Heterocyclic compounds as BCL6 modulators for use as ligand-directed degradation agents

Abstract

Provided herein are compounds and compositions thereof for modulating BCL6. In some embodiments, compounds and compositions for the treatment of cancer or autoimmune diseases are provided. # imgabs0 #

Description

Cross-reference to related applications

[0001] This application claims priority to U.S. Provisional Application No. 63 / 336,104, filed April 28, 2022, which is incorporated herein by reference in its entirety for any purpose. Technical Field

[0002] The present invention generally relates to compounds, compositions and methods for their preparation, as well as the use of the compounds and compositions for treating cancer or autoimmune diseases. Background Art

[0003] BCL6 (B cell lymphoma 6) is a member of the BTB / POZ-zinc finger family, which contains the zinc fingers at N-terminal BTB / POZ domains and C-terminal. As the transcription factor of T follicular helper (Tfh) cells, BCL6 is formed by the germinal center (GC) of primary B cells and is therefore required for antibody affinity maturation. Initially, it was found that BCL6 is an oncogene in diffuse large B cell lymphoma (DLBCL) and its effect has been related to various types of diseases, including B-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). N-terminal BTB / POZ domains are incorporated into and raise co-repressor molecules, such as SMRT, NCOR1 and BCOR, so as to form class I and class II histone deacetylase complexes, and C-terminal zinc fingers are incorporated into specific DNA recognition sequences (Yang et al., Cell Dev. Biol. 2019, 7, 272). After binding to and forming a complex with its target genes, BCL6 reduces the RNA expression of its target genes, including several important tumor suppressors. Overexpression of BCL6, which is common in malignancies such as non-Hodgkin's lymphoma (NHL), leads to ectopic inhibition of cell cycle and DNA repair checkpoint proteins, resulting in unrestrained cell proliferation and tumorigenesis.

[0004] It is known that GC reaction can cause the generation of pathogenic autoantibodies to increase, thereby causing several diseases, indicating that the method for suppressing or degrading BCL6 has potential therapeutic applicability.The structural characterization of the co-crystal structure of BCL6 BTB / POZ domains and co-inhibitors shows that it is combined to occur at the lateral groove formed by the interface between BCL6 BTB / POZ homodimers (Melnick et al., Mol.Cell Biol.2002,22,1804-1818;Ghetu et al., Mol.Cell.2008,29,384-391).Thereafter, the specific ligands for being incorporated into this position have been studied, and it is intended to make BCL6 become the target that can be targeted by drugs using the binding affinity for lateral grooves.

[0005] Protein degradation is a highly regulated and essential process for maintaining cellular homeostasis. Selective identification and removal of damaged, misfolded or excess proteins is achieved via the ubiquitin-proteasome pathway (UPP). The UPP is important for the regulation of almost all cellular processes. Ubiquitination of proteins is achieved by E3 ubiquitin ligases, which bind to proteins and add ubiquitin molecules to them, thereby marking them for proteasomal degradation.

[0006] The use of UPP for therapeutic purposes has received widespread attention (Zhou et al., Mol. Cell 2000, 6, 751-756). A promising therapy uses proteolytic targeting chimeras, commonly referred to as PROTAC, to achieve the removal of unwanted proteins by protein degradation (Scheepstra et al., Comp. Struct. Biotech. J. 2019, 17, 160-176). PROTAC is a ligand-guided degradation agent that brings together E3 ligases and target proteins to be degraded. These bivalent molecules are generally composed of E3 ligase ligands that are connected to small molecules bound to target proteins via a linker moiety. PROTAC arranges E3 ligases for target proteins at appropriate distances and orientations, thereby ubiquitinating the target protein. The ubiquitinated target protein is then recognized by the proteasome and degraded.

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

[0008] In certain embodiments, compounds and compositions thereof are described herein for modulating BCL6. In various embodiments, the compounds and compositions thereof can be used to treat cancer.

[0009]

[0046] Embodiments of the present invention may be more fully understood by reference to the detailed description and examples, which are intended to illustrate non-limiting embodiments.

[0010] Embodiment 1. A compound of formula (IA): A pharmaceutically acceptable salt thereof, wherein: X 1 and X 2 Each independently is N or CH, subject to the condition that X 1 and X 2 At least one of is N; R 1a and R 1b Each is independently H, halogen or C1-C6 alkyl; R 2a and R 2b are each independently H, C1-C6 alkyl, -O(C1-C6 alkyl), -OH, halogen, C1-C6 haloalkyl or C1-C6 alkyl-OH, or R 2a and R 2b Together with the carbon atom to which it is attached, it forms a spiro C3-C5 cycloalkyl group, or R 2a and R 2b Together they form oxygen; or R 1a and R 2a Together they form a bridged C2-C3 alkylene group; R 3a and R 3b Each is independently H, halogen or C1-C6 alkyl; R 4a and R 4b are each independently H, halogen or C1-C6 alkyl, or R 4a and R 4b Together with the carbon atom to which it is attached, it forms a spiro C3-C5 cycloalkyl group; R 5a and R 5b Each is independently H, halogen 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, with the constraint that x and y are not both 1; R 8 is Cl or -CN; R 9 is F; X 3 N or CH; z is 0 or 1; R 10a and R 10b are each independently H or halogen; 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 the heterocyclyl contains 1-3 heteroatoms selected from N, O, and S; R 12 is H, halogen or C1-C6 alkyl; R 13 is H or halogen; R 14 is H or C1-C6 alkyl; X 4 N or CR 15 ; R 15 is H or C1-C6 alkyl; X 5 and X 6 are each independently N or CH; and is a single bond or a double bond; wherein one or more hydrogen atoms in the compound are optionally replaced by deuterium.

[0011] Embodiment 2. The compound of embodiment 1 or a pharmaceutically acceptable salt thereof, wherein the compound has formula (I): in: X 1 and X 2 Each independently is N or CH, subject to the condition that X 1 and X 2 At least one of is N; R 1a and R 1b Each is independently H, halogen or C1-C6 alkyl; R 2a and R 2b are each independently H, C1-C6 alkyl, -OH, halogen or C1-C6 alkyl-OH, or R 2a and R 2b Together with the carbon atom to which it is attached, it forms a spiro C3-C5 cycloalkyl group, or R 2a and R 2b Together they form oxygen; or R1a and R 2a Together they form a bridged C2-C3 alkylene group; R 3a and R 3b Each is independently H, halogen or C1-C6 alkyl; R 4a and R 4b are each independently H, halogen or C1-C6 alkyl, or R 4a and R 4b Together with the carbon atom to which it is attached, it forms a spiro C3-C5 cycloalkyl group; R 5a and R 5b Each is independently H, halogen 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, with the constraint that x and y are not both 1; R 8 is Cl or -CN; R 9 is F; X 3 N or CH; z is 0 or 1; R 10a and R 10b are each independently H or halogen; 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 the heterocyclyl contains 1-3 heteroatoms selected from N, O, and S; R 12 is H, halogen or C1-C6 alkyl; R 13 is H or halogen; R 14 is H or C1-C6 alkyl; X 4 N or CR 15 ; R 15 is H or C1-C6 alkyl; X 5 and X 6 are each independently N or CH; and is a single bond or a double bond; wherein one or more hydrogen atoms in the compound are optionally replaced by deuterium.

[0012] Embodiment 3. The compound of embodiment 1 or 2 or a pharmaceutically acceptable salt thereof, wherein: X 1 is CH and X 2 N; or X 1 N and X 2 For CH.

[0013] Embodiment 4. The compound of embodiment 1 or 2 or a pharmaceutically acceptable salt thereof, wherein: X 1 and X 2 Each is N.

[0014] Embodiment 5. The compound according to any one of Embodiments 1-4 or a pharmaceutically acceptable salt thereof, wherein: R 1a and R 1b Each is independently H, halogen or C1-C3 alkyl.

[0015] Embodiment 6. The compound according to any one of Embodiments 1-5 or a pharmaceutically acceptable salt thereof, wherein: R 2a and R 2b are each independently H, C1-C3 alkyl, -OH, halogen or C1-C3 alkyl-OH, or R 2a and R 2b Together with the carbon atom to which it is attached, it forms a spiro C3-C4 cycloalkyl group, or R 2a and R 2b Together they form an oxo group.

[0016] Embodiment 7. The compound according to any one of Embodiments 1-6 or a pharmaceutically acceptable salt thereof, wherein: R 3a and R 3b Each is independently H, halogen or C1-C3 alkyl.

[0017] Embodiment 8. The compound according to any one of Embodiments 1-7 or a pharmaceutically acceptable salt thereof, wherein: R 4a and R 4b are each independently H, halogen or C1-C3 alkyl, or R 4a and R 4b Together with the carbon atom to which it is attached, it forms a spiro C3-C4 cycloalkyl.

[0018] Embodiment 9. The compound of embodiment 8 or a pharmaceutically acceptable salt thereof, wherein: R 5a and R 5b Each is independently H, halogen or C1-C3 alkyl.

[0019] Embodiment 10. The compound according to any one of embodiments 1-9 or a pharmaceutically acceptable salt thereof, wherein for:

[0020] Embodiment 11. The compound according to any one of Embodiments 1-10, or a pharmaceutically acceptable salt thereof, wherein: 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 the heterocyclyl contains 1-2 heteroatoms selected from N and O.

[0021] Embodiment 12. A compound according to any one of embodiments 1-11 or a pharmaceutically acceptable salt thereof, wherein for:

[0022] Embodiment 13. A compound according to any one of technical solutions 1-12 or a pharmaceutically acceptable salt thereof, wherein for:

[0023] Embodiment 14. A compound according to any one of embodiments 1 to 13, or a pharmaceutically acceptable salt thereof, wherein for:

[0024] Embodiment 15. The compound of any one of Embodiments 1-14, or a pharmaceutically acceptable salt thereof, wherein the compound has formula (II), (III) or (IV):

[0025] Embodiment 16. The compound of embodiment 15 or a pharmaceutically acceptable salt thereof, wherein the compound has formula (IIIb):

[0026] Embodiment 17. A compound and a pharmaceutically acceptable salt thereof, wherein the compound is selected from the compounds in Table 1.

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

[0028] Embodiment 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 1-17 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 18.

[0029] Embodiment 20. A method for 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 1-17 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to embodiment 18. DETAILED DESCRIPTION definition

[0030] As used herein, the terms "comprising" and "including" are used interchangeably. The terms "comprising" and "including" should be interpreted as specifying the presence of the stated features or components mentioned, but do not exclude the presence or addition of one or more features or components or groups thereof. In addition, the terms "comprising" and "including" are intended to include embodiments encompassed by the term "consisting of." Therefore, the term "consisting of" can be used in place of the terms "comprising" and "including" to provide more specific embodiments of the present invention.

[0031] The term "consisting of" means that the object has at least 90%, 95%, 97%, 98% or 99% of the stated features or components that constitute it. In another embodiment, the term "consisting of" excludes any other features or components from any subsequent list, except for features or components 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 any one or any combination. Thus, "A, B, or C" means any one of the following: "A; B; C; A and B; A and C; B and C; A, B, and C." An exception to this definition would occur only if a combination of elements, functions, steps, or actions are inherently mutually exclusive in some way.

[0033] In this specification, unless otherwise indicated, any concentration range, percentage range, ratio range, or integer range should be understood to include any integer within the recited range and, where appropriate, fractions thereof (such as tenths and hundredths of an integer). Furthermore, unless otherwise indicated, any numerical range recited herein relating to any physical characteristic, such as polymer subunits, size, or thickness, should be understood to include any integer within the recited 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 a -NH2 group.

[0035] "Cyano" refers to a -CN group.

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

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

[0038] "Oxo" refers to a =0 group.

[0039] "Thio" refers to a =S group.

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

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

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

[0043] "Alkyl" refers to a straight or branched hydrocarbon chain group consisting solely of carbon and hydrogen atoms, containing no unsaturation, and having from one to fifteen carbon atoms (e.g., C1-C 15 In certain embodiments, an alkyl group contains from one to thirteen carbon atoms (e.g., C1-C 13 In certain embodiments, the alkyl group comprises one to eight carbon atoms (e.g., C1-C8 alkyl). In other embodiments, the alkyl group comprises one to five carbon atoms (e.g., C1-C5 alkyl). In other embodiments, the alkyl group comprises one to four carbon atoms (e.g., C1-C4 alkyl). In other embodiments, the alkyl group comprises one to three carbon atoms (e.g., C1-C3 alkyl). In other embodiments, the alkyl group comprises one to two carbon atoms (e.g., C1-C2 alkyl). In other embodiments, the alkyl group comprises one carbon atom (e.g., C1 alkyl). In other embodiments, the alkyl group comprises five to fifteen carbon atoms (e.g., C5-C 15In other embodiments, the alkyl group comprises five to eight carbon atoms (e.g., C5-C8 alkyl). In other embodiments, the alkyl group comprises two to five carbon atoms (e.g., C2-C5 alkyl). In other embodiments, the alkyl group comprises three to five carbon atoms (e.g., C3-C5 alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (isopropyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (tert-butyl) and 1-pentyl (n-pentyl). The alkyl group is connected to the rest of the molecule by a single bond. Unless otherwise specifically stated in this specification, the alkyl group is optionally substituted with one or more of the following substituents: halogen, cyano, nitro, oxo, thioxo, imino, oxime, trimethylsilyl, -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 each R a and R is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0044] "Alkyl-OH" refers to an unbranched or branched alkyl group as defined above in which one or more hydrogen atoms are replaced by -OH. For example, "C1-C6 alkyl-OH" refers to a C1-C6 alkyl group substituted with one or more -OH groups. An alkyl-OH group may contain multiple hydroxyl groups attached to the same carbon atom or to multiple carbon atoms.

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

[0046] "Alkenyl" refers to a straight or branched hydrocarbon chain group consisting only of carbon atoms and hydrogen atoms, containing at least one carbon-carbon double bond and having two to twelve carbon atoms. In certain embodiments, alkenyl comprises two to eight carbon atoms. In other embodiments, alkenyl comprises two to four carbon atoms. Alkenyl is connected to the rest of the molecule by a single bond, such as ethenyl (i.e., vinyl (vinyl)), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, etc. Unless otherwise specifically stated in this specification, alkenyl is optionally substituted with one or more of the following substituents: halogen, cyano, nitro, oxo, thio, imino, oximino, trimethylsilyl, -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 each R aand R is 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 hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, and having two to twelve carbon atoms. In certain embodiments, the alkynyl group comprises two to eight carbon atoms. In other embodiments, the alkynyl group has two to four carbon atoms. The alkynyl group is connected to the rest of the molecule via a single bond, such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. Unless otherwise specifically stated in this specification, the alkynyl group is optionally substituted with one or more of the following substituents: halogen, cyano, nitro, oxo, thio, imino, oximino, trimethylsilyl, -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 each R aand R is 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 that connects the rest of the molecule to a group, consists only of carbon and hydrogen, contains no unsaturation and has one to twelve carbon atoms, such as methylene, ethylene, propylene, n-butylene, etc. The alkylene chain is connected to the rest of the molecule via a single bond and is connected to the group via a single bond. The point of attachment of the alkylene chain to the rest of the molecule and the group can be achieved via one carbon in the alkylene chain or via any two carbons in the chain. In certain embodiments, the alkylene group comprises one to eight carbon atoms (e.g., C1-C8 alkylene). In other embodiments, the alkylene group comprises one to five carbon atoms (e.g., C1-C5 alkylene). In other embodiments, the alkylene group comprises one to four carbon atoms (e.g., C1-C4 alkylene). In other embodiments, the alkylene group comprises one to three carbon atoms (e.g., C1-C3 alkylene). In other embodiments, the alkylene group comprises one to two carbon atoms (e.g., C1-C2 alkylene). In other embodiments, the alkylene group comprises one carbon atom (e.g., C1 alkylene). In other embodiments, the alkylene group comprises five to eight carbon atoms (e.g., C5-C8 alkylene). In other embodiments, the alkylene group comprises two to five carbon atoms (e.g., C2-C5 alkylene). In other embodiments, the alkylene group comprises three to five carbon atoms (e.g., C3-C5 alkylene). Unless otherwise specifically stated in this specification, the alkylene chain is optionally substituted with one or more of the following substituents: halogen, cyano, nitro, oxo, thioxo, imino, oxime, trimethylsilyl, -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(Ra )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 each R a and R is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0049] "Aryl" refers to a radical derived from an aromatic monocyclic or polycyclic hydrocarbon ring system by removing hydrogen atoms from ring carbon atoms. The aromatic monocyclic or polycyclic hydrocarbon ring system contains only hydrogen and carbon (five to eighteen carbon atoms), wherein at least one ring in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) π electron system according to Hückel theory. Ring systems from which aryl groups are derived include, but are not limited to, radicals such as benzene, fluorene, indane, indene, tetrahydronaphthalene, and naphthalene. Unless otherwise specifically stated in the specification, the term "aryl" or the prefix "ar" (such as in "aralkyl") is intended to include aryl groups that are optionally substituted with one or more substituents independently selected from alkyl, alkenyl, alkynyl, halogen, 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 、-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 each R a R is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl) or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), each R b are independently a direct bond or a straight or branched alkylene or alkenylene chain, and R c is a straight or branched alkylene or alkenylene chain, and wherein each of the above substituents is unsubstituted unless otherwise indicated.

[0050] "Aralkyl" refers to a group of the formula -R c-aryl groups, where R c is an alkylene chain as defined above, for example, 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 group.

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

[0052] "Arylalkynyl" refers to a group of the formula -R e -aryl groups, where R e is an alkynylene chain as defined above. The aryl portion of the aralkynyl group is optionally substituted as described above for an aryl group. The alkynylene chain portion of the aralkynyl group is optionally substituted as defined above for an alkynylene chain.

[0053] "Carbocyclyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting only of carbon atoms and hydrogen atoms, including fused or bridged ring systems, and having three to fifteen carbon atoms. In certain embodiments, the carbocyclyl comprises three to ten carbon atoms. In other embodiments, the carbocyclyl comprises five to seven carbon atoms. The carbocyclyl is connected to the rest of the molecule via a single bond. The carbocyclyl can be saturated (i.e., containing only a single C-C bond) or unsaturated (i.e., containing one or more double or triple bonds). Fully saturated carbocyclyls are also referred to as "cycloalkyls." 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, etc. Unless otherwise specifically stated in the specification, the term "carbocyclyl" is meant to include carbocyclyl groups that are optionally substituted with one or more substituents independently selected from alkyl, alkenyl, alkynyl, halogen, 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)Ra 、-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 each R a R is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl) or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), each R b are independently a direct bond or a straight or branched alkylene or alkenylene chain, and R c is a straight or branched alkylene or alkenylene chain, and wherein each of the above substituents is unsubstituted unless otherwise indicated.

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

[0055] "Carbonyl" refers to a group of the formula -C(O)R 10 R 20 A group in which R 10 and R 20 Independently selected from -OH, halogen, cyano, nitro, oxo, thio, imino, oxime, trimethylsilyl, -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 each R a and R is 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 halogens as defined above, for example, trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc. In some embodiments, a haloalkyl group has one to six carbon atoms and is substituted with one or more halogens (C1-C6 haloalkyl), or a haloalkyl group has one to five carbon atoms and is substituted with one or more halogens (C1-C5 haloalkyl), or a haloalkyl group has one to three carbon atoms and is substituted with one or more halogens (C1-C3 haloalkyl). The halogens may all be the same, or the halogens may be different. Unless specifically stated otherwise, a haloalkyl group is optionally substituted.

[0058] "Fluoroalkyl" refers to an alkyl group as defined above substituted with one or more fluorine groups as defined above, for example, 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 radical comprising two to twelve carbon atoms and one to six heteroatoms selected from nitrogen, oxygen, and sulfur. Unless otherwise specifically stated in this specification, a heterocyclyl is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems. The heteroatoms in the heterocyclyl may optionally be oxidized. One or more nitrogen atoms, if present, may optionally be quaternized. The heterocyclyl may be partially or fully saturated. The heterocyclyl may be attached to the remainder of the molecule via any atom in the ring. Examples of such heterocyclic groups include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thimorpholinyl, 1-oxothiomorpholinyl, and 1,1-dioxothiomorpholinyl. Unless otherwise specifically stated in the specification, the term "heterocyclyl" is meant to include heterocyclyl groups as defined above that are optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, 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 、-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 -ORc -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 each R a R is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl) or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), each R b are independently a direct bond or a straight or branched alkylene or alkenylene chain, and R c is a straight or branched alkylene or alkenylene chain, and wherein each of the above substituents is unsubstituted unless otherwise indicated.

[0060] "N-heterocyclyl" or "N-attached heterocyclyl" refers to a heterocyclyl as defined above that contains at least one nitrogen and wherein the point of attachment of the heterocyclyl to the rest of the molecule is through a nitrogen atom in the heterocyclyl. 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-attached heterocyclyl" refers to a heterocyclyl as defined above that contains at least one heteroatom and wherein the point of attachment of the heterocyclyl to the rest of the molecule is through a carbon atom in the heterocyclyl. 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-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2-piperazinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, and the like.

[0062] "Heterocyclylalkyl" refers to a group of the formula -R c -heterocyclic group, wherein R c is an alkylene chain as defined above. If the heterocyclyl group is a nitrogen-containing heterocyclyl group, the heterocyclyl group is optionally attached to the alkyl group at the nitrogen atom. The alkylene chain of the heterocyclylalkyl group 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" refers to a group of the formula -OR c - a heterocyclic group bonded via an oxygen atom, wherein R c is an alkylene chain as defined above. If the heterocyclyl group is a nitrogen-containing heterocyclyl group, the heterocyclyl group 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 two to seventeen carbon atoms and one to six 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 in the ring system is fully unsaturated, i.e., it contains a cyclic, nonlocalized (4n+2)π electron system according to the Huckel theory. Heteroaryl groups include fused or bridged ring systems. The heteroatoms in the heteroaryl group are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl group is attached to the rest of the molecule via any atom in the ring. Examples of heteroaryl groups include, but are not limited to, aza benzo[b][1,4]dioxolyl, benzofuranyl, benzoxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxolyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyrone, benzofuranyl, benzofuranone, benzothiophenyl (benzothienyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnozinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnozinyl, 6,7-dihydro-5 H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furano[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocyclooctano[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocyclooctano[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocyclooctano[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolyl, isoquinolinyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-dihydroquinazolinyl, naphthyridinyl, 1,6-naphthyridonyl, oxadiazolyl, 2-oxoazepine yl, 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, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5-[[(4-d]-1-methyl-2-oxazol-1-yl)-1H-pyrrolyl]-1H-pyrrolyl]-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5-[[(4-d]-1-methyl-2-oxazol-1-yl)-1H-pyrrolyl]-1H-pyrrolyl, , 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]pyridinyl and thienyl (i.e., thienyl). Unless otherwise specifically stated in the specification, the term "heteroaryl" is meant to include heteroaryl groups as defined above that are optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, 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)Ra 、-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 each R a R is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl) or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), each R b are independently a direct bond or a straight or branched alkylene or alkenylene chain, and R c is a straight or branched alkylene or alkenylene chain, and wherein each of the above substituents is unsubstituted unless otherwise indicated.

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

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

[0067] "Heteroarylalkyl" refers to a group of the formula -R c -heteroaryl groups, wherein R c is an alkylene chain as defined above. If the heteroaryl group is a nitrogen-containing heteroaryl group, the heteroaryl group 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" refers to a group of the formula -OR c - a heteroaryl group bonded via an oxygen atom, wherein R c is an alkylene chain as defined above. If the heteroaryl group is a nitrogen-containing heteroaryl group, the heteroaryl group 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]

[00146] Embodiments of the present invention are intended to encompass pharmaceutically acceptable salts, tautomers, isotopologues, and stereoisomers of the compounds provided herein, such as compounds of Formula (I).

[0070] As used herein, the term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic acid or base (including inorganic acids and inorganic bases and organic acids and organic bases). Suitable pharmaceutically acceptable base addition salts of the compound of formula (I) include, but are not limited to, metal salts prepared from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc, or organic salts prepared from lysine, N,N'-diphenylmethylethylenediamine, 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, ethanesulfonic 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, p-aminobenzenesulfonic acid, sulfuric acid, tartaric acid, and p-toluenesulfonic acid. Specific non-toxic acids include hydrochloric acid, hydrobromic acid, maleic acid, phosphoric acid, sulfuric acid, and methanesulfonic acid. Therefore, examples of specific salts include hydrochloride, formate, and mesylate. Other salts are well known in the art, see, for example, Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton PA (1990) or Remington: The Science and Practice of Pharmacy, 19th ed., Mack Publishing, Easton PA (1995).

[0071] As used herein and unless otherwise indicated, the term "stereoisomer" or "stereomerically pure" means one stereoisomer of a particular compound that is substantially free of other stereoisomers of the compound. For example, a stereoisomerically pure compound having one chiral center is substantially free of the enantiomer of the compound. A stereoisomerically pure compound having two chiral centers will be substantially free of other diastereomers of the compound. A typical stereoisomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of other stereoisomers of the compound, greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of other stereoisomers of the compound, or greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of 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 such isomeric forms are included within the embodiments disclosed herein, including mixtures thereof.

[0072] The embodiments disclosed herein encompass the use of stereoisomerically pure forms of the compounds disclosed herein as well as the use of mixtures of these forms. For example, mixtures comprising equal or unequal amounts of enantiomers of a particular compound can be used in the methods and compositions disclosed herein. These isomers can be asymmetric 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, EL, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SH, Tables of Resolving Agents and Optical Resolutions, page 268 (ed. EL Eliel, Univ. of Notre Dame Press, Notre Dame, IN, 1972); Todd, M., SeparationOf Enantiomers: Synthetic Methods (Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2014); Toda, F., Enantiomer Separation: Fundamentals and PracticalMethods (Springer Science&Business Media, 2007); Subramanian, G. Chiral Separation Techniques: A Practical Approach (John Wiley & Sons, 2008); Ahuja, S., Chiral Separation Methods for Pharmaceutical and Biotechnological Products (John Wiley & Sons, 2011).

[0073] "Tautomers" refer to isomeric forms of a compound that are in equilibrium with each other. The concentration of the isomeric forms will depend on the environment in which the compound is present and may vary depending, for example, on whether the compound is a solid or in an organic or aqueous solution. For example, in aqueous solution, pyrazole may exhibit the following isomeric forms, which are referred to as tautomers of each other:

[0074] As those skilled in the art readily appreciate, various functional groups and other structures may exhibit tautomerism, and all tautomers of the compounds of Formula (I) are within the scope of the present invention.

[0075] Polymers or similar infinite structures obtained by defining substituents with infinitely additional other substituents (e.g., a substituted aryl with a substituted alkyl, which is itself substituted by a substituted aryl, which is further substituted by a substituted heteroalkyl, etc.) are not intended to be included herein. Similarly, the above definition is not intended to include impermissible substitution patterns (e.g., a methyl substituted with 5 fluorines or a heteroaryl with two adjacent oxygen ring atoms). Such impermissible substitution patterns are well known to those skilled in the art.

[0076] It should also be noted that the compounds disclosed herein may contain unnatural proportions of atomic isotopes at one or more atoms. For example, the compounds may be radiolabeled with a radioactive isotope, such as tritium ( 3 H), iodine-125 ( 125 I), sulfur-35( 35 S) or carbon-14 ( 14 C), or may be isotopically enriched, such as with deuterium ( 2 H), carbon-13 ( 13 C) or nitrogen-15( 15 N) enrichment. As used herein, an "isotopologue" is an isotopically enriched compound. The term "isotopically enriched" means that an atom has an isotopic composition other than the natural isotopic composition of the atom. "Isotopically enriched" may also refer to at least one atom in a compound having an isotopic composition other than the natural isotopic composition of the atom. The term "isotopic composition" refers to the amount of each isotope present of a given atom. Radiolabeled and isotopically enriched compounds are useful as therapeutic agents (e.g., cancer therapeutics), research reagents (e.g., binding assay reagents), and diagnostic agents (e.g., in vivo imaging agents). Regardless of whether they are radioactive or not, all isotopic variants of the compounds described herein are intended to be within the scope of the embodiments provided herein. In some embodiments, isotopologues of the compounds disclosed herein are provided, for example, the isotopologues are compounds enriched with deuterium, carbon 13, and / or nitrogen 15. As used herein, "deuterated" means that at least one hydrogen (H) has been replaced by a deuterium (e.g., by a D or 2 H indicates a)-substituted compound, ie, the compound is deuterium-enriched at at least one position.

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

[0078] It will be understood that, regardless of stereoisomerism or isotopic composition, each compound disclosed herein can be provided in the form of any pharmaceutically acceptable salt discussed herein. Likewise, it will be understood that the isotopic composition can vary independently of the stereoisomerism of each compound mentioned herein. Furthermore, while limited by the elements present in each compound disclosed herein or its salt, the isotopic composition can vary independently of the choice of pharmaceutically acceptable salt of each compound.

[0079] It should be noted that if there is an inconsistency between a depicted structure and the name of that structure, the depicted structure is given greater consideration.

[0080] As used herein, "treating" means the complete or partial relief of a disorder, disease or condition or one or more symptoms associated with the disorder, disease or condition, or the slowing or arresting of further development or worsening of these symptoms, or the alleviation or eradication of the cause of the disorder, disease or condition itself. In one embodiment, the disorder is cancer or a symptom thereof as described herein.

[0081] As used herein, "prevention" means a method for delaying and / or preventing the complete or partial onset, recurrence, or spread of a disorder, disease, or condition; preventing a subject from developing a disorder, disease, or condition; or reducing the risk of a subject developing 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 connection with the compounds disclosed herein means an amount capable of treating or preventing a disorder, disease or condition disclosed herein, or a symptom thereof.

[0083] As used herein, the term "subject" or "patient" includes animals, including but not limited to animals such as cows, monkeys, horses, sheep, pigs, chickens, turkeys, quail, cats, dogs, mice, rats, rabbits, or guinea pigs, in one embodiment mammals, in another embodiment humans. In one embodiment, the subject is a human who suffers from a BCL6-mediated disease or its symptoms or is at risk of suffering from a BCL6-mediated disease or its symptoms.

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

[0085] In one aspect, provided herein is a compound of Formula (IA): or a pharmaceutically acceptable salt thereof, wherein: X 1 and X 2 Each independently is N or CH, subject to the condition that X 1 and X 2 At least one of is N; R 1a and R 1b Each is independently H, halogen or C1-C6 alkyl; R 2a and R 2b are each independently H, C1-C6 alkyl, -O(C1-C6 alkyl), -OH, halogen, C1-C6 haloalkyl or C1-C6 alkyl-OH, or R 2a and R 2b Together with the carbon atom to which it is attached, it forms a spiro C3-C5 cycloalkyl group, or R 2a and R 2b Together they form oxygen; or R 1a and R 2a Together they form a bridged C2-C3 alkylene group; R 3a and R 3b Each is independently H, halogen or C1-C6 alkyl; R 4a and R 4b are each independently H, halogen or C1-C6 alkyl, or R 4a and R 4bTogether with the carbon atom to which it is attached, it forms a spiro C3-C5 cycloalkyl group; R 5a and R 5b Each is independently H, halogen 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, with the constraint that x and y are not both 1; R 8 is Cl or -CN; R 9 is F; X 3 N or CH; z is 0 or 1; R 10a and R 10b are each independently H or halogen; 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 the heterocyclyl contains 1-3 heteroatoms selected from N, O, and S; R 12 is H, halogen or C1-C6 alkyl; R 13 is H or halogen; R 14 is H or C1-C6 alkyl; X 4 N or CR 15 ; R 15 is H or C1-C6 alkyl; X 5 and X 6 are each independently N or CH; and is a single bond or a double bond; wherein one or more hydrogen atoms in the compound are optionally replaced by deuterium.

[0086] In another aspect, provided herein are compounds of formula (I): or a pharmaceutically acceptable salt thereof, wherein: X 1 and X 2Each independently is N or CH, subject to the condition that X 1 and X 2 At least one of is N; R 1a and R 1b Each is independently H, halogen or C1-C6 alkyl; R 2a and R 2b are each independently H, C1-C6 alkyl, -OH, halogen or C1-C6 alkyl-OH, or R 2a and R 2b Together with the carbon atom to which it is attached, it forms a spiro C3-C5 cycloalkyl group, or R 2a and R 2b Together they form oxygen; or R 1a and R 2a Together they form a bridged C2-C3 alkylene group; R 3a and R 3b Each is independently H, halogen or C1-C6 alkyl; R 4a and R 4b are each independently H, halogen or C1-C6 alkyl, or R 4a and R 4b Together with the carbon atom to which it is attached, it forms a spiro C3-C5 cycloalkyl group; R 5a and R 5b Each is independently H, halogen 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, with the constraint that x and y are not both 1; R 8 is Cl or -CN; R 9 is F; X 3 N or CH; z is 0 or 1; R 10a and R 10b are each independently H or halogen; R 11is 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 the heterocyclyl contains 1-3 heteroatoms selected from N, O, and S; R 12 is H, halogen or C1-C6 alkyl; R 13 is H or halogen; R 14 is H or C1-C6 alkyl; X 4 N or CR 15 ; R 15 is H or C1-C6 alkyl; X 5 and X 6 are each independently N or CH; and is a single bond or a double bond; wherein one or more hydrogen atoms in the compound are optionally replaced by deuterium.

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

[0088] In some embodiments, R 1a is H, halogen or C1-C6 alkyl. In some embodiments, R 1a is H, halogen 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 For H.

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

[0091] In some embodiments, R 1aIn some embodiments, R 1a In some embodiments, R 1a is methyl, ethyl or propyl. In some embodiments, R 1a It is a methyl group.

[0092] In some embodiments, R 1b is H, halogen or C1-C6 alkyl. In some embodiments, R 1b is H, halogen 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 For H.

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

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

[0096] In some embodiments, R 1b In some embodiments, R 1b In some embodiments, R 1b is methyl, ethyl or propyl. In some embodiments, R 1b It is a methyl group.

[0097] In some embodiments, R 2a is H, C1-C6 alkyl, -O(C1-C6 alkyl), -OH, halogen, 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. In some embodiments, R2a It 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 For H.

[0099] In some embodiments, R 2a In some embodiments, R 2a In some embodiments, R 2a is methyl, ethyl or propyl. In some embodiments, R 2a It is a methyl group.

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

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

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

[0103] In some embodiments, R 2a is C1-C6 haloalkyl. 2a is a C1-C6 haloalkyl group containing 1 to 13 halogen atoms. 2a is C1-C3 haloalkyl. 2a is a C1-C3 haloalkyl group containing 1-7 halogen atoms. 2a In some embodiments, R 2a It is -CF3.

[0104] In some embodiments, R 2a In some embodiments, R 2a In some embodiments, R 2a is -CH2OH, -(CH2CH2)OH or -(CH2CH2CH2)OH. In some embodiments, R 2a It is -CH2OH.

[0105] In some embodiments, R 2b is H, C1-C6 alkyl, -OH, halogen or C1-C6 alkyl-OH. 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 For H.

[0107] In some embodiments, R 2b In some embodiments, R 2b In some embodiments, R 2b is methyl, ethyl or propyl. In some embodiments, R 2b It is a methyl group.

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

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

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

[0111] In some embodiments, R 2bis C1-C6 haloalkyl. 2b is a C1-C6 haloalkyl group containing 1 to 13 halogen atoms. 2b is C1-C3 haloalkyl. 2b is a C1-C3 haloalkyl group containing 1-7 halogen atoms. 2b In some embodiments, R 2b It is -CF3.

[0112] In some embodiments, R 2b In some embodiments, R 2b In some embodiments, R 2b is -CH2OH, -(CH2CH2)OH or -(CH2CH2CH2)OH. In some embodiments, R 2b It is -CH2OH.

[0113] In some embodiments, R 2a and R 2b Together with the carbon atom to which it is attached, it forms a spiro C3-C5 cycloalkyl. 2a and R 2b Together with the carbon atom to which it is attached, it forms a spiro C3-C4 cycloalkyl. 2a and R 2b Together with the carbon atom to which it is attached, it forms a spirobutyl group.

[0114] In some embodiments, R 2a and R 2b Together they form an oxo group.

[0115] In some embodiments, R 1a and R 1b 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 they form a bridged C2-C3 alkylene group. 1a and R 2a Together they form a bridged ethylene group.

[0117] In some embodiments, R3a is H, halogen or C1-C6 alkyl. In some embodiments, R 3a is 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 For H.

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

[0120] In some embodiments, R 3a In some embodiments, R 3a In some embodiments, R 3a is methyl, ethyl or propyl. In some embodiments, R 3a It is a methyl group.

[0121] In some embodiments, R 3b is H, halogen 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 For H.

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

[0124] In some embodiments, R 3b In some embodiments, R 3b In some embodiments, R 3b is methyl, ethyl or propyl. In some embodiments, R 3b It is a methyl group.

[0125] In some embodiments, R 4a is H, halogen or C1-C6 alkyl. In some embodiments, R 4ais 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 For H.

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

[0128] In some embodiments, R 4a In some embodiments, R 4a In some embodiments, R 4a is methyl, ethyl or propyl. In some embodiments, R 4a It is a methyl group.

[0129] In some embodiments, R 4b is H, halogen 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 For H.

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

[0132] In some embodiments, R 4b In some embodiments, R 4b In some embodiments, R 4b is methyl, ethyl or propyl. In some embodiments, R 4b It is a methyl group.

[0133] In some embodiments, R 4a and R 4b Together with the carbon atom to which it is attached, it forms a spiro C3-C5 cycloalkyl. 4a and R 4bTogether with the carbon atom to which it is attached, it forms a spiro C3-C4 cycloalkyl. 4a and R 4b Together with the carbon atom to which it is attached, it forms a spirobutyl group.

[0134] In some embodiments, R 3a 、R 3b 、R 4a and R 4b Each is H.

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

[0136] In some embodiments, R 5a is H, halogen or C1-C6 alkyl. In some embodiments, R 5a is 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 For H.

[0138] In some embodiments, R 5b is H, halogen 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 For H.

[0140] In some embodiments, R 5a and R 5b Each is H.

[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, R1a 、R 1b 、R 2a 、R 2b 、R 3a 、R 3b 、R 4a 、R 4b 、R 5a and R 5b One, two or three of them are not H.

[0143] 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 or both of them are not H.

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

[0145] In some embodiments, for:

[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 For H.

[0149] In some embodiments, R 6 In some embodiments, R 6 In some embodiments, R 6 is methyl, ethyl or propyl. In some embodiments, R 6 It is a methyl group.

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

[0151] In some embodiments, x is 0, y is 1 and R6 In some embodiments, x is 0, y is 1 and R 6 In some embodiments, x is 0, y is 1 and R 6 It is a methyl group.

[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 For H.

[0154] In some embodiments, R 7 In some embodiments, R 7 In some embodiments, R 7 is methyl, ethyl or propyl. In some embodiments, R 7 It is a methyl group.

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

[0156] In some embodiments, x is 1, y is 0, and R 7 In some embodiments, x is 1, y is 0 and R 7 In some embodiments, x is 1, y is 0 and R 7 It is a methyl group.

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

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

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

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

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

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

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

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

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

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

[0167] In some embodiments, 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 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- to 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 1-3 heteroatoms selected from N, O, and S. In some embodiments, R 11 is H, C1-C3 alkyl, -(C1-C3 alkylene)-(5- to 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 1-2 heteroatoms selected from N and O. In some embodiments, R 11is H, methyl, ethyl, propyl, -CD3, -(CH2)-(5- to 6-membered heterocyclyl), -(CH2CH2)-(5- to 6-membered heterocyclyl), -(CH2CH2CH2)-(5- to 6-membered heterocyclyl), -CH2OCH3, -CH2OCH2CH3, -CH2OCH2CH2CH3, -CH2CH2OCH3, -CH2CH2OCH2CH3, -CH2CH2OCH2CH3, -CH2CH2OCH3, -CH2CH2OCH2CH3, -CH2CH2CH2OCH3, -CH2CH2CH2OCH2CH3, -CH2CH2CH2OCH2CH3, -(CH2)3CF3, -(CH2)3CHF2, -(CH2)3CH2F, -CH2CF2CH3, -CH2CHFCH3, -CH2CF2CH3, -CH2CH2CF3, - CH2CH2CF2(CH3), -CH2CH2CF(CH3)2, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH2CH2CH(OH)(CH3), -CH2CH2C(OH)(CH3)2, -CH2-N(H)CH3, -CH2-N(H)CH2CH3, -CH2-N(H)CH2CH2CH3, -CH2CH2-N(H)CH3, -CH2CH2-N(H)CH2CH3, -CH2CH2-N(H)CH2CH3, -CH2CH2-N(H)CH2CH3, -CH2CH2-N(H)CH3, -CH2CH2CH2-N(H)CH3, -CH2CH2CH2-N(H)CH2CH3 or -CH2CH2CH2-N(H)CH2CH2CH3, wherein the heterocyclyl contains 1-2 heteroatoms selected from N and O.

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

[0169] In some embodiments, R 11 In some embodiments, R 11 In some embodiments, R 11 is methyl, ethyl, propyl or -CD3. In some embodiments, R 11 In some embodiments, R 11 In some embodiments, R 11 In some embodiments, R 11 In some embodiments, R 11 It is -CH(CH3)2.

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

[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 In some embodiments, R 11 It is -CH2CH2OCH3.

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

[0173] In some embodiments, R 11 In some embodiments, R 11 In some embodiments, R 11is -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH2CH2CH(OH)(CH3) or -CH2CH2C(OH)(CH3)2. In some embodiments, R 11 It is -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 In some embodiments, R 11 It is -CH2CH2N(H)CH3.

[0175] In some embodiments, for:

[0176] In some embodiments, R 12 is H, halogen 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 For H.

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

[0179] In some embodiments, R 12 In some embodiments, R 12 In some embodiments, R 12 is methyl, ethyl or propyl. In some embodiments, R12 It is a methyl group.

[0180] In some embodiments, for:

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

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

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

[0186] In some embodiments, R 14 In some embodiments, R 14 In some embodiments, R 14 is methyl, ethyl or propyl. In some embodiments, R 14 It is a methyl group.

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

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

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

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

[0191] In some embodiments, R 15 In some embodiments, R 15 In some embodiments, R 15 is methyl, ethyl or propyl. In some embodiments, R 15 It is a methyl group.

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

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

[0194] In some embodiments, Is a single bond. In some embodiments, For double bonds.

[0195] In some embodiments, for:

[0196] In some embodiments, the compound of Formula (IA) or Formula (I) is a compound of Formula (II): where 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 is as described for Formula (IA) or Formula (I).

[0197] In some embodiments, the compound of Formula (IA) or Formula (I) is a compound of Formula (IIa): where 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 is as described for Formula (IA) or Formula (I).

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

[0200] In some embodiments, the compound of Formula (IA) or Formula (I) is a compound of Formula (III): where 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 is as described for Formula (IA) or Formula (I).

[0201] In some embodiments, the compound of Formula (IA) or Formula (I) is a compound of Formula (IIIa): where 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 11 、R 12 、R 13 、R14 、R 15 、X 1 、X 2 、X 3 、X 4 、X 5 、X 6 , w, z and is as described for Formula (IA) or Formula (I).

[0202] In some embodiments, the compound of Formula (IA) or Formula (I) is a compound of Formula (IIIb): where 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) is a compound of Formula (IV): where 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 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 is as described for Formula (IA) or Formula (I).

[0204] In some embodiments, the compound of Formula (IA) or Formula (I) is a compound of Formula (IVa): where 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 is as described for Formula (IA) or Formula (I).

[0205] In some embodiments, the compound of Formula (IA) or Formula (I) is a compound of Formula (IVb): where 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) is a compound of Formula (IVc): where 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) is a compound of Formula (IVd): where R 1a 、R 1b 、R 2a 、R 2b 、R 3a 、R 3b 、R 4a and R 4b is as described for Formula (IA) or Formula (I).

[0208] It is understood that any compound described herein may include one or more hydrogen atoms replaced by deuterium. Any one or more of the substituents of Formula (IA) or Formula (I) may be deuterated, such as 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, such as -CD3.

[0209] In the description herein, it is understood that all descriptions, variations, embodiments or aspects of formula (IA) or formula (I) are equally applicable to other chemical formulas described in detail herein and are described in the same manner, as if each description, variation, embodiment or aspect were individually and individually listed. It is also understood that all descriptions, variations, embodiments or aspects of formula (IA) or formula (I) are equally applicable to other chemical formulas described in detail herein and are described in the same manner, as if each description, variation, embodiment or aspect were individually and individually listed for all chemical formulas. For example, all descriptions, variations, embodiments or aspects of formula (IA) or formula (I) are equally applicable to any chemical formula described in detail herein, such as formula (II), (IIa), (IIb), (IIc), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (IVc) and (IVd), and are described in the same manner, as if each description, variation, embodiment or aspect were individually and individually listed for all chemical formulas.

[0210] In some embodiments, a compound or a pharmaceutically acceptable salt thereof is provided that is selected from the compounds in Table 1. Although certain compounds described herein (including in Table 1) are presented as specific stereoisomers 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 the present invention (including in Table 1) are described herein. Table 1. or a pharmaceutically acceptable salt thereof.

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

[0212] The compounds described herein can be prepared using conventional organic synthesis and commercially available starting materials or methods provided herein. As an example and not limitation, compounds of Formula (Ia) to Formula (Ih) can be prepared as outlined in Schemes 1-4 and the Examples described herein. It should be noted that one skilled in the art will know how to modify the procedures described in the illustrative schemes and Examples to obtain the desired products.

[0213] As outlined in Scheme 1, compounds of formula (i-1) containing an oxindole moiety can be synthesized by coupling an indole derivative a with an intermediate compound b to form an intermediate compound c, which is then nitrated to form an intermediate compound d. The nitro group is reduced to form an intermediate compound e, which is then coupled with an intermediate f to form a compound of formula (i-1).

[0214] Scheme 2 provides two pathways for synthesizing compounds of formula (i-2) containing a glutarimide moiety. An indazole derivative g can be coupled with an intermediate compound h to provide an intermediate compound i. Intermediate compound i is deprotected and further reduced to form intermediate compound j, which undergoes deprotection to form a compound of formula (i-2). Alternatively, an indazole derivative g can be coupled with an intermediate compound k to provide an intermediate compound l. Intermediate compound l is deprotected and further reduced to form intermediate compound i, whose amine protecting group is removed to form a compound of formula (i-2).

[0215] Scheme 3 provides the synthesis of compounds of formula (i-2) containing a dihydrouridine moiety. Indazole derivatives n can be coupled with intermediate compounds h to provide intermediate compounds o, which are deprotected to form intermediate compounds p and then 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) (designated as formula (i-2a) to formula (i-2h)) to provide compounds of formula (la) to formula (Ih). How to use

[0217] Embodiments of the present invention provide methods for regulating BCL6 in a subject in need thereof, the methods comprising administering to the subject an effective amount of a compound of Formula (IA) or Formula (I). Regulation (e.g., inhibition or activation) of BCL6 can be assessed and confirmed by various methods known in the art. Kits and commercially available assays can be used to determine whether BCL6 has been regulated (e.g., inhibited or activated) and the extent of regulation.

[0218] In one aspect, provided herein are methods for regulating 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, the 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) modulate 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%, or more. 00%, 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] In certain embodiments of the present invention, methods for degrading BCL6 in a subject in need thereof are also provided, comprising administering to the subject an effective amount of a compound of Formula (IA) or Formula (I). Degradation of BCL6 can be assessed and confirmed by various methods known in the art. Kits and commercially available assays, including cell-based assays, can be used to determine whether BCL6 has been degraded and the extent of degradation.

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

[0222] In some embodiments, the 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 compound of Formula (IA) or Formula (I) degrades BCL6 by about 1-100%, 5-100%, 10-100%, 15-100%, 20-100%, 25-100%, 30-100%, 35-100%, 40-100%, 45-100%, 50-100%, 55-100%, 60-100%, 65-100%, 70-100%, 75-100%, 80-100%, 85-100%, 90-100%, 95-100%, 100-100%, 110-100%, 120-100%, 130-100%, 140-100%, 150-100%, 160-100%, 170-100%, 180-100%, 190-100%, 200-100%, 210-100%, 220-100%, 230-100%, 240-100%, 250-100%, 260-100%, 270-100%, 280-100%, 290-100%, 300-100%, 310-100%, 310-100%, 320-100%, 330-100%, 340-100%, 350-100%, 360-100%, 370-100%, 380-100%, 390-100%, 400-100%, 400-100%, 400-100%, 400-100%, 400-100%, 400- 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%.

[0223] In another aspect, provided herein are methods for treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (IA) or (I). In some embodiments, provided herein are methods for preventing cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (IA) or (I). Non-limiting examples of cancer 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, neck cancer, ovarian cancer, pancreatic cancer, prostate cancer, stomach cancer, leukemia, benign lymphoma, malignant lymphoma, Burkitt's lymphoma, Non-Hodgkin's lymphoma (NHL), benign melanoma, malignant melanoma, myeloproliferative disorders, sarcoma, Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, sarcoma), liposarcoma, myosarcoma, peripheral neuroepithelioma, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, gangliocytoma, ganglioglioma, medulloblastoma, pineal cell tumor, meningioma, meningiosarcoma, neurofibroma and schwannoma, prostate cancer, uterine cancer, testicular cancer, thyroid cancer, astrocytoma, gastric cancer, melanoma, carcinosarcoma, Hodgkin's disease, Wilms' tumor, teratocarcinoma, T-lineage acute lymphoblastic leukemia (T-ALL), T-lineage lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, early B ALL, pre-B 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 (I) to a subject in need thereof can reduce the severity of cancer in the subject (such as tumor size, tumor growth rate, metastasis). In some embodiments, administering a compound of Formula (IA) or (I) to a subject in need thereof can stabilize the cancer (prevent or delay the worsening of the cancer). In some embodiments, administering a compound of Formula (IA) or (I) to a subject in need thereof can postpone the occurrence or recurrence of cancer. In some embodiments, administering a compound of Formula (IA) or (I) to a subject in need thereof can slow the progression of cancer. In some embodiments, administering a compound of Formula (IA) or (I) to a subject in need thereof can provide partial relief of cancer. In some embodiments, administering a compound of Formula (IA) or (I) to a subject in need thereof can provide overall relief of cancer. In some embodiments, administering a compound of Formula (IA) or (I) to a subject in need thereof can reduce the dose of one or more other drugs required to treat the cancer. In some embodiments, administering a compound of Formula (IA) or (I) to a subject in need thereof can enhance the effect of another drug used to treat cancer. In some embodiments, administering a compound of Formula (IA) or (I) to a subject in need thereof can delay the progression of cancer. In some embodiments, administering a compound of Formula (IA) or (I) to a subject in need thereof can improve the quality of life of a subject with cancer. In some embodiments, administering a compound of Formula (IA) or (I) to a subject in need thereof can prolong the survival of a subject with cancer.

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

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

[0227] In other aspects, provided herein are methods for reducing the dose of one or more other drugs 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 are methods for enhancing the effect of another drug 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, the methods 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 suffering from cancer. In some embodiments, the methods extend the survival of a subject suffering from cancer.

[0229] In another aspect, provided herein are methods 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 are methods 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. Systemic autoimmune diseases occur when the immune system attacks the body without distinguishing between different types of tissues or target cells. Exemplary organ-specific autoimmune diseases include atopic dermatitis, asthma, insulin-dependent diabetes mellitus, Hashimoto's thyroiditis, Grave's disease, pernicious anemia, myasthenia gravis, pemphigus vulgaris, and Crohn's disease. Exemplary systemic autoimmune diseases include systemic lupus erythematosus (SLE), rheumatoid arthritis, scleroderma, sarcoidosis, and Guillain-Barré Syndrome (GBS). The present invention encompasses the treatment of all types of autoimmune diseases, including 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, and inflammatory bowel disease. disease), IgA nephropathy, idiopathic thrombocytopenic purpura, interstitial cystitis, mixed connective tissue disease, morphea, multiple sclerosis, myasthenia gravis, narcolepsy, neuromyotonia, pemphigus vulgaris, pernicious anemia, psoriasis, psoriatic arthritis, polymyositis, primary biliary cirrhosis, relapsing polychondritis, rheumatoid arthritis, sarcoidosis, schizophrenia, scleroderma, Sjögren's syndrome syndrome, stiff-person syndrome, temporal arteritis, ulcerative colitis, vasculitis, leukoplakia, and Wegener's granulomatosis.

[0230] In another aspect, provided herein are methods for treating a TH17-related condition, such as a TH17-related autoimmune condition, in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (IA) or Formula (I).

[0231] In some embodiments, administering a compound of Formula (IA) or (I) to a subject in need thereof can alleviate or reduce the symptoms of an autoimmune disease in the subject (such as inflammation, chronic fever, malaise, joint pain, myalgia, and fatigue). In some embodiments, administering a compound of Formula (IA) or (I) to a subject in need thereof can shorten or reduce the duration of the symptoms of an autoimmune disease. In some embodiments, administering a compound of Formula (IA) or (I) to a subject in need thereof can eliminate the symptoms of an autoimmune disease. In some embodiments, administering a compound of Formula (IA) or (I) to a subject in need thereof can delay the onset or recurrence of an autoimmune disease. In some embodiments, administering a compound of Formula (IA) or (I) to a subject in need thereof can slow the progression of an autoimmune disease. In some embodiments, administering a compound of Formula (IA) or (I) to a subject in need thereof can reduce the dose of one or more other drugs required to treat an autoimmune disease. In some embodiments, administering a compound of Formula (IA) or (I) to a subject in need thereof can enhance the effect of another drug used to treat an autoimmune disease. In some embodiments, administering a compound of Formula (IA) or (I) to a subject in need thereof delays the progression of an autoimmune disease. In some embodiments, administering a compound of Formula (IA) or (I) to a subject in need thereof improves the quality of life of a subject suffering from an autoimmune disease.

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

[0233] In other aspects, provided herein are methods for reducing the dosage of one or more other drugs required to treat an autoimmune disease in a subject, the method comprising administering to the subject a compound of Formula (IA) or (I). In some embodiments, provided herein are methods for enhancing the effect of another drug used to treat an autoimmune disease in a subject, the method comprising administering to the subject a compound of Formula (IA) or (I). Pharmaceutical compositions and routes of administration

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

[0235] The compounds disclosed herein can be administered orally, topically, or parenterally to a subject in the form of conventional preparations, such as capsules, microcapsules, tablets, granules, powders, lozenges, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions, and emulsions. Suitable preparations can be prepared by conventional 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, hydroxypropyl starch, low-substituted hydroxypropyl cellulose, sodium bicarbonate, calcium phosphate, or lemon). The pharmaceutical composition may comprise a pharmaceutical composition comprising: ...

[0236] The dosage of the compound of formula (IA) or formula (I) administered to a subject can vary widely and can be subject to the judgment of a health care practitioner. Typically, the compounds disclosed herein can be administered one to four times a day at a dosage of about 0.001 mg / kg subject weight to about 10 mg / kg subject weight, but the above dosage can be appropriately changed depending on the age, weight, and medical condition of the subject and the type of administration. In one embodiment, the dosage is about 0.001 mg / kg subject weight to about 5 mg / kg subject weight, about 0.01 mg / kg subject weight to about 5 mg / kg subject weight, about 0.05 mg / kg subject weight to about 1 mg / kg subject weight, about 0.1 mg / kg subject weight to about 0.75 mg / kg subject weight, or about 0.25 mg / kg subject weight to about 0.5 mg / kg subject weight. In one embodiment, the dosage is administered once a day. In any given case, the amount of the compound of formula (IA) or formula (I) administered will depend on factors such as the solubility of the active ingredient, the formulation 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 another embodiment, 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 specific 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 another embodiment, 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) can be administered once, twice, three times, four times or more per day. In a specific embodiment, a dose of 100 mg or less is administered as a once-daily dose, and a dose exceeding 100 mg is administered twice per day in an amount equal to half the total daily dose.

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

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

[0244] In one embodiment, provided herein are capsules containing a compound of Formula (IA) or Formula (I) without other carriers, excipients, or vehicles.

[0245] In another embodiment, provided herein is a composition 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 composition may be in the form of tablets, chewable tablets, capsules, solutions, parenteral solutions, lozenges, suppositories, and suspensions. The composition may be formulated to contain a daily dose or a suitable fraction of a daily dose in a dosage unit, which may be a single tablet or capsule or a suitable volume of liquid. In one embodiment, the solution is prepared from a water-soluble salt, such as a hydrochloride. Typically, all compositions are prepared according to known methods in pharmaceutical chemistry. Capsules can be prepared by mixing a compound of formula (IA) or formula (I) with a suitable carrier or diluent and filling an appropriate amount of the mixture into a capsule. Common carriers and diluents include, but are not limited to, inert powdered substances, such as many different types of starch; powdered cellulose, especially crystalline and microcrystalline cellulose; sugars, such as fructose, mannitol, and sucrose; cereal flours and similar edible powders.

[0247] Tablets can be prepared by direct compression, wet granulation or dry granulation. Their preparations are usually combined with diluents, binders, lubricants and disintegrants as well as compounds. Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or calcium sulfate, inorganic salts (such as sodium chloride and powdered sugar). Powdered cellulose derivatives are also suitable. Typical tablet binders are substances such as starch, gelatin and sugars, such as lactose, fructose, glucose, etc. Natural and synthetic gums are also suitable, including gum arabic, alginates, methylcellulose, polyvinyl pyrrolidone, etc. Polyethylene glycol, ethyl cellulose and waxes can also serve as binders.

[0248] Lubricants may be necessary for tablet formulations to prevent the tablet and punch from sticking in the mold. Lubricants can be selected from smooth solids (such as talc, magnesium stearate and calcium stearate), stearic acid and hydrogenated vegetable oils. Tablet disintegrants are substances that swell when wetted to break the tablet and release the compound. They include starch, clay, cellulose, fucoidan and gum. More particularly, for example, corn and potato starch, methylcellulose, agar, bentonite, wood cellulose, powdered natural sponges, cation exchange resins, alginic acid, guar gum, citrus pulp and carboxymethylcellulose and sodium lauryl sulfate can be used. Tablets can be coated with sugar as a flavoring and sealant, or coated with a film-forming protective agent to change the dissolution properties of the tablet. The composition can also be formulated into chewable tablets, 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) in the form of a suppository, typical bases may be used. Cocoa butter is a traditional suppository base, which may be modified by adding waxes to slightly raise its melting point. In particular, water-miscible suppository bases containing polyethylene glycols of various molecular weights 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 soluble granules of the compound of formula (IA) or formula (I) can be prepared and incorporated into tablets or capsules or as slow-release implantable devices. This technology also includes preparing granules with several different dissolution rates and filling capsules with a mixture of granules. The tablets or capsules can be coated with a film that resists dissolution within a predictable time period. Even parenteral preparations can be made long-acting by dissolving or suspending the compound of formula (IA) or formula (I) in an oily or emulsifying medium that slowly disperses it in the serum.

[0251] It will be understood that the pharmaceutical compositions described herein may include mixtures of compounds of Formula (IA) or Formula (I), including racemic mixtures of any of the compounds described herein. Exemplary embodiments

[0252] The present invention is further described by the following embodiments. Where appropriate and feasible, the features of each embodiment may be combined with any other embodiment.

[0253] Embodiment P1. A compound of formula (IA): or a pharmaceutically acceptable salt thereof, wherein: X 1 and X 2 Each independently is N or CH, subject to the condition that X 1 and X 2 At least one of is N; R 1a and R 1b Each is independently H, halogen or C1-C6 alkyl; R 2a and R 2b are each independently H, C1-C6 alkyl, -O(C1-C6 alkyl), -OH, halogen, C1-C6 haloalkyl or C1-C6 alkyl-OH, or R 2a and R 2b Together with the carbon atom to which it is attached, it forms a spiro C3-C5 cycloalkyl group, or R 2a and R 2b Together they form oxygen; or R 1a and R 2a Together they form a bridged C2-C3 alkylene group; R 3a and R 3b Each is independently H, halogen or C1-C6 alkyl; R 4a and R 4b are each independently H, halogen or C1-C6 alkyl, or R 4a and R 4b Together with the carbon atom to which it is attached, it forms a spiro C3-C5 cycloalkyl group; R 5a and R 5b Each is independently H, halogen 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, with the constraint that x and y are not both 1; R 8 is Cl or -CN; R9 is F; X 3 is N or CH; z is 0 or 1; R 10a and R 10b are each independently H or halogen; 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 the heterocyclyl contains 1-3 heteroatoms selected from N, O, and S; R 12 is H, halogen or C1-C6 alkyl; R 13 is H or halogen; R 14 is H or C1-C6 alkyl; X 4 N or CR 15 ; R 15 is H or C1-C6 alkyl; X 5 and X 6 are each independently N or CH; and is a single bond or a double bond; wherein one or more hydrogen atoms in the compound are optionally replaced by deuterium.

[0254] Embodiment P2. A compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: X 1 and X 2 Each independently is N or CH, subject to the condition that X 1 and X 2 At least one of is N; R 1a and R 1b Each is independently H, halogen or C1-C6 alkyl; R 2a and R 2b are each independently H, C1-C6 alkyl, -OH, halogen or C1-C6 alkyl-OH, or R 2a and R 2b Together with the carbon atom to which it is attached, it forms a spiro C3-C5 cycloalkyl group, or R 2a and R 2bTogether they form oxygen; or R 1a and R 2a Together they form a bridged C2-C3 alkylene group; R 3a and R 3b Each is independently H, halogen or C1-C6 alkyl; R 4a and R 4b are each independently H, halogen or C1-C6 alkyl, or R 4a and R 4b Together with the carbon atom to which it is attached, it forms a spiro C3-C5 cycloalkyl group; R 5a and R 5b Each is independently H, halogen 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 halogen; 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 the heterocyclyl contains 1-3 heteroatoms selected from N, O, and S; R 12 is H, halogen or C1-C6 alkyl; R 13 is H or halogen; R 14 is H or C1-C6 alkyl; X 4 N or CR 15 ; R 15 is H or C1-C6 alkyl; X 5 and X 6 are each independently N or CH; and is a single bond or a double bond; wherein one or more hydrogen atoms in the compound are optionally replaced by deuterium.

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

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

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

[0258] Embodiment P6. A compound according to any one of Embodiments P1 to P5, or a pharmaceutically acceptable salt thereof, wherein: R 1a and R 1b Each is independently H, halogen or C1-C3 alkyl.

[0259] Embodiment P7. A compound according to embodiment P6 or a pharmaceutically acceptable salt thereof, wherein: R 1a and R 1b Each is independently H or -CH3.

[0260] Embodiment P8. A compound according to any one of Embodiments P1 to P7, or a pharmaceutically acceptable salt thereof, wherein: R 2a and R 2b are each independently H, C1-C3 alkyl, -O(C1-C3 alkyl), -OH, halogen, C1-C3 haloalkyl or C1-C3 alkyl-OH, or R 2a and R 2b Together with the carbon atom to which it is attached, it forms a spiro C3-C4 cycloalkyl group, or R 2a and R 2b Together they form an oxo group.

[0261] Embodiment P9. The compound of embodiment P8 or a pharmaceutically acceptable salt thereof, wherein: R 2a and R 2b are each independently H, -CH3, -OCH3, -OH, F, -CF3 or -CH2OH, or R 2a and R 2b Together with the carbon atom to which it is attached, it forms a spirobutyl group, or R 2a and R 2b Together they form an oxo group.

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

[0263] Embodiment P11. A compound according to any one of Embodiments P1 to P9, or a pharmaceutically acceptable salt thereof, wherein: R 1a and R 2a Together they form a bridged ethylene group.

[0264] Embodiment P12. A compound according to any one of Embodiments P1 to P11, or a pharmaceutically acceptable salt thereof, wherein: R 3a and R 3b Each is independently H, halogen or C1-C3 alkyl.

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

[0266] Embodiment P14. A compound according to any one of Embodiments P1 to P13, or a pharmaceutically acceptable salt thereof, wherein: R 4a and R 4b are each independently H, halogen or C1-C3 alkyl, or R 4a and R 4b Together with the carbon atom to which it is attached, it forms a spiro C3-C4 cycloalkyl.

[0267] Embodiment P15. A compound according to embodiment P14 or a pharmaceutically acceptable salt thereof, wherein: 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 it is attached, it forms a spirobutyl group.

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

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

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

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

[0272] Embodiment P20. The compound of embodiment P19 or a pharmaceutically acceptable salt thereof, wherein: R 5a and R 5b Each is independently H, halogen or C1-C3 alkyl.

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

[0274] Embodiment P22. A compound according to any one of Embodiments P1 to P21, or a pharmaceutically acceptable salt thereof, wherein 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.

[0275] Embodiment P23. A compound according to embodiment P22 or a pharmaceutically acceptable salt thereof, wherein R 1a 、R 1b 、R 2a 、R 2b 、R 3a 、R 3b 、R 4a 、R 4b 、R 5a and R 5b One or both of them are not H.

[0276] Embodiment P24. A compound according to any one of Embodiments P1 to P23, or a pharmaceutically acceptable salt thereof, wherein for:

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

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

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

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

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

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

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

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

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

[0286] Embodiment P34. A compound according to any one of Embodiments P1 to P33, or a pharmaceutically acceptable salt thereof, wherein:

[0287] z is 0.

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

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

[0290] Embodiment P37. A compound according to any one of Embodiments P1 to P36, or a pharmaceutically acceptable salt thereof, wherein: 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 the heterocyclyl contains 1-2 heteroatoms selected from N and O.

[0291] Embodiment P38. A compound according to embodiment P37 or a pharmaceutically acceptable salt thereof, wherein: R 11is 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

[0292] Embodiment P39. A compound according to any one of Embodiments P1 to P38, or a pharmaceutically acceptable salt thereof, wherein for:

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

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

[0295] Embodiment P42. A compound according to any one of Embodiments P1 to P41, or a pharmaceutically acceptable salt thereof, wherein for:

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

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

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

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

[0300] Embodiment P47. A compound according to any one of Embodiments P1 to P45, or a pharmaceutically acceptable salt thereof, wherein: X 4 CR 15 ;and R 15 is H or C1-C3 alkyl.

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

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

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

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

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

[0306] Embodiment P53. A compound according to any one of Embodiments P1 to P52, or a pharmaceutically acceptable salt thereof, wherein: For a single bond.

[0307] Embodiment P54. A compound according to any one of Embodiments P1 to P52, or a pharmaceutically acceptable salt thereof, wherein: For double bonds.

[0308] Embodiment P55. A compound according to any one of Embodiments P1 to P54, or a pharmaceutically acceptable salt thereof, wherein for:

[0309] Embodiment P56. A compound according to any one of Embodiments P1 to P55, or a pharmaceutically acceptable salt thereof, wherein the compound has Formula (II), (III) or (IV):

[0310] Embodiment P57. The compound of embodiment P56 or a pharmaceutically acceptable salt thereof, wherein the compound has formula (IIIb):

[0311] Embodiment P58. A compound and a pharmaceutically acceptable salt thereof, wherein the compound is selected from the compounds in Table 1.

[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 according to any one of Embodiments P1-P58 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to Embodiment P59.

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

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

[0319] The following examples are presented as illustrations and not as limitations. Compounds were named using the automatic name generation tool provided in ChemBiodraw Ultra (Cambridgesoft), which generates systematic names for chemical structures with the support of the Cahn-Ingold-Prelog rules for stereochemistry. One skilled in the art can modify the procedures described in the illustrative examples to obtain the desired products.

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

[0321] The following abbreviations may be used in connection with this application. abbreviation ACN, MeCN, acetonitrile AcOH acetic acid anh anhydrous atm atmospheric pressure BF3OEt2 Boron trifluoride etherate BINAP 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl BOC tert-Butoxycarbonyl CBM Cereblon binding part Cbz-ClBenzyl chloroformate CDI 1,1'-Carbonyldiimidazole CPhos 2'-(dicyclohexylphosphanyl)-N 2 ,N 2,N 6 ,N 6 -Tetramethyl[1,1'-biphenyl]-2,6-diamine DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCE 1,2-dichloroethane DCM dichloromethane DIPEA N,N-Diisopropylethylamine DMA N,N-dimethylacetamide DMAP 4-dimethylaminopyridine DMEDA 1,2-Dimethylethylenediamine DMF dimethylformamide DMSO dimethyl sulfoxide EDC Ethylene Dichloride eq or equiv equivalent ESI electrospray ionization Et3N triethylamine Et2O ether EtOAc or EA EtOH FA Formic acid h or hr hours HATU N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethylammonium hexafluorophosphate N-oxide hex hexane HPLC High-pressure liquid chromatography iPrOH isopropyl alcohol Josiphos Pd G3 methanesulfonate {(R)-1-[(Sp)-2-(dicyclohexylphosphino)ferrocenyl]ethyl di-tert-butylphosphine}[2-(2'-amino-1,1'-biphenyl)]palladium(II) LCMS liquid chromatography mass spectrometry LHDMS lithium bis(trimethylsilyl)amide M molar concentration mCPBA meta-chloroperbenzoic acid MeOH methanol MeTHF 2-Methyltetrahydrofuran min MS N equivalent concentration NaOtBu sodium tert-butoxide NBS N-bromosuccinimide NIS N-iodosuccinimide NMP N-Methyl-2-pyrrolidone oMe mesylate oTs Tosylate Pd2dba3 tris(dibenzylideneacetone)dipalladium(0) Pd-Ruphos-G3 methanesulfonate (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-(2'-amino-1,1'-biphenyl)) palladium(II) PE, pet ether petroleum ether quant. RBF round bottom flask rt or room temperature Rt retention time SFC Supercritical Fluid Chromatography SM starting material SNAr Nucleophilic aromatic substitution TBAB Tetrabutylammonium bromide tBuOH tert-butyl alcohol TEA trimethylamine TFA trifluoroacetic acid THF Tetrahydrofuran TLC thin layer chromatography xantphos XPhos Pd G3 Synthesis Example General Procedure 1: First SNAr on Pyrimidine

[0322] To a mixture of 5-amino-1-methylindolin-2-one (1 eq) in anhydrous tetrahydrofuran [0.4 M] at -40 ° C was added DIPEA (1.1 eq). To the above mixture was slowly added a solution of 5-chloro-2,4-difluoropyrimidine (1 eq) in anhydrous tetrahydrofuran [1.5 M] and allowed to slowly 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 in vacuo to give the title compound as a brown solid. General Procedure 2: Buchwald Coupling of Amines with Indazole CBMs

[0323] A mixture of 6-bromo-3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-indazole 1a (1.1 eq), an amine (1.0 eq), Ruphos-Pd-G3 (0.20 eq), and NaOtBu (1.5 eq) in 1,4-dioxane [0.3 M] was heated to 90° C. for 16 hours and then cooled to room temperature. The mixture was filtered over 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 using a gradient of 0-100% EtOAc / hexanes to give the title compound. General Procedure 3: Methylation of Amines

[0324] To a solution of amine (1.0 eq, 14.2 mmol) in DCM [0.15 M] was added NaH (4.4 eq) and stirred at 0 ° C for 1 hour. Iodomethane (2.8 eq) was added to the mixture 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 and washed with brine, dehydrated over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography eluting with PE / EA (15: 1) to give the title compound. General Procedure 4: Reduction of CBM with Hydrogen

[0325] A mixture of the indazole intermediate (1.0 eq) and Pd / C (10 wt% palladium; 40 wt%) in EtOH:THF (1:1.5; [0.05 M]) was placed under hydrogen (1 atm) at 50 °C for 4 hours. 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 using a gradient of 0-100% EtOAc / hexane to give the title compound. General Procedure 5: Removal of BOC protecting group with HCl or TFA

[0326] To a solution of the BOC protected amine (1.0 eq) in 1,4-dioxane [0.3 M] was added 4N HCl in 1,4-dioxane (14 eq) and the reaction mixture was stirred at room temperature for 12 h. The volatiles were evaporated under reduced pressure to give the title compound as a solid (quantitative), which was used in the next step without further purification. General Procedure 6: SNAr of Modified TBMs with CBMs

[0327] A solution of amine hydrochloride (1.0 eq), chloro / fluoropyrimidine (1.0 eq), and N,N-diisopropylethylamine (3 to 5 eq) in DMSO [0.1-0.2 M] was stirred at 80° C. for 2 hours. The reaction mixture was filtered and purified by reverse phase semi-preparative HPLC (10-100% acetonitrile + 0.1% formic acid in water over 30 minutes). Fractions containing pure product were combined and lyophilized to provide the title compound.

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

[0329]

[0146] 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-pyridinyl)-1-methyl-indazole (300 mg, 0.6000 mmol), tert-butyl N-methyl-N-(piperidin-4-yl)carbamate (192.72 mg, 0.9000 mmol), cesium carbonate (390.68 mg, 1.2 mmol) and RuPhos-Pd-G3 (50.14 mg, 0.0600 mmol) were added to a 1 dram vial and purged with nitrogen for 1 minute. 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 25CV, 7% methanol / DCM 10CV) 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] + ; 1 HNMR(400MHz,DMSO-d6)δppm 7.89(d,J=8.19Hz,1H),7.26-7.51(m,11H),6.88(d,J=1.59Hz,1H),6.82(dd,J=9.17 ,1.96Hz,1H),6.57(d,J=8.19Hz,1H),5.44(d,J=13.57Hz,4H),3.97(s,3H),3.87(br d,J=12.59Hz,2H),2.77(br t,J=11.55Hz,2H),2.70(s,3H),1.71-1.89(m,2H),1.61-1.70(m,2H),1.42(s,9H).

[0330]

[0146] 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-pyridinyl)-1-methyl-indazol-6-yl]-4-piperidinyl]-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 with nitrogen again and then with hydrogen. The reaction mixture was stirred under a hydrogen balloon overnight. The slurry was filtered through celite and concentrated. The residue was loaded onto a SNAP25G column and purified with 0-50% EtOAC / hexanes with 2-5% MeOH additive to give the title compound (50 mg, 0.110 mmol, 65.6% yield) as a yellow oil.

[0331]

[0266] 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-piperidinyl)-1-methyl-indazol-6-yl]-4-piperidinyl]-N-methyl-carbamate (50 mg, 0.1100 mmol) was added to a vial equipped with a stir bar and dichloromethane (1 mL). 4N HCl in 1,4-dioxane (0.4400 mmol) was then added to the mixture and stirred for 2 hours. The stir bar was removed and the solvent was removed in vacuo to give the title compound (42 mg, 0.107 mmol, 97.6% yield) as an off-white solid. Example i-2. Synthesis of Intermediate 2: 3-(1-methyl-6-(piperidin-4-ylamino)-1H-indazol-3-yl)piperidine-2,6-dione hydrochloride

[0332] 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. and then cooled to room temperature. The volatiles were evaporated under reduced pressure. The material was purified by silica gel column chromatography using a gradient of 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 N2, and the mixture was stirred at 80°C under N2 for 17 hours. LCMS confirmed complete consumption of the reactants and the desired MS as the main peak. The reaction mixture 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 Na 2 SO 4 and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, gradient: 0-30% ethyl acetate / petroleum ether) to give the title compound (2.1 g, 4.20 mmol, 71% yield) as a light yellow solid. MS (ES) [M+H] + 500.3. 1 H NMR(400MHz, DMSO-d6)δ7.96(s,1H),7.91(d,J=8.1Hz,1H),7.62(d,J=8.7Hz,1H),7.50-7.24(m, 10H), 7.12 (dd, J=8.7, 1.4Hz, 1H), 6.60 (d, J=8.1Hz, 1H), 5.45 (s, 2H), 5.43 (s, 2H), 4.05 (s, 3H).

[0334]

[0146] Step 3: Synthesis of tert-butyl 4-[[3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-indazol-6-yl]amino]piperidine-1-carboxylate. A mixture of 6-bromo-3-(2,6-dibenzyloxy-3-pyridinyl)-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 hours and then cooled to room temperature. The mixture was filtered through celite and washed with EtOAc (3 x 10 mL). The filtrate was concentrated under reduced pressure. The material was purified by silica gel column chromatography using a gradient of 0-90% ethyl acetate / hexanes to afford tert-butyl 4-[[3-(2,6-dibenzyloxy-3-pyridinyl)-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(500MHz, CDCl3)δ7.89(d,J=8.1Hz,1H),7.47(d,J=8.7Hz,1H),7.45-7.42(m,2H),7 .39-7.27(m,7H),7.25-7.22(m,1H),6.49(d,J=8.1Hz,1H),6.36(dd,J=8.8,1.9Hz,1H), 6.31(d,J=1.7Hz,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 = 11.9Hz, 2H), 2.10 (dd, J = 13.0, 2.8Hz, 2H), 1.48 (s, 9H).

[0335]

[0146] Step 4: Synthesis of tert-butyl 4-[[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazol-6-yl]amino]piperidine-1-carboxylate. A mixture of tert-butyl 4-[[3-(2,6-dibenzyloxy-3-pyridinyl)-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. Only olefin product was observed at this time. 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 ratio, 3 x 50.0 mL). The filtrate was concentrated under reduced pressure to give tert-butyl 4-[[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazol-6-yl]amino]piperidine-1-carboxylate (495 mg, 0.9496 mmol, 98.085% yield) as a solid. MS (ESI) [M+H] + :442.4; 1H NMR (400MHz, DMSO-d6) δ10.81(s,1H),7.33(d,J=8.7Hz,1H),6.52(dd,J=8.8,1 .8Hz,1H),6.43(s,1H),5.79(d,J=8.2Hz,1H),4.18(dd,J=8.7,5.2Hz,1H),3.93 -3.86(m,2H),3.81(s,3H),2.96(br,2H),2.60(t,J=7.0Hz,2H),2.30-2.20(m, 1H),2.18-2.11(m,1H),1.94(d,J=11.0Hz,2H),1.41(s,9H),1.30-1.19(m,3H).

[0336] Step 5: Synthesis of 3-[1-methyl-6-(4-piperidinylamino)indazol-3-yl]piperidine-2,6-dione hydrochloride. To a solution of tert-butyl 4-[[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazol-6-yl]amino]piperidine-1-carboxylate (1.22 g, 2.76 mmol) in 1,4-dioxane (20 mL) was added 4N hydrogen chloride 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 (400MHz, DMSO-d6) δppm 10.85 (s, 1H), 9.01 (br d, J = 2.45Hz, 1H), 8.76-8.95 (m, 1H), 7.48 (br s,1H),6.72(brs,3H),4.21-4.30(m,1H),3.87(s,3H),3.63-3.75(m,1H),3.32(br d,J=12.59Hz,2H),2.99(br d,J=10.39Hz,2H),2.55-2.69(m,2H),2.22-2.34(m,1H),2.07-2.22(m,3H),1.72(br s,2H). Example i-3. Synthesis of Intermediate 3: 3-(6-amino-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione

[0337] 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 added to 1,4-dioxane (1600 mL) in a 3000 ml multi-neck RBF equipped with a reflux condenser under N2 atmosphere with mechanical stirring. tert-Butyl carbamate (56.2 g, 480 mmol) and K2CO3 (133 g, 959 mmol) were then added sequentially and purged for 5 minutes, followed by the addition of XPhos Pd G2 (25.2 g, 32.0 mmol), purged for another 5 minutes, and then refluxed at 110°C overnight. The reaction mixture was filtered through a bed of celite and washed with ethyl acetate. The resulting filtrate was evaporated to give the crude product, which was purified using ISCO on silica gel with 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(400MHz,DMSO-d6)δppm 9.5(s,1H),7.89-7.91(m,1H),7.28-7.54(m,12H),6.94(d,1H),6.58(d,1H),5.41-5.45(d,4H),3.96(s,3H),1.50(s,9H),1.37(s,1H).

[0338]

[0146] Step 2: Synthesis of tert-butyl (3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)carbamate. To a flask was added tert-butyl (3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazol-6-yl)carbamate (25 g, 46.6 mmol) and THF (500 mL). This mixture was purged with nitrogen for 5 minutes and then palladium on carbon (24.79 g, 23.29 mmol) was added and then stirred at 55 °C under an atmosphere of H2 overnight. The reaction mixture was then 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] + ; 1H NMR(400MHz,DMSO-d6)δppm 10.90(s,1H),9.54(s,1H),7.82(m,1H),7.55-7.57(d,1H),7.04(d,1H),4 .30(m,1H),3.90(s,3H),2.30-2.70(m,2H)2.13-2.37(m,2H),1.36(s,9H).

[0339]

[0146] 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 RBF under magnetic stirring. HCl (4 M in dioxane) (250 mL, 69.8 mmol) was slowly added and the reaction mixture was stirred at room temperature for 48 hours. The mixture was then filtered and the resulting solid was taken up in methanol and stirred thoroughly for 20 minutes before filtering again to give the title compound (18 g, 57.2 mmol, 82% yield) as a light yellow solid. MS (ESI) m / z 259.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δppm 7.80-7.82(d,1H),7.53(s,1H),7.08-7.11(d 1H),4.39-4.43(m,1H),3.99(s,3H),2.50-2.73(m,2H),2.38-2.40(m,1H),2.18-2.36(m,1H). 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

[0340]

[0146] Step 1: Synthesis of tert-butyl 4-[[3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-indazol-6-yl]amino]piperidine-1-carboxylate. A mixture of 6-bromo-3-(2,6-dibenzyloxy-3-pyridinyl)-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 hours and then cooled to room temperature. The mixture was filtered through celite and washed with EtOAc (3 x 10 mL). The filtrate was concentrated under reduced pressure. The material was purified by silica gel column chromatography using a gradient of 0-100% EtOAc / hexanes to give the title compound as a solid (550 mg, 89%). 1 H NMR(500MHz, CDCl3)δ7.89(d,J=8.1Hz,1H),7.47(d,J=8.7Hz,1H),7.45-7.41(m,2H),7 .39-7.24(m,8H),6.49(d,J=8.1Hz,1H),6.36(dd,J=8.7,1.9Hz,1H),6.31(d,J=1.7Hz, 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=12.1Hz,2H),2.10(d,J=10.8Hz,2H),1.48(s,9H),1.43-1.35(m,2H). MS(ESI)[M+H] + 620.5.

[0341]

[0146] Step 2: Synthesis of tert-butyl 4-[[3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-indazol-6-yl]-methyl-amino]piperidine-1-carboxylate. To a solution of tert-butyl 4-[[3-(2,6-dibenzyloxy-3-pyridinyl)-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 aqueous formaldehyde (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 hour. 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 x 5 mL), brine (5 mL), dried over NaSO, filtered and concentrated under reduced pressure. The material was purified by silica gel column chromatography using a gradient of 0-100% EtOAc / hexanes to afford the title compound as a solid (467 mg, 83% yield). 1 H NMR(400MHz, CDCl3)δ7.91(d,J=8.1Hz,1H),7.56(d,J=9.0Hz,1H),7.46-7.40(m,2H), 7.40-7.30(m,5H),7.29-7.23(m,3H),6.72(dd,J=9.3,2.1Hz,1H),6.50(d,J=8.1Hz,1 H),6.48(d,J=1.9Hz,1H),5.47(s,2H),5.38(s,2H),4.25(s,2H),4.01(s,3H),3.80(t d,J=10.8,5.3Hz,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]

[0266] Step 3: tert-Butyl 4-[[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazol-6-yl]-methyl-amino]piperidine-1-carboxylate. A mixture of tert-butyl 4-[[3-(2,6-dibenzyloxy-3-pyridinyl)-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 hours. The mixture was filtered through celite, washed with a mixture of MeCN and MeOH (1:1, 3 x 10 mL), and the filtrate was concentrated under reduced pressure. The material was purified by silica gel column chromatography using a gradient of 0-20% MeOH / DCM to give the title compound (258 mg, 77%) as a solid. 1 H NMR (500MHz, DMSO) δ10.83(s,1H),7.46(d,J=9.0Hz,1H),6.87(dd,J=9.2,2.0Hz,1H),6.65(d,J=1 .9Hz,1H),4.23(dd,J=9.0,5.1Hz,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-piperidinyl)amino]indazol-3-yl]piperidine-2,6-dione; hydrochloride. To a solution of tert-butyl 4-[[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazol-6-yl]-methyl-amino]piperidine-1-carboxylate (258 mg, 0.57 mmol) in 1,4-dioxane (10 mL) was added 4 M HCl in 1,4-dioxane (1.42 mL, 5.66 mmol). The reaction mixture was heated to 100° C. for 3 hours 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 in vacuo to give the title compound (217 mg, 92%) as a solid. 1H NMR(400MHz,D2O)δ7.93(d,J=8.3Hz,1H),7.65(s,1H),7.31(d,J=8.0Hz,1H ),4.56(dd,J=10.8,4.2Hz,1H),4.18-4.09(m,1H),4.07(s,3H),3.61(d,J= 12.6Hz,2H),3.33(s,3H),3.11(t,J=12.9Hz,2H),2.91-2.79(m,2H),2.61- 2.48(m,1H),2.44-2.35(m,1H),2.28(d,J=12.0Hz,2H),2.05-1.90(m,2H). Note: No exchangeable protons were observed, and the sample contained <1 wt% 1,4-dioxane. MS (ESI) [M+H] + 356.2. Example i-5. Synthesis of Intermediate 5: 5-amino-1-(2-morpholinoethyl)indolin-2-one

[0344] 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) was added diisopropyl azodicarboxylate (1.091 mL, 5.61 mmol) dropwise at 0 ° C under nitrogen and stirred for 20 minutes. 2-morpholinoethane-1-ol (736 mg, 5.61 mmol) was then added and stirred for 15 minutes. 5-nitroindolin-2-one (500 mg, 2.81 mmol) was then added and the temperature was slowly raised to 25 ° C and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure to give a crude product, which was purified by flash silica gel column chromatography with 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) 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 pad 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. Example i-6. Synthesis of Intermediate 6: 5-amino-1-(4,4,4-trifluorobutyl)indolin-2-one

[0346] Step 1: Synthesis of 5-amino-1-(4,4,4-trifluorobutyl)indolin-2-one. The synthesis of the title compound was achieved similarly to Intermediate 5 using 4,4,4-trifluorobutan-1-ol as the starting material. Example i-7. Synthesis of Intermediate 7: 5-amino-6-fluoro-1-methylindolin-2-one

[0347] 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 nitrate (51.5 mg, 0.605 mmol) at 0 ° C. The reaction mixture was allowed to warm to room temperature and stirred for 3 hours. LCMS indicated that the reaction was complete. The reaction mixture was then quenched with saturated sodium bicarbonate (25 mL) and then extracted with ethyl acetate (3×25 mL). The organic phases were combined and washed with saturated aqueous sodium chloride solution (1×25 mL). The organic layer was dehydrated over anhydrous magnesium sulfate, filtered through celite and concentrated. The crude material 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 (400MHz, DMSO-d6) δppm 8.06 (br d, J = 7.46Hz, 1H), 6.95-7.10 (m, 1H), 3.63 (s, 2H), 3.28-3.33 (m, 43H), 3.24 (s, 3H).

[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 / carbon (50.6 mg, 0.476 mmol) under hydrogen (1 atm) at room temperature 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] + . Example i-8. Synthesis of Intermediate 8: 5-amino-7-fluoro-1-methylindolin-2-one

[0349] 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), and the reaction mixture was stirred at 120° C. for 40 minutes. LCMS indicated incomplete reaction with 20% SM remaining. The reaction mixture was quenched with saturated aqueous sodium chloride solution (25 mL) and then extracted with ethyl acetate (3×25 mL). The organic phases were combined and washed with saturated aqueous sodium chloride solution (1×25 mL). The organic layer was dried (anhydrous sodium sulfate), filtered through celite, and concentrated. The crude material 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 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 similarly to Intermediate 7 using 7-fluoro-1-methylindolin-2-one as the starting material. Example i-9. Synthesis of Intermediate 9: 5-amino-4-fluoro-1-methylindolin-2-one

[0351] 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), and the reaction mixture was stirred at 120° C. for 40 minutes. LCMS indicated incomplete reaction with 20% SM remaining. The reaction mixture was quenched with saturated aqueous sodium chloride solution (25 mL) and then extracted with ethyl acetate (3×25 mL). The organic phases were combined and washed with saturated aqueous sodium chloride solution (1×25 mL). The organic layer was dried (anhydrous magnesium sulfate), filtered through celite, and concentrated. The crude material 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 was slowly added 90% nitric acid (0.195 mL, 4.53 mmol) in 98% sulfuric acid (1 mL). The reaction mixture was stirred at -30°C and warmed to 0°C over 30 minutes. The reaction mixture was poured onto 100 g of ice and extracted with ethyl acetate (3 x 25 mL). The combined organic phases were washed with saturated aqueous sodium chloride solution (1 x 25 mL). The organic layer was dried over anhydrous sodium sulfate, filtered through celite, and concentrated. The crude material was purified by silica gel column chromatography (0-100% ethyl acetate / hexanes) 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 / carbon (30.4 mg, 0.285 mmol) under hydrogen (1 atm) at room temperature for 2 hours. The reaction mixture was filtered. The eluate 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] + ; 1H NMR (400MHz, DMSO-d6) δppm 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). Example i-10. Synthesis of Intermediate 10: 5-amino-1-isopropylindolin-2-one

[0354] 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 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (25 mL) and then extracted with ethyl acetate (3×25 mL). The organic phases were combined and washed with saturated aqueous sodium chloride (1×25 mL). The organic layer was dried (anhydrous sodium sulfate), filtered, and concentrated. The crude material was purified by silica gel column chromatography (0-100% ethyl acetate / hexane). The desired fraction was 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 10 mL of 2N HCl 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 / carbon (217 mg, 2.043 mmol) under hydrogen (1 atm) at room temperature for 15 hours. The reaction mixture was filtered. The eluate 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(400MHz, DMSO-d6)δppm 6.80(d,J=8.31Hz,1H),6.55(d,J=1.96Hz,1H),6.43(dd,J=8.31,2.32Hz,1H),4.72(br s, 2H), 4.45 (spt, J = 6.99Hz, 1H), 3.35 (s, 2H), 1.34 (d, J = 7.09Hz, 6H). Example i-11. Synthesis of Intermediate 11: 5-amino-1-ethylindolin-2-one

[0356] Step 1: Synthesis of 5-amino-1-ethylindolin-2-one. The synthesis of the title compound was achieved similarly to Intermediate 10 using ethylamine hydrochloride as the starting material. Example i-12. Synthesis of Intermediate 12: 5-amino-1-(2-hydroxyethyl)indolin-2-one

[0357] Step 1: Synthesis of 5-amino-1-(2-hydroxyethyl)indolin-2-one. The synthesis of the title compound was achieved similarly to Intermediate 10 using 2-aminoethanol as the starting material. Example i-13. Synthesis of Intermediate 13: 5-amino-1-(2-methoxyethyl)indolin-2-one

[0358]

[0146] 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) at 25°C under nitrogen. 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]

[0114] 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. The reaction mixture was slowly poured into sodium bicarbonate solution at 0°C 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 pad 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] + . Example i-14. Synthesis of Intermediate 14: 5-amino-1-methyl-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one

[0361] Step 1: Synthesis of 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 tert-butanol (1 mL) and water (1 mL) was added NBS (1.37 g, 7.68 mmol) at 0°C. The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was monitored by TLC and LCMS. When the reaction was complete, 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 title compound, which was used without 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 hours. The reaction mixture was monitored by TLC and LCMS. The reaction mixture was then evaporated. The resulting residue was basified with NaOH solution (100 ml) and extracted with DCM containing 10% MeOH. The organic fraction was evaporated to give the title compound, which was used without further purification. MS (ESI) m / z 164.1 [M + H] + . Example i-15. Synthesis of Intermediate 15: 6-amino-1-(3-hydroxy-3-methylbutyl)indolin-2-one

[0363] 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) was added 3-hydroxy-3-methylbutyl 4-methylbenzenesulfonate (2, 2.30 g, 8.02 mmol) and cesium carbonate (3.01 g, 9.25 mmol) at 25°C. The reaction mixture was heated to 120°C for 16 hours. The reaction mixture was then cooled to room temperature and treated with water and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude compound, which was purified by flash silica gel column chromatography with 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) was added NBS (142 mg, 0.797 mmol) at 0°C. The reaction mixture was slowly warmed to 25°C and stirred for 2 hours. 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 material was purified by flash silica gel column chromatography using 6% methanol / DCM to give the title compound (100 mg, 0.333 mmol, 87% yield) as a brown sticky solid. MS (ESI) m / z 235.2 [M+H] + . Example i-16. Synthesis of Intermediate 16: 6-amino-1-(3-hydroxy-3-methylbutyl)-3,3-dimethylindolin-2-one

[0366] Step 1: Synthesis of N-(2-bromo-5-nitro-phenyl)-2-methyl-prop-2-enamide. To a solution of 2-bromo-5-nitro-aniline (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 (400MHz, DMSO d6): δ9.69 (s, 1H), 8.44 (s, 1H), 8.00 (d, J = 1.2Hz, 2H), 5.97 (s, 1H), 5.63 (s, 1H), 2.00 (s, 3H). MS(ESI)[M+H] + 285.1.

[0367]

[0146] 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) was added triethylamine (1.16 mL, 8.33 mmol), TBAB (1.07 g, 3.33 mmol) and Pd(OAc) (15.0 mg, 0.07 mmol) in succession under nitrogen and the reaction mixture was stirred at 80°C for 1 hour. HCOONa (227 mg, 3.33 mmol) was added and the reaction mixture was stirred at 80°C for 12 hours. Water (5 mL) and ethyl acetate (15 mL) were added and the layers were separated. The organic layer was washed with brine (3 x 10 mL), dried over NaSO, filtered and concentrated under reduced pressure. Et2O (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 (400MHz, DMSO d6): δ10.75 (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]

[0146] 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) were added (3-hydroxy-3-methyl-butyl)-4-methylbenzenesulfonate (271 mg, 1.05 mmol) and KCO (362 mg, 2.62 mmol) sequentially, and the reaction mixture was stirred at 80°C for 12 hours. 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 NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient of 0-100% EtOAc / hexane to give the title compound (145 mg, 57%) as a solid. 1H NMR(500MHz,DMSO d6): δ7.96(dd,J=8.1,2.1Hz,1H),7.77(d,J=2.1Hz,1H),7.66(d,J=8.1Hz,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 hydrogenated at room temperature (1 atm) 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 directly in the next step without further purification. MS (ESI) [M+H] + 263.2. Example i-17. Synthesis of Intermediate 17: tert-Butyl (2-(5-amino-2-oxoindolin-1-yl)ethyl)(methyl)carbamate

[0370]

[0146] 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) at 25°C under nitrogen. The reaction mixture was heated to 65°C and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure to give a crude material as a brown liquid. The crude material 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 and neutralized with sodium bicarbonate and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (400 mg, 0.909 mmol, 18% yield), which was used in the next step without further purification.

[0371]

[0266] 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) was added DIPEA (0.397 mL, 2.272 mmol) and Boc-anhydride (0.422 mL, 1.818 mmol) dropwise at 0°C under nitrogen. The reaction mixture was slowly warmed to 25°C and stirred for 16 hours. The reaction mixture was treated with water (50 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude compound, which was purified by flash silica gel column chromatography with 20-40% ethyl acetate in petroleum ether to afford the title compound (240 mg, 0.697 mmol, 77% yield).

[0372]

[0266] 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 pad was washed with ethanol (2 x 50 mL). The filtrate was concentrated under reduced pressure to give the title compound (200 mg, 0.504 mmol, 70% yield) as a dark brown liquid. The crude product was used in the next step without further purification. Example i-18. Synthesis of Intermediate 18: 5-amino-1-(2,2-difluoropropyl)indolin-2-one

[0373] 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) was added triethylamine (2.18 mL, 15.61 mmol) at 25 ° C. The mixture was cooled to 0 ° C. and 4-dimethylaminopyridine (0.127 g, 1.041 mmol) and 4-methylbenzenesulfonyl chloride (2.381 g, 12.49 mmol) were added sequentially. The reaction mixture was slowly warmed to 25 ° C. and stirred for 16 hours. 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) was added cesium carbonate (1507 mg, 4.63 mmol) and 5-nitro-1H-indole (3,500.0 mg, 3.08 mmol) at 25 ° C. The mixture was heated to 120 ° C and stirred for 16 hours. The reaction mixture was quenched by adding 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 material was purified by flash silica gel column chromatography with 35-40% ethyl acetate / petroleum ether to give the title compound (250.0 mg, 0.997 mmol, 32% yield) as a light yellow solid. MS (ESI) m / z 240.9 [M+H] + .

[0375]

[00155] 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 hours. The reaction mixture was quenched with water (15 mL) and extracted with ethyl acetate (3 x 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 light 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) was slowly added zinc powder (202 mg, 3.10 mmol) at 25 ° C and stirring was continued for 6 hours. The reaction mixture was concentrated under reduced pressure and diluted by adding 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] + . Example i-19. Synthesis of Intermediate 19: 5-amino-1-(3-fluoro-3-methylbutyl)indolin-2-one

[0377] Step 1: Synthesis of 5-amino-1-(3-fluoro-3-methylbutyl)indolin-2-one. The title compound was synthesized similarly to Intermediate 18 using 3-fluoro-3-methylbutan-1-ol as the starting material. Example i-20. Synthesis of Intermediate 20: 5-amino-1-(2-fluoro-2-methylpropyl)indolin-2-one

[0378] 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) was slowly added 2,6-lutidine (2.26 mL, 19.5 mmol) at -10 ° C and then a solution of 2-fluoro-2-methylpropan-1-ol (1.50 g, 16.3 mmol) in DCM (35 mL) was added dropwise. 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 successively with 1.0N HCl solution and saturated sodium bicarbonate solution and then with brine. The organic phase 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 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 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 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 tert-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 temperature was raised 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 material. This residue was dissolved in acetic acid (3.5 mL) and zinc powder (88 mg, 1.34 mmol) was added and stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure to give the crude product. The crude material was dissolved in 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). The crude product was used in the next step without purification. Example i-21. Synthesis of Intermediate 21: 5-amino-1-(2,2,2-trifluoroethyl)indolin-2-one

[0381] 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 minutes, 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.28 g, 5.50 mmol) was added. The reaction mixture was warmed to room temperature for 1 hour. 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 silica gel column chromatography using a gradient of 20-70% ethyl acetate in hexanes to give the title compound as a solid (910.0 mg, 66%). 1 H NMR (500MHz, DMSO) δ8.60 (dd, J=8.8, 2.5Hz, 1H), 8.30 (d, J=2.4Hz, 1H), 7.55 (d, J=8.8Hz, 1H), 4.77 (q, J=9.3Hz, 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 50 psi hydrogen atmosphere 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]

[0146] Step 3: Synthesis of 5-amino-1-(2,2,2-trifluoroethyl)indolin-2-one. A mixture of 5-amino-1-(2,2,2-trifluoroethyl)indolin-2-one (450.0 mg, 1.84 mmol) and hydrazine hydrate (65%, 10.0 mL, 133.0 mmol) was heated to 115°C for 1 hour and then cooled to room temperature. The volatiles were evaporated under reduced pressure. The material was purified by reverse phase chromatography (C18) using a gradient of 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 (500MHz, DMSO) δ6.79 (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. Example i-22. Synthesis of Intermediate 22: 4-Amino-5-methylcycloheptane-1-carboxylic acid benzyl ester

[0384] Step 1: Synthesis of 1-benzyl 4-ethyl 5-oxopiperidine-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 hours. The reaction mixture was then basified with sodium bicarbonate solution (100 mL) and the organics were extracted with EtOAc (3 x 100 mL). The combined organic fractions were dried and concentrated to give the crude material. Purification was performed by Combi-flash column chromatography, where the product was eluted in 15% EA / PE. The fractions containing product 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 4-methyl-5-oxoazepane-1,4-dicarboxylic acid 1-benzyl 4-ethyl ester. To a stirred solution of 5-oxoazepane-1,4-dicarboxylic acid 1-benzyl 4-ethyl ester (3.5 g, 10.96 mmol) in DMF (8 mL) was added CsCO (7.14 g, 21.92 mmol) and MeI (1.371 mL, 21.92 mmol) at 0°C. The reaction mixture was warmed to room temperature and stirred at 25°C for 6 hours. The reaction mixture was evaporated to give a crude material that was purified by combi-flash column chromatography. The product eluted in 25-30% EA / PE and the fractions containing the product were combined and concentrated to give 4-methyl-5-oxoazepane-1,4-dicarboxylic acid 1-benzyl 4-ethyl ester (2.5 g, 76%) as a colorless liquid. 1 H NMR(400MHz,DMSO)δ7.35(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]

[0146] Step 3: Synthesis of 4-methyl-5-oxoazepane-1-carboxylic acid benzyl ester. To a stirred solution of 4-methyl-5-oxoazepane-1,4-dicarboxylic acid 1-benzyl 4-ethyl ester (2.5 g, 5.70 mmol) in MeOH (20 mL) and water (20 mL) was added KOH (0.959 g, 17.10 mmol) at 25°C. The reaction mixture was stirred at 60°C for 4 hours. The reaction mixture was then diluted with water (50 ml) and extracted with DCM (2 x 100 ml). Purification was performed by reverse phase preparative HPLC using a gradient of 2-98% MeCN / 5 mM ammonium formate at pH 3.3. Fractions containing the desired product were combined and concentrated to give 4-methyl-5-oxoazepane-1-carboxylic acid benzyl ester (1.50 g, 80%) as a yellow oil. 1 H NMR (400MHz, DMSO) δ7.31-7.39(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 4-amino-5-methylazepane-1-carboxylic acid benzyl ester. To a stirred solution of 4-methyl-5-oxoazepane-1-carboxylic acid benzyl ester (1.0 g, 3.02 mmol) in 2-propanol (20 mL) at 25° C. was added ammonium acetate (4.66 g, 60.5 mmol) and NaCNBH 4 (1.140 g, 18.14 mmol). The reaction mixture was stirred at 50° C. for 3 hours 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 4-amino-5-methylazepane-1-carboxylic acid benzyl ester (700 mg, 65%) as a yellow solid. MS (ESI) [M+H] + 263.2,RT=0.78 Example i-23. Synthesis of Intermediate 23: 4-Amino-3-methylazepane-1-carboxylic acid benzyl ester

[0388] 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 hours. The reaction mixture was then basified with sodium bicarbonate solution (100 mL) and the organics were extracted with EtOAc (3 x 100 mL). The combined organic fractions were dried and concentrated to give the crude material. Purification was performed by Combi-flash column chromatography, where the product was eluted in 20-30% EA / PE. The fractions containing product 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 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) was added CsCO (6.53 g, 20.04 mmol) and MeI (1.253 mL, 20.04 mmol) at 0°C and the reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was warmed to room temperature and stirred at 25°C for 6 hours. The reaction mixture was evaporated to give the crude material, which was purified by combi-flash column chromatography. The product eluted in 20% EtOAc / PE and fractions containing 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. 1 H NMR (400MHz, DMSO) δ7.32-7.40(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 3-methyl-4-oxoazepane-1-carboxylic acid benzyl ester. To a stirred solution of 3-methyl-4-oxoazepane-1,3-dicarboxylic acid 1-benzyl 3-ethyl ester (1.0 g, 2.55 mmol) in MeOH (7.5 mL) and H2O (7.5 mL) was added KOH (0.429 g, 7.65 mmol) and the reaction mixture was stirred at 60 ° C for 2 hours. The reaction mixture was monitored by TLC and LCMS. The reaction mixture was stirred at 60 ° C for 4 hours. The reaction mixture was then diluted with water (50 ml) and extracted with DCM (2×100 ml). Purification was performed by reverse phase preparative HPLC using a gradient of 2-98% MeCN / 5 mM ammonium formate at pH 3.3. The fractions containing the desired product were combined and concentrated to give 3-methyl-4-oxoazepane-1-carboxylic acid benzyl ester (550 mg, 76%) as a yellow oil. 1 H NMR (400MHz, DMSO) δ7.29-7.37(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 4-amino-3-methylazepane-1-carboxylic acid benzyl ester. To a stirred solution of 3-methyl-4-oxoazepane-1-carboxylic acid benzyl ester (100 mg, 0.352 mmol) in 2-propanol (4 mL) at 25° C. was added ammonium acetate (543 mg, 7.04 mmol) and NaCNBH 4 (133 mg, 2.112 mmol). The reaction mixture was stirred at 50° C. for 3 hours. The reaction mixture was then diluted with water and extracted with EtOAC. The organic fraction was concentrated to give 4-amino-3-methylazepane-1-carboxylic acid benzyl ester (100 mg, 40%) as a yellow solid. MS (ESI) [M+H] + 263.2,RT=1.35. 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)

[0392] 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 above mixture and slowly warmed to room temperature. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was then filtered and washed with acetonitrile (about 50 mL). The solid was dried in vacuo to give the title compound as a light brown solid. MS (ESI) [M+H] + 293.1.

[0393] Step 2: Synthesis of tert-butyl 8-[[3-(2,6-dioxo-3-piperidinyl)-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) using a gradient of 0-80% MeCN and 10 mM ammonium formate in water to give the title compound (325 mg, 76%) as a solid. MS (ESI) [M+H] + 482.3. 1 H NMR (400MHz, DMSO-d6) δ10.82 (s, 1H), 7.32 (d, J = 8.7Hz, 1H), 6.52-6.40 (m, 1H), 6.48 (br s,1H),5.78(d,J=8.7Hz,1H),4.18(dd,J=8.8,5.2Hz,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 2,2,2-trifluoroacetic acid 3-[6-(5-azaspiro[3.5]nonan-8-ylamino)-1-methyl-indazol-3-yl]piperidine-2,6-dione. To a solution of 8-[[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazol-6-yl]amino]-5-azaspiro[3.5]nonane-5-carboxylic acid tert-butyl ester (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. 1H NMR (500MHz, DMSO-d6) δ10.82(s,1H),8.98(d,J=8.5Hz,1H),8.75-8.71(m,1H),7.37(d,J=8.7Hz,1H),6.55(dd,J=8.7,1.8Hz,1H),6.51(br s,1H),4.19(dd,J=8.9,5.1Hz,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=12.9Hz,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 2,2,2-trifluoroacetic acid 3-[6-(5-azaspiro[3.5]nonan-8-yl)]-1-methyl-indazol-3-yl]piperidine-2,6-dione was added under N2 (1 atm). To a solution of 5-((5-chloro-2-fluoropyrimidin-4-yl)amino)-1-methylindolin-2-one (11 mg, 40 μmol) in NMP (0.7 mL) 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) using a gradient of 0-100% MeCN and water (containing 0.1% formic acid) to give the title compound (13 mg, 44%) as a solid. LCMS: C 34 H 36 ClN9O3 theoretical value 653.3, found value 654.3 [M+H] + ; 1H NMR(500MHz,DMSO-d6)δ10.80(s,1H),8.62(s,1H),8.01(s,1H),7.39(s,1H),7.38-7.36(m,1H),7.30(d,J=8.8Hz,1H),6 .92(d,J=8.3Hz,1H),6.48-6.45(m,2H),5.65(d,J=8.8Hz,1H),4.25(d,J=12.1Hz,1H),4.17(dd,J=8.9,5.1Hz,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=10.0Hz,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). 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)

[0396] 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 methanesulfonic acid (2'-methylamino-1,1'-biphenyl-2-yl) 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 evaporated 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 and 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 (500MHz, MeOD-d4) δ8.38(s,1H),8.13(s,1H),8.00(t,J=8.1Hz,1H),7.74(d,J=11.2Hz,2H),7.62(d,J=11.4 Hz,2H),7.59-7.55(m,1H),7.51(d,J=9.0Hz,1H),7.42(dd,J=7.5,1.4Hz,1H),7.34-7.28(m,3H),7.25(t,J=7.3H z,1H),7.21(d,J=8.1Hz,1H),7.16-7.13(m,1H),7.03(d,J=8.1Hz,1H),6.84(t,J=7.7Hz,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=5.9,2.9Hz,3H),2.09(s,6H). 19 FNMR(471MHz,MeOD-d4)δ-64.20,-64.42. 31 P NMR (203MHz, MeOD-d4) δ33.80.

[0397] Step 2: Synthesis of tert-butyl N-[5-[3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-indazol-6-yl]-5-azaspiro[3.5]non-8-yl]carbamate. 6-Bromo-3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-indazole (600 mg, 1.20 mmol), tert-butyl N-(5-azaspiro[3.5]non-8-yl)carbamate (375 mg, 1.56 mmol), NaO A mixture of tBu (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 (3×15 mL). The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography using a gradient of 0-60% EtOAc / hexanes to give the title compound (600 mg, 76%) as a solid. MS (ESI) [M+H] + 660.2. 1H NMR(400MHz, DMSO-d6)δ7.88(d,J=8.1Hz,1H),7.50-7.43(m,3H),7.42-7.32(m,5H),7.32-7.25(m,3H) ),6.79(d,J=7.5Hz,1H),6.73(d,J=1.5Hz,1H),6.62(dd,J=9.0,1.8Hz,1H),6.57(d,J=8.1Hz,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-pyridinyl)-1-methyl-indazol-6-yl]-5-azaspiro[3.5]non-8-yl]-N-methyl-carbamate. To an ice-cold solution of tert-butyl N-[5-[3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-indazol-6-yl]-5-azaspiro[3.5]non-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 hours. Another batch was prepared using 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 Na2SO4, filtered and concentrated. The residue was purified by reverse phase chromatography (C18) using a gradient of 20-100% MeCN and water containing 10 mM ammonium formate to give the title compound (700 mg, 65% combined yield) as a solid. MS (ESI) [M+H] + 674.4.

[0399] Step 4: Synthesis of tert-butyl N-[5-[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazol-6-yl]-5-azaspiro[3.5]non-8-yl]-N-methyl-carbamate. A mixture of tert-butyl N-[5-[3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-indazol-6-yl]-5-azaspiro[3.5]non-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 hydrogen atmosphere (1 atm) at 50 °C for 2 h. The mixture was filtered through celite, washed with MeOH (3 x 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. 1 H NMR (400MHz, DMSO-d6) δ10.86 (s, 1H), 7.48 (d, J = 8.7Hz, 1H), 6.77 (s, 1H), 6.7 7-6.73(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-piperidinyl)-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 4N HCl in 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 Et2O (2×5 mL) and dried in vacuo 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(500MHz,DMSO-d6)δ10.49(s,1H),9.08(br s,2H),7.56(d,J=8.8Hz,1H),6.95(s,1H),6.87(dd,J=8.8,1.4Hz,1H),4.27(dd,J=8.8,5.2H z,1H),3.92(s,3H),3.60(dt,J=13.6,3.2Hz,1H),3.43-3.32(m,1H),3.25-3.16(m,1H),2.68- 2.63(m,2H),2.56(t,J=5.3Hz,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]

[0269] 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 hours. The crude reaction mixture was purified by preparative HPLC (BEH column, C18) using a gradient of 48-58% MeCN and water containing 10 mM ammonium formate to give the title compound (14.9 mg, 22%) as a solid. LCMS: C 34 H 36 ClN9O3 theoretical value 667.3, found value 668.3 [M+H] + ; 1H NMR(500MHz,DMSO-d6)δ10.49(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=8.3Hz,1H),6. 80-6.76(m,2H),4.89-4.80(m,1H),4.26(dd,J=8.6,5.2Hz,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 masked by water signal. 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)

[0402] The title compound was synthesized similarly to Example S2 using tert-butyl trans-N-(4-aminocyclohexyl)carbamate as the starting material. The title compound was isolated as an off-white solid (36.7 mg, 0.05 mmol, 20.6% yield). LCMS: C 33 H 36 ClN9O3 theoretical value 641, found 642 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.83(s,1H),8.14(s,1H),7.60(s,1H),7.54(d,J=8.2Hz,1H),7.42 (d,J=8.7Hz,1H),7.00(d,J=8.4Hz,1H),6.60(d,J=8.9Hz,1H),6.55(s,1H),4.30(s,1H),4.2 2(dd,J=9.0,5.1Hz,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=11.8Hz,1H),1.70(s,3H),1.25(s,2H). 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)

[0403] Step 1: Synthesis of N-[(2R,4R)-1-[3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-indazol-6-yl]-2-methyl-4-piperidinyl]carbamate. The title compound was synthesized in toluene at 110° C. over 18 hours according to General Procedure 2 using tert-butyl N-[(2R,4R)-2-methyl-4-piperidinyl]carbamate as a reactant. The title compound was isolated as a solid (700 mg, 86%) by reverse phase chromatography (C18) using a gradient of 30-100% MeCN and water containing 10 mM ammonium formate. LCMS: C 38 H 43 Theoretical value of N5O4 is 633.3, measured value is 635.9 [M+H] + .

[0404] Step 2: Synthesis of tert-butyl N-[(2R,4R)-1-[3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-indazol-6-yl]-2-methyl-4-piperidinyl]-N-methyl-carbamate. To a solution of tert-butyl N-[(2R,4R)-1-[3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-indazol-6-yl]-2-methyl-4-piperidinyl]carbamate (800 mg, 1.26 mmol) in DMF (13 mL) cooled to 0° C. was added NaH (151 mg, 3.8 mmol) and the reaction mixture was stirred at 0° C. for 15 minutes. Iodomethane (0.24 mL, 3.79 mmol) was added, the reaction mixture was warmed to room temperature and stirred for 1 hour. The reaction was diluted by the dropwise addition of 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 4 ), filtered, and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (C18) using a gradient of 30-100% MeCN and 10 mM ammonium formate in water to give the title compound (700 mg, 86%) as a solid. LCMS: C 39 H 45 Theoretical value of N5O4 is 647.4, measured value is 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. The synthesis of the title compound was achieved using General Procedures 4, 5 and 6 starting with tert-butyl N-[(2R,4R)-1-[3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-indazol-6-yl]-2-methyl-4-piperidinyl]-N-methyl-carbamate. The crude residue was purified by reverse phase chromatography (C18) using a gradient of 10-70% MeCN and water containing 10 mM ammonium formate to give the title compound (19 mg, 25%) as a solid. LCMS C 33 H 36 ClN9O3 theoretical value 641.3, measured value 642.3 [M+H] + ; 1 H NMR(500MHz,DMSO-d6)δ10.88(s,1H),8.60(s,1H),8.02(s,1H),7.70(s,1H) ,7.60(d,J=8.7Hz,1H),7.54(s,1H),7.29(s,1H),6.98-6.89(m,2H),4.59(br s,1H),4.33(dd,J=9.5,4.9Hz,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(brs,1H),2.68-2.5 9(m,2H),2.38-2.31(m,1H),2.22-2.13(m,1H),1.95-1.86(m,1H),1.76(d,J=10.6Hz,1H),1.70-1.58(m,2H),0.93(d,J=5.7Hz,3H). 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)

[0406]

[0146] 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) was added Boc-anhydride (2.24 mL, 9.64 mmol) at 0°C under nitrogen. The reaction mixture was slowly warmed to 25°C and stirred for 3 hours. The reaction mixture was treated with 0.5N HCl (2.0 mL), water (50 mL) and extracted with DCM (2 x 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. Copper (I) iodide (571 mg, 3.00 mmol), KCO (621 mg, 4.50 mmol) and N1,N2-dimethylethane-1,2-diamine (264 mg, 3.00 mmol) were then 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 and 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 material was purified by flash silica gel column chromatography using 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 title compound was synthesized using General Procedures 4, 5, and 6 starting with tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazol-6-yl)-3-methyl-5-oxopiperazine-1-carboxylate. LCMS C 31 H 30ClN9O4 theoretical value 627.2, measured value 628.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6): δ10.92(s,1H),8.83(s,1H),8.10(s,1H),7.73(d,J=8.5Hz,1H),7.5 9(s,1H),7.55-7.53(m,2H),7.01-6.96(m,2H),4.58-4.50(m,1H),4.39(dd,J=5.1Hz and 10.2H z,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=6.3Hz,3H).

[0409] The examples in Table 2 below were prepared according to the general procedures outlined in the table starting from their respective commercially available starting materials and intermediates found herein. 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)

[0410]

[0146] 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-piperidinylamino)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 + water containing 0.1% formic acid over 30 minutes). Fractions containing pure product were combined and freeze-dried to give the title compound (3.0 mg, 0.0049 mmol, 4.9% yield) as an off-white solid. LCMS C 31 H 32 ClN9O3 theoretical value 613.2, found value 614.2 [M+H] + ; 1 H NMR(DMSO-d6,400MHz)δ10.7-10.8(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). 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)

[0411] 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 isolated using preparative HPLC with a Regis Whelk-O1 SS, 21×250 mm, 5μ column at 22° C. (flow rate of 1 mL / min in isocratic elution with 100% MeCN (no additives)). The title compound was isolated as the first eluting peak with Rt=11.0 min. LCMS C 31 H 32 ClN9O3 theoretical value 614.2, measured value 614.2 [M+H] + ; 1 H NMR(DMSO-d6,400MHz)δ10.7-10.8(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). Example S54. 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 (single isomer, stereochemistry not determined) (54)

[0412] 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 preparative HPLC with a Regis Whelk-O1 SS, 21×250 mm, 5μ column at 22° C. (flow rate of 1 mL / min in isocratic elution of 100% MeCN (no additives)). The title compound was isolated as the second eluting peak with Rt=18.9 min. LCMS C 31 H 32 ClN9O3 theoretical value 614.2, measured value 614.2 [M+H] + ; 1 H NMR(DMSO-d6,400MHz)δ10.7-10.8(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). 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)

[0413] 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. Sodium hydride (0.150 g, 3.76 mmol) was then 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 solution (25 mL) and then extracted with ethyl acetate (3×25 mL). The organic phases were combined and washed with saturated aqueous sodium chloride solution (1×25 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered through celite, and concentrated. The crude material 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 (400MHz, DMSO-d6) δppm 8.59 (s, 1H), 7.92 (s, 1H), 4.06 (d, J = 0.98Hz, 3H).

[0414]

[0146] 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 hours. The reaction mixture was then quenched with saturated aqueous sodium chloride solution (25 mL) and then extracted with ethyl acetate (3 x 25 mL). The organic phases were combined and washed with saturated aqueous sodium chloride solution (1 x 25 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered through celite, and concentrated. The crude material 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] + ; 1H NMR(400MHz,DMSO-d6)δppm 8.25(d,J=8.44Hz,1H),8.02(d,J=8.07Hz,1H),7.45-7.51(m,2H),7.28-7.44(m,8H), 7.11(d,J=8.44Hz,1H),6.62(d,J=8.19Hz,1H),5.49(s,2H),5.44(s,2H),4.04(s,3H).

[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 degassed with argon for 1 minute and then stirred at 100 ° C for 15 hours. LCMS indicated that the reaction was complete. The reaction mixture was quenched with saturated aqueous sodium chloride solution (25 mL) and then extracted with ethyl acetate (3×25 mL). The organic phases were combined and washed with saturated aqueous sodium chloride solution (1×25 mL). The organic layer was dehydrated over anhydrous magnesium sulfate, filtered through celite and concentrated. The crude material was purified by silica gel column chromatography (0-100% ethyl acetate / hexane). The desired fraction was concentrated under reduced pressure to obtain a crude material. The crude material was further purified by reverse phase semi-preparative HPLC (10-100% acetonitrile + water containing 0.1% TFA (0.1% TFA), over 30 minutes). The fractions containing the pure product were combined and freeze-dried 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(400MHz,DMSO-d6)δppm 7.95(d,J=8.07Hz,1H),7.65(d,J=8.93Hz,1H),7.43-7.50(m,2H),7.28-7.43(m,8H),6.97(d,J=7.09Hz,1H),6.56(d,J=8.07Hz,1H),6. 24(d,J=8.93Hz,1H),5.46(s,2H),5.39-5.44(m,2H),5.18(d,J=4.65Hz,1H),3.71-3.98(m,6H),3.40(tt,J=9.00,4.63Hz,1H),2.94(br d,J=1.47Hz,1H),2.69-2.85(m,1H),1.99-2.15(m,1H),1.41(s,9H),1.24-1.34(m,1H).

[0416]

[0266] 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 10% w / w palladium on carbon (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 1 mL of TFA in DCM (1 mL) at room temperature for 30 min. The volatiles were removed under reduced pressure to give the desired product as a TFA salt (67 mg, 0.187 mmol, 99% yield) 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 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 + water containing 0.1% formic acid over 30 minutes). Fractions containing pure product were combined and freeze-dried 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] + ; 1 H NMR (400MHz, DMSO-d6) δppm 10.83(s,1H),8.68(s,1H),8.02(s,1H),7.65(d,J=8.68Hz,1H),7.54(s,1H),7.50(dd,J=8.44,2.20Hz,1H),6.99(br d,J=7.21Hz,1H),6.94(d,J=8.44Hz,1H),6.37(d,J=8.80Hz,1H),5.16(dd,J=5.07,1.77Hz,1H),4.39-4.53(m,1H),4.24-4.38(m,1H),4.1 4(dd,J=9.35,5.07Hz,1H),3.89-4.02(m,1H),3.77(s,3H),3.54(s,2H),3.44(tt,J=9.25,4.88Hz,1H),3.29(s,1H),3.11(s,3H),3.05(br t,J=11.19Hz,1H),2.88(dd,J=12.78,9.60Hz,1H),2.55-2.64(m,2H),2.21-2.31(m,1H),2.06-2.20(m,2H),1.26-1.42(m,1H).

[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)

[0419] Step 1: Synthesis of 3,3-difluoro-5-nitroindolin-2-one. To a suspension of 5-nitroindolin-2,3-dione (2.2 g, 11.5 mmol) in dichloromethane (50 mL) at -78 ° C., diethylaminosulfur trifluoride (4.06 g, 25.2 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 2 days. LCMS indicated that the reaction was complete. The reaction mixture was quenched with saturated aqueous sodium chloride solution (25 mL) and then extracted with ethyl acetate (3×25 mL). The organic phases were combined and washed with saturated aqueous sodium chloride solution (1×25 mL). The organic layer was dried (anhydrous magnesium sulfate), filtered through celite and concentrated. The crude material 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 (400MHz, DMSO-d6) δppm 11.89 (br s, 1H), 8.56-8.60 (m, 1H), 8.43 (d, J = 8.78Hz, 1H), 7.20 (d, J = 8.68Hz, 1H).

[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) and iodomethane (0.185 mL, 2.97 mmol) sequentially. The reaction mixture was stirred at room temperature for 15 hours. The reaction mixture was quenched with saturated aqueous sodium chloride solution (25 mL) and then extracted with ethyl acetate (3×50 mL). The organic phases were combined and washed with saturated aqueous sodium chloride solution (1×25 mL). The organic layer was dried (anhydrous magnesium sulfate), filtered through celite and concentrated. The crude material 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 (400MHz, DMSO-d6) δppm 8.61 (d, J = 1.96 Hz, 1H), 8.54 (d, J = 8.91 Hz, 1H), 7.46 (d, J = 8.80 Hz, 1H), 3.25 (s, 3H).

[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 at room temperature under hydrogen (45 psi) 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 (400MHz, DMSO-d6) δppm6.90 (d, J = 8.44Hz, 1H), 6.87 (d, J = 1.96Hz, 1H), 6.75 (d, J = 7.91Hz, 1H), 5.22 (s, 2H), 3.09 (s, 3H).

[0422]

[0266] 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 using General Procedures 1 and 6 with 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 in water over 30 minutes). Fractions containing pure product were combined and freeze-dried to give the title compound as a yellow solid (8 mg, 0.012 mmol, 23.46% yield); MS (ESI) m / z 664.2 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δppm10.81(s,1H),8.94(s,1H),8.03-8.14(m,2H),7.77(br d,J=8.56Hz,1H),7.31(d,J=8.80Hz,1H),7.21(d,J=8.44Hz,1H),6.51(br d,J=8.80Hz,1H),6.44(s,1H),5.70(br d,J=8.80Hz,1H),4.47(br s,2H),4.17(dd,J=8.62,5.07Hz,1H),3.81(s,3H),3.17(s,3H),3.04(br t,J=12.10Hz,1H),2.65-2.76(m,1H),2.56-2.63(m,2H),2.19-2.31(m,1H),2.11-2.19(m,1H),2.06(br d,J=10.64Hz,1H),1.46-1.66(m,1H),1.07-1.28(m,2H),0.96(d,J=6.36Hz,3H). 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-piperidinyl]amino]-1-methyl-indazol-3-yl]piperidine-2,6-dione (57)

[0423] Step 1: Synthesis of tert-butyl 4-[[(1R)-1-phenylethyl]amino]-3,6-dihydro-2H-pyridine-1,5-dicarboxylate 05-ethyl ester. To a solution of 01-tert-butyl 03-ethyl 4-oxopiperidine-1,3-dicarboxylate (22 g, 81 mmol) and (1R)-1-phenylethylamine (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 using a Dean-Stark trap for 18 hours. The mixture was cooled to room temperature, washed with saturated aqueous NaHCO3 (2×200 mL) and brine (2×200 mL). The combined organic fractions were dried over MgSO4, filtered and concentrated. The residue was filtered on a pad of silica gel, 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. 1H NMR (400MHz, CDCl3) δ9.25 (d, J = 7.5Hz, 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=13.0,6.2Hz,1H),2 .09-2.00(m,1H),1.50(d,J=6.8Hz,3H),1.43(s,9H),1.29(t,J=7.0Hz,3H).

[0424] Step 2: Synthesis of tert-butyl (3S,4R)-4-[[(1R)-1-phenylethyl]amino]piperidine-1,3-dicarboxylate 03-ethyl and tert-butyl (3R,4S)-4-[[(1R)-1-phenylethyl]amino]piperidine-1,3-dicarboxylate 03-ethyl. To a solution of tert-butyl 4-[[(1R)-1-phenylethyl]amino]-3,6-dihydro-2H-pyridine-1,5-dicarboxylate 05-ethyl (15 g, 40.1 mmol) in MeCN (200 mL) and AcOH (100 mL) cooled to 0° C. was added sodium triacetoxyborohydride (34 g, 160 mmol) 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 treated slowly with 1M aqueous NaOH solution (100 mL), 4M aqueous NaOH solution (100 mL), 6M aqueous NaOH solution (100 mL) and 50% aqueous NaOH solution (50 mL). The mixture was warmed 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 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient of 0-50% EtOAc / hexane to give a 4:1 mixture of the title compound (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 (3S,4R)-4-[[(1R)-1-phenylethyl]amino]piperidine-1,3-dicarboxylate O3-ethyl ester (3.7 g) as an oil and the title compound tert-butyl (3R,4S)-4-[[(1R)-1-phenylethyl]amino]piperidine-1,3-dicarboxylate O3-ethyl ester (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 (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 hours, then cooled to room temperature. Ice water (10 mL) was added and the mixture was concentrated under reduced pressure. The residue was extracted with EtOAc (3×30 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)silanyl]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) were added tert-butylchlorodimethylsilane (218 mg, 1.45 mmol) and imidazole (123 mg, 1.81 mmol) sequentially and the reaction mixture was stirred at room temperature for 3 hours. Water (15 mL) and EtO (20 mL) were added and the layers were separated. The aqueous layer was washed with Et2O (3 x 10 mL) and the combined organic fractions were dried over Na2SO4, 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. 1 H NMR(400MHz,DMSO-d6)δ7.35-7.26(m,4H),7.23-7.16(m,1H),3.86-3.68(m,3H) ,3.68-3.54(m,1H),3.48(t,J=9.6Hz,1H),2.89-2.68(m,1H),2.81(dd,J=13.1, 3.2Hz,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 = 3.1Hz, 6H).

[0427]

[0146] Step 5: Synthesis of tert-butyl (3S,4R)-4-amino-3-[[tert-butyl(dimethyl)silanyl]oxymethyl]piperidine-1-carboxylate. A mixture of tert-butyl (3S,4R)-3-[[tert-butyl(dimethyl)silanyl]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 hours. The mixture was filtered through celite and washed with MeOH (3 x 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 (400MHz, DMSO-d6) δ3.61 (dd, J = 10.2, 4.9Hz, 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)silanyl]oxymethyl]-4-[[3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-indazol-6-yl]amino]piperidine-1-carboxylate. A mixture of 6-bromo-3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-indazole (471 mg, 0.94 mmol), tert-butyl (3S,4R)-4-amino-3-[[tert-butyl(dimethyl)silanyl]oxymethyl]piperidine-1-carboxylate (270 mg, 0.78 mmol), CsCO (638 mg, 1.96 mmol) and RuPhosPdG (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 silica gel column chromatography using a gradient of 0-50% EtOAc / hexanes 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. 1H NMR (400MHz, DMSO-d6) δ7.87(d,J=8.1Hz,1H),7.50-7.44(m,2H),7.42-7.26(m,9H),6.55(d,J=7 .9Hz,1H),6.52(dd,J=9.0,1.9Hz,1H),6.45(d,J=1.3Hz,1H),5.78(d,J=8.6Hz,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=15.0Hz,6H).

[0429]

[0146] Step 7: Synthesis of tert-butyl (3S,4R)-3-[[tert-butyl(dimethyl)silanyl]oxymethyl]-4-[[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazol-6-yl]amino]piperidine-1-carboxylate. A mixture of tert-butyl (3S,4R)-3-[[tert-butyl(dimethyl)silanyl]oxymethyl]-4-[[3-(2,6-dibenzyloxy-3-pyridinyl)-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 hydrogenated (1 atm) at 50°C for 2 h. The mixture was filtered through celite and washed with MeOH (3 x 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]

[0269] Step 8: Synthesis of 3-[6-[[(3S,4R)-3-(hydroxymethyl)-4-piperidinyl]amino]-1-methyl-indazol-3-yl]piperidine-2,6-dione dihydrochloride. To a solution of tert-butyl (3S,4R)-3-[[tert-butyl(dimethyl)silanyl]oxymethyl]-4-[[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazol-6-yl]amino]piperidine-1-carboxylate (350 mg, 0.60 mmol) in DCM (2.5 mL) was added 4N HCl in 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 x 5 mL) and dried in vacuo 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. 1 H NMR(500MHz,DMSO-d6)δ10.82(s,1H),8.89-8.68(m,2H),7.35(d,J=8.8Hz,1H),6.6 6(dd,J=8.8,1.7Hz,1H),6.51(s,1H),4.18(dd,J=9.0,5.1Hz,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-piperidinyl]amino]-1-methyl-indazol-3-yl]piperidine-2,6-dione. Add 5-[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]-1-methyl-indolin-2-one (35 mM) to the mixture at room temperature. To a mixture of 5-[[(3S,4R)-3-(hydroxymethyl)-4-piperidinyl]amino]-1-methyl-indazol-3-yl]piperidine-2,6-dione dihydrochloride (77.8 mg, 0.14 mmol) and DIPEA (0.10 mL, 0.60 mmol) in DMF (2 mL) was added 3-[6-[[(3S,4R)-3-(hydroxymethyl)-4-piperidinyl]amino]-1-methyl-indazol-3-yl]piperidine-2,6-dione dihydrochloride (77.8 mg, 0.14 mmol) and the reaction mixture was heated to 80° C. for 2 hours. The volatiles were removed under reduced pressure and the residue was purified by preparative HPLC (BEH column, C18) using a gradient of 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 ClN9O4 theoretical value 643.2, found 644.4 [M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ10.81(s,1H),8.61(s,1H),8.00(s,1H),7.75-7.57(m,1H),7.52(d,J=7.9Hz,1H),7.33(d,J=8.7 Hz,1H),6.90(d,J=8.4Hz,1H),6.65(d,J=8.9Hz,1H),6.48(s,1H),5.85(d,J=8.5Hz,1H),4.46(s,1H),4.18(dd,J=8.4,5 .1Hz,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). 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)

[0432] 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 similarly to Example S57 starting with the other diastereomer isolated from Step 2 of Example S57. The crude reaction mixture was purified by preparative HPLC (BEH column, C18) using a gradient of 44-54% MeCN and water containing 10 mM ammonium formate to give the title compound as a solid (5.5 mg, 14%). LCMS C 32 H 34 ClN9O4 theoretical value 643.2, found 644.3 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ8.61(s,1H),8.00(s,1H),7.66(br s,1H),7.53(d,J=8.5Hz,1H),7.33(d,J=8.8Hz,1H),6.90(d,J=8.4Hz,1H),6.65(dd,J=8.8,1.7Hz, 1H),6.48(s,1H),5.85(d,J=8.5Hz,1H),4.18(dd,J=8.8,5.1Hz,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). 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)

[0433] 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, 22.7 mmol). The reaction mixture was heated to 85° C. for 18 hours and then cooled to room temperature. The volatiles were evaporated under reduced pressure and the residue was purified by silica gel column chromatography using a gradient of 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 similarly to General Procedure 3 using 6-bromo-3-iodo-1H-pyrazolo[4,3-b]pyridine as starting material.

[0435] Step 3: Synthesis of 6-bromo-3-(2,6-dibenzyloxy-3-pyridinyl)-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-pyridinyl)boronic acid (5.36 g, 7.99 mmol, intermediate provided by Celgene), Pd(PPh3)2Cl2 (374 mg, 0.53 mmol) and 2M aqueous Na2CO3 solution (2.66 mL, 5.33 mmol) in 1,4-dioxane (18 mL) was heated to 80°C for 16 hours and then cooled to room temperature. The volatiles were evaporated under reduced pressure and the residue was purified by silica gel column chromatography using a gradient of 0-20% EtOAc / hexanes 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-pyridinyl)-1-methyl-pyrazolo[4,3-b]pyridin-6-yl]-4-piperidinyl]-N-methyl-carbamate. The title compound was synthesized according to General Procedure 2 using 6-bromo-3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-pyrazolo[4,3-b]pyridine and tert-butyl N-methyl-N-(4-piperidinyl)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. The synthesis of the title compound was achieved using General Procedures 4, 5 and 6 starting with tert-butyl N-[1-[3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-pyrazolo[4,3-b]pyridin-6-yl]-4-piperidinyl]-N-methyl-carbamate. The crude reaction mixture was purified by preparative HPLC (BEH column, C18) using a gradient of 44-54% MeCN and water containing 10 mM ammonium formate to give the title compound (5.4 mg, 12%) as a solid. LCMS C 31 H 33 C1N 10 Theoretical value of O3: 628.2, measured value: 629.3 [M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ10.89-10.82 (m, 1H), 8.59 (s, 1H), 8.41 (d, J = 2.3Hz, 1H), 8.03 (s, 1H), 7. 65(s,1H),7.57(d,J=7.9Hz,1H),7.37(d,J=2.3Hz,1H),6.95(d,J=8.6Hz,1H),4.28(dd,J=9.8,5. 2Hz,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). 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)

[0438] 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 in vacuo to give the title compound (6.21 g, quantitative) as a solid. MS (ESI) [M+H] + 325.8. 1 H NMR (400MHz, DMSO-d6) δ8.44(s,1H),7.57(s,1H).

[0439]

[0148] Step 2: 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) was added NaH (60% dispersion in mineral oil, 31 mg, 0.77 mmol) at 0°C and the reaction mixture was stirred at 0°C for 15 minutes. 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 hours. Water (20 mL) and DCM (20 mL) were added and the layers were separated. The aqueous layer was extracted with DCM (2 x 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 silica gel column chromatography using a gradient of 10-35% EtOAc / hexanes to give the title compound (46 mg, 44%) as a solid. 1 H NMR (400MHz, 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-pyridinyl)-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-pyridinyl)boronic acid (595 mg, 0.89 mmol), Pd(PPh3)2Cl2 (41.5 mg, 60 μmol) and a 2M aqueous solution of Na2CO3 (300 μL, 0.59 mmol) in 1,4-dioxane (1.5 mL) was heated to 80°C for 16 hours 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 silica gel column chromatography using a gradient of 0-15% EtOAc / hexanes to give the title compound (99.0 mg, 67%) as a solid. 1 H NMR(400MHz, DMSO-d6)δ8.87(d,J=1.0Hz,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=8.2Hz,1H),5.52(s,2H),5.44(s,2H),4.06(s,3H).

[0441] Step 4: N-[1-[3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-pyrazolo[4,3-c]pyridin-6-yl]-4-piperidinyl]-N-methyl-carbamic acid tert-butyl ester. A mixture of 6-bromo-3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-pyrazolo[4,3-c]pyridine (1.44 g, 2.87 mmol), tert-butyl N-methyl-N-(4-piperidinyl)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 silica gel column chromatography using a gradient of 0-40% EtOAc / hexanes to give the title compound (1.08 g, 59%) as a solid. 1H NMR(400MHz,DMSO-d6)δ8.71(d,J=1.0Hz,1H),7.97(d,J=8.1Hz,1H),7.51-7.43 (m,2H),7.43-7.33(m,5H),7.33-7.23(m,3H),6.72(d,J=1.1Hz,1H),6.58(d,J=8 .1Hz,1H),5.51(s,2H),5.40(s,2H),4.47(d,J=12.6Hz,2H),3.93(s,3H),2.82(t ,J=12.5Hz,2H),2.72-2.66(m,1H),2.64(s,3H),1.80-1.52(m,4H),1.40(s,9H).

[0442] Step 5: N-[1-[3-(2,6-dioxo-3-piperidinyl)-1-methyl-pyrazolo[4,3-c]pyridin-6-yl]-4-piperidinyl]-N-methyl-carbamic acid tert-butyl ester. A mixture of N-[1-[3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-pyrazolo[4,3-c]pyridin-6-yl]-4-piperidinyl]-N-methyl-carbamic acid tert-butyl ester (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 hydrogenated (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 using a gradient of 0-100% EtOAc / hexanes to give the title compound (927 mg, quantitative) as a solid. MS (ESI) [M+H] + 457.4.

[0443]

[0266] Step 6: 3-[1-Methyl-6-[4-(methylamino)-1-piperidinyl]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-piperidinyl)-1-methyl-pyrazolo[4,3-c]pyridin-6-yl]-4-piperidinyl]-N-methyl-carbamate (927 mg, 2.03 mmol) in DCM (40.6 mL) was added 4N HCl in 1,4-dioxane (5.08 mL, 20.3 mmol) and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with EtO (20 mL), filtered, and rinsed with EtO (2 x 10 mL) to give the title compound as a solid (688 mg, 86%), which was used in the next step without further purification. MS (ESI) [M+H] + 357.3.1 H NMR(400MHz,DMSO-d6)δ10.99(s,1H),9.06(s,2H),8.91(s,1H),7.17(s,1H), 4.51(dd,J=10.9,4.9Hz,1H),4.33(d,J=13.3Hz,2H),3.97(s,3H),3.36-3.17 (m,1H),3.07(t,J=12.6Hz,2H),2.77-2.60(m,2H),2.56(t,J=5.4Hz,3H),2.4 8-2.38(m,1H),2.25-2.15(m,1H),2.14(d,J=13.4Hz,2H),1.75-1.57(m,2H).

[0444]

[0269] Step 7: 3-[6-[4-[[5-Chloro-4-[(1-methyl-2-oxo-indolin-5-yl)amino]pyrimidin-2-yl]-methyl-amino]-1-piperidinyl]-1-methyl-pyrazolo[4,3-c]pyridin-3-yl]piperidine-2,6-dione. To a solution of 3-[1-methyl-6-[4-(methylamino)-1-piperidinyl]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 hours and then cooled to room temperature. The crude reaction mixture was purified by preparative HPLC (BEH column, C18) using a gradient of 44-54% MeCN and water containing 10 mM ammonium formate to give the title compound (18.6 mg, 25%) as a solid. LCMSC 31 H 33 C1N 10 Theoretical value of O3: 628.2, measured value: 629.3 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ10.90(s,1H),8.64(s,1H),8.59(s,1H),8.11-7.84(m,1H),7.64(s,1H),7.58(d,J=8.4Hz,1H),6.94(d,J=8.3 Hz,1H),6.74(s,1H),4.53(d,J=12.9Hz,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). 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)

[0445] Step 1: Synthesis of 1-methyl-6-nitroindoleline-2,3-dione. To a stirred solution of 6-nitroindoleline-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 minutes. 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 hour, 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, which was purified by flash silica gel column chromatography with 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-nitroindolin-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 reactants were 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 silica gel column chromatography with 35-45% ethyl acetate / petroleum ether to give the title compound as an off-white solid (40 mg, 0.171 mmol, 18% yield). LCMS found 193.2 [M + H] + ,Rt 1.686min.

[0447]

[0146] 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 x 20 mL). The filtrate was concentrated under reduced pressure to give the title compound (35 mg, crude material), which was used in the next step without further purification. 1 H NMR (400MHz, CDCl3): δ6.86 (d, J = 8.4Hz, 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 using General Procedures 1 and 6 starting from 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. The crude material was purified by preparative HPLC to give the title compound (18 mg, 0.028 mmol, 17% yield) as an off-white solid. LCMSC 32 H 34 ClN9O3 theoretical value 627.3, measured value 628.3 [M+H] + ; 1H NMR (400MHz, DMSO-d6): δ10.84(s,1H),8.99(s,1H),8.12(s,1H),7.42(s,1H),7.32(d,J=8.80Hz,1H),7 .26(d,J=9.20Hz,1H),7.21(d,J=8.00Hz,1H),6.52(dd,J=8.80,1.60Hz,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=6.4Hz,3H). 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)

[0449]

[0266] 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, and then 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 solution (25 mL) and then extracted with ethyl acetate (3 x 25 mL). The organic phases were combined and washed with saturated aqueous sodium chloride solution (1 x 25 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered through celite, and concentrated under reduced pressure. The crude material 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] + ; 1H NMR (400MHz, DMSO-d6) δppm 7.99 (d, J = 8.31 Hz, 1H), 7.32 (d, J = 8.31 Hz, 1H), 4.03 (s, 3H).

[0450]

[0266] 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 hours. The reaction mixture was filtered and purified by reverse phase semi-preparative HPLC (10-100% acetonitrile + 0.1% formic acid in water over 30 minutes). Fractions containing pure product were combined and freeze-dried to give the title compound as a white solid (250 mg, 0.530 mmol, 31.1% yield). MS (ESI) m / z 472.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δppm 7.33 (dd, J=8.68, 1.71Hz, 1H), 7.18 (br d,J=7.83Hz,1H),6.33-6.46(m,1H),3.86-4.05(m,2H),3.81(d,J=1.83Hz,4H),2.79-2.99(m,1H),2.56-2.64(m,1H),1.98(br d,J=12.35Hz,1H),1.47-1.63(m,1H),1.41(d,J=1.71Hz,9H),1.17-1.32(m,1H),0.88(br d,J=4.89Hz,3H).

[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. 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) was added. A solution of 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 a mixed solvent of 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 solution (25 mL) and then extracted with ethyl acetate (3×25 mL). The organic phases were combined and washed with saturated aqueous sodium chloride solution (1×25 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered through celite and concentrated under reduced pressure. The crude material 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, which was further purified by reverse phase semi-preparative HPLC (10-100% acetonitrile + water containing 0.1% formic acid over 30 minutes). Fractions containing pure product were combined and freeze-dried to give the title compound (110 mg, 0.173 mmol, 32.7% yield) as a white solid. MS (ESI) m / z 372.0 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δppm 7.94(d,J=8.07Hz,1H),7.64(d,J=8.80Hz,1H),7.43-7.51(m,2H),7.36-7.42(m,4H),7.26-7 .36(m,4H),6.92(d,J=8.19Hz,1H),6.55(d,J=8.19Hz,1H),6.19(d,J=8.93Hz,1H),5.46(s,2 H),5.41(s,2H),3.86-3.99(m,2H),3.81-3.85(m,3H),3.69-3.81(m,1H),2.75-3.07(m,1H), 1.91-2.07(m,1H),1.45-1.64(m,1H),1.41(s,9H),1.24-1.32(m,2H),0.88(d,J=6.60Hz,3H).

[0452]

[0266] 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 10% w / w palladium on carbon (0.018 g, 0.017 mmol) under hydrogen (1 atm) at 50 °C for 15 h. The reaction mixture was filtered through celite, the eluent was concentrated, and the residue was then stirred with 1 mL of TFA in DCM (1 mL) at room temperature for 30 minutes. 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 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. The synthesis of the title compound was achieved using General Procedure 6 with 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 + water containing 0.1% formic acid over 30 minutes). Fractions containing pure product were combined and freeze-dried to give the title compound (13 mg, 0.02 mmol, 19.4%) as a white solid. MS (ESI) m / z 628.8 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δppm 10.83(s,1H),8.66(s,1H),8.02(s,1H),7.63(d,J=8.80Hz,1H),7.57(s,1H),7. 52(dd,J=8.44,2.08Hz,1H),6.87-6.98(m,2H),6.31(d,J=8.80Hz,1H),4.48(br s,2H),4.13(dd,J=9.35,5.07Hz,1H),3.82-3.95(m,1H),3.77(s,3H),3.53(s,2H),3.06-3.15(m,3H), 2.92-3.03(m,1H),2.64-2.73(m,1H),2.52-2.64(m,2H),2.21-2.31(m,1H),2.09-2.19(m,1H),2.02(br d,J=9.29Hz,1H),1.54-1.67(m,1H),1.21-1.37(m,1H),0.93(d,J=6.48Hz,3H). 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)

[0454] 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 similarly to Example S62 above using 3-[1-methyl-6-(4-piperidinylamino)indazol-3-yl]piperidine-2,6-dione and 5-aminoindolin-2-one as starting materials. LCMS C 30 H 30 ClN9O3 theoretical value 599.2, found value 600.0 [M+H] + ; 1H NMR(DMSO-d6,400MHz)δ10.8-10.9(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). 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)

[0455]

[0146] 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 at ambient temperature in DMSO (5 mL) and acetic acid (0.22 mL, 3.87 mmol). After 2 hours, the reaction was complete according to LCMS. The reaction mixture was diluted with methanol (1 mL), which caused effervescence. After 10 minutes, the effervescence subsided and the solution was diluted with ethyl acetate, washed sequentially with water and 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 with a gradient of 4% methanol and 0-50% ethyl acetate / hexane. The resulting intermediate 4-[[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazol-6-yl]amino]-3,3-difluoro-piperidine-1-carboxylic acid tert-butyl ester (230 mg, 0.4817 mmol, 24.8% yield) was isolated and treated with 1,4-dioxane containing 2 mL of 4N HCl and stirred for 3 hours. The reaction mixture was then concentrated to give the title compound (270 mg, 0.6524 mmol, 33.7% yield) as a light yellow solid.

[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. Indolin-2-one 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 hours. The reaction mixture was filtered and purified by reverse-phase semi-preparative HPLC (10-100% acetonitrile + 0.1% formic acid in water (0.1% formic acid) over 30 minutes). 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-d6,400MHz)δ10.8-10.9(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). 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)

[0457]

[0146] Step 1: Synthesis of 4-[[3-(2,4-dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]amino]-3,3-difluoro-piperidine-1-carboxylic acid tert-butyl ester. To a solution of 1-(6-amino-1-methyl-indazol-3-yl)hexahydropyrimidine-2,4-dione (900 mg, 3.47 mmol), 3,3-difluoro-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (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 hours. The volatiles were removed and the residue was purified by reverse phase chromatography (C18) with a gradient of 20-100% MeCN and 10 mM ammonium formate in water 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 4-[[3-(2,4-dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]amino]-3,3-difluoro-piperidine-1-carboxylic acid tert-butyl ester as starting material. LCMS C 30 H 29 ClF2N 10 Theoretical value of O3: 650.2, measured value: 651.3 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ10.47(s,1H),8.82(s,1H),8.06(s,1H),7.51(d,J=2.1Hz,1H),7.47(dd,J=8.4,2.2Hz,1H) ,7.31(d,J=8.8Hz,1H),6.95(d,J=8.4Hz,1H),6.65(dd,J=8.9,1.9Hz,1H),6.61(d,J=1.8Hz,1H),6.05(d,J=9.2Hz ,1H),4.77-4.63(m,1H),4.49-4.36(m,1H),4.33-4.17(m,1H),3.87(t,J=6.7Hz,2H),3.81(s,3H),3.55-3.51(m,2 H),3.58-3.44(m,1H),3.28-3.18(m,1H),3.11(s,3H),2.72(t,J=6.7Hz,2H),2.03-1.95(m,1H),1.70-1.57(m,1H). 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)

[0459]

[0146] 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-phenylethylamine (2.18 g, 18.0 mmol) in toluene (35 mL) was heated to reflux for 18 hours 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) portionwise over 1 hour. The mixture was heated to 50°C for 18 hours. Another portion of sodium triacetoxyborohydride (3.56 g, 16.8 mmol) was added and the reaction mixture was heated to 50°C for an additional 6 hours. The mixture was cooled to room temperature and the volatiles were removed under reduced pressure. 2M Na2CO3 solution (50 mL) was added and the mixture was stirred at room temperature for 1 hour, followed by the addition of EtOAc (50 mL). The phases were separated and the aqueous phase was extracted with EtOAc (3 × 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 silica gel column chromatography using DCM containing 0-3% MeOH to give the title compound (4.21 g, 82%) as an oil. 1 H NMR (500MHz, methanol-d4) δ7.29-7.35(m,4H),7.20-7.25(m,1H),5.48(s,1H),4.08(q,J=6.7Hz,1H),4.04(br s,1H),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=6.62Hz,3H).

[0460]

[0146] 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 hour. The volatiles were removed under reduced pressure to give a mixture of diastereomers as a solid. The crude intermediate mixture (6.07 g) was dissolved in a 10:1 mixture of acetone:EtOH (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 x 1 mL) and dried to give the first batch of the title compound, which was used in the subsequent process.

[0461] Step 3: Synthesis of tert-butyl (4R)-3,3-difluoro-4-[[(1R)-1-phenylethyl]amino]piperidine-1-carboxylate. Compound (4R)-tert-butyl 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 solution (50 mL). The organic layer was separated and the aqueous phase was extracted with EtOAc (3×40 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated under reduced pressure to give the title compound as an oil (1.30 g, 98%). MS (ESI) [M+H] + 341.3. 1 H NMR (400MHz, DMSO-d6) δ7.36-7.27(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=7.2Hz,1H),1.64-1.58(m,1H),1.38(s,9H),1.22(d,J=6.6Hz,3H).

[0462]

[00155] Step 4: Synthesis of (4R)-4-amino-3,3-difluoro-piperidine-1-carboxylic acid tert-butyl ester. A mixture of (4R)-3,3-difluoro-4-[[(1R)-1-phenylethyl]amino]piperidine-1-carboxylic acid tert-butyl ester (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 h. The mixture was filtered over 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] + 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 (4R)-4-[[3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-indazol-6-yl]amino]-3,3-difluoro-piperidine-1-carboxylic acid tert-butyl ester. To a degassed mixture of 6-bromo-3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-indazole (200 mg, 0.40 mmol), (4R)-4-amino-3,3-difluoro-piperidine-1-carboxylic acid tert-butyl ester (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 hours and cooled to room temperature. DCM (10 mL) was added and the mixture was filtered over celite and rinsed with DCM (3×10 mL). The volatiles were concentrated under reduced pressure and the residue was purified by silica gel column chromatography using a gradient of 0-60% EtOAc / hexanes to give the title compound as a solid (200 mg, 76%). MS (ESI) [M+H] + 657.6. 1H NMR (400MHz, DMSO-d6) δ7.86 (d, J=8.1Hz, 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=9.1Hz,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 (4R)-4-[[3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-indazol-6-yl]amino]-3,3-difluoro-piperidine-1-carboxylic acid tert-butyl ester as the starting material. LCMSC 31 H 30 ClF2N9O3 theoretical value 649.2, found value 650.2 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ8.82(s,1H),8.41(s,1H),8.06(s,1H),7.51(s,1H),7.47(dd,J=8.4,2.1Hz,1H),7.35 (d,J=8.7Hz,1H),6.95(d,J=8.4Hz,1H),6.66(dd,J=8.8,1.8Hz,1H),6.62(s,1H),6.00(d,J=8.9Hz,1H),4.75- 4.64(m,1H),4.41(d,J=11.6Hz,1H),4.26-4.13(m,2H),3.82(s,3H),3.60-3.42(m,3H),3.23(t,J=11.7Hz,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). 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)

[0465] 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 analogously to Example S66 starting with (1S)-1-phenylethylamine in Step 1. LCMS C 31 H 30 ClF2N9O3 theoretical value 649.2, found value 650.3 [M+H] + ; 1 H NMR (500MHz, DMSO-d6) δ10.81(s,1H),8.82(s,1H),8.06(s,1H),7.51(s,1H),7.48(d,J=8.3Hz,1H),7.35(d ,J=8.7Hz,1H),6.95(d,J=8.4Hz,1H),6.66(d,J=8.4Hz,1H),6.62(s,1H),6.00(d,J=9.0Hz,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=12.8,5.9Hz,1H),2.05-1.92(m,1H),1.70-1.56(m,1H). 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)

[0466] 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 according to General Procedures 2, 4, 5, and 6 using tert-butyl (3,3-difluoropiperidin-4-yl)carbamate as the starting material. LCMSC 31 H 30 ClF2N9O3 theoretical value 649, found 650 [M+H] + ; 1 H NMR(DMSO-d6,400MHz)δ10.8-10.9(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). 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)

[0467] 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 ClN9O3 theoretical value 641.3, found value 642.4 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δppm 10.82(s,1H),9.03(br s,1H),8.09(s,1H),7.55(s,1H),7.50(dd,J=8.50,1.90Hz,1H),7.31(d,J=8. 68Hz,1H),7.01(d,J=8.44Hz,1H),6.51(dd,J=8.68,1.59Hz,1H),6.45(s,1H) ,5.54-6.00(m,1H),4.39(brd,J=7.70Hz,2H),4.17(dd,J=8.68,5.14Hz,1H), 3.81(s,3H),3.68(q,J=7.09Hz,2H),3.54(s,2H),3.25-3.37(m,1H),3.08(br t,J=12.10Hz,1H),2.75(br t,J=12.41Hz,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=7.09Hz,3H),0.97(d,J=6.48Hz,3H). 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)

[0468] Step 1: Synthesis of (3R,4R)-4-[[3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-indazol-6-yl]amino]-3-methyl-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 24). A mixture of 6-bromo-3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-indazole (1.92 g, 3.84 mmol), (3R,4R)-4-amino-3-methyl-piperidine-1-carboxylic acid tert-butyl ester (685 mg, 3.20 mmol), RuPhos Pd G3 (668.6 mg, 0.80 mmol) and Cs2CO3 (1.25 g, 3.84 mmol) in 1,4-dioxane (15 mL) was heated to 90° C. for 20 hours. 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 silica gel column chromatography using a gradient of 0-40% EtOAc / hexanes to give the title compound as a solid (1.37 g, 68%). MS (ESI) [M+H] + 634.1. 1 H NMR(400MHz, DMSO-d6)δ7.86(d,J=8.1Hz,1H),7.50-7.46(m,1H),7.46-7.25(m,10H),6.54(d,J =8.1Hz,1H),6.43(d,J=1.8Hz,1H),6.41(d,J=2.2Hz,1H),5.70(d,J=8.9Hz,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,1 H), 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 = 6.5Hz, 3H).

[0469]

[0146] Step 2: Synthesis of (3R,4R)-4-[[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazol-6-yl]amino]-3-methyl-piperidine-1-carboxylic acid tert-butyl ester. A mixture of (3R,4R)-4-[[3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-indazol-6-yl]amino]-3-methyl-piperidine-1-carboxylic acid tert-butyl ester (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 at 50°C under H2 (1 atm) for 9 h. The mixture was filtered through celite and washed with MeOH (2 x 50 mL) and THF (2 x 100 mL). The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography using a gradient of 0-5% MeOH / DCM to give the title compound as a solid (695 mg, 69%). MS (ESI) [M+H] + 456.3. 1 H NMR (400MHz, DMSO-d6) δ10.81(s,1H),7.31(d,J=8.8Hz,1H),6.51(dd,J=8.8,1.7Hz,1H),6.4 0(s,1H),5.72(d,J=8.9Hz,1H),4.17(dd,J=8.7,5.2Hz,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=6.5Hz,3H).

[0470]

[0146] 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 (3R,4R)-4-[[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazol-6-yl]amino]-3-methyl-piperidine-1-carboxylic acid tert-butyl ester (8 g, 17.6 mmol) in ethyl acetate (35 mL) was added 4 M HCl in ethyl acetate (35 mL) at 25 °C. After the addition, 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] +356.2.400MHzMeODδ:8.04(s,1H),7.81(d,J=8.8Hz,1H),7.11(d,J=8.8Hz,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-piperidinyl]amino]-1-methyl-indazole-3-yl]piperidine-2,6-dione. To a solution of 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) in DMSO (0.50 mL) was added 5-((5-chloro-2-fluoropyrimidin-4-yl)amino)-1-methylindolin-2-one (41.1 mg, 0.140 mmol) and heated to 80° C. for 2 hours. The reaction mixture was cooled to room temperature and purified directly by preparative HPLC (BEH column, C18) using a gradient of 44-54% MeCN and water containing 10 mM ammonium formate to give the title compound (13.5 mg, 16%) as a solid. LCMS C 32 H 34 ClN9O3 theoretical value 627.3, found value 628.4 [M+H] + ; 1H NMR (500MHz, DMSO-d6) δ10.81(s,1H),8.65(s,1H),8.02(s,1H),7.57(s,1H),7.52(d,J=8.4Hz,1H),7.30(d,J=8.8Hz,1H) ,6.93(d,J=8.4Hz,1H),6.50(d,J=8.8Hz,1H),6.43(s,1H),5.68(d,J=9.1Hz,1H),4.53-4.39(m,2H),4.17(dd,J=8.7,5.2H z,1H),3.81(s,3H),3.53(s,2H),3.27-3.21(m,1H),3.10(s,3H),3.02(t,J=12.2Hz,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=6.5Hz,3H). 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)

[0472] 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 isolated using preparative HPLC (100% ACN (no additives) isocratic elution at a flow rate of 1 mL / min) with a Regis Whelk-O1 RR or SS column at 22°C. The title compound eluted as the first peak with Rt = 10.01 min. LCMS C 32 H 34 ClN9O3 theoretical value 627.3, found value 628.4 [M+H] + ; 1H NMR(DMSO-d6,400MHz)δ10.7-10.9(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). 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)

[0473] 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 isolated using preparative HPLC (1 mL / min flow rate in 100% ACN (no additives) isocratic elution) with a Regis Whelk-O1 RR or SS column at 22°C. The title compound eluted as the second peak with Rt = 14.87 min. LCMS C 32 H 34 ClN9O3 theoretical value 627.3, found value 628.4 [M+H] + ; 1H NMR(DMSO-d6,400MHz)δ10.7-10.9(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) 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)

[0474]

[00145] Step 1: Synthesis of (3R,4R)-4-[[3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-indazol-6-yl]-methyl-amino]-3-methyl-piperidine-1-carboxylic acid tert-butyl ester. To an ice-cold solution of (3R,4R)-4-[[3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-indazol-6-yl]amino]-3-methyl-piperidine-1-carboxylic acid tert-butyl ester (1.55 g, 2.45 mmol) and a 60% NaH dispersion in mineral oil (245 mg, 6.11 mmol) in DMF (20 mL) was added iodomethane (305 μL, 4.89 mmol) and the mixture was stirred at room temperature for 48 hours. Another batch was prepared using 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 x 75 mL). The combined organic fractions were washed with brine (20 mL), dried over MgSO 4 , filtered, and concentrated. The residue was purified by reverse phase chromatography (C18) using a gradient of 20-100% MeCN and water containing 10 mM ammonium formate to give the title compound (700 mg, 44%) as a solid. MS (ESI) [M+H] + 649.34. 1HNMR(400MHz,DMSO-d6)δ7.88(d,J=8.1Hz,1H),7.47(dd,J=8.7,7.1Hz,3H),7.43-7.23(m,8H ),6.78(dd,J=9.4,2.0Hz,1H),6.61(d,J=1.9Hz,1H),6.56(d,J=8.1Hz,1H),5.44(s,2H),5.4 0(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=6.5Hz,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 (3R,4R)-4-[[3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-indazol-6-yl]-methyl-amino]-3-methyl-piperidine-1-carboxylic acid tert-butyl ester as starting material. LCMS C 32 H 34 ClN9O3 theoretical value 641.3, found value 642.4 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ10.80(s,1H),8.62(s,1H),7.98(s,1H),7.55(s,1H),7.49(d,J=8.4Hz,1H),7.41(d, J=9.1Hz,1H),6.90(d,J=8.5Hz,1H),6.85(d,J=7.4Hz,1H),6.59(s,1H),4.58-4.51(m,2H),4.19(dd,J=8.9,5 .2Hz,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=6.5Hz,3H). 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)

[0476] 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 slowly warm to room temperature after 1 hour and the reaction mixture was then stirred at 25°C for 16 hours. The reaction mixture was then evaporated. The crude residue was purified by silica gel chromatography using 50-100% EtOAc / PE to give the title compound (190 mg, 0.252 mmol, 21.44% yield) as a light 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. Add stirred 5-((5-chloro-2-fluoropyrimidin-4-yl)amino)-1-methyl-1,3-dihydro-2H- To a solution of 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. LCMSC 31 H 33 C1N 10Theoretical value of O3: 628.2, measured value: 629.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6): δ10.82(s,1H),8.85(s,1H),8.36(d,J=2.00Hz,1H),8.06(s,1H),7.86(s,1H),7.31 (d,J=8.80Hz,1H),6.44-6.52(m,2H),5.69(d,J=8.80Hz,1H),4.44(d,J=9.20Hz,2H),4.17(q,J=5.20Hz,1H ),3.82(s,3H),3.61(s,2H),3.13(s,3H),δ3.02(t,J=Hz,1H),2.53-2.68(m,3H),2.33(t,J=1.60Hz,1H),2. 25(t,J=6.00Hz,1H),2.06-2.17(m,2H),1.58(d,J=4.80Hz,1H),1.15-1.17(m,1H),0.96(d,J=6.40Hz,3H). 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)

[0478]

[0146] 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) was added DIPEA (0.254 mL, 1.46 mmol) and 5-chloro-2,4-difluoropyrimidine (219 mg, 1.46 mmol) at -45 °C under a nitrogen atmosphere. 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 material. The crude product was purified by flash silica gel column chromatography with 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. Add 3-(1-methyl-6-(((3R,4R)-3-methylpiperidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione to a stirred solution at 25°C. To a solution of 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) 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 material was purified by preparative HPLC to give the title compound (24 mg, 0.028 mmol, 25% yield). LCMS C 34 H 38 ClN9O4 theoretical value 671.3, measured value 672.3 [M+H] + ; 1 H NMR (400MHz, DMSO-d6): δ10.83(s,1H),8.67(s,1H),8.02(s,1H),7.56(s,1H),7.50(d,J=8.40Hz,1H),7.31(d,J=8.80Hz, 1H),7.01(d,J=8.40Hz,1H),6.51(dd,J=1.6Hz and 8.8Hz,1H),6.44(s,1H),5.71(d,J=9.20Hz,1H),4.51-4.44(m,2H),4.18(d d,J=5.2Hz and 8.4Hz,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,1 H),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=6.40Hz,3H). 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)

[0480] 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 isolated as the first eluting peak using preparative HPLC (1 mL / min flow rate in 100% ACN (no additives) isocratic elution) with a Regis Whelk-O1 SS, 21×250 mm, 5μ column at 22° C., isolated as the first eluting peak, Rt=9.85 min. LCMS C 34 H 38 ClN9O4 theoretical value 671.3, measured value 672.3 [M+H] + ; 1 H NMR (400MHz, 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, 8.5Hz, 1H) ,7.30(d,J=8.8Hz,1H),7.00(d,J=8.6Hz,1H),6.50(dd,J=1.7,8.8Hz,1H),6.43(d,J=1.1Hz,1H),5.69(d,J=8.9 Hz,1H),4.53-4.40(m,2H),4.17(dd,J=5.2,8.7Hz,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=6.6Hz,3H). 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)

[0481] 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 isolated as the second eluting peak using preparative HPLC (1 mL / min flow rate in 100% ACN (no additives) isocratic elution) with a Regis Whelk-O1 SS, 21×250 mm, 5μ column at 22° C., with Rt=13.85 min. LCMS C 34 H 38 ClN9O4 theoretical value 671.3, measured value 672.3 [M+H] + ; 1 H NMR (400MHz, 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, 8.4Hz, 1H) ,7.30(d,J=8.7Hz,1H),7.00(d,J=8.6Hz,1H),6.50(dd,J=1.7,8.8Hz,1H),6.43(d,J=1.2Hz,1H),5.69(d,J=9.2 Hz,1H),4.52-4.41(m,2H),4.17(dd,J=5.2,8.7Hz,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=6.5Hz,3H). 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)

[0482] 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 and 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 material was purified by flash silica gel column chromatography using 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]

[0266] 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 hydroxide on carbon (192 mg) under nitrogen. The reaction mixture was stirred at 25 °C under hydrogen pressure for 8 hours. The reaction mixture was filtered through a pad of celite, and the celite pad was washed with a 1:1 mixture of acetonitrile and methanol (3 x 25 mL). The filtrate was concentrated under reduced pressure to give the crude compound. The crude material was purified by flash column chromatography on silica gel with 5% MeOH / DCM to afford 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]

[0266] Step 3: Synthesis of 3-(6-((2R,6R)-2,6-dimethylpiperazin-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione trifluoroacetate. 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]

[0266] 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 trifluoroacetate (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) 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 as an off-white solid (26 mg, 0.040 mmol, 29% yield). LCMS C 32 H 34 Theoretical value of ClN9O3 is 627.3, and the measured value is 628.2 [M+H] + ; 1H NMR (400MHz, DMSO-d6): δ10.88(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=8.40Hz,1H),6.87(d,J=8.80Hz,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=6.4Hz,6H). 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)

[0486] 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 isolated using preparative HPLC (1 mL / min flow rate in 100% ACN (no additives) isocratic elution) at 22°C with a Regis Whelk-O1 SS, 21 x 250 mm, 5μ column. The title compound was isolated as the first eluting peak with an Rt = 10.08 min. LCMS C 32 H 34 Theoretical value of ClN9O3 is 627.3, and the measured value is 628.2 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ (ppm) = 10.86 (s, 1H), 8.69 (s, 1H), 8.03 (s, 1H), 7.60 (d, J = 1.7Hz, 1H), 7 .57-7.50(m,2H),7.00(d,J=1.2Hz,1H),6.95(d,J=8.4Hz,1H),6.86(dd,J=1.6,8.9Hz,1H),4.28 (dd,J=5.1,9.5Hz,1H),3.91(s,5H),3.82-3.73(m,2H),3.67(dd,J=5.3,12.8Hz,2H),3.56(s,2 H), 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 = 6.2Hz, 6H). 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)

[0487] 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 isolated using preparative HPLC (1 mL / min flow rate in 100% ACN (no additives) isocratic elution) at 22°C with a Regis Whelk-O1 SS, 21 x 250 mm, 5μ column. The title compound was isolated as the second eluting peak with an Rt = 13.90 min. LCMS C 32 H 34 Theoretical value of ClN9O3 is 627.3, and the measured value is 628.2 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ (ppm) = 10.86 (s, 1H), 8.69 (s, 1H), 8.03 (s, 1H), 7.60 (d, J = 1.7Hz, 1H), 7 .57-7.50(m,2H),7.00(d,J=1.3Hz,1H),6.95(d,J=8.3Hz,1H),6.86(dd,J=1.6,8.9Hz,1H),4.28 (dd,J=5.2,9.4Hz,1H),3.91(s,5H),3.82-3.74(m,2H),3.67(dd,J=5.3,12.7Hz,2H),3.56(s,2 H), 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 = 6.1Hz, 6H). 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)

[0488]

[0146] Step 1: Synthesis of (2S,4R)-4-[[3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-indazol-6-yl]amino]-2-methyl-piperidine-1-carboxylic acid tert-butyl ester. A mixture of 6-bromo-3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-indazole (1.9 g, 3.80 mmol), (2S,4R)-4-amino-2-methyl-piperidine-1-carboxylic acid tert-butyl ester hydrochloride (1.05 g, 4.18 mmol) and tBuXPhos-Pd-G3 (302 mg, 0.380 mmol) and NaOtBu (912 mg, 9.49 mmol) in MeTHF (38 mL) was evaporated and backfilled with nitrogen for 3 cycles. The mixture was heated to 85°C for 1.5 hours and cooled to room temperature. DCM (30 mL) was added and the mixture was filtered over a pad of celite and rinsed with DCM (3 x 30 mL). The volatiles were concentrated under reduced pressure and the residue was purified by silica gel column chromatography using a gradient of 0-60% EtOAc / hexanes to give the title compound (2.01 g, 84%) as a solid. MS (ESI) [M+H] + 634.1. 1H NMR (400MHz, DMSO-d6) δ7.87(d,J=8.1Hz,1H),7.46(d,J=6.9Hz,2H),7.42-7.21(m,9H),6.55(d, J=8.1Hz,1H),6.47-6.36(m,2H),5.66(d,J=8.3Hz,1H),5.44(s,2H),5.41(s,2H),4.45-4.33(m,1 H),3.89(s,3H),3.88-3.86(m,1H),3.76-3.62(m,1H),3.01(t,J=13.9Hz,1H),2.05(d,J=11.5Hz, 1H),1.87-1.83(m,1H),1.48-1.43(m,1H),1.41(s,9H),1.23(d,J=7.0Hz,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 (2S,4R)-4-[[3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-indazol-6-yl]amino]-2-methyl-piperidine-1-carboxylic acid tert-butyl ester as starting material. LCMS C 32 H 34 ClN9O3 theoretical value 627.3, measured value 628.3 [M+H] + ; 1H NMR (500MHz, DMSO-d6) δ10.81(s,1H),8.63(s,1H),8.01(s,1H),7.55(s,1H),7.54-7.46(m,1H),7.33(d,J= 8.7Hz,1H),6.93(d,J=8.4Hz,1H),6.52(dd,J=8.8,1.7Hz,1H),6.47(s,1H),5.67(d,J=8.3Hz,1H),4.91(br s,1H),4.48(br s,1H),4.18(dd,J=8.8,5.1Hz,1H),3.83(s,3H),3.81-3.74(m,1H),3.5 4(s,2H),3.11(s,3H),3.06(td,J=13.1,1.7Hz,1H),2.66-2.56(m,2H), 2.31-2.22(m,1H),2.17-2.08(m,2H),1.92(d,J=11.3Hz,1H),1.47(td, J=13.0,5.7Hz,1H),1.26(d,J=6.9Hz,3H),1.15(td,J=13.9,5.3Hz,1H). 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)

[0490] 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 isolated using preparative HPLC (1 mL / min flow rate in 100% ACN (no additives) isocratic elution) at 22°C with a Regis Whelk-O1 SS, 21 x 250 mm, 5μ column. The title compound was isolated as the first eluting peak with an Rt = 11.30 min. LCMS C 32 H 34 ClN9O3 theoretical value 627.3, measured value 628.3 [M+H] + ; 1H NMR(400MHz,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=8.7Hz,1H),6.93(d,J=8.3Hz,1H),6.62-6.40(m,2H),5.67(br d,J=8.5Hz,1H),5.09-4.32(m,2H),4.18(dd,J=5.1,8.8Hz,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=10.5Hz,1H),1.46(dt,J=5.2,11.9Hz,1H),1.26(br d,J=6.7Hz,3H),1.20-1.09(m,1H). 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)

[0491] 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 isolated using preparative HPLC (1 mL / min flow rate in 100% ACN (no additives) isocratic elution) at 22°C with a Regis Whelk-O1 SS, 21 x 250 mm, 5μ column. The title compound was isolated as the second eluting peak with an Rt = 19.77 min. LCMS C 32 H 34 ClN9O3 theoretical value 627.3, measured value 628.3 [M+H] + ; 1H NMR (400MHz, 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=8.8Hz, 1H), 6.93 (br d,J=8.1Hz,1H),6.58-6.39(m,2H),5.67(br d,J=8.5Hz,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=6.6Hz,3H),1.20-1.07(m,1H). 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)

[0492]

[00155] Step 1: Synthesis of (2S,4R)-4-[[3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-indazol-6-yl]amino]-2-methyl-piperidine-1-carboxylic acid tert-butyl ester. A mixture of 6-bromo-3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-indazole (1.9 g, 3.80 mmol, intermediate provided by Celgene), (2S,4R)-4-amino-2-methyl-piperidine-1-carboxylic acid tert-butyl ester hydrochloride (1.05 g, 4.18 mmol) and tBuXPhos-Pd-G3 (302 mg, 0.380 mmol) and NaOtBu (912 mg, 9.49 mmol) in MeTHF (38 mL) was evaporated and backfilled with nitrogen for 3 cycles. The mixture was heated to 85°C for 1.5 hours and cooled to room temperature. DCM (30 mL) was added and the mixture was filtered over a pad of celite and rinsed with DCM (3 x 30 mL). The volatiles were concentrated under reduced pressure and the residue was purified by silica gel column chromatography using a gradient of 0-60% EtOAc / hexanes to give the title compound (2.01 g, 84%) as a solid. MS (ESI) [M+H] + 634.1. 1H NMR (400MHz, DMSO-d6) δ7.87(d,J=8.1Hz,1H),7.46(d,J=6.9Hz,2H),7.42-7.21(m,9H),6.55(d, J=8.1Hz,1H),6.47-6.36(m,2H),5.66(d,J=8.3Hz,1H),5.44(s,2H),5.41(s,2H),4.45-4.33(m,1 H),3.89(s,3H),3.88-3.86(m,1H),3.76-3.62(m,1H),3.01(t,J=13.9Hz,1H),2.05(d,J=11.5Hz, 1H),1.87-1.83(m,1H),1.48-1.43(m,1H),1.41(s,9H),1.23(d,J=7.0Hz,3H),1.16-1.05(m,1H).

[0493] Step 2: Synthesis of (2S,4R)-4-[[3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-indazol-6-yl]-methyl-amino]-2-methyl-piperidine-1-carboxylic acid tert-butyl ester. To a solution of (2S,4R)-4-[[3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-indazol-6-yl]amino]-2-methyl-piperidine-1-carboxylic acid tert-butyl ester (525 mg, 0.83 mmol) in DMSO (6.5 mL) were added formaldehyde solution (0.53 mL, 7.09 mmol, 37%) and decaborane (152 mg, 1.24 mmol) 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 silica gel column chromatography using a gradient of 0-50% EtOAc / hexanes to give the title compound (449 mg, 84%) as a solid. MS (ESI) [M+H] + 648.7; 1H NMR(500MHz,DMSO-d6)δ7.89(d,J=8.1Hz,1H),7.51-7.44(m,3H),7.42-7.36(m,4H),7.36-7.24(m, 4H),6.77(dd,J=9.3,2.0Hz,1H),6.63(d,J=1.8Hz,1H),6.56(d,J=8.1Hz,1H),5.48-5.41(m,2H),5. 41(s,2H),4.51-4.36(m,1H),4.10(t,J=11.9Hz,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=13.3Hz,1H),1.41(s,9H),1.25-1.19(m,3H).

[0494]

[0266] Step 3: Synthesis of (2S,4R)-4-[[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazol-6-yl]-methyl-amino]-2-methyl-piperidine-1-carboxylic acid tert-butyl ester. A mixture of (2S,4R)-4-[[3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-indazol-6-yl]-methyl-amino]-2-methyl-piperidine-1-carboxylic acid tert-butyl ester (446 mg, 0.69 mmol) and Piermann'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 hours and cooled to room temperature. The mixture was filtered on a pad of celite and rinsed with THF (3 x 30 mL). The volatiles were concentrated under reduced pressure and the residue was purified by silica gel column chromatography using a gradient of 10-100% EtOAc / hexanes to give the title compound as a solid (303 mg, 94%). MS (ESI) [M+H] + 470.3. 1H NMR (400MHz, DMSO-d6) δ10.83(s,1H),7.48(d,J=9.0Hz,1H),6.88(dd,J=9.2,1.9Hz,1H),6.64(d, J=1.7Hz,1H),4.49-4.36(m,1H),4.24(dd,J=8.9,5.1Hz,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=12.1Hz,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-piperidinyl]amino]indazol-3-yl]piperidine-2,6-dione hydrochloride. To a solution of (2S,4R)-4-[[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazol-6-yl]-methyl-amino]-2-methyl-piperidine-1-carboxylic acid tert-butyl ester (400 mg, 0.85 mmol) in 1,4-dioxane (5 mL) was added 4N HCl in 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 in Et2O (10 mL) to give the title compound as a solid (295 mg, 85%), which was used in the next step without further purification. MS (ESI) [M+H] + 370.3. 1 H NMR(500MHz,DMSO-d6)δ10.88(s,1H),9.12(brs,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=5.4Hz,3H).

[0496]

[0269] 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-piperidinyl]-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-piperidinyl]amino]indazol-3-yl]piperidine-2,6-dione hydrochloride (64.1 mg, 0.16 mmol) in DMF (2 mL) and DMSO (0.5 mL) were 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 using a gradient of 20-75% MeCN and 10 mM ammonium formate in water to give the title compound as a solid (47 mg, 48%). LCMSC 33 H 36 ClN9O3 theoretical value 641.3, measured value 642.3 [M+H] + ; 1 H NMR(500MHz,DMSO-d6)δ10.83(s,1H),8.63(s,1H),8.01(s,1H),7.56(br s,1H),7.52-7.43(m,2H),6.96-6.85(m,2H),6.65(d,J=1.6Hz,1H),5.17-4.7 8(m,1H),4.72-4.36(m,1H),4.29-4.16(m,2H),3.87(s,3H),3.54(s,2H),3.15 -3.03(m,4H),2.75(s,3H),2.68-2.54(m,2H),2.34-2.26(m,1H),2.17(td,J= 11.9, 6.0Hz, 1H), 1.86-1.71 (m, 2H), 1.71-1.52 (m, 2H), 1.25 (d, J = 6.8Hz, 3H). Example S85. 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)-3-methylpiperidine-2,6-dione (85)

[0497] Step 1: Synthesis of 6-bromo-1-methyl-indazole-3-carbaldehyde. To a solution of 6-bromo-1H-indazole-3-carbaldehyde (5.000 g, 22.22 mmol, 1.00 eq) in dimethylformamide (50 mL) was added cesium carbonate (14.480 g, 44.44 mmol, 2.00 eq) and iodomethane (3.780 g, 26.66 mmol, 1.7 mL, 1.20 eq), and the mixture was stirred at 50° C. for 12 hours. The reaction mixture was cooled to room temperature. The mixture was filtered, and ethyl acetate (100 mL) and water (50 mL) were added to the filtrate, and the organic layer was separated. The aqueous phase was extracted with ethyl acetate (50 mL×2). The combined extracts were washed with saturated brine (50 mL), dried over magnesium sulfate, filtered, and the filtrate was concentrated to give the product. The residue was purified by silica gel column (5-10% ethyl acetate / petroleum ether). The title compound was obtained as a white solid (3.500 g, 14.64 mmol, 65.9% yield). LCMS: 240.9 [M+H] +

[0498] Step 2: Synthesis of (6-bromo-1-methyl-indazol-3-yl)methanol. To a solution of 6-bromo-1-methyl-indazole-3-carboxaldehyde (2.800 g, 11.71 mmol, 1.00 eq) in ethanol (40 mL) was added sodium borohydride (0.886 g, 23.42 mmol, 2.00 eq) at 0 ° C. The mixture was stirred at 20 ° C for 1 hour. 6-bromo-1-methyl-indazole-3-carboxaldehyde was consumed and the desired substance was detected by LCMS. The mixture was filtered and ethyl acetate (50 mL) and water (50 mL) were added to the filtrate under reduced pressure and the organic layer was separated. The aqueous phase was extracted with ethyl acetate (50 mL×2). The combined extracts were washed with saturated brine (50 mL), dried over magnesium sulfate, filtered and the filtrate was concentrated to give the title compound (3.000 g, crude material) as a white solid. LCMS: 242.0 [M+H] +

[0499] Step 3: Synthesis of 6-bromo-3-(chloromethyl)-1-methyl-1H-indazole. To a solution of (6-bromo-1-methyl-indazole-3-yl)methanol (3.000 g, 12.44 mmol, 1.00 eq) in dichloromethane (50 mL) was added thionyl chloride (2.960 g, 24.89 mmol, 1.8 mL, 2.00 eq) at 0 ° C. The mixture was stirred at 20 ° C for 2 hours. (6-bromo-1-methyl-indazole-3-yl)methanol was exhausted and the desired substance was detected by LCMS. The mixture was concentrated under reduced pressure. The mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel column (5-20% ethyl acetate / petroleum ether). The title compound (1.600 g, 6.16 mmol, 49.5% yield) was obtained as a yellow solid. LCMS: 260.9 [M + 1] + . 1 H NMR (400 MHz, chloroform-d) δ, 7.69 (d, J = 8.8 Hz, 1H), 7.59 (s, 1H), 7.31 (m, J = 1.2, 8.4 Hz, 1H), 4.93 (s, 2H), 4.02 (s, 3H)

[0500] Step 4: Synthesis of 2-(6-bromo-1-methyl-1H-indazol-3-yl)acetonitrile. To a solution of 6-bromo-3-(chloromethyl)-1-methyl-1H-indazole (1.95 g, 7.51 mmol) in DMF (25.05 ml) was added sodium cyanide (0.479 g, 9.77 mmol), and the mixture was stirred at 60 ° C for 3 hours. The reaction mixture was cooled to room temperature and ethyl acetate (100 mL) and water (50 mL) were added. The aqueous phase was extracted with ethyl acetate (50 mL×2). The combined extracts were washed with saturated brine (50 mL), dried over magnesium sulfate, filtered and concentrated to give a substance as a yellow solid (1.867 g, 7.47 mmol, 99% yield). It was used in the next step as is. LCMS: 249.8 [M+H] + .

[0501] Step 5: Synthesis of 2-(6-bromo-1-methyl-1H-indazol-3-yl)propionitrile. To a solution of 2-(6-bromo-1-methyl-1H-indazol-3-yl)acetonitrile (1.867 g, 7.47 mmol) in tetrahydrofuran (46.7 ml) was added potassium tert-butoxide (1.005 g, 8.96 mmol) at -20 ° C. After the mixture was stirred at -20 ° C for 30 minutes, a solution of iodomethane (0.467 mL, 7.47 mmol) was added dropwise. The mixture was stirred overnight while warming to room temperature. The mixture was filtered and the filtrate was concentrated. The residue was purified with 20% EtOAc / hexane to obtain the title compound (0.5885 g, 2.228 mmol, 29.8% yield) as a yellow oil. LCMS: 265.1 [M+H] + . 1 H NMR (chloroform-d, 400 MHz) δ 7.6-7.8 (m, 1H), 7.5-7.6 (m, 1H), 7.3-7.5 (m, 1H), 4.3-4.4 (m, 1H), 4.39 (s, 1H), 3.9-4.1 (m, 5H), 1.6-1.9 (m, 3H)

[0502] Step 6: Synthesis of tert-butyl 4-(6-bromo-1-methyl-1H-indazol-3-yl)-4-cyanopentanoate. To a solution of 2-(6-bromo-1-methyl-1H-indazol-3-yl)propionitrile (0.300 g, 1.136 mmol) and tert-butyl acrylate (0.333 mL, 2.272 mmol) in toluene (4.54 ml) were added potassium carbonate (0.314 g, 2.272 mmol)) and N-benzyl-N,N-diethylethylammonium chloride (0.026 g, 0.114 mmol). The mixture was stirred at 65 ° C for 12 hours. After cooling, the mixture was filtered and the filtrate was concentrated. The residue was further purified by preparative TLC (20% ethyl acetate / hexane). The substance was obtained as a yellow oil (0.212 g, 0.540 mmol, 47.6% yield). LCMS: 336.1 (M- t Bu+H) + . 1 H NMR (chloroform-d, 400MHz) δ7.84(s,1H),7.8-7.9(m,1H),7.57(s,1H),7.5-7.7(m,1H),7. 30(s,1H),7.3-7.3(m,1H),4.00(s,3H),2.3-2.6(m,4H),1.87(s,3H),1.41(s,9H)

[0503] Step 7: Synthesis of tert-butyl (3R,4R)-4-((3-(5-(tert-butoxy)-2-cyano-5-oxopent...

Claims

1. A compound of formula (IA): or a pharmaceutically acceptable salt thereof, wherein: X 1 and X 2 Each independently is N or CH, subject to the condition that X 1 and X 2 At least one of is N; R 1a and R 1b Each is independently H, halogen or C1-C6 alkyl; R 2a and R 2b Each is independently H, C1-C6 alkyl, -O(C1-C6 alkyl), -OH, halogen, C1-C6 haloalkyl or C1-C6 alkyl-OH, or R 2a and R 2b Together with the carbon atom to which it is attached, it forms a spiro C3-C5 cycloalkyl group, or R 2a and R 2b Together they form oxygen; or R 1a and R 2a Together they form a bridged C2-C3 alkylene group; R 3a and R 3b Each is independently H, halogen or C1-C6 alkyl; R 4a and R 4b are each independently H, halogen or C1-C6 alkyl, or R 4a and R 4b Together with the carbon atom to which it is attached, it forms a spiro C3-C5 cycloalkyl group; R 5a and R 5b Each is independently H, halogen 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, subject to the constraint that x and y are not both 1; R 8 is Cl or -CN; R 9 is F; X 3 N or CH; z is 0 or 1; R 10a and R 10b are each independently H or halogen; 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 the heterocyclyl contains 1-3 heteroatoms selected from N, O and S; R 12 is H, halogen or C1-C6 alkyl; R 13 is H or halogen; R 14 is H or C1-C6 alkyl; X 4 N or CR 15 ; R 15 is H or C1-C6 alkyl; X 5 and X 6 are each independently N or CH; and is a single bond or a double bond; wherein one or more hydrogen atoms in the compound are optionally replaced by deuterium.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has formula (I): in: X 1 and X 2 Each independently is N or CH, subject to the condition that X 1 and X 2 At least one of is N; R 1a and R 1b Each is independently H, halogen or C1-C6 alkyl; R 2a and R 2b Each is independently H, C1-C6 alkyl, -OH, halogen or C1-C6 alkyl-OH, or R 2a and R 2b Together with the carbon atom to which it is attached, it forms a spiro C3-C5 cycloalkyl group, or R 2a and R 2b Together they form oxygen; or R 1a and R 2a Together they form a bridged C2-C3 alkylene group; R 3a and R 3b Each is independently H, halogen or C1-C6 alkyl; R 4a and R 4b are each independently H, halogen or C1-C6 alkyl, or R 4a and R 4b Together with the carbon atom to which it is attached, it forms a spiro C3-C5 cycloalkyl group; R 5a and R 5b Each is independently H, halogen 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, subject to the constraint that x and y are not both 1; R 8 is Cl or -CN; R 9 is F; X 3 N or CH; z is 0 or 1; R 10a and R 10b are each independently H or halogen; 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 the heterocyclyl contains 1-3 heteroatoms selected from N, O and S; R 12 is H, halogen or C1-C6 alkyl; R 13 is H or halogen; R 14 is H or C1-C6 alkyl; X 4 N or CR 15 ; R 15 is H or C1-C6 alkyl; X 5 and X 6 are each independently N or CH; and is a single bond or a double bond; wherein one or more hydrogen atoms in the compound are optionally replaced by deuterium.

3. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein: X 1 is CH and X 2 N; or X 1 N and X 2 For CH.

4. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein: X 1 and X 2 Each is N.

5. A compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein: R 1a and R 1b Each is independently H, halogen or C1-C3 alkyl.

6. A compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, wherein: R 2a and R 2b are each independently H, C1-C3 alkyl, -OH, halogen or C1-C3 alkyl-OH, or R 2a and R 2b Together with the carbon atom to which it is attached, it forms a spiro C3-C4 cycloalkyl group, or R 2a and R 2b Together they form oxygen.

7. A compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein: R 3a and R 3b Each is independently H, halogen or C1-C3 alkyl.

8. A compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, wherein: R 4a and R 4b are each independently H, halogen or C1-C3 alkyl, or R 4a and R 4b Together with the carbon atom to which it is attached, it forms a spiro C3-C4 cycloalkyl.

9. The compound according to claim 8 or a pharmaceutically acceptable salt thereof, wherein: R 5a and R 5b Each is independently H, halogen or C1-C3 alkyl.

10. The compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, wherein for:

11. A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein: R 11 It 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 1-2 heteroatoms selected from N and O.

12. A compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, wherein for:

13. A compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, wherein for:

14. A compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, wherein for:

15. A compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, wherein the compound has formula (II), (III) or (IV):

16. The compound of claim 15 or a pharmaceutically acceptable salt thereof, wherein the compound has formula (IIIb):

17. A compound and a pharmaceutically acceptable salt thereof, wherein the compound is selected from the compounds in Table 1.

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

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 claims 1 to 17 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 18.

20. A method for 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 claims 1 to 17 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 18.

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