BCL6 Modulators 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 the treatment of cancer or autoimmune diseases.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Application No. 63 / 336,104, filed April 28, 2022, which is incorporated by reference herein in its entirety for all purposes.

[0002] The present disclosure relates generally to compounds, compositions, and methods for their preparation and use of said compounds and compositions for the treatment of cancer or autoimmune disease. [Background technology]

[0003] BCL6 (B-cell lymphoma 6) is a member of the BTB / POZ-zinc finger family, containing a BTB / POZ domain at the N-terminus and a zinc finger at the C-terminus. As a transcription factor in follicular helper T (Tfh) cells, BCL6 is required for germinal center (GC) formation in naive B cells and, therefore, 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 disease types, including B-cell acute lymphoblastic leukemia, chronic myeloid leukemia, breast cancer, and non-small cell lung cancer (NSCLC) (Cardenas et al., Clin Cancer Res 2017, 23, 885–893). The N-terminal BTB / POZ domain binds to and recruits corepressor molecules, such as SMRT, NCOR1, and BCOR, to form class I and II histone deacetylase complexes, while the C-terminal zinc finger binds to specific DNA recognition sequences (Yang et al., Cell Dev. Biol. 2019, 7, 272). Upon binding to target genes and forming complexes, BCL6 reduces the RNA expression of its targets, including several important tumor suppressors. Overexpression of BCL6 is frequently observed in malignancies such as non-Hodgkin's lymphoma (NHL), where it causes ectopic repression of cell cycle and DNA repair checkpoint proteins, leading to uncontrolled cell proliferation and tumorigenesis.

[0004] Germinal center reactions are known to result in increased production of pathogenic autoantibodies responsible for several diseases, suggesting that strategies to inhibit or degrade BCL6 may have therapeutic applications. Structural characterization of the BCL6 BTB / POZ domain and corepressor cocrystal structures revealed that binding occurs at the lateral grooves formed by the interface between the BCL6 BTB / POZ homodimer (Melnick et al., Mol. Cell Biol. 2002, 22, 1804-1818; Ghetu et al., Mol. Cell. 2008, 29, 384-391). Subsequently, specific ligands that bind to this site were sought to exploit the binding affinity of BCL6 to make this a druggable target.

[0005] Protein degradation is a highly regulated and essential process that maintains cellular steady state. The selective identification and removal of damaged, misfolded, or excess proteins is achieved via the ubiquitin / proteasome pathway (UPP). The UPP is a central regulatory axis for almost all cellular processes. Protein ubiquitination is achieved by E3 ubiquitin ligases, which bind to proteins and attach ubiquitin molecules, thereby marking them for proteasomal degradation.

[0006] The therapeutic use of UPPs has attracted considerable interest (Zhou et al., Mol. Cell. 2000, 6, 751–756). One promising therapeutic approach involves the use of proteolysis-inducing degrading chimeric molecules, commonly referred to as PROTACs, to induce the removal of unwanted proteins by proteolysis (Scheepstra et al., Comp. Struct. Biotech. J. 2019, 17, 160–176). PROTACS are ligand-directed degraders that bring together E3 ligases and target proteins for degradation. These bivalent molecules typically consist of a small molecule bound to the target protein and an E3 ligase ligand connected via a linker moiety. PROTACs position the E3 ligase at the appropriate distance and orientation relative to the target protein, allowing the target protein to be ubiquitinated. The ubiquitinated target protein is then recognized by the proteasome for degradation.

[0007] Thus, in one aspect, provided herein are compounds that target BCL6 for degradation. Summary of the Invention

[0008] In some embodiments, the present invention describes compounds and compositions thereof for regulating BCL6.In various embodiments, the compounds and compositions thereof can be used to treat cancer.

[0009] The present embodiments may be more fully understood by reference to the detailed description and examples that are intended to be illustrative of non-limiting embodiments.

[0010] Embodiment 1. Formula (IA): [ka] or a pharmaceutically acceptable salt thereof [In the formula, X 1 and X 2are each independently N or CH, provided that X 1 and X 2 at least one of is N; R 1a and R 1b are each independently H, halo, or C1-C6 alkyl; R 2a and R 2b are each independently H, C1-C6 alkyl, —O(C1-C6 alkyl), —OH, halo, C1-C6 haloalkyl, or C1-C6 alkyl-OH; Alternatively, R 2a and R 2b together with the carbon atoms to which they are attached form a spiro C3-C5 cycloalkyl; Alternatively, R 2a and R 2b come together to form oxo; Alternatively, R 1a and R 2a together form a bridged C2-C3 alkylene; R 3a and R 3b are each independently H, halo, or C1-C6 alkyl; R 4a and R 4b are each independently H, halo, or C1-C6 alkyl; Alternatively, R 4a and R 4b together with the carbon atoms to which they are attached form a spiro C3-C5 cycloalkyl; R 5a and R 5b are each independently H, halo, or C1-C6 alkyl; w is 0 or 1; R 6 is H or C1-C6 alkyl; R 7 is H or C1-C6 alkyl; x and y are each independently 0 or 1, provided that x and y are not both 1; R8 is Cl or -CN; R 9 is F; X 3 is N or CH; z is 0 or 1; R 10a and R 10b are each independently H or halo; R 11 is H, C1-C6 alkyl, -(C1-C6 alkylene)-(5- to 6-membered heterocyclyl), -(C1-C6 alkylene)-O(C1-C6 alkyl), C1-C6 haloalkyl, C1-C6 alkyl-OH, or -(C1-C6 alkylene)-NH(C1-C6 alkyl); wherein heterocyclyl contains 1 to 3 heteroatoms selected from N, O, and S; R 12 is H, halo, or C1-C6 alkyl; R 13 is H or halo; R 14 is H or C1-C6 alkyl; X 4 is N or CR 15 and; R 15 is H or C1-C6 alkyl; X 5 and X 6 are each independently N or CH; and structure: [ka] is a single or double bond; wherein one or more hydrogen atoms in said compound may be optionally replaced with deuterium.

[0011] Embodiment 2. Formula (I): [ka] or a pharmaceutically acceptable salt thereof. [In the formula, X 1 and X 2 are each independently N or CH, provided that X 1 and X 2 at least one of is N; R 1a and R 1b are each independently H, halo, or C1-C6 alkyl; R 2a and R 2b are each independently H, C1-C6 alkyl, —OH, halo, or C1-C6 alkyl-OH; Alternatively, R 2a and R 2b together with the carbon atoms to which they are attached form a spiro C3-C5 cycloalkyl; Alternatively, R 2a and R 2b come together to form oxo; Alternatively, R 1a and R 2a together form a bridged C2-C3 alkylene; R 3a and R 3b are each independently H, halo, or C1-C6 alkyl; R 4a and R 4b are each independently H, halo, or C1-C6 alkyl; Alternatively, R 4a and R 4b together with the carbon atoms to which they are attached form a spiro C3-C5 cycloalkyl; R 5a and R 5b are each independently H, halo, or C1-C6 alkyl; w is 0 or 1; R 6 is H or C1-C6 alkyl; R 7 is H or C1-C6 alkyl; x and y are each independently 0 or 1, provided that x and y are not both 1; R 8 is Cl or -CN; R 9 is F; X 3 is N or CH; z is 0 or 1; R 10a and R 10b are each independently H or halo; R 11 is H, C1-C6 alkyl, -(C1-C6 alkylene)-(5- to 6-membered heterocyclyl), -(C1-C6 alkylene)-O(C1-C6 alkyl), C1-C6 haloalkyl, C1-C6 alkyl-OH, or -(C1-C6 alkylene)-NH(C1-C6 alkyl); wherein heterocyclyl contains 1 to 3 heteroatoms selected from N, O, and S; R 12 is H, halo, or C1-C6 alkyl; R 13 is H or halo; R 14 is H or C1-C6 alkyl; X 4 is N or CR 15 and; R 15 is H or C1-C6 alkyl; X 5 and X 6 are each independently N or CH; and structure: [ka] is a single or double bond; wherein one or more hydrogen atoms in said compound may be optionally replaced with deuterium.

[0012] Embodiment 3. X 1 is CH and X2 is N; or X 1 is N and X 2 is CH, 3. A compound according to embodiment 1 or 2, or a pharmaceutically acceptable salt thereof.

[0013] Embodiment 4. X 1 and X 2 are N, 3. A compound according to embodiment 1 or 2, or a pharmaceutically acceptable salt thereof.

[0014] Embodiment 5. R 1a and R 1b are each independently H, halo, or C1-C3 alkyl; A compound according to any one of embodiments 1 to 4, or a pharmaceutically acceptable salt thereof.

[0015] Embodiment 6. R 2a and R 2b are each independently H, C1-C3 alkyl, —OH, halo, or C1-C3 alkyl-OH; Alternatively, R 2 and R 2b together with the carbon atom to which they are attached form a spiro C3-C4 cycloalkyl, Alternatively, R 2a and R 2b together to form oxo, 6. A compound according to any one of embodiments 1 to 5, or a pharmaceutically acceptable salt thereof.

[0016] Embodiment 7. R 3a and R 3b is each independently H, halo, or C1-C3 alkyl, or a pharmaceutically acceptable salt thereof.

[0017] Embodiment 8. R 4aand R 4b are each independently H, halo, or C1-C3 alkyl; Alternatively, R 4a and R 4b together with the carbon atom to which they are attached form a spiro C3-C4 cycloalkyl; A compound according to any one of embodiments 1 to 7, or a pharmaceutically acceptable salt thereof.

[0018] Embodiment 9. R 5a and R 5b are each independently H, halo, or C1-C3 alkyl; 9. The compound of embodiment 8, or a pharmaceutically acceptable salt thereof.

[0019] Embodiment 10. structure: [ka] But the structure: [ka] 10. The compound of any one of embodiments 1 to 9, wherein:

[0020] Embodiment 11. R 11 is H, C1-C3 alkyl, -(C1-C3 alkylene)-(6-membered heterocyclyl), -(C1-C3 alkylene)-O(C1-C3 alkyl), C1-C5 haloalkyl, C1-C5 alkyl-OH, or -(C1-C3 alkylene)-NH(C1-C3 alkyl); wherein heterocyclyl contains 1 to 2 heteroatoms selected from N and O; 11. A compound according to any one of embodiments 1 to 10, or a pharmaceutically acceptable salt thereof.

[0021] Embodiment 12. structure: [ka] But the structure: [ka] 12. The compound of any one of embodiments 1 to 11, wherein:

[0022] Embodiment 13. structure: [ka] But the structure: [ka] 13. The compound of any one of embodiments 1 to 12, wherein:

[0023] Embodiment 14. structure: [ka] But the structure: [ka] 14. The compound of any one of embodiments 1 to 13, wherein:

[0024] Embodiment 15. Formula (II): [ka] Formula (III): [ka] or formula (IV): [ka] 15. The compound according to any one of embodiments 1 to 14, which is a compound of the formula: or a pharmaceutically acceptable salt thereof.

[0025] Embodiment 16. Formula (IIIb): [ka] or a pharmaceutically acceptable salt thereof.

[0026] Embodiment 17. A compound selected from the compounds set forth in Table 1, or a pharmaceutically acceptable salt thereof.

[0027] Embodiment 18. 18. A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 17, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0028] Embodiment 19. 19. A method for degrading B-cell lymphoma 6 protein (BCL6), comprising contacting BCL6 with an effective amount of a compound according to any one of embodiments 1 to 17, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 18.

[0029] Embodiment 20. 19. A method of treating cancer or an autoimmune disease in a subject in need thereof, comprising administering to the subject an effective amount of a compound according to any one of embodiments 1 to 17, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 18. DETAILED DESCRIPTION OF THE INVENTION

[0030] (Detailed Description of the Invention) (definition) As used herein, the terms "comprising" and "including" can be used interchangeably. The terms "comprising" and "including" should be interpreted to specify that the stated features or components are present exactly as stated, but do not exclude the presence or addition of one or more features, components, or groups thereof. In addition, the terms "comprising" and "including" are intended to include examples encompassed by the term "consisting of." Thus, the term "consisting of" can be used in place of the terms "comprising" and "including" to provide more specific embodiments of the invention.

[0031] The term "consisting of" means that the subject matter has at least 90%, 95%, 97%, 98%, or 99% of the recited features or components that make it up. In other embodiments, the term "consisting of" excludes from any succeeding description any other features or components, except those that are not essential to the technical effect to be achieved.

[0032] As used herein, the term "or" should be interpreted as an inclusive "or," meaning either one or any combination. Thus, "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." Exceptions to this definition occur only when combinations of elements, features, steps, or actions are, in some way, inherently mutually exclusive.

[0033] Unless otherwise indicated herein, any concentration range, percentage range, proportion range, or integer range should be understood to include any integer value within the stated range and, where appropriate, fractions thereof (e.g., tenths and hundredths of an integer value). Also, unless otherwise indicated, any numerical range stated herein with respect to any physical characteristic, such as polymer subunit, size, or thickness, should be understood to include any integer value within the stated range. As used herein, unless otherwise indicated, the terms "about" and "approximately" mean ±20%, ±10%, ±5%, or ±1% of the indicated range, value, or structure.

[0034] "Amino" refers to the group -NH2.

[0035] "Cyano" refers to the radical -CN.

[0036] "Nitro" refers to the -NO2 group.

[0037] "Oxa" refers to the group --O--.

[0038] "Oxo" refers to the group =O.

[0039] "Thioxo" refers to the group ═S.

[0040] "Imino" refers to the group =NH.

[0041] "Oximo" refers to the =N-OH group.

[0042] "Hydrazino" refers to the =N-NH2 group.

[0043] "Alkyl" refers to a straight- or branched-chain hydrocarbon group, consisting solely of carbon and hydrogen atoms, containing no unsaturation, and having from 1 to 15 carbon atoms (e.g., C1-C 15 In some embodiments, alkyl contains 1 to 13 carbon atoms (e.g., C1 to C13 In some embodiments, alkyl contains 1 to 8 carbon atoms (e.g., C1-C8 alkyl). In other embodiments, alkyl contains 1 to 5 carbon atoms (e.g., C1-C5 alkyl). In other embodiments, alkyl contains 1 to 4 carbon atoms (e.g., C1-C4 alkyl). In other embodiments, alkyl contains 1 to 3 carbon atoms (e.g., C1-C3 alkyl). In other embodiments, alkyl contains 1 to 2 carbon atoms (e.g., C1-C2 alkyl). In other embodiments, alkyl contains 1 carbon atom (e.g., C1 alkyl). In other embodiments, alkyl contains 5 to 15 carbon atoms (e.g., C5-C6 alkyl). 15 In other embodiments, alkyl contains 5 to 8 carbon atoms (e.g., C5-C8 alkyl). In other embodiments, alkyl contains 2 to 5 carbon atoms (e.g., C2-C5 alkyl). In other embodiments, alkyl contains 3 to 5 carbon atoms (e.g., C3-C5 alkyl). In other embodiments, alkyl is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (isopropyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (tert-butyl), and 1-pentyl (n-pentyl). The alkyl is attached to the remainder of the molecule by a single bond. Unless otherwise stated herein, alkyl groups are optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR a , -OC(O)-N(R a )2, -N(R a )C(O)R a , -N(R a )S(O) t R a(where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2) and -S(O) t N(R a )2 (where t is 1 or 2), where R a are each 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 a straight or branched chain alkyl group, as defined above, in which one or more hydrogen atoms are replaced with -OH. For example, "C1-C6 alkyl-OH" refers to a C1-C6 alkyl substituted with one or more -OH groups. The alkyl-OH may contain multiple hydroxy groups attached to the same carbon atom or to multiple carbon atoms.

[0045] "Alkoxy" refers to a group of the formula --O-alkyl, where alkyl is an alkyl chain as defined above, attached through an oxygen atom.

[0046] "Alkenyl" refers to a straight- or branched-chain hydrocarbon group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having from 2 to 12 carbon atoms. In some embodiments, alkenyl contains from 2 to 8 carbon atoms. In other embodiments, alkenyl contains from 2 to 4 carbon atoms. Alkenyl is attached to the remainder of the molecule by a single bond and is, 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 in the specification, alkenyl groups are optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR, and the like. a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR a , -OC(O)-N(R a )2, -N(R a )C(O)R a , -N(R a )S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2) and -S(O) t N(R a )2 (where t is 1 or 2), where R aare each 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).

[0047] "Alkynyl" refers to a straight or branched chain hydrocarbon group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, and having from 2 to 12 carbon atoms. In some embodiments, alkynyl contains from 2 to 8 carbon atoms. In other embodiments, alkynyl contains from 2 to 4 carbon atoms. An alkynyl is attached to the remainder of the molecule with a single bond and is, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise in the specification, alkynyl groups are optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR, -O-R ... a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR a , -OC(O)-N(R a )2, -N(Ra )C(O)R a , -N(R a )S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2) and -S(O) t N(R a )2 (where t is 1 or 2), where R a are each 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, consisting solely of carbon and hydrogen atoms, containing no unsaturation, having 1 to 12 carbon atoms, that links the rest of the molecule to a group, e.g., methylene, ethylene, propylene, n-butylene, etc. The alkylene chain is attached to the rest of the molecule and to the group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the group can be through one carbon atom within the alkyl chain or through any two carbon atoms within the chain. In some embodiments, alkylene contains 1 to 8 carbon atoms (e.g., C1-C8 alkylene). In other embodiments, alkylene contains 1 to 5 carbon atoms (e.g., C1-C5 alkylene). In other embodiments, alkylene contains 1 to 4 carbon atoms (e.g., C1-C4 alkylene). In other embodiments, an alkylene contains 1 to 3 carbon atoms (e.g., a C1-C3 alkylene). In other embodiments, an alkylene contains 1 to 2 carbon atoms (e.g., a C1-C2 alkylene). In other embodiments, an alkylene contains 1 carbon atom (e.g., a C1 alkylene). In other embodiments, an alkylene contains 5 to 8 carbon atoms (e.g., a C5-C8 alkylene). In other embodiments, an alkylene contains 2 to 5 carbon atoms (e.g., a C2-C5 alkylene). In other embodiments, an alkylene contains 3 to 5 carbon atoms (e.g., a C3-C5 alkylene). Unless stated otherwise in the specification, an alkylene chain is optionally substituted with one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR. a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR a , -OC(O)-N(R a )2, -N(R a )C(O)R a , -N(R a )S(O) t Ra (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2) and -S(O) t N(R a )2 (where t is 1 or 2), where R a are each 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 group derived from a monocyclic or polycyclic aromatic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The monocyclic or polycyclic aromatic hydrocarbon ring system consists solely of hydrogen and carbon and contains 5 to 18 carbon atoms, wherein at least one ring within the ring system is fully unsaturated, i.e., it contains a cyclically delocalized (4n+2) π-electron system that satisfies the Hückel rule. Ring systems from which aryl groups occur include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin, and naphthalene. Unless stated otherwise in this specification, the term "aryl" or the prefix "ar" (e.g., in "aralkyl") is intended to include aryl groups that are optionally substituted with one or more substituents independently selected from the following: 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, -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -Rb -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2), where R a are each 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); and R b are each independently a direct bond or a straight or branched chain alkylene or alkenylene; R c is a straight or branched chain alkylene or alkenylene chain, and further wherein, unless otherwise specified, each of the above substituents is unsubstituted.

[0050] "Aralkyl" means a group of the formula -Rc -aryl, where R c is an alkylene chain as defined above, e.g., methylene, ethylene, etc. The alkylene chain portion of the aralkyl group is optionally substituted as described above for an alkylene chain. The aryl portion of the aralkyl group is optionally substituted as described above for an aryl.

[0051] "Aralkenyl" means a group of the formula -R d -aryl, where R d is an alkenylene chain as defined above. The aryl part of the aralkenyl group is optionally substituted as described above for an aryl. The alkenylene chain part of the aralkenyl group is optionally substituted as described above for an alkenylene group.

[0052] "Aralkynyl" means a group of the formula -R e -aryl, where R e is an alkynylene chain as defined above. The aryl part of the aralkynyl group is optionally substituted as described above for an aryl. The alkynylene chain part of the aralkynyl group is optionally substituted as described above for an alkynylene chain.

[0053] "Carbocyclyl" refers to a stable monocyclic or polycyclic non-aromatic hydrocarbon group, consisting solely of carbon and hydrogen atoms, including fused or bridged ring systems, having 3 to 15 carbon atoms. In some embodiments, a carbocyclyl contains 3 to 10 carbon atoms. In other embodiments, a carbocyclyl contains 5 to 7 carbon atoms. A carbocyclyl is attached to the rest of the molecule by a single bond. A carbocyclyl can be saturated (i.e., consisting solely of single C-C bonds) or unsaturated (i.e., containing one or more double or triple bonds). Fully saturated carbocyclyl groups are also referred to as "carbocyclyls." Examples of monocyclic carbocyclyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Unsaturated carbocyclyls are also referred to as "cycloalkenyls." Examples of monocyclic cycloalkenyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl groups include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethylbicyclo[2.2.1]heptanyl, and the like. Unless stated otherwise in this specification, the term "carbocyclyl" is intended to include carbocyclyl groups optionally substituted with one or more substituents independently selected from the following substituents: 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, -OR a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a)C(O)OR a , -OC(O)-N(R a )2, -N(R a )C(O)R a , -N(R a )S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2) and -S(O) t N(R a )2 (where t is 1 or 2), where R a are each 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); and R b are each independently a direct bond or a straight or branched chain alkylene or alkenylene; R c is a straight or branched chain alkylene or alkenylene chain, and further wherein, unless otherwise specified, each of the above substituents is unsubstituted.

[0054] "Carbocyclylalkyl" means a group of the formula -R c-carbocyclyl, where R c is an alkylene chain as defined above. The alkylene chain and the carbocyclyl group are optionally substituted as defined above.

[0055] "Carbonyl" means a group of the formula -C(O)R 10 R 20 where R 10 and R 20 each independently represents -OH, halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -R a , -OR a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR a , -OC(O)-N(R a )2, -N(R a )C(O)R a , -N(R a )S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2), and -S(O) t N(R a )2 (where t is 1 or 2), where R aare each 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 a bromo, chloro, fluoro, or iodo substituent.

[0057] "Haloalkyl" refers to an alkyl group, as defined above, substituted with one or more halo groups, as defined above, such as 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 1 to 6 carbon atoms and is substituted with one or more halo groups (C-C haloalkyl), or the haloalkyl group has 1 to 5 carbon atoms and is substituted with one or more halo groups (C-C haloalkyl), or the haloalkyl group has 1 to 3 carbon atoms and is substituted with one or more halo groups (C-C haloalkyl). The halo groups can all be the same, or the halo groups can be different. Unless otherwise specified, the haloalkyl group is optionally substituted.

[0058] "Fluoroalkyl" refers to an alkyl group, as defined above, that is substituted with one or more fluoro groups, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc. The alkyl portion of the fluoroalkyl group may be optionally substituted as defined above for an alkyl group.

[0059] "Heterocyclyl" refers to a stable 3- to 18-membered non-aromatic ring group containing 2 to 12 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur. Unless otherwise specified herein, a heterocyclyl group is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, and may include fused or bridged ring systems. The heteroatoms of a heterocyclyl group may be optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. A heterocyclyl group may be partially or fully saturated. A heterocyclyl may be attached to the rest of the molecule through any one atom in the ring(s). Examples of such heterocyclyl groups 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-oxothiomorpholinyl, and 1,1-dioxothiomorpholinyl. Unless stated otherwise in this specification, the term "heterocyclyl" is intended to include heterocyclyl groups as defined above, optionally substituted with one or more substituents selected from the following substituents: 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, -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -Rb -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2), where R aare each 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); and R b are each independently a direct bond or a straight or branched chain alkylene or alkenylene; R c is a straight or branched chain alkylene or alkenylene chain, and further wherein, unless otherwise specified, each of the above substituents is unsubstituted.

[0060] "N-heterocyclyl" or "N-linked heterocyclyl" refers to a heterocyclyl group, as defined above, containing at least one nitrogen, and wherein the point of attachment of the heterocyclyl group to the rest of the molecule is through the nitrogen atom of the heterocyclyl group. N-heterocyclyl groups are optionally substituted as described above for heterocyclyl groups. Examples of such N-heterocyclyl groups include, but are not limited to, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl.

[0061] "C-heterocyclyl" or "C-linked heterocyclyl" refers to a heterocyclyl group, as defined above, containing at least one heteroatom, and wherein the point of attachment of the heterocyclyl group to the rest of the molecule is through a carbon atom of the heterocyclyl group. C-heterocyclyl groups are optionally substituted as described above for heterocyclyl groups. Examples of such C-heterocyclyl groups include, but are not limited to, 2-morpholinyl, 2-, 3-, or 4-piperidinyl, 2-piperazinyl, 2-, or 3-pyrrolidinyl, and the like.

[0062] "Heterocyclylalkyl" means a group of the formula -R c -heterocyclyl, where R c is an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl group at the nitrogen atom. The alkylene chain of the heterocyclylalkyl is optionally substituted as defined above for an alkylene chain. The heterocyclyl portion of the heterocyclylalkyl group is optionally substituted as defined above for a heterocyclyl group.

[0063] "Heterocyclylalkoxy" means a heterocyclyl group of the formula -OR c heterocyclyl, where R c is an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl group at the nitrogen atom. The alkylene chain of the heterocyclylalkoxy group is optionally substituted as defined above for an alkylene chain. The heterocyclyl portion of the heterocyclylalkoxy group is optionally substituted as defined above for a heterocyclyl group.

[0064] "Heteroaryl" refers to a group derived from a 3- to 18-membered aromatic ring containing 2 to 17 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur. As used herein, a heteroaryl group may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, in which at least one ring within the ring system is fully unsaturated. That is, it contains a cyclically delocalized (4n+2) π-electron system that satisfies Hückel's rule. Heteroaryl includes fused or bridged ring systems. The heteroatom(s) of a heteroaryl are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. A heteroaryl is bonded to the rest of the molecule through any atom within the ring(s). Examples of heteroaryl include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, 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]i midazo[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]pyridazinyl,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]puridinyl, and thiophenyl (i.e., thienyl). Unless otherwise stated herein, the term "heteroaryl" is intended to include heteroaryl groups, as defined above, optionally substituted with one or more substituents selected from the following: 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, -R, b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) tOR a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2), where R a are each 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); and R b are each independently a direct bond or a straight or branched chain alkylene or alkenylene; R c is a straight or branched chain alkylene or alkenylene chain, and further wherein, unless otherwise specified, each of the above substituents is unsubstituted.

[0065] "N-heteroaryl" refers to a heteroaryl group, as defined above, that contains at least one nitrogen and whose point of attachment to the rest of the molecule is through the nitrogen atom of the heteroaryl group. N-heteroaryl groups are optionally substituted as described above for heteroaryl groups.

[0066] "C-heteroaryl" refers to a heteroaryl group, as defined above, where the point of attachment of the heteroaryl group to the rest of the molecule is through a carbon atom in the heteroaryl group. C-heteroaryl groups are optionally substituted as described above for heteroaryl groups.

[0067] "Heteroarylalkyl" means a group of the formula -R c -heteroaryl group, R c is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl group at the nitrogen atom. The alkylene chain of the heteroarylalkyl group is optionally substituted as defined above for an alkylene chain. The heteroaryl portion of the heteroarylalkyl group is optionally substituted as defined above for a heteroaryl group.

[0068] "Heteroarylalkoxy" means a heteroaryl group of the formula -OR c Heteroaryl refers to a group bonded via an oxygen atom, and R c is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl group at the nitrogen atom. The alkylene chain of the heteroarylalkoxy group is optionally substituted as defined above for an alkylene chain. The heteroaryl portion of the heteroarylalkoxy group is optionally substituted as defined above for a heteroaryl group.

[0069] Embodiments of the present disclosure are intended to include pharmaceutically acceptable salts, tautomers, isotopic substitutions, and stereoisomers of the compounds provided herein, e.g., compounds of Formula (I).

[0070] As used herein, the term "pharmaceutically acceptable salt(s)" refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases, including inorganic acids and bases and organic acids and bases. Suitable pharmaceutically acceptable base addition salts of compounds of formula (I) include, but are not limited to, metallic salts formed from aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc, or organic salts formed 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 acid, alginic acid, anthranilic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethenesulfonic acid, formic acid, fumaric acid, furoic acid, galacturonic acid, gluconic acid, glucuronic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, propionic acid, salicylic acid, stearic acid, succinic acid, sulfanilic acid, sulfuric acid, tartaric acid, and p-toluenesulfonic acid. Particularly non-toxic acids include hydrochloric acid, hydrobromic acid, maleic acid, phosphoric acid, sulfuric acid, and methanesulfonic acid. Thus, examples of salts include, among others, hydrochloride, formate, and mesylate salts. For others known in the art, see, e.g., Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing (ed.), Easton PA (1990) or Remington: The Science and Practice of Pharmacy, 19th ed., Mack Publishing (ed.), Easton PA (1995).

[0071] As used herein, unless otherwise specified, the term "stereoisomer" or "stereoisomerically pure" refers to one stereoisomer of a particular compound that is substantially free of other stereoisomers of that compound. For example, a stereoisomerically pure compound with one chiral center will be substantially free of the other enantiomer of that compound. A stereoisomerically pure compound with two chiral centers will be substantially free of other diastereomers of that compound. A typical stereoisomerically pure compound contains more than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, more than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of other stereoisomers of the compound, more than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of other stereoisomers of the compound, or more than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of other stereoisomers of the compound. The compounds disclosed herein may have chiral centers and may exist as racemates, individual enantiomers or diastereomers, and mixtures thereof. All of these isomers, including mixtures thereof, are included in the embodiments disclosed herein.

[0072] The use of stereomerically pure forms of the compounds disclosed herein, as well as mixtures of those forms, are encompassed within the embodiments disclosed herein. For example, mixtures containing equivalent or unequal amounts of enantiomers of a particular compound may be used in the 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, for example, Jacques, J. et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, SH et al., Tetrahedron 33:2725 (1977); Eliel, E.L., Stereochemistry of Carbon Compounds (McGraw Hill, NY, 1962); Wilen, SH, Tables of Resolving Agents and Optical Resolutions, p. 268 (E.L. Eliel, ed., University 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 See Separation Techniques: A Practical Approach (John Wiley & Sons, 2008); Ahuja, S., Chiral Separation Methods for Pharmaceutical and Biotechnological Products (John Wiley & Sons, 2011).

[0073] "Tautomer" refers to isomers of a compound that exist in equilibrium with each other. The concentration of isomers depends on the environment in which the compound is found, and may vary depending on whether the compound is a solid or in an organic solvent or aqueous solution. For example, in aqueous solution, pyrazole may exhibit the isomers shown below, which are referred to as tautomers of each other. [ka]

[0074] As one of ordinary skill in the art would readily understand, a wide variety of functional groups and other structures may exhibit tautomerism, and all tautomers of the compounds of Formula (I) are within the scope of the present disclosure.

[0075] Polymers or similar ill-defined structures in which the substituents can be defined by an infinite series of further substituents (e.g., a substituted aryl having a substituted alkyl which is itself substituted with a substituted aryl group which is further substituted with a substituted heteroalkyl group) are not intended to be included herein. Similarly, the above definition is not intended to include impermissible substitution patterns (e.g., pentafluoromethyl or a heteroaryl group having two adjacent oxygen ring atoms). Such impermissible substitution patterns are known to those skilled in the art.

[0076] It should also be noted that the compounds disclosed herein may contain unnatural atomic isotope proportions at one or more atoms. For example, the compounds may contain tritium ( 3 H), iodine-125( 125 I), sulfur-35( 35 S), or carbon-14 ( 14 It may be labeled with a radioactive isotope such as deuterium ( 2 H), carbon-13( 13 C), or nitrogen-15( 15The term "isotopologue" refers to an isotopically enriched compound. The term "isotopically enriched" refers to an atom having an isotopic composition different from the natural isotopic composition of that atom. "Isotopically enriched" may refer to a compound containing at least one atom having an isotopic composition different from the natural isotopic composition of that atom. The term "isotopic composition" refers to the amount of each isotope present in a given atom. Radiolabeled and isotopically enriched compounds are useful as therapeutic agents, e.g., cancer therapeutic agents, research reagents, binding assay reagents, diagnostic agents, and in vivo imaging agents. All isotopic variants of the compounds described herein, whether radioactive or not, are intended to be encompassed within the scope of the embodiments provided herein. In some embodiments, isotopic substitutions of the compounds disclosed herein are provided, e.g., isotopic substitutions are compounds enriched with deuterium, carbon-13, and / or nitrogen-15. As used herein, "deuterated" refers to a compound in which at least one hydrogen (H) is replaced with a deuterium (D or 2 H), i.e., the compound is deuterium-rich in at least one position.

[0077] The present disclosure also includes "deuterated analogs" of the compounds described herein (in which 1 to n hydrogens bonded to a carbon atom have been replaced with deuterium, where n is the number of hydrogens in the molecule). When multiple deuterium atoms are present in a compound, the deuterium atoms may be in the same part of the molecule (e.g., on a single alkyl group or on a single ring) or in different parts of the molecule (e.g., on different alkyl groups or different rings). Such compounds may improve metabolic resistance and therefore may be useful for extending the half-life of any compound when administered to mammals, particularly humans. See, e.g., Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by means known in the art, e.g., using starting materials in which one or more hydrogens have been replaced with deuterium.

[0078] It is understood that, independent of the stereoisomeric or isotopic composition, each of the compounds disclosed herein can be provided in the form of any of the pharmaceutically acceptable salts discussed herein.Similarly, it is understood that the isotopic composition can vary independently of the stereoisomeric composition of each of the compounds mentioned herein.Furthermore, although the isotopic composition is limited to the elements contained in each of the compounds or their salts disclosed herein, it can otherwise vary independently of the selection of a pharmaceutically acceptable salt of each of the compounds.

[0079] It should be noted that if there is a discrepancy between a depicted structure and the name of that structure, the depicted structure should bear more weight.

[0080] "Treatment," as used herein, means alleviating, in whole or in part, a disorder, disease, or condition, or one or more symptoms associated with the disorder, disease, or condition, or slowing or arresting further progression or worsening of the symptoms, or alleviating or eradicating the cause(s) of the disorder, disease, or condition itself. In one embodiment, the disorder is cancer or a symptom thereof, as described herein.

[0081] "Prevention," as used herein, refers to a method of delaying and / or preventing, in whole or in part, the onset, recurrence, or spread of a disorder, disease, or condition, i.e., a method of protecting a subject from acquiring a disorder, disease, or condition, or a method of reducing a subject's risk of acquiring a disorder, disease, or condition. In one embodiment, the disorder is cancer or a symptom thereof, as described herein.

[0082] The term "effective amount," in reference to a compound disclosed herein, means an amount capable of treating or preventing a disorder, condition or pathology disclosed herein, or a symptom thereof.

[0083] The term "subject" or "patient," as used herein, includes, but is not limited to, animals such as cows, monkeys, horses, sheep, pigs, chickens, turkeys, quail, cats, dogs, mice, rats, rabbits, or guinea pigs, which in one embodiment are mammals, and in other embodiments are humans. In one embodiment, the subject is a human having or at risk for a BCL6-mediated disease or symptom thereof.

[0084] Although various features of the invention may be described in the context of a single embodiment, those features may also be provided separately or in any suitable subcombination. Conversely, although the invention may, for clarity, be described herein in the context of separate embodiments, the invention may also be practiced in a single embodiment.

[0085] (compound) In one aspect, provided herein is a compound of formula (IA): [ka] (IA) or a pharmaceutically acceptable salt thereof [In the formula, X 1 and X 2 are each independently N or CH, provided that X 1 and X 2 at least one of is N; R 1a and R 1b are each independently H, halo, or C1-C6 alkyl; R 2a and R 2b are each independently H, C1-C6 alkyl, —O(C1-C6 alkyl), —OH, halo, C1-C6 haloalkyl, or C1-C6 alkyl-OH; Alternatively, R 2a and R 2b together with the carbon atoms to which they are attached form a spiro C3-C5 cycloalkyl; Alternatively, R 2a and R 2b come together to form oxo; Alternatively, R 1a and R 2a together form a bridged C2-C3 alkylene; R 3a and R 3b are each independently H, halo, or C1-C6 alkyl; R 4a and R 4b are each independently H, halo, or C1-C6 alkyl; Alternatively, R 4a and R 4b together with the carbon atoms to which they are attached form a spiro C3-C5 cycloalkyl; R 5a and R 5bare each independently H, halo, or C1-C6 alkyl; w is 0 or 1; R 6 is H or C1-C6 alkyl; R 7 is H or C1-C6 alkyl; x and y are each independently 0 or 1, provided that x and y are not both 1; R 8 is Cl or -CN; R 9 is F; X 3 is N or CH; z is 0 or 1; R 10a and R 10b are each independently H or halo; R 11 is H, C1-C6 alkyl, -(C1-C6 alkylene)-(5- to 6-membered heterocyclyl), -(C1-C6 alkylene)-O(C1-C6 alkyl), C1-C6 haloalkyl, C1-C6 alkyl-OH, or -(C1-C6 alkylene)-NH(C1-C6 alkyl); wherein heterocyclyl contains 1 to 3 heteroatoms selected from N, O, and S; R 12 is H, halo, or C1-C6 alkyl; R 13 is H or halo; R 14 is H or C1-C6 alkyl; X 4 is N or CR 15 and; R 15 is H or C1-C6 alkyl; X 5 and X 6 are each independently N or CH; and structure: [ka] is a single or double bond; wherein one or more hydrogen atoms in said compound may be optionally replaced with deuterium.

[0086] In a further aspect, provided herein is a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof [In the formula, X 1 and X 2 are each independently N or CH, provided that X 1 and X 2 at least one of is N; R 1a and R 1b are each independently H, halo, or C1-C6 alkyl; R 2a and R 2b are each independently H, C1-C6 alkyl, —OH, halo, or C1-C6 alkyl-OH; Alternatively, R 2a and R 2b together with the carbon atoms to which they are attached form a spiro C3-C5 cycloalkyl; Alternatively, R 2a and R 2b come together to form oxo; Alternatively, R 1a and R 2a together form a bridged C2-C3 alkylene; R 3a and R 3b are each independently H, halo, or C1-C6 alkyl; R 4a and R 4b are each independently H, halo, or C1-C6 alkyl; Alternatively, R 4a and R 4b together with the carbon atoms to which they are attached form a spiro C3-C5 cycloalkyl; R 5a and R 5b are each independently H, halo, or C1-C6 alkyl; w is 0 or 1; R 6 is H or C1-C6 alkyl; R 7 is H or C1-C6 alkyl; x and y are each independently 0 or 1, provided that x and y are not both 1; R 8 is Cl or -CN; R 9 is F; X 3 is N or CH; z is 0 or 1; R 10a and R 10b are each independently H or halo; R 11 is H, C1-C6 alkyl, -(C1-C6 alkylene)-(5- to 6-membered heterocyclyl), -(C1-C6 alkylene)-O(C1-C6 alkyl), C1-C6 haloalkyl, C1-C6 alkyl-OH, or -(C1-C6 alkylene)-NH(C1-C6 alkyl); wherein heterocyclyl contains 1 to 3 heteroatoms selected from N, O, and S; R 12 is H, halo, or C1-C6 alkyl; R 13 is H or halo; R 14 is H or C1-C6 alkyl; X 4 is N or CR 15 and; R 15 is H or C1-C6 alkyl; X 5 and X 6 are each independently N or CH; and structure: [ka] is a single or double bond; wherein one or more hydrogen atoms in said compound may be optionally replaced with deuterium.

[0087] In some embodiments, X 1 is CH and X 2 is N. In some embodiments, X 1 is N and X 2 is CH. In some embodiments, X 1 and X 2 are both N.

[0088] In some embodiments, R 1a is H, halo, or C1-C6 alkyl. In some embodiments, R 1a is H, halo, or C1-C3 alkyl. In some embodiments, R 1a is H, F, Cl, Br, I, or C1-C3 alkyl. In some embodiments, R 1a is H, F, Cl, Br, I, methyl, ethyl, or propyl.

[0089] In some embodiments, R 1a is H.

[0090] In some embodiments, R 1a is halo. In some embodiments, R 1a is F, Cl, Br, or I. In some embodiments, R 1a is F.

[0091] In some embodiments, R 1a is C1-C6 alkyl. In some embodiments, R 1a is C1-C3 alkyl. In some embodiments, R 1a is methyl, ethyl, or propyl. In some embodiments, R 1a is methyl.

[0092] In some embodiments, R 1b is H, halo, or C1-C6 alkyl. In some embodiments, R 1b is H, halo, or C1-C3 alkyl. In some embodiments, R 1b is H, F, Cl, Br, I, or C1-C3 alkyl. In some embodiments, R 1b is H, F, Cl, Br, I, methyl, ethyl, or propyl.

[0093] In some embodiments, R 1b is H.

[0094] In some embodiments, R 1b is halo. In some embodiments, R 1b is F, Cl, Br, or I. In some embodiments, R 1b is F.

[0095] In some embodiments, R 1a and R 1b are each independently H, halo, or C1-C3 alkyl. In some embodiments, R 1a and R 1b are each independently H, F, Cl, Br, I, methyl, ethyl, or propyl. In some embodiments, R 1a and R 1b are each independently H or -CH3.

[0096] In some embodiments, R 1b is C1-C6 alkyl. In some embodiments, R 1b is C1-C3 alkyl. In some embodiments, R 1b is methyl, ethyl, or propyl. In some embodiments, R 1b is methyl.

[0097] In some embodiments, R 2ais H, C1-C6 alkyl, —O(C1-C6 alkyl), —OH, halo, C1-C6 haloalkyl, or C1-C6 alkyl-OH. 2a is H, C1-C3 alkyl, —O(C1-C3 alkyl), —OH, F, Cl, Br, I, C1-C3 haloalkyl, or C1-C3 alkyl-OH. 2a is H, methyl, ethyl, propyl, -OCH3, -OH, F, Cl, Br, I, -CF3, -CHF2, -CCl3, -CH2OH, -(CH2CH2)OH, or -(CH2CH2CH2)OH.

[0098] In some embodiments, R 2a is H.

[0099] In some embodiments, R 2a is C1-C6 alkyl. In some embodiments, R 2a is C1-C3 alkyl. In some embodiments, R 2a is methyl, ethyl, or propyl. In some embodiments, R 2a is methyl.

[0100] In some embodiments, R 2a is —O(C1-C6 alkyl). In some embodiments, R 2a is —O(C1-C3 alkyl). In some embodiments, R 2a is —OCH3, —OCH2CH3, —OCH2CH2CH3, or —OCH(CH3)2. In some embodiments, R 2a is -OCH3.

[0101] In some embodiments, R 2a is -OH.

[0102] In some embodiments, R 2a is halo. In some embodiments, R 2a is F, Cl, Br, or I. In some embodiments, R 2a is F.

[0103] In some embodiments, R 2a is C1-C6 haloalkyl. In some embodiments, R 2a is a C1-C6 haloalkyl containing 1 to 13 halogen atoms. In some embodiments, R 2a is C1-C3 haloalkyl. In some embodiments, R 2a is a C1-C3 haloalkyl containing 1 to 7 halogen atoms. In some embodiments, R 2a is —CF, —CHF, —CHF, —CCl, —CHCl, —CHCl, —CFCl, —CHCF, —CHCHF, or —CHCCl. In some embodiments, R 2a is -CF3.

[0104] In some embodiments, R 2a is C1-C6 alkyl-OH. In some embodiments, R 2a is C1-C3 alkyl-OH. In some embodiments, R 2a is —CHOH, —(CHCH)OH, or —(CHCHCH)OH. In some embodiments, R 2a is -CH2OH.

[0105] In some embodiments, R 2b is H, C1-C6 alkyl, —OH, halo, or C1-C6 alkyl-OH. In some embodiments, R 2b is H, C1-C3 alkyl, -OH, F, Cl, Br, I, or C1-C3 alkyl-OH. In some embodiments, R 2b is H, methyl, ethyl, propyl, -OH, F, Cl, Br, I, -CH2OH, -(CH2CH2)OH, or -(CH2CH2CH2)OH.

[0106] In some embodiments, R 2b is H.

[0107] In some embodiments, R 2bis C1-C6 alkyl. In some embodiments, R 2b is C1-C3 alkyl. In some embodiments, R 2b is methyl, ethyl, or propyl. In some embodiments, R 2b is methyl.

[0108] In some embodiments, R 2b is —O(C1-C6 alkyl). In some embodiments, R 2b is —O(C1-C3 alkyl). In some embodiments, R 2b is —OCH3, —OCH2CH3, —OCH2CH2CH3, or —OCH(CH3)2. In some embodiments, R 2b is -OCH3.

[0109] In some embodiments, R 2b is -OH.

[0110] In some embodiments, R 2b is halo. In some embodiments, R 2b is F, Cl, Br, or I. In some embodiments, R 2b is F.

[0111] In some embodiments, R 2b is C1-C6 haloalkyl. In some embodiments, R 2b is a C1-C6 haloalkyl containing 1 to 13 halogen atoms. In some embodiments, R 2b is C1-C3 haloalkyl. In some embodiments, R 2b is a C1-C3 haloalkyl containing 1 to 7 halogen atoms. In some embodiments, R 2b is —CF, —CHF, —CHF, —CCl, —CHCl, —CHCl, —CFCl, —CHCF, —CHCHF, or —CHCCl. In some embodiments, R 2b is -CF3.

[0112] In some embodiments, R2b is C1-C6 alkyl-OH. In some embodiments, R 2b is C1-C3 alkyl-OH. In some embodiments, R 2b is —CHOH, —(CHCH)OH, or —(CHCHCH)OH. In some embodiments, R 2b is -CH2OH.

[0113] In some embodiments, R 2a and R 2b together with the carbon atom to which they are attached form a spiro C3-C5 cycloalkyl. In some embodiments, R 2a and R 2b together with the carbon atom to which they are attached form a spiro C-C cycloalkyl. In some embodiments, R 2a and R 2b together with the carbon atom to which they are attached form a spirocyclobutyl.

[0114] In some embodiments, R 2a and R 2b together to form oxo.

[0115] In some embodiments, R 1a and R 1b are both H and R 2a and R 2b At least one of them is not H.

[0116] In some embodiments, R 1a and R 2a together form a bridged C2-C3 alkylene. In some embodiments, R 1a and R 2a together to form bridged ethylene.

[0117] In some embodiments, R 3a is H, halo, or C1-C6 alkyl. In some embodiments, R 3ais H, F, Cl, Br, I, or C1-C3 alkyl. In some embodiments, R 3a is H, F, Cl, Br, I, methyl, ethyl, or propyl.

[0118] In some embodiments, R 3a is H.

[0119] In some embodiments, R 3a is halo. In some embodiments, R 3a is F, Cl, Br, or I. In some embodiments, R 3a is F.

[0120] In some embodiments, R 3a is C1-C6 alkyl. In some embodiments, R 3a is C1-C3 alkyl. In some embodiments, R 3a is methyl, ethyl, or propyl. In some embodiments, R 3a is methyl.

[0121] In some embodiments, R 3b is H, halo, or C1-C6 alkyl. In some embodiments, R 3b is H, F, Cl, Br, I, or C1-C3 alkyl. In some embodiments, R 3b is H, F, Cl, Br, I, methyl, ethyl, or propyl.

[0122] In some embodiments, R 3b is H.

[0123] In some embodiments, R 3b is halo. In some embodiments, R 3b is F, Cl, Br, or I. In some embodiments, R 3b is F.

[0124] In some embodiments, R 3b is C1-C6 alkyl. In some embodiments, R3b is C1-C3 alkyl. In some embodiments, R 3b is methyl, ethyl, or propyl. In some embodiments, R 3b is methyl.

[0125] In some embodiments, R 4a is H, halo, or C1-C6 alkyl. In some embodiments, R 4a is H, F, Cl, Br, I, or C1-C3 alkyl. In some embodiments, R 4a is H, F, Cl, Br, I, methyl, ethyl, or propyl.

[0126] In some embodiments, R 4a is H.

[0127] In some embodiments, R 4a is halo. In some embodiments, R 4a is F, Cl, Br, or I. In some embodiments, R 4a is F.

[0128] In some embodiments, R 4a is C1-C6 alkyl. In some embodiments, R 4a is C1-C3 alkyl. In some embodiments, R 4a is methyl, ethyl, or propyl. In some embodiments, R 4a is methyl.

[0129] In some embodiments, R 4b is H, halo, or C1-C6 alkyl. In some embodiments, R 4b is H, F, Cl, Br, I, or C1-C3 alkyl. In some embodiments, R 4b is H, F, Cl, Br, I, methyl, ethyl, or propyl.

[0130] In some embodiments, R 4b is H.

[0131] In some embodiments, R 4b is halo. In some embodiments, R 4b is F, Cl, Br, or I. In some embodiments, R 4b is F.

[0132] In some embodiments, R 4b is C1-C6 alkyl. In some embodiments, R 4b is C1-C3 alkyl. In some embodiments, R 4b is methyl, ethyl, or propyl. In some embodiments, R 4b is methyl.

[0133] In some embodiments, R 4a and R 4b taken together with the carbon atom to which they are attached form a spiro C3-C5 cycloalkyl. In some embodiments, R 4a and R 4b taken together with the carbon atom to which they are attached form a spiro C-C cycloalkyl. In some embodiments, R 4a and R 4b together with the carbon atom to which they are attached form a spirocyclobutyl.

[0134] In some embodiments, R 3a , R 3b , R 4a , and R 4b are H respectively.

[0135] In some embodiments, R 3a and R 3b At least one of them is not H, but R 4a and R 4b At least one of them is not H.

[0136] In some embodiments, R 5a is H, halo, or C1-C6 alkyl. In some embodiments, R 5ais H, F, Cl, Br, I, or C1-C3 alkyl. In some embodiments, R 5a is H, F, Cl, Br, I, methyl, ethyl, or propyl.

[0137] In some embodiments, R 5a is H.

[0138] In some embodiments, R 5b is H, halo, or C1-C6 alkyl. In some embodiments, R 5b is H, F, Cl, Br, I, or C1-C3 alkyl. In some embodiments, R 5b is H, F, Cl, Br, I, methyl, ethyl, or propyl.

[0139] In some embodiments, R 5b is H.

[0140] In some embodiments, R 5a and R 5b are H respectively.

[0141] In some embodiments, R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a , and R 5b At least one of them is not H.

[0142] In some embodiments, R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a , and R 5b One, two, or three of these are not H.

[0143] In some embodiments, R1a , R 1b , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a , and R 5b One or two of these are not H.

[0144] In some embodiments, w is 0. In some embodiments, w is 1.

[0145] In some embodiments, the structure: [ka] The structure: [ka] is.

[0146] In some embodiments, x and y are each 0. In some embodiments, x is 0 and y is 1. In some embodiments, x is 1 and y is 0.

[0147] In some embodiments, R 6 is H or C1-C6 alkyl. In some embodiments, R 6 is H or C1-C3 alkyl. In some embodiments, R 6 is H, methyl, ethyl, or propyl.

[0148] In some embodiments, R 6 is H.

[0149] In some embodiments, R 6 is C1-C6 alkyl. In some embodiments, R 6 is C1-C3 alkyl. In some embodiments, R 6 is methyl, ethyl, or propyl. In some embodiments, R 6 is methyl.

[0150] In some embodiments, x is 0, y is 1, and R 6 is H.

[0151] In some embodiments, x is 0, y is 1, and R 6 is C1-C6 alkyl. In some embodiments, x is 0, y is 1, and R 6 is C1-C3 alkyl. In some embodiments, x is 0, y is 1, and R 6 is methyl.

[0152] In some embodiments, R 7 is H or C1-C6 alkyl. In some embodiments, R 7 is H or C1-C3 alkyl. In some embodiments, R 7 is H, methyl, ethyl, or propyl.

[0153] In some embodiments, R 7 is H.

[0154] In some embodiments, R 7 is C1-C6 alkyl. In some embodiments, R 7 is C1-C3 alkyl. In some embodiments, R 7 is methyl, ethyl, or propyl. In some embodiments, R 7 is methyl.

[0155] In some embodiments, x is 1, y is 0, and R 7 is H.

[0156] In some embodiments, x is 1, y is 0, and R 7 is C1-C6 alkyl. In some embodiments, x is 1, y is 0, and R 7 is C1-C3 alkyl. In some embodiments, x is 1, y is 0, and R 7 is methyl.

[0157] In some embodiments, R 8 is Cl. In some embodiments, R 8 is -CN.

[0158] In some embodiments, R 9 is F.

[0159] In some embodiments, X 3 is N. In some embodiments, X 3 is CH.

[0160] In some embodiments, z is 0. In some embodiments, z is 1.

[0161] In some embodiments, R 10a is H or halo. In some embodiments, R 10a is H, F, Cl, Br, or I.

[0162] In some embodiments, R 10a is H.

[0163] In some embodiments, R 10a is halo. In some embodiments, R 10a is H, F, Cl, Br, or I. In some embodiments, R 10a is F.

[0164] In some embodiments, R 10b is H or halo. In some embodiments, R 10b is H, F, Cl, Br, or I.

[0165] In some embodiments, R 10b is H.

[0166] In some embodiments, R 10b is halo. In some embodiments, R 10b is H, F, Cl, Br, or I. In some embodiments, R 10b is F.

[0167] In some embodiments, R 11 is H, C1-C6 alkyl, -(C1-C6 alkylene)-(5-6 membered heterocyclyl), -(C1-C6 alkylene)-O(C1-C6 alkyl), C1-C6 haloalkyl, C1-C6 alkyl-OH, or -(C1-C6 alkylene)-NH(C1-C6 alkyl), where the heterocyclyl contains 1-3 heteroatoms selected from N, O, and S. In some embodiments, R 11 is H, C1-C3 alkyl, -(C1-C3 alkylene)-(5-6 membered heterocyclyl), -(C1-C3 alkylene)-O(C1-C3 alkyl), C1-C5 haloalkyl, C1-C5 alkyl-OH, or -(C1-C3 alkylene)-NH(C1-C3 alkyl), where the heterocyclyl contains 1-3 heteroatoms selected from N, O, and S. In some embodiments, R 11 is H, C1-C3 alkyl, -(C1-C3 alkylene)-(5-6 membered heterocyclyl), -(C1-C3 alkylene)-O(C1-C3 alkyl), C1-C5 haloalkyl, C1-C5 alkyl-OH, or -(C1-C3 alkylene)-NH(C1-C3 alkyl), where the heterocyclyl contains 1-2 heteroatoms selected from N and O. In some embodiments, R 11is H, methyl, ethyl, propyl, -CD3, -(CH2)-(5-6 membered heterocyclyl), -(CH2CH2)-(5-6 membered heterocyclyl), -(CH2CH2CH2)-(5-6 membered heterocyclyl), -CH2OCH3, -CH2OCH2CH3, -CH2OCH2CH2CH3, -CH2CH2OCH3, -CH2CH2OCH2CH3, -CH2CH2CH2OCH3, -CH2CH2CH2OCH2CH3, -CH2CH2CH2OCH2CH3, -CH2CH2CH2OCH2CH3, -(CH2)3CF3, -(CH2)3CHF2, -(CH2)3CH2F, -CH2CF2CH3, -CH2CHFCH3, -CH2CF2CH3, -CH2CH2CF3, -CH2 CHCF(CH), -CHCHCF(CH), -CHOH, -CHCHOH, -CHCHCHOH, -CHCHCH(OH)(CH), -CHCHC(OH)(CH), -CH-N(H)CH, -CH-N(H)CHCH, -CH-N(H)CHCH, -CH-N(H)CHCH, -CH-N(H)CHCH, -CHCH-N(H)CH, -CHCH-N(H)CHCH, -CHCH-N(H)CHCH, -CHCHCH-N(H)CHCH, or -CHCHCH-N(H)CHCHCH, where the heterocyclyl contains 1 to 2 heteroatoms selected from N and O.

[0168] In some embodiments, R 11 is H.

[0169] In some embodiments, R 11 is C1-C6 alkyl. In some embodiments, R 11 is C1-C3 alkyl. In some embodiments, R 11 is methyl, ethyl, propyl, or -CD3. In some embodiments, R 11 is —CH3. In some embodiments, R 11 contains one or more deuterium atoms. In some embodiments, R 11 is -CD3. In some embodiments, R 11is -CH2CH3. In some embodiments, R 11 is -CH(CH3)2.

[0170] In some embodiments, R 11 is -(C1-C6 alkylene)-(5-6 membered heterocyclyl), where the heterocyclyl contains 1-3 heteroatoms selected from N, O, and S. In some embodiments, R 11 is -(C1-C3 alkylene)-(5-6 membered heterocyclyl), where the heterocyclyl contains 1-3 heteroatoms selected from N, O, and S. In some embodiments, R 11 is -(C1-C3 alkylene)-(5-6 membered heterocyclyl), where the heterocyclyl contains 1-2 heteroatoms selected from N and O. In some embodiments, R 11 The structure: [ka] is.

[0171] In some embodiments, R 11 is -(C1-C6 alkylene)-O(C1-C6 alkyl). In some embodiments, R 11 is -(C1-C3 alkylene)-O(C1-C3 alkyl). In some embodiments, R 11 is -CH2OCH3, -CH2OCH2CH3, -CH2OCH2CH2CH3, -CH2CH2OCH3, -CH2CH2OCH2CH3, -CH2CH2OCH2CH2CH3, -CH2CH2CH2OCH3, -CH2CH2CH2OCH2CH3, or -CH2CH2CH2OCH2CH2CH3. In some embodiments, R 11 is -CH2CH2OCH3.

[0172] In some embodiments, R 11 is C1-C6 haloalkyl. In some embodiments, R 11 is C1-C5 haloalkyl. In some embodiments, R 11is -CF3, -CH2CH2F3, -(CH2)2CHF3, -(CH2)3CF3, -CH2CF(CH3)2, -CH2CF2CH3, -CH2CF3, -CH2CH2CF(CH3)2, -CH2CH2CF2CH3, or -CH2CH2CF3. In some embodiments, R 11 is -(CH2)3CF3, -CH2CF2CH3, -CH2CH2CF(CH3)2, or -CH2CF(CH3)2.

[0173] In some embodiments, R 11 is C1-C6 alkyl-OH. In some embodiments, R 11 is C1-C5 alkyl-OH. In some embodiments, R 11 is —CHOH, —CHCHOH, —CHCHCHOH, —CHCHCH(OH)(CH), or —CHCHC(OH)(CH). In some embodiments, R 11 teeth -CH2CH2C(OH)(CH3)2.

[0174] In some embodiments, R 11 is -(C1-C6 alkylene)-NH(C1-C6 alkyl). In some embodiments, R 11 is -(C1-C3 alkylene)-NH(C1-C3 alkyl). In some embodiments, R 11 is -CH2-N(H)CH3, -CH2-N(H)CH2CH3, -CH2-N(H)CH2CH2CH3, -CH2CH2-N(H)CH3, -CH2CH2-N(H)CH2CH2CH3, -CH2CH2-N(H)CH2CH2CH3, -CH2CH2CH2-N(H)CH3, -CH2CH2CH2-N(H)CH2CH2CH3, or -CH2CH2CH2-N(H)CH2CH2CH3. In some embodiments, R 11 is -CH2CH2N(H)CH3.

[0175] In some embodiments, the structure: [ka] The structure: [ka] is.

[0176] In some embodiments, R 12 is H, halo, or C1-C6 alkyl. In some embodiments, R 12 is H, F, Cl, Br, I, or C1-C3 alkyl. In some embodiments, R 12 is H, F, Cl, Br, I, methyl, ethyl, or propyl.

[0177] In some embodiments, R 12 is H.

[0178] In some embodiments, R 12 is halo. In some embodiments, R 12 is F, Cl, Br, or I. In some embodiments, R 12 is F.

[0179] In some embodiments, R 12 is C1-C6 alkyl. In some embodiments, R 12 is C1-C3 alkyl. In some embodiments, R 12 is methyl, ethyl, or propyl. In some embodiments, R 12 is methyl.

[0180] In some embodiments, the structure: [ka] The structure: [ka] is.

[0181] In some embodiments, R 13 is H or halo. In some embodiments, R 13is H, F, Cl, Br, or I.

[0182] In some embodiments, R 13 is H.

[0183] In some embodiments, R 13 is halo. In some embodiments, R 13 is F, Cl, Br, or I. In some embodiments, R 13 is F.

[0184] In some embodiments, R 14 is H or C1-C6 alkyl. In some embodiments, R 14 is H or C1-C3 alkyl. In some embodiments, R 14 is H, methyl, ethyl, or propyl.

[0185] In some embodiments, R 14 is H.

[0186] In some embodiments, R 14 is C1-C6 alkyl. In some embodiments, R 14 is C1-C3 alkyl. In some embodiments, R 14 is methyl, ethyl, or propyl. In some embodiments, R 14 is methyl.

[0187] In some embodiments, R 14 is H. In some embodiments, R 14 is methyl.

[0188] In some embodiments, X 4 is N. In some embodiments, X 4 is CR 15 is.

[0189] In some embodiments, R 15 is H or C1-C6 alkyl. In some embodiments, R 15is H or C1-C3 alkyl. In some embodiments, R 15 is H, methyl, ethyl, or propyl.

[0190] In some embodiments, R 15 is H.

[0191] In some embodiments, R 15 is C1-C6 alkyl. In some embodiments, R 15 is C1-C3 alkyl. In some embodiments, R 15 is methyl, ethyl, or propyl. In some embodiments, R 15 is methyl.

[0192] In some embodiments, X 5 is N. In some embodiments, X 5 is CH.

[0193] In some embodiments, X 6 is N. In some embodiments, X 6 is CH.

[0194] In some embodiments, the structure: [ka] is a single bond. In some embodiments, the structure: [ka] is a double bond.

[0195] In some embodiments, structure: [ka] The structure: [ka] is.

[0196] In some embodiments, the compound of Formula (IA) or Formula (I) has Formula (II): [ka] is a compound of [In the formula, R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 7 , R 8 , R 9 , R 10a , R 10b , R 11 , R 12 , R 13 , R 14 , R 15 , X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , w, z, and structure: [ka] is as described for formula (IA) or formula (I)].

[0197] In some embodiments, the compound of Formula (IA) or Formula (I) has the formula (IIa): [ka] is a compound of [In the formula, R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 7 , R 8 , R 9 , R 11, R 12 , R 13 , R 14 , R 15 , X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , w, z, and structure: [ka] is as described for formula (IA) or formula (I)].

[0198] In some embodiments, the compound of Formula (IA) or Formula (I) has Formula (IIb): [ka] is a compound of [In the formula, R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 7 , X 1 , X 2 and w is as described for formula (IA) or formula (I)].

[0199] In some embodiments, the compound of Formula (IA) or Formula (I) has Formula (IIc): [ka] is a compound of [In the formula, R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 7 , X 1 , and X 2is as described for formula (IA) or formula (I)].

[0200] In some embodiments, the compound of Formula (IA) or Formula (I) has Formula (III): [ka] is a compound of [In the formula, R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6 , R 8 , R 9 , R 10a , R 10b , R 11 , R 12 , R 13 , R 14 , R 15 , X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , w, z, and structure: [ka] is as described for formula (IA) or formula (I)].

[0201] In some embodiments, the compound of Formula (IA) or Formula (I) has Formula (IIIa): [ka] is a compound of [In the formula, R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a , R5b , R 6 , R 8 , R 9 , R 11 , R 12 , R 13 , R 14 , R 15 , X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , w, z, and structure: [ka] is as described for formula (IA) or formula (I)].

[0202] In some embodiments, the compound of Formula (IA) or Formula (I) has Formula (IIIb): [ka] is a compound of [In the formula, R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , and R 11 is as described for formula (IA) or formula (I)].

[0203] In some embodiments, the compound of Formula (IA) or Formula (I) has Formula (IV): [ka] is a compound of [In the formula, R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 8 , R9 , R 10a , R 10b , R 11 , R 12 , R 13 , R 14 , R 15 , X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , w, z, and structure: [ka] is as described for formula (IA) or formula (I)].

[0204] In some embodiments, the compound of Formula (IA) or Formula (I) is (IVa): [ka] is a compound of [In the formula, R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 8 , R 9 , R 11 , R 12 , R 13 , R 14 , R 15 , X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , w, z, and structure: [ka] is as described for formula (IA) or formula (I)].

[0205] In some embodiments, the compound of Formula (IA) or Formula (I) has Formula (IVb): [ka] is a compound of [In the formula, R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , X 1 , X 2 and w is as described for formula (IA) or formula (I)].

[0206] In some embodiments, the compound of Formula (IA) or Formula (I) has Formula (IVc): [ka] is a compound of [In the formula, R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , X 1 , and X 2 is as described for formula (IA) or formula (I)].

[0207] In some embodiments, the compound of Formula (IA) or Formula (I) has Formula (IVd): [ka] is a compound of [In the formula, R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , R 4a , and R 4bis as described for formula (IA) or formula (I)].

[0208] It is understood that any compound described herein may contain one or more deuterium replacements of hydrogen atoms. Any one or more substituents of Formula (IA) or Formula (I) may be deuterated, e.g., X 1 , X 2 , X 3 , X 5 , X 6 , R 1a , R 1b , R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6 , R 7 , R 10a , R 10b , R 11 , R 12 , R 13 , R 14 , and R 15 For example, in some embodiments, R 11 is a deuterated group, for example, -CD3.

[0209] In this description, it is understood that every statement, variation, embodiment, or aspect of Formula (IA) or Formula (I) applies equally to, and is equally described, other formulas detailed herein, where applicable, in the same manner as if every statement, variation, embodiment, or aspect were listed separately and individually. It is also understood that every statement, variation, embodiment, or aspect of Formula (IA) or Formula (I) applies equally to, and is equally described, other formulas detailed herein, where applicable, in the same manner as if every statement, variation, embodiment, or aspect were listed separately and individually for all formulas. For example, any statement, variation, embodiment, or aspect of Formula (IA) or Formula (I) applies equally to, and is equally described as, any formula described herein, e.g., Formulas (II), (IIa), (IIb), (IIc), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (IVc), and (IVd), where applicable, in the same manner as if every statement, variation, embodiment, or aspect were listed separately and individually for all formulas.

[0210] In some embodiments, provided is a compound selected from the compounds set forth in Table 1, or a pharmaceutically acceptable salt thereof. Although some compounds described in this disclosure, including those in Table 1, are presented as specific stereoisomeric and / or non-stereochemical forms, it is understood that any or all stereochemical forms, including any enantiomeric or diastereomeric forms, and any tautomeric or other forms of any compound of this disclosure, including the structures set forth in Table 1, are described herein. [Table 1] [Table 2] [Table 3] [Table 4]

Table 5

Table 6

Table 7

Table 8

Table 9

Table 11

Table 14

Table 15

Table 17

Table 19

[0211] All compounds of formula (IA) or formula (I) that exist in free base or free acid form can be converted into their pharmaceutically acceptable salts by treatment with an appropriate inorganic or organic base or acid, by methods known to those skilled in the art. Salts of compounds of formula (IA) or formula (I) can be converted into the free base or free acid form by standard methods.

[0212] (Synthesis method) The compounds described herein can be synthesized using conventional organic synthesis methods and commercially available starting materials, or using the methods provided herein. By way of example, and not limitation, compounds of formula (Ia) through formula (Ih) can be prepared according to Schemes 1-4 and the Examples described herein. It should be noted that one of ordinary skill in the art would understand how to modify the procedures shown in the illustrative schemes and Examples to obtain the desired products. [ka] In the scheme, X 3 , R 8 , R 9 , R 10a , R 10b , R 11 , R 12 and z are as defined for formula (IA) or formula (I); LG1 is a leaving group, for example, an OT, an OM, or I; LG2 and LG3 are each independently a leaving group, for example, F or Cl. [ka] In the scheme, X 5 , X 6 , R 6 , and R 7 is as defined for formula (IA) or formula (I); LG4 is a leaving group, for example, Br or Cl; Y is H, C1-C6 alkyl, 6- or 7-membered heterocyclyl, or Boc, where heterocyclyl contains 1 to 3 heteroatoms selected from N, O, and S; PG is a protecting group, for example, Boc; R b is R 1a , R 2a , R 3a , R 4a , R 5a , R 2b , R 3b , R 4b , and R 5b X' is CH, CH, N, or NH; and the structure: [ka] is a 6- or 7-membered heterocyclyl; Bn is benzyl. [ka] In the scheme, PG is a protecting group, for example, Fmoc or Boc; LG4 is a leaving group, for example, Br or Cl; R 6 is as defined for formula (IA) or formula (I); Y is H, C1-C6 alkyl, 6- or 7-membered heterocyclyl, or Boc, where the heterocyclyl contains 1 to 3 heteroatoms selected from N, O, and S. [ka] In the scheme, X 3 , X 4 , R 6 , R 8 , R 9 , R 10a , R 10b , R 11 , R 12 , R 13 , z is as defined for formula (IA) or formula (I); LG3 is a leaving group, e.g., OTs, OMs, F, Cl, or I; R b is R 1a , R 2a , R 3a , R 4a , R 5a , R 2b , R 3b , R 4b , or R 5b which are as defined for formula (IA) or formula (I); [ka] is a 6- or 7-membered heterocyclyl.

[0213] As shown in Scheme 1, compounds of formula (i-1) containing an oxoindole structure can be synthesized by coupling indole derivative a with intermediate compound b to form intermediate compound c, which is then treated with nitric acid to form intermediate compound d, whose nitro group is reduced to form intermediate compound e, which is subsequently coupled with intermediate f to form compounds of formula (i-1).

[0214] Scheme 2 provides two routes for synthesizing compounds of formula (i-2) containing a glutarimide structure. Indazole derivative g can be coupled with intermediate compound h to give intermediate compound i. Intermediate compound i is deprotected and further reduced to form intermediate compound j, which is then deprotected to form compounds of formula (i-2). Alternatively, indazole derivative g can be coupled with intermediate compound k to give intermediate compound l. Intermediate compound l is deprotected and further reduced to form intermediate compound i, which is then deprotected at the amine to form compounds of formula (i-2).

[0215] Scheme 3 provides the synthesis of compounds of formula (i-2) containing a dihydrouridine structure. Indazole derivative n can be coupled with intermediate compound h to give intermediate compound o, which is deprotected to form intermediate compound p, which is subsequently deprotected to form compounds of formula (i-2).

[0216] Scheme 4 provides multiple routes for synthesizing various compounds of formula (IA) or formula (I). Compounds of formula (i-1) can be coupled with various derivatives of compounds of formula (i-2) (represented as formulas (i-2a) to (i-2h)) to obtain compounds of formula (Ia) to (Ih).

[0217] (How to use) Embodiments of the present disclosure provide a method for modulating BCL6 in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (IA) or Formula (I). Modulation (e.g., inhibition or activation) of BCL6 can be assessed and demonstrated by various means known in the art. Kits and commercially available assays can be used to determine whether and to what extent BCL6 is modulated (inhibited or activated).

[0218] In one aspect, provided herein are methods of modulating BCL6, comprising contacting BCL6 with an effective amount of a compound of Formula (IA) or Formula (I), or any embodiment or variation thereof. In some embodiments, the compound of Formula (IA) or Formula (I) inhibits BCL6. In some embodiments, the compound of Formula (IA) or Formula (I) causes degradation of BCL6.

[0219] In some embodiments, a compound of Formula (IA) or 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, the compounds of Formula (IA) or Formula (I) enhance 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%, 100-100%, 110-100%, 120-100%, 130-100%, 140-100%, 150-100%, 160-100%, 170-100%, 180-100%, 190-100%, 210-100%, 220-100%, 230-100%, 240-100%, 250-100%, 260-100%, 270-100%, 280-100%, 290-100%, 300-100%, 310-100%, 320-100%, 330-100%, 340-100%, 350-100%, 360-100%, 370-100%, 380-100%, 390-100%, 400-100%, 410-100%, 420-100%, 430-100%, 440-100%, 450-100%, 460-100%, 470 Adjust from 0%, 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%.

[0220] Some embodiments of the present disclosure also provide a method for degrading BCL6 in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (IA) or Formula (I). BCL6 degradation can be assessed and demonstrated by various means known in the art. Kits and commercially available assays, including cell-based assays, can be used to determine whether and to what extent BCL6 has been degraded.

[0221] In one aspect, provided herein are methods of degrading BCL6, comprising contacting BCL6 with an effective amount of a compound of Formula (IA) or Formula (I), or any embodiment or variation thereof. In some embodiments, the compound of Formula (IA) or Formula (I) partially degrades BCL6. In some embodiments, the compound of Formula (IA) or Formula (I) completely degrades BCL6.

[0222] In some embodiments, a compound of Formula (IA) or 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, the compounds of Formula (IA) or Formula (I) inhibit 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%, 90-100%, 95-100%, 100-100%, 110-100%, 120-100%, 130-100%, 140-100%, 150-100%, 160-100%, 170-100%, 180-100%, 190-100%, 210-100%, 220-100%, 230-100%, 240-100%, 250-100%, 260-100%, 270-100%, 280-100%, 290-100%, 300-100%, 310-100%, 320-100%, 330-100%, 340-100%, 350-100%, 360-100%, 370-100%, 380-100%, 390-100%, 400-100%, 410-100%, 420-100%, 430-100%, 440-100%, 450-100%, 460-100%, 470-100%, 480-1 %, 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% decomposition.

[0223] In another aspect, provided herein is a method for treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (IA) or Formula (I). In some embodiments, provided herein is a method for preventing cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (IA) or Formula (I). Non-limiting examples of cancers include squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma, renal cell carcinoma, bladder cancer, intestinal cancer, breast cancer, cervical cancer, colon cancer, esophageal cancer, head cancer, kidney cancer, liver cancer, lung cancer, head and neck cancer, ovarian cancer, pancreatic cancer, prostate cancer, gastric cancer, leukemia, benign lymphoma, malignant lymphoma, Burkitt lymphoma, non-Hodgkin's lymphoma (NHL), benign melanoma, malignant melanoma, myeloproliferative disorders, sarcoma, uterine cancer, thyroid ... Ing's sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcoma, peripheral neuroepithelioma, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, ganglioneuromas, ganglioneuroblastoma, medulloblastoma, pinealocytoma, meningioma, meningeal sarcoma, neurofibroma, and These include schwannoma, prostate cancer, uterine cancer, testicular cancer, thyroid cancer, astrocytoma, gastric cancer, melanoma, carcinosarcoma, Hodgkin's disease, Wilms' tumor, teratoma, T-cell acute lymphoblastic leukemia (T-ALL), T-cell lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, precursor B-cell ALL, precursor B-cell lymphoma, diffuse large B-cell lymphoma, B-cell ALL, Philadelphia chromosome positive ALL, Philadelphia chromosome positive CML, follicular lymphoma, marginal zone lymphoma, mantle cell lymphoma, Waldenstrom's 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.

[0224] In some embodiments, administering a compound of Formula (IA) or Formula (I) to a subject in need thereof reduces the extent of cancer in the subject (e.g., tumor size, tumor growth rate, metastasis). In some embodiments, administering a compound of Formula (IA) or Formula (I) to a subject in need thereof stabilizes the cancer (prevents or slows the progression of the cancer). In some embodiments, administering a compound of Formula (IA) or Formula (I) to a subject in need thereof delays the onset or recurrence of cancer. In some embodiments, administering a compound of Formula (IA) or Formula (I) to a subject in need thereof slows the progression of cancer. In some embodiments, administering a compound of Formula (IA) or Formula (I) to a subject in need thereof provides a partial remission of cancer. In some embodiments, administering a compound of Formula (IA) or Formula (I) to a subject in need thereof provides a complete remission of cancer. In some embodiments, administering a compound of Formula (IA) or Formula (I) to a subject in need thereof reduces the dosage of one or more other drugs required to treat cancer. In some embodiments, administering a compound of Formula (IA) or Formula (I) to a subject in need thereof enhances the effectiveness of other drugs used to treat cancer. In some embodiments, administering a compound of Formula (IA) or Formula (I) to a subject in need thereof slows the progression of cancer. In some embodiments, administering a compound of Formula (IA) or Formula (I) to a subject in need thereof improves the quality of life of a subject with cancer. In some embodiments, administering a compound of Formula (IA) or Formula (I) to a subject in need thereof prolongs the survival of a subject with cancer.

[0225] In some aspects, provided herein are methods for slowing the progression of cancer in a subject, comprising administering to the subject a compound of Formula (IA) or Formula (I). In some embodiments, provided herein are methods for stabilizing cancer in a subject, comprising administering to the subject a compound of Formula (IA) or Formula (I). In some embodiments, the methods prevent the progression of cancer. In some embodiments, the methods delay the progression of cancer. In some embodiments, the methods provide a partial or complete remission of cancer.

[0226] In another aspect, provided herein is a method of delaying the onset or recurrence of cancer in a subject, comprising administering to the subject a compound of Formula (IA) or Formula (I).

[0227] In a further aspect, provided herein is a method of reducing the dosage of one or more other agents required to treat cancer in a subject, the method comprising administering to the subject a compound of Formula (IA) or Formula (I). In some embodiments, provided herein is a method of increasing the effectiveness of other agents used to treat cancer in a subject, the method comprising administering to the subject a compound of Formula (IA) or Formula (I).

[0228] Also provided herein are methods for delaying the progression of cancer in a subject, comprising administering to the subject a compound of Formula (IA) or Formula (I). In some embodiments, the methods improve the quality of life of a subject with cancer. In some embodiments, the methods extend the survival of a subject with cancer.

[0229] 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 (IA) or 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 (IA) or 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; and systemic autoimmune diseases occur when the immune system attacks the entire body without distinguishing between different types of tissues or target cells. Examples of organ-specific autoimmune diseases include atopic dermatitis, asthma, insulin-dependent diabetes mellitus, Hashimoto's thyroiditis, Graves' disease, pernicious anemia, myasthenia gravis, pemphigus vulgaris, and Crohn's disease. Examples of systemic autoimmune diseases include systemic lupus erythematosus (SLE), rheumatoid arthritis, scleroderma, sarcoidosis, and Guillain-Barré syndrome (GBS). The present disclosure relates to the treatment of all types of autoimmune diseases (organ-specific and systemic autoimmune diseases, including but not limited to lupus erythematosus, ankylosing spondylitis, Chagas disease, chronic obstructive pulmonary disease, Crohn's disease, dermatomyositis, type 1 diabetes, 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, The term "dermatitis" encompasses the treatment of conditions including localized scleroderma, multiple sclerosis, myasthenia gravis, narcolepsy, neuromyotonia, pemphigus vulgaris, pernicious anemia, psoriasis, psoriatic arthritis, polymyositis, primary biliary cirrhosis, relapsing polychondritis, rheumatoid arthritis, sarcoidosis, schizophrenia, scleroderma, Sjogren's syndrome, stiff-person syndrome, temporal arteritis, ulcerative colitis, vasculitis, leukoplakia, and Wegener's granulomatosis.

[0230] In another aspect, provided herein is a method for treating a TH17-associated condition, e.g., a TH17-associated autoimmune condition, in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (IA) or Formula (I).

[0231] In some embodiments, administering a compound of Formula (IA) or Formula (I) to a subject in need thereof diminishes or reduces symptoms of an autoimmune disease (e.g., inflammation, chronic fever, fatigue, joint pain, muscle pain, and tiredness) in the subject. In some embodiments, administering a compound of Formula (IA) or Formula (I) to a subject in need thereof shortens or reduces the duration of symptoms of an autoimmune disease. In some embodiments, administering a compound of Formula (IA) or Formula (I) to a subject in need thereof eliminates symptoms of an autoimmune disease. In some embodiments, administering a compound of Formula (IA) or Formula (I) to a subject in need thereof delays the onset or recurrence of an autoimmune disease. In some embodiments, administering a compound of Formula (IA) or Formula (I) to a subject in need thereof slows the progression of an autoimmune disease. In some embodiments, administering a compound of Formula (IA) or Formula (I) to a subject in need thereof reduces the dose of one or more other drugs required to treat the autoimmune disease. In some embodiments, administering a compound of Formula (IA) or Formula (I) to a subject in need thereof enhances the effectiveness of other drugs used to treat autoimmune diseases. In some embodiments, administering a compound of Formula (IA) or Formula (I) to a subject in need thereof slows the progression of an autoimmune disease. In some embodiments, administering a compound of Formula (IA) or Formula (I) to a subject in need thereof improves the quality of life of a subject with an autoimmune disease.

[0232] In some aspects, provided herein are methods of slowing the progression of an autoimmune disease in a subject, comprising administering to the subject a compound of Formula (IA) or Formula (I). In some embodiments, provided herein are methods of stabilizing an autoimmune disease in a subject, comprising administering to the subject a compound of Formula (IA) or Formula (I). 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 improves the quality of life of a subject with an autoimmune disease.

[0233] In a further aspect, provided herein is a method of reducing the dosage of one or more other agents required to treat an autoimmune disease in a subject, the method comprising administering to the subject a compound of Formula (IA) or Formula (I). In some embodiments, provided herein is a method of enhancing the effectiveness of other agents used to treat an autoimmune disease in a subject, the method comprising administering to the subject a compound of Formula (IA) or Formula (I).

[0234] Pharmaceutical Compositions and Routes of Administration The compounds provided herein can be administered to a subject orally, topically, or parenterally in conventional dosage forms, such as capsules, microcapsules, tablets, granules, powders, troches, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions, and emulsions.

[0235] The compounds disclosed herein can be administered to a subject orally, topically, or parenterally in conventional dosage forms, such as capsules, microcapsules, tablets, granules, powders, troches, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions, and emulsions. Suitable formulations can be prepared by commonly used methods using conventional organic or inorganic additives, such as: excipients (e.g., sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate, or calcium carbonate), binders (e.g., cellulose, methylcellulose, hydroxymethylcellulose, polypropylpyrrolidone, polyvinylpyrrolidone, gelatin, gum arabic, polyethylene glycol, sucrose, or starch), disintegrants (e.g., starch, carboxymethylcellulose, hydroxy ... The pharmaceutical composition may contain a lubricant (e.g., hydroxypropyl starch, low-substituted hydroxypropyl cellulose, sodium bicarbonate, calcium phosphate, or calcium citrate), a lubricant (e.g., magnesium stearate, light anhydrous silicic acid, talc, or sodium lauryl sulfate), a flavoring (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., hydroxypropyl methylcellulose), a diluent (e.g., water), and a wax base (e.g., cocoa butter, white petrolatum, or polyethylene glycol). The effective amount of the compound of formula (IA) or formula (I) in the pharmaceutical composition may be an amount that produces the desired effect, for example, about 0.005 mg to about 10 mg per kg of subject body weight per unit dose for oral and parenteral administration.

[0236] The dose of a compound of Formula (IA) or Formula (I) to be administered to a subject can vary widely and be left to the discretion of the physician. Generally, the compounds disclosed herein can be administered at a dose of about 0.001 mg to about 10 mg per kg of subject body weight, 1 to 4 times per day, although this dose may vary appropriately depending on the age, weight, and health condition of the subject, as well as the administration form. In one embodiment, the dose is about 0.001 mg to about 5 mg, about 0.01 mg to about 5 mg, about 0.05 mg to about 1 mg, about 0.1 mg to about 0.75 mg, or about 0.25 mg to about 0.5 mg per kg of subject body weight. In one embodiment, one dose is given per day. In any case, the dose of a compound of Formula (IA) or Formula (I) will depend on factors such as the solubility of the active ingredient, the dosage form used, and the route of administration.

[0237] In some embodiments, the compound of Formula (IA) or Formula (I) is administered to a subject at a dose of about 0.01 mg / day to about 750 mg / day, about 0.1 mg / day to about 375 mg / day, about 0.1 mg / day to about 150 mg / day, about 0.1 mg / day to about 75 mg / day, about 0.1 mg / day to about 50 mg / day, about 0.1 mg / day to about 25 mg / day, or about 0.1 mg / day to about 10 mg / day.

[0238] In other embodiments, provided herein are unit dose formulations comprising about 0.1 mg to 500 mg, about 1 mg to 250 mg, about 1 mg to about 100 mg, about 1 mg to about 50 mg, about 1 mg to about 25 mg, or about 1 mg to about 10 mg of a compound of Formula (IA) or Formula (I).

[0239] In certain embodiments, provided herein are unit dose formulations comprising about 0.1 mg or 100 mg of a compound of Formula (IA) or Formula (I).

[0240] In other embodiments, provided herein are unit dose formulations comprising 0.5 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 35 mg, 50 mg, 70 mg, 100 mg, 125 mg, 140 mg, 175 mg, 200 mg, 250 mg, 280 mg, 350 mg, 500 mg, 560 mg, 700 mg, 750 mg, 1000 mg, or 1400 mg of a compound of Formula (IA) or Formula (I).

[0241] The compound of Formula (IA) or Formula (I) may be administered once, twice, three times, four or more times daily, hi certain embodiments, doses of 100 mg or less are administered as a single dose daily, and doses of more than 100 mg are administered twice daily in an amount equal to half of the total daily dose.

[0242] The compound of formula (IA) or formula (I) can be conveniently administered orally. In one embodiment, when administered orally, the compound of formula (IA) or formula (I) is administered with food and water. In another embodiment, the compound of formula (IA) or formula (I) is dispersed in water or juice (e.g., apple juice or orange juice) or any other liquid and orally administered as a solution or suspension.

[0243] The compounds disclosed herein may also be administered intradermally, intramuscularly, intraperitoneally, transdermally, intravenously, subcutaneously, intranasally, epidurally, sublingually, intracerebrally, intravaginally, transdermally, rectally, mucosally, by inhalation, or topically to the ear, nose, eye, or skin. The mode of administration is left to the discretion of the physician, and may depend in part on the site of the condition.

[0244] In one embodiment, provided herein is a capsule comprising a compound of Formula (IA) or Formula (I) without any additional carrier, excipient, or vehicle.

[0245] In other embodiments, provided herein are compositions comprising an effective amount of a compound of Formula (IA) or Formula (I) and a pharmaceutically acceptable carrier or vehicle, wherein the pharmaceutically acceptable carrier or vehicle may comprise an excipient, a diluent, or a mixture thereof. In one embodiment, the composition is a pharmaceutical composition.

[0246] The compositions may be in the form of tablets, chewable tablets, capsules, liquids, injectables, lozenges, suppositories, suspensions, and the like. The compositions may be formulated to contain a daily dose or an appropriate fraction of a daily dose in a dosage unit, which may be a single tablet, a single capsule, or a suitable amount of liquid. In one embodiment, liquids are prepared from water-soluble salts, such as hydrochlorides. Generally, all compositions are prepared according to methods known in the pharmaceutical sciences. Capsules may be prepared by mixing a compound of Formula (IA) or Formula (I) with a suitable carrier or diluent and filling a capsule with the appropriate amount of the mixture. Typical carriers and diluents include, but are not limited to, inert powdered substances such as various types of starch, powdered cellulose, especially crystalline and microcrystalline cellulose, sugars such as fructose, mannitol, and sucrose, grain flours, and similar edible powders.

[0247] Tablets can be prepared by direct compression, wet granulation, or dry granulation. These formulations usually contain not only the compound but also diluents, binders, lubricants, and disintegrants. Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride, and powdered sugars. Powdered cellulose derivatives are also useful. Typical tablet binders include starch, gelatin, and sugars such as lactose, fructose, and glucose. Natural and synthetic gums, including acacia, alginates, methylcellulose, and polyvinylpyrrolidine, are also useful. Polyethylene glycol, ethylcellulose, and waxes can also function as binders.

[0248] Lubricants may be necessary in tablet manufacture to prevent colorants from adhering to the tablet and punch. Lubricants can be selected from slippery solids such as talc, magnesium and calcium stearate, stearic acid, and hydrogenated vegetable oils. Tablet disintegrants are substances that swell upon absorption of water, breaking the tablet and releasing the compound. Disintegrants include starch, clay, cellulose, algin, and gums. More specifically, for example, corn starch and potato starch, methylcellulose, agar, bentonite, wood cellulose, natural sponge powder, cation exchange resin, alginic acid, guar gum, citrus syrup, carboxymethylcellulose, and sodium lauryl sulfate can be used. Tablets can be coated with sugar as a flavor and sealant, or with a film-forming protective agent to modify the tablet's dissolution. The composition can also be formulated as a chewable tablet, for example, by using substances such as mannitol in the formulation.

[0249] When it is desired to administer the compound of formula (IA) or formula (I) as a suppository, a typical base can be used. Cocoa butter is a conventional suppository base, and can be modified by adding wax to slightly increase the melting point. Water-miscible suppository bases include, in particular, polyethylene glycols of various molecular weights, and are widely used.

[0250] The effect of the compound of formula (IA) or formula (I) can be delayed or prolonged by appropriate formulation. For example, slowly dissolving pellets of the compound of formula (IA) or formula (I) can be prepared and incorporated into tablets or capsules, or as a sustained-release implantable device. Such techniques include creating pellets with several different dissolution rates and filling a mixture of the pellets into capsules. The tablet or capsule can be coated with a film that prevents dissolution for a predictable period of time. Even for injections, the duration of effect can be extended by dissolving or suspending the compound of formula (IA) or formula (I) in an oily or emulsion vehicle that allows for slow dispersion into the blood serum.

[0251] It is understood that the pharmaceutical compositions described herein may contain mixtures of compounds of formula (IA) or formula (I), including any racemic mixtures of the compounds described herein.

[0252] Illustrative Embodiments The present disclosure is further described by the following embodiments, the features of each embodiment may be combined with any of the other embodiments where appropriate and practical.

[0253] Embodiment P1. Formula (IA): [ka] (IA) or a pharmaceutically acceptable salt thereof [In the formula, X 1 and X 2 are each independently N or CH, provided that X 1 and X 2 at least one of is N; R 1a and R 1b are each independently H, halo, or C1-C6 alkyl; R 2a and R2b are each independently H, C1-C6 alkyl, —O(C1-C6 alkyl), —OH, halo, C1-C6 haloalkyl, or C1-C6 alkyl-OH; Alternatively, R 2a and R 2b together with the carbon atoms to which they are attached form a spiro C3-C5 cycloalkyl; Alternatively, R 2a and R 2b come together to form oxo; Alternatively, R 1a and R 2a together form a bridged C2-C3 alkylene; R 3a and R 3b are each independently H, halo, or C1-C6 alkyl; R 4a and R 4b are each independently H, halo, or C1-C6 alkyl; Alternatively, R 4a and R 4b together with the carbon atoms to which they are attached form a spiro C3-C5 cycloalkyl; R 5a and R 5b are each independently H, halo, or C1-C6 alkyl; w is 0 or 1; R 6 is H or C1-C6 alkyl; R 7 is H or C1-C6 alkyl; x and y are each independently 0 or 1, provided that x and y are not both 1; R 8 is Cl or -CN; R 9 is F; X 3 is N or CH; z is 0 or 1; R 10a and R 10bare each independently H or halo; R 11 is H, C1-C6 alkyl, -(C1-C6 alkylene)-(5- to 6-membered heterocyclyl), -(C1-C6 alkylene)-O(C1-C6 alkyl), C1-C6 haloalkyl, C1-C6 alkyl-OH, or -(C1-C6 alkylene)-NH(C1-C6 alkyl); wherein heterocyclyl contains 1 to 3 heteroatoms selected from N, O, and S; R 12 is H, halo, or C1-C6 alkyl; R 13 is H or halo; R 14 is H or C1-C6 alkyl; X 4 is N or CR 15 and; R 15 is H or C1-C6 alkyl; X 5 and X 6 are each independently N or CH; and structure: [ka] is a single or double bond; wherein one or more hydrogen atoms in said compound may be optionally replaced with deuterium.

[0254] Embodiment P2. Formula (I): [ka] or a pharmaceutically acceptable salt thereof [In the formula, X 1 and X 2 are each independently N or CH, provided that X 1 and X 2 at least one of is N; R 1a and R1b are each independently H, halo, or C1-C6 alkyl; R 2a and R 2b are each independently H, C1-C6 alkyl, —OH, halo, or C1-C6 alkyl-OH; Alternatively, R 2a and R 2b together with the carbon atoms to which they are attached form a spiro C3-C5 cycloalkyl; Alternatively, R 2a and R 2b come together to form oxo; Alternatively, R 1a and R 2a together form a bridged C2-C3 alkylene; R 3a and R 3b are each independently H, halo, or C1-C6 alkyl; R 4a and R 4b are each independently H, halo, or C1-C6 alkyl; Alternatively, R 4a and R 4b together with the carbon atoms to which they are attached form a spiro C3-C5 cycloalkyl; R 5a and R 5b are each independently H, halo, or C1-C6 alkyl; w is 0 or 1; R 6 is H or C1-C6 alkyl; R 7 is H or C1-C6 alkyl; x and y are each independently 0 or 1, provided that x and y are not both 1; R 8 is Cl or -CN; R 9 is F; X 3 is N or CH; z is 0 or 1; R 10a and R 10b are each independently H or halo; R 11 is H, C1-C6 alkyl, -(C1-C6 alkylene)-(5- to 6-membered heterocyclyl), -(C1-C6 alkylene)-O(C1-C6 alkyl), C1-C6 haloalkyl, C1-C6 alkyl-OH, or -(C1-C6 alkylene)-NH(C1-C6 alkyl); wherein heterocyclyl contains 1 to 3 heteroatoms selected from N, O, and S; R 12 is H, halo, or C1-C6 alkyl; R 13 is H or halo; R 14 is H or C1-C6 alkyl; X 4 is N or CR 15 and; R 15 is H or C1-C6 alkyl; X 5 and X 6 are each independently N or CH; and structure: [ka] is a single or double bond; wherein one or more hydrogen atoms in said compound may be optionally replaced with deuterium.

[0255] Embodiment P3. X 1 is CH; X 2 is N, A compound according to embodiment P1 or P2, or a pharmaceutically acceptable salt thereof.

[0256] Embodiment P4. X 1 is N; X 2 is CH, A compound according to embodiment P1 or P2, or a pharmaceutically acceptable salt thereof.

[0257] Embodiment P5. X 1 and X 2 are N, A compound according to embodiment P1 or P2, or a pharmaceutically acceptable salt thereof.

[0258] Embodiment P6. R 1 and R 1b are each independently H, halo, or C1-C3 alkyl; A compound according to any one of embodiments P1 to P5, or a pharmaceutically acceptable salt thereof.

[0259] Embodiment P7. R 1a and R 1b are each independently H or -CH3; 7. The compound of embodiment 6, or a pharmaceutically acceptable salt thereof.

[0260] Embodiment P8. R 2a and R 2b are each independently H, C1-C3 alkyl, —O(C1-C3 alkyl), —OH, halo, C1-C3 haloalkyl, or C1-C3 alkyl-OH; Alternatively, R 2a and R 2b together with the carbon atom to which they are attached form a spiro C3-C4 cycloalkyl, Alternatively, R 2a and R 2b together to form oxo, A compound according to any one of embodiments P1 to P7, or a pharmaceutically acceptable salt thereof.

[0261] Embodiment P9. R 2a and R 2bare each independently H, -CH3, -OCH3, -OH, F, -CF3, or -CH2OH; Alternatively, R 2a and R 2b together with the carbon atom to which they are attached to form a spirocyclobutyl, Alternatively, R 2a and R 2b together to form oxo, A compound according to embodiment P8, or a pharmaceutically acceptable salt thereof.

[0262] Embodiment P10. R 1a and R 1b are H and R 2a and R 2b At least one of is not H, A compound according to any one of embodiments P1 to P9, or a pharmaceutically acceptable salt thereof.

[0263] Embodiment P11 R 1a and R 2a together to form a bridged ethylene, A compound according to any one of embodiments P1 to P9, or a pharmaceutically acceptable salt thereof.

[0264] Embodiment P12. R 3a and R 3b are each independently H, halo, or C1-C3 alkyl; A compound according to any one of embodiments P1 to P11, or a pharmaceutically acceptable salt thereof.

[0265] Embodiment P13. R 3a and R 3b are each independently H, F, or -CH3; A compound according to embodiment P12, or a pharmaceutically acceptable salt thereof.

[0266] Embodiment P14. R 4a and R 4b are each independently H, halo, or C1-C3 alkyl; Alternatively, R 4a and R 4b together with the carbon atom to which they are attached form a spiro C3-C4 cycloalkyl; A compound according to any one of embodiments P1 to P13, or a pharmaceutically acceptable salt thereof.

[0267] Embodiment P15. R 4a and R 4b are each independently H, F, or -CH3; Or R 4a and R 4b together with the carbon atom to which they are attached to form a spirocyclobutyl; A compound according to embodiment P14, or a pharmaceutically acceptable salt thereof.

[0268] Embodiment P16. R 3a , R 3b , R 4a , and R 4b are H, A compound according to any one of embodiments P1 to P15, or a pharmaceutically acceptable salt thereof.

[0269] Embodiment P17. R 3a and R 3b At least one of them is not H, but R 4a and R 4b At least one of is not H, A compound according to any one of embodiments P1 to P15, or a pharmaceutically acceptable salt thereof.

[0270] Embodiment P18. w is 0, A compound according to any one of embodiments P1 to P17, or a pharmaceutically acceptable salt thereof.

[0271] Embodiment P19. w is 1, A compound according to any one of embodiments P1 to P17, or a pharmaceutically acceptable salt thereof.

[0272] Embodiment P20. R 5a and R 5b are each independently H, halo, or C1-C3 alkyl; A compound according to embodiment P19, or a pharmaceutically acceptable salt thereof.

[0273] Embodiment P21. R 5a and R 5b are H, A compound according to embodiment P20, or a pharmaceutically acceptable salt thereof.

[0274] Embodiment P22. R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a , and R 5b The compound according to any one of embodiments P1 to P21, or a pharmaceutically acceptable salt thereof, wherein at least one of is not H.

[0275] Embodiment P23. R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a , and R 5b is not H; or a pharmaceutically acceptable salt thereof.

[0276] Embodiment P24. structure: [ka] But the structure: [ka] The compound of any one of embodiments P1 to P23, wherein:

[0277] Embodiment P25. x is 1; y is 0; and R 7 is H or C1-C3 alkyl; A compound according to any one of embodiments P1 to P24, or a pharmaceutically acceptable salt thereof.

[0278] Embodiment P26. R 7 is H or -CH3, A compound according to embodiment P25, or a pharmaceutically acceptable salt thereof.

[0279] Embodiment P27. x is 0; y is 1; and R 6 is H or C1-C3 alkyl; A compound according to any one of embodiments P1 to P24, or a pharmaceutically acceptable salt thereof.

[0280] Embodiment P28. R 6 is H or -CH3, A compound according to embodiment P27, or a pharmaceutically acceptable salt thereof.

[0281] Embodiment P29. x and y are each 0, A compound according to any one of embodiments P1 to P24, or a pharmaceutically acceptable salt thereof.

[0282] Embodiment P30. R 8 is Cl, A compound according to any one of embodiments P1 to P29, or a pharmaceutically acceptable salt thereof.

[0283] Embodiment P31. R 8 is -CN, A compound according to any one of embodiments P1 to P29, or a pharmaceutically acceptable salt thereof.

[0284] Embodiment P32. X 3 is CH, A compound according to any one of embodiments P1 to P31, or a pharmaceutically acceptable salt thereof.

[0285] Embodiment P33. X 3 is N, A compound according to any one of embodiments P1 to P31, or a pharmaceutically acceptable salt thereof.

[0286] Embodiment P34. z is 0,

[0287] A compound according to any one of embodiments P1 to P33, or a pharmaceutically acceptable salt thereof.

[0288] Embodiment P35. z is 1, A compound according to any one of embodiments P1 to P33, or a pharmaceutically acceptable salt thereof.

[0289] Embodiment P36. R 10a and R 10b are each independently H or F; A compound according to any one of embodiments P1 to P35, or a pharmaceutically acceptable salt thereof.

[0290] Embodiment P37. R11 is H, C1-C3 alkyl, -(C1-C3 alkylene)-(6-membered heterocyclyl), -(C1-C3 alkylene)-O(C1-C3 alkyl), C1-C5 haloalkyl, C1-C5 alkyl-OH, or -(C1-C3 alkylene)-NH(C1-C3 alkyl); wherein the heterocyclyl contains 1 to 2 heteroatoms selected from N and O; A compound according to any one of embodiments P1 to P36, or a pharmaceutically acceptable salt thereof.

[0291] Embodiment P38. R 11 is H, -CH3, -CD3, -CH2CH3, -CH(CH3)2, -CH2CH2OCH3, -CH2CH2OH, -CH2CH2C(OH)(CH3)2, -CH2CH2N(H)CH3, -(CH2)3CF3, -CH2CF2CH3, -CH2CH2CF(CH3)2, -CH2CF(CH3)2, or the structure: [ka] That is, A compound according to embodiment P37, or a pharmaceutically acceptable salt thereof.

[0292] Embodiment P39. structure: [ka] But the structure: [ka] That is, A compound according to any one of embodiments P1 to P38, or a pharmaceutically acceptable salt thereof.

[0293] Embodiment P40. R 12 is H, halo, or C1-C3 alkyl; A compound according to any one of embodiments P1 to P39, or a pharmaceutically acceptable salt thereof.

[0294] Embodiment P41. R 12 is H, F, or -CH3; A compound according to embodiment P40, or a pharmaceutically acceptable salt thereof.

[0295] Embodiment P42. structure: [ka] But the structure: [ka] The compound of any one of embodiments P1 to P41, wherein:

[0296] Embodiment P43. R 13 is H or F, A compound according to any one of embodiments P1 to P42, or a pharmaceutically acceptable salt thereof.

[0297] Embodiment P44. R 14 is H or C1-C3 alkyl; A compound according to any one of embodiments P1 to P43, or a pharmaceutically acceptable salt thereof.

[0298] Embodiment P45. R 14 is H or -CH3, A compound according to embodiment P44, or a pharmaceutically acceptable salt thereof.

[0299] Embodiment P46. X 4 is N, A compound according to any one of embodiments P1 to P45, or a pharmaceutically acceptable salt thereof.

[0300] Embodiment P47. X4 is CR 15 and R 15 is H or C1-C3 alkyl; A compound according to any one of embodiments P1 to P45, or a pharmaceutically acceptable salt thereof.

[0301] Embodiment P48. X 4 is CR 15 and R 15 is H or -CH3, A compound according to embodiment P47, or a pharmaceutically acceptable salt thereof.

[0302] Embodiment P49. X 5 is N, A compound according to any one of embodiments P1 to P48, or a pharmaceutically acceptable salt thereof.

[0303] Embodiment P50. X 5 is CH, A compound according to any one of embodiments P1 to P48, or a pharmaceutically acceptable salt thereof.

[0304] Embodiment P51. X 6 is N, A compound according to any one of embodiments P1 to P50, or a pharmaceutically acceptable salt thereof.

[0305] Embodiment P52. X 6 is CH, A compound according to any one of embodiments P1 to P50, or a pharmaceutically acceptable salt thereof.

[0306] Embodiment P53. structure: [ka] is a single bond, A compound according to any one of embodiments P1 to P52, or a pharmaceutically acceptable salt thereof.

[0307] Embodiment P54. structure: [ka] is a double bond, A compound according to any one of embodiments P1 to P52, or a pharmaceutically acceptable salt thereof.

[0308] Embodiment P55. structure: [ka] The structure: [ka] The compound of any one of embodiments P1 to P54, wherein:

[0309] Embodiment P56. The compound has the formula (II): [ka] Formula (III): [ka] or formula (IV): [ka] That is, A compound according to any one of embodiments P1 to P55, or a pharmaceutically acceptable salt thereof.

[0310] Embodiment P57. The compound has formula (IIIb): [ka] or a pharmaceutically acceptable salt thereof.

[0311] Embodiment P58. A compound selected from the compounds in Table 1 and pharmaceutically acceptable salts thereof.

[0312] Embodiment P59. A pharmaceutical composition comprising a compound according to any one of embodiments P1 to P58, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0313] Embodiment P60. A method for degrading B-cell lymphoma 6 protein (BCL6), comprising contacting BCL6 with an effective amount of a compound described in any one of embodiments P1 to P58, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in embodiment P59.

[0314] Embodiment P61. A method of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound of any one of embodiments P1 to P58, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment P59.

[0315] Embodiment P62. The method of embodiment P61, wherein the cancer is lymphoma.

[0316] Embodiment P63. The method of embodiment P62, wherein the lymphoma is diffuse large B-cell lymphoma.

[0317] Embodiment P64. A method of treating an autoimmune disease in a subject in need thereof, comprising administering to the subject an effective amount of a compound of any one of embodiments P1 to P58, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment P59.

[0318] Embodiment P65. The method of embodiment P64, wherein the autoimmune disease is atopic dermatitis, asthma, lupus erythematosus, ankylosing spondylitis, Chagas disease, chronic obstructive pulmonary disease, Crohn's disease, dermatomyositis, type 1 diabetes, endometriosis, Goodpasture's syndrome, Graves' disease, Guillain-Barré syndrome (GBS), Hashimoto's disease, hidradenitis suppurativa, Kawasaki disease, IgA nephropathy, idiopathic thrombocytopenic purpura, interstitial cystitis, or mixed connective tissue disease. , localized scleroderma, multiple sclerosis, myasthenia gravis, narcolepsy, neuromyotonia, pemphigus vulgaris, pernicious anemia, psoriasis, psoriatic arthritis, polymyositis, primary biliary cirrhosis, relapsing polychondritis, rheumatoid arthritis, sarcoidosis, schizophrenia, scleroderma, Sjogren's syndrome, stiff-person syndrome, temporal arteritis, ulcerative colitis, vasculitis, leukoplakia, and Wegener's granulomatosis. [Example]

[0319] The following examples are provided by way of non-limiting example. Compounds are named using the automated naming tool provided in ChemBiodraw Ultra (Cambridgesoft), which generates systematic names based on chemical structure and conforms to the Cahn-Ingold-Prelog rules for stereochemistry. Those skilled in the art can modify the procedures of the examples provided to obtain the desired products.

[0320] Salts of the compounds described herein can be prepared by standard methods, for example, by including an acid (e.g., TFA, formic acid, or HCl) in the mobile phase during chromatographic purification, or by stirring the product after chromatographic purification with an acidic solution (e.g., aqueous HCl).

[0321] The following abbreviations may be relevant to this application: Abbreviation [Table 31] [Table 32]

[0322] Synthesis Example General Procedure 1: Primary Aromatic Nucleophilic Substitution Reaction on Pyrimidines [ka] To a mixture of 5-amino-1-methylindolin-2-one (1 equivalent) in anhydrous tetrahydrofuran (0.4 M) at -40°C, DIPEA (1.1 equivalents) was added. A solution of 5-chloro-2,4-difluoropyrimidine (1 equivalent) in anhydrous tetrahydrofuran (1.5 M) was slowly added to the mixture, and the mixture was allowed to warm to room temperature. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was then filtered and washed with acetonitrile. The solid was dried under vacuum to give the title compound as a light brown solid.

[0323] General Procedure 2: Buchwald Coupling of Amines with Indazole CBMs [ka] A mixture of 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole 1a (1.1 equiv.), amine (1.0 equiv.), Ruphos-Pd-G3 (0.20 equiv.), and NaOtBu (1.5 equiv.) in 1,4-dioxane [0.3 M] was heated to 90 °C for 16 h and then cooled to room temperature. 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 silica gel column chromatography (gradient: 0-100% EtOAc / hexane) to give the title compound.

[0324] General Procedure 3: Methylation of Amines [ka] To a 0.15 M solution of the amine (1.0 equiv., 14.2 mmol) in DMF, NaH (4.4 equiv.) was added and stirred at 0° C. for 1 hour. To the mixture, iodomethane (2.8 equiv.) was added at 0° C. The resulting reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was then quenched with water and extracted with EA. The extracts were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluted with PE / EA (15:1)) to give the title compound.

[0325] General Procedure 4: Reduction of CBM with Hydrogen [ka] A mixture of the indazole intermediate (1.0 equiv.) and Pd / C (10 wt.% palladium; 40 wt.%) in EtOH:THF (1:1.5; [0.05 M]) was exposed 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 silica gel column chromatography (gradient: 0-100% EtOAc / hexane) to give the title compound.

[0326] General Procedure 5: BOC Deprotection with HCl or TFA [ka] To a 0.3 M solution of the BOC-protected amine (1.0 equiv.) in 1,4-dioxane was added 4N HCl / 1,4-dioxane (14 equiv.), and the reaction mixture was stirred at room temperature for 12 h. The volatiles were evaporated under reduced pressure to give the title compound (quantitative) as a solid, which was used in the next step without further purification.

[0327] General Procedure 6: Nucleophilic aromatic substitution reaction of modified TBM with CBM [ka] A 0.1-0.2 M solution of amine hydrochloride (1.0 equiv.), chloro / fluoropyrimidine (1.0 equiv.), and N,N-diisopropylethylamine (3-5 equiv.) in DMSO was stirred at 80°C for 2 h. The reaction mixture was filtered and purified by reverse-phase semi-preparative HPLC (10-100% acetonitrile + 0.1% formic acid / 0.1% formic acid in water, 30 min). Fractions containing pure product were combined and lyophilized to give the title compound.

[0328] Example i-1. Intermediate 1: Synthesis of 3-(1-methyl-6-(4-(methylamino)piperidin-1-yl)-1H-indazol-3-yl)piperidine-2,6-dione hydrochloride [ka]

[0329] 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, 0.6000 mmol), tert-butyl N-methyl-N-(piperidin-4-yl)carbamate (192.72 mg, 0.9000 mmol), cesium carbonate (390.68 mg, 1.2 mmol), and RuPhos-Pd-G3 (50.14 mg, 0.0600 mmol) were added to a 1-drum vial and purged with nitrogen for 1 min. 1,4-Dioxane (0.8 mL) was then added, and the reaction mixture was stirred at 100 °C overnight. The product was purified from the crude mixture 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).

[0330] 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 stir 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 with hydrogen. A hydrogen balloon was attached, and the reaction was stirred overnight. The slurry was filtered through Celite and concentrated. The residue was loaded onto a SNAP25G column and purified with 0-50% EtOAc / hexane (with 2-5% MeOH as an additive) to give the title compound (50 mg, 0.110 mmol, 65.6% yield) as a yellow oil.

[0331] 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 placed in a vial equipped with a stir bar and dichloromethane (1 mL) was added. Then, HCl (4 N) / 1,4-dioxane (0.4400 mmol) was added to the mixture and stirred for 2 hours. The stir bar was removed, and the solvent was removed under reduced pressure to give the title compound (42 mg, 0.107 mmol, 97.6% yield) as an off-white solid.

[0332] Example i-2. Intermediate 2: Synthesis of 3-(1-methyl-6-(piperidin-4-ylamino)-1H-indazol-3-yl)piperidine-2,6-dione hydrochloride [ka] 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 1 hour and then cooled to room temperature. Volatiles were evaporated under reduced pressure. The material was purified by column chromatography on silica gel (gradient: 0-20% ethyl acetate / hexanes) to give the title compound (4.95 g, 14.7 mmol, 39% yield) as a solid. MS (ESI) [M+H] + 336.90.

[0333] 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 nitrogen. The mixture was then stirred at 80 °C under nitrogen for 17 h. LCMS showed complete consumption of the reactant, with the desired MS peak being the main peak. The reaction was then cooled to room temperature and filtered. The filtrate was extracted with ethyl acetate (3 × 40 mL), washed with brine (2 × 40 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica, gradient: 0-30% ethyl acetate / 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. 1 H 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).

[0334] 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), and Cs2CO3 (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 room temperature. The mixture was filtered through Celite and washed with EtOAc (3 × 10 mL). The filtrate was concentrated under reduced pressure. The material was purified by column chromatography on silica gel (gradient: 0-90% ethyl acetate / hexanes) to give 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; 1 H 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).

[0335] 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 hydrogenated at 1 atm and 50°C for 4 hours. At this point, only the alkene product was observed. Additional Pearlman's catalyst (33.4 mg, 0.0500 mmol) was added, and the mixture was hydrogenated at 1 atm and 50°C for 24 hours. The mixture was filtered through Celite and washed with MeOH:MeCN (1:1, 3 x 50.0 mL). The filtrate was concentrated under reduced pressure to give 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; 1 H 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).

[0336] Step 5: Synthesis of 3-[1-methyl-6-(4-piperidylamino)indazol-3-yl]piperidine-2,6-dione hydrochloride To a solution of tert-butyl 4-[[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-6-yl]amino]piperidine-1-carboxylate (1.22 g, 2.76 mmol) in 1,4-dioxane (20 mL) was added a solution of hydrochloric acid (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] + . 1 H 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, 3H), 1.72 (br s, 2 H).

[0337] Example i-3. Intermediate 3: Synthesis of 3-(6-amino-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione [ka] 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 (160 g, 320 mmol) was dissolved in 1,4-dioxane (1600 mL) in a 3000 mL multi-necked round-bottom flask equipped with a reflux condenser under a nitrogen atmosphere with mechanical stirring. Next, tert-butyl carbamate (56.2 g, 480 mmol) was added, followed by K2CO3 (133 g, 959 mmol), followed by purging for 5 minutes, followed by XPhos Pd G2 (25.2 g, 32.0 mmol), followed by purging again for 5 minutes, followed by refluxing at 110 °C overnight. The reaction mixture was filtered through a pad of Celite and washed with ethyl acetate. The resulting filtrate was evaporated to give the crude product, which was purified by ISCO on silica gel using PE / EtOAc as eluent to give the title compound (148 g, 275 mmol, 86% yield) as a white solid. MS (ESI) m / z 537.30 [M+H] + . 1 H 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).

[0338] 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). The mixture was purged with nitrogen for 5 minutes, after which palladium on carbon (24.79 g, 23.29 mmol) was added, followed by stirring overnight at 55° C. under a hydrogen atmosphere. After this time, the reaction mixture was filtered through Celite, washed with THF (2 L), and the resulting 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] + ; 1 H 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).

[0339] Step 3: Synthesis of 3-(6-amino-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione hydrochloride tert-Butyl (3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)carbamate (25 g, 69.8 mmol) was dissolved in 1,4-dioxane (250 mL) in a 2 L round-bottom flask with magnetic stirring. HCl (4 M / dioxane) (250 mL, 69.8 mmol) was slowly added, and the reaction was then stirred at room temperature for 48 hours. After this time, the mixture was filtered, and the resulting solid was dissolved in methanol and then stirred thoroughly for 20 minutes before being 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).

[0340] Example i-4. Synthesis of Intermediate 4: 3-(1-methyl-6-(methyl(piperidin-4-yl)amino)-1H-indazol-3-yl)piperidine-2,6-dione hydrochloride [ka] Step 1: Synthesis of tert-butyl 4-[[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazol-6-yl]amino]piperidine-1-carboxylate A mixture of 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole (500 mg, 1 mmol), tert-butyl 4-aminopiperidine-1-carboxylate (240 mg, 1.2 mmol), RuPhos-Pd-G3 (83 mg, 0.1000 mmol), and Cs2CO3 (651 mg, 2 mmol) in 1,4-dioxane (5 mL) was heated to 90 °C for 18 h and then cooled to room temperature. The mixture was filtered through Celite and washed with EtOAc (3 × 10 mL). The filtrate was concentrated under reduced pressure. The material was purified by column silica gel chromatography (gradient: 0–100% EtOAc / hexanes) to afford the title compound (550 mg, 89%) as a solid. 1H NMR (500 MHz,CDCl3) δ 7.89 (d,J = 8.1 Hz,1H),7.47 (d,J = 8.7 Hz,1H),7.45 - 7.41 (m,2H),7.39 - 7.24 (m,8H),6.49 (d,J = 8.1 Hz,1H),6.36 (dd,J = 8.7,1.9 Hz,1H),6.31 (d,J = 1.7 Hz,1H),5.46 (s,2H),5.38 (s,2H),4.13 - 4.03 (m,2H),3.98 (s,3H),3.73 (s,1H),3.57 - 3.50 (m,1H),3.00 (t,J = 12.1 Hz,2H),2.10 (d,J = 10.8 Hz,2H),1.48 (s,9H),1.43 - 1.35 (m,2H).MS (ESI) [M+H] + 620.5.

[0341] Step 2: Synthesis of tert-butyl 4-[[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazol-6-yl]-methyl-amino]piperidine-1-carboxylate To a solution of tert-butyl 4-[[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazol-6-yl]amino]piperidine-1-carboxylate (550 mg, 0.89 mmol) in DMSO (3.6 mL) and acetic acid (0.9 mL) was added formaldehyde solution (0.13 mL, 1.8 mmol) and NaBH(OAc) (282 mg, 1.3 mmol) sequentially. The reaction mixture was stirred at room temperature for 1 h. Water (10 mL) and EtOAc (25 mL) were added, and the layers were separated. The organic layer was washed with saturated aqueous NaHCO (5 mL), water (3 × 5 mL), brine (5 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The material was purified by column silica gel chromatography (gradient: 0–100% EtOAc / hexanes) to afford the title compound (467 mg, 83% yield) as a solid. 1H NMR (400 MHz,CDCl3) δ 7.91 (d,J = 8.1 Hz,1H),7.56 (d,J = 9.0 Hz,1H),7.46 - 7.40 (m,2H),7.40 - 7.30 (m,5H),7.29 - 7.23 (m,3H),6.72 (dd,J = 9.3,2.1 Hz,1H),6.50 (d,J = 8.1 Hz,1H),6.48 (d,J = 1.9 Hz,1H),5.47 (s,2H),5.38 (s,2H),4.25 (s,2H),4.01 (s,3H),3.80 (td,J = 10.8,5.3 Hz,1H),2.84 (s,3H),2.83 - 2.74 (m,2H),1.81 - 1.64 (m,4H),1.49 (s,9H).MS (ESI) [M+H] + 635.5.

[0342] Step 3: tert-butyl 4-[[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-6-yl]-methyl-amino]piperidine-1-carboxylate A mixture of tert-butyl 4-[[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazol-6-yl]-methyl-amino]piperidine-1-carboxylate (467 mg, 0.74 mmol) and 20% Pd(OH)2 / C (117 mg, 25 wt%) in THF (7 mL) and EtOH (7 mL) was hydrogenated at 1 atm and 50 °C for 2 h. The mixture was filtered through Celite, washed with a mixture of MeCN and MeOH (1:1, 3 × 10 mL), and the filtrate was concentrated under reduced pressure. The material was purified by silica gel column chromatography (gradient: 0–20% MeOH / DCM) to give the title compound (258 mg, 77%) as a solid. 1H NMR (500 MHz,DMSO) δ 10.83 (s,1H),7.46 (d,J = 9.0 Hz,1H),6.87 (dd,J = 9.2,2.0 Hz,1H),6.65 (d,J = 1.9 Hz,1H),4.23 (dd,J = 9.0,5.1 Hz,1H),4.09 - 3.99 (m,2H),3.98 - 3.91 (m,1H),3.87 (s,3H),2.86 (br s,2H),2.76 (s,3H),2.64 - 2.56 (m,2H),2.33 - 2.25 (m,1H),2.21 - 2.13 (m,1H),1.67 - 1.54 (m,4H),1.41 (s,9H).MS (ESI) [M+H] + 456.3.

[0343] Step 4: Synthesis of 3-[1-methyl-6-[methyl(4-piperidyl)amino]indazol-3-yl]piperidine-2,6-dione hydrochloride To a solution of tert-butyl 4-[[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-6-yl]-methyl-amino]piperidine-1-carboxylate (258 mg, 0.57 mmol) in 1,4-dioxane (10 mL) was added HCl (4 M) / 1,4-dioxane (1.42 mL, 5.66 mmol). The reaction mixture was heated to 100 °C for 3 h and then cooled to room temperature. The volatiles were evaporated under reduced pressure. EtO (5 × mL) was added, and the resulting precipitate was collected by filtration, washed with 1,4-dioxane (3 × 1 mL) and EtO (10 × 2 mL), and then dried under vacuum to give the title compound (217 mg, 92%) as a solid. 1H NMR (400 MHz,D2O) δ 7.93 (d,J = 8.3 Hz,1H),7.65 (s,1H),7.31 (d,J = 8.0 Hz,1H),4.56 (dd,J = 10.8,4.2 Hz,1H),4.18 - 4.09 (m,1H),4.07 (s,3H),3.61 (d,J = 12.6 Hz,2H),3.33 (s,3H),3.11 (t,J = 12.9 Hz,2H),2.91 - 2.79 (m,2H),2.61 - 2.48 (m,1H),2.44 - 2.35 (m,1H),2.28 (d,J = 12.0 Hz,2H),2.05 - 1.90 (m,2H). Note: No exchangeable protons were observed, containing less than 1% by weight of 1,4-dioxane. MS (ESI) [M+H] + 356.2.

[0344] Example i-5. Intermediate 5: Synthesis of 5-amino-1-(2-morpholinoethyl)indolin-2-one [ka] Step 1: Synthesis of 1-(2-morpholinoethyl)-5-nitroindolin-2-one To a stirred solution of triphenylphosphine (1.104 g, 4.21 mmol) in THF (20 mL) at 0 °C under nitrogen, diisopropyl azodicarboxylate (1.091 mL, 5.61 mmol) was added dropwise and stirred for 20 min. 2-Morpholinoethan-1-ol (736 mg, 5.61 mmol) was then added and stirred for 15 min. 5-Nitroindolin-2-one (50 mg, 2.81 mmol) was then added, and the mixture was slowly warmed to 25 °C and stirred for 16 h. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by flash column silica gel chromatography (60-80% ethyl acetate / petroleum ether) to give the title compound (273 mg, 0.937 mmol, 24% yield) as an off-white solid. MS (ESI) [M+H] + 292.0.

[0345] Step 2: Synthesis of 5-amino-1-(2-morpholinoethyl)indolin-2-one To a stirred suspension of 1-(2-morpholinoethyl)-5-nitroindolin-2-one (300 mg, 1.030 mmol) in ethanol (5.0 mL) and THF (5.0 mL) was added 10% Pd / C (150 mg) under nitrogen at 25° C. The reaction mixture was stirred under a hydrogen atmosphere for 8 hours. The reaction mixture was filtered through Celite, and the Celite layer was washed with ethanol (2×50 mL). The filtrate was concentrated under reduced pressure to give the title compound (280 mg, 1.071 mmol, 45% yield) as a gray liquid. The crude product was used in the next step without further purification. MS (ESI) [M+H] + 262.2.

[0346] Example i-6. Intermediate 6: Synthesis of 5-amino-1-(4,4,4-trifluorobutyl)indolin-2-one [ka] Step 1: Synthesis of 5-amino-1-(4,4,4-trifluorobutyl)indolin-2-one The synthesis of the title compound was achieved by a method similar to that of Intermediate 5 using 4,4,4-trifluorobutan-1-ol as the starting material.

[0347] Example i-7. Intermediate 7: Synthesis of 5-amino-6-fluoro-1-methylindolin-2-one [ka] Step 1: Synthesis of 6-fluoro-1-methyl-5-nitroindolin-2-one To a solution of 6-fluoro-1-methylindolin-2-one (100 mg, 0.605 mmol) in TFA (1 mL) was added sodium nitrite (51.5 mg, 0.605 mmol) at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred for 3 h. LCMS confirmed the completion of the reaction. The reaction mixture was then quenched with saturated sodium bicarbonate (25 mL) and then extracted with ethyl acetate (3 × 25 mL). The combined organic layers were washed with saturated aqueous sodium chloride (1 × 25 mL). The organic layers were dried over anhydrous magnesium sulfate, filtered through Celite, and concentrated. The crude product was purified by silica gel column chromatography (0–100% ethyl acetate / hexane) to give the title compound (100 mg, 0.476 mmol, 79% yield) as a white solid. MS (ESI) m / z 211.0 [M+H] + ; 1 H NMR (400 MHz,DMSO-d6) δ ppm 8.06 (br d,J=7.46 Hz,1 H),6.95 - 7.10 (m,1 H),3.63 (s,2 H),3.28 - 3.33 (m,43 H),3.24 (s,3 H).

[0348] Step 2: Synthesis of 5-amino-6-fluoro-1-methylindolin-2-one A suspension of 6-fluoro-1-methyl-5-nitroindolin-2-one (100 mg, 0.476 mmol) in methanol (10 mL) was stirred with palladium on carbon (50.6 mg, 0.476 mmol) at room temperature under hydrogen (1 atm) for 2 hours. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give the title compound (80 mg, 0.444 mmol, 93% yield) as an off-white solid. MS (ESI) m / z 181.2 [M+H] + .

[0349] Example i-8. Intermediate 8: Synthesis of 5-amino-7-fluoro-1-methylindolin-2-one [ka] Step 1: Synthesis of 7-fluoro-1-methylindolin-2-one To a suspension of 7-fluoroindolin-2-one (0.400 g, 2.65 mmol) in water (10 mL) was added 1N sodium hydroxide (3.97 mL, 3.97 mmol) and dimethyl sulfate (0.379 mL, 3.97 mmol). The reaction mixture was stirred at 120 °C for 40 minutes. LCMS showed the reaction was incomplete, with 20% SM remaining. The reaction mixture was quenched with saturated aqueous sodium chloride (25 mL) and then extracted with ethyl acetate (3 × 25 mL). The combined organic layers were washed with saturated aqueous sodium chloride (1 × 25 mL). The organic layer was dried (anhydrous sodium sulfate), filtered through Celite, and concentrated. The crude product was purified by silica gel column chromatography (0–50% ethyl acetate / hexanes). The desired fractions were concentrated under reduced pressure to give the title compound 7-fluoro-1-methylindolin-2-one (0.3 g, 1.82 mmol, 69% yield) as a yellow solid. MS (ESI) m / z 331.2 [M+H] + .

[0350] Step 2: Synthesis of 5-amino-7-fluoro-1-methylindolin-2-one The synthesis of the title compound was achieved by a method similar to that of Intermediate 7 using 7-fluoro-1-methylindolin-2-one as the starting material.

[0351] Example i-9. Intermediate 9: Synthesis of 5-amino-4-fluoro-1-methylindolin-2-one [ka] Step 1: Synthesis of 4-fluoro-1-methylindolin-2-one To a suspension of 4-fluoroindolin-2-one (1.0 g, 6.62 mmol) in water (18 mL) was added 1N sodium hydroxide (9.92 mL, 9.92 mmol) and dimethyl sulfate (0.695 mL, 7.28 mmol). The reaction mixture was stirred at 120 °C for 40 minutes. LCMS showed the reaction was incomplete, with 20% SM remaining. The reaction mixture was quenched with saturated aqueous sodium chloride (25 mL) and then extracted with ethyl acetate (3 × 25 mL). The combined organic layers were washed with saturated aqueous sodium chloride (1 × 25 mL). The organic layers were dried (anhydrous magnesium sulfate), filtered through Celite, and concentrated. The crude product was purified by silica gel column chromatography (0–50% ethyl acetate / hexane). The desired fractions were concentrated under reduced pressure to give the title compound (1.48 g, 100%) as a white solid; MS (ESI) m / z 166.2 [M+H] + .

[0352] Step 2: Synthesis of 4-fluoro-1-methyl-5-nitroindolin-2-one To a solution of 4-fluoro-1-methylindolin-2-one (0.68 g, 4.12 mmol) in sulfuric acid (10 mL) at −30°C, 90% nitric acid (0.195 mL, 4.53 mmol) in 98% sulfuric acid (1 mL) was slowly added. The reaction mixture was stirred at −30°C and allowed to warm to 0°C over 30 minutes. The reaction mixture was poured onto 100 g of ice and then extracted with ethyl acetate (3 × 25 mL). The combined organic layers were washed with saturated aqueous sodium chloride (1 × 25 mL). The organic layer was dried over anhydrous sodium sulfate, filtered through Celite, and concentrated. The crude product was purified by silica gel column chromatography (0–100% ethyl acetate / hexane) to give the title compound, 4-fluoro-1-methyl-5-nitroindolin-2-one (0.260 g, 1.24 mmol, 30.0% yield), as a yellow solid. MS(ESI)m / z 211.2[M+H] + .

[0353] Step 3: Synthesis of 5-amino-4-fluoro-1-methylindolin-2-one A suspension of 4-fluoro-1-methyl-5-nitroindolin-2-one (60 mg, 0.285 mmol) in methanol (10 mL) was stirred with palladium on carbon (30.4 mg, 0.285 mmol) at room temperature under hydrogen (1 atm) for 2 hours. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give the title compound (44 mg, 0.244 mmol, 86% yield) as a white solid. MS (ESI) m / z 181.2 [M+H] + ; 1 H NMR (400 MHz,DMSO-d6) δ ppm 6.68 (t,J = 8.56 Hz,1H),6.54 (d,J = 8.07 Hz,1H),4.76 (s,2H),3.52 (s,2H),3.04 (s,3H).

[0354] Example i-10. Intermediate 10: Synthesis of 5-amino-1-isopropylindolin-2-one [ka] Step 1: Synthesis of 1-isopropyl-5-nitroindolin-2-one A solution of 2-(2-fluoro-5-nitrophenyl)acetic acid (0.5 g, 2.51 mmol) and propan-2-amine (0.445 g, 7.53 mmol) in DMSO (4 mL) was stirred at 60 °C for 15 h. The reaction mixture was quenched with saturated aqueous ammonium chloride (25 mL) and then extracted with ethyl acetate (3 × 25 mL). The combined organic layers were washed with saturated aqueous sodium chloride (1 × 25 mL). The organic layers were dried (anhydrous sodium sulfate), filtered, and concentrated. The crude product was purified by silica gel column chromatography (0–100% ethyl acetate / hexane / hexane). The desired fractions were concentrated under reduced pressure to give 2-(2-(isopropylamino)-5-nitrophenyl)acetic acid (0.528 g, 87%) as a yellow solid. Solid 2-(2-(isopropylamino)-5-nitrophenyl)acetic acid (0.528 g) was then stirred with 2N HCl (10 mL) at room temperature for 15 hours. The resulting solid was collected by filtration to give the title compound (0.45 g, 2.043 mmol, 81% yield) as a yellow solid. MS (ESI) m / z 221.2 [M+H] + .

[0355] Step 2: Synthesis of 5-amino-1-isopropylindolin-2-one A suspension of 1-isopropyl-5-nitroindolin-2-one (450 mg, 2.043 mmol) in methanol (10 mL) was stirred with palladium on carbon (217 mg, 2.043 mmol) under hydrogen (1 atm) at room temperature for 15 hours. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give the title compound, 5-amino-1-isopropylindolin-2-one (350 mg, 1.840 mmol, 90% yield), as an off-white solid. MS (ESI) m / z 191.2 [M+H] + ; 1H NMR (400 MHz,DMSO-d6) δ ppm 6.80 (d,J=8.31 ​​Hz,1 H),6.55 (d,J=1.96 Hz,1 H),6.43 (dd,J=8.31,2.32 Hz,1 H),4.72 (br s,2 H),4.45 (spt,J=6.99 Hz,1 H),3.35 (s,2 H),1.34 (d,J=7.09 Hz,6 H).

[0356] Example i-11. Intermediate 11: Synthesis of 5-amino-1-ethylindolin-2-one [ka] Step 1: Synthesis of 5-amino-1-ethylindolin-2-one The synthesis of the title compound was achieved by a method similar to that of Intermediate 10 using ethylamine as the starting material.

[0357] Example i-12. Intermediate 12: Synthesis of 5-amino-1-(2-hydroxyethyl)indolin-2-one [ka] Step 1: Synthesis of 5-amino-1-(2-hydroxyethyl)indolin-2-one The synthesis of the title compound was achieved by a method similar to that of Intermediate 10 using 2-aminoethanol as the starting material.

[0358] Example i-13. Intermediate 13: Synthesis of 5-amino-1-(2-methoxyethyl)indolin-2-one [ka] Step 1: Synthesis of 2-(2-((2-methoxyethyl)amino)-5-nitrophenyl)acetic acid To a solution of 2-(2-fluoro-5-nitrophenyl)acetic acid (1.500 mg, 2.51 mmol) in THF (5.0 mL) was added 2-methoxyethan-1-amine (2.377 mg, 5.02 mmol) and DIPEA (0.877 mL, 5.02 mmol) under nitrogen at 25° C. The reaction mixture was heated to 60° C. and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure to give the title compound (550 mg, 0.543 mmol, 21% yield) as a yellow solid.

[0359] Step 2: Synthesis of 1-(2-methoxyethyl)-5-nitroindolin-2-one To a solution of 2-(2-((2-methoxyethyl)amino)-5-nitrophenyl)acetic acid (550 mg, 2.16 mmol) in water (2.0 mL) was added 1.5 N HCl (3.0 mL). The reaction mixture was heated to 60° C. and stirred for 16 hours. At 0° C., the reaction mixture was slowly poured into sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (240 mg, 0.95 mmol, 44% yield) as a light brown solid.

[0360] Step 3: Synthesis of 5-amino-1-(2-methoxyethyl)indolin-2-one To a stirred solution of 1-(2-methoxyethyl)-5-nitroindolin-2-one (240 mg, 0.945 mmol) in ethanol (10 mL) was added 10% Pd / C (101 mg) at 25° C. under nitrogen. The reaction mixture was stirred under a hydrogen atmosphere for 8 hours. The reaction mixture was filtered through Celite, and the Celite layer was washed with ethanol (3×10 mL). The filtrate was concentrated under reduced pressure to give the title compound (200 mg, 0.563 mmol, 59% yield). The product was used in the next step without further purification. MS (ESI) m / z 207.2 [M+H] + .

[0361] Example i-14. Intermediate 14: Synthesis of 5-amino-1-methyl-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one [ka] Step 1: 3,3-Dibromo-1-methyl-5-nitro-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one To a stirred solution of 1-methyl-5-nitro-1H-pyrrolo[2,3-b]pyridine (800 mg, 3.66 mmol) in t-butanol (1 mL) and water (1 mL) at 0° C. was added NBS (1.37 g, 7.68 mmol). The reaction mixture was stirred at 25° C. for 2 hours. The reaction mixture was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3×100 ml). The combined organic layers were evaporated to give the crude title compound, which was used without further purification.

[0362] Step 2: Synthesis of 5-amino-1-methyl-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one To a stirred solution of 3,3-dibromo-1-methyl-5-nitro-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (1.4 g, 3.99 mmol) in AcOH (20 mL) was added zinc powder (1.30 g, 20.0 mmol), and the reaction mixture was stirred at 25 °C for 6 h. The reaction mixture was monitored by TLC and LCMS. After this time, the reaction mixture was evaporated. The resulting residue was basified with NaOH solution (100 ml) and extracted with 10% MeOH in DCM. The organic fraction was evaporated to give the title compound, which was used without further purification. MS (ESI) m / z 164.1 [M+H] + .

[0363] Example i-15. Intermediate 15: Synthesis of 6-amino-1-(3-hydroxy-3-methylbutyl)indolin-2-one [ka] Step 1: Synthesis of 2-methyl-4-(6-nitro-1H-indol-1-yl)butan-2-ol To a stirred solution of 6-nitro-1H-indole (1, 1.0 g, 6.17 mmol) in DMF (10 mL) at 25 °C, 3-hydroxy-3-methylbutyl 4-methylbenzenesulfonate (2, 2.30 g, 8.02 mmol) and cesium carbonate (3.01 g, 9.25 mmol) were added. The reaction mixture was heated to 120 °C for 16 h. The reaction mixture was then cooled to room temperature, treated with water, and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product, which was purified by flash column silica chromatography (20–30% ethyl acetate / petroleum ether) to give the title compound (1.4 g, 5.44 mmol, 88% yield) as a brown semisolid. MS (ESI) m / z 249.1 [M+H] + .

[0364] Step 2: Synthesis of 3,3-dibromo-1-(3-hydroxy-3-methylbutyl)-6-nitroindolin-2-one To a stirred solution of 2-methyl-4-(6-nitro-1H-indol-1-yl)butan-2-ol (100 mg, 0.380 mmol) in t-BuOH (1 mL) and water (1.0 mL) at 0 °C was added NBS (142 mg, 0.797 mmol). The reaction mixture was slowly warmed to 25 °C and stirred for 2 h. The reaction mixture was treated with water (30 mL) and extracted with ethyl acetate (2 × 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (150 mg, 94% yield). The crude product was used in the next step without further purification.

[0365] Step 3: Synthesis of 6-amino-1-(3-hydroxy-3-methylbutyl)indolin-2-one To a stirred solution of 3,3-dibromo-1-(3-hydroxy-3-methylbutyl)-6-nitroindolin-2-one (150 mg) in AcOH (3.0 mL) was added zinc powder (116 mg, 1.78 mmol) at 0° C. The reaction mixture was slowly warmed to 25° C. and stirred for 8 hours. The reaction mixture was concentrated under reduced pressure to give the crude compound. The crude product was purified by flash column silica chromatography (6% methanol / DCM) to give the title compound (100 mg, 0.333 mmol, 87% yield) as a brown gummy solid. MS (ESI) m / z 235.2 [M+H] + .

[0366] Example i-16. Intermediate 16: Synthesis of 6-amino-1-(3-hydroxy-3-methylbutyl)-3,3-dimethylindolin-2-one [ka] Step 1: Synthesis of N-(2-bromo-5-nitro-phenyl)-2-methyl-prop-2-enamide To a solution of 2-bromo-5-nitroaniline (1.00 g, 4.61 mmol) in DMA (20 mL) was added 2-methylprop-2-enoyl chloride (0.45 mL, 4.61 mmol), and the reaction mixture was stirred at room temperature for 12 hours. Water (5.0 mL) was added, and the resulting precipitate was collected by filtration, washed with water (20 mL), and then dried in vacuo to give the title compound (950 mg, 72%) as a solid. 1 H NMR (400 MHz,DMSO d6): δ 9.69 (s,1H),8.44 (s,1H),8.00 (d,J = 1.2 Hz,2H),5.97 (s,1H),5.63 (s,1H),2.00 (s,3H).MS (ESI) [M+H] + 285.1.

[0367] Step 2: Synthesis of 3,3-dimethyl-6-nitro-indolin-2-one To a solution of N-(2-bromo-5-nitro-phenyl)-2-methyl-prop-2-enamide (950 mg, 3.33 mmol) in DMF (33 mL) under nitrogen, triethylamine (1.16 mL, 8.33 mmol), TBAB (1.07 g, 3.33 mmol), and Pd(OAc) (15.0 mg, 0.07 mmol) were added sequentially, and the reaction mixture was stirred at 80 °C for 1 h. HCOONa (227 mg, 3.33 mmol) was added, and the reaction mixture was stirred at 80 °C for 12 h. Water (5 mL) and ethyl acetate (15 mL) were added, and the layers were separated. The organic layer was washed with brine (3 × 10 mL), dried over NaSO, filtered, and concentrated under reduced pressure. EtO (5 mL) was added, and the resulting precipitate was collected by filtration and dried in vacuo to give the title compound (180 mg, 26%) as a solid. 1 H NMR (400 MHz,DMSO d6): δ 10.75 (s,1H),7.90 (dd,J = 8.2,2.1 Hz,1H),7.60 (d,J = 8.2 Hz,1H),7.57 (d,J = 2.1 Hz,1H),1.30 (s,6H).MS (ESI) [M+H] + 207.0.

[0368] Step 3: Synthesis of 1-(3-hydroxy-3-methyl-butyl)-3,3-dimethyl-6-nitro-indolin-2-one To a solution of 3,3-dimethyl-6-nitro-indolin-2-one (180 mg, 0.87 mmol) in DMF (3 mL), (3-hydroxy-3-methyl-butyl) 4-methylbenzenesulfonate (271 mg, 1.05 mmol) and K2CO3 (362 mg, 2.62 mmol) were added sequentially, and the reaction mixture was stirred at 80 °C for 12 h. Water (10 mL) and ethyl acetate (60 mL) were added, and the layers were separated. The organic layer was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (gradient: 0–100% EtOAc / hexanes) to give the title compound (145 mg, 57%) as a solid. 1H NMR (500 MHz,DMSO d6): δ 7.96 (dd,J = 8.1,2.1 Hz,1H),7.77 (d,J = 2.1 Hz,1H),7.66 (d,J = 8.1 Hz,1H),4.50 (s,1H),3.86 - 3.78 (m,2H),1.69 - 1.62 (m,2H),1.31 (s,6H),1.17 (s,6H).MS (ESI) [M+H] + 275.2.

[0369] Step 4: Synthesis of 6-amino-1-(3-hydroxy-3-methyl-butyl)-3,3-dimethyl-indolin-2-one A mixture of 1-(3-hydroxy-3-methyl-butyl)-3,3-dimethyl-6-nitro-indolin-2-one (145 mg, 0.50 mmol) and Pd(OH)2 / C (70.0 mg, 0.10 mmol) in iPrOH (3 mL) was subjected to hydrogenation (1 atm) at room temperature overnight. The mixture was filtered through Celite and washed with MeOH (10 mL). The filtrate was concentrated under reduced pressure to give the title compound (125 mg, 96%) as a solid, which was used in the next step without further purification. MS (ESI) [M+H] + 263.2.

[0370] Example i-17. Intermediate 17: Synthesis of tert-butyl (2-(5-amino-2-oxoindolin-1-yl)ethyl)(methyl)carbamate [ka] Step 1: Synthesis of 1-(2-(methylamino)ethyl)-5-nitroindolin-2-one To a stirred solution of 2-(2-fluoro-5-nitrophenyl)acetic acid (1, 1.0 g, 5.02 mmol) in THF (30 mL) was added tert-butyl(2-aminoethyl)(methyl)carbamate (2, 1.750 g, 10.04 mmol) and DIPEA (1.754 mL, 10.04 mmol) under nitrogen at 25° C. The reaction mixture was heated to 65° C. and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure to give the crude product as a brown liquid. The crude product was dissolved in water (20 mL), and 6.0 N HCl (6 mL, 36.0 mmol) was added dropwise at 25° C. The reaction mixture was heated to 65° C. and stirred for 16 hours. The reaction mixture was cooled to room temperature, neutralized with sodium bicarbonate, and extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (400 mg, 0.909 mmol, 18% yield) which was used in the next step without further purification.

[0371] Step 2: Synthesis of tert-butyl methyl (2-(5-nitro-2-oxoindolin-1-yl)ethyl)carbamate To a stirred solution of 1-(2-(methylamino)ethyl)-5-nitroindolin-2-one (400 mg, 0.909 mmol) in DCM (10 mL) at 0 °C under nitrogen, DIPEA (0.397 mL, 2.272 mmol) and Boc-anhydride (0.422 mL, 1.818 mmol) were added dropwise. The reaction mixture was slowly warmed to 25 °C and stirred for 16 h. The reaction mixture was treated with water (50 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude compound, which was purified by flash column silica gel chromatography (20–40% ethyl acetate / petroleum ether) to give the title compound (240 mg, 0.697 mmol, 77% yield).

[0372] Step 3: Synthesis of tert-butyl (2-(5-amino-2-oxoindolin-1-yl)ethyl)(methyl)carbamate To a stirred solution of tert-butyl methyl (2-(5-nitro-2-oxoindolin-1-yl)ethyl)carbamate (240 mg, 0.716 mmol) in ethanol (2.5 mL) and THF (2.5 mL) was added 10% Pd / C (120 mg) at 25° C. under nitrogen. The reaction mixture was stirred under a hydrogen atmosphere for 6 hours. The reaction mixture was filtered through Celite, and the Celite layer was washed with ethanol (2×50 mL). The filtrate was concentrated under reduced pressure to give compound 5 (200 mg, 0.504 mmol, 70% yield) as a dark brown liquid. The crude product was used in the next step without further purification.

[0373] Example i-18. Intermediate 18: Synthesis of 5-amino-1-(2,2-difluoropropyl)indolin-2-one [ka] Step 1: Synthesis of 2,2-difluoropropyl 4-methylbenzenesulfonate To a solution of 2,2-difluoropropan-1-ol (1, 1.0 g, 10.4 mmol) in DCM (10 mL) at 25 °C was added triethylamine (2.18 mL, 15.61 mmol). The mixture was cooled to 0 °C, and 4-dimethylaminopyridine (0.127 g, 1.041 mmol) was added, followed by 4-methylbenzenesulfonyl chloride (2.381 g, 12.49 mmol). The reaction mixture was slowly warmed to 25 °C and stirred for 16 h. The resulting reaction mixture was added to water (25 mL) and extracted with DCM (3 × 50 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (2.0 g, 7.95 mmol, 76% yield) as an off-white solid. The crude product was used in the next step without further purification. MS(ESI) m / z 268.0 [M+H2O].

[0374] Step 2: Synthesis of 1-(2,2-difluoropropyl)-5-nitro-1H-indole To a solution of 2,2-difluoropropyl 4-methylbenzenesulfonate (931 mg, 3.70 mmol) in DMF (5 mL) at 25 °C, cesium carbonate (1507 mg, 4.63 mmol) and 5-nitro-1H-indole (3, 500.0 mg, 3.08 mmol) were added. The mixture was heated to 120 °C and stirred for 16 h. The reaction mixture was quenched by the addition of water (15 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by flash column silica chromatography (35-40% ethyl acetate / petroleum ether) to give the title compound (250.0 mg, 0.997 mmol, 32% yield) as a pale yellow solid. MS (ESI) m / z 240.9 [M+H] + .

[0375] Step 3: Synthesis of 3,3-dibromo-1-(2,2-difluoropropyl)-5-nitroindolin-2-one To a solution of 1-(2,2-difluoropropyl)-5-nitro-1H-indole (250.0 mg, 0.997 mmol) in tert-butanol (2.5 mL, 26.1 mmol) and water (2.5 mL) was added NBS (373 mg, 2.094 mmol) portionwise at 0 °C. The reaction mixture was slowly warmed to 25 °C and stirred for 6 h. The reaction mixture was quenched with water (15 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (350.0 mg, 0.619 mmol, 62% yield) as a pale yellow solid. MS (ESI) m / z 415.0 [M+H] + .

[0376] Step 4: Synthesis of 5-amino-1-(2,2-difluoropropyl)indolin-2-one To a stirred solution of 3,3-dibromo-1-(2,2-difluoropropyl)-5-nitroindolin-2-one (350.0 mg, 0.619 mmol) in acetic acid (5.0 mL) at 25° C., zinc powder (202 mg, 3.10 mmol) was slowly added, and stirring was continued for 6 hours. The reaction mixture was concentrated under reduced pressure and diluted with water (15 mL). The resulting residue was extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (150.0 mg, 0.299 mmol, 48% yield) as a brown solid. The crude product was used in the next step without further purification. MS (ESI) m / z 227.0 [M+H] + .

[0377] Example i-19. Intermediate 19: Synthesis of 5-amino-1-(3-fluoro-3-methylbutyl)indolin-2-one [ka] Step 1: Synthesis of 5-amino-1-(3-fluoro-3-methylbutyl)indolin-2-one The title compound was synthesized by a method similar to Intermediate 18 using 3-fluoro-3-methylbutan-1-ol as the starting material.

[0378] Example i-20. Intermediate 20: Synthesis of 5-amino-1-(2-fluoro-2-methylpropyl)indolin-2-one [ka] Step 1: Synthesis of 2-fluoro-2-methylpropyl trifluoromethanesulfonate To a stirred mixture of trifluoromethanesulfonic anhydride (2.75 mL, 16.28 mmol) in DCM (10 mL) at −10° C., 2,6-dimethylpyridine (2.26 mL, 19.5 mmol) was slowly added, followed by dropwise addition of a solution of 2-fluoro-2-methylpropan-1-ol (1.50 g, 16.3 mmol) in DCM (35 mL). The reaction mixture was stirred at 0° C. for 4 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in DCM and washed with 1.0 N HCl solution, followed by saturated bicarbonate solution, and then brine. The organic layer was dried over sodium sulfate, filtered, and concentrated to give the title compound (2.5 g, 11.2 mmol, 68% yield) as a brown liquid. The crude product was used in the next step without further purification.

[0379] Step 2: Synthesis of 1-(2-fluoro-2-methylpropyl)-5-nitro-1H-indole To a stirred solution of 5-nitro-1H-indole (700 mg, 4.32 mmol) in DMF (10 mL) was added the compound 2-fluoro-2-methylpropyl trifluoromethanesulfonate (2419 mg, 10.79 mmol). The reaction mixture was heated to 100° C. and stirred for 4 hours. The reaction mixture was poured into ice-cold water and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give the title compound (600 mg, 2.41 mmol, 56% yield). The crude product was used in the next step without further purification. MS (ESI) m / z 237.1 [M+H] + .

[0380] Synthesis of 5-amino-1-(2-fluoro-2-methylpropyl)indolin-2-one To a stirred solution of 1-(2-fluoro-2-methylpropyl)-5-nitro-1H-indole (100 mg, 0.423 mmol) in t-butanol (2.0 mL) was added bromine (0.218 mL, 4.23 mmol) at 0° C., and the reaction mixture was stirred for 5 minutes. Water (2 mL) was then slowly added, and the mixture was warmed to 25° C. and stirred for 4 hours. The reaction mixture was treated with water and extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 110 mg of crude product. This residue was dissolved in acetic acid (3.5 mL), and zinc powder (88 mg, 1.34 mmol) was added. The mixture was stirred at 25° C. for 1 hour. The reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was added to ethyl acetate and treated with sodium bicarbonate solution. The organic layer was dried over sodium sulfate, filtered, and concentrated to give the title compound (55 mg, 0.132 mmol, 49% yield), which was used crude in the next step without further purification.

[0381] Example i-21. Intermediate 21: Synthesis of 5-amino-1-(2,2,2-trifluoroethyl)indolin-2-one [ka] Step 1: Synthesis of 5-nitro-1-(2,2,2-trifluoroethyl)indoline-2,3-dione To a solution of 5-nitroindoline-2,3-dione (0.96 g, 5.00 mmol) in DMF (35.0 mL) cooled to 0 °C was added NaH (60%, dispersion in mineral oil, 220.0 mg, 5.50 mmol). After stirring at 0 °C for 45 min, 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.28 g, 5.50 mmol) was added. The reaction mixture was allowed to warm to room temperature over 1 h. Saturated aqueous NH4Cl (300.0 mL) and EtOAc were added, and the layers were separated. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with water, brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The material was purified by column silica gel chromatography (gradient: 20–70% ethyl acetate / hexanes) to afford the title compound (910.0 mg, 66%) as a solid.1 H NMR (500 MHz,DMSO) δ 8.60 (dd,J = 8.8,2.5 Hz,1H),8.30 (d,J = 2.4 Hz,1H),7.55 (d,J = 8.8 Hz,1H),4.77 (q,J = 9.3 Hz,2H).

[0382] Step 2: Synthesis of 5-amino-1-(2,2,2-trifluoroethyl)indoline-2,3-dione A mixture of 5-nitro-1-(2,2,2-trifluoroethyl)indoline-2,3-dione (548.0 mg, 2.00 mmol) and 10% Pd / C (106.0 mg, 0.10 mmol) in methanol (25.0 mL) was shaken in a Parr flask under a hydrogen atmosphere (50 psi) at room temperature for 1 hour. The mixture was filtered through Celite and washed with MeOH. The filtrate was concentrated under reduced pressure to give the title compound (450.0 mg, 92%) as a solid, which was used in the next step without further purification. MS (ESI) [M+H] + 247.1.

[0383] Step 3: Synthesis of 5-amino-1-(2,2,2-trifluoroethyl)indolin-2-one A mixture of 5-amino-1-(2,2,2-trifluoroethyl)indoline-2,3-dione (450.0 mg, 1.84 mmol) and hydrazine hydrate (65%, 10.0 mL, 133.0 mmol) was heated to 115 °C for 1 h and then cooled to room temperature. The volatiles were evaporated under reduced pressure. The material was purified by reverse-phase chromatography (C18) (gradient: 10-70% acetonitrile and water (ammonium formate buffer pH 4)) to give the title compound (150.0 mg, 35%) as a solid. 1 H NMR (500 MHz,DMSO) δ 6.79 (d,J = 8.3 Hz,1H),6.57 (s,1H),6.47 (dd,J = 8.3,2.1 Hz,1H),4.81 (s,2H),4.47 (q,J = 9.5 Hz,2H),3.54 (s,2H).MS (ESI) [M+H] + 231.1.

[0384] Example i-22. Intermediate 22: Synthesis of benzyl 4-amino-5-methylcycloheptane-1-carboxylate [ka] Step 1: Synthesis of 1-benzyl 4-ethyl 5-oxoazepane-1,4-dicarboxylate To a stirred solution of benzyl 4-oxopiperidine-1-carboxylate (2.5 g, 10.72 mmol) and ethyl 2-diazoacetate (9.78 g, 12.86 mmol) in THF (50 mL) was added BFOEt (1.358 mL, 10.72 mmol) at −25° C. The reaction mixture was stirred at 25° C. for 4 h. The reaction mixture was then basified with sodium bicarbonate solution (100 mL), and the organic layer was extracted with EtOAc (3×100 mL). The combined organic fractions were dried and concentrated to give the crude product, which was purified by CombiFlash column chromatography (product eluted with 15% EA / PE). The product-containing fractions were combined and concentrated to give 1-benzyl 4-ethyl 5-oxoazepane-1,4-dicarboxylate (3.5 g, 3.40 mmol, 31.7% yield) as a colorless liquid. (ESI) [M+H] + 320.0, RT=2.15.

[0385] Step 2: Synthesis of 1-benzyl 4-ethyl 4-methyl-5-oxoazepane-1,4-dicarboxylate To a stirred solution of 1-benzyl 4-ethyl 5-oxoazepane-1,4-dicarboxylate (3.5 g, 10.96 mmol) in DMF (8 mL) at 0 °C, CsCO (7.14 g, 21.92 mmol) and MeI (1.371 mL, 21.92 mmol) were added. The reaction mixture was warmed to room temperature and stirred at 25 °C for 6 h. The reaction mixture was evaporated to give the crude product, which was purified by CombiFlash column chromatography. The product eluted with 25-30% EA / PE. Fractions containing the product were combined and concentrated to give 1-benzyl 4-ethyl 4-methyl-5-oxoazepane-1,4-dicarboxylate (2.5 g, 76%) as a colorless liquid. 1 H NMR (400 MHz,DMSO) δ 7.35 (br m,5H),5.07 (br m,2H),4.15 (br m,2H),3.68 (m,2H),3.40 (br m,1H),2.81 (br m,2H),2.15 (br m,1H),1.59 (br m,1H),1.19 - 1.24 (br m,6H).MS (ESI) [M+H] + 334.1

[0386] Step 3: Synthesis of benzyl 4-methyl-5-oxoazepane-1-carboxylate To a stirred solution of 1-benzyl 4-ethyl 4-methyl-5-oxoazepane-1,4-dicarboxylate (2.5 g, 5.70 mmol) in MeOH (20 mL) and water (20 mL) at 25 °C, KOH (0.959 g, 17.10 mmol) was added. The reaction mixture was stirred at 60 °C for 4 h. The reaction mixture was then diluted with water (50 mL) and extracted with DCM (2 × 100 mL). This was purified by reverse-phase preparative HPLC (gradient: 2 to 98% MeCN / 5 mm ammonium formate (pH 3.3)). Fractions containing the desired product were combined and concentrated to give benzyl 4-methyl-5-oxoazepane-1-carboxylate (1.50 g, 80%) as a yellow oil. 1H NMR (400 MHz,DMSO) δ 7.31 - 7.39 (m,5H),5.07 (s,2H),3.82 - 3.98 (m,2H),3.46 (m,1H),3.34 (m,1H),3.19 (m,1H),3.01 (m,1H).2.59 (m,1H),1.66 (m,1H),1.30 (m,1H),0.95 (d,2H).MS (ESI) [M+H] + 262.2

[0387] Step 4: Synthesis of benzyl 4-amino-5-methylazepane-1-carboxylate To a stirred solution of benzyl 4-methyl-5-oxoazepane-1-carboxylate (1.0 g, 3.02 mmol) in 2-propanol (20 mL) at 25 °C, ammonium acetate (4.66 g, 60.5 mmol) and NaCNBH (1.140 g, 18.14 mmol) were added. The reaction mixture was stirred at 50 °C for 3 h and monitored by TLC and LCMS. The reaction mixture was then diluted with water (80 mL) and extracted with DCM (3 × 80 mL). The organic fraction was concentrated to give benzyl 4-amino-5-methylazepane-1-carboxylate (700 mg, 65%) as a yellow solid. MS (ESI) [M+H] + 263.2, RT=0.78

[0388] Example i-23. Intermediate 23: Synthesis of benzyl 4-amino-3-methylazepane-1-carboxylate [ka] Step 1: Synthesis of 1-benzyl 3-ethyl 4-oxoazepane-1,3-dicarboxylate To a stirred solution of benzyl 3-oxopiperidine-1-carboxylate (5.0 g, 21.43 mmol) and ethyl 2-diazoacetate (21.20 g, 27.9 mmol) in THF (50 mL) was added BFOEt (2.72 mL, 21.43 mmol) at −78 °C. The reaction mixture was warmed to room temperature and stirred at 25 °C for 4 h. The reaction mixture was then basified with sodium bicarbonate solution (100 mL), and the organics were extracted with EtOAc (3 × 100 mL). The combined organic fractions were dried and concentrated to give the crude product, which was purified by CombiFlash column chromatography (product eluted with 20–30% EA / PE). The product-containing fractions were combined and concentrated to give 1-benzyl 3-ethyl 4-oxoazepane-1,3-dicarboxylate (4.5 g, 10.00 mmol, 46.7% yield) as a colorless liquid. (ESI) [M+H] + 320.1, RT=2.11

[0389] Step 2: Synthesis of 1-benzyl 3-ethyl 3-methyl-4-oxoazepane-1,3-dicarboxylate To a stirred solution of 1-benzyl 3-ethyl 4-oxoazepane-1,3-dicarboxylate (4.0 g, 10.02 mmol) in DMF (1 mL) at 0 °C, CsCO (6.53 g, 20.04 mmol) and MeI (1.253 mL, 20.04 mmol) were added, and the reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was warmed to room temperature and stirred at 25 °C for 6 h. The reaction mixture was evaporated to give the crude product, which was purified by CombiFlash column chromatography. The product was eluted with 20% EtOAc / PE. Fractions containing the product were combined and concentrated to give 1-benzyl 3-ethyl 3-methyl-4-oxoazepane-1,3-dicarboxylate (2.2 g, 5.61 mmol, 56.0% yield) as a colorless liquid. 1H NMR (400 MHz,DMSO) δ 7.32 - 7.40 (m,5H),5.08 (s,2H),3.34 - 4.04 (m,6H),2.71 (m,2H),1.64 - 1.78 (m,3H).1.10 - 1.24 (m,5H).MS (ESI) [M+H]+ 334.2

[0390] Step 3: Synthesis of benzyl 3-methyl-4-oxoazepane-1-carboxylate To a stirred solution of 1-benzyl 3-ethyl 3-methyl-4-oxoazepane-1,3-dicarboxylate (1.0 g, 2.55 mmol) in MeOH (7.5 mL) and HO (7.5 mL) was added KOH (0.429 g, 7.65 mmol), and the reaction mixture was stirred at 60 °C for 2 h. The reaction mixture was monitored by TLC and LCMS. The reaction mixture was stirred at 60 °C for 4 h. The reaction mixture was then diluted with water (50 mL) and extracted with DCM (2 × 100 mL). This was purified by reverse-phase preparative HPLC (gradient: 2 to 98% MeCN / 5 mm ammonium formate (pH 3.3)). Fractions containing the desired product were combined and concentrated to give benzyl 3-methyl-4-oxoazepane-1-carboxylate (550 mg, 76%) as a yellow oil. 1 H NMR (400 MHz,DMSO) δ 7.29 - 7.37 (m,5H),5.08 (s,2H),3.33 - 4.04 (m,6H),2.51 (m,2H),1.99 (m,1H),1.76 (m,1H),1.64 (m,1H).1.09 - 1.23 (m,6H).MS (ESI) [M+H] + 262.1

[0391] Step 4: Synthesis of benzyl 4-amino-3-methylazepane-1-carboxylate To a stirred solution of benzyl 3-methyl-4-oxoazepane-1-carboxylate (100 mg, 0.352 mmol) in 2-propanol (4 mL) at 25 °C, ammonium acetate (543 mg, 7.04 mmol) and NaCNBH (133 mg, 2.112 mmol) were added. The reaction mixture was stirred at 50 °C for 3 h. The reaction mixture was then diluted with water and extracted with EtOAc. The organic fraction was concentrated to give benzyl 4-amino-3-methylazepane-1-carboxylate (100 mg, 40%) as a yellow solid. MS (ESI) [M+H] + 263.2, RT=1.35.

[0392] Example S1. Synthesis of 3-(6-((5-(5-chloro-4-((1-methyl-2-oxoindolin-5-yl)amino)pyrimidin-2-yl)-5-azaspiro[3.5]nonan-8-yl)amino)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (1) [ka] Step 1: Synthesis of 5-((5-chloro-2-fluoropyrimidin-4-yl)amino)-1-methylindolin-2-one To a solution of 5-amino-1-methylindolin-2-one (2.0 g, 12.3 mmol) in tetrahydrofuran (32 mL) was added DIPEA (2.37 ml, 13.6 mmol) at -40°C. A solution of 5-chloro-2,4-difluoropyrimidine (1.86 g, 12.3 mmol) in anhydrous tetrahydrofuran (8 mL) was slowly added to the mixture, which was then allowed to warm slowly to room temperature. The reaction mixture was stirred at room temperature for 16 hours. After this time, the reaction mixture was filtered and washed with acetonitrile (approximately 50 mL). The solid was dried under vacuum to give the title compound as a tan solid. MS (ESI) [M+H] + 293.1.

[0393] Step 2: Synthesis of tert-butyl 8-[[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-6-yl]amino]-5-azaspiro[3.5]nonane-5-carboxylate To a solution of 3-(6-amino-1-methyl-indazol-3-yl)piperidine-2,6-dione hydrochloride (200 mg, 0.68 mmol), tert-butyl 8-oxo-5-azaspiro[3.5]nonane-5-carboxylate (201 mg, 0.81 mmol), and AcOH (1 mL) in DMSO (5 mL) was added decaborane (38 mg, 0.34 mmol). The reaction mixture was stirred at room temperature for 5 hours, and the volatiles were evaporated under reduced pressure. The residue was purified by reverse-phase chromatography (C18) (gradient: 0-80% MeCN / 10 mM aqueous ammonium formate) to give the title compound (325 mg, 76%) as a solid. MS (ESI) [M+H] + 482.3. 1 H NMR (400 MHz,DMSO-d6) δ 10.82 (s,1H),7.32 (d,J = 8.7 Hz,1H),6.52 - 6.40 (m,1H),6.48 (br s,1H),5.78 (d,J = 8.7 Hz,1H),4.18 (dd,J = 8.8,5.2 Hz,1H),3.82 (s,3H),3.73 - 3.68 (m,2H),2.75 - 2.68 (m,1H),2.62 - 2.59 (m,2H),2.30 - 2.13 (m,4H),1.98 - 1.86 (m,4H),1.72 - 1.60 (m,3H),1.40 (s,9H),1.06 - 0.98 (m,1H).

[0394] Step 3: Synthesis of 3-[6-(5-azaspiro[3.5]nonan-8-ylamino)-1-methyl-indazol-3-yl]piperidine-2,6-dione 2,2,2-trifluoroacetic acid To a solution of tert-butyl 8-[[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-6-yl]amino]-5-azaspiro[3.5]nonane-5-carboxylate (325 mg, 0.67 mmol) in DCM (5 mL) was added trifluoroacetic acid (0.31 mL, 4.1 mmol), and the reaction mixture was stirred at room temperature for 18 hours. The volatiles were evaporated under reduced pressure to give the title compound as a solid, which was used in the next step without further purification. MS (ESI) [M+H] + 382.3. 1 H NMR (500 MHz,DMSO-d6) δ 10.82 (s,1H),8.98 (d,J = 8.5 Hz,1H),8.75 - 8.71 (m,1H),7.37 (d,J = 8.7 Hz,1H),6.55 (dd,J = 8.7,1.8 Hz,1H),6.51 (br s,1H),4.19 (dd,J = 8.9,5.1 Hz,1H),3.83 (s,3H),3.63 - 3.57 (m,1H),3.30 - 3.27 (m,1H),3.02 - 2.96 (m,1H),2.63 - 2.60 (m,2H),2.36 (d,J = 12.9 Hz,1H),2.30 - 2.23 (m,4H),2.17 - 2.12 (m,2H),2.01 - 1.97 (m,1H),1.95 - 1.87 (m,2H),1.63 - 1.58 (m,1H),1.40 - 1.32 (m,1H).

[0395] Step 4: Synthesis of 3-[6-[[5-[5-chloro-4-[(1-methyl-2-oxo-indolin-5-yl)amino]pyrimidin-2-yl]-5-azaspiro[3.5]nonan-8-yl]amino]-1-methyl-indazol-3-yl]piperidine-2,6-dione To a solution of 3-[6-(5-azaspiro[3.5]nonan-8-ylamino)-1-methyl-indazol-3-yl]piperidine-2,6-dione 2,2,2-trifluoroacetic acid (20 mg, 40 μmol) in NMP (0.7 mL) under nitrogen (1 atm) was added 5-((5-chloro-2-fluoropyrimidin-4-yl)amino)-1-methylindolin-2-one (11 mg, 40 μmol). The reaction mixture was heated to 160° C. for 18 hours and then cooled to room temperature. The crude reaction mixture was purified by reverse-phase chromatography (C18) (gradient: 0-100% MeCN / water (with 0.1% formic acid)) to give the title compound (13 mg, 44%) as a solid. LCMS: C 34 H 36 ClNO3 Calculated: 653.3, Found: 654.3 [M+H] + ; 1 H NMR (500 MHz,DMSO-d6) δ 10.80 (s,1H),8.62 (s,1H),8.01 (s,1H),7.39 (s,1H),7.38 - 7.36 (m,1H),7.30 (d,J = 8.8 Hz,1H),6.92 (d,J = 8.3 Hz,1H),6.48 - 6.45 (m,2H),5.65 (d,J = 8.8 Hz,1H),4.25 (d,J = 12.1 Hz,1H),4.17 (dd,J = 8.9,5.1 Hz,1H),3.83 -3.80 (m,1H),3.81 (s,3H) 3.51 - 3.50 (m,2H),3.09 (s,3H),2.88 (t,J = 10.0 Hz,1H),2.62 - 2.59 (m,2H),2.38 -2.34 (m,2H),2.26 - 2.24 (m,1H),2.19 - 2.12 (m,2H),1.96 -1.88 (m,3H),1.67 - 1.56 (m,3H),1.07 - 0.99 (m,1H).

[0396] Example S2. Synthesis of 3-(6-(8-((5-chloro-4-((1-methyl-2-oxoindolin-5-yl)amino)pyrimidin-2-yl)(methyl)amino)-5-azaspiro[3.5]nonan-5-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (2) [ka] Step 1: Synthesis of 2-[2-bis-[3,5-bis-(trifluoromethyl)phenyl]phosphanyl-3,6-dimethoxy-phenyl]-N1,N1,N3,N3-tetramethyl-benzene-1,3-diamine[2-[2-(methylamino)phenyl]phenyl]-methylsulfonyloxy-palladium A mixture of (2'-methylamino-1,1'-biphenyl-2-yl)methanesulfonate palladium(II) dimer (406 mg, 0.53 mmol) and 2-[2-bis-[3,5-bis-(trifluoromethyl)phenyl]phosphanyl-3,6-dimethoxy-phenyl]-N1,N1,N3,N3-tetramethyl-benzene-1,3-diamine (800 mg, 1.06 mmol) was evacuated and backfilled with argon. DCM (5 mL) was added via syringe, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with Et2O (5 mL) and filtered. The filtrate was concentrated, pentane (5 mL) was added to the residue, and the mixture was concentrated under reduced pressure to give the title compound (1.08 g, 90%) as a yellow solid. 1H NMR (500 MHz,MeOD-d4) δ 8.38 (s,1H),8.13 (s,1H),8.00 (t,J = 8.1 Hz,1H),7.74 (d,J = 11.2 Hz,2H),7.62 (d,J = 11.4 Hz,2H),7.59 - 7.55 (m,1H),7.51 (d,J = 9.0 Hz,1H),7.42 (dd,J = 7.5,1.4 Hz,1H),7.34 - 7.28 (m,3H),7.25 (t,J = 7.3 Hz,1H),7.21 (d,J = 8.1 Hz,1H),7.16 - 7.13 (m,1H),7.03 (d,J = 8.1 Hz,1H),6.84 (t,J = 7.7 Hz,1H),6.33 - 6.29 (m,1H),3.71 (s,3H),3.42 (s,3H),2.78 (s,6H),2.69 (s,3H),2.61 - 2.54 (m,1H),2.15 (dd,J = 5.9,2.9 Hz,3H),2.09 (s,6H). 19 F NMR (471 MHz,MeOD-d4) δ -64.20,-64.42. 31 P NMR (203 MHz, MeOD-d4) δ 33.80.

[0397] Step 2: Synthesis of tert-butyl N-[5-[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazol-6-yl]-5-azaspiro[3.5]nonan-8-yl]carbamate A mixture of 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole (600 mg, 1.20 mmol), tert-butyl N-(5-azaspiro[3.5]nonan-8-yl)carbamate (375 mg, 1.56 mmol), NaOtBu (288 mg, 3.0 mmol), 2-[2-bis-[3,5-bis-(trifluoromethyl)phenyl]phosphanyl-3,6-dimethoxy-phenyl]-N1,N1,N3,N3-tetramethyl-benzene-1,3-diamine[2-[2-(methylamino)phenyl]phenyl]-methylsulfonyloxy-palladium (137 mg, 0.12 mmol) in cyclopentyl methyl ether (12 mL) was heated to 85° C. for 4 hours and then cooled to room temperature. The mixture was filtered through Celite and washed with EtOAc (3 x 15 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (gradient: 0-60% EtOAc / hexanes) to give the title compound (600 mg, 76%) as a solid. MS (ESI) [M+H] + 660.2. 1 H NMR (400 MHz,DMSO-d6) δ 7.88 (d,J = 8.1 Hz,1H),7.50 - 7.43 (m,3H),7.42 - 7.32 (m,5H),7.32 - 7.25 (m,3H),6.79 (d,J = 7.5 Hz,1H),6.73 (d,J = 1.5 Hz,1H),6.62 (dd,J = 9.0,1.8 Hz,1H),6.57 (d,J = 8.1 Hz,1H),5.44 (s,2H),5.42 (s,2H),3.95 (s,3H),3.69 - 3.57 (m,1H),3.51 - 3.43 (m,1H),3.12 - 3.00 (m,1H),2.17 - 2.04 (m,4H),1.98 - 1.89 (m,1H),1.80 - 1.68 (m,2H),1.59 - 1.48 (m,2H),1.38 (s,9H),1.27 - 1.16 (m,1H).

[0398] Step 3: Synthesis of tert-butyl N-[5-[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazol-6-yl]-5-azaspiro[3.5]nonan-8-yl]-N-methyl-carbamate To an ice-cold solution of tert-butyl N-[5-[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazol-6-yl]-5-azaspiro[3.5]nonan-8-yl]carbamate (1.05 g, 1.59 mmol) and NaH (159 mg, 3.98 mmol, 60% dispersion in mineral oil) in DMF (6 mL) was added iodomethane (198 μL, 3.18 mmol), and the mixture was stirred at room temperature for 2 h. Another batch was prepared by the same procedure. Water (50 mL) was added, and the combined mixture was extracted with EtOAc (3 × 75 mL). The organic fraction was washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by reverse-phase chromatography (C18) (concentration gradient: 20-100% MeCN / 10 mM ammonium formate aqueous solution) to give the title compound (700 mg, total yield 65%) as a solid. MS (ESI) [M+H] + 674.4.

[0399] Step 4: Synthesis of tert-butyl N-[5-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-6-yl]-5-azaspiro[3.5]nonan-8-yl]-N-methyl-carbamate A mixture of tert-butyl N-[5-[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazol-6-yl]-5-azaspiro[3.5]nonan-8-yl]-N-methyl-carbamate (700 mg, 1.04 mmol) and Pearlman's catalyst (365 mg, 0.26 mmol) in EtOH (15 mL) and THF (15 mL) was stirred under a hydrogen atmosphere (1 atm) at 50° C. for 2 hours. The mixture was filtered through Celite, washed with MeOH (3×15 mL), and the filtrate was concentrated to give the title compound (425 mg, 83%) as a solid, which was used in the next step without further purification. MS (ESI) [M+H] + 496.2. 1H NMR (400 MHz,DMSO d6) δ 10.86 (s,1H),7.48 (d,J = 8.7 Hz,1H),6.77 (s,1H),6.77 - 6.73 (m,1H),4.30 - 4.22 (m,1H),3.89 (s,3H),3.62 - 3.53 (m,1H),3.16 - 3.05 (m,1H),2.70 - 2.57 (m,5H),2.38 - 2.25 (m,1H),2.19 - 2.07 (m,4H),2.06 - 1.93 (m,2H),1.93 - 1.81 (m,1H),1.78 - 1.67 (m,1H),1.62 - 1.31 (m,4H), 1.41 (s,9H).

[0400] Step 5: Synthesis of 3-[1-methyl-6-[8-(methylamino)-5-azaspiro[3.5]nonan-5-yl]indazol-3-yl]piperidine-2,6-dione hydrochloride To a solution of tert-butyl N-[5-[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-6-yl]-5-azaspiro[3.5]nonan-8-yl]-N-methyl-carbamate (425 mg, 0.86 mmol) in DCM (4 mL) was added HCl (4N) / 1,4-dioxane (4 mL, 16 mmol), and the mixture was stirred at room temperature for 4 hours. The resulting precipitate was collected by filtration, washed with EtO (2 × 5 mL), and dried under vacuum to give the title compound (340 mg, 92%) as a solid, which was used in the next step without further purification. MS (ESI) [M+H] + 396.3. 1H NMR (500 MHz,DMSO-d6) δ 10.49 (s,1H),9.08 (br s,2H),7.56 (d,J = 8.8 Hz,1H),6.95 (s,1H),6.87 (dd,J = 8.8,1.4 Hz,1H),4.27 (dd,J = 8.8,5.2 Hz,1H),3.92 (s,3H),3.60 (dt,J = 13.6,3.2 Hz,1H),3.43 - 3.32 (m,1H),3.25 - 3.16 (m,1H),2.68 - 2.63 (m,2H),2.56 (t,J = 5.3 Hz,3H),2.49 - 2.43 (m,1H),2.39 - 2.29 (m,1H),2.27 - 2.20 (m,2H),2.20 - 2.13 (m,2H),2.13 - 2.04 (m,2H),1.96 - 1.89 (m,1H),1.82 - 1.70 (m,1H),1.64 - 1.53 (m,2H).

[0401] Step 6: Synthesis of 3-[6-[8-[[5-chloro-4-[(1-methyl-2-oxo-indolin-5-yl)amino]pyrimidin-2-yl]-methyl-amino]-5-azaspiro[3.5]nonan-5-yl]-1-methyl-indazol-3-yl]piperidine-2,6-dione To a mixture of 3-[1-methyl-6-[8-(methylamino)-5-azaspiro[3.5]nonan-5-yl]indazol-3-yl]piperidine-2,6-dione hydrochloride (46.5 mg, 0.11 mmol) and DIPEA (110 μL, 0.61 mmol) in DMSO (1 mL) was added 5-((5-chloro-2-fluoropyrimidin-4-yl)amino)-1-methylindolin-2-one (30 mg, 0.10 mmol) at room temperature, and the reaction mixture was heated to 80 °C for 16 h. The crude reaction mixture was purified by preparative HPLC (BEH column, C18) (gradient: 48-58% MeCN / 10 mM ammonium formate in water) to give the title compound (14.9 mg, 22%) as a solid. LCMS: C 34 H 36 ClNO3 Calculated: 667.3, Found: 668.3 [M+H] + ; 1H NMR (500 MHz,DMSO-d6) δ 10.49 (br s,1H),8.29 (s,1H),8.00 (s,1H),7.56 (s,1H),7.54 - 7.49 (m,2H),6.93 (d,J = 8.3 Hz,1H),6.80 - 6.76 (m,2H),4.89 - 4.80 (m,1H),4.26 (dd,J = 8.6,5.2 Hz,1H),3.91 (s,3H),3.57 (d,J = 13.3 Hz,1H),3.54 (s,2H),3.15 (s,3H),2.89 (s,3H),2.74 - 2.60 (m,2H),2.40 - 2.30 (m, 1H), 2.27 - 2.16 (m, 2H), 2.13 - 2.05 (m, 2H), 2.01 - 1.88 (m, 3H), 1.69 - 1.55 (m, 2H), 1.55 - 1.41 (m, 2H). Note: One CH is obscured by the water signal.

[0402] Example S3. Synthesis of 3-(6-(((trans)-4-((5-chloro-4-((1-methyl-2-oxoindolin-5-yl)amino)pyrimidin-2-yl)(methyl)amino)cyclohexyl)amino)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (3) [ka] The title compound was synthesized by a method similar to Example S2, using trans-tert-butyl N-(4-aminocyclohexyl)carbamate as the starting material. The title compound (36.7 mg, 0.05 mmol, 20.6% yield) was isolated as an off-white solid. LCMS: C 33 H 36 ClNO3 Calculated: 641, Found: 642 [M+H] + ; 1H NMR (400 MHz,DMSO-d6) δ 10.83 (s,1H),8.14 (s,1H),7.60 (s,1H),7.54 (d,J = 8.2 Hz,1H),7.42 (d,J = 8.7 Hz,1H),7.00 (d,J = 8.4 Hz,1H),6.60 (d,J = 8.9 Hz,1H),6.55 (s,1H),4.30 (s,1H),4.22 (dd,J = 9.0,5.1 Hz,1H),3.86(s,3H),3.59 (s,2H),3.36 (s,1H),3.15 (s,3H),2.95 (s,3H),2.62 (s,2H),2.28 (s,1H),2.20 - 2.09 (m,3H),1.76 (d,J = 11.8 Hz,1H),1.70 (s,3H),1.25 (s,2H).

[0403] Example S4. Synthesis of 3-(6-((2R,4R)-4-((5-chloro-4-((1-methyl-2-oxoindolin-5-yl)amino)pyrimidin-2-yl)(methyl)amino)-2-methylpiperidin-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (4) [ka] Step 1: Synthesis of N-[(2R,4R)-1-[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazol-6-yl]-2-methyl-4-piperidyl]carbamate The title compound was synthesized according to General Procedure 2 using tert-butyl N-[(2R,4R)-2-methyl-4-piperidyl]carbamate as the reactant in toluene at 110° C. for 18 hours. The title compound (700 mg, 86%) was isolated as a solid by reverse phase chromatography (C18) (gradient: 30-100% MeCN / 10 mM aqueous ammonium formate). LCMS: C 38 H 43 Calculated N5O4 value: 633.3, Measured value: 635.9 [M+H] + .

[0404] Step 2: Synthesis of tert-butyl N-[(2R,4R)-1-[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazol-6-yl]-2-methyl-4-piperidyl]-N-methyl-carbamate To a solution of tert-butyl N-[(2R,4R)-1-[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazol-6-yl]-2-methyl-4-piperidyl]carbamate (800 mg, 1.26 mmol) in DMF (13 mL) cooled to 0 °C, NaH (151 mg, 3.8 mmol) was added, and the reaction mixture was stirred at 0 °C for 15 minutes. Iodomethane (0.24 mL, 3.79 mmol) was added, and the reaction mixture was allowed to warm to room temperature and stir for 1 hour. The reaction was diluted dropwise with water (5 mL). Water (50 mL) and EtOAc (100 mL) were added, and the layers were separated. The organic layer was washed with water (5 × 20 mL), brine (50 mL), dried (MgSO), filtered, and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (C18) (gradient: 30-100% MeCN / 10 mM aqueous ammonium formate) to give the title compound (700 mg, 86%) as a solid. LCMS: C 39 H 45 Calculated N5O4 value: 647.4, Measured value: 648.4 [M+H] + .

[0405] Step 3: Synthesis of 3-(6-((2R,4R)-4-((5-chloro-4-((1-methyl-2-oxoindolin-5-yl)amino)pyrimidin-2-yl)(methyl)amino)-2-methylpiperidin-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione Synthesis of the title compound was achieved by general procedures 4, 5, and 6 using tert-butyl N-[(2R,4R)-1-[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazol-6-yl]-2-methyl-4-piperidyl]-N-methyl-carbamate as the starting material. The crude residue was purified by reverse-phase chromatography (C18) (gradient: 10-70% MeCN / 10 mM aqueous ammonium formate) to afford the title compound (19 mg, 25%) as a solid. LCMS C 33 H 36 ClNO3 Calculated: 641.3, Found: 642.3 [M+H] + ; 1 H NMR (500 MHz,DMSO-d6) δ 10.88 (s,1H),8.60 (s,1H),8.02 (s,1H),7.70 (s,1H),7.60 (d,J = 8.7 Hz,1H),7.54 (s,1H),7.29 (s,1H),6.98 - 6.89 (m,2H),4.59 (br s,1H),4.33 (dd,J = 9.5,4.9 Hz,1H),3.97 (s,3H),3.59 (s,2H),3.28 - 3.21 (m,2H),3.10 (s,3H),2.96 (s,3H),2.81 (br s,1H),2.68 - 2.59 (m,2H),2.38 - 2.31 (m,1H),2.22 - 2.13 (m,1H),1.95 - 1.86 (m,1H),1.76 (d,J = 10.6 Hz,1H),1.70 - 1.58 (m,2H),0.93 (d,J = 5.7 Hz,3H).

[0406] Example S5. Synthesis of 3-(6-(4-(5-chloro-4-((1-methyl-2-oxoindolin-5-yl)amino)pyrimidin-2-yl)-2-methyl-6-oxopiperazin-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (5) [ka] Step 1: Synthesis of 6-methylpiperazin-2-one To a stirred solution of 6-methylpiperazin-2-one (1.0 g, 8.76 mmol) and triethylamine (1.83 mL, 13.14 mmol) in CHCl (20 mL) under nitrogen at 0 °C, Boc-anhydride (2.24 mL, 9.64 mmol) was added. The reaction mixture was slowly warmed to 25 °C and stirred for 3 h. The reaction mixture was treated with HCl (0.5 N, 2.0 mL), water (50 mL), and extracted with DCM (2 × 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (1.81 g, 8.43 mmol, 96% yield) as an off-white solid. The crude product was used in the next step without further purification.

[0407] Step 2: Synthesis of tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazol-6-yl)-3-methyl-5-oxopiperazine-1-carboxylate A stirred solution of 6-methylpiperazin-2-one (750 mg, 3.49 mmol) and 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-1-methyl-1H-indazole (1.50 g, 3.00 mmol) in DMF (10 mL) was degassed with nitrogen for 5 minutes. Then, copper(I) iodide (571 mg, 3.00 mmol), K2CO3 (621 mg, 4.50 mmol), and N1,N2-dimethylethane-1,2-diamine (264 mg, 3.00 mmol) were added and degassed for 10 minutes. The reaction mixture was heated to 100 °C and stirred for 16 hours. The reaction mixture was cooled to room temperature, treated with water (30 mL), and extracted with ethyl acetate (2 × 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude compound. The crude product was purified by flash column silica chromatography (80-100% ethyl acetate / petroleum ether) to give the title compound (650 mg, 0.779 mmol, 26% yield) as an off-white solid. MS (ESI) m / z 634.8 [M+H] + .

[0408] Step 3: Synthesis of 3-(6-(4-(5-chloro-4-((1-methyl-2-oxoindolin-5-yl)amino)pyrimidin-2-yl)-2-methyl-6-oxopiperazin-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione The synthesis of the title compound was achieved by general procedures 4, 5, and 6 using tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazol-6-yl)-3-methyl-5-oxopiperazine-1-carboxylate as the starting material. LCMS C 31 H 30 ClNO4 Calculated: 627.2, Found: 628.2 [M+H] + ; 1 H NMR (400 MHz,DMSO-d6): δ 10.92 (s,1H),8.83 (s,1H),8.10 (s,1H),7.73 (d,J = 8.5 Hz,1H),7.59 (s,1H),7.55-7.53 (m,2H),7.01 - 6.96 (m,2H),4.58 - 4.50 (m,1H),4.39 (dd,J = 5.1 Hz and 10.2 Hz,1H),4.24 - 4.16 (m,2H),4.25 - 4.07 (m,1H),3.98 (s,3H),3.90 - 3.83 (m,1H),3.55 (s,2H),3.12 (s,3H),2.73 - 2.66 (m,2H),2.66 - 2.61 (m,1H),2.43 - 2.36 (m,1H),1.07 (d,J = 6.3 Hz,3H).

[0409] The examples set forth in Table 2 below were prepared from respective commercially available starting materials and intermediates found herein according to the general procedures set forth within the table. [Table 33] [Table 34] [Table 35] [Table 36] [Table 37] [Table 38] [Table 39] [Table 40] [Table 41] [Table 42] [Table 43] [Table 44] [Table 45] [Table 46] [Table 47]

[0410] Example S52. Synthesis of 3-(6-((1-(5-chloro-4-((1-methyl-2-oxoindolin-5-yl)amino)pyrimidin-2-yl)piperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (52) [ka] Step 1: Synthesis of 3-(6-((1-(5-chloro-4-((1-methyl-2-oxoindolin-5-yl)amino)pyrimidin-2-yl)piperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione 3-[1-Methyl-6-(4-piperidylamino)indazol-3-yl]piperidine-2,6-dione (40.3 mg, 0.120 mmol), 5-((5-chloro-2-fluoropyrimidin-4-yl)amino)-1-methylindolin-2-one (28.8 mg, 0.100 mmol), N,N-diisopropylethylamine (0.03 mL, 0.2000 mmol), and DMSO (0.1969 mL) were added to a 1-dram vial equipped with a stir bar and heated to 80 °C overnight. The reaction mixture was filtered and purified by reverse-phase semi-preparative HPLC (10–100% acetonitrile + 0.1% formic acid / 0.1% formic acid in water, 30 min). Fractions containing pure product were combined and lyophilized to give the title compound (3.0 mg, 0.0049 mmol, 4.9% yield) as an off-white solid. LCMS C 31 H 32 Calculated value for ClN9O3: 613.2, Found: 614.2 [M+H] + ; 1 H NMR (DMSO-d6,400 MHz) δ 10.7-10.8 (m,1H),8.5-8.6 (m,1H),7.95 (s,1H),7.45 (s,2H),7.2-7.3 (m,1H),6.8-6.9 (m,1H),6.4-6.5 (m,3H),5.7-5.7 (m,1H),4.2-4.4 (m,2H),4.0-4.1 (m,1H),3.75 (s,3H),3.5-3.6 (m,1H),3.4-3.5 (m,2H),3.03 (s,5H),2.5-2.6 (m,1H),2.0-2.2 (m,3H),1.9-2.0 (m,2H),1.2-1.3 (m,2H).

[0411] Example S53. Synthesis of rel-(R)-3-(6-((1-(5-chloro-4-((1-methyl-2-oxoindolin-5-yl)amino)pyrimidin-2-yl)piperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (single isomer, stereochemistry not determined) (53) [ka] Step 1: Synthesis of rel-(R)-3-(6-((1-(5-chloro-4-((1-methyl-2-oxoindolin-5-yl)amino)pyrimidin-2-yl)piperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione The product of Example S52 was then separated using preparatory HPLC (Regis Whelk-O1 SS, 21 x 250 mm, 5u column, flow rate 1 mL / min, 100% MeCN (no additives) isocratic eluent, 22°C). The title compound was isolated as the first eluting peak (Rt = 11.0 min). LCMS C 31 H 32 Calculated value for ClN9O3: 614.2, Found: 614.2 [M+H] + ; 1 H NMR (DMSO-d6,400 MHz) δ 10.7-10.8 (m,1H),8.5-8.6 (m,1H),7.95 (s,1H),7.45 (s,2H),7.2-7.3 (m,1H),6.8-6.9 (m,1H),6.4-6.5 (m,3H),5.7-5.7 (m,1H),4.2-4.4 (m,2H),4.0-4.1 (m,1H),3.75 (s,3H),3.5-3.6 (m,1H),3.4-3.5 (m,2H),3.03 (s,5H),2.5-2.6 (m,1H),2.0-2.2 (m,3H),1.9-2.0 (m,2H),1.2-1.3 (m,2H).

[0412] Example S54. rel-(S)-3-(6-((1-(5-chloro-4-((1-methyl-2-oxoindolin-5-yl)amino)pyrimidin-2-yl)piperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (single isomer, stereochemistry not determined) (54) [ka] Step 1: Synthesis of rel-(S)-3-(6-((1-(5-chloro-4-((1-methyl-2-oxoindolin-5-yl)amino)pyrimidin-2-yl)piperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione The product of Example S52 was then isolated using preparatory HPLC (Regis Whelk-O1 SS, 21 x 250 mm, 5μ column, flow rate 1 mL / min, 100% MeCN (no additives) isocratic eluent, 22°C). The title compound was isolated as the first eluting peak (Rt = 18.9 min). LCMS C 31 H 32 Calculated value for ClN9O3: 614.2, Found: 614.2 [M+H] + ; 1 H NMR (DMSO-d6,400 MHz) δ 10.7-10.8 (m,1H),8.5-8.6 (m,1H),7.95 (s,1H),7.45 (s,2H),7.2-7.3 (m,1H),6.8-6.9 (m,1H),6.4-6.5 (m,3H),5.7-5.7 (m,1H),4.2-4.4 (m,2H),4.0-4.1 (m,1H),3.75 (s,3H),3.5-3.6 (m,1H),3.4-3.5 (m,2H),3.03 (s,5H),2.5-2.6 (m,1H),2.0-2.2 (m,3H),1.9-2.0 (m,2H),1.2-1.3 (m,2H).

[0413] Example S55. Synthesis of 3-(6-(((3R,4R)-1-(5-chloro-4-((1-methyl-2-oxoindolin-5-yl)amino)pyrimidin-2-yl)-3-hydroxypiperidin-4-yl)amino)-1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)piperidine-2,6-dione (55) [ka] Step 1: Synthesis of 6-chloro-3-iodo-1-methyl-1H-pyrazolo[3,4-b]pyridine To a solution of 6-chloro-3-iodo-1H-pyrazolo[3,4-b]pyridine (1 g, 3.58 mmol) in DMF (20 mL) at 0 °C was added sodium hydride (0.150 g, 3.76 mmol). The reaction mixture was stirred for 30 minutes. Then, sodium hydride (0.150 g, 3.76 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for an additional hour. The reaction mixture was quenched with saturated aqueous sodium chloride (25 mL) and then extracted with ethyl acetate (3 × 25 mL). The combined organic layers were washed with saturated aqueous sodium chloride (1 × 25 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and concentrated. The crude product was purified by silica gel column chromatography (0–100% ethyl acetate / hexane). The desired fractions were concentrated under reduced pressure to give the title compound (0.75 g, 2.56 mmol, 71% yield) as a white solid; MS (ESI) m / z 293.8 [M+H] + ; 1 H NMR (400 MHz,DMSO-d6) δ ppm 8.59 (s,1 H),7.92 (s,1 H),4.06 (d,J=0.98 Hz,3 H).

[0414] Step 2: Synthesis of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-chloro-1-methyl-1H-pyrazolo[3,4-b]pyridine A solution of 6-chloro-3-iodo-1-methyl-1H-pyrazolo[3,4-b]pyridine (500 mg, 1.704 mmol), (2,6-bis(benzyloxy)pyridin-3-yl)boronic acid (628 mg, 1.874 mmol), and sodium carbonate (379 mg, 3.58 mmol) in 1,4-dioxane (6 mL) and water (2 mL) was stirred with tetrakis(triphenylphosphine)palladium(0) (197 mg, 0.170 mmol) at 100 °C for 15 h. The reaction mixture was then quenched with saturated aqueous sodium chloride (25 mL) and extracted with ethyl acetate (3 × 25 mL). The combined organic layers were washed with saturated aqueous sodium chloride (1 × 25 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and concentrated. The crude product was purified by silica gel column chromatography (0–50% ethyl acetate / hexane). The desired fractions were concentrated under reduced pressure to give the title compound (520 mg, 1.14 mmol, 67% yield) as a white solid; MS (ESI) m / z 456.8 [M+H] + ; 1 H NMR (400 MHz,DMSO-d6) δ ppm 8.25 (d,J=8.44 Hz,1 H),8.02 (d,J=8.07 Hz,1 H),7.45 - 7.51 (m,2 H),7.28 - 7.44 (m,8 H),7.11 (d,J=8.44 Hz,1 H),6.62 (d,J=8.19 Hz,1 H),5.49 (s,2 H),5.44 (s,2 H),4.04 (s,3 H).

[0415] Step 3: Synthesis of tert-butyl (3R,4R)-4-((3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridin-6-yl)amino)-3-hydroxypiperidine-1-carboxylate To a solution of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-chloro-1-methyl-1H-pyrazolo[3,4-b]pyridine (500 mg, 1.094 mmol), RuPhos Pd G3 (92 mg, 0.109 mmol), and tert-butyl (3R,4R)-4-amino-3-hydroxypiperidine-1-carboxylate (237 mg, 1.094 mmol) in 1,4-dioxane (5 mL) was added cesium carbonate (713 mg, 2.189 mmol). The reaction mixture was evacuated with argon for 1 minute and then stirred at 100° C. for 15 hours. LCMS confirmed the completion of the reaction. The reaction mixture was quenched with saturated aqueous sodium chloride (25 mL) and then extracted with ethyl acetate (3×25 mL). The organic layers were combined and washed with saturated aqueous sodium chloride (1×25 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and concentrated. The crude product was purified by silica gel column chromatography (0-100% ethyl acetate / hexane). The desired fractions were concentrated under reduced pressure to give the crude product. The crude product was further purified by reverse-phase semi-preparative HPLC (10-100% acetonitrile + 0.1% TFA / water 0.1% TFA, 30 min). Fractions containing pure product were combined and lyophilized to give the title compound (120 mg, 0.188 mmol, 17% yield) as a white solid; MS (ESI) m / z 636.8 [M+H] + ; 1H NMR (400 MHz,DMSO-d6) δ ppm 7.95 (d,J=8.07 Hz,1 H),7.65 (d,J=8.93 Hz,1 H),7.43 - 7.50 (m,2 H),7.28 - 7.43 (m,8 H),6.97 (d,J=7.09 Hz,1 H),6.56 (d,J=8.07 Hz,1 H),6.24 (d,J=8.93 Hz,1 H),5.46 (s,2 H),5.39 - 5.44 (m,2 H),5.18 (d,J=4.65 Hz,1 H),3.71 - 3.98 (m,6 H),3.40 (tt,J=9.00,4.63 Hz,1 H),2.94 (br d,J=1.47 Hz,1 H),2.69 - 2.85 (m,1 H),1.99 - 2.15 (m,1 H),1.41 (s,9 H),1.24 - 1.34 (m,1 H).

[0416] Step 4: Synthesis of 3-(6-(((3R,4R)-3-hydroxypiperidin-4-yl)amino)-1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)piperidine-2,6-dione A solution of tert-butyl (3R,4R)-4-((3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridin-6-yl)amino)-3-hydroxypiperidine-1-carboxylate (0.120 g, 0.188 mmol) in ethanol (10 mL) was stirred with palladium on carbon 10% w / w (0.020 g, 0.019 mmol) under hydrogen (1 atm) at 50° C. for 15 h. The reaction mixture was filtered through Celite, the filtrate was concentrated, and the residue was then stirred with TFA (1 mL) in DCM (1 mL) at room temperature for 30 min. The volatiles were removed under reduced pressure to give the desired product (67 mg, 0.187 mmol, 99% yield) as the TFA salt, which was used without further purification.

[0417] Step 5: Synthesis of 3-(6-(((3R,4R)-1-(5-chloro-4-((1-methyl-2-oxoindolin-5-yl)amino)pyrimidin-2-yl)-3-hydroxypiperidin-4-yl)amino)-1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)piperidine-2,6-dione To a solution of 3-(6-(((3R,4R)-3-hydroxypiperidin-4-yl)amino)-1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)piperidine-2,6-dione (68 mg, 0.190 mmol) and 5-((5-chloro-2-fluoropyrimidin-4-yl)amino)-1-methylindolin-2-one (55.5 mg, 0.190 mmol) in DMSO (3 mL) was added DIPEA (0.10 mL, 0.57 mmol). The reaction mixture was stirred at 80° C. for 16 hours. The reaction mixture was filtered and purified by reverse-phase semi-preparative HPLC (10–100% acetonitrile with 0.1% formic acid / water 0.1% formic acid, 30 min). Fractions containing pure product were combined and lyophilized to give the title compound (3.7 mg, 5.86 μmol, 3.09% yield) as a white solid; MS (ESI) m / z 630.8 [M+H] + ; 1H NMR (400 MHz,DMSO-d6) δ ppm 10.83 (s,1 H),8.68 (s,1 H),8.02 (s,1 H),7.65 (d,J=8.68 Hz,1 H),7.54 (s,1 H),7.50 (dd,J=8.44,2.20 Hz,1 H),6.99 (br d,J=7.21 Hz,1 H),6.94 (d,J=8.44 Hz,1 H),6.37 (d,J=8.80 Hz,1 H),5.16 (dd,J=5.07,1.77 Hz,1 H),4.39 - 4.53 (m,1 H),4.24 - 4.38 (m,1 H),4.14 (dd,J=9.35,5.07 Hz,1 H),3.89 - 4.02 (m,1 H),3.77 (s,3 H),3.54 (s,2 H),3.44 (tt,J=9.25,4.88 Hz,1 H),3.29 (s,1 H),3.11 (s,3 H),3.05 (br t,J=11.19 Hz,1 H),2.88 (dd,J=12.78,9.60 Hz,1 H),2.55 - 2.64 (m,2 H),2.21 - 2.31 (m,1 H),2.06 - 2.20 (m,2 H),1.26 - 1.42 (m,1 H).

[0418] Example S56. Synthesis of 3-(6-(((3R,4R)-1-(5-chloro-4-((3,3-difluoro-1-methyl-2-oxoindolin-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (56) [ka]

[0419] Step 1: Synthesis of 3,3-difluoro-5-nitroindolin-2-one Diethylaminosulfur trifluoride (4.06 g, 25.2 mmol) was added dropwise to a suspension of 5-nitroindoline-2,3-dione (2.2 g, 11.5 mmol) in dichloromethane (50 mL) at -78 °C. The reaction mixture was allowed to warm to room temperature and stirred for 2 days. LCMS confirmed the completion of the reaction. The reaction mixture was quenched with saturated aqueous sodium chloride (25 mL) and then extracted with ethyl acetate (3 × 25 mL). The combined organic layers were washed with saturated aqueous sodium chloride (1 × 25 mL). The organic layer was dried (anhydrous magnesium sulfate), filtered through Celite, and concentrated. The crude product was purified by silica gel column chromatography (0–75% ethyl acetate / hexane). The desired fractions were concentrated under reduced pressure to give the title compound 3,3-difluoro-5-nitroindolin-2-one (1.52 g, 7.10 mmol, 62.0% yield) as a yellow solid; MS (ESI) m / z 215.2 [M+H] + ; 1 H NMR (400 MHz,DMSO-d6) δ ppm 11.89 (br s,1 H),8.56 - 8.60 (m,1 H),8.43 (d,J=8.78 Hz,1 H),7.20 (d,J=8.68 Hz,1 H).

[0420] Step 2: Synthesis of 3,3-difluoro-1-methyl-5-nitroindolin-2-one To a solution of 3,3-difluoro-5-nitroindolin-2-one (0.53 g, 2.475 mmol) in DMF (1 mL) was added DBU (0.485 mL, 3.22 mmol), followed by iodomethane (0.185 mL, 2.97 mmol). The reaction mixture was stirred at room temperature for 15 hours. The reaction mixture was quenched with saturated aqueous sodium chloride (25 mL) and then extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with saturated aqueous sodium chloride (1 × 25 mL). The organic layers were dried (anhydrous magnesium sulfate), filtered through Celite, and concentrated. The crude product was purified by silica gel column chromatography (0–80% ethyl acetate / hexane). The desired fractions were concentrated under reduced pressure to give the title compound (0.339 g, 1.485 mmol, 60% yield) as a yellow solid; MS (ESI) m / z 229.2 [M+H] + ; 1 H NMR (400 MHz,DMSO-d6) δ ppm 8.61 (d,J=1.96 Hz,1 H),8.54 (d,J=8.91 Hz,1 H),7.46 (d,J=8.80 Hz,1 H),3.25 (s,3 H).

[0421] Step 3: Synthesis of 5-amino-3,3-difluoro-1-methylindolin-2-one A suspension of 3,3-difluoro-1-methyl-5-nitroindolin-2-one (360 mg, 1.578 mmol) in ethanol (15 mL) was stirred under hydrogen (45 psi) at room temperature for 15 hours. The reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure to give the title compound (300 mg, 1.514 mmol, 96% yield) as a yellow solid; MS (ESI) m / z 199.2 [M+H] + ; 1 H NMR (400 MHz,DMSO-d6) δ ppm 6.90 (d,J=8.44 Hz,1 H),6.87 (d,J=1.96 Hz,1 H),6.75 (d,J=7.91 Hz,1 H),5.22 (s,2 H),3.09 (s,3 H).

[0422] Step 4: Synthesis of 3-(6-(((3R,4R)-1-(5-chloro-4-((3,3-difluoro-1-methyl-2-oxoindolin-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione The synthesis of the title compound was achieved by general procedures 1 and 6 using 5-amino-3,3-difluoro-1-methylindolin-2-one and 3-(1-methyl-6-(((3R,4R)-3-methylpiperidin-4-yl)amino)-1H-indazol-3-yl)piperidine-2,6-dione hydrochloride as starting materials. The reaction mixture was filtered and purified by reverse-phase semi-preparative HPLC (10-100% acetonitrile + 0.1% formic acid / water 0.1% formic acid, 30 min). Fractions containing pure product were combined and lyophilized to afford the title compound (8 mg, 0.012 mmol, 23.46% yield) as a yellow solid; MS (ESI) m / z 664.2 [M+H] + ; 1 H NMR (400 MHz,DMSO-d6) δ ppm 10.81 (s,1 H),8.94 (s,1 H),8.03 - 8.14 (m,2 H),7.77 (br d,J=8.56 Hz,1 H),7.31 (d,J=8.80 Hz,1 H),7.21 (d,J=8.44 Hz,1 H),6.51 (br d,J=8.80 Hz,1 H),6.44 (s,1 H),5.70 (br d,J=8.80 Hz,1 H),4.47 (br s,2 H),4.17 (dd,J=8.62,5.07 Hz,1 H),3.81 (s,3 H),3.17 (s,3 H),3.04 (br t,J=12.10 Hz,1 H),2.65 - 2.76 (m,1 H),2.56 - 2.63 (m,2 H),2.19 - 2.31 (m,1 H),2.11 - 2.19 (m,1 H),2.06 (br d,J=10.64 Hz,1 H),1.46 - 1.66 (m,1 H),1.07 - 1.28 (m,2 H),0.96 (d,J=6.36 Hz,3 H).

[0423] Example S57. Synthesis of 3-[6-[[(3S,4R)-1-[5-chloro-4-[(1-methyl-2-oxo-indolin-5-yl)amino]pyrimidin-2-yl]-3-(hydroxymethyl)-4-piperidyl]amino]-1-methyl-indazol-3-yl]piperidine-2,6-dione (57) [ka] Step 1: Synthesis of tert-butyl O5-ethyl 4-[[(1R)-1-phenylethyl]amino]-3,6-dihydro-2H-pyridine-1,5-dicarboxylate To a solution of O1-tert-butyl O3-ethyl 4-oxopiperidine-1,3-dicarboxylate (22 g, 81 mmol) and (1R)-1-phenylethanamine (12.5 mL, 97.2 mmol) in toluene (400 mL) was added PTSA (1.39 g, 8.1 mmol), and the mixture was heated to reflux with a Dean-Stark trap for 18 h. The mixture was cooled to room temperature and washed with saturated aqueous NaHCO3 (2 x 200 mL) and brine (2 x 200 mL). The combined organic fractions were dried over MgSO4, filtered, and concentrated. The residue was filtered through a silica pad, rinsed with DCM (2 x 100 mL), and concentrated to give the title compound (30.2 g, 99%) as an oil, which was used in the next step without further purification. MS (ESI) [M+H] + 375.2. 1 H NMR (400 MHz,CDCl3) δ 9.25 (d,J = 7.5 Hz,1H),7.36 - 7.28 (m,2H),7.26 - 7.18 (m,3H),4.66 - 4.54 (m,1H),4.24 - 4.14 (m,2H),4.07 (br s,2H),3.48 - 3.35 (m,1H),3.35 - 3.24 (m,1H),2.39 (dd,J = 13.0,6.2 Hz,1H),2.09 - 2.00 (m,1H),1.50 (d,J = 6.8 Hz,3H),1.43 (s,9H),1.29 (t,J = 7.0 Hz,3H).

[0424] Step 2: Synthesis of tert-butyl O3-ethyl (3S,4R)-4-[[(1R)-1-phenylethyl]amino]piperidine-1,3-dicarboxylate and tert-butyl O3-ethyl (3R,4S)-4-[[(1R)-1-phenylethyl]amino]piperidine-1,3-dicarboxylate To a solution of tert-butyl O5-ethyl 4-[[(1R)-1-phenylethyl]amino]-3,6-dihydro-2H-pyridine-1,5-dicarboxylate (15 g, 40.1 mmol) in MeCN (200 mL) and AcOH (100 mL) cooled to 0 °C, sodium triacetoxyborohydride (34 g, 160 mmol) was added portionwise over 2 h, and the reaction mixture was stirred at 0 °C for 2 h. The mixture was then cooled to -10 °C and slowly treated with 1 M aqueous NaOH (100 mL), 4 M aqueous NaOH (100 mL), 6 M aqueous NaOH (100 mL), and then 50% aqueous NaOH (50 mL). The mixture was allowed to warm to room temperature, and the layers were separated. The aqueous layer was extracted with DCM (3 × 80 mL). The combined organic layers were dried over MgSO, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (gradient: 0-50% EtOAc / hexane) to give a 4:1 mixture of the title compounds (14.8 g, 98%) as an oil. A portion (7 g) of the 4:1 mixture of the title compounds was separated by SFC to give tert-butyl O3-ethyl (3S,4R)-4-[[(1R)-1-phenylethyl]amino]piperidine-1,3-dicarboxylate (3.7 g) as an oil, and the title compound tert-butyl O3-ethyl (3R,4S)-4-[[(1R)-1-phenylethyl]amino]piperidine-1,3-dicarboxylate (1.1 g) as an oil.

[0425] Step 3: Synthesis of tert-butyl (3S,4R)-3-(hydroxymethyl)-4-[[(1R)-1-phenylethyl]amino]piperidine-1-carboxylate To a solution of tert-butyl O3-ethyl (3S,4R)-4-[[(1R)-1-phenylethyl]amino]piperidine-1,3-dicarboxylate (500 mg, 1.33 mmol) in THF (3 mL) was added LiBH4 (1.33 mL, 2.66 mmol), and the mixture was heated to reflux for 2 h, then cooled to room temperature. Ice-cold water (10 mL) was added, and the mixture was concentrated under reduced pressure. The residue was extracted with EtOAc (3 x 30 mL). The combined organic fractions were dried over Na2SO4, filtered, and concentrated to give the title compound (404 mg, 91%) as an oil, which was used in the next step without further purification. MS (ESI) [M+H] + 335.3.

[0426] Step 4: Synthesis of tert-butyl (3S,4R)-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-[[(1R)-1-phenylethyl]amino]piperidine-1-carboxylate To a solution of tert-butyl (3S,4R)-3-(hydroxymethyl)-4-[[(1R)-1-phenylethyl]amino]piperidine-1-carboxylate (404 mg, 1.21 mmol) in DCM (5 mL), tert-butylchlorodimethylsilane (218 mg, 1.45 mmol) and imidazole (123 mg, 1.81 mmol) were added sequentially, and the reaction mixture was stirred at room temperature for 3 h. Water (15 mL) and EtO (20 mL) were added, and the layers were separated. The aqueous layer was washed with EtO (3 × 10 mL), and the combined organic fractions were dried over NaSO, filtered, and concentrated to give the title compound (540 mg, 99%) as an oil, which was used in the next step without further purification. Note: SFC analysis confirmed the presence of only one diastereomer. MS (ESI) [M+H] + 449.4. 1H NMR (400 MHz,DMSO-d6) δ 7.35 - 7.26 (m,4H),7.23 - 7.16 (m,1H),3.86 - 3.68 (m,3H),3.68 - 3.54 (m,1H),3.48 (t,J = 9.6 Hz,1H),2.89 - 2.68 (m,1H),2.81 (dd,J = 13.1,3.2 Hz,1H),2.59 - 2.52 (m,1H),1.82 - 1.72 (m,1H),1.36 (s,9H),1.34 - 1.27 (m,1H),1.26 - 1.18 (m,1H),1.22 (d,J = 6.7Hz,3H),0.90 (s,9H),0.07 (d,J = 3.1 Hz,6H).

[0427] Step 5: Compound of tert-butyl (3S,4R)-4-amino-3-[[tert-butyl(dimethyl)silyl]oxymethyl]piperidine-1-carboxylate A mixture of tert-butyl (3S,4R)-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-[[(1R)-1-phenylethyl]amino]piperidine-1-carboxylate (530 mg, 1.18 mmol), ammonium formate (596 mg, 9.45 mmol), and Pd / C (126 mg, 0.12 mmol) in EtOH (15 mL) was heated to 65 °C for 2 h. The mixture was filtered through Celite and washed with MeOH (3 × 15 mL). The filtrate was concentrated under reduced pressure to give the title compound (320 mg, 79%) as a solid, which was used in the next step without further purification. MS (ESI) [M+H] + 345.3. 1 H NMR (400 MHz,DMSO-d6) δ 3.61 (dd,J = 10.2,4.9 Hz,1H),3.49 - 3.41 (m,2H),3.39 - 3.24 (m,3H),3.23 - 3.08 (m,1H),3.06 - 2.98 (m,1H),1.71 - 1.55 (m,2H),1.55 - 1.44 (m,1H),1.40 - 1.33 (m,1H),1.38 (s,9H),0.89 - 0.84 (m,9H),0.06 - 0.01 (m,6H).

[0428] Step 6: Synthesis of tert-butyl (3S,4R)-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-[[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazol-6-yl]amino]piperidine-1-carboxylate A mixture of 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole (471 mg, 0.94 mmol), tert-butyl (3S,4R)-4-amino-3-[[tert-butyl(dimethyl)silyl]oxymethyl]piperidine-1-carboxylate (270 mg, 0.78 mmol), CsCO (638 mg, 1.96 mmol), and RuPhos Pd G (98.3 mg, 0.12 mmol) in 1,4-dioxane (7 mL) was heated to 90 °C for 16 h and then cooled to room temperature. The residue was purified by column chromatography on silica gel (gradient: 0-50% EtOAc / hexane) to give the title compound (458 mg, 67%) as a solid. Note: The reaction was repeated and the crude residues were combined before purification. MS (ESI) [M+H] + 764.4. 1 H NMR (400 MHz,DMSO-d6) δ 7.87 (d,J = 8.1 Hz,1H),7.50 - 7.44 (m,2H),7.42 - 7.26 (m,9H),6.55 (d,J = 7.9 Hz,1H),6.52 (dd,J = 9.0,1.9 Hz,1H),6.45 (d,J = 1.3 Hz,1H),5.78 (d,J = 8.6 Hz,1H),5.44 (s,2H),5.41 (s,2H),3.88 (s,3H),3.85 - 3.77 (m,1H),3.67 - 3.61 (m,1H),3.60 - 3.41 (m,4H),3.39 - 3.32 (m,1H),2.10 - 2.00 (m,1H),1.67 - 1.53 (m,2H),1.41 (s,9H),0.82 (s,9H),-0.05 (d,J = 15.0 Hz,6H).

[0429] Step 7: Synthesis of tert-butyl (3S,4R)-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-[[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-6-yl]amino]piperidine-1-carboxylate A mixture of tert-butyl (3S,4R)-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-[[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazol-6-yl]amino]piperidine-1-carboxylate (458 mg, 0.60 mmol) and Pearlman's catalyst (210 mg, 0.15 mmol) in EtOH (10 mL) and THF (10 mL) was subjected to hydrogenation (1 atm) at 50 °C for 2 hours. The mixture was filtered through Celite and washed with MeOH (3 × 15 mL). The filtrate was concentrated under reduced pressure to give the title compound (350 mg, quantitative) as a solid, which was used in the next step without further purification. MS (ESI) [M+H] + 586.4.

[0430] Step 8: Synthesis of 3-[6-[[(3S,4R)-3-(hydroxymethyl)-4-piperidyl]amino]-1-methyl-indazol-3-yl]piperidine-2,6-dione hydrochloride To a solution of tert-butyl (3S,4R)-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-[[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-6-yl]amino]piperidine-1-carboxylate (350 mg, 0.60 mmol) in DCM (2.5 mL) was added HCl (4N) / 1,4-dioxane (1.5 mL, 6.0 mmol), and the mixture was stirred at room temperature for 2 hours. The resulting precipitate was collected by filtration, washed with EtO (3 × 5 mL), and dried under vacuum to give the title compound (250 mg, 77%) as a solid, which was used in the next step without further purification. MS (ESI) [M+H] + 372.2. 1H NMR (500 MHz,DMSO-d6) δ 10.82 (s,1H),8.89 - 8.68 (m,2H),7.35 (d,J = 8.8 Hz,1H),6.66 (dd,J = 8.8,1.7 Hz,1H),6.51 (s,1H),4.18 (dd,J = 9.0,5.1 Hz,1H),3.99 - 3.92 (m,1H),3.82 (s,3H),3.51 - 3.41 (m,2H),3.27 - 3.15 (m,2H),3.15 - 3.04 (m,2H),2.67 - 2.54 (m,2H),2.32 - 2.21 (m,2H),2.18 - 2.10 (m,1H),1.98 - 1.89 (m,1H),1.87 - 1.78 (m,1H).

[0431] Step 9: Synthesis of 3-[6-[[(3S,4R)-1-[5-chloro-4-[(1-methyl-2-oxo-indolin-5-yl)amino]pyrimidin-2-yl]-3-(hydroxymethyl)-4-piperidyl]amino]-1-methyl-indazol-3-yl]piperidine-2,6-dione To a mixture of 5-[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]-1-methyl-indolin-2-one (35 mg, 0.12 mmol) and DIPEA (0.10 mL, 0.60 mmol) in DMF (2 mL) was added 3-[6-[[(3S,4R)-3-(hydroxymethyl)-4-piperidyl]amino]-1-methyl-indazol-3-yl]piperidine-2,6-dione hydrochloride (77.8 mg, 0.14 mmol) at room temperature, and the reaction mixture was heated to 80 °C for 2 h. The volatiles were removed under reduced pressure, and the residue was purified by preparative HPLC (BEH column, C18) (gradient: 31-41% MeCN and 10 mM ammonium formate in water) to give the title compound (22.1 mg, 28%) as a solid. LCMS C 32 H 34 ClNO4 Calculated: 643.2, Found: 644.4 [M+H] + ; 1H NMR (500 MHz,DMSO-d6) δ 10.81 (s,1H),8.61 (s,1H),8.00 (s,1H),7.75 - 7.57 (m,1H),7.52 (d,J = 7.9 Hz,1H),7.33 (d,J = 8.7 Hz,1H),6.90 (d,J = 8.4 Hz,1H),6.65 (d,J = 8.9 Hz,1H),6.48 (s,1H),5.85 (d,J = 8.5 Hz,1H),4.46 (s,1H),4.18 (dd,J = 8.4,5.1 Hz,1H),3.96 - 3.85 (m,2H),3.81 (s,3H),3.80 - 3.75 (m,1H),3.75 - 3.63 (m,2H),3.52 (s,2H),3.51 - 3.46 (m,1H),3.09 (s,3H),2.66 - 2.55 (m,2H),2.31 - 2.21 (m,1H),2.20 - 2.11 (m,1H),2.11 - 2.02 (m,1H),1.79 - 1.69 (m,1H),1.67 - 1.56 (m,1H).

[0432] Example S58. Synthesis of 3-(6-(((3R,4S)-1-(5-chloro-4-((1-methyl-2-oxoindolin-5-yl)amino)pyrimidin-2-yl)-3-(hydroxymethyl)piperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (58) [ka] Step 1: Synthesis of 3-(6-(((3R,4S)-1-(5-chloro-4-((1-methyl-2-oxoindolin-5-yl)amino)pyrimidin-2-yl)-3-(hydroxymethyl)piperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione The title compound was synthesized by a method similar to that of Example S57, starting from the other diastereomer isolated in Step 2 of Example S57. The crude reaction mixture was purified by preparative HPLC (BEH column, C18) (gradient: 44-54% MeCN and 10 mM aqueous ammonium formate) to give the title compound (5.5 mg, 14%) as a solid. LCMS C 32 H 34 ClNO4 Calculated: 643.2, Found: 644.3 [M+H] + ; 1 H NMR (400 MHz,DMSO-d6) δ 8.61 (s,1H),8.00 (s,1H),7.66 (br s,1H),7.53 (d,J = 8.5 Hz,1H),7.33 (d,J = 8.8 Hz,1H),6.90 (d,J = 8.4 Hz,1H),6.65 (dd,J = 8.8,1.7 Hz,1H),6.48 (s,1H),5.85 (d,J = 8.5 Hz,1H),4.18 (dd,J = 8.8,5.1 Hz,1H),3.92 - 3.84 (m,2H),3.81 (s,3H),3.80 - 3.74 (m,1H),3.52 (s,2H),3.51 - 3.46 (m,2H),3.39 - 3.29 (m,2H),3.09 (s,3H),2.63 - 2.57 (m,2H),2.30 - 2.19 (m,1H),2.19 - 2.11 (m,1H),2.11 - 2.01 (m,1H),1.78 - 1.69 (m,1H),1.67 - 1.52 (m,1H).

[0433] Example S59. Synthesis of 3-(6-(4-((5-chloro-4-((1-methyl-2-oxoindolin-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 (59) [ka] Step 1: Synthesis of 6-bromo-3-iodo-1H-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, 22.5 mmol). The reaction mixture was heated to 85 °C for 18 h and then cooled to room temperature. The volatiles were evaporated under reduced pressure, and the residue was purified by column chromatography on silica gel (gradient: 0-15% EtOAc / hexanes) to give the title compound (6.05 g, 98%) as a solid. MS (ESI) [M+H] + 324.0.

[0434] Step 2: Synthesis of 6-bromo-3-iodo-1-methyl-pyrazolo[4,3-b]pyridine The title compound was synthesized by a method similar to general procedure 3 using 6-bromo-3-iodo-1H-pyrazolo[4,3-b]pyridine as the starting material.

[0435] Step 3: Synthesis of 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, Celgene-provided intermediate), Pd(PPh3)2Cl2 (374 mg, 0.53 mmol), and 2 M aqueous 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 room temperature. The volatiles were evaporated under reduced pressure, and the residue was purified by column chromatography on silica gel (gradient: 0–20% EtOAc / hexane) to give the title compound (835 mg, 62%) as a solid. MS (ESI) [M+H] + 502.2.

[0436] Step 4: Synthesis of 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 2 using 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-pyrazolo[4,3-b]pyridine and tert-butyl N-methyl-N-(4-piperidyl)carbamate in toluene as starting materials.

[0437] Step 5: Synthesis of 3-(6-(4-((5-chloro-4-((1-methyl-2-oxoindolin-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 Synthesis of the title compound was achieved by general procedures 4, 5, and 6 using tert-butyl N-[1-[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-pyrazolo[4,3-b]pyridin-6-yl]-4-piperidyl]-N-methyl-carbamate as the starting material. The crude reaction mixture was purified by preparative HPLC (BEH column, C18) (gradient: 44-54% MeCN and 10 mM aqueous ammonium formate) to afford the title compound (5.4 mg, 12%) as a solid. LCMS C 31 H 33 ClN 10 O3 calculated value: 628.2, measured value: 629.3 [M+H] + ; 1H NMR (500 MHz,DMSO-d6) δ 10.89 - 10.82 (m,1H),8.59 (s,1H),8.41 (d,J = 2.3 Hz,1H),8.03 (s,1H),7.65 (s,1H),7.57 (d,J = 7.9 Hz,1H),7.37 (d,J = 2.3 Hz,1H),6.95 (d,J = 8.6 Hz,1H),4.28 (dd,J = 9.8,5.2 Hz,1H),3.97 - 3.91 (m,5H),3.55 (s,2H),3.28 (s,2H),3.08 (s,3H),2.92 (s,3H),2.87 - 2.72 (m,2H),2.72 - 2.64 (m,1H),2.62 - 2.55 (m,1H),2.22 - 2.10 (m,1H),1.97 - 1.84 (m,2H),1.76 - 1.66 (m,2H).

[0438] Example S60. Synthesis of 3-(6-(4-((5-chloro-4-((1-methyl-2-oxoindolin-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 (60) [ka] Step 1: 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 hours and then cooled to room temperature. 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 give the title compound (6.21 g, quantitative) as a solid. MS (ESI) [M+H] + 325.8. 1 H NMR (400 MHz,DMSO-d6) δ 8.44 (s,1H),7.57 (s,1H).

[0439] Step 2: Synthesis of 6-bromo-3-iodo-1-methyl-pyrazolo[4,3-c]pyridine To a mixture of 6-bromo-3-iodo-1H-pyrazolo[4,3-c]pyridine (100 mg, 0.31 mmol) in DMF (2 mL) at 0 °C was added NaH (60% dispersion in mineral oil, 31 mg, 0.77 mmol), and the reaction mixture was stirred at 0 °C for 15 min. A solution of iodomethane (50 μL, 0.77 mmol) in DMF (1 mL) was added, and the reaction was warmed to room temperature and stirred for 2 h. Water (20 mL) and DCM (20 mL) were added, and the layers were separated. The aqueous layer was extracted with DCM (2 × 20 mL). The combined organic fractions were washed with brine (40 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by column silica gel chromatography (gradient: 10–35% EtOAc / hexanes) to give the title compound (46 mg, 44%) as a solid. 1 H 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).

[0440] Step 3: 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 2 M aqueous 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 room temperature. Water (40 mL) and EtOAc (40 mL) were added, and the layers were separated. The aqueous layer was extracted with EtOAc (2 × 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 silica gel chromatography (gradient: 0-15% EtOAc / hexanes) to give 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).

[0441] Step 4: tert-Butyl N-[1-[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-pyrazolo[4,3-c]pyridin-6-yl]-4-piperidyl]-N-methyl-carbamate A mixture of 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-pyrazolo[4,3-c]pyridine (1.44 g, 2.87 mmol), tert-butyl N-methyl-N-(4-piperidyl)carbamate (677 mg, 3.16 mmol), RuPhos-Pd-G3 (480 mg, 0.57 mmol), and NaOtBu (552 mg, 5.74 mmol) in 1,4-dioxane (58 mL) was heated to 90 °C for 16 h and then cooled to room temperature. The volatiles were evaporated under reduced pressure, and the residue was purified by column chromatography on silica gel (gradient: 0–40% EtOAc / hexane) to give the title compound (1.08 g, 59%) as a solid. 1 H 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).

[0442] Step 5: tert-Butyl N-[1-[3-(2,6-dioxo-3-piperidyl)-1-methyl-pyrazolo[4,3-c]pyridin-6-yl]-4-piperidyl]-N-methyl-carbamate A mixture 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 (1.59 g, 1.88 mmol) and Pd(OH)2 / C (200 mg, 0.38 mmol) in THF (12.5 mL) and EtOH (12.5 mL) was subjected to hydrogenation (1 atm) at room temperature for 2 hours. The mixture was filtered through Celite and washed with DMF (60 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (gradient: 0-100% EtOAc / hexane) to give the title compound (927 mg, quantitative yield) as a solid. MS (ESI) [M+H] + 457.4.

[0443] Step 6: 3-[1-methyl-6-[4-(methylamino)-1-piperidyl]pyrazolo[4,3-c]pyridin-3-yl]piperidine-2,6-dione hydrochloride To a solution 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 (927 mg, 2.03 mmol) in DCM (40.6 mL) was added HCl (4N) / 1,4-dioxane (5.08 mL, 20.3 mmol), and the reaction mixture was stirred at room temperature for 16 hours. The reaction was diluted with EtO (20 mL), filtered, and rinsed with EtO (2 x 10 mL) to give the 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).

[0444] Step 7: 3-[6-[4-[[5-chloro-4-[(1-methyl-2-oxo-indolin-5-yl)amino]pyrimidin-2-yl]-methyl-amino]-1-piperidyl]-1-methyl-pyrazolo[4,3-c]pyridin-3-yl]piperidine-2,6-dione To a solution of 3-[1-methyl-6-[4-(methylamino)-1-piperidyl]pyrazolo[4,3-c]pyridin-3-yl]piperidine-2,6-dione hydrochloride (50 mg, 0.13 mmol) in DMSO (1.6 mL) was added 5-((5-chloro-2-fluoropyrimidin-4-yl)amino)-1-methylindolin-2-one (34 mg, 0.12 mmol) and DIPEA (0.2 mL, 1.16 mmol) sequentially. The reaction mixture was heated to 100 °C for 18 h and then cooled to room temperature. The crude reaction mixture was purified by preparative HPLC (BEH column, C18) (gradient: 44-54% MeCN and 10 mM ammonium formate in water) to give the title compound (18.6 mg, 25%) as a solid. LCMS C 31 H 33 ClN 10 O3 calculated value: 628.2, measured value: 629.3 [M+H] + ; 1H NMR (400 MHz,DMSO-d6) δ 10.90 (s,1H),8.64 (s,1H),8.59 (s,1H),8.11 - 7.84 (m,1H),7.64 (s,1H),7.58 (d,J = 8.4 Hz,1H),6.94 (d,J = 8.3 Hz,1H),6.74 (s,1H),4.53 (d,J = 12.9 Hz,2H),4.35 - 4.25 (m,1H),3.98 - 3.82 (m,3H),3.54 (s,1H),3.30 - 3.26 (m,3H),3.09 (s,2H),2.91 -2.73 (m,4H),2.73 - 2.54 (m,3H),2.41 - 2.29 (m,1H),2.23 - 2.13 (m,1H),1.82 - 1.59 (m,4H).

[0445] Example S61. Synthesis of 3-(6-(((3R,4R)-1-(5-chloro-4-((1-methyl-2-oxoindolin-6-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (61) [ka] Step 1: Synthesis of 1-methyl-6-nitroindoline-2,3-dione To a stirred solution of 6-nitroindoline-2,3-dione (1.0 g, 5.20 mmol) in DMF (20 mL) was added sodium hydride (0.312 g, 7.81 mmol) at 0 °C under nitrogen and stirred for 10 min. Methyl iodide (0.651 mL, 10.41 mmol) was added to the reaction mixture, and the temperature was slowly raised to 25 °C. The reaction mixture was stirred for 1 h, treated with saturated NH4Cl solution (100 mL), and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude compound. The crude product was purified by flash column silica gel chromatography (40–50% ethyl acetate / petroleum ether) to give the title compound (320 mg, 1.531 mmol, 29% yield) as an off-white solid.

[0446] Step 2: Synthesis of 1-methyl-6-nitroindolin-2-one To a stirred solution of 1-methyl-6-nitroindoline-2,3-dione (200 mg, 0.957 mmol) in n-butanol (5.0 mL) was added hydrazine hydrate (144 mg, 2.87 mmol) at 25 °C. The reaction was heated to 80 °C and stirred for 4 hours. The reaction mixture was then cooled to 25 °C, and triethylamine (0.533 mL, 3.83 mmol) was added and stirred at 80 °C for 14 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give the crude compound, which was purified by flash column silica gel chromatography (35-45% ethyl acetate / petroleum ether) to give the title compound (40 mg, 0.171 mmol, 18% yield) as an off-white solid. LCMS found: 193.2 [M+H] + , Rt:1.686 minutes.

[0447] Step 3: Synthesis of 6-amino-1-methylindolin-2-one To a stirred solution of 1-methyl-6-nitroindolin-2-one (40 mg, 0.171 mmol) in ethanol (2.5 mL) and THF (2.5 mL) was added 10% Pd / C (20 mg) at 25° C. under nitrogen. The reaction mixture was stirred under a hydrogen atmosphere for 6 hours. The reaction mixture was filtered through Celite, and the Celite pad was washed with ethanol (2×20 mL). The filtrate was concentrated under reduced pressure to give the title compound (35 mg, crude), which was used in the next step without further purification. 1 H NMR (400 MHz,CDCl3): δ 6.86 (d,J = 8.4 Hz,1H),6.20-6.18 (m,2H),5.11 (brs,2H),3.32 (s,2H),3.02 (s,3H).

[0448] Step 4: Synthesis of 3-(6-(((3R,4R)-1-(5-chloro-4-((1-methyl-2-oxoindolin-6-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione The synthesis of the title compound was achieved by general procedures 1 and 6 using 6-amino-1-methylindolin-2-one and 3-(1-methyl-6-(((3R,4R)-3-methylpiperidin-4-yl)amino)-1H-indazol-3-yl)piperidine-2,6-dione as starting materials. The crude product was purified by preparative HPLC to afford the title compound (18 mg, 0.028 mmol, 17% yield) as an off-white solid. LCMS C 32 H 34 ClNO3 Calculated: 627.3, Found: 628.3 [M+H] + ; 1 H NMR (400 MHz,DMSO-d6): δ 10.84 (s,1H),8.99 (s,1H),8.12 (s,1H),7.42 (s,1H),7.32 (d,J = 8.80 Hz,1H),7.26 (d,J = 9.20 Hz,1H),7.21 (d,J = 8.00 Hz,1H),6.52 (dd,J = 8.80,1.60 Hz,1H),6.45 (s,1H),5.79 (brs,1H),4.55-4.47 (m,2H),4.19-4.16 (m,1H),3.81 (s,3H),3.12-3.06 (m,4H),2.75-2.70 (m,1H),2.66-2.58 (m,3H),2.28-2.19 (m,1H),2.16-2.08 (m,2H),1.62-1.53 ​​(m,1H),1.25-1.18 (m,1H), 0.97 (d,J = 6.4 Hz,3H).

[0449] Example S62. Synthesis of 3-(6-(((3R,4R)-1-(5-chloro-4-((1-methyl-2-oxoindolin-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)piperidine-2,6-dione (62) [ka] Step 1: 6-chloro-3-iodo-1-methyl-1H-pyrazolo[3,4-b]pyridine To a solution of 6-chloro-3-iodo-1H-pyrazolo[3,4-b]pyridine (2 g, 7.16 mmol) in DMF (20 mL) at 0 °C was added sodium hydride (0.301 g, 7.51 mmol). The reaction mixture was stirred for 30 minutes, after which sodium hydride (0.301 g, 7.51 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was treated with saturated aqueous sodium chloride (25 mL) and then extracted with ethyl acetate (3 × 25 mL). The combined organic layers were washed with saturated aqueous sodium chloride (1 × 25 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (0–100% ethyl acetate / hexane). The desired fractions were concentrated under reduced pressure to give the title compound, 6-chloro-3-iodo-1-methyl-1H-pyrazolo[3,4-b]pyridine (1.7 g, 5.79 mmol, 81% yield) as a white solid; MS (ESI) m / z 293.8 [M+H] + ; 1 H NMR (400 MHz,DMSO-d6) δ ppm 7.99 (d,J=8.31 ​​Hz,1 H),7.32 (d,J=8.31 ​​Hz,1 H),4.03 (s,3 H).

[0450] Step 2: tert-butyl (3R,4R)-4-((3-iodo-1-methyl-1H-pyrazolo[3,4-b]pyridin-6-yl)amino)-3-methylpiperidine-1-carboxylate To a solution of 6-chloro-3-iodo-1-methyl-1H-pyrazolo[3,4-b]pyridine (500 mg, 1.704 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.607 mL, 3.41 mmol) in DMSO (1 mL) was added tert-butyl (3R,4R)-4-amino-3-methylpiperidine-1-carboxylate (365 mg, 1.704 mmol). The reaction mixture was stirred at 120 °C for 48 h. The reaction mixture was filtered and purified by reverse-phase semi-preparative HPLC (10–100% acetonitrile with 0.1% formic acid / 0.1% formic acid in water, 30 min). Fractions containing pure product were combined and lyophilized to afford the title compound (250 mg, 0.530 mmol, 31.1% yield) as a white solid. MS(ESI)m / z 472.2[M+H] + ; 1 H NMR (400 MHz,DMSO-d6) δ ppm 7.33 (dd,J=8.68,1.71 Hz,1 H),7.18 (br d,J=7.83 Hz,1 H),6.33 - 6.46 (m,1 H),3.86 - 4.05 (m,2 H),3.81 (d,J=1.83 Hz,4 H),2.79 - 2.99 (m,1 H),2.56 - 2.64 (m,1 H),1.98 (br d,J=12.35 Hz,1 H),1.47 - 1.63 (m,1 H),1.41 (d,J=1.71 Hz,9 H),1.17 - 1.32 (m,1 H),0.88 (br d,J=4.89 Hz,3 H).

[0451] Step 3: tert-butyl (3R,4R)-4-((3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridin-6-yl)amino)-3-methylpiperidine-1-carboxylate A solution of tert-butyl (3R,4R)-4-((3-iodo-1-methyl-1H-pyrazolo[3,4-b]pyridin-6-yl)amino)-3-methylpiperidine-1-carboxylate (250 mg, 0.530 mmol), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (243 mg, 0.583 mmol), and sodium bicarbonate (98 mg, 1.167 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was stirred with tetrakis(triphenylphosphine)palladium(0) (61.3 mg, 0.053 mmol) at 80° C. for 15 hours. The reaction mixture was quenched with saturated aqueous sodium chloride (25 mL) and then extracted with ethyl acetate (3×25 mL). The organic layers were combined and washed with saturated aqueous sodium chloride (1 × 25 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (0–100% ethyl acetate / hexanes). The desired fractions were concentrated under reduced pressure to give the crude product, which was further purified by reverse-phase semi-preparative HPLC (10–100% acetonitrile + 0.1% formic acid / 0.1% formic acid in water, 30 min). Fractions containing the pure product were combined and lyophilized to give the title compound as a white solid (110 mg, 0.173 mmol, 32.7% yield). MS (ESI) m / z 372.0 [M+H] + ; 1H NMR (400 MHz,DMSO-d6) δ ppm 7.94 (d,J=8.07 Hz,1 H),7.64 (d,J=8.80 Hz,1 H),7.43 - 7.51 (m,2 H),7.36 - 7.42 (m,4 H),7.26 - 7.36 (m,4 H),6.92 (d,J=8.19 Hz,1 H),6.55 (d,J=8.19 Hz,1 H),6.19 (d,J=8.93 Hz,1 H),5.46 (s,2 H),5.41 (s,2 H),3.86 - 3.99 (m,2 H),3.81 - 3.85 (m,3 H),3.69 - 3.81 (m,1 H),2.75 - 3.07 (m,1 H),1.91 - 2.07 (m,1 H),1.45 - 1.64 (m,1 H),1.41 (s,9 H),1.24 - 1.32 (m,2 H),0.88 (d,J=6.60 Hz,3 H).

[0452] Step 4: 3-(1-methyl-6-(((3R,4R)-3-methylpiperidin-4-yl)amino)-1H-pyrazolo[3,4-b]pyridin-3-yl)piperidine-2,6-dione A solution of tert-butyl (3R,4R)-4-((3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridin-6-yl)amino)-3-methylpiperidine-1-carboxylate (0.105 g, 0.165 mmol) in ethanol (10 mL) was stirred with palladium on carbon (10% by weight) (0.018 g, 0.017 mmol) under hydrogen pressure (1 atm) at 50° C. for 15 hours. The reaction mixture was filtered through Celite, the eluate was concentrated, and the residue was stirred with TFA (1 mL) in DCM (1 mL) at room temperature for 30 minutes. The TFA and solvent were removed under reduced pressure to give the desired product, 3-(1-methyl-6-(((3R,4R)-3-methylpiperidin-4-yl)amino)-1H-pyrazolo[3,4-b]pyridin-3-yl)piperidine-2,6-dione (60 mg, 0.168 mmol, quantitative yield) as a TFA salt, which was used in the next step without further purification.

[0453] Step 5: 3-(6-(((3R,4R)-1-(5-chloro-4-((1-methyl-2-oxoindolin-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)piperidine-2,6-dione Synthesis of the title compound was achieved by general procedure 6 using 3-(1-methyl-6-(((3R,4R)-3-methylpiperidin-4-yl)amino)-1H-pyrazolo[3,4-b]pyridin-3-yl)piperidine-2,6-dione hydrochloride (40 mg, 0.102 mmol) and 5-((5-chloro-2-fluoropyrimidin-4-yl)amino)-1-methylindolin-2-one (29.8 mg, 0.102 mmol). The reaction mixture was filtered and purified by reverse-phase semi-preparative HPLC (10-100% acetonitrile + 0.1% formic acid / 0.1% formic acid in water, 30 min). Fractions containing pure product were combined and lyophilized to afford the title compound as a white solid (13 mg, 0.02 mmol, 19.4%). MS (ESI) m / z 628.8 [M+H] + ; 1H NMR (400 MHz,DMSO-d6) δ ppm 10.83 (s,1 H),8.66 (s,1 H),8.02 (s,1 H),7.63 (d,J=8.80 Hz,1 H),7.57 (s,1 H),7.52 (dd,J=8.44,2.08 Hz,1 H),6.87 - 6.98 (m,2 H),6.31 (d,J=8.80 Hz,1 H),4.48 (br s,2 H),4.13 (dd,J=9.35,5.07 Hz,1 H),3.82 - 3.95 (m,1 H),3.77 (s,3 H),3.53 (s,2 H),3.06 - 3.15 (m,3 H),2.92 - 3.03 (m,1 H),2.64 - 2.73 (m,1 H),2.52 - 2.64 (m,2 H),2.21 - 2.31 (m,1 H),2.09 - 2.19 (m,1 H),2.02 (br d,J=9.29 Hz,1 H),1.54 - 1.67 (m,1 H),1.21 - 1.37 (m,1 H),0.93 (d,J=6.48 Hz,3 H).

[0454] Example S63. Synthesis of 3-(6-((1-(5-chloro-4-((2-oxoindolin-5-yl)amino)pyrimidin-2-yl)piperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (63) [ka] Step 1: Synthesis of 3-(6-((1-(5-chloro-4-((2-oxoindolin-5-yl)amino)pyrimidin-2-yl)piperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione The title compound was synthesized in a similar manner to Example S62 above, using 3-[1-methyl-6-(4-piperidylamino)indazol-3-yl]piperidine-2,6-dione and 5-aminoindolin-2-one as starting materials. LCMS C 30 H 30 ClNO3 Calculated: 599.2, Found: 600.0 [M+H]+ ; 1 H NMR (DMSO-d6,400 MHz) δ 10.8-10.9 (m,1H),10.3-10.4 (m,1H),8.0-8.1 (m,1H),7.4-7.5 (m,1H),7.3-7.4 (m,2H),6.8-6.8 (m,1H),6.4-6.6 (m,2H),4.2-4.4 (m,2H),4.1-4.2 (m,1H),3.9-4.0 (m,2H),3.84 (s,3H),3.6-3.7 (m,1H),3.49 (s,2H),3.1-3.2 (m,2H),2.6-2.6 (m,2H),2.2-2.3 (m,1H),2.1-2.2 (m,1H),2.0-2.1 (m,2H),1.3-1.4 (m,2H).

[0455] Example S64. Synthesis of 3-(6-((1-(5-chloro-4-((1-methyl-2-oxoindolin-5-yl)amino)pyrimidin-2-yl)-3,3-difluoropiperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (64) [ka] Step 1: Synthesis of 3-(6-((3,3-difluoropiperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione hydrochloride A mixture of 3-(6-amino-1-methyl-indazol-3-yl)piperidine-2,6-dione (500 mg, 1.94 mmol), tert-butyl 3,3-difluoro-4-oxopiperidine-1-carboxylate hydrate (500.9 mg, 2.13 mmol), and decaborane (14) (108.54 mg, 0.9700 mmol) was stirred in DMSO (5 mL) and acetic acid (0.22 mL, 3.87 mmol) at ambient temperature. After 2 h, the reaction was confirmed to be complete by LCMS. The reaction was diluted with methanol (1 mL), and gas effervescence occurred. After 10 min, the effervescence subsided, and the solution was diluted with ethyl acetate, washed with water, then brine, dried (sodium sulfate), filtered, and concentrated. The resulting solid was triturated with diethyl ether. The resulting solid was then purified using silica gel chromatography (4% methanol and a gradient of 0 to 50% ethyl acetate / hexane). The resulting intermediate, tert-butyl 4-[[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-6-yl]amino]-3,3-difluoro-piperidine-1-carboxylate (230 mg, 0.4817 mmol, 24.8% yield), was isolated and treated with 2 mL of HCl (4N) / 1,4-dioxane and stirred for 3 hours. After this time, the reaction mixture was concentrated to give the title compound (270 mg, 0.6524 mmol, 33.7% yield) as a pale yellow powder.

[0456] Step 2: Synthesis of 3-(6-((1-(5-chloro-4-((1-methyl-2-oxoindolin-5-yl)amino)pyrimidin-2-yl)-3,3-difluoropiperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione 3-{6-[(3,3-difluoropiperidin-4-yl)amino]-1-methyl-1H-indazol-3-yl}piperidine-2,6-dione hydrochloride (278 mg, 0.650 mmol), 5-((5-chloro-2-fluoropyrimidin-4-yl)amino)-1-methylindolin-2-one (172 mg, 0.590 mmol), N,N-diisopropylethylamine (0.2 mL, 1.17 mmol), and DMSO (1.17 mL) were added to a 1-dram vial equipped with a stir bar and heated to 80 °C for 15 h. The reaction mixture was filtered and purified by reverse-phase semi-preparative HPLC (10–100% acetonitrile + 0.1% formic acid / 0.1% formic acid in water, 30 min). Fractions containing pure product were combined and lyophilized to give the title compound (12 mg, 0.0184 mmol, 3.14% yield). 1 H NMR (DMSO-d6,400 MHz) δ 10.8-10.9 (m,1H),8.8-8.9 (m,1H),8.2-8.2 (m,1H),8.0-8.1 (m,1H),7.4-7.5 (m,2H),7.3-7.4 (m,1H),6.9-7.0 (m,1H),6.6-6.7 (m,2H),5.9-6.1 (m,1H),4.6-4.8 (m,1H),4.4-4.5 (m,1H),4.2-4.3 (m,2H),3.8-3.9 (m,3H),3.4-3.6 (m,3H),3.2-3.3 (m,1H),3.1-3.1 (m,3H),2.6-2.7 (m,2H),2.5-2.6 (m,4H),2.2-2.3 (m,1H),2.1-2.2 (m,1H),1.9-2.0 (m,1H),1.5-1.7 (m,1H).

[0457] Example S65. Synthesis of 1-(6-((1-(5-chloro-4-((1-methyl-2-oxoindolin-5-yl)amino)pyrimidin-2-yl)-3,3-difluoropiperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (65) [ka] Step 1: Synthesis of tert-butyl 4-[[3-(2,4-dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]amino]-3,3-difluoro-piperidine-1-carboxylate To a solution of 1-(6-amino-1-methyl-indazol-3-yl)hexahydropyrimidine-2,4-dione (900 mg, 3.47 mmol) and tert-butyl 3,3-difluoro-4-oxo-piperidine-1-carboxylate (980 mg, 4.17 mmol) in acetic acid (5 mL) and DMSO (25 mL) was added decaborane (14) (195 mg, 1.74 mmol), and the mixture was stirred at room temperature for 6 h. The volatiles were removed, and the residue was purified by reverse-phase chromatography (C18) (gradient: 20-100% MeCN / 10 mM ammonium formate) to give the title compound (450 mg, 27%) as a solid. MS (ESI) [MH] - 477.3.

[0458] Step 2: Synthesis of 1-(6-((1-(5-chloro-4-((1-methyl-2-oxoindolin-5-yl)amino)pyrimidin-2-yl)-3,3-difluoropiperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione The title compound was synthesized according to general procedures 5 and 6 using tert-butyl 4-[[3-(2,4-dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]amino]-3,3-difluoro-piperidine-1-carboxylate as the starting material. LCMS C 30 H 29 ClF2N 10 O3 calculated value: 650.2, measured value: 651.3 [M+H] + ; 1H NMR (400 MHz,DMSO-d6) δ 10.47 (s,1H),8.82 (s,1H),8.06 (s,1H),7.51 (d,J = 2.1 Hz,1H),7.47 (dd,J = 8.4,2.2 Hz,1H),7.31 (d,J = 8.8 Hz,1H),6.95 (d,J = 8.4 Hz,1H),6.65 (dd,J = 8.9,1.9 Hz,1H),6.61 (d,J = 1.8 Hz,1H),6.05 (d,J = 9.2 Hz,1H),4.77 - 4.63 (m,1H),4.49 - 4.36 (m,1H),4.33 - 4.17 (m,1H),3.87 (t,J = 6.7 Hz,2H),3.81 (s,3H),3.55 - 3.51 (m,2H),3.58 - 3.44 (m,1H),3.28 - 3.18 (m,1H),3.11 (s,3H),2.72 (t,J = 6.7 Hz,2H),2.03 - 1.95 (m,1H),1.70 - 1.57 (m,1H).

[0459] Example S66. Synthesis of 3-(6-(((R)-1-(5-chloro-4-((1-methyl-2-oxoindolin-5-yl)amino)pyrimidin-2-yl)-3,3-difluoropiperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (66) [ka] Step 1: Synthesis of tert-butyl 3,3-difluoro-4-(((R)-1-phenylethyl)amino)piperidine-1-carboxylate A mixture of tert-butyl 3,3-difluoro-4-oxo-piperidine-1-carboxylate (3.53 g, 15.0 mmol) and (1R)-1-phenylethanamine (2.18 g, 18.0 mmol) in toluene (35 mL) was heated to reflux for 18 h using a Dean-Stark trap. The mixture was cooled to room temperature, and the volatiles were removed under reduced pressure. DCM (35 mL) was added, followed by the addition of sodium triacetoxyborohydride (7.15 g, 33.7 mmol) in portions over 1 h. The mixture was heated to 50 °C for 18 h. An additional batch of sodium triacetoxyborohydride (3.56 g, 16.8 mmol) was added, and the reaction mixture was heated to 50 °C for an additional 6 h. The mixture was cooled to room temperature, and the volatiles were removed under reduced pressure. A solution of Na2CO3 (50 mL, 2 M) was added, and the mixture was stirred at room temperature for 1 h, followed by the addition of EtOAc (50 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (3 x 50 mL). The combined organic fractions were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-3% MeOH / DCM) to give the title compound (4.21 g, 82%) as an oil. 1 H NMR (500 MHz,methanol-d4) δ 7.29 - 7.35 (m,4H),7.20 - 7.25 (m,1H),5.48 (s,1H),4.08 (q,J = 6.7 Hz,1H),4.04 (br s,1 H),3.73 - 3.79 (m,1H),3.17 (br s,1H),2.91 (br s,1H),2.70 - 2.80 (m,1H),1.65 - 1.72 (m,1H),1.45 - 1.50 (m,1H),1.44 (s,9H),1.31 (d,J = 6.62 Hz,3H).

[0460] Step 2: Synthesis of tert-butyl (4R)-3,3-difluoro-4-[[(1R)-1-phenylethyl]amino]piperidine-1-carboxylate 4-methylbenzenesulfonate To a solution of tert-butyl 3,3-difluoro-4-[[(1R)-1-phenylethyl]amino]piperidine-1-carboxylate (4.21 g, 12.4 mmol) in EtOH (50 mL) was added 4-methylbenzenesulfonic acid hydrate (2.35 g, 12.4 mmol) at room temperature, and the mixture was heated to 60 °C for 1 h. The volatiles were removed under reduced pressure to give a diastereomeric mixture as a solid. The intermediate crude product mixture (6.07 g) was dissolved in a mixture of acetone:EtOH (10:1, 68.5 mL), and the mixture was heated to reflux. The flask was removed from the oil bath and allowed to stand overnight. The precipitated solid was filtered, rinsed with cold acetone (2 × 1 mL), and dried to give the first crop of the title compound, which was used in the next step.

[0461] Step 3: Synthesis of tert-butyl (4R)-3,3-difluoro-4-[[(1R)-1-phenylethyl]amino]piperidine-1-carboxylate The compound tert-butyl (4R)-3,3-difluoro-4-[[(1R)-1-phenylethyl]amino]piperidine-1-carboxylate 4-methylbenzenesulfonate (1.99 g, 3.88 mmol) was partitioned between EtOAc (50 mL) and saturated aqueous NaHCO3 (50 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (3 x 40 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated under reduced pressure to give the title compound (1.30 g, 98%) as an oil. MS (ESI) [M+H] + 341.3. 1 H NMR (400 MHz,DMSO-d6) δ 7.36 - 7.27 (m,4H),7.26 - 7.15 (m,1H),4.01 - 3.95 (m,1H),3.94 - 3.80 (m,1H),3.66 - 3.54 (m,1H),3.29 - 3.20 (m,1H),3.04 - 2.91 (m,1H),2.71 - 2.64 (m,1H),2.37 (t,J = 7.2 Hz,1H),1.64 - 1.58 (m,1H),1.38 (s,9H),1.22 (d,J = 6.6 Hz,3H).

[0462] Step 4: Synthesis of tert-butyl (4R)-4-amino-3,3-difluoro-piperidine-1-carboxylate A mixture of tert-butyl (4R)-3,3-difluoro-4-[[(1SR)-1-phenylethyl]amino]piperidine-1-carboxylate (1.29 g, 3.79 mmol) and 10% Pd / C (202 mg, 0.19 mmol) in EtOH (41 mL) was shaken in a Parr flask under a hydrogen atmosphere (50 psi) at room temperature for 18 hours. The mixture was filtered through Celite and washed with MeOH (3 x 50 mL). The filtrate was concentrated under reduced pressure to give the title compound (845 mg, 94%) as an oil, which was used in the next step without further purification. MS (ESI) [M-Butene] + 181.0. [α]D +0.19° (c=0.142, EtOH). 1 H NMR (400 MHz, methanol-d4) δ 4.22–4.12 (m, 1H), 3.96 (dt, J = 13.7, 4.0 Hz, 1H), 3.25–3.15 (m, 1H), 3.14–3.00 (m, 2H), 1.93–1.82 (m, 1H), 1.59–1.48 (m, 1H), 1.46 (s, 9H).

[0463] Step 5: Synthesis of tert-butyl (4R)-4-[[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazol-6-yl]amino]-3,3-difluoro-piperidine-1-carboxylate To a degassed mixture of 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole (200 mg, 0.40 mmol), tert-butyl (4R)-4-amino-3,3-difluoro-piperidine-1-carboxylate (123 mg, 0.520 mmol), and tBuONa (57.7 mg, 0.60 mmol) in THF (2 mL) was added tBuXPhos-Pd-G3 (33.9 mg, 40 μmol) at room temperature. The reaction vessel was sealed, and the reaction mixture was heated to 80 °C for 18 h and cooled to room temperature. DCM (10 mL) was added, and the mixture was filtered through Celite and rinsed with DCM (3 × 10 mL). The volatile components were concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (gradient: 0-60% EtOAc / hexanes) to give the title compound (200 mg, 76%) as a solid. MS (ESI) [M+H] + 657.6. 1 H NMR (400 MHz,DMSO-d6) δ 7.86 (d,J = 8.1 Hz,1H),7.50 - 7.43 (m,2H),7.42 - 7.23 (m,9H),6.59 (s,1H),6.58 - 6.52 (m,2H),6.00 (d,J = 9.1 Hz,1H),5.44 (s,2H),5.41 (s,2H),4.25 - 4.08 (m,2H),3.97 - 3.92 (m,1H),3.89 (s,3H),3.50 - 3.36 (m,1H),3.19 - 3.00 (m,1H),1.97 - 1.87 (m,1H),1.65 - 1.52 (m,1H),1.42 (s,9H).

[0464] Step 6: Synthesis of 3-(6-(((R)-1-(5-chloro-4-((1-methyl-2-oxoindolin-5-yl)amino)pyrimidin-2-yl)-3,3-difluoropiperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione The title compound was synthesized according to general procedures 4, 5, and 6 using tert-butyl (4R)-4-[[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazol-6-yl]amino]-3,3-difluoro-piperidine-1-carboxylate as the starting material. LCMS C 31 H 30 ClF2N9O3 Calculated: 649.2, Found: 650.2 [M+H] + ; 1 H NMR (400 MHz,DMSO-d6) δ 8.82 (s,1H),8.41 (s,1H),8.06 (s,1H),7.51 (s,1H),7.47 (dd,J = 8.4,2.1 Hz,1H),7.35 (d,J = 8.7 Hz,1H),6.95 (d,J = 8.4 Hz,1H),6.66 (dd,J = 8.8,1.8 Hz,1H),6.62 (s,1H),6.00 (d,J = 8.9 Hz,1H),4.75 - 4.64 (m,1H),4.41 (d,J = 11.6 Hz,1H),4.26 - 4.13 (m,2H),3.82 (s,3H),3.60 - 3.42 (m,3H),3.23 (t,J = 11.7 Hz,1H),3.11 (s,3H),2.65 - 2.55 (m,2H),2.30 - 2.22 (m,1H),2.20 - 2.11 (m,1H),2.04 - 1.94 (m,1H),1.70 - 1.52 (m,1H).

[0465] Example S67. Synthesis of 3-(6-(((S)-1-(5-chloro-4-((1-methyl-2-oxoindolin-5-yl)amino)pyrimidin-2-yl)-3,3-difluoropiperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (67) [ka] Step 1: Synthesis of 3-(6-(((S)-1-(5-chloro-4-((1-methyl-2-oxoindolin-5-yl)amino)pyrimidin-2-yl)-3,3-difluoropiperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione The title compound was synthesized by a method similar to Example S66, starting with (1S)-1-phenylethanamine in step 1. LCMS C 31 H 30 ClF2N9O3 Calculated: 649.2, Found: 650.3 [M+H] + ; 1 H NMR (500 MHz,DMSO-d6) δ 10.81 (s,1H),8.82 (s,1H),8.06 (s,1H),7.51 (s,1H),7.48 (d,J = 8.3 Hz,1H),7.35 (d,J = 8.7 Hz,1H),6.95 (d,J = 8.4 Hz,1H),6.66 (d,J = 8.4 Hz,1H),6.62 (s,1H),6.00 (d,J = 9.0 Hz,1H),4.78 - 4.63 (m,1H),4.47 - 4.33 (m,1H),4.30 - 4.18 (m,2H),3.82 (s,3H),3.60 - 3.45 (m,3H),3.26 - 3.19 (m,1H),3.11 (s,3H),2.69 - 2.57 (m,2H),2.31 - 2.23 (m,1H),2.15 (dd,J= 12.8,5.9 Hz,1H),2.05 - 1.92 (m,1H),1.70 - 1.56 (m,1H).

[0466] Example S68. Synthesis of 3-(6-(4-((5-chloro-4-((1-methyl-2-oxoindolin-5-yl)amino)pyrimidin-2-yl)amino)-3,3-difluoropiperidin-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (68) [ka] Step 1: Synthesis of 3-(6-(4-((5-chloro-4-((1-methyl-2-oxoindolin-5-yl)amino)pyrimidin-2-yl)amino)-3,3-difluoropiperidin-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione The title compound was synthesized following general procedures 2, 4, 5, and 6 using tert-butyl (3,3-difluoropiperidin-4-yl)carbamate as the starting material. LCMS C 31 H 30 ClF2N9O3 Calculated: 649, Found: 650 [M+H] + ; 1 H NMR (DMSO-d6,400 MHz) δ 10.8-10.9 (m,1H),8.5-8.7 (m,1H),7.9-8.1 (m,1H),7.6-7.8 (m,1H),7.4-7.6 (m,2H),7.2-7.4 (m,1H),6.9-7.0 (m,3H),4.2-4.4 (m,1H),4.0-4.2 (m,1H),3.92 (s,4H),3.56 (s,2H),3.3-3.3 (m,1H),3.1-3.2 (m,3H),3.0-3.1 (m,1H),2.9-2.9 (m,1H),2.7-2.7 (m,1H),2.6-2.7 (m,1H),2.2-2.3 (m,1H),2.1-2.2 (m,1H),1.9-2.0 (m,2H).

[0467] Example S69. Synthesis of 3-(6-(((3R,4R)-1-(5-chloro-4-((1-ethyl-2-oxoindolin-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (69) [ka] Step 1: Synthesis of 3-(6-(((3R,4R)-1-(5-chloro-4-((1-ethyl-2-oxoindolin-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione The title compound was synthesized according to general procedures 1 and 6 using 5-amino-1-ethylindolin-2-one and 3-(1-methyl-6-(((3R,4R)-3-methylpiperidin-4-yl)amino)-1H-indazol-3-yl)piperidine-2,6-dione as starting materials. LCMS C 33 H 36 ClNO3 Calculated: 641.3, Found: 642.4 [M+H] + ; 1 H NMR (400 MHz,DMSO-d6) δ ppm 10.82 (s,1H),9.03 (br s,1H),8.09 (s,1H),7.55 (s,1H),7.50 (dd,J = 8.50,1.90 Hz,1H),7.31 (d,J = 8.68 Hz,1H),7.01 (d,J = 8.44 Hz,1H),6.51 (dd,J = 8.68,1.59 Hz,1H),6.45 (s,1H),5.54 - 6.00 (m,1H),4.39 (br d,J = 7.70 Hz,2H),4.17 (dd,J = 8.68,5.14 Hz,1H),3.81 (s,3H),3.68 (q,J = 7.09 Hz,2H),3.54 (s,2H),3.25 - 3.37 (m,1H),3.08 (br t,J = 12.10 Hz,1H),2.75 (br t,J = 12.41 Hz,1H),2.54 - 2.64 (m,2H),2.20 - 2.31 (m,1H),2.04 - 2.19 (m,2H),1.52 - 1.69 (m,1H),1.16 - 1.27 (m,1H),1.13 (t,J = 7.09 Hz,3 H),0.97 (d,J = 6.48 Hz,3H).

[0468] Example S70. Synthesis of 3-(6-(((3R,4R)-1-(5-chloro-4-((1-methyl-2-oxoindolin-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (70) [ka] 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 (Intermediate 24) 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 CsCO3 (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 room temperature, filtered through Celite, and washed with EtOAc (4 × 30 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (gradient: 0–40% EtOAc / hexane) to give the title compound (1.37 g, 68%) as a solid. MS (ESI) [M+H] + 634.1. 1 H 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).

[0469] 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 hydrogen pressure (1 atm) at 50 °C for 9 h. The mixture was filtered through Celite and washed with MeOH (2 × 50 mL) and THF (2 × 100 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (gradient: 0–5% MeOH / DCM) to give the title compound (695 mg, 69%) as a solid. MS (ESI) [M+H] + 456.3. 1 H 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).

[0470] 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 HCl (4 M) / ethyl acetate (35 mL) at 25° C. After the addition was complete, the reaction mixture was stirred at 25° C. for 16 hours. The reaction mixture was filtered to give the title compound (8 g, 100% yield) as an off-white solid. MS (ESI) [M+H] + 356.2. 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,2H),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).

[0471] Step 4: Synthesis of 3-[6-[[(3R,4R)-1-[5-chloro-4-[(1-methyl-2-oxo-indolin-5-yl)amino]pyrimidin-2-yl]-3-methyl-4-piperidyl]amino]-1-methyl-indazol-3-yl]piperidine-2,6-dione To a solution of 3-(1-methyl-6-(((3R,4R)-3-methylpiperidin-4-yl)amino)-1H-indazol-3-yl)piperidine-2,6-dione hydrochloride (50.0 mg, 0.130 mmol) in DMSO (0.50 mL), 5-((5-chloro-2-fluoropyrimidin-4-yl)amino)-1-methylindolin-2-one (41.1 mg, 0.140 mmol) and DIPEA (90 μL, 0.510 mmol) were added sequentially and heated to 80 °C for 2 h. The reaction mixture was cooled to room temperature and directly purified by preparative HPLC (BEH column, C18) (gradient: 44-54% MeCN / 10 mM ammonium formate in water) to give the title compound (13.5 mg, 16%) as a solid. LCMS C 32 H 34 ClNO3 Calculated: 627.3, Found: 628.4 [M+H] + ; 1 H NMR (500 MHz,DMSO-d6) δ 10.81 (s,1H),8.65 (s,1H),8.02 (s,1H),7.57 (s,1H),7.52 (d,J = 8.4 Hz,1H),7.30 (d,J = 8.8 Hz,1H),6.93 (d,J = 8.4 Hz,1H),6.50 (d,J = 8.8 Hz,1H),6.43 (s,1H),5.68 (d,J = 9.1 Hz,1H),4.53 - 4.39 (m,2H),4.17 (dd,J = 8.7,5.2 Hz,1H),3.81 (s,3H),3.53 (s,2H),3.27 - 3.21 (m,1H),3.10 (s,3H),3.02 (t,J = 12.2 Hz,1H),2.76 - 2.65 (m,1H),2.64 - 2.56 (m,2H),2.32 - 2.19 (m,1H),2.18 - 2.09 (m,1H),2.10 - 2.02 (m,1H),1.65 - 1.51 (m,1H),1.21 - 1.11 (m,1H),0.97 (d,J = 6.5 Hz,3H).

[0472] Example S71. Synthesis of (R)-3-(6-(((3R,4R)-1-(5-chloro-4-((1-methyl-2-oxoindolin-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (71) [ka] Step 1: Synthesis of (R)-3-(6-(((3R,4R)-1-(5-chloro-4-((1-methyl-2-oxoindolin-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione The product of Example S70 was then separated by preparative HPLC (Regis Whelk-O1 RR or SS column, flow rate 1 mL / min, isocratic eluent of 100% ACN (no additives), 22°C). The title compound elutes as the first peak (Rt = 10.01 min). LCMS C 32 H 34 ClNO3 Calculated: 627.3, Found: 628.4 [M+H] + ; 1 H NMR (DMSO-d6,400 MHz) δ 10.7-10.9 (m,1H),8.5-8.8 (m,1H),7.9-8.1 (m,1H),7.5-7.7 (m,2H),7.2-7.4 (m,1H),6.9-7.1 (m,1H),6.4-6.7 (m,2H),5.6-5.7 (m,1H),4.4-4.7 (m,2H),4.0-4.3 (m,1H),3.8-3.9 (m,3H),3.4-3.6 (m,2H),2.9-3.2 (m,4H),2.7-2.8 (m,2H),2.0-2.3 (m,5H),1.5-1.6 (m,1H),1.1-1.3 (m,1H),0.8-1.1 (m,3H).

[0473] Example S72. Synthesis of (S)-3-(6-(((3R,4R)-1-(5-chloro-4-((1-methyl-2-oxoindolin-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (72) [ka] Step 1: Synthesis of (S)-3-(6-(((3R,4R)-1-(5-chloro-4-((1-methyl-2-oxoindolin-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione The product of Example S70 was then separated by preparative HPLC (Regis Whelk-O1 RR or SS column, flow rate 1 mL / min, isocratic elution with 100% ACN (no additives), 22°C). The title compound elutes as the second peak (Rt = 14.87 min). LCMS C 32 H 34 ClNO3 Calculated: 627.3, Found: 628.4 [M+H] + ; 1 H NMR (DMSO-d6,400 MHz) δ 10.7-10.9 (m,1H),8.6-8.8 (m,1H),7.9-8.1 (m,1H),7.5-7.7 (m,2H),7.2-7.4 (m,1H),6.9-7.0 (m,1H),6.3-6.6 (m,2H),5.6-5.9 (m,1H),4.4-4.6 (m,2H),4.1-4.4 (m,1H),3.8-3.9 (m,3H),3.5-3.6 (m,2H),2.9-3.2 (m,4H),2.7-2.8 (m,2H),2.0-2.3 (m,5H),1.5-1.7 (m,1H),1.1-1.3 (m,1H),0.9-1.0 (m,3H)

[0474] Example S73. Synthesis of 3-(6-(((3R,4R)-1-(5-chloro-4-((1-methyl-2-oxoindolin-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)(methyl)amino)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (73) [ka] Step 1: Synthesis of tert-butyl (3R,4R)-4-[[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazol-6-yl]-methyl-amino]-3-methyl-piperidine-1-carboxylate To an ice-cold solution of tert-butyl (3R,4R)-4-[[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazol-6-yl]amino]-3-methyl-piperidine-1-carboxylate (1.55 g, 2.45 mmol) and 60% NaH (245 mg, 6.11 mmol) dispersed in mineral oil in DMF (20 mL) was added iodomethane (305 μL, 4.89 mmol), and the mixture was stirred at room temperature for 48 h. Another batch was prepared by the same procedure. Water (50 mL) was added to the combined mixture, and the layers were separated. The aqueous layer was extracted with EtOAc (3 × 75 mL). The combined organic fractions were washed with brine (20 mL), dried over MgSO4, filtered, and concentrated. The residue was purified by reverse-phase chromatography (C18) (concentration gradient: 20-100% MeCN / 10 mM ammonium formate aqueous solution) to give the title compound (700 mg, 44%) as a solid. MS (ESI) [M+H] + 649.34. 1H NMR (400 MHz,DMSO-d6) δ 7.88 (d,J = 8.1 Hz,1H),7.47 (dd,J = 8.7,7.1 Hz,3H),7.43 - 7.23 (m,8H),6.78 (dd,J = 9.4,2.0 Hz,1H),6.61 (d,J = 1.9 Hz,1H),6.56 (d,J = 8.1 Hz,1H),5.44 (s,2H),5.40 (s,2H),4.05 - 3.99 (m,2H),3.94 (s,3H),3.65 - 3.59 (m,1H),2.92 - 2.85 (m,1H),2.75 (s,3H),2.60 - 2.54 (m,1H),1.72 - 1.77 (m,1H),1.60 - 1.54 (m,2H),1.42 (s,9H),0.75 (d,J = 6.5 Hz,3H).

[0475] Step 2: Synthesis of 3-(6-(((3R,4R)-1-(5-chloro-4-((1-methyl-2-oxoindolin-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)(methyl)amino)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione The title compound was synthesized according to general procedures 4, 5 and 6 using tert-butyl (3R,4R)-4-[[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazol-6-yl]-methyl-amino]-3-methyl-piperidine-1-carboxylate as the starting material. LCMS C 32 H 34 ClNO3 Calculated: 641.3, Found: 642.4 [M+H] + ; 1H NMR (400 MHz,DMSO-d6) δ 10.80 (s,1H),8.62 (s,1H),7.98 (s,1H),7.55 (s,1H),7.49 (d,J = 8.4 Hz,1H),7.41 (d,J = 9.1 Hz,1H),6.90 (d,J = 8.5 Hz,1H),6.85 (d,J = 7.4 Hz,1H),6.59 (s,1H),4.58 - 4.51 (m,2H),4.19 (dd,J = 8.9,5.2 Hz,1H),3.83 (s,3H),3.74 - 3.65 (m,1H),3.49 (s,2H),3.07 (s,3H),2.97 - 2.90 (m,1H),2.69 (s,3H),2.63 - 2.57 (m,3H),2.30 - 2.23 (m,1H),2.16 - 2.09 (m,1H),1.86 - 1.76 (m,1H),1.60 - 1.53 (m,2H),0.77 (d,J = 6.5 Hz,3H).

[0476] Example S74. Synthesis of 3-(6-(((3R,4R)-1-(5-chloro-4-((1-methyl-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (74) [ka] Step 1: Synthesis of 5-((5-chloro-2-fluoropyrimidin-4-yl)amino)-1-methyl-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one To a stirred solution of 5-amino-1-methyl-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (1.2 g, 1.18 mmol) in EtOH (30 mL) was added DIPEA (0.617 mL, 3.53 mmol) and 5-chloro-2,4-difluoropyrimidine (0.266 g, 1.765 mmol) at -25 °C. The reaction was allowed to warm slowly to room temperature over 1 h, after which the reaction was stirred at 25 °C for 16 h. After this time, the reaction mixture was evaporated. The crude residue was purified by silica gel chromatography (50-100% EtOAc / PE) to afford the title compound (190 mg, 0.252 mmol, 21.44% yield) as a pale yellow solid. MS (ESI) m / z 294.0 [M+H] + .

[0477] Step 2: Synthesis of 3-(6-(((3R,4R)-1-(5-chloro-4-((1-methyl-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione To a stirred solution of 5-((5-chloro-2-fluoropyrimidin-4-yl)amino)-1-methyl-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (80 mg, 0.104 mmol) and 3-(1-methyl-6-(((3R,4R)-3-methylpiperidin-4-yl)amino)-1H-indazol-3-yl)piperidine-2,6-dione (49.1 mg, 0.104 mmol) in DMSO (1 mL) was added DIPEA (0.054 mL, 0.311 mmol) and the reaction mixture was stirred at 90° C. for 4 hours. The reaction mixture was purified by preparative HPLC to give the title compound (30 mg, 0.047 mmol, 45.8% yield) as an off-white solid. LCMS C 31 H 33 ClN 10 O3 calculated value: 628.2, measured value: 629.2 [M+H] + ; 1H NMR (400 MHz,DMSO-d6): δ 10.82 (s,1H),8.85 (s,1H),8.36 (d,J = 2.00 Hz,1H),8.06 (s,1H),7.86 (s,1H),7.31 (d,J = 8.80 Hz,1H),6.44-6.52 (m,2H),5.69 (d,J = 8.80 Hz,1H),4.44 (d,J = 9.20 Hz,2H),4.17 (q,J = 5.20 Hz,1H),3.82 (s,3H),3.61 (s,2H),3.13 (s,3H),δ 3.02 (t,J = Hz,1H),2.53-2.68 (m,3H),2.33 (t,J = 1.60 Hz,1H),2.25 (t,J = 6.00 Hz,1H),2.06-2.17 (m,2H),1.58 (d,J = 4.80 Hz,1H),1.15-1.17 (m,1H),0.96 (d,J = 6.40 Hz,3H).

[0478] Example S75. Synthesis of 3-(6-(((3R,4R)-1-(5-chloro-4-((1-(2-methoxyethyl)-2-oxoindolin-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (75) [ka] Step 1: Synthesis of 5-((5-chloro-2-fluoropyrimidin-4-yl)amino)-1-(2-methoxyethyl)indolin-2-one To a stirred solution of 5-amino-1-(2-methoxyethyl)indolin-2-one (200 mg, 0.97 mmol) in THF (5 mL) at −45° C. under a nitrogen atmosphere, DIPEA (0.254 mL, 1.46 mmol) and 5-chloro-2,4-difluoropyrimidine (219 mg, 1.46 mmol) were added. The reaction mixture was slowly warmed to 25° C. and stirred for 12 hours. The reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by flash column silica gel chromatography (30% ethyl acetate / petroleum ether) to give the title compound (80 mg, 0.210 mmol, 21% yield) as an off-white solid. MS: 337.0 [M+H] + .

[0479] Step 2: Synthesis of 3-(6-(((3R,4R)-1-(5-chloro-4-((1-(2-methoxyethyl)-2-oxoindolin-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione To a stirred solution of 3-(1-methyl-6-(((3R,4R)-3-methylpiperidin-4-yl)amino)-1H-indazol-3-yl)piperidine-2,6-dione (117 mg, 0.238 mmol) in DMSO (2.0 mL) at 25° C. was added 5-((5-chloro-2-fluoropyrimidin-4-yl)amino)-1-(2-methoxyethyl)indolin-2-one (80 mg, 0.238 mmol) and DIPEA (0.166 mL, 0.95 mmol). The reaction mixture was heated to 80° C. and stirred for 4 hours. The crude product was purified by preparative HPLC to give the title compound (24 mg, 0.028 mmol, 25% yield). LCMS C 34 H 38 ClNO4 Calculated: 671.3, Found: 672.3 [M+H] + ; 1H NMR (400 MHz, DMSO-d6): δ 10.83 (s, 1H), 8.67 (s, 1H), 8.02 (s, 1H), 7.56 (s, 1H), 7.50 (d, J = 8.40 Hz, 1H), 7.31 (d, J = 8.80 Hz, 1H), 7.01 (d, J = 8.40 Hz, 1H), 6.51 (dd, J = 1.6 Hz and 8.8 Hz, 1H), 6.44 (s, 1H), 5.71 (d, J = 9.20 Hz, 1H), 4.51-4.44 (m, 2H), 4.18 (dd, J = 5.2 Hz and 8.4 Hz, 1H), 3.84-3.82 (m, 2H), 3.82 (s,3H),3.56-3.52 (m,4H),3.22 (s,3H),3.05-2.99 (m,1H),2.68-2.65 (m,1H),2.62-2.58 (m,2H),2.28-2.23 (m,1H),2.17-2.06 (m,2H),1.60-1.57 (m,1H),1.18-1.16 (m,1H),0.97 (d,J = 6.40 Hz,3H).

[0480] Example S76. Synthesis of (R)-3-(6-(((3R,4R)-1-(5-chloro-4-((1-(2-methoxyethyl)-2-oxoindolin-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (76) [ka] Step 1: Synthesis of (R)-3-(6-(((3R,4R)-1-(5-chloro-4-((1-(2-methoxyethyl)-2-oxoindolin-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione The product of Example S75 was then separated by preparative HPLC (Regis Whelk-O1 SS, 21 x 250 mm, 5u column, flow rate 1 mL / min, isocratic elution with 100% ACN (no additives), 22°C) and isolated as the first eluting peak (Rt = 9.85 min). LCMS C 34 H 38 ClNO4 Calculated: 671.3, Found: 672.3 [M+H] + ; 1 H NMR (400 MHz,DMSO-d6) δ (ppm) = 10.81 (s,1H),8.65 (s,1H),8.02 (s,1H),7.56 (s,1H),7.49 (dd,J = 2.0,8.5 Hz,1H),7.30 (d,J = 8.8 Hz,1H),7.00 (d,J = 8.6 Hz,1H),6.50 (dd,J = 1.7,8.8 Hz,1H),6.43 (d,J = 1.1 Hz,1H),5.69 (d,J = 8.9 Hz,1H),4.53 - 4.40 (m,2H),4.17 (dd,J = 5.2,8.7 Hz,1H),3.86 - 3.79 (m,5H),3.58 - 3.48 (m,4H),3.21 (s,3H),3.06 - 2.96 (m,1H),2.73 - 2.56 (m,3H),2.35 - 2.01 (m,4H),1.63 - 1.50 (m,1H),1.23 - 1.10 (m,1H),0.96 (d,J = 6.6 Hz,3H).

[0481] Example S77. Synthesis of (S)-3-(6-(((3R,4R)-1-(5-chloro-4-((1-(2-methoxyethyl)-2-oxoindolin-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (77) [ka] Step 1: Synthesis of (S)-3-(6-(((3R,4R)-1-(5-chloro-4-((1-(2-methoxyethyl)-2-oxoindolin-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione The product of Example S75 was then separated by preparative HPLC (Regis Whelk-O1 SS, 21 x 250 mm, 5u column, flow rate 1 mL / min, isocratic elution with 100% ACN (no additives), 22°C) and isolated as the second eluting peak (Rt = 13.85 min). LCMS C 34 H 38 ClNO4 Calculated: 671.3, Found: 672.3 [M+H] + ; 1 H NMR (400 MHz,DMSO-d6) δ (ppm) = 10.81 (s,1H),8.65 (s,1H),8.02 (s,1H),7.56 (s,1H),7.49 (dd,J = 2.1,8.4 Hz,1H),7.30 (d,J = 8.7 Hz,1H),7.00 (d,J = 8.6 Hz,1H),6.50 (dd,J = 1.7,8.8 Hz,1H),6.43 (d,J = 1.2 Hz,1H),5.69 (d,J = 9.2 Hz,1H),4.52 - 4.41 (m,2H),4.17 (dd,J = 5.2,8.7 Hz,1H),3.86 - 3.79 (m,5H),3.58 - 3.48 (m,4H),3.21 (s,3H),3.07 - 2.96 (m,1H),2.73 - 2.56 (m,3H),2.34 - 2.02 (m,4H),1.63 - 1.53 (m,1H),1.22 - 1.10 (m,1H),0.97 (d,J = 6.5 Hz,3H).

[0482] Example S78. Synthesis of 3-(6-((2R,6R)-4-(5-chloro-4-((1-methyl-2-oxoindolin-5-yl)amino)pyrimidin-2-yl)-2,6-dimethylpiperazin-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (78) [ka] Step 1: Synthesis of tert-butyl (3R,5R)-4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazol-6-yl)-3,5-dimethylpiperazine-1-carboxylate A stirred solution of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-1-methyl-1H-indazole (2.335 g, 4.67 mmol) and tert-butyl (3R,5R)-3,5-dimethylpiperazine-1-carboxylate (1.0 g, 4.67 mmol) in toluene (25 mL) was degassed with nitrogen for 15 minutes. Sodium tert-butoxide (0.673 g, 7.00 mmol) and CPhos-Pd-G3 (0.188 g, 0.233 mmol) were then added. The reaction mixture was heated to 100 °C and stirred for 8 hours. The reaction mixture was cooled to room temperature, treated with water (150 mL), and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude compound. The crude product was purified by flash column silica chromatography (35-40% ethyl acetate / petroleum ether) to give the title compound (950 mg, 1.364 mmol, 29% yield) as an off-white solid. MS (ESI) m / z 634.8 [M+H] + .

[0483] Step 2: Synthesis of tert-butyl (3R,5R)-4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)-3,5-dimethylpiperazine-1-carboxylate To a stirred solution of tert-butyl (3R,5R)-4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazol-6-yl)-3,5-dimethylpiperazine-1-carboxylate (950 mg, 1.364 mmol) in ethanol (20 mL) and THF (20 mL) was added 20% palladium hydride on carbon (192 mg) under nitrogen. The reaction mixture was stirred under hydrogen pressure at 25° C. for 8 hours. The reaction mixture was filtered through a Celite pad, and the Celite pad was washed with a 1:1 mixture of acetonitrile and methanol (3×25 mL). The filtrate was concentrated under reduced pressure to give the crude compound. The crude product was purified by flash column silica chromatography (5% MeOH / DCM) to give the title compound (330 mg, 0.719 mmol, 52.7% yield) as an off-white solid. MS(ESI)m / z 456.2[M+H] + .

[0484] Step 3: Synthesis of the TFA salt of 3-(6-((2R,6R)-2,6-dimethylpiperazin-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione To a stirred solution of tert-butyl (3R,5R)-4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)-3,5-dimethylpiperazine-1-carboxylate (250 mg, 0.450 mmol) in DCM (5 mL) was added TFA (0.34 mL) at 0° C. The reaction mixture was slowly warmed to 25° C. and stirred for 4 hours. The reaction mixture was concentrated under reduced pressure to give the crude compound. The crude compound was triturated with diethyl ether and dried under reduced pressure to give the title compound (220 mg, 0.410 mmol, 91% yield) as an off-white solid. The crude product was used in the next step without further purification. MS (ESI) m / z 356.0 [M+H] + .

[0485] Step 4: Synthesis of 3-(6-((2R,6R)-4-(5-chloro-4-((1-methyl-2-oxoindolin-5-yl)amino)pyrimidin-2-yl)-2,6-dimethylpiperazin-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione To a stirred solution of 3-(6-((2R,6R)-2,6-dimethylpiperazin-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione TFA salt (70 mg, 0.137 mmol) and 5-((5-chloro-2-fluoropyrimidin-4-yl)amino)-1-methylindolin-2-one (40.2 mg, 0.137 mmol) in DMSO (1 mL) at 25° C. was added DIPEA (0.096 mL, 0.549 mmol). The reaction mixture was heated to 80° C. and stirred for 6 hours. The reaction mixture was cooled to room temperature and purified by preparative HPLC to give the title compound (26 mg, 0.040 mmol, 29% yield) as an off-white solid. LCMS C 32 H 34 ClNO3 Calculated: 627.3, Found: 628.2 [M+H] + ; 1 H NMR (400 MHz,DMSO-d6): δ 10.88 (s,1H),8.72 (s,1H),8.04 (s,1H),7.60 (s,1H),7.57-7.52 (m,2H),7.01 (s,1H),6.96 (d,J = 8.40 Hz,1H),6.87 (d,J = 8.80 Hz,1H),4.31-4.27 (m,1H),3.92 (s,3H),3.93-3.90 (m,2H),3.81-3.77 (m,2H),3.69-3.65 (m,2H),3.57 (s,2H),3.12 (s,3H),2.67-2.64 (m,2H),2.33-2.30 (m,1H).2.19-2.15 (m,1H),0.96 (d,J = 6.4 Hz,6H).

[0486] Example S79. Synthesis of (R)-3-(6-((2R,6R)-4-(5-chloro-4-((1-methyl-2-oxoindolin-5-yl)amino)pyrimidin-2-yl)-2,6-dimethylpiperazin-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (79) [ka] Step 1: Synthesis of (R)-3-(6-((2R,6R)-4-(5-chloro-4-((1-methyl-2-oxoindolin-5-yl)amino)pyrimidin-2-yl)-2,6-dimethylpiperazin-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione The product of Example S78 was then separated by preparative HPLC (Regis Whelk-O1 SS, 21 x 250 mm, 5u column, flow rate 1 mL / min, isocratic elution with 100% ACN (no additives), 22°C). The title compound was isolated as the first eluting peak (Rt = 10.08 min). LCMS C 32 H 34 ClNO3 Calculated: 627.3, Found: 628.2 [M+H] + ; 1 H NMR (400 MHz,DMSO-d6) δ (ppm) = 10.86 (s,1H),8.69 (s,1H),8.03 (s,1H),7.60 (d,J = 1.7 Hz,1H),7.57 - 7.50 (m,2H),7.00 (d,J = 1.2 Hz,1H),6.95 (d,J = 8.4 Hz,1H),6.86 (dd,J = 1.6,8.9 Hz,1H),4.28 (dd,J = 5.1,9.5 Hz,1H),3.91 (s,5H),3.82 - 3.73 (m,2H),3.67 (dd,J = 5.3,12.8 Hz,2H),3.56 (s,2H),3.12 (s,3H),2.69 - 2.58 (m,2H),2.38 - 2.26 (m,1H),2.21 - 2.10 (m,1H),0.95 (d,J = 6.2 Hz,6H).

[0487] Example S80. Synthesis of (S)-3-(6-((2R,6R)-4-(5-chloro-4-((1-methyl-2-oxoindolin-5-yl)amino)pyrimidin-2-yl)-2,6-dimethylpiperazin-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (80) [ka] Step 1: Synthesis of (S)-3-(6-((2R,6R)-4-(5-chloro-4-((1-methyl-2-oxoindolin-5-yl)amino)pyrimidin-2-yl)-2,6-dimethylpiperazin-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione The product of Example S78 was then separated by preparative HPLC (Regis Whelk-O1 SS, 21 x 250 mm, 5u column, flow rate 1 mL / min, isocratic elution with 100% ACN (no additives), 22°C). The title compound was isolated as the second eluting peak (Rt = 13.90 min). LCMS C 32 H 34 ClNO3 Calculated: 627.3, Found: 628.2 [M+H] + ; 1 H NMR (400 MHz,DMSO-d6) δ (ppm) = 10.86 (s,1H),8.69 (s,1H),8.03 (s,1H),7.60 (d,J = 1.7 Hz,1H),7.57 - 7.50 (m,2H),7.00 (d,J = 1.3 Hz,1H),6.95 (d,J = 8.3 Hz,1H),6.86 (dd,J = 1.6,8.9 Hz,1H),4.28 (dd,J = 5.2,9.4 Hz,1H),3.91 (s,5H),3.82 - 3.74 (m,2H),3.67 (dd,J = 5.3,12.7 Hz,2H),3.56 (s,2H),3.12 (s,3H),2.70 - 2.56 (m,2H),2.37 - 2.29 (m,2H),2.22 - 2.12 (m,1H),0.95 (d,J = 6.1 Hz,6H).

[0488] Example S81. Synthesis of 3-(6-(((2S,4R)-1-(5-chloro-4-((1-methyl-2-oxoindolin-5-yl)amino)pyrimidin-2-yl)-2-methylpiperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (81) [ka] Step 1: Synthesis of tert-butyl (2S,4R)-4-[[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazol-6-yl]amino]-2-methyl-piperidine-1-carboxylate A mixture of 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole (1.9 g, 3.80 mmol), tert-butyl (2S,4R)-4-amino-2-methyl-piperidine-1-carboxylate hydrochloride (1.05 g, 4.18 mmol), tBuXPhos-Pd-G3 (302 mg, 0.380 mmol), and NaOtBu (912 mg, 9.49 mmol) in MeTHF (38 mL) was evacuated and refilled with nitrogen three times. The mixture was heated to 85 °C for 1.5 h and cooled to room temperature. DCM (30 mL) was added, and the mixture was filtered through a pad of Celite and rinsed with DCM (3 × 30 mL). The volatile components were concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (gradient: 0-60% EtOAc / hexanes) to give the title compound (2.01 g, 84%) as a solid. MS (ESI) [M+H] + 634.1. 1H NMR (400 MHz,DMSO-d6) δ 7.87 (d,J = 8.1 Hz,1H),7.46 (d,J = 6.9 Hz,2H),7.42 - 7.21 (m,9H),6.55 (d,J = 8.1 Hz,1H),6.47 - 6.36 (m,2H),5.66 (d,J = 8.3 Hz,1H),5.44 (s,2H),5.41 (s,2H),4.45 - 4.33 (m,1H),3.89 (s,3H),3.88 - 3.86 (m,1H),3.76 - 3.62 (m,1H),3.01 (t,J = 13.9 Hz,1H),2.05 (d,J = 11.5 Hz,1H),1.87 - 1.83 (m,1H),1.48 - 1.43 (m,1H),1.41 (s,9H),1.23 (d,J= 7.0 Hz,3H),1.16 - 1.05 (m,1H).

[0489] Step 2: Synthesis of 3-(6-(((2S,4R)-1-(5-chloro-4-((1-methyl-2-oxoindolin-5-yl)amino)pyrimidin-2-yl)-2-methylpiperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione The title compound was synthesized according to general procedures 4, 5, and 6 using tert-butyl (2S,4R)-4-[[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazol-6-yl]amino]-2-methyl-piperidine-1-carboxylate as the starting material. LCMS C 32 H 34 ClNO3 Calculated: 627.3, Found: 628.3 [M+H] + ; 1H NMR (500 MHz,DMSO-d6) δ 10.81 (s,1H),8.63 (s,1H),8.01 (s,1H),7.55 (s,1H),7.54 - 7.46 (m,1H),7.33 (d,J = 8.7 Hz,1H),6.93 (d,J = 8.4 Hz,1H),6.52 (dd,J = 8.8,1.7 Hz,1H),6.47 (s,1H),5.67 (d,J = 8.3 Hz,1H),4.91 (br s,1H),4.48 (br s,1H),4.18 (dd,J = 8.8,5.1 Hz,1H),3.83 (s,3H),3.81 - 3.74 (m,1H),3.54 (s,2H),3.11 (s,3H),3.06 (td,J = 13.1,1.7 Hz,1H),2.66 - 2.56 (m,2H),2.31 - 2.22 (m,1H),2.17 - 2.08 (m,2H),1.92 (d,J = 11.3 Hz,1H),1.47 (td,J = 13.0,5.7 Hz,1H),1.26 (d,J = 6.9 Hz,3H),1.15 (td,J = 13.9,5.3 Hz,1H).

[0490] Example S82. Synthesis of (R)-3-(6-(((2S,4R)-1-(5-chloro-4-((1-methyl-2-oxoindolin-5-yl)amino)pyrimidin-2-yl)-2-methylpiperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (82) [ka] Step 1: Synthesis of (R)-3-(6-(((2S,4R)-1-(5-chloro-4-((1-methyl-2-oxoindolin-5-yl)amino)pyrimidin-2-yl)-2-methylpiperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione The product of Example S81 was then separated by preparative HPLC (Regis Whelk-O1 SS, 21 x 250 mm, 5u column, flow rate 1 mL / min, isocratic elution with 100% ACN (no additives), 22°C). The title compound was isolated as the first eluting peak (Rt = 11.30 min). LCMS C 32 H 34 ClNO3 Calculated: 627.3, Found: 628.3 [M+H] + ; 1 H NMR (400 MHz,DMSO-d6) δ (ppm) 10.81 (s,1H),8.62 (s,1H),8.01 (s,1H),7.61 - 7.42 (m,2H),7.33 (d,J = 8.7 Hz,1H),6.93 (d,J = 8.3 Hz,1H),6.62 - 6.40 (m,2H),5.67 (br d,J = 8.5 Hz,1H),5.09 - 4.32 (m,2H),4.18 (dd,J = 5.1,8.8 Hz,1H),3.91 - 3.69 (m,4H),3.54 (s,2H),3.11 (s,4H),2.31 - 2.06 (m,3H),1.91 (br d,J = 10.5 Hz,1H),1.46 (dt,J = 5.2,11.9 Hz,1H),1.26 (br d,J = 6.7 Hz,3H),1.20 - 1.09 (m,1H).

[0491] Example S83. Synthesis of (S)-3-(6-(((2S,4R)-1-(5-chloro-4-((1-methyl-2-oxoindolin-5-yl)amino)pyrimidin-2-yl)-2-methylpiperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (83) [ka] Step 2: Synthesis of (S)-3-(6-(((2S,4R)-1-(5-chloro-4-((1-methyl-2-oxoindolin-5-yl)amino)pyrimidin-2-yl)-2-methylpiperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione The product of Example S81 was then separated by preparative HPLC (Regis Whelk-O1 SS, 21 x 250 mm, 5u column, flow rate 1 mL / min, isocratic elution with 100% ACN (no additives), 22°C). The title compound was isolated as the second eluting peak (Rt = 19.77 min). LCMS C 32 H 34 ClNO3 Calculated: 627.3, Found: 628.3 [M+H] + ; 1 H NMR (400 MHz,DMSO-d6) δ (ppm) 10.81 (br s,1H),8.62 (br s,1H),8.01 (br s,1H),7.65 - 7.44 (m,2H),7.33 (br d,J = 8.8 Hz,1H),6.93 (br d,J = 8.1 Hz,1H),6.58 - 6.39 (m,2H),5.67 (br d,J = 8.5 Hz,1H),5.13 - 4.32 (m,2H),4.31 - 4.10 (m,1H),3.97 - 3.71 (m,4H),3.54 (br s,2H),3.11 (br s,4H),2.33 - 2.08 (m,3H),1.97 - 1.86 (m,1H),1.55 - 1.41 (m,1H),1.26 (br d,J = 6.6 Hz,3H),1.20 - 1.07 (m,1H).

[0492] Example S84. Synthesis of 3-(6-(((2S,4R)-1-(5-chloro-4-((1-methyl-2-oxoindolin-5-yl)amino)pyrimidin-2-yl)-2-methylpiperidin-4-yl)(methyl)amino)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (84) [ka] Step 1: Synthesis of tert-butyl (2S,4R)-4-[[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazol-6-yl]amino]-2-methyl-piperidine-1-carboxylate A mixture of 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole (1.9 g, 3.80 mmol, Celgene intermediate), tert-butyl (2S,4R)-4-amino-2-methyl-piperidine-1-carboxylate hydrochloride (1.05 g, 4.18 mmol), tBuXPhos-Pd-G3 (302 mg, 0.380 mmol), and NaOtBu (912 mg, 9.49 mmol) in MeTHF (38 mL) was evacuated and refilled with nitrogen three times. The mixture was heated to 85 °C for 1.5 h and cooled to room temperature. DCM (30 mL) was added, and the mixture was filtered through a pad of Celite and rinsed with DCM (3 × 30 mL). The volatile components were concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (gradient: 0-60% EtOAc / hexanes) to give the title compound (2.01 g, 84%) as a solid. MS (ESI) [M+H] + 634.1. 1 H NMR (400 MHz,DMSO-d6) δ 7.87 (d,J = 8.1 Hz,1H),7.46 (d,J = 6.9 Hz,2H),7.42 - 7.21 (m,9H),6.55 (d,J = 8.1 Hz,1H),6.47 - 6.36 (m,2H),5.66 (d,J = 8.3 Hz,1H),5.44 (s,2H),5.41 (s,2H),4.45 - 4.33 (m,1H),3.89 (s,3H),3.88 - 3.86 (m,1H),3.76 - 3.62 (m,1H),3.01 (t,J = 13.9 Hz,1H),2.05 (d,J = 11.5 Hz,1H),1.87 - 1.83 (m,1H),1.48 - 1.43 (m,1H),1.41 (s,9H),1.23 (d,J= 7.0 Hz,3H),1.16 - 1.05 (m,1H).

[0493] Step 2: Synthesis of tert-butyl (2S,4R)-4-[[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazol-6-yl]-methyl-amino]-2-methyl-piperidine-1-carboxylate To a solution of tert-butyl (2S,4R)-4-[[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazol-6-yl]amino]-2-methyl-piperidine-1-carboxylate (525 mg, 0.83 mmol) in DMSO (6.5 mL), formaldehyde solution (0.53 mL, 7.09 mmol, 37%) and decaborane (152 mg, 1.24 mmol) were added sequentially. The mixture was stirred at room temperature for 2 hours. Water (25 mL) was added, and the precipitated solid was collected by filtration. The residue was purified by column chromatography on silica gel (gradient: 0-50% EtOAc / hexane) to give the title compound (449 mg, 84%) as a solid. MS (ESI) [M+H] + 648.7; 1 H NMR (500 MHz,DMSO-d6) δ 7.89 (d,J = 8.1 Hz,1H),7.51 - 7.44 (m,3H),7.42 - 7.36 (m,4H),7.36 - 7.24 (m,4H),6.77 (dd,J = 9.3,2.0 Hz,1H),6.63 (d,J = 1.8 Hz,1H),6.56 (d,J = 8.1 Hz,1H),5.48 - 5.41 (m,2H),5.41 (s,2H),4.51 - 4.36 (m,1H),4.10 (t,J = 11.9 Hz,1H),4.00 - 3.86 (m,4H),3.17 - 2.96 (m,1H),2.75 (s,3H),1.83 - 1.72 (m,1H),1.70 - 1.55 (m,2H),1.48 (d,J = 13.3 Hz,1H),1.41 (s,9H),1.25 - 1.19 (m,3H).

[0494] Step 3: Synthesis of tert-butyl (2S,4R)-4-[[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-6-yl]-methyl-amino]-2-methyl-piperidine-1-carboxylate A mixture of tert-butyl (2S,4R)-4-[[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazol-6-yl]-methyl-amino]-2-methyl-piperidine-1-carboxylate (446 mg, 0.69 mmol) and Pearlman's catalyst (96.7 mg, 0.340 mmol) in THF (9 mL) and EtOH (9 mL) was stirred under a hydrogen atmosphere (1 atm) at 50 °C for 6 h and then cooled to room temperature. The mixture was filtered through a pad of Celite and rinsed with THF (3 × 30 mL). The volatiles were concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (gradient: 10–100% EtOAc / hexanes) to give the title compound (303 mg, 94%) as a solid. MS (ESI) [M+H] + 470.3. 1 H NMR (400 MHz,DMSO-d6) δ 10.83 (s,1H),7.48 (d,J = 9.0 Hz,1H),6.88 (dd,J = 9.2,1.9 Hz,1H),6.64 (d,J = 1.7 Hz,1H),4.49 - 4.36 (m,1H),4.24 (dd,J = 8.9,5.1 Hz,1H),4.18 - 4.08 (m,1H),3.99 - 3.91 (m,1H),3.86 (s,3H),3.15 - 2.97 (m,1H),2.75 (s,3H),2.68 - 2.55 (m,2H),2.33 - 2.23 (m,1H),2.22 - 2.12 (m,1H),1.84 - 1.71 (m,1H),1.71 - 1.55 (m,2H),1.49 (d,J = 12.1 Hz,1H),1.41 (s,9H),1.25 - 1.17 (m,3H).

[0495] Step 4: Synthesis of 3-[1-methyl-6-[methyl-[(2S,4R)-2-methyl-4-piperidyl]amino]indazol-3-yl]piperidine-2,6-dione hydrochloride To a solution of tert-butyl (2S,4R)-4-[[3-(2,6-dioxo-3-piperidyl)-1-methyl-indazol-6-yl]-methyl-amino]-2-methyl-piperidine-1-carboxylate (400 mg, 0.85 mmol) in 1,4-dioxane (5 mL) was added HCl (4N) / 1,4-dioxane (2.13 mL, 8.52 mmol), and the mixture was stirred at room temperature for 15 hours. The volatiles were evaporated under reduced pressure, and the residue was triturated with EtO (10 mL) to give the title compound (295 mg, 85%) as a solid, which was used in the next step without further purification. MS (ESI) [M+H] + 370.3. 1 H NMR (500 MHz,DMSO-d6) δ 10.88 (s,1H),9.12 (br s,1H),9.05 - 8.83 (m,1H),7.71 (br s,1H),7.21 (br s,1H),4.40 - 4.30 (m,1H),4.27 - 3.98 (m,6H),3.95 (s,3H),3.89 - 3.73 (m,1H),3.34 - 3.24 (m,1H),3.22 - 3.11 (m,1H),3.07 - 2.85 (m,2H),2.75 - 2.55 (m,2H),2.42 - 2.29 (m,1H),2.19 - 2.11 (m,1H),1.35 (d,J = 5.4 Hz, 3H).

[0496] Step 5: Synthesis of 3-[6-[[(2S,4R)-1-[5-chloro-4-[(1-methyl-2-oxo-indolin-5-yl)amino]pyrimidin-2-yl]-2-methyl-4-piperidyl]-methyl-amino]-1-methyl-indazol-3-yl]piperidine-2,6-dione To a solution of 3-[1-methyl-6-[methyl-[(2S,4R)-2-methyl-4-piperidyl]amino]indazol-3-yl]piperidine-2,6-dione hydrochloride (64.1 mg, 0.16 mmol) in DMF (2 mL) and DMSO (0.5 mL) was added 5-[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]-1-methyl-indolin-2-one (42 mg, 0.14 mmol) and DIPEA (0.2 mL, 1.15 mmol) sequentially. The mixture was heated to 100 °C for 18 h and then cooled to room temperature. The volatiles were removed under reduced pressure, and the residue was purified by a gradient of 20-75% MeCN / 10 mM aqueous ammonium formate to give the title compound (47 mg, 48%) as a solid. LCMS C 33 H 36 ClNO3 Calculated: 641.3, Found: 642.3 [M+H] + ; 1 H NMR (500 MHz,DMSO-d6) δ 10.83 (s...

Claims

1. Formula (IA): 【Chemistry 1】 Compounds of or pharmaceutically acceptable salts thereof [In the formula, X １ and X ２ Each is independently N or CH, except X １ and X ２ At least one of them is N; R １ａ and R １ｂ These are H, Halo, or C, respectively, independently. １ ~C ６ It is alkyl; R ２ａ and R ２ｂ are each independently H, C １ ~C ６ alkyl, -O(C １ ~C ６ alkyl), -OH, halo, C １ ~C ６ haloalkyl, or C １ ~C ６ alkyl-OH, and Alternatively, R ２ａ and R ２ｂ Together with the carbon atoms to which they are bonded, spiro C ３ ~C ５ Forming a cycloalkyl group, Alternatively, R ２ａ and R ２ｂ They combine to form an oxo; Alternatively, R １ａ and R ２ａ Together, bridge C ２ ~C ３ Forms alkylenes; R ３ａ and R ３ｂ These are H, Halo, or C, respectively, independently. １ ~C ６ It is alkyl; R ４ａ and R ４ｂ These are H, Halo, or C, respectively, independently. １ ~C ６ It is alkyl, Alternatively, R ４ａ and R ４ｂ Together with the carbon atoms to which they are bonded, spiro C ３ ~C ５ Forms a cycloalkyl group; R ５ａ and R ５ｂ These are H, Halo, or C, respectively, independently. １ ~C ６ It is alkyl; w is either 0 or 1; R ６ is H or C １ ~C ６ It is alkyl; R ７ is H or C １ ~C ６ It is alkyl; x and y are either 0 or 1 independently, except that both x and y are not 1; R ８ is Cl or -CN; R ９ is F; X ３ is N or CH; z is either 0 or 1; R １０ａ and R １０ｂ Each of these is independently H or halo; R １１ H, C １ ~C ６ Alkyl, -(C １ ~C ６ Alkilen) - (5-6 member heterocycline), - (C) １ ~C ６ Alkylene)-O(C) １ ~C ６ Alkyl), C １ ~C ６ Haloalkyl, C １ ~C ６ Alkyl-OH, or -(C １ ~C ６ Alkylene)-NH(C) １ ~C ６ It is alkyl, Here, a heterocyclyl comprises one to three heteroatoms selected from N, O, and S; R １２ is H, halo, or C １ ~C ６ It is alkyl; R １３ is H or halo; R １４ is H or C １ ~C ６ It is alkyl; X ４ is N or CR １５ And; R １５ is H or C １ ~C ６ It is alkyl; X ５ and X ６ Each is independently N or CH; and structure: 【Chemistry 2】 It is either a single bond or a double bond; Here, one or more hydrogen atoms in the compound may be appropriately substituted with deuterium.

2. Equation (I): 【Transformation 3】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof. [In the formula, X １ and X ２ are each independently N or CH, provided that at least one of X １ and X ２ is N; R １ａ and R １ｂ These are H, Halo, or C, respectively, independently. １ ~C ６ It is alkyl; R ２ａ and R ２ｂ are each independently H, C １ -C ６ alkyl, -OH, halo, or C １ -C ６ alkyl-OH, Alternatively, R ２ａ and R ２ｂ Together with the carbon atoms to which they are bonded, spiro C ３ ~C ５ Forming a cycloalkyl group, Alternatively, R ２ａ and R ２ｂ They combine to form an oxo; Alternatively, R １ａ and R ２ａ Together, bridge C ２ ~C ３ Forms alkylenes; R ３ａ and R ３ｂ These are H, Halo, or C, respectively, independently. １ ~C ６ It is alkyl; R ４ａ and R ４ｂ These are H, Halo, or C, respectively, independently. １ ~C ６ It is alkyl, Alternatively, R ４ａ and R ４ｂ Together with the carbon atoms to which they are bonded, spiro C ３ ~C ５ Forms a cycloalkyl group; R ５ａ and R ５ｂ These are H, Halo, or C, respectively, independently. １ ~C ６ It is alkyl; w is either 0 or 1; R ６ is H or C １ ~C ６ It is alkyl; R ７ is H or C １ ~C ６ It is alkyl; x and y are either 0 or 1 independently, except that both x and y are not 1; R ８ is Cl or -CN; R ９ is F; X ３ is N or CH; z is either 0 or 1; R １０ａ and R １０ｂ Each of these is independently H or halo; R １１ H, C １ ~C ６ Alkyl, -(C １ ~C ６ Alkilen) - (5-6 member heterocycline), - (C) １ ~C ６ Alkylene)-O(C) １ ~C ６ Alkyl), C １ ~C ６ Haloalkyl, C １ ~C ６ Alkyl-OH, or -(C １ ~C ６ Alkylene)-NH(C) １ ~C ６ It is alkyl, Here, a heterocyclyl comprises one to three heteroatoms selected from N, O, and S; R １２ is H, halo, or C １ ~C ６ It is alkyl; R １３ is H or halo; R １４ is H or C １ ~C ６ It is alkyl; X ４ is N or CR １５ And; R １５ is H or C １ ~C ６ It is alkyl; X ５ and X ６ Each is independently N or CH; and structure: 【Chemistry 4】 It is either a single bond or a double bond; Here, one or more hydrogen atoms in the compound may be appropriately substituted with deuterium.

3. X １ CH is, X ２ Is N; or X １ N is X ２ CH is A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

4. X １ and X ２ Each of these is N, A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

5. R １ａ and R １ｂ However, each is independently H, halo, or C. １ ~C ３ It is alkyl. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

6. R ２ａ and R ２ｂ However, H and C are independent of each other. １ ~C ３ Alkyl, -OH, halo, or C １ ~C ３ Is it an alkyl-OH group? Alternatively, R ２ａ and R ２ｂ However, together with the carbon atoms to which they are bonded, spiro C ３ ~C ４ Forms a cycloalkyl group, Alternatively, R ２ａ and R ２ｂ However, together they form an oxo. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

7. R ３ａ and R ３ｂ However, each is independently H, halo, or C. １ ~C ３ It is alkyl. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

8. R ４ａ and R ４ｂ However, each is independently H, halo, or C. １ ~C ３ Is it alkyl? Alternatively, R ４ａ and R ４ｂ However, together with the carbon atoms to which they are bonded, spiro C ３ ~C ４ Forms a cycloalkyl group, The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

9. R ５ａ and R ５ｂ However, each is independently H, halo, or C. １ ~C ３ It is alkyl. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

10. structure: 【Transformation 5】 However, the structure: 【Transformation 6】 The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

11. R １１ However, H, C １ ~C ３ Alkyl, -(C １ ~C ３ Alkilen)-(6-membered heterocycline),-(C) １ ~C ３ Alkylene)-O(C) １ ~C ３ Alkyl), C １ ~C ５ Haloalkyl, C １ ~C ５ Alkyl-OH, or -(C １ ~C ３ Alkylene)-NH(C) １ ~C ３ It is alkyl, Here, the heterocyclyl contains one or two heteroatoms selected from N and O. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

12. structure: 【Transformation 7】 However, the structure: 【Transformation 8】 The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

13. structure: 【Chemistry 9】 However, the structure: 【Chemistry 10】 The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

14. structure: 【Chemistry 11】 However, the structure: 【Chemistry 12】 The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

15. Formula (II): 【Chemistry 13】 Formula (III): 【Chemistry 14】 Or formula (IV): 【Chemistry 15】 A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

16. Formula (IIIb): 【Chemistry 16】 The compound according to claim 15, or a pharmaceutically acceptable salt thereof.

17. A compound selected from the following, or a pharmaceutically acceptable salt thereof. Table 1 Table 2 Table 3 Table 4 Table 5 Table 6 Table 7 Table 8 Table 9 Table 10 Table 11 Table 12 Table 13 Table 14 Table 15 Table 16 Table 17 Table 18 Table 19 Table 20 Table 21 Table 22 Table 23 Table 24

18. A pharmaceutical composition comprising a compound according to any one of claims 1, 2, and 17, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

19. The pharmaceutical composition according to claim 18 for degrading B-cell lymphoma 6 protein (BCL6).

20. The pharmaceutical composition according to claim 18 for treating cancer or autoimmune disease in a subject requiring treatment.

21. Compounds of the following formula, or pharmaceutically acceptable salts thereof. 【Chemistry 17】

22. A pharmaceutical composition comprising the compound described in claim 21, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

23. The pharmaceutical composition according to claim 22 for treating non-Hodgkin lymphoma in a patient requiring treatment.

24. The pharmaceutical composition according to claim 22 for treating diffuse large B-cell lymphoma in a patient requiring treatment.

25. The pharmaceutical composition according to claim 22 for treating follicular lymphoma in a subject requiring treatment.

26. The compound according to claim 21, represented by the following formula. [Chemistry 18]

27. A pharmaceutical composition comprising the compound described in claim 26 and a pharmaceutically acceptable excipient.

28. The pharmaceutical composition according to claim 27 for treating non-Hodgkin lymphoma in a patient requiring treatment.

29. The pharmaceutical composition according to claim 27 for treating diffuse large B-cell lymphoma in a patient requiring treatment.

30. The pharmaceutical composition according to claim 27 for treating follicular lymphoma in a patient requiring treatment.

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