloromethyl)- 4-methoxy-benzene (6.44 mL, 46.1 mmol) at rt. The reaction mixture was heated to 80 ℃ overnight and then cooled to rt. Water (50.0 mL) and ethyl acetate (50.0 mL) were added and the layers were separated. The organic layer was washed with a saturated aqueous solution of NH4Cl (50.0 mL) and brine (50.0 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. Diethyl ether (150.0 mL) was added and the resulting precipitate was collected by filtration, then dried under vacuum to afford the title compound (5.14 g, 84%) as a solid, which was used in the next step without further purification.1H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 8.1 Hz, 1H), 7.53 (s, 1H), 7.22 (d, J = 8.0 Hz, 2H), 6.86 (d, J = 7.8 Hz, 2H), 4.72 (s, 2H), 4.22 (s, 2H), 3.79 (s, 3H); MS (ESI) [M+H]+332.1.

[0453] Step 2: Synthesis of 5-[4-[benzyl(methyl)amino]-1-piperidyl]-2-[(4- methoxyphenyl)methyl]isoindolin-1-one. To a solution of 5-bromo-2-[(4- methoxyphenyl)methyl]isoindolin-1-one (1.40 g, 4.21 mmol) in 1,4-dioxane (15.0 mL) was sequentially added N-benzyl-N-methyl-piperidin-4-amine (1.40 mL, 6.53 mmol), Cs2CO3(2.75 g, 8.43 mmol) and X Phos Pd G3 (357.0 mg, 0.42 mmol). The reaction mixture was heated to 80 ^C overnight and then cooled to rt. Water (60.0 mL) and ethyl acetate (60.0 mL) were added and the layers were separated. The aqueous layer was extracted with ethyl acetate (3 x 60.0 mL), and the combined organic extracts were washed with brine, then dried (Na2SO4), filtered and concentrated under reduced pressure. The resulting material was purified by column chromatography on silica gel using a gradient of 0-100% ethyl acetate in hexanes to afford the title compound (592.0 mg, 31%) as a solid. MS (ESI) [M+H]+456.4.

[0454] Step 3: Synthesis of 5-[4-[benzyl(methyl)amino]-1-piperidyl]isoindolin-1-one. A solution of 5-[4-[benzyl(methyl)amino]-1-piperidyl]-2-[(4-methoxyphenyl)methyl]isoindolin-1- one (450 mg, 0.99 mmol) in a mixture of TFA and anisole (1:1.12.0 mL) was refluxed overnight and then cooled to rt. The volatiles were evaporated under reduced pressure. Water (15.0 mL) and DCM (15.0 mL) were added and the layers were separated. The organic layer was washed with a saturated aqueous solution of NaHCO3(20.0 mL) and brine (15.0 mL), then dried (MgSO4), filtered and concentrated under reduced pressure. The material was purified by column chromatography on silica gel using a gradient of 0-30% MeOH in DCM to afford the title compound (262.0 mg, 79%) as a solid.1H NMR (400 MHz, DMSO) δ 9.45 (s, 1H), 8.14 (s, 1H), 7.55 – 7.49 (m, 5H), 7.10 – 7.07 (m, 2H), 4.53 (d, J = 13.0 Hz, 1H), 4.26 (s, 1H), 4.21 – 4.16 (m, 1H), 4.06 – 4.02 (m, 2H), 3.52 – 3.48 (m, 1H), 2.87 – 2.81 (m, 2H), 2.62 (s, 3H), 2.19 – 2.15 (m, 2H), 1.99 – 1.98 (m, 1H), 1.85 – 1.79 (m, 2H); MS (ESI) [M+H]+336.2.

[0455] Step 4: Synthesis of 3-[5-[4-[benzyl(methyl)amino]-1-piperidyl]-1-oxo- isoindolin-2-yl]piperidine-2,6-dione. To a solution of 5-[4-[benzyl(methyl)amino]-1-piperidyl]isoindolin-1-one (3.65 g, 10.9 mmol) in THF (110 mL) cooled to 0 °C was added NaH (60% dispersion in mineral oil, 652 mg, 16.35 mmol). The mixture was stirred at rt for 1 h. 3- bromopiperidine-2,6-dione (2.51 g, 13.1 mmol) and additional NaH (60% dispersion in mineral oil, 435.0 mg, 10.9 mmol) were sequentially added. The reaction mixture was stirred at rt for 2 h and at 50 °C overnight, and then cooled to rt. Water (50.0 mL) and ethyl acetate (200.0 mL) were added and the layers were separated. The organic layer was washed with brine (150.0 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The material was purified by column chromatography on silica gel using a gradient of 0-100% ethyl acetate in hexane to afford the title compound (510.0 mg, 10.5%) as a solid.1H NMR (500 MHz, DMSO) δ 10.93 (s, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.31 (d, J = 4.4 Hz, 4H), 7.25 – 7.21 (m, 1H), 7.07 – 7.01 (m, 2H), 5.04 (dd, J = 13.3, 5.1 Hz, 1H), 4.24 (dd, J = 37.2, 23.0 Hz, 2H), 3.95 – 3.89 (m, 1H), 3.57 (s, 2H), 2.93 – 2.77 (m, 3H), 2.65 – 2.57 (m, H), 2.36 (qd, J = 13.3, 4.5 Hz, 1H), 2.10 (s, 3H), 2.98 – 1.95 (m, 1H), 1.85 (d, J = 12.0 Hz, 2H), 1.59 (qd, J = 12.0, 8.8 Hz, 2H); MS (ESI) [M+H]+447.3.

[0456] Step 5: Synthesis of 3-[5-[4-(methylamino)-1-piperidyl]-1-oxo-isoindolin-2- yl]piperidine-2,6-dione. A mixture of 3-[5-[4-[benzyl(methyl)amino]-1-piperidyl]-1-oxo- isoindolin-2-yl]piperidine-2,6-dione (510 mg, 1.14 mmol) and Pd(OH)2 (160 mg, 0.22 mmol) in DMF (38 mL) was hydrogenated under a hydrogen atmosphere at rt overnight. The mixture was filtered through Celite and washed with DMF (500.0 mL). The filtrate was concentrated under reduced pressure to afford the title compound (353.0 mg, 85.1%) as a solid.1H NMR (500 MHz, DMSO) δ 10.89 (brs, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.05 – 7.03 (m, 2H), 5.04 (dd, J = 13.3, 5.1 Hz, 1H), 4.31 (d, J = 16.8 Hz, 1H), 4.19 (d, J = 16.8 Hz, 1H), 3.78 (d, J = 12.9 Hz, 2H), 2.93 – 2.86 (m, 3H), 2.60 – 2.56 (m, 1H), 2.48 – 2.46 (m, 1H), 2.40 – 2.31 (m, 1H), 2.29 (s, 3H), 1.96 – 1.94 (m, 1H), 1.88 – 1.84 (m, 2H), 1.29 (td, J = 13.5, 3.7 Hz, 2H).

[0457] Step 6: Synthesis of 3-[5-[4-[[5-chloro-4-[[3-(3-hydroxy-3-methyl-butyl)-1- methyl-2-oxo-benzimidazol-5-yl]amino]pyrimidin-2-yl]-methyl-amino]-1-piperidyl]-1-oxo- isoindolin-2-yl]piperidine-2,6-dione. Following General Procedure 10 using 5-[(5-chloro-2- fluoro-pyrimidin-4-yl)amino]-3-(3-hydroxy-3-methyl-butyl)-1-methyl-benzimidazol-2-one (10.6 mg, 0.030 mmol) and 3-[5-[4-(methylamino)-1-piperidyl]-1-oxo-isoindolin-2-yl]piperidine-2,6- dione (10 mg, 0.030 mmol) afforded the title compound (7.2 mg, 0.0099 mmol, 35% yield) as a white solid. MS (ESI) m / z 716.2 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ ppm 10.94 (s, 1 H), 8.66 (s, 1 H), 8.03 (s, 1 H), 7.51 (d, J=9.29 Hz, 1 H), 7.38 (br d, J=8.19 Hz, 1 H), 7.02 - 7.15 (m, 3 H), 5.05 (dd, J=13.33, 5.01 Hz, 1 H), 4.65 (s, 1 H), 4.44 (s, 1 H), 4.31 (s, 1 H), 4.23 (s, 1 H), 3.98 (br d, J=12.23 Hz, 2 H), 3.81 - 3.90 (m, 2 H), 3.29 (s, 3 H), 2.72 - 2.98 (m, 5 H), 2.54 - 2.64 (m, 1 H), 2.34 - 2.44 (m, 1 H), 1.91 - 2.03 (m, 1 H), 1.59 - 1.85 (m, 6 H), 1.16 (s, 6 H).Example S31.3-(5-(((1-(5-chloro-4-((3-(3-hydroxy-3-methylbutyl)-1-methyl-2-oxo-2,3- dihydro-1H-benzo[d]imidazol-5-yl)amino)pyrimidin-2-yl)piperidin-4- yl)(methyl)amino)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound 31)

[0458] Step 1: Synthesis of methyl 4-bromo-2-methyl-benzoate. To a solution of 4- bromo-2-methyl-benzoic acid (120 g, 558 mmol) in methanol (1.0 L) was added concentrated sulfuric acid (109 g, 1.12 mol, 60 mL) between 20-40 °C, then the mixture was heated to 65 °C for 18 hrs. TLC (petroleum ether / ethyl acetate = 3:1, Rf (reactant) = 0.1, Rf (product) = 0.4) indicated that the reaction was finished. The reaction mixture was concentrated, and the residue was separated between aqueous phase and organic layer. The aqueous phase was extacted with ethyl acetate (1 L x 3). The combined organic layers were washed with saturated aqueous sodium bicarbonate (500 mL) and brine (500 mL), then dried over anhydrous sodium sulfate. The mixture was filtered and the filtrate was concentrated to give methyl ...

Claims

CLAIMS 1. A compound of Formula (I)or a pharmaceutically acceptable salt thereof, wherein: R1is halo, -CN, C1-C6alkyl, or C1-C6haloalkyl; Ring A is 4- to 10-membered monocyclic or fused bicyclic heterocyclylene, 6- to 10-membered monocyclic or fused bicyclic arylene, 5- to 10-membered monocyclic or fused bicyclic heteroarylene, C4-C6cycloalkylene, or C4-C6cycloalkenylene, wherein the heterocyclylene and heteroarylene contain 1-3 heteroatoms selected from N and O; Ring B is a fused 5-membered heterocyclyl or 5-membered heteroaryl, wherein the heterocyclyl and heteroaryl contain 1-3 nitrogen atoms and are optionally substituted with 1-2 groups selected from C1-C6alkyl, halo, and oxo; each R2is independently C1-C6alkyl, halo, C1-C6haloalkyl, or C1-C6alkyl-OH, or 2 R2groups on the same carbon atom are taken together to form an oxo group, or 2 R2groups are taken together with the carbon atom to which they are attached to form a spiro C3-C6cycloalkyl, or 2 R2groups on different carbon atoms are taken together to form C1-C6alkylene or -(C1-C4alkylene)O(C1-C4alkylene)-; L1is a bond, O, C1-C6alkylene, -N(H)-, -N(C1-C6alkyl)-, or -N(C1-C6alkyl-OH)-; L2is a bond, -N(H)-, -N(C1-C6alkyl)-, -N(H)C(O)-, -N(H)C(O)(C1-C6alkylene)-, -(C1-C6alkylene)N(C1-C6alkyl)-, O, or C1-C6alkylene; Y1and Y2are independently CR4or N;R3is H, C1-C6alkyl, C1-C6alkyl-OH, -(C1-C6alkylene)O(C1-C6alkyl), -(C1-C6alkylene)NR3aR3b, or -(C1-C6alkylene)(4- to 6-membered heterocyclyl), wherein the heterocyclyl contains 1-3 heteroatoms selected from N and O, and wherein the heterocyclyl is optionally substituted by 1-5 groups selected from halo, -OH, C1-C6alkyl, and C1-C6haloalkyl; each R3aand R3bis independently H or C1-C6alkyl; each R4is independently H, halo, or C1-C6alkyl; each R5is independently halo, C1-C6alkyl, or C1-C6haloalkyl; W1is C or N; W2is C or N; Z is C or N; each R6is independently halo, C1-C6alkyl, or C1-C6haloalkyl; R7is C1-C6alkyl, C1-C6alkyl-OH, -(C1-C6alkylene)NR3aR3b, -(C1-C6alkylene)C(O)NR3aR3b, -(C1-C6alkylene)CO2(C1-C6alkyl), C3-C6cycloalkyl, -(C1-C6alkylene)(C3-C6cycloalkyl), 4- to 6-membered heterocyclyl, or -(C1-C6alkylene)(4- to 6-membered heterocyclyl), wherein the heterocyclyl contains 1-3 heteroatoms selected from N and O, and the cycloalkyl and heterocyclyl are optionally substituted by 1-5 groups selected from -OH, C1-C6alkoxy, C1-C6alkyl, halo, and C1-C6haloalkyl; m is 0-2; n is 0-5; z is 0-3; * indicates alternative points of attachment to L2; and is a single or double bond; wherein one or more hydrogen atoms in the compound are optionally replaced by deuterium.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: R1is halo, -CN, C1-C3alkyl, or C1-C3haloalkyl.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: R1is Cl, -CN, or F.

4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein: Ring A is 4- to 7-membered monocyclic heterocyclylene, 8- to 10-membered fused bicyclic heterocyclylene, phenylene, 5- to 6-membered monocyclic heteroarylene, 8- to 10- membered fused bicyclic heteroarylene, C5-C6 cycloalkylene, or C5-C6 cycloalkenylene, wherein the heterocyclylene and heteroarylene contain 1-3 heteroatoms selected from N and O; each R2is independently C1-C3alkyl, halo, C1-C3haloalkyl, or C1-C3alkyl-OH, or 2 R2groups on the same carbon atom are taken together to form an oxo group, or 2 R2groups are taken together with the carbon atom to which they are attached to for a spiro C3-C5cycloalkyl, or 2 R2groups on different carbon atoms are taken together to form C1-C3alkylene or -(C1-C3alkylene)O(C1-C3alkylene)-; and n is 0-3.

5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein:.

6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein: L1is a bond, O, C1-C3alkylene, -N(H)-, -N(C1-C3alkyl)-, or -N(C1-C3alkyl-OH)-; and L2is a bond, -N(H)-, -N(C1-C3alkyl)-, -N(H)C(O)-, -N(H)C(O)(C1-C3alkylene)-, -(C1-C3alkylene)N(C1-C3alkyl)-, O, or C1-C3alkylene.

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein: L1is a bond, O, -CH2-, -N(H)-, -N(CH3)-, or -N(CH2CH2OH)-; and L2is a bond, -N(H)-, -N(CH3)-, -N(H)C(O)-, -N(H)C(O)(CH2)-, -(CH2)N(CH3)-, O, or -CH2-.

8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein: (i) Y1and Y2are independently CR4; or (ii) Y1and Y2are each N; wherein each R4is independently H, halo, or C1-C3alkyl.

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

10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein: R3is H, C1-C3alkyl, C1-C5alkyl-OH, -(C1-C3alkylene)O(C1-C3alkyl), -(C1-C3alkylene)NR3aR3b, or -(C1-C3alkylene)(4- to 6-membered heterocyclyl), wherein the heterocyclyl contains 1-2 heteroatoms selected from N and O, and wherein the heterocyclyl is optionally substituted by 1-3 groups selected from halo, -OH, C1-C3alkyl, and C1-C3haloalkyl; R7is C1-C3alkyl, C4-C6alkyl-OH, -(C4-C6alkylene)NR3aR3b, -(C1-C3alkylene)C(O)NR3aR3b, -(C1-C3alkylene)CO2(C4-C6alkyl), C4-C6cycloalkyl, -(C1-C3alkylene)(C4-C6cycloalkyl), 4- to 6-membered heterocyclyl, or -(C1-C3alkylene)(4- to 6-membered heterocyclyl), wherein the heterocyclyl contains 1-2 heteroatoms selected from N and O, and the cycloalkyl and heterocyclyl are optionally substituted by 1-3 groups selected from -OH, C1-C3alkoxy, C1-C3alkyl, halo, and C1-C3haloalkyl; and each R3aand R3bis independently H or C1-C3alkyl.

11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein: R3is H, -CH3, -CD3, -CH2CH3, -CH(CH3)2, -CH2CH(CH3)OH, -CH2C(CH3)2OH, -CH2CH2OCH3, -CH2CH2N(CH3)2, -CH2CH2CH2N(CH3)2, -CH2CH2N(H)(CH3),R7is -CH3, -CH2CH2C(CH3)2OH, -CH2CH2CH2C(CH3)2OH, -CH2CH2CH(CH3)OH, -CH2CH2C(CH3)2NH2, -CH2CH2C(O)N(H)CH3, -CH2CH2CO2C(CH3)3,.

12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein: each R5is independently halo, C1-C3alkyl, or C1-C3haloalkyl; and z is 0 or 1.

13. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein: each R6is independently halo, C1-C3alkyl, or C1-C3haloalkyl; and m is 0 or 1.

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

15. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein: Ring B is a fused 5-membered heterocyclyl or 5-membered heteroaryl, wherein the heterocyclyl and heteroaryl contain 1-3 nitrogen atoms and are optionally substituted with 1-2 groups selected from C1-C3alkyl, halo, and oxo.

16. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt thereof, wherein:.

17. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (II), (III), (IV), (Va), or (Vb):.

18. A compound selected from the compounds of Table 1 and pharmaceutically acceptable salts thereof.

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

20. A method of (i) degrading B-cell lymphoma 6 protein (BCL6) comprising contacting BCL6 with an effective amount of the compound of any one of claims 1-18, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 19, or (ii) treating a cancer or an autoimmune disease in a subject in need thereof, comprising administering to the subject an effective amount of the compound of any one of claims 1-18, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 19.

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