Bcl6 modulators as ligand-directed degraders

Abstract

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

Description

[0001] Cross-reference to related applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 595,058, filed November 1, 2023, which is incorporated herein by reference in its entirety for any purpose.

[0003] Invention Field

[0004] This disclosure generally relates to compounds, compositions and methods of preparing the same, and the use of said compounds and compositions in the treatment of cancer or autoimmune diseases. Background of the Invention

[0006] BCL6 (B-cell lymphoma 6) is a member of the BTB / POZ-zinc finger family, containing an N-terminal BTB / POZ domain and a C-terminal zinc finger. As a transcription factor for T-follicular helper (Tfh) cells, BCL6 is essential for the formation of germinal centers (GCs) in naïve B cells and thus for antibody affinity maturation. Initially identified as an oncogene in diffuse large B-cell lymphoma (DLBCL), BCL6's role has been linked to various disease types, including B-cell acute lymphoblastic leukemia, chronic myeloid leukemia, breast cancer, and non-small cell lung cancer (NSCLC) (Cardenas et al., Clin Cancer Res 2017, 23, 885-893). The N-terminal BTB / POZ domain binds to and recruits co-repressor molecules such as SMRT, NCOR1, and BCOR, thereby forming class I and II histone deacetylase complexes, and the C-terminal zinc finger binds to specific DNA recognition sequences (Yang et al., CellDev. Biol. 2019, 7, 272). After binding to its target genes and forming complexes, BCL6 reduces the RNA expression of its target genes, including several important tumor suppressors. Overexpression of BCL6, commonly found in malignancies such as non-Hodgkin's lymphoma (NHL), causes ectopic inhibition of cell cycle and DNA repair checkpoint proteins, leading to unrestricted cell proliferation and tumorigenesis.

[0007] It is known that GC reactions increase the production of pathogenic autoantibodies, leading to several diseases, suggesting the potential therapeutic applicability of methods for inhibiting or degrading BCL6. Structural characterization of the cocrystal structure of the BCL6 BTB / POZ domain and co-inhibitor indicates that binding occurs at the side 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). Subsequently, specific ligands binding to this site have been investigated, aiming to utilize binding affinity against the side groove to make BCL6 a druggable target.

[0008] Protein degradation is a highly regulated and essential process for maintaining cellular homeostasis. The selective identification and removal of damaged, misfolded, or excess proteins is achieved via the ubiquitin-proteasome pathway (UPP). UPP is important for the regulation of almost all cellular processes. Protein ubiquitination is achieved by E3 ubiquitin ligases, which bind to proteins and add ubiquitin molecules, thereby labeling proteins for proteasome degradation.

[0009] The therapeutic use of UPPs has garnered significant attention (Zhou et al., Mol. Cell 2000, 6, 751-756). One promising therapy utilizes proteolytically targeted chimeras, commonly known as PROTACs, to remove unwanted proteins through protein degradation (Scheepstra et al., Comp. Struct. Biotech. J. 2019, 17, 160-176). PROTACs are ligand-directed degraders that aggregate E3 ligases and the target protein to be degraded. These divalent molecules typically consist of E3 ligase ligands linked via a linker portion to a small molecule that binds to the target protein. PROTACs position the E3 ligase at an appropriate distance and orientation from the target protein, thereby ubiquitinizing the target protein. The ubiquitinated target protein is then recognized by the proteasome, leading to its degradation.

[0010] Therefore, compounds that target BCL6 for degradation are needed. Invention Overview

[0012] In some embodiments, compounds and compositions thereof for regulating BCL6 are described herein. In many embodiments, the compounds and compositions thereof can be used to treat cancer.

[0013] The embodiments of the present invention can be more fully understood by referring to the specific implementation methods and examples, which are intended to illustrate non-limiting implementation methods.

[0014] In one aspect, compounds of formula (I) are provided:

[0015] ,

[0016] Or its pharmaceutically acceptable salts, wherein variables (e.g., cyclic A, L) 1 L 2 R 1 R 2 R 3 R 4 The value of ) is as described in this article.

[0017] In another aspect, pharmaceutical compositions are provided comprising compounds described herein (e.g., compounds of formulas (I)-(IV) or Table 1 or pharmaceutically acceptable salts of any of the foregoing compounds) and pharmaceutically acceptable excipients.

[0018] In another aspect, a method for degrading B-cell lymphoma 6 protein (BCL6) is provided, the method comprising contacting BCL6 with an effective amount of a compound described herein (e.g., a compound of formula (I)-(IV) or Table 1 or a pharmaceutically acceptable salt of any of the foregoing compounds), for example, in the form of a pharmaceutical composition.

[0019] In another aspect, methods for treating cancer or autoimmune diseases in individuals in need are provided, the methods comprising administering to the individual an effective amount of the compounds described herein (e.g., compounds of formulas (I)-(IV) or Table 1 or pharmaceutically acceptable salts of any of the foregoing compounds), for example, in the form of a pharmaceutical composition.

[0020] This document also provides the compounds described herein (e.g., compounds of formulas (I)-(IV) or Table 1 or pharmaceutically acceptable salts of any of the foregoing compounds) or pharmaceutical compositions comprising the compounds described herein (e.g., compounds of formulas (I)-(IV) or Table 1 or pharmaceutically acceptable salts of any of the foregoing compounds) for the purposes described herein (e.g., degradation of BCL6, such as in cells and / or individuals, such as in individuals in need; treatment of cancer or autoimmune diseases in individuals in need).

[0021] This document also provides for the use of the compounds described herein (e.g., compounds of formulas (I)-(IV) or Table 1, or pharmaceutically acceptable salts of any of the foregoing compounds) in the preparation of medicaments for the purposes described herein (e.g., degradation of BCL6, such as in cells and / or individuals, such as in individuals in need; treatment of cancer or autoimmune diseases in individuals in need). Invention Details

[0023] definition

[0024] As used herein, the terms “comprising” and “including” are used interchangeably. The terms “comprising” and “including” should be construed as specifically describing the presence of the mentioned features or components, but do not exclude the presence or addition of one or more features or components or groups thereof. Furthermore, the terms “comprising” and “including” are intended to include instances covered by the term “consisting of”. Therefore, the term “consisting of” can be used in place of the terms “comprising” and “including” to provide a more specific embodiment.

[0025] The term "constituting of" means that the target object has at least 90%, 95%, 97%, 98%, or 99% of the stated features or components constituting it. In another embodiment, the term "constituting of" excludes any other features or components from any of the following enumerated ranges, except those features or components that are not essential to the technical effect to be achieved.

[0026] As used herein, the term “or” should be interpreted as inclusive “or,” meaning either one or any combination thereof. Therefore, “A, B, or C” means any of the following: “A; B; C; A and B; A and C; B and C; A, B, and C.” Exceptions to this definition will only occur if the combination of elements, functions, steps, or actions is inherently mutually exclusive in some way.

[0027] In this specification, unless otherwise indicated, any concentration range, percentage range, ratio range, or integer range shall be understood to include any integer within the stated range and (where applicable) its fractions (such as one-tenth and one-hundredth of an integer). Furthermore, unless otherwise indicated, any numerical ranges listed herein relating to any physical characteristic such as polymer subunits, size, or thickness shall be understood to include any integer within the stated range. As used herein, unless otherwise indicated, the terms “about” and “approximately” mean ±20%, ±10%, ±5%, or ±1% of the indicated range, value, or structure.

[0028] "Amino" refers to the -NH2 group.

[0029] "Cyano" refers to the -CN group.

[0030] "Nitro" refers to the -NO2 group.

[0031] "O-" refers to the -O- group.

[0032] "Oxide group" refers to the =O group.

[0033] "Thio" refers to the =S group.

[0034] "Imine" refers to the =NH group.

[0035] "Oxime group" refers to the =N-OH group.

[0036] "Hydrazine" refers to the =N-NH2 group.

[0037] "Alkyl" refers to a straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, without any unsaturation, and having one to fifteen carbon atoms (e.g., C1-C1). 15 Alkyl groups. In some embodiments, the alkyl group comprises one to thirteen carbon atoms (e.g., C1-C1). 13 Alkyl group. In some embodiments, the alkyl group comprises one to eight carbon atoms (e.g., C1-C8 alkyl). In other embodiments, the alkyl group comprises one to six carbon atoms (e.g., C1-C6 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-C6 alkyl). 15 Alkyl group. In 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 linked to the rest of the molecule by a single bond. Unless otherwise specifically stated in this specification, the alkyl group may optionally be substituted with one or more of the following substituents: halogen, cyano, nitro, oxo, thio, 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)Ra -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 Independently, it is hydrogen, alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclic (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), carbocyclic alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heterocyclic (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heterocyclic alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl).

[0038] "alkyl-OH" or "hydroxyalkyl" refers to an alkyl group as defined above, in which one or more hydrogen atoms are replaced by -OH groups. For example, "C1-C6 alkyl-OH" or "hydroxyalkyl" refers to a C1-C6 alkyl group substituted with one or more -OH groups. Alkyl-OH or hydroxyalkyl may contain multiple hydroxyl groups attached to the same or multiple carbon atoms. Examples of hydroxyalkyl groups include, for example, -CH2OH, -CH2CH2OH, and -CH2CH2C(CH3)2OH.

[0039] "Alkoxy" refers to a group of the formula -O-alkyl that is bonded via an oxygen atom, wherein the alkyl group is as defined above.

[0040] "Alkenyl" refers to a straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, containing at least one carbon-carbon double bond and having two to twelve carbon atoms. In some embodiments, the alkenyl group contains two to eight carbon atoms. In other embodiments, the alkenyl group contains two to four carbon atoms. The alkenyl group is connected to the rest of the molecule by a single bond, such as ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl, pentenyl, pentenyl, pent-1,4-dienyl, etc. Unless otherwise specifically stated in this specification, the alkenyl group may optionally be substituted with one or more of the following substituents: halogen, cyano, nitro, oxo, thio, 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 Independently, it is hydrogen, alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclic (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), carbocyclic alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heterocyclic (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heterocyclic alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl).

[0041] "Alynyl" refers to a straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, and having two to twelve carbon atoms. In some embodiments, the alkynyl group contains 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 by a single bond, such as ethynyl, propynyl, butynyl, pentylyl, hexynyl, etc. Unless otherwise specifically stated in this specification, the alkynyl group may optionally be substituted with one or more of the following substituents: halogen, cyano, nitro, oxo, thio, 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 Independently, it is hydrogen, alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclic (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), carbocyclic alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heterocyclic (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heterocyclic alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl).

[0042] "Aryl" refers to an aromatic monocyclic or polycyclic hydrocarbon cyclic group having five to eighteen carbon atoms, wherein at least one ring in the cyclic system is aromatic. Aryl groups include, but are not limited to, phenyl, fluorenyl, indenyl, indenyl, tetrahydronaphthyl, and naphthyl. Unless otherwise specifically stated in this specification, the term "aryl" or the prefix "aromatic" (such as in "arylalkyl") is intended to include aryl groups optionally substituted with one or more substituents independently selected from: alkyl, alkenyl, ynyl, halogen, fluoroalkyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted areneyl, optionally substituted arynyl, optionally substituted carbocyclic, optionally substituted carbocyclic alkyl, optionally substituted heterocyclic, optionally substituted heterocyclic alkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R b -OR a -R b -OC(O)-R a -R b -OC(O)-OR a -R b -OC(O)-N(R a )2、-R b -N(R a )2、-R b -C(O)R a -R b -C(O)OR a -R b -C(O)N(R a )2、-R b -OR c -C(O)N(R a )2、-R b -N(R a )C(O)OR a -R b -N(R a )C(O)R a -R b -N(R a S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) 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 Ra Independently, it is hydrogen, alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclic (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), carbocyclic alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heterocyclic (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heterocyclic alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), each R b It is independently a direct bond or a straight-chain or branched alkylene or alkenylene chain, and Rc is a straight-chain or branched alkylene or alkenylene chain, and wherein each of the above substituents is unsubstituted unless otherwise indicated.

[0043] "Aryl group" refers to the formula -R c -aryl groups, where R c It is an alkylene group, such as methylene, ethylene, etc. The alkylene portion of an aralkyl group may be substituted as described above regarding alkyl groups. The aryl portion of an aralkyl group may be substituted as described above regarding aryl groups.

[0044] "Aryl" refers to the formula -R d -aryl groups, where R d It is an alkenyl group. The aryl moiety of the aryl group may be substituted as described above regarding the aryl group. The alkenyl moiety of the aryl group may be substituted as defined above regarding the alkenyl group.

[0045] "Arotyne group" refers to the formula -R e -aryl groups, where R e It is an alkynyl group. The aryl moiety of the arynyl group may be substituted as described above regarding the aryl group. The alkynyl chain moiety of the arynyl group may be substituted as defined above regarding the alkynyl group.

[0046] A "carbocyclic group" refers to a non-aromatic monocyclic or polycyclic hydrocarbon group consisting only of carbon and hydrogen atoms, including fused or bridged ring systems, and having three to fifteen carbon atoms. In some embodiments, the carbocyclic group has five to twelve carbon atoms (5- to 12-membered carbocyclic groups). In some embodiments, the carbocyclic group has three to ten carbon atoms (3- to 10-membered carbocyclic groups). In other embodiments, the carbocyclic group has five to seven carbon atoms (5- to 7-membered carbocyclic groups). The carbocyclic group is connected to the rest of the molecule by a single bond. The carbocyclic group 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 carbocyclic groups are also referred to as "cycloalkyl groups". Examples of monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Unsaturated carbocyclic groups are also referred to as "cycloalkenyl groups". Examples of monocyclic alkenyl groups include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclic groups include, for example, adamantyl, norbornel (i.e., bicyclic [2.2.1]heptyl), norbornel, decahydronaphthyl, 7,7-dimethylbicyclo[2.2.1]heptyl, etc. Unless otherwise specified in this specification, the term "carbocyclic" means a carbocyclic group optionally substituted with one or more substituents independently selected from: alkyl, alkenyl, ynyl, halogen, fluoroalkyl, oxo, thio, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted arenel, optionally substituted arynyl, optionally substituted carbocyclic, optionally substituted carbocyclic alkyl, optionally substituted heterocyclic, optionally substituted heterocyclic alkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -OR a -SR a -OC(O)-R a -N(R) a )2、-C(O)R a -C(O)OR a -C(O)N(R) a )2、-N(R a )C(O)OR a -OC(O)- N(R) a )2、-N(R a )C(O)R a -N(R) a S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2) and -S(O) t N(Ra )2 (where t is 1 or 2), where each R a Independently, Rb is hydrogen, alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclic (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), carbocyclic alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heterocyclic (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heterocyclic alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), each Rb is independently a direct bond or a straight-chain or branched alkylene or alkenyl chain, and R c It is a straight-chain or branched alkylene or alkenylene chain, and wherein, unless otherwise indicated, each of the above substituents is unsubstituted.

[0047] "Carbocycloalkyl" refers to the formula -R c - A carbocyclic group, wherein R c It is an alkylene group. The alkylene chain and carbocyclic group are optionally substituted as defined above for alkyl and carbocyclic groups, respectively.

[0048] "Carbonyl" refers to the formula -C(O)R x R y The group, wherein R x and R y 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) tR 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 Independently, it is hydrogen, alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclic (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), carbocyclic alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heterocyclic (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heterocyclic alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl).

[0049] "Deuterated alkyl" refers to an alkyl group as defined above, in which one or more hydrogen atoms are replaced by a corresponding number of deuterium atoms, such as -CD3, -CHD2, -CH2D, etc.

[0050] When used as a suffix herein, "alkylene" or "alkylene" refers to a group modified by that suffix that is attached to the remainder of the molecule via two or more connection points (usually two), such as alkylene, carbocyclic, arylene, heteroarylene, etc., where alkyl, heterocyclic, carbocyclic, aryl, and heteroaryl are as defined herein. The group can be attached to the remainder of the molecule via any two suitable atoms of the group.

[0051] "Halogen" or "halogen" refers to bromine, chlorine, fluorine, or iodine. In some embodiments, the halogen is chlorine or fluorine. In some embodiments, the halogen is fluorine.

[0052] "Halogenated alkyl" means an alkyl group as defined above that is substituted with one or more halogens as defined above, such as trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-chloropropyl, 1,2-dibromoethyl, etc. In some embodiments, the halogenated alkyl group has one to six carbon atoms and is substituted with one or more halogens (C1-C6 halogenated alkyl), or has one to five carbon atoms and is substituted with one or more halogens (C1-C5 halogenated alkyl), or has one to three carbon atoms and is substituted with one or more halogens (C1-C3 halogenated alkyl). The halogens may be all the same or different. Unless otherwise specified, the halogenated alkyl group is optionally substituted.

[0053] A "heterocyclic group" refers to a 3- to 18-membered non-aromatic ring group comprising two to twelve carbon atoms and one to six heteroatoms selected from nitrogen, oxygen, and sulfur. Unless otherwise specified in this specification, the heterocyclic group is a monocyclic, bicyclic, tricyclic, or tetracyclic system, which may include fused, bridged, or spirocyclic systems. The heteroatoms in the heterocyclic group may optionally be oxidized. One or more nitrogen atoms (if present) may optionally be quaternized. The heterocyclic group may be partially or fully saturated. The heterocyclic group may be attached to the remainder of the molecule via any atom in the ring. Examples of heterocyclic groups include, but are not limited to, dioxapentyl, thiophene[1,3]dithiaalkyl, decahydroisoquinolinyl, azacyclic butyl, imidazolinyl, imidazoalkyl, isothiazolyl, isoxazolyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopiperidinyl, oxazolyl, piperidinyl, piperazinyl, 4-piperidinoneyl, and pyrroleyl. Alkyl, 2,6-diazaspiro[3.4]octyl, 2,8-diazaspiro[4.5]decyl, 8-azabicyclo[3.2.1]octyl, octahydro-1H-pyrrolo[3,2-c]pyridinyl, quininecyclo, thiazolyl, tetrahydrofuranyl, trithiaalkyl, tetrahydropyranyl, thiomorpholinyl, thiomorpholinyl, 1-oxothiomorpholinyl and 1,1-dioxothiomorpholinyl. Unless otherwise specified in this specification, the term "heterocyclic" means a heterocyclic group as defined above, optionally substituted with one or more substituents selected from the following: alkyl, alkenyl, ynyl, halogen, fluoroalkyl, oxo, thio, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted arenel, optionally substituted arynyl, optionally substituted carbocyclic, optionally substituted carbocyclic alkyl, optionally substituted heterocyclic, optionally substituted heterocyclic alkyl, 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(Ra )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 Independently, it is hydrogen, alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclic (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), carbocyclic alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heterocyclic (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heterocyclic alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), each R b Independently, it is a direct bond or a straight-chain or branched alkylene or alkenylene chain, and R c It is a straight-chain or branched alkylene or alkenylene chain, and wherein, unless otherwise indicated, each of the above substituents is unsubstituted.

[0054] "Nitrogen-containing heterocyclic group" refers to a heterocyclic group as defined above, which contains at least one nitrogen, such as an N-heterocyclic group or a C-heterocyclic group. In some embodiments, the nitrogen-containing heterocyclic group is an N-heterocyclic group.

[0055] "N-heterocyclic group" or "N-linked heterocyclic group" refers to a heterocyclic group as defined above, containing at least one nitrogen atom, wherein the connection point between the heterocyclic group and the remainder of the molecule is achieved via a nitrogen atom in the heterocyclic group. The N-heterocyclic group may be substituted as described above regarding heterocyclic groups. Examples of N-heterocyclic groups include, but are not limited to, 1-morpholino, 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolyl, imidazolinyl, and imidazoalkyl. When "N-heterocyclic group" is used in the context of N-heterocyclic sub-heterocyclic group, a nitrogen atom serves as a connection point from the sub-heterocyclic group to the remainder of the molecule. Any other atom present in the ring of the sub-heterocyclic group may serve as a second connection point to the remainder of the molecule.

[0056] A “C-heterocyclic group” or “C-linked heterocyclic group” refers to a heterocyclic group as defined above, containing at least one heteroatom and wherein the connection between the heterocyclic group and the rest of the molecule is achieved via a carbon atom in the heterocyclic group. The C-heterocyclic group may be substituted as described above regarding heterocyclic groups. Examples of C-heterocyclic groups include, but are not limited to, 2-morpholino, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2-piperazinyl, 2-pyrrolidinyl, or 3-pyrrolidinyl.

[0057] "Heterocyclic alkyl" refers to formula -R c - A heterocyclic group, wherein R c It is an alkylene group. If the heterocyclic group is a nitrogen-containing heterocyclic group, the heterocyclic group may optionally be attached to an alkylene group at the nitrogen atom. The alkylene portion of the heterocyclic alkyl group may optionally be substituted as defined above with respect to alkyl groups. The heterocyclic portion of the heterocyclic alkyl group may optionally be substituted as defined above with respect to heterocyclic groups.

[0058] "Heterocyclic alkoxy" refers to the formula -OR c Heterocyclic groups are groups bonded via oxygen atoms, where R c It is an alkylene group. If the heterocyclic group is a nitrogen-containing heterocyclic group, the heterocyclic group is optionally linked to an alkylene group at the nitrogen atom. The alkylene moiety of the heterocyclic alkoxy group is optionally substituted as defined above with respect to alkyl groups. The heterocyclic moiety of the heterocyclic alkoxy group is optionally substituted as defined above with respect to heterocyclic groups.

[0059] "Heteroaryl" refers to a 3- to 18-membered monocyclic, bicyclic, tricyclic, or tetracyclic cyclic group consisting of 2 to 17 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur, wherein at least one ring in the cyclic system is aromatic. Heteroaryls include fused and bridged cyclic 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 remainder of the molecule via any atom in the ring.Examples of heteroaryl groups include, but are not limited to, aziridine, acridine, benzimidazolyl, benzoindolyl, 1,3-benzodioxacyclopentenyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxazolyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxane, benzonaphthofuranyl, benzooxazolyl, benzodioxacyclopentenyl, benzodioxacyclohexenyl, benzopyranyl, benzopyranoneyl, benzofuranyl, benzofuranoneyl, benzothiophene (benzothiophene), benzothiophene[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a] Pyridyl, carbazolyl, cyclopentano[d]pyrimidinyl, 6,7-dihydro-5H-cyclopentano[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]thienolyl, 6,7-dihydro-5H-benzo[6,7]cycloheptano[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothienoyl, furanyl, furanoneyl, 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]pyridazinyl Isothiazolyl, imidazolyl, indazole, indole, indazole, isoindole, indolinyl, isoindolinyl, isoquinolinyl, indoleazinyl, isoxazolyl, 5,8-methylbridged-5,6,7,8-tetrahydroquinazolinyl, naphridinyl, 1,6-naphridinone, oxadiazolyl, 2-oxoazapyridine, oxazolyl, ethylene oxide, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrroleyl, phenazinyl, phenthiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purine, pyrroleyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3, [4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrroloyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cycloheptano[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 thienoyl (i.e., thienoyl).Unless otherwise specified in this specification, the term "heteroaryl" means a heteroaryl group as defined above that is optionally substituted with one or more substituents selected from the following: alkyl, alkenyl, alkynyl, halogen, fluoroalkyl, haloalkenyl, haloalkynyl, oxo, thio, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted arene, optionally substituted arynyl, optionally substituted carbocyclic, optionally substituted carbocyclic alkyl, optionally substituted heterocyclic, optionally substituted heterocyclic alkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R. b -OR a -R b -OC(O)-R a -R b -OC(O)-OR a -R b -OC(O)-N(R a )2、-R b -N(R a )2、-R b -C(O)R a -R b -C(O)OR a -R b -C(O)N(R a )2、-R b -OR c -C(O)N(R a )2、-R b -N(R a )C(O)OR a -R b -N(R a )C(O)R a -R b -N(R a S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) 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 aIndependently, it is hydrogen, alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclic (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), carbocyclic alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heterocyclic (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heterocyclic alkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxyl, methoxy, or trifluoromethyl), each R b Independently, it is a direct bond or a straight-chain or branched alkylene or alkenylene chain, and R c It is a straight-chain or branched alkylene or alkenylene chain, and wherein, unless otherwise indicated, each of the above substituents is unsubstituted.

[0060] "Nitrogen-containing heteroaryl" refers to a heteroaryl group as defined above, which contains at least one nitrogen, such as N-heteroaryl or C-heteroaryl.

[0061] "N-Heteroaryl" refers to a heteroaryl group as defined above, containing at least one nitrogen atom, wherein the connection between the heteroaryl group and the remainder of the molecule is achieved via a nitrogen atom in the heteroaryl ring system. The N-heterocyclic group may be substituted as described above for heteroaryl groups. When "N-heteroaryl" is used in the context of N-heteroaryl, a nitrogen atom serves as a connection point from the heteroaryl group to the remainder of the molecule. Any other atom present in the heteroaryl ring may serve as a second connection point to the remainder of the molecule.

[0062] "C-heteroaryl" refers to a heteroaryl group as defined above, wherein the connection between the heteroaryl group and the rest of the molecule is achieved via a carbon atom in the heteroaryl ring system. The C-heteroaryl group may be replaced as described above regarding heteroaryl groups.

[0063] "Heteroarylalkyl" refers to the formula -R c - A heteroaryl group, wherein R c It is an alkylene group. If the heteroaryl group is a nitrogen-containing heteroaryl group, the heteroaryl group may optionally be attached to an alkylene group at the nitrogen atom. The alkylene portion of the heteroaryl alkyl group may optionally be substituted as defined above with respect to alkyl groups. The heteroaryl portion of the heteroaryl alkyl group may optionally be substituted as defined above with respect to heteroaryl groups.

[0064] "Heteroarylalkoxy" refers to the formula -OR c A heteroaryl group bonded via an oxygen atom, wherein R cIt is an alkylene group. If the heteroaryl group is a nitrogen-containing heteroaryl group, the heteroaryl group may optionally be attached to an alkylene group at the nitrogen atom. The alkylene moiety of the heteroarylalkoxy group may optionally be substituted as defined above with respect to alkyl groups. The heteroaryl moiety of the heteroarylalkoxy group may optionally be substituted as defined above with respect to heteroaryl groups.

[0065] Embodiments of the present invention are intended to cover pharmaceutically acceptable salts, tautomers, isotopes, stereoisomers, and mixtures of stereoisomers of the compounds provided herein (such as compounds of formula (I)).

[0066] 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, as well as organic acids and organic bases). Suitable pharmaceutically acceptable base addition salts of compounds 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-methylglucosamine), 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, hydroxyethylsulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucilage, nitric acid, dihydroxynaphthyl 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, specific examples of salts include hydrochloride salts, formate salts, and methanesulfonate salts. Other salts are well known in the art; see, for example, Remington's Pharmaceutical Sciences, 18th edition, Mack Publishing, Easton PA (1990) or Remington: The Science and Practice of Pharmacy, 19th edition, Mack Publishing, Easton PA (1995).

[0067] As used herein and unless otherwise indicated, the terms "stereoisomer" or "stereoisopure" mean a specific stereoisomer of a particular compound that is substantially free of other stereoisomers of that compound. For example, a stereoisopure compound having one chiral center is substantially free of its enantiomers. A stereoisopure compound having two chiral centers will be substantially free of its other diastereomers. Typical stereoisopure compounds contain more than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, more than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of other stereoisomers of the compound, more than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of other stereoisomers of the compound, or more than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of other stereoisomers of the compound. The compounds disclosed herein may have a chiral center and may exist as racemic, enantiomers alone, diastereomers, or mixtures thereof. All such isomers are included in the embodiments disclosed herein, including mixtures thereof.

[0068] The embodiments disclosed herein cover the use of the stereoisomeric 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 may be used in the methods and compositions disclosed herein. These isomers may be resolved by asymmetric synthesis or using standard techniques such as chiral columns or chiral resolving agents. See, for example, Jacques, J. et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen, SH et al., Tetrahedron 33:2725 (1977); Eliel, E. L., Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SH, Tables of Resolving Agents and OpticalResolutions (ed. EL Eliel, Univ. of Notre Dame Press, Notre Dame, IN, 1972); Todd, M., Separation Of Enantiomers: Synthetic Methods (Wiley-VCHVerlag GmbH & Co. KGaA, Weinheim, Germany, 2014); Toda, F., EnantiomerSeparation: Fundamentals and Practical Methods (Springer Science & BusinessMedia, 2007); Subramanian, G. Chiral Separation Techniques: A PracticalApproach (John Wiley & Sons, 2008); Ahuja, S., Chiral Separation Methods for Pharmaceutical and Biotechnological products (John Wiley & Sons, (2011).

[0069] "Tautomers" refer to the isomers of a compound that are in equilibrium with each other. The concentration of the isomers depends on the environment in which the compound exists and can vary, for example, whether the compound is a solid or in an organic or aqueous solution. For example, in an aqueous solution, pyrazole can exist in the following isomers, which are called tautomers of each other:

[0070] .

[0071] As will be readily understood by those skilled in the art, various functional groups and other structures can exhibit tautomerism, and all tautomers of the compounds of formula (I) are within the scope of this invention.

[0072] Polymers or similar infinite structures obtained by defining substituents by an infinite number of additional substituents (e.g., a substituted aryl group having a substituted alkyl group itself substituted by the substituted aryl group, which is further substituted by a substituted heteroalkyl group, etc.) are not intended to be included herein. Similarly, the above definitions are not intended to include unacceptable substitution modes (e.g., a methyl group substituted with five fluorine atoms or a heteroaryl group having two adjacent oxygen ring atoms). Such unacceptable substitution modes are well known to those skilled in the art.

[0073] It should also be noted that the compounds disclosed herein may contain atomic isotopes in non-natural proportions at one or more atoms. For example, the compounds may be radiolabeled with radioactive isotopes such as tritium ( 3 H), Iodine-125 ( 125 I), sulfur-35 ( 35 S) or carbon-14 ( 14 C), or may be enriched by isotopes, such as through deuterium ( 2 H), carbon-13 ( 13 C) or nitrogen-15 ( 15N) enrichment. As used herein, “isotope” refers to a compound enriched by isotopes. The term “isotope enrichment” means that an atom has an isotopic composition other than that of its natural atom. “Isotope enrichment” can also mean that at least one atom in a compound has an isotopic composition other than that of its natural atom. The term “isotopic composition” refers to the amount of each isotope present in a given atom. Radiolabeled and isotope enriched compounds are suitable as therapeutic agents (e.g., cancer therapeutic agents), research reagents (e.g., binding analytical reagents), and diagnostic agents (e.g., in vivo imaging agents). All isotopic variants of the compounds described herein, whether radioactive or not, are intended to be covered within the scope of the embodiments provided herein. In some embodiments, isotopes of the compounds disclosed herein are provided, for example, compounds enriched by deuterium, carbon-13, and / or nitrogen-15. As used herein, “deuteration” means that at least one hydrogen (H) has been converted from deuterium (from D or 2 The compound that is replaced by H (indicator), that is, the compound is enriched by deuterium at at least one position.

[0074] This invention also includes “deuterated analogues” of the compounds described herein, wherein one to n hydrogen atoms bonded to carbon atoms are replaced with deuterium, where n is the number of hydrogen atoms in the molecule. When multiple deuterium atoms are present in the 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 suitable for prolonging the half-life of any compound when administered to mammals, particularly humans. 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 hydrogen atoms have been replaced with deuterium.

[0075] It should be understood that, independent of stereoisomerism or isotopic composition, the compounds disclosed herein may be provided in any pharmaceutically acceptable salt form discussed herein. Similarly, it should be understood that the isotopic composition of each compound mentioned herein may vary independently of its stereoisomerism. Furthermore, while the isotopic composition is limited to those elements present in the individual compounds disclosed herein or their salts, it may otherwise vary independently of the choice of pharmaceutically acceptable salts for each compound.

[0076] It should be noted that if there is an inconsistency between the described structure and its name, the described structure should be given greater weight.

[0077] As used herein, “treatment” means complete or partial relief of an obstacle, disease, or symptom, or one or more symptoms associated with an obstacle, disease, or symptom, or slowing or preventing the further development or worsening of these symptoms, or alleviating or eradicating the cause of the obstacle, disease, or symptom itself. In one implementation, the symptom is cancer or its symptoms as described herein.

[0078] As used herein, “prevention” means a method used for the purpose of: delaying and / or preventing the complete or partial onset, recurrence, or spread of a disorder, disease, or condition; preventing an individual from developing a disorder, disease, or condition; or reducing an individual’s risk of developing a disorder, disease, or condition. In one implementation, the condition is cancer or its symptoms as described herein.

[0079] The term “effective amount” in relation to the compounds disclosed herein means an amount sufficient to treat or prevent the disorder, disease, or ailment or its symptoms disclosed herein.

[0080] As used herein, the terms “individual” or “patient” include animals, including but not limited to animals such as cattle, monkeys, horses, sheep, pigs, chickens, turkeys, quails, cats, dogs, mice, rats, rabbits, or guinea pigs, and in one embodiment, mammals, and in another embodiment, humans. In one embodiment, an individual is a human suffering from a BCL6-mediated disease or its symptoms, or at risk of suffering from a BCL6-mediated disease or its symptoms.

[0081] While various features of the technology described herein may be described in the context of a single implementation, these features may also be provided separately or in any suitable combination. Conversely, although the technology may be described herein in the context of an independent implementation for clarity, it may also be implemented in a single implementation.

[0082] compound

[0083] In one aspect, this paper provides compounds of formula (I):

[0084] ,

[0085] Or its pharmaceutically acceptable salt, wherein:

[0086] Ring A is a 4- to 12-membered nitrogen-containing heterocyclic group, a 5- to 12-membered carbocyclic group, a 5- to 6-membered nitrogen-containing heteroaryl group, or a phenylene group. or , or does not exist, where ring A, when it exists, is (R 10 ) x replace;

[0087] Each R10 Independently, it is a halogen, a C1-C6 alkyl, a C1-C6 alkoxy, a C1-C6 hydroxyalkyl, or a C1-C6 haloalkyl, or two Rs. 10 Together with the carbon atoms they are connected to, they form oxo groups;

[0088] x is 0, 1, 2, 3 or 4;

[0089] L 1 It is N(R) 11 ) or N(R 11 CH2C(O) or not present;

[0090] R 11 It is hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, or C1-C6 haloalkyl;

[0091] L 2 It is -(CH2) y N(R 12 )-、-O(CH2) y -、-N(R 12 )C(O)-、-C(O)N(R 12 (CH2) z -、-C(O)N(R 12 (CH2) z N(R 12 )-、-C(O)N(R 12 (CH2) z O-, -(CH2) z C(O)N(R 12 )- or (CH2) z Or it may not exist;

[0092] Each R 12 It is independently hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 deuterated alkyl, or C1-C6 haloalkyl;

[0093] y is 0 or 1;

[0094] z is 1, 2, 3, 4 or 5;

[0095] R 1 It is hydrogen or C1-C6 alkyl;

[0096] R 2 It is a C1-C6 alkyl group;

[0097] R 3 It is either halogen or cyano;

[0098] R 4 yes , , , , , , , , , or ;

[0099] X 1 It is C(R) 13 ) or N;

[0100] X 2 X 3 and X 4 It is C(H); or X 2 and X 4 It is C(H), and X 3 It is N; or X 2 It is N, and X 3 and X 4 It is C(H); or X 2 and X 3 It is C(H), and X 4 It is N;

[0101] R 13 It is hydrogen or C1-C6 alkyl;

[0102] Each R 14 Halogens are independent of each other;

[0103] R 52 It is hydrogen or C1-C6 alkyl; and

[0104] p is 0, 1, 2 or 3.

[0105] In another respect, this paper provides compounds of formula (II):

[0106] ,

[0107] Or its pharmaceutically acceptable salt, wherein the value of the variable (e.g., ring A, L) 2 R 1 R 2 R 3 R 4 As described with respect to compounds of formula (I) or elsewhere in this document.

[0108] In another aspect, this paper provides compounds of formula (III):

[0109] ,

[0110] Or a pharmaceutically acceptable salt thereof, wherein the value of the variable (e.g., R) 1 R2 R 3 R 4 R 10 R 11 (x) as described with respect to compounds of formula (I) or elsewhere herein.

[0111] In another respect, this paper provides compounds of formula (IV):

[0112] ,

[0113] Or its pharmaceutically acceptable salt, wherein the value of the variable (e.g., ring A, R) 1 R 2 R 3 R 4 As described with respect to compounds of formula (I) or elsewhere in this document.

[0114] In some embodiments, ring A is a 4- to 12-membered nitrogen-containing heterocyclic group or a 5- to 6-membered nitrogen-containing heterocyclic group, which is bound by (R) 10 ) x Replacement. In some embodiments, ring A is a 4- to 12-membered nitrogen-containing heterocyclic group, which is replaced by (R 10 ) x Replacement. For example, in some embodiments, ring A is a 4- to 6-membered monocyclic nitrogen-containing heterocyclic group, an 8- to 10-membered spirocyclic nitrogen-containing heterocyclic group, or an 8- to 10-membered fused bicyclic nitrogen-containing heterocyclic group, which is replaced by (R 10 ) x Replacement. In one specific embodiment, ring A is a 4- to 6-membered monocyclic nitrogen-containing heterocyclic group or an 8- to 10-membered spirocyclic nitrogen-containing heterocyclic group, which is replaced by (R 10 ) x replace.

[0115] In some implementations, ring A is a 5- to 12-membered carbocyclic group or a phenylene group.

[0116] In some embodiments, ring A is piperidinyl, piperazineyl, azacyclobutane, pyrrolidine, 2,6-diazaspiro[3.4]octyl, 2,8-diazaspiro[4.5]decyl, 8-azabicyclo[3.2.1]octyl, octahydro-1H-pyrrolo[3,2-c]pyridinyl, cyclohexenyl, pyrazolyl, or Its being (R) 10 ) x Replacement. In some embodiments, ring A is piperidinyl, piperazine, or...

[0117] 2,8-diazaspiro[4,5]decanediol, phenylene, or Its being (R) 10 ) xReplacement. In one specific embodiment, ring A is a piperidinyl or piperazine group, which is replaced by (R 10 ) x Replacement. In a more specific embodiment, ring A is a piperidinyl group, which is replaced by (R 10 ) x replace.

[0118] In the alternative implementation, ring A does not exist.

[0119] In some implementations, each R 10 Independently halogen, C1-C6 alkyl or C1-C6 hydroxyalkyl, or two R 10 Together with the carbon atoms they are linked to, they form oxo groups. In one specific implementation, each R... 10 Independently fluorine, methyl or hydroxymethyl, or two R 10 Together with the carbon atoms they are linked to, they form oxo groups. In some implementations, each R... 10 Independently, it is halogen, C1-C6 alkyl, or C1-C6 alkoxy. In one specific embodiment, each R 10 Independently fluorine, methyl, or methoxy. In some embodiments, each R... 10 Independently halogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, or C1-C6 alkoxy, or two R 10 Together with the carbon atoms they are linked to, they form oxo groups. In one specific implementation, each R... 10 Independently fluorine, methyl, hydroxymethyl or methoxy, or two R 10 Together with the carbon atoms they are connected to, they form oxo groups.

[0120] In some implementations, x is 0, 1, or 2. In some implementations, x is 0 or 1. In one specific implementation, x is 0. In another specific implementation, x is 1.

[0121] In some implementations, L 1 It is N(R) 11 In some implementations, L 1 It does not exist.

[0122] In some implementation schemes, R 11 It is hydrogen, C1-C6 alkyl, or C1-C6 hydroxyalkyl. In some embodiments, R 11 It is hydrogen or a C1-C6 alkyl group. In one specific embodiment, R 11 It is hydrogen or methyl. In a more specific implementation, R 11 It is hydrogen. In another embodiment, R 11It is methyl. In some embodiments, R 11 It is a C1-C6 alkyl, C1-C6 hydroxyalkyl, or C1-C6 haloalkyl.

[0123] In some implementations, L 2 It is -(CH2) y N(R 12 )-、-O(CH2) y -、-N(R 12 )C(O)-、-C(O)N(R 12 (CH2) z -、-C(O)N(R 12 (CH2) z N(R 12 )-、-(O)N(R 12 (CH2) z O-, -(CH2) z C(O)N(R 12 )- or (CH2) z In some implementations, L 2 It is -(CH2) y N(R 12 )-、-O(CH2) y -、-N(R 12 C(O)- or -(CH2) z C(O)N(R 12 In one specific implementation scheme, L 2 It is (CH2) y N(R 12 ) or -O(CH2) y - In a more specific implementation plan, L 2 It is -N(H)-, -N(CH3)-, -N(CH2CH2OH)-, -CH2N(H)-, -CH2N(CH3)-, -CH2N(CD3)-, -O-, -OCH2-, -N(H)C(O)-, -C(O)N(H)CH2CH2N(H)-, -C(O)N(H)CH2CH2CH2N(H)-, -C(O)N(H)CH2CH2O-, -CH2C(O)N(H)-, or -CH2-. In some embodiments, L 2 It is -N(H)-, -N(CH3)-, -CH2N(H)-, -O-, -N(H)C(O)-, or -CH2C(O)N(H)-. In some embodiments, L 2 It is -O- or -CH2-. In some implementations, L 2 It is -N(H)- or -N(CH3)-.

[0124] In the alternative implementation scheme, L 2 It does not exist.

[0125] In some implementations, each R 12 Independently, it is hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, or C1-C6 deuterated alkyl. In one specific embodiment, each R 12 Independently hydrogen, methyl, hydroxyethyl, or -CD3. In some embodiments, each R 12 Independently hydrogen or C1-C6 alkyl. In one specific embodiment, each R 12 Independently hydrogen or methyl. In a more specific embodiment, each R 12 It is hydrogen. In another implementation, each R 12 It is methyl. In some embodiments, each R 12 It is independently a C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 deuterated alkyl or C1-C6 haloalkyl.

[0126] In some implementations, y is 0. In some implementations, y is 1.

[0127] In some implementations, z is 1, 2, 3, or 4. In some implementations, z is 1, 2, or 3. In some implementations, z is 1 or 2. In some implementations, z is 1.

[0128] In some implementation schemes, R 1 It is hydrogen or methyl. In one specific implementation, R 1 It is hydrogen or methyl, and R 2 It is methyl. In a more specific implementation, R 1 It is hydrogen, and R 2 It is methyl. In another embodiment, R 1 It is methyl, and R 2 It is a methyl group.

[0129] In some implementation schemes, R 2 It is a methyl group.

[0130] In some implementation schemes, R 3 It is chlorine or cyanide. In one specific implementation, R 3 It is chlorine. In another specific implementation, R 3 It is a cyano group.

[0131] In some implementation schemes, R 4 yes:

[0132] , , , , or In some implementations, R 4 yes:

[0133] , , , , , , , , , , or In some implementations, R 4 yes: or In one specific implementation plan, R 4 yes , or In a more specific implementation plan, R 4 yes or .

[0134] In some implementation schemes, R 4 yes:

[0135] , , , , , , , , , , , , , , , or In one specific implementation plan, R 4 yes:

[0136] , , ,

[0137] , , , , , or In a more specific implementation plan, R 4 yes ,For example, In another specific implementation, R 4 yes ,For example, or In another specific implementation, R 4 yes .

[0138] In some implementation schemes, X 2 X 3 and X 4 It is C(H). In some implementations, X 2 X 3 and X 4 One is N, and the other two are C(H). In some implementations, X 2 and X 4 It is C(H), and X 3 It is N. In some implementations, X 2 It is N, and X 3 and X 4 It is C(H). In some implementations, X 2 and X 3 It is C(H), and X 4 It is N.

[0139] In some implementation schemes, R 13 It is hydrogen or methyl. In one specific implementation, R 13 It is hydrogen.

[0140] In some implementation schemes, R 14 It's fluorine.

[0141] In some implementation schemes, R 52 It is hydrogen or methyl. In one specific implementation, R 52 It is hydrogen. In another specific implementation, R 52 It is a methyl group.

[0142] In some implementations, p is 0 or 1. In one specific implementation, p is 0. In another specific implementation, p is 1.

[0143] It should be understood that any compound described herein may include one or more hydrogen atoms replaced by deuterium. For example, any one or more substituents of formula (I) may be deuterated, such as ring A, L 1 L 2 R 1 R 2 R 4R 10 R 11 R 12 R 13 One or more.

[0144] In the description herein, it should be understood that all descriptions, variations, embodiments, or aspects of formula (I) apply equally, where applicable, to other chemical formulas described in detail herein, and are described equally, as if each description, variation, embodiment, or aspect were listed separately and individually for all chemical formulas. It should also be understood that all descriptions, variations, embodiments, or aspects of formula (I) apply equally, where applicable, to other chemical formulas described in detail herein, and are described equally, as if each description, variation, embodiment, or aspect were listed separately and individually for all chemical formulas. For example, all descriptions, variations, embodiments, or aspects of formula (I) apply equally, where applicable, to any chemical formula described in detail herein, such as formulas (II), (III), and (IV), and are described equally, as if each description, variation, embodiment, or aspect were listed separately and individually for all chemical formulas.

[0145] In some embodiments, compounds selected from those in Table 1 or pharmaceutically acceptable salts thereof are provided. Although some compounds described in this invention (including those in Table 1) are presented as specific stereoisomers and / or non-stereochemical forms, it should be understood that any or all stereochemical forms (including any enantiomers or diastereomers) and any tautomers or other forms of any compound in this disclosure (including those in Table 1) are described herein.

[0146] Table 1.

[0147]

[0148]

[0149]

[0150]

[0151]

[0152]

[0153]

[0154]

[0155]

[0156]

[0157]

[0158]

[0159]

[0160]

[0161]

[0162]

[0163]

[0164]

[0165]

[0166]

[0167]

[0168]

[0169]

[0170]

[0171]

[0172] Or its pharmaceutically acceptable salt.

[0173] In some implementations, the compound is Or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is... Or its pharmaceutically acceptable salt.

[0174] All compounds of formula (I) existing in the form of a free base or acid can be converted into their pharmaceutically acceptable salts by methods known to those skilled in the art, by treatment with a suitable inorganic or organic base or acid. Salts of compounds of formula (I) (e.g., pharmaceutically acceptable salts) can be converted into their free base or free acid forms by standard techniques.

[0175] The compounds described herein can be prepared using conventional organic synthesis and commercially available starting materials or the methods provided herein. By way of example and not limitation, compounds of formula (I) can be prepared as outlined in the procedures and examples described herein. It should be noted that those skilled in the art will recognize how to modify the procedures set forth herein to obtain the desired products.

[0176] Process 1.

[0177]

[0178] Where R1, R2, and R3 are respectively as shown in relation to the compound of formula (I) 1 R 2 and R 3 The above; and LG is a leaving group.

[0179] Process 2.

[0180]

[0181]

[0182] Where X 5 X 6 X 7 For example, regarding the X of compound (I) 2 X 3 and X 4 The aforementioned; R 10 R 12 And x as described for compounds of formula (I), for example, R 12 It is H, methyl, ethyl, or -(CH2)2OH; X is C(H) or N; Y is C(H), N, or C(=O); Z is C(H), N, or N(CH3); LG is a leaving group, such as bromine; M is -NH2, -NHCH3, or -OH; M' is -NH-, -NCH3-, or -O-; PG and PG 1 Protecting groups, such as Bn; R 12’ It is hydrogen, C1-C6 alkyl, C1-C6 alkyl-O-PG 1 C1-C6 deuterated alkyl or C1-C6 haloalkyl, such as H, methyl, ethyl or -(CH2)2OBn; ​​Bn is benzyl; X' is C or NPG; and X" is C or N(H).

[0183] Step 3.

[0184]

[0185]

[0186] Where X 1 R10 R 12 And x as described with respect to compounds of formula (I), for example, X 1 It is C(H), C(CH3) or N; G is C(H), C(CH3) or N; W is C or C(CH); W' is C(H) or C(CH2); X is C(H) or N; Y is C(H), N or C(=O); Z is C(H), N or N(CH3); LG is a leaving group, such as bromine; M is -NH2, -NHCH3 or -OH; M' is -NH-, -NCH3- or -O-; PG and PG 1 Protecting groups, such as Bn; R 12’ It is hydrogen, C1-C6 alkyl, C1-C6 alkyl-O-PG 1 C1-C6 deuterated alkyl or C1-C6 haloalkyl, such as H, methyl, ethyl or -(CH2)2OBn; ​​Bn is benzyl; X' is C or NPG; and X" is C or N(H).

[0187] Step 4.

[0188]

[0189] Where R 10 And x is as described with respect to compound (I); M is NH2, NHCH3 or OH; M' is N(H), N(CH3) or O; and PG is a protecting group.

[0190] Step 5.

[0191]

[0192]

[0193] The values ​​of the variables are defined as in process 1-4.

[0194] Step 6.

[0195]

[0196] Where R 10 R 12 And x is as described with respect to compound (I); M is NH2, NHCH3, or OH; M' is N(H), N(CH3), or O; X is CH or absent, and when X is absent, the nitrogen atom to which X is attached forms part of the ring; and PG is a protecting group.

[0197] Step 7.

[0198]

[0199] Where R 10 R12 And x is as described with respect to compound (I); M is NH2, NHCH3 or OH; M' is N(H), N(CH3) or O; X is CH or absent, and when X is absent, the nitrogen atom to which X is attached forms part of the ring; and PG is a protecting group.

[0200] Step 8.

[0201]

[0202] The values ​​of the variables are defined as in processes 1, 6, and 7.

[0203] As outlined in Process 1, compound e can be synthesized by coupling compound a with compound b to form compound c, then reducing it to form compound d, and further coupling it to form compound e.

[0204] Procedure 2 provides routes for the synthesis of compounds A, B, and C. Compound g (e.g., any of compounds g-1 to g-8) can be coupled with compound h to give compound i. Compound i is deprotected and further reduced to form compound j, which is optionally deprotected to form compound A. Compound i, where M' is N(H), can be methylated to form compound k. Compound k is deprotected and further reduced to form compound l, which is optionally deprotected to form compound B. Alternatively, compound g (e.g., any of compounds g-1 to g-8) can be coupled with compound m to give compound n. Compound n is deprotected and further reduced to form compound o, which is optionally deprotected with an amine to form compound C.

[0205] Procedure 3 provides the synthesis of compounds D, E, and F. Compound p (e.g., any one of compounds p-1 to p-5) can be coupled with compound q to give compound r, which is optionally deprotected to form compound D. Compound r, where W' is N(H), can be methylated to form compound s. Compound s is optionally deprotected to form compound E. Alternatively, compound p (e.g., any one of compounds p-1 to p-5) can be coupled with compound t to form compound u, which is subsequently optionally deprotected to form compound F.

[0206] Procedure 4 provides routes for the synthesis of compounds G and H. Compound v can be coupled with compound w to form compound x, which can then be optionally deprotected to form compound G. Alternatively, compound v can be coupled with compound y to form compound z, which can then be optionally deprotected to form compound H.

[0207] Procedure 5 provides the routes for synthesizing compounds A' to H'. Compounds A to H are coupled with compound e, respectively, to form compounds A' to H' accordingly.

[0208] Procedures 6 and 7 provide routes for the synthesis of compounds I, J, K, L, and M. In procedure 6, compound cc is coupled with compound bb to form compound aa, which is then optionally deprotected to form compound I. Alternatively, compound cc is coupled with compound dd to form compound ee, which is then optionally deprotected to form compound J. Compound ee, where R¹² is H, may optionally be methylated to form compound ff, which is then optionally deprotected to form compound K. In procedure 7, compound gg is coupled with compound hh to form compound ii, which is then optionally deprotected to form compound L. Alternatively, compound gg is coupled with compound jj to form compound kk, which is then optionally deprotected to form compound M.

[0209] Procedure 8 provides the route for synthesizing compounds J' to M'. Compounds J to M are coupled with compound e, respectively, to form compounds J' to M' accordingly.

[0210] How to use

[0211] Embodiments of this disclosure provide a method for regulating BCL6 in an individual in need, the method comprising administering to the individual an effective amount of a compound provided herein (e.g., a compound of formula (I), or a pharmaceutically acceptable salt thereof). Regulation (e.g., inhibition or activation) of BCL6 can be assessed and confirmed by a variety of methods known in the art. Kits and commercially available analytical methods can be used to determine whether BCL6 has been regulated (e.g., inhibited or activated) and the extent of regulation.

[0212] In one aspect, a method for regulating BCL6 is provided herein, comprising contacting BCL6 with an effective amount of a compound provided herein (e.g., a compound of formula (I), or a pharmaceutically acceptable salt thereof). In some embodiments, the compound inhibits BCL6. In some embodiments, the compound causes degradation of BCL6.

[0213] In some embodiments, the compounds provided herein regulate the activity of BCL6 to 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 provided herein regulate the activity of BCL6 to 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%, or 80-100%. 85-100%, 90-100%, 95-100%, 5-95%, 5-90%, 5-85%, 5-80%, 5-75%, 5-70%, 5-65%, 5-60%, 5-55%, 5-50%, 5-45%, 5-40%, 5-35%, 5-30%, 5-25%, 5-20%, 5-15%, 5-10%, 10-90%, 20-80%, 30-70%, or 40-60%.

[0214] Some embodiments of the present invention also provide a method for degrading BCL6 in an individual in need, the method comprising administering to the individual an effective amount of a compound provided herein (e.g., a compound of formula (I), or a pharmaceutically acceptable salt thereof). The degradation of BCL6 can be assessed and confirmed by a variety of methods known in the art. Kits and commercially available analytical methods, including cell-based assays, can be used to determine whether BCL6 has been degraded and the extent of that degradation.

[0215] In one aspect, a method for degrading BCL6 is provided herein, the method comprising contacting BCL6 with an effective amount of a compound provided herein (e.g., a compound of formula (I), or a pharmaceutically acceptable salt thereof). In some embodiments, the compound causes partial degradation of BCL6. In some embodiments, the compound causes complete degradation of BCL6.

[0216] In some embodiments, the compounds provided herein degrade 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 provided herein degrade 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%, or 80-100%. 85-100%, 90-100%, 95-100%, 5-95%, 5-90%, 5-85%, 5-80%, 5-75%, 5-70%, 5-65%, 5-60%, 5-55%, 5-50%, 5-45%, 5-40%, 5-35%, 5-30%, 5-25%, 5-20%, 5-15%, 5-10%, 10-90%, 20-80%, 30-70%, or 40-60%.

[0217] In another aspect, this document provides methods for treating cancer in individuals in need, the methods comprising administering to the individual an effective amount of a compound provided herein (e.g., a compound of formula (I), or a pharmaceutically acceptable salt thereof). In some embodiments, this document provides methods for preventing cancer in individuals in need, the methods comprising administering to the individual an effective amount of a compound provided herein (e.g., a compound of formula (I), or a pharmaceutically acceptable salt thereof).

[0218] Non-limiting examples of cancer include squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma, renal cell carcinoma, bladder cancer, colorectal 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, and Ewing's sarcoma. Sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, sarcoma, peripheral neuroepithelial tumor, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, gangliocytoma, ganglioglioma, medulloblastoma, pineal cell carcinoma, meningioma, meningeal sarcoma, neurofibroma and schwannoma, prostate cancer, uterine cancer, testicular cancer, thyroid cancer, astrocytoma, gastric cancer, melanoma, carcinosarcoma, Hodgkin's disease, Wilms' tumor. Tumors, teratomas, T-cell acute lymphoblastic leukemia (T-ALL), T-cell lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, pre-B-cell ALL, pre-B-cell lymphoma, diffuse large B-cell lymphoma, B-cell ALL, Philadelphia chromosome-positive ALL, Philadelphia chromosome-positive CML, follicular lymphoma, marginal zone lymphoma, mantle cell lymphoma, Waldenstroms macroglobulinemia, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), intravascular large B-cell lymphoma, B-cell leukemia, chronic myeloid leukemia, and non-small cell lung cancer.

[0219] In some embodiments, administration of the compounds provided herein to an individual in need may reduce the severity of cancer in that individual (such as tumor size, tumor growth rate, metastasis). In some embodiments, administration of the compounds provided herein to an individual in need may stabilize cancer (prevent or delay cancer progression). In some embodiments, administration of the compounds provided herein to an individual in need may delay the onset or recurrence of cancer. In some embodiments, administration of the compounds provided herein to an individual in need may slow the progression of cancer. In some embodiments, administration of the compounds provided herein to an individual in need may provide partial remission of cancer. In some embodiments, administration of the compounds provided herein to an individual in need may provide overall remission of cancer. In some embodiments, administration of the compounds provided herein to an individual in need may reduce the dosage of one or more other drugs required to treat cancer. In some embodiments, administration of the compounds provided herein to an individual in need may enhance the effect of another drug used to treat cancer. In some embodiments, administration of the compounds provided herein to an individual in need may delay the progression of cancer. In some embodiments, administration of the compounds provided herein to an individual in need may improve the quality of life of an individual with cancer. In some embodiments, administration of the compounds provided herein to an individual in need may prolong the survival of an individual with cancer.

[0220] In some aspects, methods for slowing the progression of cancer in an individual are provided herein, the methods comprising administering to the individual an effective amount of a compound provided herein. In some embodiments, methods for stabilizing cancer in an individual are provided herein, the methods comprising administering to the individual an effective amount of a compound provided herein. In some embodiments, the method blocks the progression of cancer. In some embodiments, the method delays the progression of cancer. In some embodiments, the method provides partial or overall remission of cancer.

[0221] In another aspect, this document provides a method for delaying the onset or recurrence of cancer in an individual, the method comprising administering to the individual an effective amount of the compound provided herein.

[0222] In a further aspect, this document provides a method for reducing the dosage of one or more other drugs required to treat cancer in an individual, the method comprising administering an effective amount of the compound provided herein to the individual. In some embodiments, this document provides a method for enhancing the effect of another drug used to treat cancer in an individual, the method comprising administering an effective amount of the compound provided herein to the individual.

[0223] This document also provides methods for delaying the progression of cancer in an individual, the methods comprising administering to the individual an effective amount of the compounds provided herein. In some embodiments, the method improves the quality of life of an individual with cancer. In some embodiments, the method prolongs the survival of an individual with cancer.

[0224] In a further aspect, methods are provided herein for treating autoimmune diseases in individuals in need, comprising administering to the individual an effective amount of a compound provided herein (e.g., a compound of formula (I), or a pharmaceutically acceptable salt thereof). In some embodiments, methods are provided herein for preventing autoimmune diseases in individuals in need, comprising administering to the individual an effective amount of a compound provided herein (e.g., a compound of formula (I), or a pharmaceutically acceptable salt thereof).

[0225] 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, Graves' 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). This disclosure covers 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 mellitus, endometriosis, Goodpasture's syndrome, Graves' disease, Guillain-Barré syndrome (GBS), Hashimoto's disease, hidradenitis suppurativa, and Kawasaki disease. Diseases including IgA nephropathy, idiopathic thrombocytopenic purpura, interstitial cystitis, mixed connective tissue disease, scleroderma, multiple sclerosis, myasthenia gravis, narcolepsy, neuromuscular rigidity, 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.

[0226] In another respect, this article provides a method for treating TH17-related conditions, such as TH17-related autoimmune diseases, in individuals in need, which includes administering to the individual an effective amount of a compound provided herein (e.g., a compound of formula (I), or a pharmaceutically acceptable salt thereof).

[0227] In some embodiments, administration of the compounds provided herein to an individual in need may alleviate or reduce symptoms of an autoimmune disease (such as inflammation, chronic fever, malaise, joint pain, myalgia, and fatigue). In some embodiments, administration of the compounds provided herein to an individual in need may shorten or reduce the duration of symptoms of an autoimmune disease. In some embodiments, administration of the compounds provided herein to an individual in need may eliminate symptoms of an autoimmune disease. In some embodiments, administration of the compounds provided herein to an individual in need may delay the onset or recurrence of an autoimmune disease. In some embodiments, administration of the compounds provided herein to an individual in need may slow the progression of an autoimmune disease. In some embodiments, administration of the compounds provided herein to an individual in need may reduce the dosage of one or more other drugs required to treat an autoimmune disease. In some embodiments, administration of the compounds provided herein to an individual in need may enhance the effect of another drug used to treat an autoimmune disease. In some embodiments, administration of the compounds provided herein to an individual in need may delay the progression of an autoimmune disease. In some embodiments, administration of the compounds provided herein to an individual in need may improve the quality of life of an individual with an autoimmune disease.

[0228] In some aspects, methods for slowing the progression of an autoimmune disease in an individual are provided herein, the methods comprising administering an effective amount of a compound provided herein to the individual. In some embodiments, methods for stabilizing an autoimmune disease in an individual are provided herein, the methods comprising administering an effective amount of a compound provided herein to the individual. In some embodiments, the method blocks the progression of an autoimmune disease. In some embodiments, the method delays the progression of an autoimmune disease. In some embodiments, the method improves the quality of life of an individual suffering from an autoimmune disease.

[0229] In other aspects, this document provides methods for reducing the dosage of one or more other drugs needed to treat an autoimmune disease in an individual, the methods comprising administering an effective amount of the compound provided herein to the individual. In some embodiments, this document provides methods for enhancing the effect of another drug used to treat an autoimmune disease in an individual, the methods comprising administering an effective amount of the compound provided herein to the individual.

[0230] Pharmaceutical Compositions and Routes of Administration

[0231] The compounds disclosed herein can be administered to individuals 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. Suitable formulations can be prepared using conventional organic or inorganic additives via common methods, such additives as excipients (e.g., sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate, or calcium carbonate), binders (e.g., cellulose, methylcellulose, hydroxymethylcellulose, polypropylene pyrrolidone, polyvinylpyrrolidone, gelatin, gum arabic, polyethylene glycol, sucrose, or starch), and disintegrants (e.g., starch, carboxymethylcellulose, hydroxypropyl starch, low-substituted hydroxypropylcellulose, sodium bicarbonate, calcium phosphate, or lime). The pharmaceutical formulation may contain calcium citrate, lubricants (e.g., magnesium stearate, light anhydrous silicate, talc, or sodium lauryl sulfate), flavoring agents (e.g., citric acid, menthol, glycine, or orange powder), preservatives (e.g., sodium benzoate, sodium bisulfite, methylparaben, or propylparaben), stabilizers (e.g., citric acid, sodium citrate, or acetic acid), suspensions (e.g., methylcellulose, polyvinylpyrrolidone, or aluminum stearate), powders (e.g., hydroxypropyl methylcellulose), diluents (e.g., water), and base waxes (e.g., cocoa butter, white petrolatum, or polyethylene glycol). The amount of a compound in the pharmaceutical formulation may be a level that will produce the desired effect, such as an effective amount.

[0232] The compounds provided herein (e.g., compounds of formula (I) or pharmaceutically acceptable salts thereof) may be administered once, twice, three times, four times or more daily. Typically, the compounds disclosed herein are administered one to four times daily (e.g., once daily; twice; three times; four times; or once to twice daily). In one embodiment, the compound is administered once daily. In another embodiment, the compound is administered twice daily. In yet another embodiment, the compound is administered once or twice daily. In a specific embodiment, a dose of 100 mg or less is administered as a once-daily dose, and a dose greater than 100 mg is administered twice daily in an amount equal to half the total daily dose.

[0233] The compounds provided herein (e.g., compounds of formula (I) or pharmaceutically acceptable salts thereof) are for oral administration. In one embodiment, when administered orally, the compound is given with food and water. In another embodiment, the compound is dispersed in water or juice (e.g., apple juice or orange juice) or any other liquid and administered orally as a solution or suspension.

[0234] The compounds disclosed herein may also be administered intradermally, intramuscularly, intraperitoneally, transdermally, intravenously, subcutaneously, intranasally, epidurally, sublingually, intracerebrally, intravaginally, transdermally, transrectally, transmucosally, by inhalation, or topically to the ear, nose, eye, or skin. The mode of administration is determined by the judgment of the healthcare professional and may be partly dependent on the location of the medical condition.

[0235] In one embodiment, capsules containing the compounds provided herein (e.g., compounds of formula (I), or pharmaceutically acceptable salts thereof) and free from other carriers, excipients, or media are provided herein.

[0236] In another embodiment, a composition is provided herein comprising a compound provided herein (e.g., an effective amount of a compound provided herein, such as a compound of formula (I) or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable carrier or medium, wherein the pharmaceutically acceptable carrier or medium may comprise excipients, diluents, or mixtures thereof. In one embodiment, the composition is a pharmaceutical composition.

[0237] The composition may be in the form of tablets (e.g., chewable tablets), capsules, solutions, parenteral solutions, lozenges, suppositories, suspensions, etc. The composition may be formulated to contain a daily dose or a suitable fraction of a daily dose in a dosing 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 hydrochloride. Generally, all compositions are prepared according to methods known in medicinal chemistry. Capsules may be prepared by mixing the compound 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 powders and similar edible powders.

[0238] Tablets can be prepared by direct compression, wet granulation, or dry granulation. Their formulations typically include diluents, binders, lubricants, disintegrants, and compounds. Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or calcium sulfate, and inorganic salts (such as sodium chloride and powdered sugars). Powdered cellulose derivatives are also suitable. Typical tablet binders include substances such as starch, gelatin, and sugars such as lactose, fructose, and glucose. Natural and synthetic gums are also suitable, including gum arabic, alginate, methylcellulose, and polyvinylpyrrolidone. Polyethylene glycol, ethylcellulose, and waxes can also act as binders.

[0239] Lubricants may be necessary for tablet formulations to prevent tablets and punches from sticking to 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 upon wetting to break up the tablet and release a compound. These include starch, clay, cellulose, alginate, and gum. More specifically, corn and potato starch, methylcellulose, agar, bentonite, wood cellulose, powdered natural sponges, cation exchange resins, alginate, guar gum, citrus pomace, carboxymethyl cellulose, and sodium lauryl sulfate can be used. Tablets may be coated with sugar as a flavoring and sealing agent, or with a film-forming protectant to modify the tablet's dissolution properties. The composition may also be formulated into chewable tablets, for example, by using a substance such as mannitol in the formulation.

[0240] When the compounds described herein need to be administered in suppository form, typical suppository bases can be used. Cocoa butter is a conventional suppository base, which can be modified by adding wax to slightly increase its melting point. In particular, water-miscible suppository bases containing polyethylene glycol of various molecular weights are widely used.

[0241] The action of a compound can be delayed or prolonged through appropriate formulation. For example, slow-dissolving microspheres of the compound can be prepared and incorporated into tablets or capsules or as slow-release implantable devices. The technology also includes preparing microspheres with several different dissolution rates and filling capsules with mixtures of microspheres. Tablets or capsules can be coated with a film that resists dissolution over a predictable period. Even parenteral formulations can be made long-acting by dissolving or suspending the compound in an oily or emulsified medium that allows it to disperse slowly in serum.

[0242] It should be understood that the pharmaceutical compositions described herein may include mixtures of the compounds described herein, including racemic mixtures of any of the compounds described herein.

[0243] Exemplary Implementation

[0244] Implementation Scheme 1. Compound of Formula (I):

[0245] ,

[0246] Or its pharmaceutically acceptable salt, wherein:

[0247] Ring A is a 4- to 12-membered nitrogen-containing heterocyclic group, a 5- to 12-membered carbocyclic group, a 5- to 6-membered nitrogen-containing heteroaryl group, or a phenylene group. or , or does not exist, where ring A, when it exists, is (R 10 ) x replace;

[0248] Each R 10Independently, it is a halogen, a C1-C6 alkyl, a C1-C6 alkoxy, a C1-C6 hydroxyalkyl, or a C1-C6 haloalkyl, or two Rs. 10 Together with the carbon atoms they are connected to, they form oxo groups;

[0249] x is 0, 1, 2, 3 or 4;

[0250] L 1 It is N(R) 11 ) or N(R 11 CH2C(O) or not present;

[0251] R 11 It is hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, or C1-C6 haloalkyl;

[0252] L 2 It is -(CH2) y N(R 12 )-、-O(CH2) y -、-N(R 12 )C(O)-、-C(O)N(R 12 (CH2) z -、-C(O)N(R 12 (CH2) z N(R 12 )-、-C(O)N(R 12 (CH2) z O-, -(CH2) z C(O)N(R 12 )- or (CH2) z Or it may not exist;

[0253] Each R 12 It is independently hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 deuterated alkyl, or C1-C6 haloalkyl;

[0254] y is 0 or 1;

[0255] z is 1, 2, 3, 4 or 5;

[0256] R 1 It is hydrogen or C1-C6 alkyl;

[0257] R 2 It is a C1-C6 alkyl group;

[0258] R 3 It is either halogen or cyano;

[0259] R 4 yes , , , , , , , , , or ;

[0260] X 1 It is C(R) 13 ) or N;

[0261] X 2 X 3 and X 4 It is C(H); or X 2 and X 4 It is C(H), and X 3 It is N; or X 2 It is N, and X 3 and X 4 It is C(H); or X 2 and X 3 It is C(H), and X 4 It is N;

[0262] R 13 It is hydrogen or C1-C6 alkyl;

[0263] Each R 14 Halogens are independent of each other;

[0264] R 52 It is hydrogen or C1-C6 alkyl; and

[0265] p is 0, 1, 2 or 3.

[0266] Implementation Scheme 2. The compound of Implementation Scheme 1, wherein ring A is a 4- to 12-membered nitrogen-containing heterocyclic group.

[0267] Implementation Scheme 3. The compound of Implementation Scheme 2, wherein ring A is a 4- to 6-membered monocyclic nitrogen-containing heterocyclic group, an 8- to 10-membered spirocyclic nitrogen-containing heterocyclic group, or an 8- to 10-membered fused bicyclic nitrogen-containing heterocyclic group.

[0268] Implementation Scheme 4. The compound of Implementation Scheme 1, wherein ring A is piperidinyl, piperazineyl, azacyclobutane, pyrrolidine, 2,6-diazaspiro[3.4]octyl, 2,8-diazaspiro[4.5]decyl, 8-azabicyclo[3.2.1]octyl, octahydro-1H-pyrrolo[3,2-c]pyridinyl, cyclohexenyl, pyrazolyl or Its being (R) 10 ) x replace.

[0269] Implementation Scheme 5. The compound of Implementation Scheme 4, wherein ring A is a piperidinyl or piperazine group, which is bonded by (R 10 ) x replace.

[0270] Implementation Scheme 6. The compound of Implementation Scheme 1, wherein ring A is absent.

[0271] Implementation Scheme 7. A compound of any one of Implementation Schemes 1-6, wherein each R 10 Independently halogen, C1-C6 alkyl or C1-C6 hydroxyalkyl, or two R 10 Together with the carbon atoms they are connected to, they form oxo groups.

[0272] Implementation Scheme 8. The compound of Implementation Scheme 7, wherein each R 10 Independently fluorine, methyl or hydroxymethyl, or two R 10 Together with the carbon atoms they are connected to, they form oxo groups.

[0273] Implementation Scheme 9. A compound of any one of Implementation Schemes 1-8, wherein x is 0, 1 or 2.

[0274] Implementation Scheme 10. A compound of any one of Implementation Schemes 1-9, wherein L 1 It is N(R) 11 ).

[0275] Implementation Scheme 11. The compound of Implementation Scheme 10, wherein R 11 It is hydrogen, C1-C6 alkyl, or C1-C6 hydroxyalkyl.

[0276] Implementation Scheme 12. The compound of Implementation Scheme 11, wherein R 11 It is either hydrogen or methyl.

[0277] Implementation Scheme 13. A compound of any one of Implementation Schemes 1-9, wherein L 1 It does not exist.

[0278] Implementation Scheme 14. A compound of any one of Implementation Schemes 1-13, wherein L 2 It is -(CH2) y N(R 12 )-、-O(CH2) y -、-N(R 12 )C(O)-、-C(O)N(R 12 (CH2) z -、-C(O)N(R 12 (CH2) z N(R 12 )-、-C(O)N(R 12 (CH2)z O-, -(CH2) z C(O)N(R 12 )- or (CH2) z .

[0279] Implementation Scheme 15. The compound of Implementation Scheme 14, wherein L 2 It is (CH2) y N(R 12 ) or -O(CH2) y -

[0280] Implementation Scheme 16. A compound of any one of Implementation Schemes 1-15, wherein each R 12 It is independently hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl or C1-C6 deuterated alkyl.

[0281] Implementation Scheme 17. The compound of Implementation Scheme 16, wherein each R 12 It can be hydrogen, methyl, hydroxyethyl, or -CD3 independently.

[0282] Implementation Scheme 18. A compound of any one of Implementation Schemes 1-17, where y is 0.

[0283] Implementation Scheme 19. A compound of any one of Implementation Schemes 1-17, wherein y is 1.

[0284] Implementation Scheme 20. A compound of any one of Implementation Schemes 1-18, wherein z is 1, 2 or 3.

[0285] Implementation Scheme 21. A compound of any one of Implementation Schemes 1-13, wherein L 2 is -N(H)-, -N(CH3)-, -N(CH2CH2OH)-, -CH2N(H)-, -CH2N(CH3)-, -CH2N(CD3)-, -O-, -OCH2-, -N(H)C(O)-, -C(O) N(H)CH2-, -C(O)N(H)CH2CH2N(H)-, -C(O)N(H)CH2CH2CH2N(H)-, -C(O)N(H)CH2CH2O-, -CH2C(O)N(H)-, or -CH2-.

[0286] Implementation Scheme 22. A compound of any one of Implementation Schemes 1-13, wherein L 2 It does not exist.

[0287] Implementation Scheme 23. A compound of any one of Implementation Schemes 1-22, wherein R 1 It is either hydrogen or methyl.

[0288] Implementation Scheme 24. A compound of any one of Implementation Schemes 1-23, wherein R 2 It is a methyl group.

[0289] Implementation Scheme 25. A compound of any one of Implementation Schemes 1-24, wherein R 3 It is either chlorine or cyanide.

[0290] Implementation Scheme 26. A compound of any one of Implementation Schemes 1-25, wherein R 4 yes:

[0291] , , , , or .

[0292] Implementation Scheme 27. The compound of Implementation Scheme 26, wherein R 4 yes:

[0293] , , , , , , , , , , or .

[0294] Implementation Scheme 28. The compound of Implementation Scheme 27, wherein R 4 yes or .

[0295] Implementation Scheme 29. A compound of any one of Implementation Schemes 1-28, wherein X 2 X 3 and X 4 It is C(H).

[0296] Implementation scheme 30. The compound of scheme 27, wherein R 4 yes , or .

[0297] Implementation Scheme 31. The compound of Implementation Scheme 26, wherein R 4 yes or .

[0298] Implementation Scheme 32. A compound of any one of Implementation Schemes 1-31, wherein R13 It is either hydrogen or methyl.

[0299] Implementation Scheme 33. The compound of Implementation Scheme 32, wherein R 13 It is hydrogen.

[0300] Implementation Scheme 34. A compound of any one of Implementation Schemes 1-33, wherein R 14 It's fluorine.

[0301] Implementation Scheme 35. A compound of any one of Implementation Schemes 1-25 and 32-34, wherein R 52 It is either hydrogen or methyl.

[0302] Implementation Scheme 36. A compound of any one of Implementation Schemes 1-35, wherein p is 0 or 1.

[0303] Implementation Scheme 37. A compound of any one of Implementation Schemes 1-9, 14-21 and 23-36, having formula (II):

[0304] ,

[0305] Or its pharmaceutically acceptable salt.

[0306] Implementation Scheme 38. A compound of any one of Implementation Schemes 1, 7-12 and 23-35, having formula (III):

[0307] ,

[0308] Or its pharmaceutically acceptable salt.

[0309] Implementation Scheme 39. A compound of any one of Implementation Schemes 1-9 and 23-35, having formula (IV):

[0310] ,

[0311] Or its pharmaceutically acceptable salt.

[0312] Implementation scheme 40. The compounds in Table 1 or their pharmaceutically acceptable salts.

[0313] Implementation Scheme 41. A pharmaceutical composition comprising a compound of any one of Implementation Schemes 1-40 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0314] Implementation Scheme 42. A method for degrading B-cell lymphoma 6 protein (BCL6), the method comprising contacting BCL6 with an effective amount of a compound of any one of Implementation Schemes 1-40 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of Implementation Scheme 41.

[0315] Implementation Scheme 43. A method for treating cancer or an autoimmune disease in an individual in need, the method comprising administering to the individual an effective amount of any one of the compounds of Implementation Schemes 1-40 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of Implementation Scheme 41.

[0316] Example

[0317] The following examples are presented illustratively and not as limiting. Compounds were named using an automatic name generation tool provided in ChemBiodraw Ultra (Cambridgesoft), which generates systematic names of chemical structures supported by the Cahn-Ingold-Prelog rule for stereochemistry. Those skilled in the art can modify the procedures illustrated in the illustrative examples to obtain desired products.

[0318] Salts of the compounds described herein can be prepared by standard methods, such as incorporating an acid (e.g., TFA, formic acid, or HCl) into the mobile phase during chromatographic purification, or stirring the chromatographically purified product with a solution of an acid (e.g., an aqueous solution of HCl).

[0319] The following abbreviations may be relevant to this application.

[0320] abbreviation

[0321]

[0322]

[0323] Synthesis Examples

[0324] General Procedure 1: Buchwald coupling of amine with indazole CBM.

[0325]

[0326] A mixture of 6-bromo-3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-indazole (1.1 equivalents), an amine (1.0 equivalent), Ruphos-Pd-G3 (0.20 equivalents), and sodium tert-butoxide (1.5 equivalents) 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 through a Celite filter, and the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using a gradient elution of 0-100% ethyl acetate in hexane to give the title compound.

[0327] General Procedure 2: Coupling of alcohols with general CBM.

[0328]

[0329] Where Z = C(H), N(CH3), N; Y = C(H), N; X = C, N

[0330] A solution of 2,6-dibenzyloxy-3-pyridyl)-arylbromine (1 equivalent), quinine ring (1.1 equivalent), 4,4'-di-tert-butyl-2,2'-dipyridyl (0.05 equivalent), nickel(II) glycol dimethyl ether complex (0.05 equivalent), and acetonitrile (.25 M) was added to a 2-dram vial equipped with a stir bar. In a separate 1-dram vial, [4,42-bis(1,1-dimethylethyl)-2,22-bipyridine-N1,N12]bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl-N]phenyl-C]iridium(III) hexafluorophosphate (0.10 equivalent) and 200 μL of acetonitrile were added. The solution was sonicated and added to the reaction vial. Ethanol (3 equivalents) was added, and argon gas was bubbled into the solution for 10 minutes. The reaction vials were sealed with sealing film and irradiated with blue light for 48 hours without fan cooling (reaction temperature ~55°C). The reaction was stirred at 1000 RPM. Afterward, the reaction was quenched with ethyl acetate after 16 hours, filtered, and concentrated. The crude substance was purified by normal-phase chromatography to give the title compound.

[0331] General Procedure 3: Buchwald coupling of amines with isoindolinone CBM.

[0332]

[0333] A mixture of amine (2 equivalents), 3-(bromo-1-oxo-isodihydroindol-2-yl)piperidine-2,6-dione (1 equivalent), cesium carbonate (4 equivalents), [2-(2-aminophenyl)phenyl]-[dicyclohexyl-[2-(2,6-diisobutoxyphenyl)phenyl]-λ^5-phosphino]palladium (1+); methanesulfonate (0.10 equivalents), and 1,4-dioxane (0.1 M) was added to a 2-duralam flask, degassed, and stirred overnight at 110°C. The reaction mixture was diluted with water and 1 M hydrochloric acid and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography using a 0-100% gradient elution with methanol in 10% ethyl acetate / hexane. Any fraction containing the product was collected and concentrated to give the title compound.

[0334] General Procedure 4: Coupling of alcohols with isoindolinone CBM.

[0335]

[0336] A solution of 3-(5-bromo-1-oxo-isodihydroindol-2-yl)piperidin-2,6-dione (1 equivalent), quinine ring (1.1 equivalent), 4,4'-di-tert-butyl-2,2'-dipyridyl (0.05 equivalent), nickel(II) glycol dimethyl ether complex (0.05 equivalent), and acetonitrile (0.25 M) was added to a 2-dextran vial equipped with a stir bar. In a separate 1-dextran vial, [4,42-bis(1,1-dimethylethyl)-2,22-bipyridine-N1,N12]bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl-N]phenyl-C]iridium(III) hexafluorophosphate (0.10 equivalent) and 200 μL of acetonitrile were added. This solution was sonicated and added to the reaction vial. Ethanol (3 equivalents) was added, and argon gas was bubbled into the solution for 10 minutes. The reaction vial was sealed with sealing film and irradiated with blue light for 48 hours with fanless cooling (reaction temperature ~55°C). The reaction was stirred at 1000 RPM. After 16 hours, the reaction was quenched with ethyl acetate, filtered, and concentrated. The crude substance was purified by normal-phase chromatography to give the title compound.

[0337] General Procedure 5: Amine substitution of benzimidazolone CBM.

[0338]

[0339] 3-[5-(bromomethyl)-1-oxo-isodihydroindol-2-yl]piperidine-2,6-dione (1 equivalent), amine (1.2 equivalent), N,N-diisopropylethylamine (3 equivalent), and N,N-dimethylformamide (0.5 M) were added to a flask equipped with a stir bar. The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was then added to stirred ethyl acetate, and the solid was collected by vacuum filtration, washed with diethyl ether, and dried under high vacuum to give the title compound. If desired, the product was purified with ethyl acetate in 0-100% hexane to give the title compound.

[0340] General Procedure 6: Amide Coupling

[0341]

[0342] A solution of amine (1.1 equivalents), 2-(2,6-dioxo-3-piperidinyl)-1-oxo-isodihydroindole-5-carboxylic acid (1.0 equivalents), and N,N-diisopropylethylamine (2.0 equivalents) in DMF (0.20 M) was treated with HATU (1.1 equivalents) and stirred overnight at ambient temperature. The reaction mixture was then diluted with water, extracted with ethyl acetate, and the organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude product was absorbed onto silica gel and purified by rapid chromatography. The purified fractions were combined and concentrated to give the title compound.

[0343] General Procedure 7: Reductive Amination of Amines (CBM) to the Connector

[0344]

[0345] To a solution of the ketone (1 equivalent) in DMSO (0.1 M), tert-butyl 4-oxopiperidin-1-carboxylate (1.1 equivalent), acetic acid (1 equivalent), and sodium triacetoxyborohydride (2 equivalent) were added sequentially. The reaction mixture was stirred at room temperature for 18 hours. The crude material was filtered through a syringe filter and purified by reversed-phase chromatography (C18) using a gradient elution of 5–100% acetonitrile and water (containing 0.1% formic acid) to give the title compound.

[0346] General Procedure 8: Methylation of Amines

[0347]

[0348] Sodium hydride (4.4 equivalents) was added to a solution of amine (1.0 equivalents) in N,N-dimethylformamide [0.15 M] at 0°C. After stirring for 1 hour, iodomethane (2.8 equivalents) was added dropwise 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 ethyl acetate. The extracts were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography by elution with petroleum ether / ethyl acetate to give the title compound.

[0349] General Procedure 9: Reduce CBM with hydrogen.

[0350]

[0351] A mixture of an indazole intermediate (1.0 equivalent) and palladium / carbon (10 wt.% palladium; 40% by weight) in ethanol:tetrahydrofuran (1:1.5; [0.05 M]) was placed at 50°C under hydrogen (1 atm) for 4 hours. The mixture was degassed with nitrogen and filtered through a Celite filter. The filter cake was washed successively with ethanol and tetrahydrofuran. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using a gradient elution of 0-100% ethyl acetate in hexane to give the title compound.

[0352] General Procedure 10: Deprotection of Boc using HCl or TFA.

[0353]

[0354] 4N hydrochloric acid (14 equivalents) in 1,4-dioxane was added to a solution of Boc-protected amine (1.0 equivalents) in 1,4-dioxane [0.3 M], and the reaction mixture was stirred at room temperature for 12 hours. The volatiles were evaporated under reduced pressure to give amine hydrochloride (quantitatively), as a solid, which was used in the next step without further purification.

[0355] General Program 11: Modifying the SNAr of TBM and CBM

[0356]

[0357] A solution of amine hydrochloride (1.0 equivalent), chloro / fluoropyrimidine (1.0 equivalent), and N,N-diisopropylethylamine (3 to 5 equivalents) in DMSO [0.1–0.2 M] was stirred at 80°C for 2 hours. The reaction mixture was filtered and purified by reversed-phase semi-preparative HPLC (10–100% acetonitrile + 0.1% formic acid in water (containing 0.1% formic acid) for 30 minutes). The fractions containing the purified product were combined and lyophilized to give the title compound.

[0358] Synthesis of intermediate i-1: 3-(6-amino-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione

[0359]

[0360] Step i-1.1: Synthesis of tert-butyl carbamate (3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazole-6-yl)carbamate. Under N2 atmosphere and with mechanical stirring, 160 g (320 mmol) of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-1-methyl-1H-indazole was dissolved in 1600 mL of 1,4-dioxane in a 3000 mL multi-necked round-bottom flask equipped with a reflux condenser. Next, tert-butyl carbamate (56.2 g, 480 mmol) was added, followed by potassium carbonate (133 g, 959 mmol), and the mixture was purged for 5 min. XPhos Pd G2 (25.2 g, 32.0 mmol) was then added, followed by purging for another 5 min, and the mixture was refluxed overnight at 110°C. The reaction mixture was filtered through a Celite bed and washed with ethyl acetate. The filtrate was evaporated to give a crude product, which was purified by normal-phase silica gel column chromatography using petroleum ether / ethyl acetate as eluent to give the title compound (148 g, 275 mmol, 86% yield) as a white solid. MS (ESI) m / z 537.30 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.5 (s, 1H), 7.89 - 7.91 (m, 1H), 7.28 -7.54 (m, 12 H), 6.94 (d, 1 H), 6.58 (d, 1 H), 5.41-5.45 (d, 4 H), 3.96 (s, 3H), 1.50 (s, 9H), 1.37 (s, 1H).

[0361] Step i-1.2: Synthesis of tert-butyl (3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazole-6-yl)carbamate. Tert-butyl (3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazole-6-yl)carbamate (25 g, 46.6 mmol) and tetrahydrofuran (500 mL) were added to a flask. The mixture was purged with nitrogen for 5 min, then palladium / carbon (24.79 g, 23.29 mmol) was added, and the mixture was stirred overnight at 55°C under H2 atmosphere. After this time, the reaction mixture was filtered through a Celite filter, washed with tetrahydrofuran (2 L), and the filtrate was evaporated to give the title compound (15.69 g, 43.8 mmol, 94% yield) as a white solid. MS (ESI) m / z 359.1 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ ppm 10.90 (s, 1H), 9.54 (s, 1H), 7.82 (m, 1H), 7.55 - 7.57(d, 1 H), 7.04 (d, 1 H), 4.30 (m, 1 H), 3.90 (s, 3 H), 2.30 - 2.70 (m, 2 H)2.13 - 2.37 (m, 2 H), 1.36 (s, 9H).

[0362] Step i-1.3: Synthesis of 3-(6-amino-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione, HCl salt. Tert-butyl 3-(3-(2,6-dioxadiidine-3-yl)-1-methyl-1H-indazol-6-yl)carbamate (25 g, 69.8 mmol) was dissolved in 1,4-dioxane (250 mL) in a 2 L round-bottom flask under magnetic stirring. HCl (4 M, in dioxane) (250 mL, 69.8 mmol) was slowly added, and the reaction was stirred at room temperature for 48 h. After this time, the mixture was filtered, and the resulting solid was dissolved in methanol, stirred thoroughly for 20 min, and then filtered again to give the title compound (18 g, 57.2 mmol, 82% yield) as a pale yellow solid. MS (ESI) m / z 259.1 [M+H] + . 1 ¹H NMR (400MHz, DMSO-d⁶) δ ppm 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). Note: No exchangeable protons were observed.

[0363] Synthesis of intermediate i-2: 3-(1-methyl-6-(piperidin-4-ylamino)-1H-indazol-3-yl)piperidin-2,6-dione hydrochloride

[0364]

[0365] Step i-2.1: Synthesis of 6-bromo-3-iodo-1-methyl-indazole. N-iodosuccinimide (25.58 g, 113.7 mmol) was added to a solution of 6-bromo-1-methyl-indazole (8.00 g, 37.9 mmol) in N,N-dimethylformamide (100 mL). The reaction mixture was heated to 150°C for 16 hours and then cooled to room temperature. The volatiles were evaporated under reduced pressure. The substance was purified by silica gel column chromatography using a gradient elution of 0-20% ethyl acetate in hexane to give the title compound (4.95 g, 14.7 mmol, 39% yield) as a solid. MS (ESI) m / z [M+H] + 336.90.

[0366] Step i-2.2: Synthesis of 6-bromo-3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-indazole. Under N2, (2,6-dibenzyloxy-3-pyridinyl)boronic acid (1.99 g, 5.94 mmol), potassium phosphate (3.78 g, 17.81 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(ii) (0.43 g, 0.5900 mmol) were added 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). The mixture was then stirred at 80°C under N2 for 17 hours. LC-MS showed complete consumption of the reactants, with the target MS peak as the dominant peak. The reaction was then cooled to room temperature and filtered. The filtrate was extracted with ethyl acetate (3 x 40 mL), washed with brine (2 x 40 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, gradient: 0-30% ethyl acetate in petroleum ether), the title compound (2.1 g, 4.20 mmol, 71% yield) as a pale yellow solid. MS (ES) [M+H] + 500.3. 1 HNMR (400 MHz, DMSO-d6) δ 7.96 (s, 1H), 7.91 (d, J= 8.1 Hz, 1H), 7.62 (d, J=8.7 Hz, 1H), 7.50 - 7.24 (m, 10H), 7.12 (dd, J= 8.7, 1.4 Hz, 1H), 6.60 (d, J=8.1 Hz, 1H), 5.45 (s, 2H), 5.43 (s, 2H), 4.05 (s, 3H).

[0367] Step i-2.3: Synthesis of tert-butyl 4-[[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole-6-yl]amino]piperidine-1-carboxylic acid. A mixture of 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole (4.0 g, 7.99 mmol), tert-butyl 4-aminopiperidine-1-carboxylic acid (1.92 g, 9.59 mmol), XPhos-Pd-G3 (1.35 g, 1.6 mmol), and cesium carbonate (5.2 g, 15.99 mmol) in 1,4-dioxane (53.292 mL) was heated to 110°C for 28 hours and then cooled to room temperature. The mixture was filtered through Celite and washed with ethyl acetate (3 x 10 mL). The filtrate was concentrated under reduced pressure. The substance was purified by silica gel column chromatography using a gradient elution of 0-90% ethyl acetate in hexane to give 4-[[3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-indazole-6-yl]amino]piperidine-1-carboxylic acid tert-butyl ester (2.81 g, 4.53 mmol, 57% yield), as a solid. MS (ESI) [M+H + 620.4; 1 H NMR (500 MHz, CDCl3) δ 7.89 (d, J = 8.1 Hz, 1H), 7.47 (d, J = 8.7 Hz, 1H), 7.45 - 7.42 (m,2H), 7.39 - 7.27 (m, 7H), 7.25 - 7.22 (m, 1H), 6.49 (d, J = 8.1 Hz, 1H), 6.36 (dd, J = 8.8, 1.9 Hz, 1H), 6.31 (d, J = 1.7 Hz, 1H), 5.46 (s, 2H), 5.38 (s,2H), 4.06 (br, 2H), 3.98 (s, 3H), 3.73 (br, 1H), 3.57 - 3.46 (m, 2H), 3.00 (t, J = 11.9 Hz, 2H), 2.10 (dd, J = 13.0, 2.8 Hz, 2H), 1.48 (s, 9H).

[0368] Step i-2.4: Synthesis of tert-butyl 4-[[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-6-yl]amino]piperidin-1-carboxylic acid. A mixture of tert-butyl 4-[[3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-indazole-6-yl]amino]piperidin-1-carboxylic acid (600 mg, 0.970 mmol) and Pearlman catalyst (167 mg, 0.240 mmol) in tetrahydrofuran (5 mL) and ethanol (3 mL) was hydrogenated at 1 atm and 50°C for 4 h. At this point, only the olefin product was observed. Additional Pearlman catalyst (33.4 mg, 0.0500 mmol) was added, and the mixture was hydrogenated at 1 atm and 50°C for 24 h. The mixture was filtered through a Celite filter and washed with methanol:acetonitrile (1:1 ratio, 3 x 50.0 mL). The filtrate was concentrated under reduced pressure to give 4-[[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-6-yl]amino]piperidin-1-carboxylic acid tert-butyl ester (495 mg, 0.9496 mmol, 98.085% yield) as a solid. MS (ESI) [M+H] + : 442.4; 1 H NMR(400 MHz, DMSO-d6) δ 10.81 (s, 1H), 7.33 (d, J = 8.7 Hz, 1H), 6.52 (dd, J =8.8, 1.8 Hz, 1H), 6.43 (s, 1H), 5.79 (d, J = 8.2 Hz, 1H), 4.18 (dd, J = 8.7,5.2 Hz, 1H), 3.93 - 3.86 (m, 2H), 3.81 (s, 3H), 2.96 (br, 2H), 2.60 (t, J =7.0 Hz, 2H), 2.30 - 2.20 (m, 1H), 2.18 - 2.11 (m, 1H), 1.94 (d, J = 11.0 Hz, 2H), 1.41 (s, 9H), 1.30 - 1.19 (m, 3H).

[0369] Step i-2.5: Synthesis of 3-[1-methyl-6-(4-piperidinylamino)indazole-3-yl]piperidine-2,6-dione hydrochloride. To a solution of 4-[[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-6-yl]amino]piperidine-1-carboxylic acid tert-butyl ester (1.22 g, 2.76 mmol) in 1,4-dioxane (20 mL), 4N hydrogen chloride in 1,4-dioxane (3.45 mL, 13.8 mmol) was added. 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) δ ppm 10.85 (s, 1 H), 9.01 (br d, J=2.45 Hz, 1 H), 8.76 - 8.95 (m, 1 H), 7.48 (br s, 1 H), 6.72 (br s, 3 H), 4.21 - 4.30 (m, 1 H), 3.87 (s,3 H), 3.63 - 3.75 (m, 1 H), 3.32 (br d, J=12.59 Hz, 2 H), 2.99 (br d, J=10.39Hz, 2 H), 2.55 - 2.69 (m, 2 H), 2.22 - 2.34 (m, 1 H), 2.07 - 2.22 (m, 2 H), 1.72 (br s, 2 H).

[0370] Synthesis of intermediate i-3: 3-(1-methyl-6-(4-(methylamino)piperidin-1-yl)-1H-indazol-3-yl)piperidin-2,6-dione hydrochloride

[0371]

[0372] Step i-3.1: Synthesis of tert-butyl 1-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazole-6-yl)piperidin-4-yl)(methyl)carbamate. 6-bromo-3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-indazole (300 mg, 0.6000 mmol), 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-duralumin vial and purged with nitrogen for 1 minute. Subsequently, 1,4-dioxane (0.8 mL) was added, and the reaction mixture was stirred overnight at 100°C. The product was purified from the crude mixture by column chromatography (10 g SNAP column, 0-7% methanol / dichloromethane 25 CV, 7% methanol / dichloromethane 10 CV) to give the title compound (106 mg, 0.1673 mmol, 27.8% yield) as a white solid. MS (ESI) m / z 634.0 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6 ) δ ppm7.89 (d, J=8.19 Hz, 1 H), 7.26 - 7.51 (m, 11 H), 6.88 (d, J=1.59 Hz, 1 H), 6.82 (dd, J=9.17, 1.96 Hz, 1 H), 6.57 (d, J=8.19 Hz, 1 H), 5.44 (d, J=13.57Hz, 4 H), 3.97 (s, 3 H), 3.87 (br d, J=12.59 Hz, 2 H), 2.77 (br t, J=11.55Hz, 2 H), 2.70 (s, 3 H), 1.71 - 1.89 (m, 2 H), 1.61 - 1.70 (m, 2 H), 1.42 (s, 9 H).

[0373] Step i-3.2: Synthesis of tert-butyl (1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazole-6-yl)piperidin-4-yl)(methyl)carbamate. N-[1-[3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-indazole-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 / carbon (17.8 mg, 0.1700 mmol) was added. The mixture was purged again with nitrogen and then with hydrogen. The reaction was stirred overnight under a hydrogen balloon. The slurry was filtered through a Celite filter and concentrated. The residue was loaded onto a SNAP 25G column and purified using 0-50% ethyl acetate / hexane with 2-5% methanol additive to give the title compound (50 mg, 0.110 mmol, 65.6% yield) as a yellow oil.

[0374] Step i-3.3: Synthesis of 3-(1-methyl-6-(4-(methylamino)piperidin-1-yl)-1H-indazol-3-yl)piperidin-2,6-dione hydrochloride. N-[1-[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazol-6-yl]-4-piperidinyl]-N-methyl-carbamate tert-butyl ester (50 mg, 0.1100 mmol) was added to a vial equipped with a stir bar, and dichloromethane (1 mL) was added. Then, HCl (0.4400 mmol) in 4 N in 1,4-dioxane was added to the mixture, and the mixture was stirred for 2 hours. The stir bar was removed, and the solvent was removed under vacuum to give the title compound (42 mg, 0.107 mmol, 97.6% yield) as a creamy white solid.

[0375] Synthesis of intermediate i-4: 3-(1-methyl-6-(methyl(piperidin-4-yl)amino)-1H-indazol-3-yl)piperidin-2,6-dione hydrochloride

[0376]

[0377] Step i-4.1: Synthesis of tert-butyl 4-[[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole-6-yl]amino]piperidine-1-carboxylic acid. A mixture of 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole (500 mg, 1 mmol), tert-butyl 4-aminopiperidine-1-carboxylic acid (240 mg, 1.2 mmol), RuPhos-Pd-G3 (83 mg, 0.1000 mmol), and cesium carbonate (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 ethyl acetate (3 x 10 mL). The filtrate was concentrated under reduced pressure. The substance was purified by silica gel column chromatography using a gradient elution of ethyl acetate in hexane from 0-100% to give the title compound (550 mg, 89%) as a solid. MS (ESI) [M+H] + 620.5; 1 H NMR (500 MHz, CDCl3)δ 7.89 (d, J = 8.1 Hz, 1H), 7.47 (d, J = 8.7 Hz, 1H), 7.45 - 7.41 (m, 2H), 7.39 - 7.24 (m, 8H), 6.49 (d, J = 8.1 Hz, 1H), 6.36 (dd, J = 8.7, 1.9 Hz,1H), 6.31 (d, J = 1.7 Hz, 1H), 5.46 (s, 2H), 5.38 (s, 2H), 4.13 - 4.03 (m,2H), 3.98 (s, 3H), 3.73 (s, 1H), 3.57 - 3.50 (m, 1H), 3.00 (t, J = 12.1 Hz, 2H), 2.10 (d, J = 10.8 Hz, 2H), 1.48 (s, 9H), 1.43 - 1.35 (m, 2H).

[0378] Step i-4.2: Synthesis of tert-butyl 4-[[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole-6-yl]-methyl-amino]piperidine-1-carboxylic acid. To a solution of tert-butyl 4-[[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole-6-yl]amino]piperidine-1-carboxylic acid (550 mg, 0.89 mmol) in dimethyl sulfoxide (3.6 mL) and acetic acid (0.9 mL), aqueous formaldehyde solution (0.13 mL, 1.8 mmol) and sodium triacetoxyborohydride (282 mg, 1.3 mmol) were added sequentially. The reaction mixture was stirred at room temperature for 1 hour. Water (10 mL) and ethyl acetate (25 mL) were added, and the layers were separated. The organic layer was washed with saturated sodium bicarbonate aqueous solution (5 mL), water (3 x 5 mL), and brine (5 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The substance was purified by silica gel column chromatography using a gradient elution of ethyl acetate from 0-100% in hexane to give the title compound (467 mg, 83% yield) as a solid. MS (ESI) [M+H + 635.5; 1 H NMR(400 MHz, CDCl3) δ 7.91 (d, J = 8.1 Hz, 1H), 7.56 (d, J = 9.0 Hz, 1H), 7.46 -7.40 (m, 2H), 7.40 - 7.30 (m, 5H), 7.29 - 7.23 (m, 3H), 6.72 (dd, J = 9.3,2.1 Hz, 1H), 6.50 (d, J = 8.1 Hz, 1H), 6.48 (d, J = 1.9 Hz, 1H), 5.47 (s,2H), 5.38 (s, 2H), 4.25 (s, 2H), 4.01 (s, 3H), 3.80 (td, J = 10.8, 5.3 Hz,1H), 2.84 (s, 3H), 2.83 - 2.74 (m, 2H), 1.81 - 1.64 (m, 4H), 1.49 (s, 9H).

[0379] Step i-4.3: 4-[[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-6-yl]-methyl-amino]piperidin-1-carboxylic acid tert-butyl ester. A mixture of 4-[[3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-indazole-6-yl]-methyl-amino]piperidin-1-carboxylic acid tert-butyl ester (467 mg, 0.74 mmol) and 20% Pearlman catalyst (117 mg, 25 wt%) in tetrahydrofuran (7 mL) and ethanol (7 mL) was hydrogenated at 1 atm and 50°C for 2 h. The mixture was filtered through a Celite filter, washed with a mixture of acetonitrile and methanol (1:1, 3 x 10 mL), and the filtrate was concentrated under reduced pressure. The substance was purified by silica gel column chromatography using a gradient elution of 0-20% methanol and dichloromethane solution to give the title compound (258 mg, 77%) as a solid. MS (ESI) [M+H] + 456.3; 1 H NMR (500 MHz, DMSO) δ 10.83 (s, 1H), 7.46 (d, J = 9.0 Hz, 1H), 6.87 (dd, J = 9.2, 2.0 Hz, 1H), 6.65 (d, J = 1.9Hz, 1H), 4.23 (dd, J = 9.0, 5.1 Hz, 1H), 4.09 - 3.99 (m, 2H), 3.98 - 3.91 (m,1H), 3.87 (s, 3H), 2.86 (br s, 2H), 2.76 (s, 3H), 2.64 - 2.56 (m, 2H), 2.33 -2.25 (m, 1H), 2.21 - 2.13 (m, 1H), 1.67 - 1.54 (m, 4H), 1.41 (s, 9H).

[0380] Step i-4.4: Synthesis of 3-[1-methyl-6-[methyl(4-piperidinyl)amino]indazole-3-yl]piperidine-2,6-dione; hydrochloride. 4M HCl (1.42 mL, 5.66 mmol) in 1,4-dioxane was added to a solution of 4-[[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-6-yl]-methyl-amino]piperidine-1-carboxylic acid tert-butyl ester (258 mg, 0.57 mmol) in 1,4-dioxane (10 mL). The reaction mixture was heated to 100°C for 3 hours and then cooled to room temperature. The volatiles were evaporated under reduced pressure. Add diethyl ether (5 x mL), and collect the precipitate by filtration. Wash with 1,4-dioxane (3 x 1 mL) and diethyl ether (10 x 2 mL), then dry under vacuum to give the title compound (217 mg, 92%) as a solid. MS (ESI) [M+H] + 356.2; 1 H NMR (400 MHz, D2O) δ 7.93 (d, J = 8.3 Hz, 1H), 7.65 (s, 1H), 7.31 (d, J = 8.0 Hz, 1H), 4.56 (dd, J = 10.8, 4.2 Hz, 1H), 4.18 -4.09 (m, 1H), 4.07 (s, 3H), 3.61 (d, J = 12.6 Hz, 2H), 3.33 (s, 3H), 3.11 (t,J = 12.9 Hz, 2H), 2.91 - 2.79 (m, 2H), 2.61 - 2.48 (m, 1H), 2.44 - 2.35 (m,1H), 2.28 (d, J = 12.0 Hz, 2H), 2.05 - 1.90 (m, 2H). Note: No exchangeable protons were observed; contains < 1 wt% 1,4-dioxane.

[0381] Intermediate i-5: Synthesis of 3-(1-methyl-6-(((3R,4R)-3-methylpiperidin-4-yl)amino)-1H-indazol-3-yl)piperidin-2,6-dione.

[0382]

[0383] Step i-5.1: Synthesis of tert-butyl ester of (3R,4R)-4-[[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole-6-yl]amino]-3-methyl-piperidine-1-carboxylic acid. 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-piperidin-1-carboxylic acid tert-butyl ester (685.23 mg, 3.20 mmol, J&W PharmLab #60R1019, lot JWY790-124B, 98.63% ee), RuPhos Pd G3 (668.6 mg, 0.80 mmol), and Cs2CO3 (1.25 g, 3.84 mmol) in 1,4-dioxane (15 mL) was heated to 90°C for 20 hours. The mixture was cooled to room temperature, filtered through Celite, and washed with ethyl acetate (4 x 30 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using a gradient elution of 0-40% ethyl acetate in hexane to give the title compound (1.37 g, 68%) as a solid. MS (ESI) [M+H + 634.1. 1 H NMR (400MHz, DMSO-d6) δ 7.86 (d, J = 8.1 Hz, 1H), 7.50 - 7.46 (m, 1H), 7.46 - 7.25(m, 10H), 6.54 (d, J = 8.1 Hz, 1H), 6.43 (d, J = 1.8 Hz, 1H), 6.41 (d, J =2.2 Hz, 1H), 5.70 (d, J = 8.9 Hz, 1H), 5.44 (s, 2H), 5.40 (s, 2H), 3.97 -3.89 (m, 2H), 3.88 (s, 3H), 3.24 - 3.14 (m, 1H), 2.99 - 2.87 (m, 1H), 2.05 -2.01 (m, 1H), 2.01 - 1.98 (m, 1H), 1.57 - 1.47 (m, 1H), 1.41 (s, 9H), 1.17 -1.08 (m, 1H), 0.93 (d, J = 6.5 Hz, 3H).

[0384] Step i-5.2: Synthesis of tert-butyl (3R,4R)-4-[[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-6-yl]amino]-3-methyl-piperidin-1-carboxylic acid. A mixture of tert-butyl (3R,4R)-4-[[3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-indazole-6-yl]amino]-3-methyl-piperidin-1-carboxylic acid (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 for 9 hours under H₂ (1 atm). The mixture was filtered through a Celite filter 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 0-5% MeOH gradient elution in DCM to give the title compound (695 mg, 69%) as a solid. MS (ESI) [M+H + 456.3. 1 H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H), 7.31 (d, J = 8.8 Hz, 1H), 6.51 (dd, J = 8.8, 1.7Hz, 1H), 6.40 (s, 1H), 5.72 (d, J = 8.9 Hz, 1H), 4.17 (dd, J = 8.7, 5.2 Hz,1H), 3.98 - 3.88 (m, 2H), 3.80 (s, 3H), 3.26 - 3.14 (m, 1H), 3.00 - 2.86 (m,1H), 2.65 - 2.56 (m, 3H), 2.34 - 2.20 (m, 1H), 2.18 - 2.09 (m, 1H), 2.05 -1.94 (m, 1H), 1.60 - 1.46 (m, 1H), 1.41 (s, 9H), 1.22 - 1.05 (m, 1H), 0.92(d, J = 6.5 Hz, 3H).

[0385] Step i-5.3: Synthesis of 3-(1-methyl-6-(((3R,4R)-3-methylpiperidin-4-yl)amino)-1H-indazole-3-yl)piperidin-2,6-dione. HCl (3.81 mL, 15.26 mmol) in dioxane was added to a solution of (3R,4R)-4-[[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-6-yl]amino]-3-methyl-piperidin-1-carboxylic acid tert-butyl ester (695.0 mg, 1.53 mmol) in 1,4-dioxane (5 mL). The reaction mixture was stirred at room temperature for 16 hours, and the volatiles were evaporated under reduced pressure. Add 10 mL of Et₂O, collect the precipitate by filtration, wash with 3 x 10 mL of Et₂O, and dry under vacuum to give the title compound (673 mg, quantified) as a solid. MS (ESI) [M+H] + 356.2. 1 H NMR (500 MHz, acetic acid-d4) δ 7.93 (d, J = 8.6 Hz, 1H), 7.42 (d, J = 8.3Hz, 1H), 4.59 (dd, J = 10.7, 5.1 Hz, 1H), 4.15 (s, 3H), 4.01 - 3.90 (m, 1H),3.67 - 3.61 (m, 2H), 3.24 (t, J = 12.3 Hz, 1H), 3.07 (t, J = 12.6 Hz, 1H),2.98 (dt, J = 17.7, 4.8 Hz, 1H), 2.91 (dd, J = 10.6, 5.3 Hz, 1H), 2.88 - 2.78(m, 1H), 2.69 - 2.57 (m, 1H), 2.48 - 2.41 (m, 1H), 2.35 - 2.22 (m, 1H), 1.36 (d, J = 6.5 Hz, 3H). Note: Exchangeable protons are not visible; trace amounts of diethyl ether (0.3%) and dioxane (0.9%).

[0386] Intermediate i-6: Synthesis of 3-[1-methyl-6-(4-piperidinoxy)indazol-3-yl]piperidin-2,6-dione; hydrochloride

[0387]

[0388] Step i-6.1: Synthesis of tert-butyl 4-[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole-6-yl]oxypiperidine-1-carboxylic acid. 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole (250.2 mg, 0.5000 mmol), quinine ring (61.15 mg, 0.5500 mmol), 4,4'-di-tert-butyl-2,2'-dipyridyl (6.71 mg, 0.0200 mmol), nickel(II) ethylene glycol dimethyl ether complex (5.49 mg, 0.0200 mmol), and 200 μL of acetonitrile were added to a 2-dopan vial equipped with a stir bar. In another 1-drylan vial, [4,42-bis(1,1-dimethylethyl)-2,22-bipyridine-N1,N12]bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C]iridium(III) hexafluorophosphate (5.61 mg, 0 mmol) and 200 μL acetonitrile were added. The solution was sonicated and added to the reaction vial. 1-Boc-4-hydroxypiperidine (301.89 mg, 1.5 mmol) was added, and argon gas was bubbled into the solution for 10 minutes. The reaction vial was sealed with sealing film and irradiated with blue light for 48 hours under fanless cooling (reaction temperature ~55°C). The reaction was stirred at 1000 RPM. After 16 hours, the reaction was quenched with ethyl acetate, filtered, and concentrated. The crude residue was purified by SNAP 25G column using hexane / ethyl acetate to give the title compound (279.3 mg, 0.450 mmol, 90%).

[0389] Step i-6.2: Synthesis of tert-butyl 4-[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-6-yl]oxypiperidin-1-carboxylic acid. Tert-butyl 4-[3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-indazole-6-yl]oxypiperidin-1-carboxylic acid (510 mg, 0.8200 mmol) (contaminated with hydroxypiperidine) was added to a 30 mL vial and diluted with ethanol (20.54 mL). The mixture was stirred and purged with nitrogen. Palladium / carbon (87.42 mg, 0.8200 mmol) was then added, and the mixture was purged with nitrogen again. A hydrogen balloon was added to the reaction vial, and the mixture was stirred overnight at room temperature. Subsequently, the reaction vial was purged with nitrogen and filtered through a Celite filter. The filtrate was concentrated and purified by elution with silica gel using 0-50% ethyl acetate / hexane containing 5% methanol. The fraction containing the product was collected and proceeded to the next step.

[0390] Step i-6.3: Synthesis of 3-[1-methyl-6-(4-piperidinyloxy)inzol-3-yl]piperidine-2,6-dione; hydrochloride. 4-[3-(2,6-dioxo-3-piperidinyl)-1-methyl-inzol-6-yl]oxypiperidine-1-carboxylic acid tert-butyl ester (140 mg, 0.3200 mmol) was added to a vial equipped with a stir bar. HCl (0.24 mL, 0.9500 mmol) in dioxane was added, and the mixture was stirred for 2 hours. LC-MS indicated complete deprotection, and the reaction mixture was concentrated to give 3-[1-methyl-6-(4-piperidinyloxy)inzol-3-yl]piperidine-2,6-dione; hydrochloride (123 mg, 0.3247 mmol, 102.62% yield), as a white solid.

[0391] Synthesis of intermediate i-7: 3-(7-amino-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione

[0392] Step i-7.1. Synthesis of 7-bromo-3-iodo-1H-indazole. Potassium hydroxide (11.390 g, 203.01 mmol, 2 equivalents) was added to a solution of 7-bromo-1H-indazole (20.000 g, 101.51 mmol, 1 equivalent) and iodine (51.530 g, 203.01 mmol, 2 equivalents) in dimethylformamide (500 mL) at 0°C. The mixture was stirred at 16°C for 12 hours. LC-MS showed the reaction was complete. The reaction mixture was quenched with water (1 L) and a saturated aqueous solution of sodium sulfite (40 mL). The reaction mixture was filtered, and the filter cake was diluted with ethyl acetate (600 mL) and extracted with sodium sulfite (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. It was used directly in the next step without further purification. 7-Bromo-3-iodo-1H-indazole (32.700 g, 101.26 mmol, 99.8% yield) was obtained as a yellow solid. MS (ESI) m / z: 322.9 [M+1]+; 1 H NMR (400 MHz, DMSO-d6) δ 13.93 (s, 1 H), 7.64 - 7.79 (m, 1H), 7.47 (d, J = 8.0 Hz, 1 H), 7.08 - 7.26 (m, 1 H).

[0393] Step i-7.2. Synthesis of 7-bromo-3-iodo-1-methyl-1H-indazole. Potassium tert-butoxide (22.730 g, 202.52 mmol, 2 equivalents) was added to a solution of 7-bromo-3-iodo-1H-indazole (32.700 g, 101.26 mmol, 1 equivalent) in tetrahydrofuran (300 mL) at 0°C, and the reaction was stirred at 0°C for 1 hour. Then, a solution of methyl iodine (28.750 g, 202.52 mmol, 2 equivalents) in tetrahydrofuran (50 mL) was added dropwise to the reaction mixture at 0°C. The mixture was then stirred at 17°C for 12 hours. The target mass was detected by LCMS. TLC showed that 7-bromo-3-iodo-1H-indazole was completely consumed, and new spots were detected. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel chromatography (2-67% ethyl acetate in petroleum ether). A total of 28 g of the desired product was obtained, yielding 7-bromo-3-iodo-1-methyl-1H-indazole (21.240 g, 63.04 mmol, 62.3% yield) as a white solid. MS (ESI) m / z: 336.9 [M+1]+; 1 H NMR (400 MHz, DMSO-d6) δ 7.66 (d, J = 7.6 Hz, 1 H), 7.40 (d, J = 8.0 Hz, 1 H), 6.95 - 7.16 (m, 1 H), 4.31 (s, 3 H).

[0394] Step i-7.3. Synthesis of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-7-bromo-1-methyl-1H-indazole. To a solution of 7-bromo-3-iodo-1-methyl-1H-indazole (5.000 g, 14.84 mmol, 1 equivalent) in dioxane (50 mL) and water (5 mL), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyridine (6.190 g, 14.84 mmol, 1 equivalent), (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (1.090 g, 1.48 mmol, 0.1 equivalent), and cesium carbonate (14.500 g, 44.52 mmol, 3 equivalent) were added. The mixture was stirred at 100°C for 12 hours. 7-Bromo-3-iodo-1-methyl-1H-indazole was completely consumed, and the target mass was detected by LCMS. TLC showed retention of 7-bromo-3-iodo-1-methyl-1H-indazole, with new spots detected. The reaction mixture was concentrated under vacuum. The residue was purified by silica gel chromatography (0-8.5% ethyl acetate in petroleum ether) to give the desired product. 3-(2,6-bis(benzyloxy)pyridin-3-yl)-7-bromo-1-methyl-1H-indazole (4.240 g, 8.47 mmol, 57.1% yield) was given as a yellow solid. MS (ESI) m / z: 500.1 [M+1]+; 1H NMR (400 MHz, DMSO-d6) δ 7.86 (d, J = 8.0 Hz, 1 H), 7.57 -7.69 (m, 2 H), 7.45 - 7.50 (m, 2 H), 7.25 - 7.43 (m, 8 H), 6.93 (t, J = 7.6Hz, 1 H), 6.60 (d, J = 8.0 Hz, 1 H), 5.43 (s, 4 H), 4.36 (s, 3 H).

[0395] Step i-7.4. Synthesis of tert-butyl carbamate (3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazole-7-yl)carbamate. [2-(2-aminophenyl)phenyl]-chloro-palladium; dicyclohexyl-[3-(2,4,6-triisopropylphenyl)phenyl]phosphine (1.310 g, 1.67 mmol, 0.05 equivalents) was added to a solution of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-7-bromo-1-methyl-1H-indazole (74% purity, 16.700 g, 33.37 mmol, 1 equivalent), tert-butyl carbamate (3.910 g, 33.37 mmol, 1 equivalent), and cesium carbonate (21.750 g, 66.75 mmol, 2 equivalents) in dioxane (300 mL). The mixture was heated to 100°C and stirred for 16 hours. LCMS showed that the target product was detected by mass. The solution was filtered, and the filtrate was concentrated to obtain the residue. The residue was purified by silica gel chromatography (1% to 12% ethyl acetate in petroleum ether). 3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazol-7-yl)carbamate (6.600 g, 12.30 mmol, 36.85% yield) w, was a yellow oil, detected by NMR MS (ESI) m / z: 537.0 [M+1]+; 1 H NMR (400 MHz, CDCl3) δ = 7.85 (d, J = 8.0 Hz, 1H), 7.57 (d, J= 8.0 Hz, 1H), 7.44-7.47 (m, 1H), 7.36-7.41 (m, 2H), 7.27-7.35 (m, 4H), 7.21-7.27 (m, 3H), 6.97 (t, J = 7.6 Hz, 1H), 6.52 (d, J = 8.0 Hz, 1H), 6.40 (s,1H), 5.45 (s, 2H), 5.41 (s, 2H), 4.29 (s, 3H), 1.54 (s, 9H).

[0396] Step i-7.5. Synthesis of tert-butyl carbamate (3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazole-7-yl)carbamate. Palladium / carbon (1.000 g, 10% purity) was added to a solution of tert-butyl carbamate (8.000 g, 14.91 mmol, 1 equivalent) in tetrahydrofuran (150 mL). The mixture was stirred under hydrogen (50 psi) at 25°C for 24 hours. The mass number of the target product was detected by LCMS. The solution was filtered, and the filtrate was concentrated to give the residue. The residue was purified by silica gel chromatography (10% to 67% ethyl acetate in petroleum ether). (3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)tert-butyl carbamate (3.600 g, 10.04 mmol, 67.38% yield) was a yellow solid, as detected by ¹H NMR. MS (ESI) m / z: 359.1 [M+1]+; 1 H NMR (400 MHz, DMSO-d6) δ = 10.91 (s, 1H), 9.10 (s, 1H), 7.57 (d, J = 7.2 Hz, 1H), 7.02-7.12 (m, 2H), 4.34-4.40 (m, 1H), 4.07 (s, 3H), 2.60-2.73 (m, 2H), 2.32-2.40 (m, 1H), 2.12-2.20 (m, 1H), 1.47 (s, 9H).

[0397] Step i-7.6. Synthesis of 3-(7-amino-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione. Tert-butyl 3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazole-7-yl)carbamate (3.500 g, 9.77 mmol, 1 equivalent) was added to an aqueous hydrogen chloride solution (12 M, 50 mL, 61.44 equivalents) at 0°C, and the mixture was stirred at 25°C for 2 hours. A clear yellow solution was obtained, and LCMS showed the target product by mass. The solution was poured into cold water (500 mL) at 0°C and then lyophilized. The title compound, 3-(7-amino-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione (2673.81 mg, 8.73 mmol, 89.36% yield, 96.2% purity, HCl salt), was collected as a yellow solid. MS (ESI) m / z: 259.2 [M+1]+; 1¹H NMR (400 MHz, DMSO-d⁶) δ = 10.91 (s, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.50 (d, J = 7.2 Hz, 1H), 7.15 (t, J = 7.6 Hz, 1H), 4.39–4.45 (m, 1H), 4.32 (s, 3H), 2.57–2.75 (m, 2H), 2.32–2.45 (m, 1H), 2.13–2.21 (m, 1H). Note: Exchangeable protons are not visible.

[0398] Synthesis of intermediate i-8: 1-(6-amino-1-methyl-indazol-3-yl)hexahydropyrimidine-2,4-dione

[0399]

[0400] Step i-8.1. Synthesis of 1-(1-methyl-6-nitro-indazole-3-yl)hexahydropyrimidine-2,4-dione. A mixture of 3-bromo-1-methyl-6-nitro-indazole (3.00 g, 11.72 mmol), hexahydropyrimidine-2,4-dione (1.60 g, 14.06 mmol), tripotassium phosphate (6.22 g, 29.29 mmol), tetramethyltBuXPhos (281.0 mg, 0.58 mmol), and tris(dibenzylpyrone)dipalladium(O) (268.0 mg, 0.29 mmol) in tert-butanol (125.0 mL) was degassed three times with nitrogen. The reaction mixture was heated to 100°C for 24 hours and then cooled to room temperature. Add additional tris(dibenzyleneacetone)dipalladium(O) (268.0 mg, 0.29 mmol) and tetramethyltBuXPhos (281.0 mg, 0.58 mmol). Reheat the reaction mixture to 100°C for 16 hours, then cool to room temperature. Evaporate the volatiles under reduced pressure. Add water (200.0 mL), and collect the precipitate by filtration (Buchner funnel), then wash with water (3 x 50.0 mL) and dry under vacuum. Grind the substance in diethyl ether (100.0 mL) and collect by filtration to give the title compound (2.64 g, 78%) as a solid, which was used in the next step without further purification. MS (ESI) [M+H]+: 290.2; 1H NMR (500 MHz, DMSO) δ10.67 (s, 1H), 8.70 (dd, J = 1.7, 0.7 Hz, 1H), 7.95 - 7.84 (m, 2H), 4.14 (s,3H), 3.97 (t, J = 6.7 Hz, 2H), 2.77 (t, J = 6.7 Hz, 2H).

[0401] Step i-8.2. Synthesis of 1-(6-amino-1-methyl-indazole-3-yl)hexahydropyrimidine-2,4-dione. A mixture of 1-(1-methyl-6-nitro-indazole-3-yl)hexahydropyrimidine-2,4-dione (2.64 g, 9.13 mmol) and 10% palladium / carbon (0.97 g, 0.91 mmol) in methanol (250.0 mL) was hydrogenated at room temperature for 6.5 h under a hydrogen atmosphere (1 atm). The mixture was filtered through a Celite filter and washed with methanol (5 x 45.0 mL). The filtrate was concentrated under reduced pressure, ground in diethyl ether, and collected by filtration to give the title compound (1.92 g, 81%) as a solid. MS (ESI) [M+H]+: 260.1; 1 H NMR (400 MHz, DMSO) δ 10.45 (s, 1H), 7.27 (d, J = 8.7 Hz, 1H), 6.48 (dd, J = 8.7, 1.8 Hz, 1H), 6.39 (d, J = 1.3 Hz, 1H), 5.39 (s, 2H), 3.85 (t, J= 6.7 Hz, 2H), 3.76 (s, 3H), 2.71 (t, J= 6.7 Hz, 2H).

[0402] Synthesis of intermediate i-9: [3-(2,4-dioxohexahydropyrimidin-1-yl)-1-methyl-indazole-6-yl]boronic acid.

[0403]

[0404] Step i-9.1. Synthesis of 1-(6-iodo-1-methyl-indazole-3-yl)hexahydropyrimidine-2,4-dione. A solution of 1-(6-amino-1-methyl-indazole-3-yl)hexahydropyrimidine-2,4-dione, intermediate 8 (2.1 g, 8.1 mmol) in acetic acid (21 mL) cooled to 0°C was successively added to a solution of sulfuric acid (1.11 mL, 20.3 mmol) in water (5 mL) and sodium nitrite (838 mg, 12.15 mmol) in water (5 mL), and the reaction mixture was stirred at 0°C for 2 hours. A solution of potassium iodide (4 g, 24 mmol) in water (5 mL) was added, and the mixture was stirred at 0°C for 2 hours, then cooled to room temperature. A 50% aqueous solution of sodium bicarbonate (50 mL) was added to the mixture, and the mixture was stirred for 18 hours. The precipitate was collected by filtration, washed with water (3 x 10 mL) and diethyl ether (3 x 10 mL), and then dried under vacuum to give the title compound (1.98 g, 66%) as a solid, which was used in the next step without further purification. MS (ESI) [M+H]+ 371.3. 1 H NMR(400 MHz, DMSO-d6) δ 10.58 (s, 1H), 8.12 (d, J = 0.6 Hz, 1H), 7.47 (d, J =8.6 Hz, 1H), 7.39 (dd, J = 8.6, 1.3 Hz, 1H), 3.97 (s, 3H), 3.92 (t, J = 6.7Hz, 2H), 2.75 (t, J = 6.7Hz, 2H).

[0405] Step i-9.2. Synthesis of 1-[1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)indazole-3-yl]hexahydropyrimidine-2,4-dione. A mixture of 1-(6-iodo-1-methyl-indazole-3-yl)hexahydropyrimidine-2,4-dione (500 mg, 1.35 mmol), pinacol diboronate (412 mg, 1.62 mmol), palladium(II) acetate (30 mg, 0.14 mmol), and potassium acetate (398 mg, 4.05 mmol) in N,N-dimethylformamide (14 mL) was heated to 80°C for 18 hours and then cooled to room temperature. The mixture was filtered through a Celite filter and washed with ethyl acetate (5 x 15 mL). Water (50 mL) was added to the filtrate, and the layers were separated. The organic layer was washed with water (5 x 25 mL) and brine (25 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient elution of 50-100% ethyl acetate in hexane to give the title compound (335 mg, 67%) as a solid. MS (ESI) [M+H]+ 371.2; 1 H NMR(400 MHz, DMSO-d6) δ 10.56 (s, 1H), 7.90 (s, 1H), 7.66 (dd, J = 8.2, 0.8 Hz,1H), 7.38 (d, J = 8.7 Hz, 1H), 4.04 (s, 3H), 3.93 (t, J = 6.7 Hz, 2H), 2.77(t, J = 6.7 Hz, 2H), 1.33 (s, 12H).

[0406] Step i-9.3. Synthesis of [3-(2,4-dioxohexahydropyrimidin-1-yl)-1-methyl-indazole-6-yl]boronic acid. Sodium periodate (698 mg, 3.27 mmol) and 1M HCl aqueous solution (2.2 mL, 2.2 mmol) were added sequentially to a solution of 1-[1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)indazole-3-yl]hexahydropyrimidin-2,4-dione (403 mg, 1.09 mmol) in tetrahydrofuran (5 mL) and water (5 mL). The reaction mixture was stirred at room temperature for 18 hours. The volatiles were evaporated under reduced pressure, and the precipitate was collected by filtration, washed with water (3 x 2 mL) and diethyl ether (3 x 1 mL), and then dried under vacuum to give the title compound (240 mg, 76%) as a solid, which was used in the next step without further purification. MS (ESI) [M+H]+ 289.1;1 H NMR (400 MHz, DMSO-d6) δ 10.54 (s,1H), 8.16 (s, 2H), 8.01 (s, 1H), 7.59 (d, J = 8.2 Hz, 1H), 7.52 (d, J = 8.3Hz, 1H), 4.00 (s, 3H), 3.92 (t, J = 6.7 Hz, 2H), 2.76 (t, J = 6.6 Hz, 2H).

[0407] Synthesis of intermediate i-10: 1-[6-(4-amino-1-piperidinyl)-1-methyl-indazole-3-yl]hexahydropyrimidine-2,4-dione hydrochloride.

[0408]

[0409] Step i-10.1. Synthesis of N-[1-[3-(2,4-dioxohexahydropyrimidin-1-yl)-1-methyl-indazole-6-yl]-4-piperidinyl]carbamate tert-butyl ester. A mixture of [3-(2,4-dioxohexahydropyrimidin-1-yl)-1-methyl-indazole-6-yl]boronic acid (240 mg, 0.83 mmol, intermediate 9), N-(4-piperidinyl)carbamate tert-butyl ester (334 mg, 1.67 mmol), copper(II) acetate (183 mg, 0.92 mmol), triethylamine (0.23 mL, 1.67 mmol), and 3 Å MS (200 mg) in dichloroethane (12 mL) was heated to 50°C for 24 hours. The mixture was filtered through a Celite filter and washed with a 1:1 mixture of acetonitrile and methanol (3 x 5 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using a gradient elution of ethyl acetate in hexane from 0 to 100% to give the title compound (96 mg, 23%) as a solid. MS (ESI) [M+H]+ 443.2.

[0410] Step i-10.2. Synthesis of 1-[6-(4-amino-1-piperidinyl)-1-methyl-indazole-3-yl]hexahydropyrimidine-2,4-dione hydrochloride. HCl (0.44 mL, 1.78 mmol) in 1,4-dioxane was added to a solution of N-[1-[3-(2,4-dioxohexahydropyrimidine-1-yl)-1-methyl-indazole-6-yl]-4-piperidinyl]carbamate tert-butyl ester (175 mg, 0.36 mmol) in 1,4-dioxane (5 mL). The reaction mixture was heated to 100°C for 2 hours, then cooled to room temperature, and the volatiles were evaporated under reduced pressure. Diethyl ether (5 mL) was added, and the resulting precipitate was collected by filtration, washed with diethyl ether (3 x 2 mL), and then dried under vacuum to give the title compound (138 mg, quantified) as a solid, which was used in the next step without further purification. MS (ESI) [M+H]+ 343.2.

[0411] Synthesis of intermediate i-11: (R)-3-(7-amino-1-methyl-1H-indazol-3-yl)-3-methylpiperidin-2,6-dione

[0412]

[0413] Step i-11.1. Synthesis of 3-iodo-7-nitro-1H-indazole. Diiodine (311.170 g, 1230.00 mmol, 2.00 equivalents) and potassium hydroxide (68.790 g, 1230.00 mmol, 2 equivalents) were added to a solution of 7-nitro-1H-indazole (100.000 g, 613.00 mmol, 1 equivalent) in N,N-dimethylformamide (2000 mL). The mixture was stirred at 15°C for 12 hours. The 7-nitro-1H-indazole was completely consumed, and the desired mass was determined by LCMS. The reaction mixture was added to ice water (2000 mL) with stirring. The precipitate was collected by filtration. The crude product was diluted with ethyl acetate (3000 mL) and washed with saturated sodium sulfite (3 x 50 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was washed with ethyl acetate (20 mL), filtered, and dried under vacuum to give 3-iodo-7-nitro-1H-indazole (168.000 g, 581.26 mmol, 94.8% yield) as a yellow solid. MS (ESI) m / z: 289.9 [M+1]+; 1H NMR (400 MHz, DMSO-d6) δ 11.63 (s, 1H), 8.43 (d, J = 8.0 Hz, 2H), 7.93 (d,J = 8.0 Hz, 2H), 7.40 (t, J = 8.0 Hz, 2H).

[0414] Step i-11.2. Synthesis of 3-iodo-1-methyl-7-nitro-1H-indazole. Methyl iodine (193.490 g, 1360.00 mmol, 85 mL, 2 equivalents) and cesium carbonate (333.110 g, 1020.00 mmol, 1.5 equivalents) were added to a solution of 3-iodo-7-nitro-1H-indazole (197.000 g, 681.59 mmol, 1000 mL) in tetrahydrofuran (1000 mL), and the mixture was stirred at 50°C for 12 hours. The 3-iodo-7-nitro-1H-indazole was completely consumed, and the desired mass number was detected by LCMS. The mixture was filtered, and the filtrate was concentrated to give a brown solid. The filtrate was concentrated under vacuum to give a residue. The 3-iodo-7-nitro-1H-indazole was completely consumed, and the desired mass number was detected by LCMS. The residue was purified by silica gel column chromatography (2–100% ethyl acetate in petroleum ether). 3-Iodo-1-methyl-7-nitro-indazole (2.65 g, 8.74 mmol, 1.28% yield) was given as a yellow solid. Another batch of 3-iodo-1-methyl-7-nitro-indazole (128 g, 282.98 mmol, 41.52% yield, 67% purity) was given as a yellow solid. MS (ESI) m / z: 304.0 [M+1]+; 1 H NMR (400 MHz, DMSO-d6) δ 8.29 (dd, J= 0.8 Hz, 7.6 Hz, 1 H), 7.90 (d, J= 8.0 Hz, 1 H), 7.40 (t, J= 8.0 Hz, 1 H), 4.15 (s, 3 H).

[0415] Step i-11.3. Synthesis of 1-methyl-7-nitro-3-(prop-1-en-2-yl)-1H-indazole. Tetra(triphenylphosphine)palladium (3.104 g, 2.72 mmol, 0.01 equivalent) was added to a solution of 3-iodo-1-methyl-7-nitro-indazole (123.000 g, 271.93 mmol, 1 equivalent), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborhecyclopentane (68.540 g, 407.90 mmol, 1.5 equivalent), and potassium phosphate (2 M, 1020 mL, 7.5 equivalent) in dioxane (3000 mL). The reaction mixture was stirred at 90°C under a nitrogen atmosphere for 12 hours. 3-Iodo-1-methyl-7-nitro-indazole was consumed, and the desired product was determined by LCMS. The mixture was extracted with ethyl acetate (3 x 500 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (100% petroleum ether). 1-Methyl-7-nitro-3-(prop-1-en-2-yl)-1H-indazole (56.000 g, 257.80 mmol, 94.8% yield) was given as a yellow solid. MS (ESI) m / z: 218.1 [M+1]+; 1 H NMR (400 MHz, DMSO-d6) δ 8.41 (d, J = 8.0 Hz, 1H), 8.17 (d, J = 8.0 Hz, 1 H), 7.35 (t, J = 8.0 Hz, 1 H), 5.80 (s, 1 H), ,5.48 (s, 1 H), 4.09 (s, 3 H), 2.24 (s, 3 H).

[0416] Step i-11.4. Synthesis of 2-(1-methyl-7-nitro-1H-indazole-3-yl)prop-1-ol. A solution of a boronane dimethyl sulfide complex (10 M, 64.45 mL, 2.5 equivalents) was added dropwise to 1-methyl-7-nitro-3-(prop-1-en-2-yl)-1H-indazole (56.000 g, 257.80 mmol, 1 equivalent) in tetrahydrofuran (1200 mL). The reaction mixture was cooled to 15°C and stirred for 2 hours. Then, at -5°C, the mixture was added to a solution of sodium perborate (63.260 g, 773.40 mmol, 3.0 equivalents) in water (300 mL). The resulting mixture was stirred at 15°C for 12 hours. 1-Methyl-7-nitro-3-(prop-1-en-2-yl)-1H-indazole was completely consumed, and the desired mass was determined by LCMS. The mixture was filtered, and the filtrate was concentrated. The residue was dissolved in ethyl acetate (1000 mL), and the aqueous layer was separated. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was washed with ethyl acetate (20 mL), and the precipitate was collected by filtration. The product 2-(1-methyl-7-nitro-1H-indazole-3-yl)prop-1-ol (60.000 g, 255.06 mmol, 98.9% yield) was given as a yellow solid. MS (ESI) m / z: 236.2 [M+1]+; 1 H NMR (400 MHz, DMSO-d6) δ8.25 (d, J = 8.0 Hz, 1 H), 8.14 (dd, J= 0.8 Hz, 7.6 Hz, 1 H), 7.27 (t, J= 8.0Hz, 1 H), 4.78 (t, J = 5.6 Hz, 1 H), 4.05 (s, 3 H), 3.72~3.63 (m, 1 H), 1.34 (d, J = 6.8 Hz, 3 H).

[0417] Step i-11.5. Synthesis of 2-(1-methyl-7-nitro-1H-indazol-3-yl)propionic acid. 2,2,6,6-Tetramethyl-piperidine-1-oxy radical (8.020 g, 51.01 mmol, 0.2 equivalents), sodium dihydrogen phosphate (192.180 g, 1.60 mol, 6.28 equivalents), and sodium chlorite (57.670 g, 510.12 mmol, 80% purity, 2 equivalents) were added dropwise to 2-(1-methyl-7-nitro-1H-indazol-3-yl)prop-1-ol (60.000 g, 255.06 mmol, 1 equivalent) in acetonitrile (2400 mL) and water (1200 mL), and the mixture was stirred at 15°C. A solution of sodium hypochlorite (75.230 g, 53.56 mmol, 62.17 mL, 5.3% purity, 0.21 equivalents) in water (240 mL) was added dropwise, and the mixture was stirred at 15°C for 12 hours. 2-(1-methyl-7-nitro-1H-indazole-3-yl)prop-1-ol was consumed completely, and the desired mass was determined by LCMS. The mixture was extracted with ethyl acetate (3 x 1000 mL). The organic layer was concentrated to obtain a residue. The residue was washed with ethyl acetate (100 mL). The precipitate was collected by filtration. The product 2-(1-methyl-7-nitro-1H-indazole-3-yl)propionic acid (62.000 g, 248.77 mmol, 97.5% yield) was given as a yellow solid. MS (ESI) m / z: 250.1 [M+1]+; 1 H NMR (400 MHz, DMSO-d6) δ 12.57 (s,1H), 8.21 (d, J = 8.0 Hz, 1 H), 8.17 (d, J= 7.6 Hz, 1 H), 7.39~7.26 (m, 1 H), 4.28 (q, J = 7.2 Hz, 1 H), 4.08 (s, 3 H), 1.55 (d, J = 7.2 Hz, 3 H).

[0418] Step i-11.6. Synthesis of methyl 2-(1-methyl-7-nitro-1H-indazole-3-yl)propionate. At 0°C, (diazomethyl)trimethylsilane (2 M, 248.77 mL, 2 equivalents) was added dropwise to 2-(1-methyl-7-nitro-1H-indazole-3-yl)propionate (62.000 g, 248.77 mmol, 1 equivalent) in methanol (500 mL) and toluene (500 mL), and the mixture was stirred at 15°C for 2 hours. The 2-(1-methyl-7-nitro-1H-indazole-3-yl)propionate was completely consumed, and the desired mass was detected by LCMS. TLC showed the formation of a new spot, and the mixture was concentrated to give the residue. The residue was purified by silica gel column chromatography (10–50% ethyl acetate in petroleum ether). The product methyl 2-(1-methyl-7-nitro-1H-indazole-3-yl)propionate (61.000 g, 231.72 mmol, 93.1% yield) was obtained as a yellow solid. MS (ESI) m / z: 264.1 [M+1]+; 1 HNMR (400 MHz, DMSO-d6) δ 8.20~8.17 (m, 2 H), 7.40~7.31 (m, 1 H), 4.45~4.39(m, 1 H), 4.13 (s, 3 H), 3.59 (s, 3 H), 1.57 (d, J = 7.2 Hz, 3 H).

[0419] Step i-11.7. Synthesis of methyl 4-cyano-2-methyl-2-(1-methyl-7-nitro-1H-indazole-3-yl)butyrate. Methyl 2-(1-methyl-7-nitro-1H-indazole-3-yl)propionate (61.000 g, 231.72 mmol, 1 equivalent) and acrylonitrile (122.960 g, 2.32 mol, 10 equivalents) were added to acetonitrile (1500 mL), and the mixture was stirred at 80°C for 12 hours. The methyl 2-(1-methyl-7-nitro-1H-indazole-3-yl)propionate was completely consumed, and the desired mass was determined by LCMS. A new spot was detected by TLC, and the mixture was concentrated. The residue was purified by silica gel column chromatography (10–33% ethyl acetate in petroleum ether). The product, methyl 4-cyano-2-methyl-2-(1-methyl-7-nitro-1H-indazole-3-yl)butyrate (70.000 g, 221.30 mmol, 95.5% yield), was given as a yellow oil. MS (ESI) m / z: 317.1 [M+1]+; 1HNMR (400 MHz, DMSO-d6) δ 8.18 (d, J= 7.6 Hz, 1 H), 8.03 (d, J= 8.0 Hz, 1 H), 7.33 (t, J= 8.0 Hz, 1 H), 4.09 (s, 3H), 3.63 (s, 3 H), 2.79~2.73 (m, 2H), 2.61~2.46 (m, 2H), 1.69 (s, 3H).

[0420] Step i-11.8 Synthesis of 5-amino-2-methyl-2-(1-methyl-7-nitro-1H-indazole-3-yl)-5-oxovaleric acid. Sodium hydroxide (1 M, 360.72 mL, 1.63 equivalents) and hydrogen peroxide (116.320 g, 1.03 mol, 98.58 mL, 30% purity, 4.64 equivalents) were added to methyl 4-cyano-2-methyl-2-(1-methyl-7-nitro-1H-indazole-3-yl)butyrate in dimethyl sulfoxide (200 mL) and methanol (200 mL) at 0°C, and the mixture was stirred at 15°C for 3 hours. Methyl 4-cyano-2-methyl-2-(1-methyl-7-nitro-1H-indazole-3-yl)butyrate was consumed, and the desired mass was determined by LCMS. 100 mL of saturated sodium sulfite was added to the mixture to quench excess hydrogen peroxide. The mixture was adjusted to pH 5.0 and extracted with ethyl acetate (3 x 200 mL). The organic layer was washed with water (3 x 50 mL). The organic layer was dried over anhydrous sodium sulfate. It was filtered, and the filtrate was concentrated. The product 5-amino-2-methyl-2-(1-methyl-7-nitro-1H-indazole-3-yl)-5-oxovaleric acid (70.000 g, 218.55 mmol, 98.8% yield) was given as a yellow solid. MS (ESI) m / z: 321.1 [M+1]+; 1 H NMR (400 MHz, DMSO-d6) δ 12.25(s, 1H), 8.15 (dd, J= 5.2 Hz, 7.6 Hz, 1 H), 8.06 (d, J= 8.0 Hz, 1 H), 7.32~7.27 (m, 1 H), 7.13 (s, 1H), 4.08 (s, 3H), 2.43~2.39 (m, 1H), 2.34~2.32 (m,1H), 2.09~2.06 (m, 1H), 1.91 (m, 1H), 1.57 (s, 3H).

[0421] Step i-11.9. Synthesis of 3-methyl-3-(1-methyl-7-nitro-1H-indazole-3-yl)piperidine-2,6-dione. Di(1H-imidazol-1-yl) ketone (42.520 g, 262.25 mmol, 1.2 equivalent) and N,N-dimethylpyridin-4-amine (2.670 g, 21.85 mmol, 0.1 equivalent) were added to 5-amino-2-methyl-2-(1-methyl-7-nitro-1H-indazole-3-yl)-5-oxovalerate in tetrahydrofuran (500 mL), and the mixture was stirred at 70°C for 12 hours. 5-Amino-2-methyl-2-(1-methyl-7-nitro-1H-indazol-3-yl)-5-oxovaleric acid was completely consumed, and the desired mass was detected by LCMS. A new spot was detected by TLC. The mixture was concentrated. The residue was purified by silica gel column chromatography (10–33% ethyl acetate in petroleum ether). The product 3-methyl-3-(1-methyl-7-nitro-1H-indazol-3-yl)piperidine-2,6-dione (42.000 g, 138.94 mmol, 63.6% yield) was given as a yellow solid. MS (ESI) m / z: 303.1 [M+1]+; 1 H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.28 (d, J= 8.0 Hz, 1H), 8.16 (d, J = 7.2 Hz, 1H), 7.31 (t, J= 8.0 Hz, 1H), 4.07 (s,3H), 2.65~2.59 (m, 2H), 2.47~2.46 (m, 1H), 2.15~2.11 (m, 1H), 1.70 (s, 3H).

[0422] Step i-11.10. Synthesis of (R)-3-methyl-3-(1-methyl-7-nitro-1H-indazol-3-yl)piperidine-2,6-dione. 3-methyl-3-(1-methyl-7-nitro-1H-indazol-3-yl)piperidine-2,6-dione (20.000 g, 66.16 mmol, 1 equivalent) was purified by SFC (column: DAICEL CHIRALPAK AD (250 mm)) at 15°C. The mobile phase was [Neu-methanol]; B%: 55%-55%, 5.3 min; 1050 min) for 12 hours. The two fractions were concentrated under reduced pressure below 45°C. The product (R)-3-methyl-3-(1-methyl-7-nitro-1H-indazol-3-yl)piperidin-2,6-dione (P1, Rt = 1.80 min, 7.100 g, 23.21 mmol, 35.07% yield, 98.8% purity) was given as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.28 (d, J = 8.0 Hz, 1H), 8.17 (d, J = 7.6 Hz, 1H), 7.32(t, J = 8.0 Hz, 1H), 4.06 (s, 3H), 2.66~2.58 (m, 3H), 2.15~2.10 (m, 1H), 1.70 (s, 3H).

[0423] Step i-11.11. Synthesis of (R)-3-(7-amino-1-methyl-1H-indazole-3-yl)-3-methylpiperidine-2,6-dione. Iron powder (6.560 g, 117.44 mmol, 5 equivalents) and ammonium chloride (12.560 g, 234.88 mmol, 10 equivalents) were added to (R)-3-methyl-3-(1-methyl-7-nitro-1H-indazole-3-yl)piperidine-2,6-dione in ethanol (100 mL) and water (50 mL), and the mixture was stirred at 80°C for 2 hours. The desired mass number of (R)-3-methyl-3-(1-methyl-7-nitro-1H-indazole-3-yl)piperidine-2,6-dione was determined by LCMS after complete consumption. A new spot was detected by TLC, and the mixture was filtered and the filtrate concentrated. The residue was purified by silica gel column chromatography (2–33% ethyl acetate in petroleum ether). The product (R)-3-(7-amino-1-methyl-1H-indazol-3-yl)-3-methylpiperidin-2,6-dione (6.000 g, 21.83 mmol, 92.9% yield, 99.1% purity) was given as a yellow solid. MS (ESI) m / z: 273.1 [M+1]+; 1H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H), 7.01 (d, J = 8.0Hz, 1H), 6.78 (t, J = 8.0 Hz, 1H), 6.55 (t, J = 7.2 Hz, 1H), 5.18 (s, 2H), 4.19 (s, 3H), 2.55~2.52 (m, 1H), 2.48~2.47 (m, 1H), 2.34~2.32 (m, 1 H), 2.07~2.05 (m, 1 H), 1.60 (s, 3 H).

[0424] Synthesis of intermediate i-12: (3R)-3-(6-amino-1-methyl-indazol-3-yl)-3-methyl-piperidin-2,6-dione

[0425]

[0426] Step i-12.1: Synthesis of 3-iodo-6-nitro-1H-indazole. Potassium hydroxide (41.270 g, 735.59 mmol, 2 equivalents) and iodine (186.700 g, 735.59 mmol, 2 equivalents) were added to a solution of 6-nitro-1H-indazole (60.000 g, 367.80 mmol, 1 equivalent) in N,N-dimethylformamide (1200 mL) at 0°C. The mixture was stirred at 20°C for 12 hours. LC-MS showed the reaction was complete. The mixture was poured into a sodium sulfite solution (4000 mL), filtered, and concentrated to give the residue. 3-iodo-6-nitro-1H-indazole (200.000 g, crude) was given as a yellow solid, as detected by ¹H NMR. MS (ESI) m / z: 289.9 [M+1]+. 1 H NMR (400MHz, DMSO-d6) δ 14.13 (s, 1H), 8.43 (d, J=1.6 Hz, 1H), 7.97 - 7.93 (m, 1H), 7.63 (d, J=8.8 Hz, 1H).

[0427] Step i-12.2: Synthesis of 3-iodo-1-methyl-6-nitro-1H-indazole. Cesium carbonate (169.090 g, 518.98 mmol, 1.5 equivalent) and iodomethane (54.020 g, 380.58 mmol, 1.1 equivalent) were added to a solution of 3-iodo-6-nitro-1H-indazole (100.000 g, 345.99 mmol, 1 equivalent) in N,N-dimethylformamide (1500 mL). The mixture was stirred at 50°C for 12 hours. TLC and LCMS showed the reaction was complete. The mixture was poured into water (3000 mL), filtered, and concentrated to give a residue. The residue was purified by silica gel column chromatography (5% to 50% in ethyl acetate solution in petroleum ether). 3-Iodo-1-methyl-6-nitro-indazole (29.000 g, 95.69 mmol, 7.25% yield) was given as a yellow solid. MS (ESI) m / z: 304.0 [M+1]+.

[0428] Step i-12.3: Synthesis of 1-methyl-6-nitro-3-(prop-1-en-2-yl)-1H-indazole. Tetra(triphenylphosphine)palladium (1.110 g, 0.96 mmol, 0.01 equivalent), isopropenylboronic acid (9.860 g, 114.83 mmol, 1.2 equivalent), and potassium phosphate (2 M, 143.5 mL, 3 equivalent) were added to a solution of 3-iodo-1-methyl-6-nitro-indazole (29.000 g, 95.69 mmol, 1 equivalent) in dioxane (435.0 mL) and water (145.0 mL). The mixture was stirred at 90°C for 12 hours. LC-MS showed the reaction was complete. The residue was diluted with water (200 mL) and extracted with ethyl acetate (200 mL × 3). The combined organic layers were washed with brine (200 mL × 3), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. 3-Isopropenyl-1-methyl-6-nitro-indazole (22.000 g, crude product) was given as a yellow solid. MS (ESI) m / z: 218.1 [M+1]+.

[0429] Step i-12.4: Synthesis of 2-(1-methyl-6-nitro-1H-indazole-3-yl)prop-1-ol. A solution of borane dimethyl sulfide complex (10 M, 25.3 mL, 2.5 equivalents) in tetrahydrofuran (400 mL) was added dropwise at -5°C under a nitrogen atmosphere to 22.000 g (101.28 mmol, 1 equivalent) of 3-isopropenyl-1-methyl-6-nitro-indazole (400 mL). The reaction mixture was cooled to 15°C and stirred for 2 hours. Then, at -5°C, the mixture was added to a solution of sodium perborate (24.850 g, 303.83 mmol, 3 equivalents) in water (100 mL). The resulting mixture was stirred at 15°C for 12 hours. TLC and LCMS showed the reaction was complete. The mixture was filtered and concentrated. The residue was dissolved in ethyl acetate (300 mL), and the aqueous layer was separated. The organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (10% to 50% in ethyl acetate solution in petroleum ether). 2-(1-methyl-6-nitro-indazol-3-yl)prop-1-ol (20.000 g, 85.02 mmol, 83.95% yield) was given as a yellow solid, detectable by ¹H NMR. MS (ESI) m / z: 236.1 [M+1]+. 1 H NMR(400MHz, DMSO-d6) δ 8.61 (d, J=1.6 Hz, 1H), 8.01 (d, J=8.8 Hz, 1H), 7.87 (dd,J=2.0, 8.8 Hz, 1H), 4.78 (t, J=5.6 Hz, 1H), 4.11 (s, 3H), 3.74 - 3.61 (m,2H), 3.37 (s, 1H), 1.35 (d, J=7.2 Hz, 3H).

[0430] Step i-12.5: Synthesis of 2-(1-methyl-6-nitro-1H-indazol-3-yl)propionic acid. 2,2,6,6-Tetramethyl-1-piperidinyloxy (2.410 g, 15.30 mmol, 0.2 equivalents), sodium dihydrogen phosphate (57.650 g, 480.53 mmol, 6.28 equivalents), and sodium chlorite (17.300 g, 153.04 mmol, 80% purity, 2 equivalents) were added dropwise to 2-(1-methyl-6-nitro-1H-indazol-3-yl)prop-1-ol (18.000 g, 76.52 mmol, 1 equivalent) in acetonitrile (360.0 mL) and water (180.0 mL), and the mixture was stirred at 0°C. A solution of sodium hypochlorite (32.240 g, 22.96 mmol, 26.7 mL, 5.3% purity, 0.3 equivalents) in water (36 mL) was added dropwise, and the mixture was stirred at 15°C for 12 hours. TLC and LCMS showed the reaction was complete. The mixture was extracted with ethyl acetate (3 × 200 mL). The organic layer was concentrated to give the residue. The residue was purified by silica gel column chromatography (10% to 50% ethyl acetate solution in petroleum ether). 2-(1-methyl-6-nitro-indazole-3-yl)propionic acid (19.000 g, 76.24 mmol, 99.63% yield) was given as a yellow solid. MS (ESI) m / z: 250.1 [M+1]+.

[0431] Step i-12.6: Synthesis of methyl 2-(1-methyl-6-nitro-1H-indazole-3-yl)propionate. Trimethylsilane-diazomethane (2 M, 114.4 mL, 3 equivalents) was added dropwise to 2-(1-methyl-6-nitro-indazole-3-yl)propionic acid (19.000 g, 76.24 mmol, 1 equivalent) in methanol (150 mL) and toluene (150 mL), and the mixture was stirred at 15°C for 2 hours. LC-MS showed the reaction was complete. The mixture was concentrated to give the residue. Methyl 2-(1-methyl-6-nitro-indazole-3-yl)propionate (20.000 g, crude) was given as a gray solid. MS (ESI) m / z: 264.1 [M+1]+.

[0432] Step i-12.7: Synthesis of methyl 4-cyano-2-methyl-2-(1-methyl-6-nitro-1H-indazole-3-yl)butyrate. Benzyltrimethylammonium hydroxide (6.350 g, 15.19 mmol, 40% purity, 0.2 equivalents) and propion-2-acrylonitrile (40.310 g, 759.74 mmol, 10 equivalents) were added to a solution of methyl 2-(1-methyl-6-nitro-indazole-3-yl)propionate (20.000 g, 75.97 mmol, 1 equivalent) in acetonitrile (300.0 mL). The mixture was stirred at 80°C for 12 hours. TLC and LCMS showed the reaction was complete. The mixture was concentrated to give the residue. The residue was purified by silica gel column chromatography (5% to 50% solution in ethyl acetate in petroleum ether). Methyl 4-cyano-2-methyl-2-(1-methyl-6-nitro-indazole-3-yl)butyrate (20.000 g, 63.23 mmol, 83.22% yield) was obtained as a yellow solid. MS (ESI) m / z: 317.1 [M+1]+.

[0433] Step i-12.8: Synthesis of 5-amino-2-methyl-2-(1-methyl-6-nitro-1H-indazole-3-yl)-5-oxovaleric acid. Sodium hydroxide (1 M, 63.2 mL, 1 equivalent) and hydrogen peroxide (73.750 g, 650.45 mmol, 62.5 mL, 30% purity, 10.29 equivalent) were added to methyl 4-cyano-2-methyl-2-(1-methyl-6-nitro-indazole-3-yl)butyrate (20.000 g, 63.23 mmol, 1 equivalent) in DMSO (150 mL) and methanol (150 mL), and the mixture was stirred at 15°C for 12 hours. LC-MS showed the reaction was complete. 100 mL of saturated sodium sulfite was added to the mixture to quench excess hydrogen peroxide. The mixture was adjusted to pH 5.0 (1 M hydrogen chloride) and extracted with ethyl acetate (3 × 300 mL). The organic layer was washed with water (3 × 200 mL). The organic layer was dried over sodium sulfate. It was filtered and the filtrate was concentrated to give 5-amino-2-methyl-2-(1-methyl-6-nitro-indazol-3-yl)-5-oxo-pentanoic acid (15.000 g, crude) as a yellow solid. MS (ESI) m / z: 321.1 [M+1]+.

[0434] Step i-12.9: Synthesis of 3-methyl-3-(1-methyl-6-nitro-1H-indazole-3-yl)piperidine-2,6-dione. To a solution of 5-amino-2-methyl-2-(1-methyl-6-nitro-indazole-3-yl)-5-oxo-pentanoic acid (15.000 g, 46.83 mmol, 1 equivalent) in tetrahydrofuran (300 mL), 1,1'-carbonyldiimidazole (18.980 g, 117.08 mmol, 2.5 equivalent) and dimethylaminopyridine (0.572 g, 4.68 mmol, 0.1 equivalent) were added. The mixture was stirred at 70°C for 12 hours. The reaction was confirmed by LCMS, HPLC, and TLC. The mixture was concentrated to give a residue. The residue was purified by silica gel column chromatography (5% to 50% solution in ethyl acetate in petroleum ether). 3-Methyl-3-(1-methyl-6-nitro-indazol-3-yl)piperidine-2,6-dione (15.000 g, crude product) was obtained as a yellow solid. MS (ESI) m / z: 303.1 [M+1]+.

[0435] Step i-12.10: Synthesis of rel-(R)-3-methyl-3-(1-methyl-6-nitro-1H-indazole-3-yl)piperidine-2,6-dione. 3-methyl-3-(1-methyl-6-nitro-indazole-3-yl)piperidine-2,6-dione (15.000 g, 49.62 mmol, 1 equivalent) was purified preparatively by SFC (column: Chiralcel OJ-3 50 × 4.6 mm ID, 3 μm; mobile phase: methanol (0.05% DEA), in CO2, from 5% to 40%). (3R)-3-methyl-3-(1-methyl-6-nitro-indazol-3-yl)piperidine-2,6-dione (6.500 g, 21.37 mmol, 43.07% yield, 99.4% purity) was obtained as a yellow solid, which was detected by HPLC and SFC.

[0436] Step i-12.11: Synthesis of (R)-3-(6-amino-1-methyl-1H-indazol-3-yl)-3-methylpiperidine-2,6-dione. Iron (6.000 g, 107.51 mmol, 5 equivalents) and ammonium chloride (11.500 g, 215.03 mmol, 10 equivalents) were added to a solution of (3R)-3-methyl-3-(1-methyl-6-nitro-indazol-3-yl)piperidine-2,6-dione (6.500 g, 21.50 mmol, 1 equivalent) in ethanol (100 mL) and water (50 mL). The mixture was stirred at 80°C for 2 hours. TLC showed the reaction was complete. The mixture was filtered and concentrated to give the residue. The residue was purified by silica gel column chromatography (1% to 5% methanol in dichloromethane). (3R)-3-(6-amino-1-methyl-indazole-3-yl)-3-methyl-piperidin-2,6-dione (4.600 g, 16.83 mmol, 92.74% yield, 99.5% purity) was obtained as a brown solid and detected by ¹H NMR, HPLC, SFC and QC-LCMS. MS (ESI) m / z: 273.3 [M+1]+. 1 H NMR (400MHz, DMSO-d6) δ 10.77 (s, 1H), 7.43 (d, J=8.8 Hz, 1H), 6.47 (dd, J=1.6, 8.8 Hz, 1H), 6.41 (s, 1H), 5.36 (s,2H), 3.75 (s, 3H), 2.49 - 2.29 (m, 3H), 2.13 - 2.01 (m, 1H), 1.58 (s, 3H).

[0437] Synthesis of intermediate i-13: 3-[5-[4-(methylamino)-1-piperidinyl]benzimidazol-1-yl]piperidin-2,6-dione dihydrochloride

[0438]

[0439] Step i-13.1: Synthesis of 2,6-dibenzyloxypyridine-3-amine. Iron powder (8.3 g, 148 mmol) was added to a solution of 2,6-dibenzyloxy-3-nitro-pyridine (10.0 g, 29.7 mmol) in acetic acid (297 mL). The reaction mixture was stirred at 80°C for 2 hours, then cooled to room temperature and allowed to stand for 12 hours. The mixture was filtered through a Celite filter, washed with methanol (200 mL), and the filtrate was concentrated under reduced pressure. Ethyl acetate (500 mL) and a saturated aqueous solution of sodium bicarbonate (400 mL) were added, and the layers were separated. The organic layer was washed with water (400 mL) and brine (300 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (9.3 g, quantitative) as an oil, which was used in the next step without further purification. MS (ESI) [M+H]+ 307.2.

[0440] Step i-13.2: Synthesis of 2,6-dibenzyloxy-N-(4-bromo-2-nitro-phenyl)pyridine-3-amine. A solution of 1M bis(trimethylsilyl)aminolithium in tetrahydrofuran (68.6 mL, 68.6 mmol) was added dropwise to a solution of 2,6-dibenzyloxypyridine-3-amine (10.0 g, 32.6 mmol) and 4-bromo-1-fluoro-2-nitro-benzene (2.8 mL, 22.9 mmol) in tetrahydrofuran (163 mL) for 30 minutes at 0°C. After the addition was complete, the reaction mixture was stirred at room temperature for 3 hours, then cooled to 0°C. A saturated ammonium chloride solution (150 mL) and ethyl acetate (300 mL) were added, and the layers were separated. The organic layer was washed with saturated aqueous sodium bicarbonate solution (150 mL), water (150 mL), and brine (150 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient elution of 0-50% ethyl acetate in hexane to give the title compound (8.7 g, 53%). MS (ESI) [M+H]+ 50 8.2; 1 H NMR (400 MHz, CDCl3) δ 9.11 (s,1H), 8.30 (d, J = 2.3 Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.42 - 7.26 (m, 8H),7.26 - 7.24 (m, 2H), 7.23 (s, 1H), 6.70 (d, J = 9.1 Hz, 1H), 6.42 (d, J = 8.3Hz, 1H), 5.35 (s, 2H), 5.33 (s, 2H).

[0441] Step i-13.3: Synthesis of 4-bromo-N1-(2,6-dibenzyloxy-3-pyridyl)benzene-1,2-diamine. Iron powder (4.8 g, 86 mmol) was added to a solution of 2,6-dibenzyloxy-N-(4-bromo-2-nitro-phenyl)pyridin-3-amine (8.7 g, 17 mmol) and calcium chloride (3.8 g, 34 mmol) in ethanol (104 mL) and water (5.5 mL). The reaction mixture was refluxed for 12 hours and then cooled to room temperature. The mixture was filtered through a Celite filter, washed with ethyl acetate (200 mL), and the filtrate was concentrated under reduced pressure. Ethyl acetate (400 mL) and water (300 mL) were added, and the layers were separated. The organic layer was washed with brine (300 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (7.1 g, 87%) as an oil, which was used without further purification. MS (ESI) [M+H]+ 476.2.

[0442] Step i-13.4: Synthesis of 5-bromo-1-(2,6-dibenzyloxy-3-pyridyl)benzimidazole. Formic acid (9.7 mL, 256 mmol) was added to a solution of 4-bromo-N1-(2,6-dibenzyloxy-3-pyridyl)benzene-1,2-diamine (6.1 g, 12.8 mmol) in triethyl orthoformate (19.1 mL, 115 mmol). The reaction mixture was stirred at 100°C for 15 min and then cooled to room temperature. The volatiles were evaporated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient elution of 0-100% ethyl acetate in hexane to give the title compound (5.4 g, 87%) as a semi-solid. MS (ESI) [M+H]+ 487.2; 1 HNMR (500 MHz, DMSO) δ 8.41 (s, 1H), 8.13 (s, 1H), 7.95 (d, J = 8.3 Hz, 1H), 7.93 (d, J = 1.8 Hz, 1H), 7.49 - 7.46 (m, 2H), 7.42 - 7.35 (m, 4H), 7.28 -7.24 (m, 4H), 7.24 - 7.21 (m, 1H), 6.67 (d, J = 8.3 Hz, 1H), 5.43 (s, 2H), 5.40 (s, 2H).

[0443] Step i-13.5: Synthesis of N-[1-[1-(2,6-dibenzyloxy-3-pyridyl)benzimidazole-5-yl]-4-piperidinyl]-N-methyl-carbamate tert-butyl ester. A mixture of 5-bromo-1-(2,6-dibenzyloxy-3-pyridyl)benzimidazole (500 mg, 1.03 mmol), N-methyl-N-(4-piperidinyl)carbamate tert-butyl ester (440 mg, 2.1 mmol), sodium tert-butoxide (296 mg, 3.1 mmol), and tBuXPhos-Pd-G3 (82 mg, 0.10 mmol) in tetrahydrofuran (12.5 mL) was heated to 70°C for 18 hours and then cooled to room temperature. The mixture was filtered through a Celite filter, washed with methanol, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient elution of ethyl acetate from 0-100% in hexane to give the title compound (284 mg, 45% yield) as an oil. MS (ESI) [M+H]+ 621.4; 1 H NMR(500 MHz, DMSO) δ 8.21 (s, 1H), 7.89 (d, J = 8.3 Hz, 1H), 7.49 - 7.46 (m,2H), 7.42 - 7.38 (m, 2H), 7.37 - 7.33 (m, 1H), 7.30 - 7.27 (m, 5H), 7.20 (d,J = 2.2 Hz, 1H), 7.11 - 7.08 (m, 1H), 7.02 - 6.98 (m, 1H), 6.65 (d, J = 8.3Hz, 1H), 5.42 (s, 2H), 5.40 (s, 2H), 3.66 (m, 2H), 3.30 - 3.27 (m, 1H), 2.73- 2.68 (m, 2H), 2.71 (s, 3H), 1.88 - 1.79 (m, 2H), 1.67 - 1.59 (m, 2H), 1.41 (s, 9H).

[0444] Step i-13.6: Synthesis of N-[1-[1-(2,6-dioxo-3-piperidinyl)benzimidazol-5-yl]-4-piperidinyl]-N-methyl-carbamate tert-butyl ester. A mixture of N-[1-[1-(2,6-dibenzyloxy-3-pyridinyl)benzimidazol-5-yl]-4-piperidinyl]-N-methyl-carbamate tert-butyl ester (285 mg, 0.46 mmol) and 20% Pearlman catalyst (42 mg, 0.06 mmol) in tetrahydrofuran (6 mL) and ethanol (6 mL) was hydrogenated at 1 atm and 50°C for 5 h. The mixture was filtered through a Celite filter and washed with methanol (3 x 10 mL). The filtrate was concentrated under reduced pressure to give the title compound (192 mg) as a semi-solid, which was used in the next step without further purification. MS (ESI) [M+H]+442.3.

[0445] Step i-13.7: Synthesis of 3-[5-[4-(methylamino)-1-piperidinyl]benzimidazol-1-yl]piperidin-2,6-dione dihydrochloride. HCl (0.9 mL, 3.5 mmol) in 1,4-dioxane was added to a solution of N-[1-[1-(2,6-dioxo-3-piperidinyl)benzimidazol-5-yl]-4-piperidinyl]-N-methyl-carbamate tert-butyl ester (192 mg, 0.43 mmol) in 1,4-dioxane (10 mL). The reaction mixture was heated to 100°C for 1 hour and then cooled to room temperature. The volatiles were evaporated under reduced pressure to give the title compound (210 mg) as a solid, which was used in the next step without further purification. MS (ESI) [M+H]+ 342.2.

[0446] Synthesis of intermediate i-14: 3-[5-(4-amino-1-piperidinyl)benzimidazol-1-yl]piperidin-2,6-dione dihydrochloride

[0447]

[0448] Step i-14.1: Synthesis of N-[1-[1-(2-benzyloxy-6-phenoxy-3-pyridyl)benzimidazol-5-yl]-4-piperidinyl]tert-butyl carbamate. Two batches of 5-bromo-1-(2,6-dibenzyloxy-3-pyridyl)benzimidazol (500 mg, 1.03 mmol, see above), N-(4-piperidinyl)carbamate tert-butyl ester (412 mg, 2.06 mmol), sodium tert-butoxide (296 mg, 3.08 mmol), and tBuXPhos-Pd-G3 (82 mg, 0.10 mmol) were stirred in tetrahydrofuran (10 mL) at 25°C for 2 hours. The mixtures were combined, filtered through a Celite filter, and washed with methanol (20 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using a gradient elution of ethyl acetate in hexane from 0 to 100%, followed by a second silica gel chromatography gradient elution using dichloromethane in methanol from 0 to 20% to give the title compound (768 mg, 62%) as an oil. MS (ESI) [M+H]+ 608.4.

[0449] Step i-14.2: Synthesis of N-[1-[1-(2,6-dioxo-3-piperidinyl)benzimidazol-5-yl]-4-piperidinyl]tert-butyl carbamate. A mixture of N-[1-[1-(2,6-dibenzyloxy-3-pyridinyl)benzimidazol-5-yl]-4-piperidinyl]tert-butyl carbamate (768 mg, 1.27 mmol) and Pearlman catalyst (116 mg, 0.16 mmol) in tetrahydrofuran (18 mL) and ethanol (18 mL) was hydrogenated at 1 atm and 50°C for 10 h. The mixture was filtered through a Celite filter and washed with methanol (3 x 10 mL). The filtrate was concentrated under reduced pressure to give the title compound (419 mg, 77%) as a semi-solid. MS (ESI) [M+H]+ 428.6. 1H NMR (400 MHz, DMSO-d6) δ 11.16 (s,1H), 8.12 (s, 1H), 7.35 (d, J = 8.9 Hz, 1H), 7.13 (d, J = 2.0 Hz, 1H), 7.01 -6.97 (m, 1H), 6.85 (d, J = 7.5 Hz, 1H), 5.60 (dd, J = 12.8, 5.1 Hz, 1H), 3.52(d, J = 12.3 Hz, 2H), 3.34 - 3.30 (m, 1H), 2.93 - 2.73 (m, 2H), 2.72 - 2.66(m, 3H), 2.23 - 2.17 (m, 1H), 1.85 - 1.79 (m, 2H), 1.59 - 1.50 (m, 2H), 1.39 (s, 9H).

[0450] Step i-14.3: Synthesis of 3-[5-(4-amino-1-piperidinyl)benzimidazol-1-yl]piperidin-2,6-dione dihydrochloride. A solution of 4N HCl in 1,4-dioxane (1.0 mL, 4.2 mmol) was added to a solution of N-[1-[1-(2,6-dioxo-3-piperidinyl)benzimidazol-5-yl]-4-piperidinyl] tert-butyl carbamate (148 mg, 0.35 mmol) in 1,4-dioxane (10.0 mL). The reaction mixture was heated to 100°C for 2 hours and then cooled to room temperature. The volatiles were evaporated under reduced pressure to give the title compound (138 mg, 91%) as a solid, which was used directly in the next step without further purification. MS (ESI) [M+H]+ 328.2.

[0451] Synthesis of intermediate i-15: 3-[5-(2,8-diazaspiro[4.5]decane-8-yl)benzimidazol-1-yl]piperidine-2,6-dione hydrochloride.

[0452]

[0453] Step i-15.1: Synthesis of tert-butyl 8-[1-(2,6-dibenzyloxy-3-pyridyl)benzimidazole-5-yl]-2,8-diazaspiro[4.5]decane-2-carboxylic acid. A mixture of 5-bromo-1-(2,6-dibenzyloxy-3-pyridyl)benzimidazole (350 mg, 0.72 mmol), tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylic acid (346 mg, 0.72 mmol), sodium tert-butoxide (207 mg, 2.16 mmol), and tBuXPhos-Pd-G3 (57 mg, 80 µmol) in tetrahydrofuran (3 mL) was heated to 70°C for 5 hours and then cooled to room temperature. The mixture was filtered through a Celite filter and washed with methanol (20 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using a gradient elution of ethyl acetate in hexane from 0-100% to give the title compound (296 mg, 64%) as a solid. MS (ESI) [M+H + 646.0. 1 H NMR (400MHz, CDCl3) δ 7.88 (s, 1H), 7.54 (d, J = 8.3 Hz, 1H), 7.42 - 7.25 (m, 6H), 7.24 - 7.14 (m, 5H), 7.05 (d, J = 8.7 Hz, 1H), 6.96 (d, J = 8.2 Hz, 1H), 6.46(d, J = 8.3 Hz, 1H), 5.33 (s, 2H), 5.31 (s, 2H), 3.43 - 3.28 (m, 2H), 3.26 -3.09 (m, 4H), 3.09 - 2.98 (m, 2H), 1.78 - 1.64 (m, 6H), 1.40 (s, 9H).

[0454] Step i-15.2: Synthesis of tert-butyl 8-[1-(2,6-dioxo-3-piperidinyl)benzimidazol-5-yl]-2,8-diazaspiro[4.5]decane-2-carboxylic acid. A mixture of tert-butyl 8-[1-(2,6-dibenzyloxy-3-pyridinyl)benzimidazol-5-yl]-2,8-diazaspiro[4.5]decane-2-carboxylic acid (105 mg, 0.16 mmol) and Pearlman catalyst (22 mg, 30 µmol, STRM Esc 1951) in tetrahydrofuran (3 mL) and ethanol (3 mL) was hydrogenated at 50°C (1 atm) for 3 h. The mixture was filtered through a Celite filter and washed with ethanol (25 mL). The filtrate was concentrated under reduced pressure to give the title compound (75 mg, 98% yield) as a solid, which was used in the next step without further purification. MS (ESI) [M+H + 469.3. 1 H NMR (500 MHz, DMSO-d6) δ 11.15 (s, 1H), 8.12 (s, 1H), 7.36 (d, J = 8.9 Hz, 1H), 7.15 (d, J = 1.8 Hz, 1H), 7.01 (dd, J = 8.9, 2.1Hz, 1H), 5.60 (dd, J = 13.0, 5.2 Hz, 1H), 3.30 (m, 1H) 3.18 - 2.98 (m, 5H), 3.13 (s, 2H), 2.91 - 2.85 (m, 1H), 2.80 - 2.67 (m, 2H), 2.22 - 2.18 (m, 1H),1.76 - 1.73 (m, 2H), 1.68 - 1.61 (m, 4H), 1.40 (s, 9H).

[0455] Step i-15.3: Synthesis of 3-[5-(2,8-diazaspiro[4.5]decane-8-yl)benzimidazol-1-yl]piperidine-2,6-dione hydrochloride. To a solution of tert-butyl 8-[1-(2,6-dioxo-3-piperidinyl)benzimidazol-5-yl]-2,8-diazaspiro[4.5]decane-2-carboxylate (299 mg, 0.64 mmol) in 1,4-dioxane (6 mL), 4N in HCl (0.23 mL, 0.92 mmol) in 1,4-dioxane was added, and the reaction mixture was stirred at room temperature for 18 hours. The volatiles were removed under reduced pressure to give the title compound (250 mg, 96%) as a solid, which was used in the next step without further purification. MS (ESI) [M+H]+ 368.2.

[0456] Synthesis of intermediate i-16: 3-(5-aminobenzimidazol-1-yl)piperidine-2,6-dione; hydrochloride

[0457]

[0458] Step i-16.1: Synthesis of tert-butyl (4S)-5-amino-4-(4-bromo-2-nitro-anilino)-5-oxo-valerate. Tert-butyl (4S)-4,5-diamino-5-oxo-valerate, hydrochloride (20.0 g, 83.8 mmol), and N,N-diisopropylethylamine (50.0 mL) were added sequentially to a solution of 4-bromo-1-fluoro-2-nitro-benzene (19.0 g, 86.4 mmol) in N,N-dimethylformamide (400.0 mL). The reaction mixture was heated to 90°C for 3 hours and then cooled to room temperature. The volatiles were evaporated under reduced pressure. A saturated solution of ammonium chloride (500.0 mL) and ethyl acetate (500.0 mL) were added, and the layers were separated. The organic layer was washed with brine (200.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (32.3 g, 96%) as a solid, which was used in the next step without further purification. MS (ESI) [MH]-400.2.

[0459] Step i-16.2: Synthesis of tert-butyl 5-amino-4-(2-amino-4-bromo-anilino)-5-oxo-valerate. Zinc powder (47.0 g, 718.0 mmol) and ammonium chloride (19.0 g, 355.0 mmol) were added sequentially to a suspension of (4S)-5-amino-4-(4-bromo-2-nitro-anilino)-5-oxo-valerate (32.1 g, 79.8 mmol) in tetrahydrofuran (260.0 mL) cooled to 0°C. Water (80.0 mL) was slowly added, and the reaction mixture was stirred at 0°C for 1 hour. The mixture was filtered through a Celite filter and washed with tetrahydrofuran (200.0 mL). The filtrate was concentrated under reduced pressure. The substance was purified by silica gel column chromatography using a gradient elution of 10-20% methanol in dichloromethane to give the title compound (28.1 g, 95%) as a solid. MS (ESI) [M+H]+ 374.2; 1H NMR (400 MHz, DMSO) δ 7.39 (bs, 1H), 7.06 (bs, 1H), 6.69 (d, J = 2.3 Hz, 1H), 6.55 (dd, J = 8.4, 2.3 Hz, 1H), 6.23(d, J = 8.5 Hz, 1H), 4.93 (s, 2H), 4.63 (d, J = 8.1 Hz, 1H), 3.68 - 3.60 (m,1H), 2.42 - 2.29 (m, 2H), 1.96 - 1.84 (m, 2H), 1.39 (s, 9H).

[0460] Step i-16.3: Synthesis of 2-(5-bromobenzimidazol-1-yl)-5-oxo-hexanoamide; formate. Formic acid (20.0 mL, 529.0 mmol) was added to a solution of (4S)-5-amino-4-(2-amino-4-bromo-aniline)-5-oxo-pentanoic acid tert-butyl ester (10.0 g, 27.0 mmol) in triethyl orthoformate (40.0 mL, 241.0 mmol). The reaction mixture was heated to 100°C for 15 minutes and then cooled to room temperature. The volatiles were evaporated under reduced pressure. The substance was purified by silica gel column chromatography using a gradient elution of 0-20% methanol in dichloromethane to give the title compound (10.2 g, 89%) as a solid. MS (ESI) [M+H]+ 384.2; 1 H NMR (500 MHz, DMSO) δ 8.33 (s, 1H), 8.14 (s, 1H), 7.86 (d, J = 1.8 Hz, 1H), 7.83 (s, 1H), 7.54 (d, J = 8.6 Hz, 1H), 7.44 - 7.40 (m,2H), 5.09 (dd, J = 9.2, 6.3 Hz, 1H), 2.41 - 2.25 (m, 2H), 2.19 - 1.98 (m,2H), 1.33 (s, 9H).

[0461] Step i-16.4: Synthesis of 3-(5-bromobenzimidazol-1-yl)piperidine-2,6-dione; trifluoroacetate. Potassium tert-butoxide (1.9 g, 16.6 mmol) was added to a solution of tert-butyl 5-amino-4-(5-bromobenzimidazol-1-yl)-5-oxo-valerate (5.3 g, 13.9 mmol) in tetrahydrofuran (69.0 mL) cooled to 0°C. The reaction mixture was stirred at 0°C for 15 min and then at room temperature for 2 h. Acetic acid (0.95 mL, 17.0 mmol) was added, and the mixture was stirred at room temperature for another 2 h. The precipitate was collected by filtration, washed with water (100 mL), diethyl ether (20.0 mL), tetrahydrofuran (10.0 mL), and acetonitrile (10.0 mL), and then dried under vacuum. The substance was purified by reversed-phase chromatography (C18) using a gradient elution of 5-100% acetonitrile and water (containing 0.1% TFA) to give the title compound (3.9 g, 65%) as a solid. MS (ESI) [M+H]+ 308.1, 310.1; 1 ¹H NMR (400 MHz, DMSO) δ 11.25 (s, 1H), 8.59 (s, 1H), 7.94 (d, J = 1.7 Hz, 1H), 7.63 (d, J = 8.7 Hz, 1H), 7.50 (dd, J = 8.7, 1.8 Hz, 1H), 5.77 (dd, J = 12.7, 5.0 Hz, 1H), 2.95 - 2.66 (m, 3H), 2.34 - 2.23 (m, 1H), missing three exchangeable protons; ¹⁹F NMR (376 MHz, DMSO) δ -74.87 (s).

[0462] Step i-16.5: Synthesis of N-[1-(2,6-dioxo-3-piperidinyl)benzimidazol-5-yl]tert-butyl carbamate. A mixture of 3-(5-bromobenzimidazol-1-yl)piperidin-2,6-dione; 2,2,2-trifluoroacetate (425.0 mg, 1.01 mmol), tert-butyl carbamate (177.0 mg, 1.51 mmol), tBuXPhos-Pd-G3 (160.0 mg, 0.2 mmol), and sodium tert-butoxide (242.0 mg, 2.52 mmol) in 1,4-dioxane (13.0 mL) was heated to 50°C for 18 hours and then cooled to room temperature. Acetic acid (0.2 mL, 3.0 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. The volatiles were evaporated under reduced pressure. Acetonitrile (10.0 mL) was added, and insoluble substances were removed by filtration. The filtrate was concentrated under reduced pressure. Diethyl ether (10.0 mL) was added, and the resulting precipitate was collected by filtration, washed with diethyl ether (3 x 5.0 mL), and then dried under vacuum to give the title compound (357.0 mg, 87%) as a solid, which was used in the next step without further purification. MS (ESI) [M+H]+ 345.3; 1 H NMR (400 MHz, DMSO) δ 11.23 (bs, 1H), 9.30 (bs,1H), 8.24 (s, 1H), 7.84 (bs, 1H), 7.45 (d, J = 8.7 Hz, 1H), 7.39 - 7.35 (m,1H), 5.69 (dd, J = 12.9, 5.1 Hz, 1H), 2.90 - 2.75 (m, 3H), 2.31 - 2.24 (m,1H), 1.55 (s, 9H).

[0463] Step i-16.6: Synthesis of 3-(5-aminobenzimidazol-1-yl)piperidin-2,6-dione; hydrochloride. HCl (2.6 mL, 10.4 mmol) in 1,4-dioxane was added to a solution of N-[1-(2,6-dioxo-3-piperidinyl)benzimidazol-5-yl]carbamate tert-butyl ester (357.0 mg, 1.04 mmol) in 1,4-dioxane (4.0 mL). The reaction mixture was stirred at room temperature for 1 hour. The volatiles were evaporated under reduced pressure. The substance was purified by reversed-phase chromatography (C18) using a gradient elution of 5-100% acetonitrile and water (containing 0.1% formic acid) to give the title compound (173.0 mg, 68% yield) as a solid. MS (ESI) [M+H]+ 245.2; 1¹H NMR (400 MHz, DMSO) δ 11.33 (s, 1H), 9.09 (bs, 1H), 7.70 (d, J = 8.7 Hz, 1H), 7.36 (bs, 1H), 7.17 - 7.06 (m, 1H), 5.90 (d, J = 12.1 Hz, 1H), 2.94 - 2.73 (m, 3H), 2.37 - 2.31 (m, 1H). Note: No exchangeable protons were observed.

[0464] Synthesis of intermediate i-17: 3-(4-amino-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione.

[0465]

[0466] Step i-17.1: Synthesis of tert-butyl carbamate (2-fluoro-3-nitrophenyl)carbamate. To a solution of 1-bromo-2-fluoro-3-nitrobenzene (30.000 g, 136.37 mmol, 1.0 equivalent) in toluene (400 mL), 4,5-bis(diphenylphosphino)-9,9-dimethyl (7.890 g, 13.64 mmol, 0.1 equivalent), tert-butyl carbamate (19.170 g, 163.64 mmol, 1.2 equivalent), cesium carbonate (53.320 g, 163.64 mmol, 1.2 equivalent), and tris(dibenzylacetone)dipalladium (6.240 g, 6.82 mmol, 0.05 equivalent) were added. The mixture was stirred at 90°C for 12 hours. TLC and LCMS showed the reaction was complete. The mixture was concentrated to obtain a residue. The residue was purified by silica gel column chromatography (petroleum ether). N-(2-fluoro-3-nitro-phenyl)carbamate tert-butyl ester (32.000 g, crude) was given as a yellow solid, detectable by ¹H NMR. MS (ESI) m / z: 279.9 [M+Na] + . 1 H NMR (400MHz, DMSO-d6) δ 9.49 (s, 1H), 8.01 (t, J=7.2 Hz,1H), 7.83 - 7.80 (m, 1H), 7.37 - 7.31 (m, 1H), 1.47 (s, 9H).

[0467] Step i-17.2: Synthesis of 2-fluoro-3-nitroaniline. Hydrogen chloride (12 M, 39 mL, 3.8 equivalents) was added to a solution of tert-butyl N-(2-fluoro-3-nitro-phenyl)carbamate (32.000 g, 124.89 mmol, 1.0 equivalent) at 0°C. The mixture was stirred at 0°C for 1 hour. TLC and LCMS showed the reaction was complete. The mixture was diluted with water (300 mL), concentrated, and lyophilized to give the residue. The residue was dissolved in acetonitrile (150 mL) and water (15 mL), and sodium bicarbonate (15.000 g) was added. The mixture was stirred for 0.5 hours, filtered, and concentrated to give the residue. The residue was purified by silica gel column chromatography (1% to 10% solution in ethyl acetate in petroleum ether). 2-Fluoro-3-nitro-aniline (15.300 g, 98.0 mmol, 78.47% yield) was obtained as a yellow solid and detected by ¹H NMR. MS (ESI) m / z: 157.1 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ 7.20 - 7.12 (m, 1H), 7.12 - 7.03 (m, 2H), 5.83 (s, 2H).

[0468] Step i-17.3: Synthesis of 2,6-bis(benzyloxy)-N-(2-fluoro-3-nitrophenyl)pyridine-3-amine. Potassium carbonate (39.840 g, 288.25 mmol, 3.0 equivalent), 2,6-dibenzyloxy-3-bromopyridine (42.690 g, 115.30 mmol, 1.2 equivalent), and [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium; dicyclohexyl-[3,6-dimethoxy-2-(2,4,6-triisopropylphenyl)phenyl]phosphine (6.530 g, 7.21 mmol, 0.075 equivalent) were added to a solution of 2-fluoro-3-nitrophenylamine (15.000 g, 96.08 mmol, 1.0 equivalent) in dioxane (400 mL). The mixture was stirred at 100°C for 12 hours. TLC and LCMS showed the reaction was complete. The mixture was filtered and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (1% to 5% in ethyl acetate solution in petroleum ether). 2,6-Dibenzyloxy-N-(2-fluoro-3-nitro-phenyl)pyridine-3-amine (20.000 g, crude) was obtained as a brown oil, as determined by HPLC. MS (ESI) m / z: 446.2 [M+1] + .

[0469] Step i-17.4: Synthesis of N1-(2,6-bis(benzyloxy)pyridin-3-yl)-N2-methyl-3-nitrobenzene-1,2-diamine. Methylamine (1 M, 50 mL, 1.3 equivalents) and triethylamine (11.450 g, 113.15 mmol, 15.8 mL, 3.0 equivalents) were added to a solution of 2,6-dibenzyloxy-N-(2-fluoro-3-nitro-phenyl)pyridin-3-amine (20.000 g, 37.72 mmol, 1.0 equivalents). The reaction mixture was then stirred at 110°C for 12 hours in a sealed container. TLC and LCMS showed the reaction was complete. The mixture was concentrated to give a residue. This residue was then diluted with water (100 mL) and extracted with ethyl acetate (150 mL × 3). The combined organic layers were washed with saturated brine (100 mL × 2) and dried over anhydrous sodium sulfate. The organic layers were filtered and concentrated to obtain the residue. The residue was purified by silica gel column chromatography (1% to 10% solution in ethyl acetate in petroleum ether). N1-(2,6-dibenzyloxy-3-pyridyl)-N2-methyl-3-nitro-benzene-1,2-diamine (16.500 g, crude) was given as a brown oil. MS (ESI) m / z: 457.1 [M+1] + .

[0470] Step i-17.5: Synthesis of 1-(2,6-bis(benzyloxy)pyridin-3-yl)-3-methyl-4-nitro-1H-benzo[d]imidazol-2(3H)-one. Dimethylaminopyridine (0.442 g, 3.61 mmol, 0.1 equivalent) was added to a solution of N1-(2,6-dibenzyloxy-3-pyridinyl)-N2-methyl-3-nitro-phenyl-1,2-diamine (16.500 g, 36.15 mmol, 1.0 equivalent) in Boc anhydride (50 mL). The mixture was stirred at 60°C for 2 hours. TLC and LCMS showed the reaction was complete. The mixture was concentrated to give the residue. The residue was purified by silica gel column chromatography (2% to 20% in ethyl acetate solution in petroleum ether). 1-(2,6-Dibenzyloxy-3-pyridyl)-3-methyl-4-nitro-benzimidazol-2-one (15.500 g, 32.13 mmol, 88.88% yield) was given as a yellow solid. MS (ESI) m / z: 483.2 [M+1] + .

[0471] Step i-17.6: Synthesis of 4-amino-1-(2,6-bis(benzyloxy)pyridin-3-yl)-3-methyl-1H-benzimidazole-2(3H)-one. Iron (8.970 g, 160.63 mmol, 5.0 equivalent) and ammonium chloride (17.180 g, 321.25 mmol, 10.0 equivalent) were added to a solution of 1-(2,6-dibenzyloxy-3-pyridinyl)-3-methyl-4-nitro-benzimidazole-2-one (15.500 g, 32.13 mmol, 1.0 equivalent) in ethanol (100 mL) and water (50 mL). The mixture was stirred at 85°C for 1 hour. TLC and LCMS showed the reaction was complete. The reaction mixture was filtered and concentrated. The residue was diluted with water (150 mL) and extracted with ethyl acetate (200 mL × 3). The combined organic layers were washed with brine (200 mL × 3), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. 4-Amino-1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-benzimidazol-2-one (17.000 g, crude) was given as a yellow solid by HPLC. MS (ESI) m / z: 453.0 [M+1] + .

[0472] Step i-17.7: Synthesis of tert-butyl carbamate (1-(2,6-bis(benzyloxy)pyridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)carbamate. Potassium carbonate (12.460 g, 90.17 mmol, 3.0 equivalent) and Boc anhydride (19.680 g, 90.17 mmol, 3.0 equivalent) were added to a solution of 4-amino-1-(2,6-dibenzyloxy-3-pyridinyl)-3-methyl-benzimidazol-2-one (17.000 g, 30.06 mmol, 1.0 equivalent) in tetrahydrofuran (80 mL) and water (80 mL). The mixture was stirred at 20°C for 12 hours. TLC and LCMS showed the reaction was complete. The mixture was then concentrated. Then water (150 mL) and ethyl acetate (150 mL × 3) were added. The combined organic layers were washed with brine (150 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by silica gel column chromatography (1% to 50% solution in ethyl acetate in petroleum ether). Tert-butyl carbamate (1-(2,6-bis(benzyloxy)pyridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)carbamate (12.000 g, 21.71 mmol, 72.25% yield) was given as a yellow solid, detectable by 1H NMR. MS (ESI) m / z: 553.3 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ 8.94 (s, 1H), 7.80 (d, J=8.4 Hz, 1H), 7.46 - 7.42 (m, 2H), 7.41 -7.33 (m, 3H), 7.27 (s, 5H), 6.96 - 6.89 (m, 1H), 6.89 - 6.81 (m, 1H), 6.61 (d, J=8.4 Hz, 1H), 6.54 (d, J=7.6 Hz, 1H), 5.45 - 5.34 (m, 4H), 3.50 (s, 3H), 1.47 (s, 9H).

[0473] Step i-17.8: Synthesis of tert-butyl carbamate (1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)carbamate. Under a nitrogen atmosphere, a palladium / carbon catalyst (14.000 g, 10% purity, 1.0 equivalent) was added to a solution of tert-butyl carbamate (7.000 g, 12.67 mmol, 1.0 equivalent) in tetrahydrofuran (400 mL). The suspension was degassed under vacuum and purified several times with hydrogen. The mixture was stirred at 20°C for 12 hours under hydrogen (50 psi). TLC and LCMS showed the reaction was complete. The mixture was filtered and concentrated to give the residue. The residue was purified by silica gel column chromatography (1% to 5% methanol in dichloromethane). Tert-butyl carbamate (1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)carbamate (7.500 g, 19.87 mmol, 74.40% yield, 99.2% purity) was given as a white solid, detected by ¹H NMR and HPLC. MS (ESI) m / z: 375.1 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ 11.09 (s, 1H), 8.90 (s, 1H), 7.05 -6.94 (m, 2H), 6.82 (dd, J=1.2, 7.6 Hz, 1H), 5.37 (dd, J=5.2, 12.8 Hz, 1H),3.45 (s, 3H), 2.96 - 2.83 (m, 1H), 2.77 - 2.59 (m, 2H), 2.09 - 1.99 (m, 1H),1.46 (s, 9H).

[0474] Step i-17.9: Synthesis of 3-(4-amino-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione. Hydrogen chloride (12 M, 20 mL, 22.5 equivalents) was added to a solution (4.000 g, 10.68 mmol, 1.0 equivalent) of tert-butyl carbamate. The mixture was stirred at 0°C for 0.5 h. LCMS showed the reaction was complete. Water (100 mL) was added to the mixture. The mixture was freeze-dried to give the residue. 3-(4-amino-3-methyl-2-oxo-benzimidazol-1-yl)piperidin-2,6-dione (2.550 g, 9.20 mmol, 86.15% yield, 98.9% purity) was obtained as a white solid, detected by ¹H NMR and LCMS. MS (ESI) m / z: 275.2 [M+1] + . 1 ¹H NMR (400MHz, DMSO-d⁶) δ 11.11 (s, 1H), 7.15 - 6.99 (m, 3H), 5.41 (dd, J=5.2, 12.8 Hz, 1H), 3.66 (s, 3H), 2.94 - 2.84 (m, 1H), 2.76 - 2.59 (m, 2H), 2.09 - 1.99 (m, 1H). Note: No exchangeable protons were observed.

[0475] Synthesis of intermediate i-18: 3-(5-amino-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0476]

[0477] Step i-18.1: Synthesis of 2,6-bis(benzyloxy)-3-nitropyridine. Cesium carbonate (120.000 g, 368.30 mmol, 2.95 equivalents) and phenylmethanol (29.120 g, 269.29 mmol, 28 mL, 2.16 equivalents) were added to a solution of 2,6-dibenzyloxy-3-nitropyridine (20.000 g, 124.940 mmol, 1.00 equivalents) in acetonitrile (300 mL) at 10°C. The mixture was stirred at 80°C for 12 hours. TLC showed the reaction was complete. The solid was filtered off, and the filtrate was concentrated under vacuum to give the product. 2,6-Dibenzyloxy-3-nitropyridine (40.000 g, 118.93 mmol, 95.2% yield) was given as a yellow solid. ¹H NMR confirmed the product. 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.44 (d, J = 8.8 Hz, 1H), 7.26-7.52 (m, 10 H), 6.62 (d, J = 8.8 Hz, 1 H), 5.57 (s, 2 H), 5.47 (s, 2H).

[0478] Step i-18.2: Synthesis of 2,6-bis(benzyloxy)pyridine-3-amine. Iron (37.360 g, 668.96 mmol, 5.00 equivalent) and ammonium chloride (71.570 g, 1340.00 mmol, 10.00 equivalent) were added to a solution of 2,6-dibenzyloxy-3-nitro-pyridine (45.000 g, 133.79 mmol, 1.00 equivalent) in ethanol (500 mL) and water (50 mL). The mixture was stirred at 80°C for 2 hours. LC-MS showed the reaction was complete. The solvent was removed under vacuum. The residue was purified by column chromatography (SiO2, ethyl acetate in petroleum ether = 10% to 20%). 2,6-Dibenzyloxypyridine-3-amine (33.000 g, 107.72 mmol, 80.5% yield) was obtained as a yellow solid. The product was confirmed by ¹H NMR. MS (ESI) m / z: 307.2 [M+1]+; 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.45 (d, J = 7.6 Hz, 2 H), 7.30-7.38 (m, 8H), 6.99 (d, J = 8.0 Hz, 1 H), 6.24 (d, J = 8.0 Hz, 1 H), 5.35 (s, 2 H), 5.19 (s, 2 H), 4.39 (s, 2 H).

[0479] Step i-18.3: Synthesis of methyl 2-((2,6-bis(benzyloxy)pyridin-3-yl)amino)-5-nitrobenzoate. To a solution of 2,6-dibenzyloxypyridin-3-amine (30.000 g, 97.92 mmol, 1.00 equivalent) in dioxane (300 mL), chloro(2-dicyclohexylphosphino-2,4,6-tri-isopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium(II) (3.850 g, 4.90 mmol, 0.05 equivalent), methyl 2-bromo-5-nitrobenzoate (35.000 g, 134.59 mmol, 1.37 equivalent) and potassium carbonate (40.600 g, 293.77 mmol, 3.00 equivalent) were added. The mixture was stirred at 100°C under a nitrogen atmosphere for 12 hours. The desired product was determined by LCMS. The solvent was removed under vacuum. The residue was purified by column chromatography (SiO2, 1%–10% ethyl acetate in petroleum ether). Methyl 2-((2,6-bis(benzyloxy)pyridin-3-yl)amino)-5-nitrobenzene (27.000 g, 55.61 mmol, 56.8% yield) was given as a yellow solid. The product was confirmed by ¹H NMR. MS (ESI) m / z: 486.2 [M+1]+; 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.72 (s, 1 H), 8.68 (d, J = 2.8 Hz, 1 H), 8.12 (dd, J = 9.6, 2.8 Hz, 1 H), 7.74 (d, J = 8.4 Hz, 1H), 7.21-7.50 (m, 10 H), 6.74 (d, J = 9.6 Hz, 1 H), 6.55 (d, J = 8.4 Hz, 1H), 5.38 (d, J = 18.4 Hz, 4 H), 3.91 (s, 3 H).

[0480] Step i-18.4: Synthesis of 2-((2,6-bis(benzyloxy)pyridin-3-yl)amino)-5-nitrobenzoic acid. Sodium hydroxide (9.060 g, 226.58 mmol, 5.00 equivalents) was added to a solution of methyl 2-((2,6-bis(benzyloxy)pyridin-3-yl)amino)-5-nitrobenzoate (22.000 g, 45.32 mmol, .001 equivalents) in tetrahydrofuran (100 mL) and water (100 mL). The mixture was stirred at 80°C for 2 hours. LC-MS showed the reaction was complete. The mixture was extracted with ethyl acetate (200 mL x 3), dried over sodium sulfate, filtered, and concentrated. 2-((2,6-bis(benzyloxy)pyridin-3-yl)amino)-5-nitrobenzoic acid (21.000 g, 44.54 mmol, 98.3% yield) was obtained as a yellow solid. MS (ESI) m / z: 472.2 [M+1]+

[0481] Step i-18.5: Synthesis of 1-(2,6-bis(benzyloxy)pyridin-3-yl)-5-nitro-1H-benzo[d]imidazol-2(3H)-one. Diphenylphosphoazide (16.690 g, 60.66 mmol, 1.30 equivalent) and triethylamine (12.300 g, 121.58 mmol, 2.61 equivalent) were added to a solution of 2-((2,6-bis(benzyloxy)pyridin-3-yl)amino)-5-nitrobenzoic acid (22.000 g, 46.66 mmol, 1.00 equivalent) in toluene (300 mL) at 0°C. The mixture was stirred at 100°C under a nitrogen atmosphere for 12 hours. The desired product was determined by LCMS. The solvent was removed under vacuum to obtain the residue. The residue was purified by preparative-TLC (SiO2, ethyl acetate, petroleum ether). 3-(2,6-dibenzyloxy-3-pyridyl)-6-nitro-1H-benzimidazol-2-one (20.500 g, 43.76 mmol, 93.8% yield) was given as a yellow solid. The product was confirmed by ¹H NMR. MS (ESI) m / z: 469.2 [M+1]+; 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.69 (s,1 H), 7.76-7.99 (m, 3 H), 7.43-7.50 (m, 2 H), 7.32-7.41 (m, 3 H), 7.23-7.29(m, 5 H), 6.85 (d, J = 8.8 Hz, 1 H), 6.65 (d, J = 8.4 Hz, 1 H), 5.30-5.48 (m, 4 H).

[0482] Step i-18.6: Synthesis of 1-(2,6-bis(benzyloxy)pyridin-3-yl)-3-methyl-5-nitro-1H-benzimidazole-2(3H)-one. Sodium hydride (2.050 g, 51.23 mmol, 60% purity, 2.00 equivalent) and methyl 4-methylbenzylsulfonate (6.000 g, 32.22 mmol, 1.26 equivalent) were added to a solution of 3-(2,6-dibenzyloxy-3-pyridinyl)-6-nitro-1H-benzimidazole-2-one (12.000 g, 25.62 mmol, 1.00 equivalent) in tetrahydrofuran (120 mL). The mixture was stirred at 20°C for 12 hours. LC-MS showed the reaction was complete. The mixture was quenched with water (100 mL), then extracted with ethyl acetate (100 mL x 3), the organic layers were combined, dried over sodium sulfate, filtered, and concentrated under vacuum to give the product. 1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-5-nitro-benzimidazol-2-one (10.500 g, 21.76 mmol, 84.9% yield) was given as a yellow solid. MS (ESI) m / z: 483.1 [M+1]+

[0483] Step i-18.7: Synthesis of 5-amino-1-(2,6-bis(benzyloxy)pyridin-3-yl)-3-methyl-1H-benzimidazole-2(3H)-one. Iron (6.000 g, 107.44 mmol, 4.94 equivalents) and ammonium chloride (12.000 g, 224.34 mmol, 10.31 equivalents) were added to a solution of 1-(2,6-dibenzyloxy-3-pyridinyl)-3-methyl-5-nitro-benzimidazole-2-one (10.500 g, 21.76 mmol, 1.00 equivalents) in ethanol (100 mL) and water (20 mL). The mixture was stirred at 80°C for 2 hours. LC-MS showed that the reaction was complete. The mixture was filtered, and the filtrate was extracted with ethyl acetate (100 mL x 3). The organic phase was dried over sodium sulfate, filtered, and concentrated. 5-Amino-1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-benzimidazol-2-one (9.800 g, 21.66 mmol, 99.5% yield) was given as a yellow solid. MS (ESI) m / z: 453.2 [M+1]+

[0484] Step i-18.8: Synthesis of (1-(2,6-bis(benzyloxy)pyridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)carbamate. Potassium carbonate (6.000 g, 43.41 mmol, 2.00 equivalent) and di-tert-butyl dicarbonate (6.000 g, 27.49 mmol, 1.27 equivalent) were added to a solution of 5-amino-1-(2,6-dibenzyloxy-3-pyridinyl)-3-methyl-benzimidazol-2-one (9.800 g, 21.66 mmol, 1.00 equivalent) in tetrahydrofuran (100 mL) and water (100 mL). The mixture was stirred at 20°C for 12 hours. LC-MS showed the reaction was complete. The mixture was extracted with ethyl acetate (100 mL x 3), the organic layers were combined, dried over sodium sulfate, filtered, and concentrated under vacuum. The resulting product was (1-(2,6-bis(benzyloxy)pyridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbamate (11.500 g, 20.81 mmol, 96.0% yield), a yellow solid. MS (ESI) m / z: 553.1 [M+1]+

[0485] Step i-18.9: Synthesis of (1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbamate. Palladium / carbon (6.000 g, 10% purity) was added to a solution of tert-butyl (1-(2,6-bis(benzyloxy)pyridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbamate (6.000 g, 10.86 mmol, 1.00 equivalent) in tetrahydrofuran (400 mL). The mixture was stirred at 25°C under hydrogen (50 Psi) for 12 hours. LCMS showed the reaction was complete. The mixture was filtered. The filtrate was concentrated under vacuum to give the residue. The residue was stirred in 150 mL of solvent (ethyl acetate / petroleum ether = 10:1) for 1 hour, and the solid was collected by filtration. This yielded (1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbamate (3.600 g, 9.62 mmol, 88.5% yield) as a white solid. The product was confirmed by ¹H NMR. MS (ESI) m / z: 375.3 [M+1]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 11.07 (s, 1 H), 9.27 (s, 1H), 7.41 (s, 1 H), 6.98 (s, 2 H), 5.31 (dd, J = 12.8, 5.26 Hz, 1 H), 3.29 (s, 3 H), 2.84-2.95 (m, 1 H), 2.59-2.74 (m, 2 H), 1.99-2.05 (m, 1 H), 1.48 (s, 9H).

[0486] Step i-18.10: Synthesis of 3-(5-amino-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione. A mixture of tert-butyl carbamate (3.600 g, 9.62 mmol, 1 equivalent) and hydrogen chloride (12 M, 25 mL, 31.20 equivalent) was stirred at 0°C for 2 hours. LCMS showed that the reaction was complete. Water (100 mL) was added to the mixture, and the mixture was lyophilized. The mixture was stirred in acetonitrile (200 mL) for 12 hours. The solid was collected by filtration. 3-(5-amino-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (2.754 g, 8.77 mmol, 91.2% yield, 99.0% purity, hydrogen chloride) was obtained as a yellow solid. The product was confirmed by ¹H NMR. HPLC showed a purity of 95.8%, and QC-LCMS showed a purity of 99.0%. MS (ESI) m / z: 275.0 [M+1]+; 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.13 (s, 1 H), 10.49 (s, 2 H), 7.24 (d, J = 8.2 Hz, 1 H), 7.19 (d, J = 1.6 Hz, 1 H), 7.09 (dd, J =8.2, 1.6 Hz, 1 H), 5.44 (dd, J = 12.8, 5.2 Hz, 1 H), 3.35 (s, 3 H), 2.85-3.00 (m, 1 H), 2.58-2.79 (m, 2 H), 1.96-2.12 (m, 1 H).

[0487] Synthesis of intermediate i-19: 5-bromo-1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-benzimidazol-2-one.

[0488]

[0489] Step i-19.1: Synthesis of 2,6-dibenzyloxy-N-(4-bromo-2-nitro-phenyl)pyridine-3-amine. 4-bromo-1-fluoro-2-nitro-benzene (4.16 mL, 43.1 mmol) was added to a solution of 2,6-dibenzyloxypyridine-3-amine (11 g, 35.9 mmol) in pyridine (100 mL), and the reaction mixture was heated to 55°C for 48 hours, 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 elution of 0-60% ethyl acetate in hexane to give the title compound (8.8 g, 48%) as a solid. MS (ESI) [M+H] + 506.1. 1 H NMR (400 MHz, DMSO-d6) δ 9.22 (s, 1H), 8.21 (d, J = 2.4 Hz, 1H), 7.70 (d, J = 8.3 Hz, 1H), 7.55(dd, J = 9.2, 2.4 Hz, 1H), 7.48 - 7.22 (m, 10H), 6.68 (d, J = 9.2 Hz, 1H), 6.55 (d, J = 8.2 Hz, 1H), 5.37 (s, 2H), 5.35 (s, 2H).

[0490] Step i-19.2: Synthesis of 4-bromo-N1-(2,6-dibenzyloxy-3-pyridyl)benzene-1,2-diamine. Solid zinc (4.55 g, 69.5 mmol) and ammonium chloride (3.72 g, 69.5 mmol) were added sequentially to a solution of 2,6-dibenzyloxy-N-(4-bromo-2-nitro-phenyl)pyridin-3-amine (8.8 g, 17.4 mmol) cooled to 0°C in tetrahydrofuran (52 mL) and water (17 mL). The reaction mixture was stirred at room temperature for 16 hours. The mixture was filtered through a Celite filter and washed with dichloromethane (2 x 50 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using a gradient elution of 0–15% methanol in dichloromethane to give the title compound (6.5 g, 79%) as a solid. MS (ESI) [M+H) + 476.1.

[0491] Step i-19.3: Synthesis of 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1H-benzimidazole-2-one. 1,1'-carbonyldiimidazole (4.43 g, 27.3 mmol) was added to a solution of 4-bromo-N1-(2,6-dibenzyloxy-3-pyridyl)benzene-1,2-diamine (6.5 g, 13.6 mmol) in tetrahydrofuran (136 mL), and the reaction mixture was stirred at 80°C 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 elution of 0-15% methanol in dichloromethane to give the title compound (4.2 g, 61%) as a solid. MS (ESI) [M+H] + 504.0.

[0492] Step i-19.4: Synthesis of 5-bromo-1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-benzimidazol-2-one. Sodium hydride (300 mg, 12.54 mmol) and methyl iodoforme (0.78 mL, 12.54 mmol) dispersed in mineral oil were added sequentially to a solution of 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1H-benzimidazol-2-one (4.2 g, 8.36 mmol) in tetrahydrofuran (47 mL). The reaction mixture was stirred at 0°C for 15 min, then at room temperature for 48 h. The volatiles were evaporated under reduced pressure, and the residue was purified by silica gel column chromatography using a gradient elution of ethyl acetate from 0-60% in hexane to give the title compound (3.4 g, 79%) as a solid. MS (ESI) [M+H] + 516.1.

[0493] Synthesis of intermediate i-20: 3-[5-(bromomethyl)-1-oxo-isodihydroindol-2-yl]piperidine-2,6-dione

[0494]

[0495] Step i-20.1: Synthesis of 3-[5-(hydroxymethyl)-1-oxo-isodihydroindol-2-yl]piperidine-2,6-dione. Tributyltinyl methanol (108 g, 338 mmol) and palladium-tetra(triphenylphosphine) (15 g, 13 mmol) were added to a degassed solution of 3-(5-bromo-1-oxo-isodihydroindol-2-yl)piperidine-2,6-dione (84 g, 260 mmol) in dry dioxane (1.8 L) at 20°C. After addition, the reaction mixture was stirred at 100°C for 16 hours. TLC showed that the starting material was completely consumed. The reaction mixture was filtered through a celite pad, and the filtrate was concentrated. The residue was washed with ethyl acetate (500 mL) to give 3-[5-(hydroxymethyl)-1-oxo-isodihydroindol-2-yl]piperidine-2,6-dione (50 g, 70.1% yield) as a creamy white solid. 1 H NMR (400 MHz CDCl3) δ: 10.98 (s, 1H), 7.67 (d, J =8.0 Hz, 1H), 7.55 (s, 1H), 7.45 (d, J = 8.0 Hz, 1H), 5.39 (t, J = 7.6 Hz,1H), 5.11 (dd, J = 4.8, 13.2 Hz, 1H), 4.62 (d, J = 6.0 Hz, 2H), 4.38 (dd, J =17.2, 53.6 Hz, 2H), 2.93-2.88 (m, 1H), 2.62-2.58 (m, 1H), 2.41-2.38 (m, 1H),2.02-1.99 (m, 1H)

[0496] Step i-20.2: Synthesis of 3-[5-(bromomethyl)-1-oxo-isodihydroindol-2-yl]piperidine-2,6-dione. Thionyl bromide (49.0 g, 236 mmol, 18.3 mL) was added dropwise to a mixture of 3-[5-(hydroxymethyl)-1-oxo-isodihydroindol-2-yl]piperidine-2,6-dione (38.0 g, 138 mmol) in anhydrous dichloromethane (160 mL) at 0°C under N2. The mixture was stirred at 30°C for 16 hours. The combined organic layers were washed with dichloromethane (250 mL), filtered, and the filter cake was washed with methanol (150 mL) and dried to give 3-[5-(bromomethyl)-1-oxo-isodihydroindol-2-yl]piperidine-2,6-dione (37.0 g, 79.2% yield) as a gray solid. 1H NMR (400 MHz, DMSO-d6) δ 11.01 (s,1H),7.73 (t, J = 8.0 Hz, 2H), 7.61 (d, J = 7.6 Hz, 1H), 5.15-5.11 (m, 1H), 4.84(s, 2H), 4.51 (d, J = 17.6 Hz, 1H), 4.37 (d, J = 9.2 Hz, 1H), 2.97-2.88 (m,1H), 2.64-2.39 (m, 2H), 2.05-2.01 (m, 1H).

[0497] Synthesis of intermediate i-21: [1-[2-(2,6-dioxo-3-piperidinyl)-1-oxo-isodihydroindol-5-yl]-4-piperidinyl]-methyl-ammonium; benzenesulfonate.

[0498]

[0499] Step i-21.1: Synthesis of tert-butyl (4S)-5-amino-4-[5-[4-[tert-butoxycarbonyl(methyl)amino]-1-piperidinyl]-1-oxo-isodihydroindol-2-yl]-5-oxo-valerate. To a solution of tert-butyl (4S)-5-amino-4-(5-bromo-1-oxo-isodihydroindol-2-yl)-5-oxo-valerate (100.0 mg, 252.0 µmol) in N,N-dimethylformamide (2.0 mL), N-methyl-N-(4-piperidinyl)carbamate tert-butyl ester (162.0 mg, 755.0 µmol), cesium carbonate (164.0 mg, 503.0 µmol), and XPhos Pd G3 (22.4 mg, 25.1 µmol) were added sequentially, and the reaction vessel was sealed. The reaction mixture was heated to 100°C for 1 hour under microwave irradiation, and then cooled to room temperature. The volatiles were evaporated under reduced pressure. 1.0 N HCl (1.5 mL) and dichloromethane (50.0 mL) were added, and the layers were separated. The aqueous layer was extracted with dichloromethane (2 x 25.0 mL), and the combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The substance was purified by reversed-phase chromatography (C18) using a gradient elution of 0-80% acetonitrile and water (containing 0.1% formic acid) to give the title compound (15.0 mg, 10%) as a solid. MS (ESI) [M+H] + 531.4; 1H NMR (400 MHz, DMSO) δ 7.48(d, J = 8.5 Hz, 2H), 7.17 - 6.98 (m, 3H), 4.67 (dd, J = 10.3, 4.3 Hz, 1H), 4.40 (AB q, J = 17.3 Hz, 2H), 3.97 -3.93 (m, 2H), 2.94 - 2.80 (m, 2H), 2.66(s, 3H), 2.19 - 2.03 (m, 3H), 2.05 - 1.85 (m, 2H), 1.82 - 1.66 (m, 2H), 1.67- 1.56 (m, 2H), 1.40 (s, 9H), 1.33 (s, 9H).

[0500] Step i-21.2: Synthesis of [1-[2-(2,6-dioxo-3-piperidinyl)-1-oxo-isodihydroindol-5-yl]-4-piperidinyl]-methyl-ammonium; benzenesulfonate. Benzenesulfonic acid (18.0 mg, 113.0 µmol) was added to a solution of tert-butyl 5-amino-4-[5-[4-[tert-butoxycarbonyl(methyl)amino]-1-piperidinyl]-1-oxo-isodihydroindol-2-yl]-5-oxo-valerate (40.0 mg, 75.4 µmol) in acetonitrile (3.0 mL) at room temperature. The reaction mixture was heated to 75°C for 18 hours and then cooled to room temperature. Volatile substances were removed under reduced pressure. The substance was purified by reversed-phase chromatography (C18) using a gradient elution of 0-80% acetonitrile and water (containing 0.1% formic acid) to give the title compound (22.0 mg, 57%) as a solid. MS (ESI) [M+H] + 357.2

[0501] Synthesis of intermediate i-22: 2-[[6-[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]-1-methyl-2-oxo-3-quinolinyl]oxy]-N-methylacetamide

[0502]

[0503] Step i-22.1. Synthesis of 2-(methylamino)-5-nitro-benzaldehyde. A solution of methylamine (3.0 mL, 5.91 mmol, 2 M, in tetrahydrofuran) was added to a solution of 2-fluoro-5-nitro-benzaldehyde (1.0 g, 5.91 mmol) in dimethyl sulfoxide (18 mL) at 0°C under a nitrogen atmosphere. The mixture was stirred at room temperature for 4 hours and then diluted with water (5 mL). The aqueous phase was extracted with ethyl acetate (2 x 50 mL), and the combined organic phases were washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The substance was purified by silica gel column chromatography (40 g column) using a gradient elution of 0–20% ethyl acetate in hexane to give the title compound (0.80 g, 75%) as a pale yellow solid. MS (ESI) [M+H] + 181.1. 1 H NMR (500 MHz, CDCl3) δ 9.87 (d, J = 0.6 Hz, 1H), 9.01 (s, 1H), 8.47 (d, J = 2.7 Hz, 1H), 8.27 (ddd, J = 9.4, 2.7, 0.7 Hz, 1H), 6.72 (d, J = 9.4Hz, 1H), 3.06 (d, J = 5.2 Hz, 3H).

[0504] Step i-22.2. Synthesis of 2-[(1-methyl-6-nitro-2-oxo-3-quinolinyl)oxy]acetic acid. Sodium hydride (222 mg, 5.55 mmol) was added to a solution of 2-(methylamino)-5-nitrobenzaldehyde (400 mg, 2.22 mmol) in anhydrous N,N-dimethylformamide (7.00 mL) at room temperature. The deep red reaction mixture was stirred for 30 min, followed by the addition of 1,4-dioxane-2,6-dione (515 mg, 4.44 mmol), and the mixture was stirred at 110°C for 18 h. The mixture was diluted with dichloromethane (25 mL), and the resulting solid (sodium salt of the product) was filtered, washed with dichloromethane (2 x 15 mL), and dried under reduced pressure. The solid (sodium salt) was dissolved in water (50 mL), and the aqueous layer was acidified to pH 2 with 1 N HCl. The obtained solid was filtered and dried under reduced pressure to give the title compound (186 mg, 30%) as a dark brown solid. MS (ESI) [M+H]+ 280.1.

[0505] Step i-22.3. Synthesis of N-methyl-2-[(1-methyl-6-nitro-2-oxo-3-quinolinyl)oxy]acetamide. Hydroxybenzotriazole (135 mg, 0.997 mmol) and 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride (192 mg, 0.997 mmol) were added sequentially to a solution of 2-[(1-methyl-6-nitro-2-oxo-3-quinolinyl)oxy]acetic acid (185 mg, 0.665 mmol) in N,N-dimethylformamide (9 mL) under a nitrogen atmosphere at 0°C. The reaction mixture was stirred at 0°C for 15 min, followed by the slow sequential addition of methylamine hydrochloride (49 mg, 0.73 mmol) and diisopropylethylamine (0.46 mL, 2.66 mmol). The reaction mixture was then cooled to room temperature and stirred for 18 h. The mixture was diluted with an aqueous solution of ammonium chloride (2.0 mL), and the aqueous phase was extracted with dichloromethane (3 x 10 mL). The combined organic layers were washed with brine (3.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The substance was purified by silica gel rapid chromatography (4 g column) using a gradient elution of 0-10% methanol in dichloromethane solution to give the title compound (145 mg, 76%) as a brown solid. MS (ESI) [M+H]+ 291.2; 1 H NMR (500 MHz, DMSO) δ 8.61 (d, J = 2.6 Hz, 1H), 8.27 (dd, J = 9.3, 2.7 Hz, 1H), 8.01 (s, 1H), 7.70 (d, J = 9.3 Hz, 1H), 7.54 (s, 1H), 4.60 (s, 2H), 3.73 (s, 3H), 2.66 (d, J = 4.6 Hz, 3H).

[0506] Step i-22.4. Synthesis of 2-[(6-amino-1-methyl-2-oxo-3-quinolinyl)oxy]-N-methylacetamide. N-methyl-2-[(1-methyl-6-nitro-2-oxo-3-quinolinyl)oxy]acetamide (50.0 mg, 0.172 mmol) was suspended in a mixture of ethanol (6.00 mL) and water (3.00 mL), and ammonium chloride (55.1 mg, 1.03 mmol) and iron powder (28.8 mg, 0.52 mmol) were added sequentially to the suspension at room temperature. The reaction mixture was heated to reflux for 2 hours and then cooled to room temperature. The mixture was filtered through a Celite filter, the filter cake was washed with methanol (2 x 5 mL), and the filtrate was concentrated under reduced pressure. The substance was purified by silica gel rapid chromatography (4 g column) using a gradient elution of 0-10% methanol in dichloromethane solution to give the title compound (26 mg, 58%) as a white solid. MS (ESI) [M+H]+ 262.2; 1 H NMR (500 MHz, DMSO) δ 7.92 (s, 1H). 7.20 (d, J = 8.9 Hz, 1H), 7.05 (s, 1H), 6.80 (dd, J = 8.9, 2,5 Hz, 1H), 6,70 (d, J = 2.5 Hz, 1H), 5.05 (s, 2H), 4.51 (s,2H), 3.58 (s, 3H), 2.66 (d, J= 4.7 Hz, 3H).

[0507] Step i-22.5. Synthesis of 2-[[6-[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]-1-methyl-2-oxo-3-quinolinyl]oxy]-N-methyl-acetamide. At -40°C, 5-chloro-2,4-difluoro-pyrimidin (431.0 µL, 4.48 mmol) and diisopropylethylamine (2.55 mL, 14.9 mmol) were added sequentially to a solution of 2-[(6-amino-1-methyl-2-oxo-3-quinolinyl)oxy]-N-methyl-acetamide (1.40 g, 3.73 mmol) in a mixture of tetrahydrofuran / N,N-dimethylformamide (7:1, 40.0 mL). The reaction mixture was slowly warmed to room temperature and stirred for 16 hours. The resulting precipitate was collected by filtration and then dissolved in dimethyl sulfoxide (30.0 mL). Water was slowly added, and the precipitate was collected by filtration, washed with methanol (40.0 mL) and diethyl ether (40.0 mL), and then dried under vacuum to give the title compound (950.0 mg, 65%) as a solid. MS (ESI) [M+H]+ 392.1; 1H NMR (500 MHz, DMSO) δ 9.71 (s, 1H), 8.39 (s,1H), 7.93 (bs, 1H), 7.79 (d, J = 2.1 Hz, 1H), 7.65 (dd, J = 9.0, 2.2 Hz, 1H), 7.53 (d, J = 9.1 Hz, 1H), 7.25 (s, 1H), 4.58 (s, 2H), 3.69 (s, 3H), 2.67 (d,J = 4.6 Hz, 3H).

[0508] Synthesis of intermediate i-23: 2-((6-((2-chloro-5-cyanopyrimidin-4-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N-methylacetamide

[0509]

[0510] Step i-23.1: Synthesis of 2-[(6-bromo-1-methyl-2-oxo-3-quinolinyl)oxy]-N-methylacetamide. To a solution of 6-bromo-3-hydroxy-1-methylquinolin-2-one (10 g, 39.36 mmol) in N,N-dimethylformamide (200 mL), 2-bromo-N-methylacetamide (11.96 g, 78.72 mmol) and cesium carbonate (19.24 g, 59.04 mmol) were added sequentially, and the reaction mixture was stirred at room temperature for 24 hours. Water (100 mL) was added, and the precipitate was collected by filtration, washed with water (3 x 20 mL), and then dried under vacuum to give the title compound (11.0 g, 84%) as a solid. MS (ESI) [M+H]+ 325.1.

[0511] Step i-23.2: Synthesis of N-[1-methyl-3-[2-(methylamino)-2-oxo-ethoxy]-2-oxo-6-quinolinyl] tert-butyl carbamate. A mixture of 2-[(6-bromo-1-methyl-2-oxo-3-quinolinyl)oxy]-N-methylacetamide (2.16 g, 6.64 mmol), tert-butyl carbamate (1.17 g, 9.96 mmol), XPhos Pd G3 (1.41 g, 1.66 mmol), and cesium carbonate (2.60 g, 7.97 mmol) in 1,4-dioxane (5 mL) was heated to 100°C for 16 hours and then cooled to room temperature. The mixture was filtered through a Celite filter and washed with ethyl acetate (2 x 25 mL) and dichloromethane (2 x 25 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by reversed-phase chromatography (C18) using a gradient elution of 5-50% acetonitrile and 10 mM ammonium formate in aqueous solution to give the title compound (200 mg, 8%) as a solid. MS (ESI) [M+H]+ 362.2; 1 H NMR (400 MHz, DMSO-d6) δ 9.45 (s, 1H), 8.01 (d, J = 4.3 Hz,1H), 7.79 (s, 1H), 7.46 (dd, J = 9.1, 2.4 Hz, 1H), 7.40 (d, J = 9.2 Hz, 1H), 7.21 (s, 1H), 4.55 (s, 2H), 3.63 (s, 3H), 2.66 (d, J = 4.7 Hz, 3H), 1.50 (s, 9H).

[0512] Step i-23.3: Synthesis of 2-[(6-amino-1-methyl-2-oxo-3-quinolinyl)oxy]-N-methyl-acetamide 2,2,2-trifluoroacetic acid. Trifluoroacetic acid (1 mL, 13.07 mmol) was added to a solution of N-[1-methyl-3-[2-(methylamino)-2-oxo-ethoxy]-2-oxo-6-quinolinyl]carbamate tert-butyl ester (0.2 g, 0.55 mmol) in dichloromethane (5 mL), and the reaction mixture was stirred at room temperature for 4 hours. The volatiles were evaporated under reduced pressure. Diethyl ether (10 mL) was added, and the resulting precipitate was collected by filtration, washed with diethyl ether (10 mL), and then dried under vacuum to give the title compound (0.21 g, 99%) as a solid, which was used in the next step without further purification. MS (ESI) [M+H]+262.1.

[0513] Step i-23.4: Synthesis of 2-[[6-[(2-chloro-5-cyanopyrimidin-4-yl)amino]-1-methyl-2-oxo-3-quinolinyl]oxy]-N-methylacetamide. To a solution of 2-[(6-amino-1-methyl-2-oxo-3-quinolinyl)oxy]-N-methylacetamide (260 mg, 0.69 mmol) cooled to -40°C in tetrahydrofuran (2.5 mL) and N,N-dimethylformamide (0.5 mL), 2,4-dichloropyrimidin-5-carboxynitrile (133 mg, 0.76 mmol) and diisopropylethylamine (300 µL, 1.73 mmol) were added sequentially. The mixture was stirred at -40°C for 1 hour and then at room temperature for 16 hours. The precipitate was collected by filtration, washed with tetrahydrofuran (2 x 10 mL), and then dried under vacuum to give the title compound (190 mg, 69%) as a solid, which was used in the next step without further purification. MS (ESI) [M+H]+ 399.1.

[0514] Synthesis of intermediate i-24: 2-[[6-[(2,5-dichloropyrimidin-4-yl)amino]-1-methyl-2-oxo-3-quinolinyl]oxy]-N-methylacetamide

[0515]

[0516] Step i-24.1. Synthesis of 2-(methylamino)-5-nitro-benzaldehyde. A solution of methylamine (3.0 mL, 5.91 mmol, 2 M, in tetrahydrofuran) was added to a solution of 2-fluoro-5-nitro-benzaldehyde (1.0 g, 5.91 mmol) in dimethyl sulfoxide (18 mL) at 0°C under a nitrogen atmosphere. The mixture was stirred at room temperature for 4 hours and then diluted with water (5 mL). The aqueous phase was extracted with ethyl acetate (2 x 50 mL), the combined organic phases were washed with brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The substance was purified by silica gel column chromatography (40 g column) using a gradient elution of 0-20% ethyl acetate in hexane to give the title compound (0.80 g, 75%) as a pale yellow solid. MS (ESI) [M+H]+ [M+H]+ 181.1; 1H NMR (500 MHz, CDCl3) δ 9.87 (d, J = 0.6 Hz, 1H), 9.01 (s, 1H), 8.47 (d, J = 2.7 Hz, 1H), 8.27 (ddd, J = 9.4, 2.7, 0.7 Hz, 1H), 6.72 (d, J =9.4 Hz, 1H), 3.06 (d, J = 5.2 Hz, 3H).

[0517] Step i-24.2. Synthesis of 2-[(1-methyl-6-nitro-2-oxo-3-quinolinyl)oxy]acetic acid. Sodium hydride (222 mg, 5.55 mmol) was added to a solution of 2-(methylamino)-5-nitrobenzaldehyde (400 mg, 2.22 mmol) in anhydrous N,N-dimethylformamide (7.00 mL) at room temperature. The deep red reaction mixture was stirred for 30 min, followed by the addition of 1,4-dioxane-2,6-dione (515 mg, 4.44 mmol), and the reaction mixture was stirred at 110°C for 18 h. The mixture was diluted with dichloromethane (25 mL), and the resulting solid (sodium salt of the product) was filtered, washed with dichloromethane (2 x 15 mL), and dried under reduced pressure. The solid (sodium salt) was dissolved in water (50 mL), and the aqueous layer was acidified to pH 2 with 1 N HCl. The obtained solid was filtered and dried under reduced pressure to give the title compound (186 mg, 30%) as a dark brown solid. MS (ESI) [M+H]+ 280.1.

[0518] Step i-24.3. Synthesis of N-methyl-2-[(1-methyl-6-nitro-2-oxo-3-quinolinyl)oxy]acetamide. Hydroxybenzotriazole (135 mg, 0.997 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (192 mg, 0.997 mmol) were added sequentially to a solution of 2-[(1-methyl-6-nitro-2-oxo-3-quinolinyl)oxy]acetic acid (185 mg, 0.665 mmol) in N,N-dimethylformamide (9 mL) under a nitrogen atmosphere at 0°C. The reaction mixture was stirred at 0°C for 15 min, followed by the slow sequential addition of methylamine hydrochloride (49 mg, 0.73 mmol) and N,N-diisopropylethylamine (0.46 mL, 2.66 mmol). The reaction mixture was then cooled to room temperature and stirred for 18 h. The mixture was diluted with an aqueous solution of ammonium chloride (2.0 mL), and the aqueous phase was extracted with dichloromethane (3 x 10 mL). The combined organic layers were washed with brine (3.0 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The substance was purified by silica gel rapid chromatography (4 g column) using a gradient elution of 0-10% methanol in dichloromethane solution to give the title compound (145 mg, 76%) as a brown solid. MS (ESI) [M+H]+ 291.2; 1 H NMR (500 MHz, DMSO) δ 8.61 (d, J = 2.6Hz, 1H), 8.27 (dd, J = 9.3, 2.7 Hz, 1H), 8.01 (s, 1H), 7.70 (d, J = 9.3 Hz,1H), 7.54 (s, 1H), 4.60 (s, 2H), 3.73 (s, 3H), 2.66 (d, J = 4.6 Hz, 3H).

[0519] Step i-24.4. Synthesis of 2-[(6-amino-1-methyl-2-oxo-3-quinolinyl)oxy]-N-methylacetamide. N-methyl-2-[(1-methyl-6-nitro-2-oxo-3-quinolinyl)oxy]acetamide (50.0 mg, 0.172 mmol) was suspended in a mixture of ethanol (6.00 mL) and water (3.00 mL), and ammonium chloride (55.1 mg, 1.03 mmol) and iron powder (28.8 mg, 0.52 mmol) were added sequentially to the suspension at room temperature. The reaction mixture was heated to reflux for 2 hours and then cooled to room temperature. The mixture was filtered through a Celite filter, the filter cake was washed with methanol (2 x 5 mL), and the filtrate was concentrated under reduced pressure. The substance was purified by silica gel rapid chromatography (4 g column) using a gradient elution of 0-10% methanol in dichloromethane solution to give the title compound (26 mg, 58%) as a white solid. MS (ESI) [M+H]+ 262.2; 1 H NMR (500MHz, DMSO) δ 7.92 (s, 1H). 7.20 (d, J = 8.9 Hz, 1H), 7.05 (s, 1H), 6.80 (dd, J= 8.9, 2,5 Hz, 1H), 6,70 (d, J = 2.5 Hz, 1H), 5.05 (s, 2H), 4.51 (s, 2H), 3.58 (s, 3H), 2.66 (d, J= 4.7 Hz, 3H).

[0520] Step i-24.5. Synthesis of 2-[[6-[(2,5-dichloropyrimidin-4-yl)amino]-1-methyl-2-oxo-3-quinolinyl]oxy]-N-methylacetamide. Under a nitrogen atmosphere at room temperature, 2,4,5-trichloropyrimidine (9.0 μL, 0.08 mmol) and sodium bicarbonate (23.3 mg, 0.22 mmol) were added sequentially to a solution of 2-[(6-amino-1-methyl-2-oxo-3-quinolinyl)oxy]-N-methylacetamide (23.0 mg, 0.09 mmol) in a mixture of ethanol and dichloromethane (1:1, 4.00 mL). The reaction mixture was stirred at room temperature for 18 hours, and then the solvent was evaporated under reduced pressure. The substance was purified by rapid silica gel chromatography (4 g column) using a gradient elution of 0-10% methanol in dichloromethane solution to give the title compound (29 mg, 80%) as a white solid. MS (ESI) [M+H]+ 408.0; 1H NMR (500 MHz, DMSO) δ 9.65 (s,1H), 8.37 (s, 1H), 7.93 (s, 1H), 7.74 (s, 1H), 7.66 (d, J = 9.0 Hz, 1H), 7.53(d, J = 9.1 Hz, 1H), 7.23 (s, 1H), 4.58 (s, 2H), 3.69 (s, 3H), 2.67 (d, J =3.8 Hz, 3H).

[0521] Synthesis of intermediate i-25: 2-((6-((5-chloro-2-fluoropyrimidin-4-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)oxy)-N,N-dimethylacetamide.

[0522]

[0523] Step i-25.1. Synthesis of 1-methyl-5-nitro-dihydroindole-2,3-dione. Sodium hydride (60% dispersed in mineral oil, 6.87 g, 172 mmol) was added dropwise to a solution of 5-bromodihydroindole-2,3-dione (30.0 g, 156.0 mmol) in N,N-dimethylformamide (250.0 mL), and the mixture was stirred for 15 min. Iodomethane (11.7 mL, 187.0 mmol) was added dropwise, and the reaction mixture was stirred at 0°C for 30 min. Water (400.0 mL) was added, and the resulting precipitate was collected by filtration, washed with water and diethyl ether, and dried under vacuum to give the title compound (27.8 g, 86%) as a solid, which was used in the next step without further purification. 1 H NMR (400 MHz) δ 8.55 (dd, J = 8.8,2.4 Hz, 1H), 8.23 ​​(d, J = 2.3 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H), 3.22 (s,3H).

[0524] Step i-25.2. Synthesis of ethyl 3-hydroxy-1-methyl-6-nitro-2-oxo-quinoline-4-carboxylate. Ethyl diazonate (15.0%, in toluene, 14.8 mL, 17.5 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.33 mL, 2.18 mmol) were added sequentially to a suspension of 1-methyl-5-nitro-dihydroindole-2,3-dione (3.0 g, 14.6 mmol) in ethanol (50.0 mL). The mixture was stirred at room temperature for 3 hours, followed by the addition of rhodium(II) acetate (106.0 mg, 240.0 µmol). The reaction mixture was then stirred at room temperature for another 3 hours. The precipitate was collected by filtration, washed with water (3 x 25.0 mL) and diethyl ether (2 x 25.0 mL), and dried under vacuum to give the title compound (2.97 g, 70%) as a solid, which was used in the next step without further purification. 1 H NMR (400 MHz) δ 10.92 (s,1H), 8.31 (d, J = 2.6 Hz, 1H), 8.26 (dd, J = 9.3, 2.6 Hz, 1H), 7.75 (d, J =9.3 Hz, 1H), 4.45 (q, J = 7.1 Hz, 2H), 3.77 (s, 3H), 1.35 (t, J = 7.1 Hz, 3H).

[0525] Step i-25.3. Synthesis of 3-hydroxy-1-methyl-6-nitro-quinoline-2-one. Lithium hydroxide (5.13 g, 122.0 mmol) was added to a suspension of ethyl 8-bromo-3-hydroxy-1-methyl-6-nitro-2-oxo-quinoline-4-carboxylate (11.9 g, 40.7 mmol) in a mixture of tetrahydrofuran and water (3:1, 585.0 mL). The reaction mixture was heated to 80°C for 16 hours and then cooled to room temperature. The volatiles were evaporated under reduced pressure, and the pH was adjusted to 2 using a 2N HCl aqueous solution (65.0 mL). The solution was heated to 100°C for 16 hours and then cooled to room temperature. The precipitate was collected by filtration, washed with water (50.0 mL) and diethyl ether (50.0 mL), and dried under vacuum to give the title compound (6.82 g, 72%) as a solid, which was used in the next step without further purification. MS (ESI) [M+H]+ 221.2; 1H NMR (400 MHz)δ 10.06 (s, 1H), 8.54 (d, J = 2.7 Hz, 1H), 8.19 (dd, J = 9.3, 2.7 Hz, 1H), 7.65 (d, J = 9.3 Hz, 1H), 7.33 (s, 1H), 3.74 (s, 3H).

[0526] Step i-25.4. Synthesis of N,N-dimethyl-2-[(1-methyl-6-nitro-2-oxo-3-quinolinyl)oxy]acetamide. Cesium carbonate (3.33 g, 10.2 mmol), potassium iodide (283.0 mg, 1.70 mmol), and 2-chloro-N,N-dimethylacetamide (0.42 mL, 4.09 mmol) were added sequentially to a solution of 3-hydroxy-1-methyl-6-nitro-quinolin-2-one (750.0 mg, 3.41 mmol) in N,N-dimethylformamide (15.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. Water was added, and the precipitate was collected by filtration, washed with water (3 x 30.0 mL) and ethyl acetate (30.0 mL), and then dried under vacuum to give the title compound (1.02 g, 98%) as a solid. 1 H NMR (400 MHz, DMSO)δ 8.57 (d, J = 2.7 Hz, 1H), 8.25 (dd, J = 9.3, 2.7 Hz, 1H), 7.67 (d, J = 9.3Hz, 1H), 7.43 (s, 1H), 4.93 (s, 2H), 3.72 (s, 3H), 3.03 (s, 3H).

[0527] Step i-25.5. Synthesis of 2-[(6-amino-1-methyl-2-oxo-3-quinolinyl)oxy]-N,N-dimethylacetamide. A mixture of N,N-dimethyl-2-[(1-methyl-6-nitro-2-oxo-3-quinolinyl)oxy]acetamide (650.0 mg, 2.13 mmol) and 10% palladium / carbon (227.0 mg, 0.21 mmol) in N,N-dimethylformamide (50.0 mL) was hydrogenated at room temperature for 18 hours under a hydrogen atmosphere. The mixture was filtered through a Celite filter and washed with methanol (10.0 mL). The filtrate was concentrated under reduced pressure to give the title compound (464.0 mg, 79%) as a solid, which was used in the next step without further purification. MS (ESI) [M+H]+ 276.2.

[0528] Step i-25.6. Synthesis of 2-[[6-[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]-1-methyl-2-oxo-3-quinolinyl]oxy]-N,N-dimethyl-acetamide. Diisopropylethylamine (317.0 µL, 1.85 mmol) and 5-chloro-2,4-difluoro-pyrimidinium (279.0 mg, 1.85 mmol) were added sequentially to a solution of 2-[(6-amino-1-methyl-2-oxo-3-quinolinyl)oxy]-N,N-dimethyl-acetamide (464.0 mg, 1.69 mmol) in a mixture of tetrahydrofuran (10.0 mL) and N,N-dimethylformamide (5.0 mL). The reaction mixture was slowly warmed to room temperature and stirred for 16 hours. The volatiles were evaporated under reduced pressure. Water was added, and the precipitate was collected by filtration. The precipitate was washed with water (3 x 30.0 mL) and ethyl acetate (30.0 mL), and then dried under vacuum to give the title compound (395.0 mg, 58%) as a solid. MS (ESI) [M+H]+406.2. 1 H NMR (400 MHz, DMSO) δ 9.69 (s, 1H), 8.38 (d, J = 1.3 Hz, 1H), 7.77 (d, J = 2.3 Hz, 1H), 7.62 (dd, J = 9.0, 2.4 Hz, 1H), 7.51 (d, J = 9.1 Hz,1H), 7.16 (s, 1H), 4.91 (s, 2H), 3.68 (s, 3H), 3.02 (s, 3H), 2.86 (s, 3H).

[0529] Synthesis of intermediate i-26: 1-(5-chloro-4-((1-methyl-3-(2-(methylamino)-2-oxoethoxy)-2-oxo-1,2-dihydroquinolin-6-yl)amino)pyrimidin-2-yl)piperidin-4-carboxylic acid

[0530]

[0531] Step i-26.1. Synthesis of 1-(5-chloro-4-((1-methyl-3-(2-(methylamino)-2-oxoethoxy)-2-oxo-1,2-dihydroquinolin-6-yl)amino)pyrimidin-2-yl)piperidine-4-carboxylic acid. Isopiperidine acid (643.0 mg, 4.98 mmol) and diisopropylethylamine (1.44 mL, 8.30 mmol) were added sequentially to a solution of 2-[[6-[(2,5-dichloropyrimidin-4-yl)amino]-1-methyl-2-oxo-3-quinolinyl]oxy]-N-methylacetamide (1.30 g, 3.32 mmol, intermediate 24) in dimethyl sulfoxide (40.0 mL). The reaction mixture was heated to 100°C for 3 hours and then cooled to room temperature. The solvent was removed by vacuum distillation. Water was added, and the precipitate was collected by filtration, washed with methanol, and dried under vacuum to give the title compound (1.24 g, 75%) as a solid. MS (ESI) ⇌ [M+H]+ 50 1.2. 1 H NMR (500 MHz, DMSO) δ12.15 (s, 1H), 8.83 (s, 1H), 8.04 (s, 1H), 7.95 (d, J = 4.7 Hz, 1H), 7.90 (d,J = 2.4 Hz, 1H), 7.75 (dd, J = 9.1, 2.5 Hz, 1H), 7.48 (d, J = 9.1 Hz, 1H), 7.12 (s, 1H), 4.57 (s, 2H), 4.40 - 4.28 (m, 2H), 3.67 (s, 3H), 3.00 (ddd, J =13.6, 11.4, 2.9 Hz, 2H), 2.66 (d, J = 4.6 Hz, 3H), 2.51 - 2.56 (m, 1H, partially masked by DMSO peak), 1.84 (dd, J = 13.3, 3.8 Hz, 2H), 1.40 - 1.52 (m, 2H).

[0532] Synthesis of intermediate i-27: 4-[benzyl(methyl)amino]piperidin-2-one.

[0533]

[0534] Step i-27.1: Synthesis of 4-[benzyl(methyl)amino]piperidin-2-one. N-methyl-1-phenyl-methylamine (1.1 mL, 8.8 mmol) and acetic acid (0.5 mL, 8.8 mmol) were added sequentially to a solution of piperidin-2,4-dione (1.0 g, 8.8 mmol) in 1,2-dichloroethane (25 mL), and the mixture was stirred at room temperature for 2 hours. Sodium cyanoborohydride (833 mg, 13.3 mmol) was added to the reaction mixture, and stirring continued for 36 hours. A saturated aqueous solution of sodium bicarbonate (100 mL) and dichloromethane (100 mL) were added, and the layers were separated. The organic layer was washed with water (100 mL) and brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient elution of ethyl acetate from 0-100% in hexane to give the title compound (790 mg, 41%) as a semi-solid. MS (ESI) [M+H]+ 219.2. 1 H NMR(400 MHz, DMSO-d6) δ 7.45 (br s, 1H), 7.35 - 7.28 (m, 4H), 7.27 - 7.19 (m,1H), 3.54 (q, J = 13.5 Hz, 2H), 3.22 - 3.16 (m, 1H), 3.08 - 2.99 (m, 1H),2.89 - 2.80 (m, 1H), 2.31 - 2.20 (m, 2H), 2.09 (s, 3H), 1.97 - 1.87 (m, 1H),1.68- 1.54 (m, 1H).

[0535] The examples in the table below were prepared using their respective commercially available starting materials and intermediates described herein, according to the general procedures outlined in the table.

[0536]

[0537]

[0538]

[0539]

[0540]

[0541]

[0542]

[0543]

[0544]

[0545]

[0546]

[0547]

[0548]

[0549]

[0550]

[0551]

[0552]

[0553]

[0554]

[0555]

[0556]

[0557] Example 62. Synthesis of 2-((6-((5-chloro-2-((2-(4-((3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)amino)piperidin-1-yl)-2-oxoethyl)amino)pyrimidin-4-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinoline-3-yl)oxy)-N-methylacetamide

[0558]

[0559] Step 62.1: Synthesis of tert-butyl N-[2-[4-[[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-6-yl]amino]-1-piperidinyl]-2-oxo-ethyl]carbamate. Hydroxybenzotriazole (32.2 mg, 0.24 mmol), 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride (45.7 mg, 0.24 mmol), 3-[1-methyl-6-(4-piperidinylamino)indazole-3-yl]piperidin-2,6-dione hydrochloride (60.0 mg, 0.16 mmol), and N,N-diisopropylethylamine (0.11 mL, 0.64 mmol) were added sequentially to a solution of 2-(tert-butoxycarbonylamino)acetic acid (33.4 mg, 0.19 mmol) in N,N-dimethylformamide (2 mL). The reaction mixture was stirred at room temperature for 12 hours. Water (2 mL) and ethyl acetate (75 mL) were added, and the layers were separated. The organic layer was washed with brine (3 x 5 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient elution of ethyl acetate from 0-100% in hexane to give the title compound (57 mg, 72%) as a solid. MS (ESI) [M-Boc+H]+ 399.2.

[0560] Step 62.2: Synthesis of 3-[6-[[1-(2-aminoacetyl)-4-piperidinyl]amino]-1-methyl-indazole-3-yl]piperidine-2,6-dione hydrochloride. At room temperature, 4N in dioxane and HCl (0.14 mL, 0.55 mmol) were added to a solution of N-[2-[4-[[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-6-yl]amino]-1-piperidinyl]-2-oxo-ethyl]carbamate (55.0 mg, 0.11 mmol) in 1,4-dioxane (2 mL), and the reaction mixture was stirred for 18 hours. The volatiles were removed under vacuum, and the residue was ground with diethyl ether (4 mL), filtered, and dried under vacuum to give the title compound (42 mg) as a solid, which was used in the next step without further purification.

[0561] Step 62.3: Synthesis of 2-[[6-[[5-chloro-2-[[2-[4-[[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazol-6-yl]amino]-1-piperidinyl]-2-oxo-ethyl]amino]pyrimidin-4-yl]amino]-1-methyl-2-oxo-3-quinolinyl]oxy]-N-methyl-acetamide. To a solution of crude 3-[6-[[1-(2-aminoacetyl)-4-piperidinyl]amino]-1-methyl-indazol-3-yl]piperidin-2,6-dione hydrochloride (42 mg, 0.11 mmol) in dimethyl sulfoxide (0.60 mL), 2-[[6-[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]-1-methyl-2-oxo-3-quinolinyl]oxy]-N-methylacetamide (30.3 mg, 80.0 µmol, intermediate 22) and N,N-diisopropylethylamine (80.0 µL, 0.44 mmol) were added sequentially. The reaction mixture was heated to 100°C for 12 hours and then cooled to room temperature. The crude reaction mixture was purified by preparative HPLC (BEH column, C18) using a gradient elution of 25-35% acetonitrile and 10 mM ammonium formate in aqueous solution to give the title compound (11.4 mg, 13%) as a solid. MS (ESI) [M+H]+ 770.3; 1H NMR (400 MHz, DMSO d6)δ 10.82 (s, 1H), 8.75 (s, 1H), 8.36 - 8.08 (m, 1H), 8.00 (s, 1H), 7.94 (d, J= 3.8 Hz, 1H), 7.78 (d, J = 8.7 Hz, 1H), 7.43 (d, J = 7.9 Hz, 1H), 7.34 (d, J= 8.8 Hz, 1H), 7.30 (s, 1H), 6.81 (t, J = 5.6 Hz, 1H), 6.53 (dd, J = 8.8, 0.9Hz, 1H), 6.43 (s, 1H), 5.81 (s, 1H), 4.57 (s, 2H), 4.23 - 4.15 (m, 2H), 4.14- 4.07 (m, 2H), 3.83 (s, 3H), 3.71 - 3.68 (m, 1H), 3.69 (s, 3H), 2.95 - 2.83(m, 1H), 2.66 (d, J = 4.5 Hz, 3H), 2.67 - 2.57 (m, 2H), 2.32 - 2.21 (m, 1H), 2.18 - 2.10 (m, 1H), 2.07 - 1.79 (m, 3H), 1.34 - 1.11 (m, 3H).

[0562] Example 63. Synthesis of 2-[[6-[[5-chloro-2-[[1-[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazol-6-yl]-4-piperidinyl]-(2-hydroxyethyl)amino]pyrimidin-4-yl]amino]-1-methyl-2-oxo-3-quinolinyl]oxy]-N-methyl-acetamide

[0563]

[0564] Step 63.1: Synthesis of tert-butyl 4-[2-benzyloxyethyl-(2-nitrophenyl)sulfonyl-amino]piperidine-1-carboxylic acid. 2-Nitrobenzenesulfonyl chloride (366 mg, 1.65 mmol) was added to a solution of tert-butyl 4-(2-benzyloxyethylamino)piperidine-1-carboxylic acid (502 mg, 1.5 mmol) and triethylamine (250 µL, 1.8 mmol) in dichloromethane (20 mL). The mixture was stirred at room temperature for 18 hours and diluted with dichloromethane (25 mL). The mixture was washed with saturated sodium bicarbonate solution (20 mL), water (20 mL), and brine (20 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient elution of 15–60% ethyl acetate in hexane to give the title compound (530 mg, 68%) as a solid. MS (ESI) [M-Boc+H]+ 420.1. 1 H NMR (500 MHz, DMSO-d6) δ 8.08(dd, J = 7.9, 1.4 Hz, 1H), 7.95 (dd, J = 8.0, 1.3 Hz, 1H), 7.87 (td, J = 7.7,1.3 Hz, 1H), 7.79 (td, J = 7.7, 1.3 Hz, 1H), 7.38 - 7.31 (m, 2H), 7.31 - 7.26(m, 3H), 4.45 (s, 2H), 3.95 (br s, 2H), 3.77 (tt, J = 11.8, 4.0 Hz, 1H), 3.52(t, J = 6.3 Hz, 2H), 3.46 (t, J = 5.6 Hz, 2H), 2.70 (br s, 2H), 1.58 (qd, J =12.2, 4.5 Hz, 2H), 1.52 - 1.46 (m, 2H), 1.38 (s, 9H).

[0565] Step 63.2: Synthesis of N-(2-benzyloxyethyl)-2-nitro-N-(4-piperidinyl)benzenesulfonamide. 4-[2-benzyloxyethyl-(2-nitrophenyl)sulfonyl-amino]piperidin-1-carboxylic acid tert-butyl ester (530 mg, 1.02 mmol) was added to a solution of TFA (5 mL, 65.3 mmol) in dichloromethane (10 mL) at room temperature. The mixture was stirred at room temperature for 4 hours, and volatiles were removed under reduced pressure. The residue was dissolved in methanol (5 mL), and the solution was filtered through two 500 mg SP-HCO3 SPE columns to give the title compound (332 mg, 77%) as a solid. MS (ESI) [M+H]+420.1. 1 H NMR (500 MHz, MeOD-d4) δ 8.09 (dd, J = 7.9, 1.3 Hz, 1H), 7.81 - 7.75(m, 1H), 7.78 - 7.73 (m, 1H), 7.74 - 7.68 (m, 1H), 7.36 - 7.26 (m, 5H), 4.46(s, 2H), 3.92 (tt, J = 11.9, 4.1 Hz, 1H), 3.63 - 3.57 (m, 2H), 3.57 - 3.51(m, 2H), 3.25 - 3.20 (m, 1H), 3.23 - 3.18 (m, 1H), 2.81 (td, J = 12.8, 3.0 Hz, 2H), 1.85 (qd, J = 12.7, 4.2 Hz, 2H), 1.80 - 1.71 (m, 2H). Note: A exchangeable proton is invisible.

[0566] Step 63.3: Synthesis of N-(2-benzyloxyethyl)-N-[1-[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole-6-yl]-4-piperidinyl]-2-nitro-benzenesulfonamide. A mixture of N-(2-benzyloxyethyl)-2-nitro-N-(4-piperidinyl)benzenesulfonamide (320 mg, 0.76 mmol), 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole (573 mg, 1.14 mmol), RuPhos Pd G3 (160 mg, 0.19 mmol), and cesium carbonate (373 mg, 1.14 mmol) in 1,4-dioxane (5 mL) was heated at 80°C for 16 hours and then cooled to room temperature. The mixture was filtered through a Celite filter, washed with dichloromethane (50 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient elution of 0-50% ethyl acetate in hexane to give the title compound (384 mg, 60%) as a solid. MS (ESI) [M+H]+ 839.3.

[0567] Step 63.4: Synthesis of N-(2-benzyloxyethyl)-1-[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole-6-yl]piperidine-4-amine. Cesium carbonate (280 mg, 0.86 mmol) and thiophenol (47.3 mg, 0.43 mmol) were added sequentially to a solution of N-(2-benzyloxyethyl)-N-[1-[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole-6-yl]-4-piperidine]-2-nitro-benzenesulfonamide (360 mg, 0.43 mmol) in acetonitrile (2 mL), and the mixture was stirred at room temperature for 3 hours. Water (20 mL) and ethyl acetate (30 mL) were added, and the layers were separated. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient elution of 0-20% methanol in dichloromethane to give the title compound (230 mg, 82%). MS (ESI) [M+H]+ 654.3. 1H NMR (400MHz, DMSO-d6) δ 7.88 (d, J = 8.1 Hz, 1H), 7.51 - 7.24 (m, 15H), 6.83 (s, 1H), 6.80 (dd, J = 9.1, 1.9 Hz, 1H), 6.56 (d, J = 8.1 Hz, 1H), 5.44 (s, 2H), 5.41(s, 2H), 4.49 (s, 2H), 3.95 (s, 3H), 3.72 (d, J = 12.6 Hz, 2H), 3.52 (t, J =5.6 Hz, 2H), 3.17 (d, J = 4.9 Hz, 1H), 2.84 - 2.76 (m, 3H), 2.70 - 2.58 (m, 1H), 1.96 - 1.87 (m, 2H), 1.45 - 1.33 (m, 2H). Note: One exchangeable proton and one aromatic proton are not visible.

[0568] Step 63.5: Synthesis of 3-[6-[4-(2-hydroxyethylamino)-1-piperidinyl]-1-methyl-indazole-3-yl]piperidine-2,6-dione. A mixture of N-(2-benzyloxyethyl)-1-[3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-indazole-6-yl]piperidine-4-amine (230 mg, 0.35 mmol) and Pearlman catalyst (187 mg, 0.180 mmol) in methanol (20 mL) and tetrahydrofuran (30 mL) was stirred at 50°C for 9 hours under a hydrogen atmosphere (1 atm). The mixture was filtered through a Celite filter and washed with methanol (100 mL) and tetrahydrofuran (200 mL). The filtrate was concentrated under reduced pressure to give the title compound (130 mg, 96%) as an oil, which was used in the next step without further purification. MS (ESI)[M+H]+ 386.3.

[0569] Step 63.6: Synthesis of 2-[[6-[[5-chloro-2-[[1-[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazol-6-yl]-4-piperidinyl]-(2-hydroxyethyl)amino]pyrimidin-4-yl]amino]-1-methyl-2-oxo-3-quinolinyl]oxy]-N-methyl-acetamide. To a solution of 3-[6-[4-(2-hydroxyethylamino)-1-piperidinyl]-1-methyl-indazol-3-yl]piperidin-2,6-dione (34.0 mg, 90 µmol) in dimethyl sulfoxide (0.5 mL), 2-[[6-[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]-1-methyl-2-oxo-3-quinolinyl]oxy]-N-methylacetamide (34.6 mg, 90 µmol, intermediate i-22) and diisopropylethylamine (60 µL, 0.35 mmol) were added sequentially, and the mixture was heated to 120°C for 20 hours, then cooled to room temperature. The crude reaction mixture was purified by preparative HPLC (BEH column, C18) using a gradient elution of 31–41% acetonitrile and 10 mM ammonium formate in aqueous solution to give the title compound (17 mg, 25%) as a solid. MS (ESI)[M+H]+ 757.3. 1H NMR (500 MHz, DMSO-d6, 90°C) δ 10.49 (s, 1H), 8.50 (s, 1H), 8.05 (s, 1H), 8.01 (s, 1H), 7.78 - 7.73 (m, 1H), 7.65 (s, 1H), 7.49 (d, J =8.9 Hz, 1H), 7.44 (d, J = 9.1 Hz, 1H), 7.32 (s, 1H), 6.88 (d, J = 8.9 Hz,1H), 6.79 (d, J = 7.4 Hz, 1H), 4.49 (s, 3H), 4.47 (s, 1H), 4.23 (dd, J = 8.4,5.2 Hz, 1H), 4.07 - 4.05 (m, 1H), 3.89 (s, 3H), 3.88 - 3.85 (m, 1H), 3.63 (s,2H), 3.62 - 3.61 (m, 1H), 3.57 (d, J = 5.7 Hz, 2H), 3.53 (d, J = 5.6 Hz, 2H),2.80 - 2.73 (m, 2H), 2.69 (d, J = 4.7 Hz, 3H), 2.68 - 2.62 (m, 2H), 2.37 -2.28 (m, 1H), 2.27 - 2.19 (m, 1H), 1.96 - 1.87 (m, 2H), 1.81 - 1.75 (m, 2H).

[0570] Example 64. 2-[[6-[[2-[butyl-[1-[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazol-6-yl]-4-piperidinyl]amino]-5-chloro-pyrimidin-4-yl]amino]-1-methyl-2-oxo-3-quinolinyl]oxy]-N-methyl-acetamide

[0571]

[0572] Step 64.1: Synthesis of 1-[3-(2,6-dihydroxy-3-pyridyl)-1-methyl-indazole-6-yl]piperidin-4-one.

[0573] A mixture of 6-bromo-3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-indazole (6.0 g, 11.99 mmol), piperidin-4-one hydrochloride (2.44 g, 17.99 mmol), sodium tert-butoxide (3.0 g, 31.2 mmol), and tBuXPhos Pd G3 (952.5 mg, 1.2 mmol) in anhydrous tetrahydrofuran (120 mL) was heated to 70°C for 2 hours and then cooled to room temperature. The reaction mixture was filtered through a Celite filter and washed with dichloromethane (3 x 100 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using a gradient elution of 0-80% ethyl acetate in hexane to give the title compound (4.01 g, 65%) as a solid. MS (ESI) [M+H]+ 518.9.

[0574] Step 64.2: Synthesis of 3-[1-methyl-6-(4-oxo-1-piperidinyl)indazole-3-yl]piperidin-2,6-dione. A mixture of 1-[3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-indazole-6-yl]piperidin-4-one (2.58 g, 4.97 mmol) and 20% Pearlman catalyst (0.87 g, 1.24 mmol) in tetrahydrofuran (25 mL) and ethanol (25 mL) was hydrogenated at 50°C (1 atm) for 18 h. The reaction mixture was cooled to room temperature, and then the second portion of 20% Pearlman catalyst (0.87 g, 1.24 mmol) was hydrogenated at 50°C (1 atm) for 22 h. The reaction mixture was cooled to room temperature and filtered through a Celite filter, followed by washing with dichloromethane (3 x 300 mL) and N,N-dimethylformamide (3 x 25 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using a gradient elution of 0-10% methanol in dichloromethane to give the title compound (1.15 g, 64%) as a solid. MS (ESI) [M+H]+341.7. 1H NMR (500 MHz, DMSO-d6) δ 10.85 (s, 1H), 7.54 (d, J = 8.9 Hz, 1H), 7.00 (dd, J = 9.0, 2.1 Hz, 1H), 6.97 (d, J = 1.7 Hz, 1H), 4.26 (dd, J = 9.3,5.1 Hz, 1H), 3.90 (s, 3H), 3.69 (t, J = 6.0 Hz, 4H), 2.68 - 2.56 (m, 2H),2.46 (t, J = 6.0 Hz, 4H), 2.35 - 2.26 (m, 1H), 2.20 - 2.12 (m, 1H).

[0575] Step 64.3: Synthesis of 3-[6-[4-(butylamino)-1-piperidinyl]-1-methyl-indazole-3-yl]piperidin-2,6-dione. Acetic acid (0.4 mL) was added to a solution of 3-[1-methyl-6-(4-oxo-1-piperidinyl)indazole-3-yl]piperidin-2,6-dione (94 mg, 0.28 mmol), 3-[tert-butyl(dimethyl)silyl]oxypropyl-1-amine (110 mg, 0.55 mmol), and sodium triacetoxyborohydride (117 mg, 0.55 mmol) in dimethyl sulfoxide (2 mL), followed by the addition of scandium(III) trifluoromethanesulfonate (13.6 mg, 30 µmol), and the reaction mixture was stirred at room temperature for 1 hour. The crude reaction mixture was purified by preparative HPLC (BEH column, C18) using a gradient elution of 55-65% acetonitrile and 10 mM ammonium bicarbonate aqueous solution to give the title compound (39.1 mg, 27%) as a solid. 1H NMR (500 MHz, DMSO-d6) δ 10.85 (s,1H), 7.47 (d, J = 9.0 Hz, 1H), 6.90 (dd, J = 9.0, 1.8 Hz, 1H), 6.82 (d, J =1.7 Hz, 1H), 4.24 (dd, J = 9.2, 5.1 Hz, 1H), 3.88 (s, 3H), 3.71 (d, J = 12.5Hz, 2H), 3.65 (t, J = 6.2 Hz, 2H), 2.80 (dd, J = 17.3, 6.7 Hz, 2H), 2.65 -2.59 (m, 4H), 2.57 - 2.53 (m, 1H), 2.34 - 2.24 (m, 1H), 2.19 - 2.11 (m, 1H), 1.89 (d, J = 10.8 Hz, 2H), 1.63 - 1.55 (m, 2H), 1.42 - 1.30 (m, 2H), 0.87 (s, 9H), 0.03 (s, 6H). Note: One signal is not visible, most likely due to solvent exchange.

[0576] Step 64.4: Synthesis of 2-[[6-[[2-[butyl-[1-[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazol-6-yl]-4-piperidinyl]amino]-5-chloro-pyrimidin-4-yl]amino]-1-methyl-2-oxo-3-quinolinyl]oxy]-N-methyl-acetamide. To a solution of 20 mg, 40 mmol of 3-[6-[4-[3-[tert-butyl(dimethyl)silyl]oxypropylamino]-1-piperidinyl]-1-methyl-indazol-3-yl]piperidin-2,6-dione in dimethyl sulfoxide (0.4 mL), 2-[[6-[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]-1-methyl-2-oxo-3-quinolinyl]oxy]-N-methylacetamide (30.5 mg, 80 µmol, intermediate i-22) and diisopropylethylamine (30 µL, 0.16 mmol) were added sequentially. The reaction mixture was heated to 80°C for 20 hours and then cooled to room temperature. A second portion of diisopropylethylamine (30 µL, 0.16 mmol) was added to the reaction mixture, and the mixture was stirred at 90°C for 64 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (BEH column, C18) using a gradient elution of 29-39% acetonitrile and 10 mM ammonium formate in aqueous solution to give the title compound as a solid. The desired product was detected by MS (ESI) [M+H]+ 771.4.1 H NMR (500MHz, DMSO-d6, 90°C) δ 10.47 (s, 1H), 8.48 (s, 1H), 8.04 (s, 1H), 7.84 (d, J =2.3 Hz, 1H), 7.77 (dd, J = 9.0, 2.4 Hz, 1H), 7.64 (br s, 1H), 7.49 (d, J =8.9 Hz, 1H), 7.44 (d, J = 9.1 Hz, 1H), 7.25 (s, 1H), 6.87 (d, J = 9.1 Hz,1H), 6.79 (s, 1H), 4.50 (s, 3H), 4.23 (dd, J = 8.4, 5.1 Hz, 1H), 4.13 (br s,1H), 3.89 (s, 3H), 3.87 (s, 1H), 3.85 (s, 1H), 3.63 (s, 3H), 3.48 - 3.44 (m,2H), 3.38 (s, 2H), 2.74 (t, J = 12.1 Hz, 2H), 2.69 (d, J = 4.7 Hz, 3H), 2.67- 2.62 (m, 2H), 2.37 - 2.28 (m, 1H), 2.26 - 2.18 (m, 1H), 1.98 - 1.89 (m,2H), 1.78 (d, J = 10.5 Hz, 2H), 1.75 - 1.68 (m, 2H).

[0577] Example 65. Synthesis of 2-((6-((5-chloro-2-((2-(4-((3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)amino)piperidin-1-yl)-2-oxoethyl)amino)pyrimidin-4-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinoline-3-yl)oxy)-N-methylacetamide

[0578]

[0579] Step 65.1: Synthesis of tert-butyl 4-[[(1R)-1-phenylethyl]amino]-3,6-dihydro-2H-pyridine-1,5-dicarboxylate O5-ethyl ester. To a solution of 4-oxopiperidinyl-1,3-dicarboxylate O1-tert-butyl ester O3-ethyl ester (22 g, 81 mmol) and (1R)-1-phenylethylamine (12.5 mL, 97.2 mmol) in toluene (400 mL), p-toluenesulfonic acid (1.39 g, 8.1 mmol) was added, and the mixture was heated to reflux for 18 hours using a Dean-Stark separator. The mixture was cooled to room temperature and washed with saturated aqueous solutions of sodium bicarbonate (2 x 200 mL) and brine (2 x 200 mL). The combined organic fractions were dried over magnesium sulfate, filtered, and concentrated. The residue was filtered through a silica gel pad, washed with dichloromethane (2 x 100 mL), and concentrated to give the title compound (30.2 g, 99%) as an oil, which was used in the next step without further purification. MS (ESI) [M+H] + 375.2. 1 H NMR (400 MHz, CDCl3) δ 9.25 (d, J = 7.5 Hz, 1H), 7.36 - 7.28(m, 2H), 7.26 - 7.18 (m, 3H), 4.66 - 4.54 (m, 1H), 4.24 - 4.14 (m, 2H), 4.07(br s, 2H), 3.48 - 3.35 (m, 1H), 3.35 - 3.24 (m, 1H), 2.39 (dd, J = 13.0, 6.2Hz, 1H), 2.09 - 2.00 (m, 1H), 1.50 (d, J = 6.8 Hz, 3H), 1.43 (s, 9H), 1.29(t, J = 7.0 Hz, 3H).

[0580] Step 65.2: Synthesis of (3S,4R)-4-[[(1R)-1-phenylethyl]amino]piperidine-1,3-dicarboxylic acid tert-butyl ester O3-ethyl ester. Sodium triacetoxyborohydride (34 g, 160 mmol) was added in portions to a solution of 4-[[(1R)-1-phenylethyl]amino]-3,6-dihydro-2H-pyridine-1,5-dicarboxylic acid tert-butyl ester O5-ethyl ester (15 g, 40.1 mmol) cooled to 0°C in acetonitrile (200 mL) and acetic acid (100 mL), and the reaction mixture was stirred at 0°C for 2 hours. The mixture was then cooled to -10°C and slowly treated with 1M sodium hydroxide aqueous solution (100 mL), 4M sodium hydroxide aqueous solution (100 mL), 6M sodium hydroxide aqueous solution (100 mL), and subsequently treated with 50% sodium hydroxide aqueous solution (50 mL). The mixture was cooled to room temperature, and the layers were separated. The aqueous layer was extracted with dichloromethane (3 x 80 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient elution of 0-50% ethyl acetate in hexane to give a 4:1 isomer mixture (14.8 g, 98%) as an oil. A portion (7 g) of the 4:1 mixture was separated by SFC to give the title compound (3.7 g) as an oil. MS (ESI) [M+H] + 377.2. 1 H NMR (400MHz, DMSO-d6) δ 7.36 - 7.25 (m, 4H), 7.24 - 7.15 (m, 1H), 4.09 (q, J = 6.8Hz, 2H), 3.82 - 3.66 (m, 2H), 3.60 - 3.46 (m, 1H), 3.24 - 3.11 (m, 1H), 3.07- 2.86 (m, 1H), 2.82 - 2.75 (m, 1H), 2.73 -2.66 (m, 1H), 1.64 - 1.52 (m, 1H),1.42 - 1.37 (m, 1H), 1.35 (s, 9H), 1.22 (t, J = 7.0 Hz, 3H), 1.17 (d, J = 6.6Hz, 3H).

[0581] Step 65.3: Synthesis of tert-butyl piperidine-1-carboxylate (3S,4R)-3-(hydroxymethyl)-4-[[(1R)-1-phenylethyl]amino]piperidine-1,3-dicarboxylate tert-butyl ester O3-ethyl ester (500 mg, 1.33 mmol) in tetrahydrofuran (3 mL) was mixed with lithium borohydride (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 ethyl acetate (3 x 30 mL). The combined organic fractions were dried over sodium sulfate, 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.

[0582] Step 65.4: Synthesis of tert-butyl(3S,4R)-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-[[(1R)-1-phenylethyl]amino]piperidine-1-carboxylic acid tert-butyl ester. Tert-butylchlorodimethylsilane (218 mg, 1.45 mmol) and imidazole (123 mg, 1.81 mmol) were added sequentially to a solution of (3S,4R)-3-(hydroxymethyl)-4-[[(1R)-1-phenylethyl]amino]piperidine-1-carboxylic acid tert-butyl ester (404 mg, 1.21 mmol) in dichloromethane (5 mL), and the reaction mixture was stirred at room temperature for 3 hours. Water (15 mL) and diethyl ether (20 mL) were added, and the layers were separated. The aqueous layer was washed with diethyl ether (3 x 10 mL), and the combined organic fractions were dried over sodium sulfate, filtered, and concentrated to give the title compound (540 mg, 99%) as an oil, which was used in the next step without further purification. Note: SFC analysis confirmed the presence of only one diastereomer. MS (ESI) [M+H] + 449.4. 1H NMR (400 MHz, DMSO-d6) δ 7.35 - 7.26 (m, 4H), 7.23 - 7.16 (m, 1H), 3.86 - 3.68 (m, 3H), 3.68 - 3.54 (m, 1H), 3.48 (t, J =9.6 Hz, 1H), 2.89 - 2.68 (m, 1H), 2.81 (dd, J = 13.1, 3.2 Hz, 1H), 2.59 -2.52 (m, 1H), 1.82 - 1.72 (m, 1H), 1.36 (s, 9H), 1.34 - 1.27 (m, 1H), 1.26 -1.18 (m, 1H), 1.22 (d, J = 6.7 Hz, 3H), 0.90 (s, 9H), 0.07 (d, J = 3.1 Hz, 6H). Note: One exchangeable proton is not shown.

[0583] Step 65.5: Synthesis of tert-butyl piperidine-1-carboxylate (3S,4R)-4-amino-3-[[tert-butyl(dimethyl)silyl]oxymethyl]piperidine-1-carboxylate. A mixture of tert-butyl piperidine-1-carboxylate (530 mg, 1.18 mmol), ammonium formate (596 mg, 9.45 mmol), and palladium / carbon (126 mg, 0.12 mmol) in ethanol (15 mL) was heated to 65°C for 2 hours. The mixture was filtered through a Celite filter and washed with methanol (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 (400 MHz, DMSO-d6) δ 3.61 (dd, J = 10.2, 4.9 Hz, 1H), 3.49 - 3.41 (m, 2H), 3.39 - 3.24 (m, 3H), 3.23 - 3.08 (m, 1H), 3.06 - 2.98 (m, 1H), 1.71 - 1.55(m, 2H), 1.55 - 1.44 (m, 1H), 1.40 - 1.33 (m, 1H), 1.38 (s, 9H), 0.89 - 0.84(m, 9H), 0.06 - 0.01 (m, 6H).

[0584] Step 65.6: Synthesis of (3S, 4R)-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-[[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole-6-yl]amino]piperidine-1-carboxylic acid tert-butyl ester. A mixture of 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole (471 mg, 0.94 mmol), (3S,4R)-4-amino-3-[[tert-butyl(dimethyl)silyl]oxymethyl]piperidine-1-carboxylic acid tert-butyl ester (270 mg, 0.78 mmol), cesium carbonate (638 mg, 1.96 mmol), and RuPhos Pd G3 (98.3 mg, 0.12 mmol) in 1,4-dioxane (7 mL) was heated to 90°C for 16 hours and then cooled to room temperature. The residue was purified by silica gel column chromatography using a gradient elution of 0-50% ethyl acetate in hexane to give the title compound (458 mg, 67%) as a solid. Note: The reaction was repeated, and the crude residues were combined and then purified. MS (ESI) [M+H] + 764.4. 1 H NMR (400 MHz, DMSO-d6) δ 7.87 (d,J = 8.1 Hz, 1H), 7.50 - 7.44 (m, 2H), 7.42 - 7.26 (m, 9H), 6.55 (d, J = 7.9Hz, 1H), 6.52 (dd, J = 9.0, 1.9 Hz, 1H), 6.45 (d, J = 1.3 Hz, 1H), 5.78 (d, J= 8.6 Hz, 1H), 5.44 (s, 2H), 5.41 (s, 2H), 3.88 (s, 3H), 3.85 - 3.77 (m, 1H),3.67 - 3.61 (m, 1H), 3.60 - 3.41 (m, 4H), 3.39 - 3.32 (m, 1H), 2.10 - 2.00(m, 1H), 1.67 - 1.53 (m, 2H), 1.41 (s, 9H), 0.82 (s, 9H), -0.05 (d, J = 15.0Hz, 6H).

[0585] Step 65.7: Synthesis of tert-butyl (3S,4R)-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-[[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-6-yl]amino]piperidin-1-carboxylic acid tert-butyl ester. A mixture of (3S,4R)-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-[[3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-indazole-6-yl]amino]piperidin-1-carboxylic acid tert-butyl ester (458 mg, 0.60 mmol) and Pearlman catalyst (210 mg, 0.15 mmol) in ethanol (10 mL) and tetrahydrofuran (10 mL) was hydrogenated at 50°C (1 atm) for 2 hours. The mixture was filtered through a Celite filter and washed with methanol (3 x 15 mL). The filtrate was concentrated under reduced pressure to give the title compound (350 mg, quantified) as a solid, which was used in the next step without further purification. MS (ESI) [M+H + 586.4.

[0586] Step 65.8: Synthesis of 3-[6-[[(3S,4R)-3-(hydroxymethyl)-4-piperidinyl]amino]-1-methyl-indazole-3-yl]piperidine-2,6-dione dihydrochloride. A solution of (3S,4R)-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-[[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-6-yl]amino]piperidine-1-carboxylic acid tert-butyl ester (350 mg, 0.60 mmol) in dichloromethane (2.5 mL) was added to HCl (1.5 mL, 6.0 mmol) in 1,4-dioxane, and the mixture was stirred at room temperature for 2 hours. The precipitate was collected by filtration, washed with diethyl ether (3 x 5 mL), and dried under vacuum to give the title compound (250 mg, 77%) as a solid, which was used in the next step without further purification. MS (ESI) [M+H + 372.2. 1H NMR (500 MHz, DMSO-d6) δ 10.82 (s, 1H),8.89 - 8.68 (m, 2H), 7.35 (d, J = 8.8 Hz, 1H), 6.66 (dd, J = 8.8, 1.7 Hz,1H), 6.51 (s, 1H), 4.18 (dd, J = 9.0, 5.1 Hz, 1H), 3.99 - 3.92 (m, 1H), 3.82(s, 3H), 3.51 - 3.41 (m, 2H), 3.27 - 3.15 (m, 2H), 3.15 - 3.04 (m, 2H), 2.67- 2.54 (m, 2H), 2.32 - 2.21 (m, 2H), 2.18 - 2.10 (m, 1H), 1.98 - 1.89 (m, 1H), 1.87 - 1.78 (m, 1H). Note: Exchangeable signals are not visible.

[0587] Step 65.9: Synthesis of 2-[[6-[[5-chloro-2-[(3S,4R)-4-[[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazol-6-yl]amino]-3-(hydroxymethyl)-1-piperidinyl]pyrimidin-4-yl]amino]-1-methyl-2-oxo-3-quinolinyl]oxy]-N-methyl-acetamide. 3-[6-[[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]-1-methyl-2-oxo-3-quinolinyl]oxy]-N-methyl-acetamide (35 mg, 90 µmol, intermediate 22) and diisopropylethylamine (80 µL, 0.45 mmol) in dimethyl sulfoxide (1 mL) were added to a mixture of 2-[[6-[(3S,4R)-3-(hydroxymethyl)-4-piperidinyl]amino]-1-methyl-indazol-3-yl]piperidine-2,6-dione dihydrochloride (58.2 mg, 0.11 mmol) and heated to 80°C for 16 hours. The crude reaction mixture was purified by preparative HPLC (BEH column, C18) using a gradient elution of 30-40% acetonitrile and 10 mM ammonium formate in aqueous solution to give the title compound (46.9 mg, 71%) as a solid. MS (ESI) [M+H] + 743.4. 1H NMR (500 MHz, DMSO-d6) δ 8.80 (s, 1H), 8.35 (s,1H), 8.06 (s, 1H), 7.93 - 7.88 (m, 1H), 7.82 (dd, J = 9.2, 2.0 Hz, 1H), 7.44(d, J = 9.1 Hz, 1H), 7.33 (d, J = 8.8 Hz, 1H), 7.19 (br s, 1H), 6.65 (dd, J =8.8, 1.7 Hz, 1H), 6.49 (s, 1H), 5.87 (d, J = 8.6 Hz, 1H), 4.54 (s, 2H), 4.18(dd, J = 8.9, 5.1 Hz, 1H), 3.94 - 3.85 (m, 2H), 3.81 (s, 3H), 3.79 - 3.73 (m, 1H), 3.65 (s, 3H), 3.56 - 3.50 (m, 1H), 3.45 - 3.29 (m, 4H), 2.66 - 2.56 (m, 2H), 2.61 (d, J = 4.0 Hz, 3H), 2.31 - 2.22 (m, 1H), 2.20 - 2.07 (m, 2H), 1.79 - 1.70 (m, 1H), 1.70 - 1.60 (m, 1H). Note: Glutarimide NH signal is not visible.

[0588] Example 66. 2-[[6-[[5-chloro-2-[(3R,4R)-4-[[3-(2,4-dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]amino]-3-methyl-1-piperidinyl]pyrimidin-4-yl]amino]-1-methyl-2-oxo-3-quinolinyl]oxy]-N-methylacetamide

[0589]

[0590] Step 66.1: Synthesis of tert-butyl ester of (3R,4R)-4-[[3-(2,4-dioxohexahydropyrimidin-1-yl)-1-methyl-indazole-6-yl]amino]-3-methyl-piperidine-1-carboxylic acid. A mixture of [3-(2,4-dioxohexahydropyrimidin-1-yl)-1-methyl-indazole-6-yl]boronic acid (200 mg, 0.69 mmol, intermediate 9), (3R,4R)-4-amino-3-methyl-piperidin-1-carboxylic acid tert-butyl ester (228 mg, 1.04 mmol), copper(II) acetate (152 mg, 0.76 mmol), triethylamine (190 µL, 1.39 mmol), and 3 Å MS (100 mg) in 1,2-dichloroethane (12.6 mL) was heated to 50°C for 18 hours under O2 (1 atm). The mixture was filtered through a Celite filter and washed with a 1:1 mixture of acetonitrile and methanol (3 x 10 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by preparative HPLC (BEH column, C18) using a gradient elution of 10-80% acetonitrile and 10 mM ammonium formate in aqueous solution to give the title compound (76 mg, 24%) as a solid. MS (ESI) [M+H]+ 457.3.

[0591] Step 66.2: Synthesis of 1-[1-methyl-6-[[(3R,4R)-3-methyl-4-piperidinyl]amino]indazole-3-yl]hexahydropyrimidine-2,4-dione hydrochloride. A solution of 4N HCl in 1,4-dioxane (0.42 mL, 1.66 mmol) was added to a solution of (3R,4R)-4-[[3-(2,4-dioxohexahydropyrimidine-1-yl)-1-methyl-indazole-6-yl]amino]-3-methyl-piperidin-1-carboxylic acid tert-butyl ester (76 mg, 0.166 mmol) in 1,4-dioxane (1.66 mL), and the mixture was stirred at room temperature for 20 hours. The volatiles were removed under reduced pressure, and the residue was washed with diethyl ether (5 mL) and dried under vacuum to give the title compound (45 mg, 70%) as a solid, which was used in the next step without further purification. MS (ESI) [M+H]+ 357.3.

[0592] Step 66.3: Synthesis of 2-[[6-[[5-chloro-2-[(3R,4R)-4-[[3-(2,4-dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]amino]-3-methyl-1-piperidinyl]pyrimidin-4-yl]amino]-1-methyl-2-oxo-3-quinolinyl]oxy]-N-methyl-acetamide. Diisopropylethylamine (40 µL, 0.17 mmol) was added to a mixture of 2-[[6-[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]-1-methyl-2-oxo-3-quinolinyl]oxy]-N-methylacetamide (24 mg, 60 µmol, intermediate 22) and 1-[1-methyl-6-[[(3R,4R)-3-methyl-4-piperidinyl]amino]indazol-3-yl]hexahydropyrimidin-2,4-dione hydrochloride (22 mg, 60 µmol) in N,N-dimethylformamide (1.1 mL). The mixture was heated to 80°C for 1 hour and then cooled to room temperature. The volatiles were removed under reduced pressure, and the residue was purified by preparative HPLC (BEH column, C18) using a gradient elution of 39-49% acetonitrile and 10 mM ammonium formate in aqueous solution to give the title compound (4.33 mg, 11%) as a solid. MS (ESI) [M+H]+ 728.4. 1 H NMR (400 MHz, DMSO-d6) δ 10.40(br s, 1H), 8.90 (s, 1H), 8.07 (s, 1H), 7.96 (d, J = 4.8 Hz, 1H), 7.90 (s,1H), 7.82 - 7.70 (m, 1H), 7.47 (d, J = 9.1 Hz, 1H), 7.25 (d, J = 8.9 Hz, 1H), 7.13 (s, 1H), 6.49 (d, J = 8.9 Hz, 1H), 6.42 (s, 1H), 5.77 (d, J = 8.8 Hz, 1H), 4.59 - 4.37 (m, 4H), 3.85 (t, J = 6.7 Hz, 2H), 3.80 (s, 3H), 3.66 (s,3H), 3.04 (t, J = 12.1 Hz, 1H), 2.73 - 2.69 (m, 2H), 2.61 (d, J = 4.6 Hz,3H), 2.08 (d, J = 10.3 Hz, 1H), 1.59 (br s, 1H), 1.27 - 1.08 (m, 2H), 0.95 (d, J = 6.4 Hz, 3H).

[0593] Example 67. 2-[[6-[[5-chloro-2-[4-[3-(2,4-dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]-1-piperidinyl]pyrimidin-4-yl]amino]-1-methyl-2-oxo-3-quinolinyl]oxy]-N-methyl-acetamide.

[0594]

[0595] Step 67.1: Synthesis of N-(6-bromo-1-methyl-indazole-3-yl)carbamate tert-butyl ester. Boc anhydride (1.16 g, 5.31 mmol) was added to a solution of 6-bromo-1-methyl-indazole-3-amine (1.0 g, 4.42 mmol) in 1,4-dioxane (25 mL), and the reaction mixture was heated to 100°C for 16 hours, 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 elution of ethyl acetate from 0-100% in hexane to give the title compound (1.18 g, 82%) as a solid. MS (ESI) [M-tBu]+ 271.0. 1 H NMR (400 MHz, DMSO-d6) δ9.62 (s, 1H), 7.89 (s, 1H), 7.67 (dd, J = 8.6, 2.4 Hz, 1H), 7.20 (dd, J =8.7, 1.6 Hz, 1H), 3.91 (s, 3H), 1.47 (s, 9H).

[0596] Step 67.2: Synthesis of N-(6-bromo-1-methyl-indazole-3-yl)-N-(2-cyanoethyl)carbamate tert-butyl ester. Potassium fluoride (429.4 mg, 7.39 mmol), acrylonitrile (0.83 mL, 12.6 mmol), and alumina(III) (1.29 g, 12.6 mmol) were added sequentially to a solution of N-(6-bromo-1-methyl-indazole-3-yl)carbamate (1.18 g, 3.61 mmol) in acetonitrile (15 mL). The reaction mixture was heated to reflux for 18 hours and then cooled to room temperature. The mixture was filtered through a Celite filter and washed with acetonitrile (20 mL). The filtrate was concentrated under reduced pressure to give the title compound (1.0 g, 73%) as an oil, which was used in the next step without further purification. MS (ESI) [M-tBu]+324.6.

[0597] Step 67.3: Synthesis of N-(3-amino-3-oxopropyl)-N-(6-bromo-1-methyl-indazole-3-yl)carbamate tert-butyl ester. At 0°C, 30% hydrogen peroxide (128 mL, 1.23 mol) and ammonium hydroxide (118 mL, 0.92 mol) were added sequentially to a solution of N-(6-bromo-1-methyl-indazole-3-yl)-N-(2-cyanoethyl)carbamate tert-butyl ester (12 g, 31.6 mmol) in methanol (90 mL). The reaction mixture was then cooled to room temperature and stirred for 6 hours. Water (500 mL) and dichloromethane (500 mL) were added, and the layers were separated. The organic layer was washed with a saturated aqueous solution of sodium sulfite (200 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient elution of ethyl acetate in hexane from 0 to 100%, followed by a second purification using dichloromethane in methanol from 0 to 20% to give the title compound (10.6 g, 84%) as a solid. MS (ESI) [M+H]+ 397.1.

[0598] Step 67.4: Synthesis of 1-(6-bromo-1-methyl-indazole-3-yl)hexahydropyrimidine-2,4-dione. Potassium tert-butoxide (6.0 g, 53.4 mmol) was added to a solution of N-(3-amino-3-oxo-propyl)-N-(6-bromo-1-methyl-indazole-3-yl)carbamate (10.6 g, 26.7 mmol) in tetrahydrofuran (125 mL), and the reaction mixture was stirred at 0°C for 2 hours. Ethyl acetate (100 mL) and 1N HCl (40 mL) were added, and the layers were separated. The organic layer was washed with brine (40 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient of 0-100% ethyl acetate eluted with hexane to give the title compound (2.1 g, 24%) as a solid. MS (ESI) [M+H]+ 323.1.

[0599] Step 67.5: Synthesis of tert-butyl 4-[3-(2,4-dioxohexahydropyrimidin-1-yl)-1-methyl-indazole-6-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid. A mixture of 1-(6-bromo-1-methyl-indazol-3-yl)hexahydropyrimidine-2,4-dione (600 mg, 1.86 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (603 mg, 1.95 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (75.8 mg, 90 µmol), and tripotassium phosphate (1.18 g, 5.57 mmol) in 1,4-dioxane (16 mL) and water (4 mL) was heated to 90°C for 4 hours and then cooled to room temperature. Volatile substances were removed, and the residue was purified by reversed-phase chromatography (C18) using a gradient elution of 20–100% acetonitrile and 10 mM ammonium formate in aqueous solution to give the title compound (200 mg, 25%) as a solid. MS (ESI) [MH]- 424.3. 1 H NMR (500 MHz, DMSO-d6) δ 10.54 (s, 1H), 7.62- 7.57 (m, 2H), 7.26 (dd, J = 8.6, 1.4 Hz, 1H), 6.29 (s, 1H), 4.07 - 4.02 (m,2H), 3.99 (s, 3H), 3.92 (t, J = 6.7 Hz, 2H), 3.61 - 3.55 (m, 2H), 2.76 (t, J= 6.7 Hz, 2H), 2.61 - 2.55 (m, 2H), 1.44 (s, 9H).

[0600] Step 67.6: Synthesis of tert-butyl 4-[3-(2,4-dioxohexahydropyrimidin-1-yl)-1-methyl-indazole-6-yl]piperidine-1-carboxylic acid. A mixture of tert-butyl 4-[3-(2,4-dioxohexahydropyrimidin-1-yl)-1-methyl-indazole-6-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid (200 mg, 0.470 mmol) and 10% palladium / carbon (250 mg, 0.24 mmol) in methanol (15 mL) was hydrogenated at room temperature (1 atm) for 4 hours. The mixture was filtered through a Celite filter and washed with methanol (3 x 10 mL). The filtrate was concentrated under reduced pressure to give the title compound (200 mg, quantified) as a solid, which was used in the next step without further purification. MS (ESI) [MH] - 426.3.

[0601] Step 67.7: Synthesis of 1-[1-methyl-6-(4-piperidinyl)indazole-3-yl]hexahydropyrimidine-2,4-dione hydrochloride. To a solution of 4-[3-(2,4-dioxohexahydropyrimidine-1-yl)-1-methyl-indazole-6-yl]piperidin-1-carboxylic acid tert-butyl ester (200 mg, 0.47 mmol) in dichloromethane (2.5 mL), HCl (2.5 mL, 10 mmol) in 1,4-dioxane was added, and the mixture was stirred at room temperature for 4 hours. The resulting precipitate was collected by filtration, washed with diethyl ether (2 x 10 mL), and dried under vacuum to give the title compound (163 mg, 96%, from step 2), as a solid, which was used in the next step without further purification. MS (ESI) [M+H]+ 328.1; 1 H NMR (500 MHz, DMSO-d6) δ 10.54(s, 1H), 7.61 (d, J = 8.5 Hz, 1H), 7.39 (s, 1H), 7.02 (dd, J = 8.6, 1.4 Hz,1H), 3.98 (s, 3H), 3.91 (t, J = 6.6 Hz, 2H), 3.42 - 3.36 (m, 3H), 3.09 - 2.95 (m, 3H), 2.75 (t, J = 6.7 Hz, 2H), 2.04 - 1.95 (m, 3H), 1.97 - 1.87 (m, 2H).

[0602] Step 67.8: Synthesis of 2-[[6-[[5-chloro-2-[4-[3-(2,4-dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]-1-piperidinyl]pyrimidin-4-yl]amino]-1-methyl-2-oxo-3-quinolinyl]oxy]-N-methyl-acetamide. 1-[1-methyl-6-(4-piperidinyl)inzolium-3-yl)amino]-1-methyl-2-oxo-3-quinolinyl]oxy]-N-methylacetamide (30 mg, 80 µmol, intermediate 22) and diisopropylethylamine (50 µL, 0.310 mmol) in dimethyl sulfoxide (1 mL) were added to a mixture at room temperature, and the reaction mixture was heated to 80°C for 2 hours. The crude reaction mixture was purified by preparative HPLC (BEH column, C18) using a gradient elution of 30-50% acetonitrile and 10 mM ammonium formate to give the title compound (26.2 mg, 48%) as a solid. MS (ESI) [M+H]+ 699.3. 1 H NMR (500 MHz, DMSO-d6) δ10.52 (s, 1H), 8.85 (s, 1H), 8.08 (s, 1H), 7.95 (d, J = 2.4 Hz, 1H), 7.93 -7.88 (m, 1H), 7.78 (dd, J = 9.1, 2.4 Hz, 1H), 7.54 (d, J = 8.6 Hz, 1H), 7.47 (d, J = 9.2 Hz, 1H), 7.45 (s, 1H), 7.11 (s, 1H), 7.05 (dd, J = 8.6, 1.1 Hz,1H), 4.76 - 4.65 (m, 2H), 4.55 (s, 2H), 3.95 (s, 3H), 3.90 (t, J = 6.7 Hz, 2H), 3.66 (s, 3H), 3.01 - 2.91 (m, 3H), 2.74 (t, J = 6.7 Hz, 2H), 2.61 (d, J= 4.7 Hz, 3H), 1.93 - 1.86 (m, 2H), 1.74 - 1.61 (m, 2H).

[0603] Example 68. 2-[[6-[[5-chloro-2-[[4-[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazol-6-yl]cyclohex-3-en-1-yl]-methyl-amino]pyrimidin-4-yl]amino]-1-methyl-2-oxo-3-quinolinyl]oxy]-N-methyl-acetamide

[0604]

[0605] Step 68.1: Synthesis of N-[4-[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole-6-yl]-4-hydroxy-cyclohexyl]-N-methylcarbamate tert-butyl ester. Tert-butyllithium (13.7 mL, 22 mmol) was added dropwise to a solution of 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole (10 g, 20 mmol) in tetrahydrofuran (200 mL) cooled to -78°C, and the reaction mixture was stirred at -78°C for 30 min. A solution of N-methyl-N-(4-oxocyclohexyl)carbamate tert-butyl ester (5.0 g, 22 mmol) in tetrahydrofuran (30 mL) was added dropwise to the reaction mixture at -78°C. The mixture was stirred at -78°C for 1 hour, then cooled to room temperature and stirred for 18 hours. A saturated ammonium chloride solution (20 mL) and ethyl acetate (300 mL) were added, and the layers were separated. The organic layer was washed with water (10 mL) and brine (10 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient elution of ethyl acetate from 0-100% in hexane to give a diastereomeric mixture of the title compound (5.4 g, 42%) as a solid. MS (ESI) [M+H]+649.5.

[0606] Step 68.2: Synthesis of N-[4-[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-6-yl]-4-hydroxy-cyclohexyl]-N-methylcarbamate tert-butyl ester. A mixture of N-[4-[3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-indazole-6-yl]-4-hydroxy-cyclohexyl]-N-methylcarbamate tert-butyl ester (1.0 g, 1.54 mmol) and Pearlman catalyst (250 mg, 25 wt% loading) in ethanol (12 mL) and tetrahydrofuran (12 mL) was hydrogenated at 50°C (1 atm) for 3 h. The mixture was filtered through Celite and washed with methanol (3 x 50 mL). The filtrate was concentrated under reduced pressure. Methanol (2 mL) and diethyl ether (200 mL) were added sequentially, and the precipitate was collected by filtration, washed with diethyl ether (20 mL), and then dried under vacuum to give the title compound (506 mg, 70%) as a solid. MS (ESI) [M+H]+ 471.3. 1 H NMR (400 MHz, DMSO-d6) δ 10.92 - 10.91 (m, 1H), 7.72 - 7.53 (m, 2H), 7.39- 7.25 (m, 1H), 5.01 - 4.99 (m, 1H), 4.41 - 4.29 (m, 1H), 4.02 - 3.98 (m,3H), 2.77 - 2.57 (m, 4H), 2.46 (s, 2H), 2.43 - 2.29 (m, 1H), 2.23 - 2.11 (m,1H), 2.04 - 1.88 (m, 1H), 1.83 - 1.69 (m, 2H), 1.57 - 1.54 (m, 1H), 1.47 -1.34 (m, 12H). Note: One exchangeable proton is not shown.

[0607] Step 68.3: Synthesis of 2,2,2-trifluoroacetic acid (3-[1-methyl-6-[4-(methylamino)cyclohexen-1-yl]indazole-3-yl]piperidine-2,6-dione). Trifluoroacetic acid (1.84 mL, 24.1 mmol) was added to a solution of N-[4-[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-6-yl]-4-hydroxy-cyclohexyl]-N-methylcarbamate tert-butyl ester (453 mg, 0.96 mmol) in 1,2-dichloroethane (10 mL) at room temperature. The mixture was heated to 60°C and stirred for 1 hour, and then the volatiles were evaporated under reduced pressure. Methanol (2 mL) and diethyl ether (150 mL) were added sequentially, and the precipitate was collected by filtration, washed with diethyl ether (50 mL), and then dried under vacuum to give the title compound (423 mg, 89%) as a solid. MS(ESI) [M+H]+ 353.3. 1 H NMR (500 MHz, DMSO-d6, 90°C) δ 10.52 (s, 1H), 8.49 (s,2H), 7.67 (d, J = 8.5 Hz, 1H), 7.53 (s, 1H), 7.25 (dd, J = 8.6, 1.3 Hz, 1H), 6.18 - 6.17 (m, 1H), 4.34 (dd, J = 9.0, 5.2 Hz, 1H), 4.00 (s, 3H), 3.40 -3.35 (m, 1H), 2.75 - 2.62 (m, 8H), 2.41 - 2.32 (m, 2H), 2.28 - 2.22 (m, 2H),1.88 - 1.80 (m, 1H).

[0608] Step 68.4: Synthesis of 2-[[6-[[5-chloro-2-[[4-[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazol-6-yl]cyclohex-3-en-1-yl]-methyl-amino]pyrimidin-4-yl]amino]-1-methyl-2-oxo-3-quinolinyl]oxy]-N-methyl-acetamide. To a solution of 3-[1-methyl-6-[4-(methylamino)cyclohexen-1-yl]indazol-3-yl]piperidine-2,6-dione; 2,2,2-trifluoroacetic acid (48.0 mg, 0.100 mmol) in dimethyl sulfoxide (1.5 mL), 2-[[6-[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]-1-methyl-2-oxo-3-quinolinyl]oxy]-N-methylacetamide (35 mg, 90 µmol, intermediate i-22) and diisopropylethylamine (80 µL, 0.450 mmol) were added. The mixture was heated to 90°C and stirred for 18 hours. The residue was purified by preparative HPLC (BEH column, C18) using a gradient elution of 37-47% acetonitrile and 10 mM ammonium formate in aqueous solution to give the title compound (42.1 mg, 63%) as a solid. MS (ESI) [M+H]+ 724.4. 1 H NMR (500 MHz, DMSO-d6, 90°C) δ 8.51 (s, 1H), 8.34 (s, 1H), 8.04 (s,1H), 7.92 (d, J = 2.3 Hz, 1H), 7.81 (dd, J = 9.0, 2.4 Hz, 1H), 7.63 (d, J =8.5 Hz, 1H), 7.47 (s, 1H), 7.39 (d, J = 9.1 Hz, 1H), 7.21 - 7.18 (m, 2H), 6.24 - 6.22 (m, 1H), 4.81 - 4.74 (m, 1H), 4.43 (s, 2H), 4.33 (dd, J = 8.9,5.2 Hz, 1H), 3.99 (s, 3H), 3.57 (s, 3H), 3.02 (s, 3H), 2.71 - 2.62 (m, 7H), 2.46 - 2.31 (m, 3H), 2.28 - 2.22 (m, 1H), 2.03 - 1.95 (m, 1H), 1.94 - 1.90 (m, 1H). Note: Glutarimide NH signal is not visible.

[0609] Example 69. 2-[[6-[[5-chloro-2-[8-[3-(2,4-dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]-2,8-diazaspiro[4.5]decane-2-yl]pyrimidin-4-yl]amino]-1-methyl-2-oxo-3-quinolinyl]oxy]-N-methyl-acetamide

[0610]

[0611] Step 69.1: Synthesis of tert-butyl 8-[3-(2,4-dioxohexahydropyrimidin-1-yl)-1-methyl-indazole-6-yl]-2,8-diazaspiro[4.5]decane-2-carboxylic acid. A mixture of [3-(2,4-dioxohexahydropyrimidin-1-yl)-1-methyl-indazole-6-yl]boronic acid (intermediate i-9) (124 mg, 0.43 mmol), tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylic acid (207 mg, 0.86 mmol), copper(II) acetate (95 mg, 0.47 mmol), triethylamine (0.12 mL, 0.86 mmol), and 3 Å MS (200 mg) in 1,2-dichloroethane (8 mL) was heated to 50°C for 24 hours under O2 (1 atm). The mixture was filtered through a Celite filter and washed with a 1:1 mixture of acetonitrile and methanol (3 x 5 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by reversed-phase chromatography (C18) using a gradient elution of 10–70% acetonitrile and 10 mM ammonium formate to give the title compound (84 mg, 36%) as a solid. MS (ESI) [M+H]+ 484.3. 1 H NMR (400MHz, DMSO-d6) δ 10.49 (s, 1H), 7.44 (d, J = 9.1 Hz, 1H), 6.91 (d, J = 9.1 Hz,1H), 6.84 (s, 1H), 3.89 (t, J = 6.8 Hz, 2H), 3.88 (s, 3H), 3.30 - 3.17 (m,6H), 3.14 (s, 2H), 2.73 (t, J = 6.7 Hz, 2H), 1.80 - 1.71 (m, 2H), 1.63 (br s,4H), 1.40 (s, 9H).

[0612] Step 69.2: Synthesis of 1-[6-(2,8-diazaspiro[4.5]decane-8-yl)-1-methyl-indazole-3-yl]hexahydropyrimidine-2,4-dione hydrochloride. A solution of 4N HCl in 1,4-dioxane (0.39 mL, 1.57 mmol) was added to a mixture of 8-[3-(2,4-dioxohexahydropyrimidine-1-yl)-1-methyl-indazole-6-yl]-2,8-diazaspiro[4.5]decane-2-carboxylic acid tert-butyl ester (84 mg, 0.16 mmol) in 1,4-dioxane (5 mL). The reaction mixture was heated to 100°C for 2 hours and then cooled to room temperature. The volatiles were evaporated under reduced pressure to give the title compound (78 mg, quantified) as a solid, which was used in the next step without further purification. MS (ESI) [M+H]+ 384.2.

[0613] Step 69.3: Synthesis of 2-[[6-[[5-chloro-2-[8-[3-(2,4-dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]-2,8-diazaspiro[4.5]decane-2-yl]pyrimidin-4-yl]amino]-1-methyl-2-oxo-3-quinolinyl]oxy]-N-methyl-acetamide. To a mixture of 2-[[6-[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]-1-methyl-2-oxo-3-quinolinyl]oxy]-N-methyl-acetamide (15 mg, 40 µmol, intermediate i-22) in dimethyl sulfoxide (0.5 mL), 1-[6-(2,8-diazaspiro[4.5]decane-8-yl)-1-methyl-indazol-3-yl]hexahydropyrimidin-2,4-dione hydrochloride (20 mg, 50 µmol) and diisopropylethylamine (80 µL, 0.48 mmol) were added 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 elution of 34-44% acetonitrile and 10 mM ammonium formate in aqueous solution to give the title compound (10.5 mg, 29%) as a solid. MS (ESI) [M+H]+ 754.4. 1H NMR (500 MHz, DMSO-d6) δ 10.49 (s, 1H), 8.75 (s, 1H), 8.09 (s, 1H), 8.04 (s, 1H), 7.91 (d, J = 9.3 Hz, 2H), 7.44 (d, J =9.0 Hz, 2H), 7.15 (s, 1H), 6.92 (d, J = 10.2 Hz, 1H), 6.84 (s, 1H), 4.62 -4.45 (m, 3H), 3.96 - 3.82 (m, 2H), 3.88 (s, 3H), 3.67 (s, 3H), 3.56 (t, J =6.9 Hz, 2H), 3.41 (s, 2H), 3.27 - 3.17 (m, 3H), 2.73 (t, J = 6.7 Hz, 2H), 2.66 (s, 3H), 1.89 (t, J = 7.1 Hz, 2H), 1.77 - 1.63 (m, 4H).

[0614] Example 70. 6-((5-chloro-2-(4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)-3,5-dimethyl-1H-pyrazol-1-yl)pyrimidin-4-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinoline-3-yl)oxy)-N-methylacetamide

[0615]

[0616] Step 70.1: Synthesis of tert-butyl 4-[3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-indazole-6-yl]-3,5-dimethyl-pyrazole-1-carboxylic acid. A mixture of 6-bromo-3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-indazole (2.5 g, 5.0 mmol), (1-tert-butoxycarbonyl-3,5-dimethyl-pyrazole-4-yl)boronic acid (1.44 g, 6.0 mmol), [1,1′-bis(diphenylphosphine)ferrocene]palladium(II) dichloro(II) (0.18 g, 0.22 mmol) and tripotassium phosphate (2.65 g, 12.5 mmol) in 1,4-dioxane (15 mL) and water (2.5 mL) was heated to 90°C for 3 hours and then cooled to room temperature. The mixture was filtered through a Celite filter and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient elution of 0-50% ethyl acetate in hexane to give the title compound (2.70 g, 88%) as a solid. MS (ESI) [M+H]+ 616.3. 1H NMR (500 MHz, DMSO-d6) δ 7.93 (d, J = 8.1 Hz, 1H), 7.74 (d, J = 8.5Hz, 1H), 7.51 (s, 1H), 7.50 - 7.25 (m, 10H), 6.91 (dd, J = 8.4, 1.3 Hz, 1H), 6.61 (d, J = 8.1 Hz, 1H), 5.46 (s, 2H), 5.44 (s, 2H), 4.08 (s, 3H), 2.43 (s, 3H), 2.18 (s, 3H), 1.60 (s, 9H).

[0617] Step 70.2: Synthesis of tert-butyl 4-[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-6-yl]-3,5-dimethyl-pyrazole-1-carboxylic acid. A mixture of tert-butyl 4-[3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-indazole-6-yl]-3,5-dimethyl-pyrazole-1-carboxylic acid (2.64 g, 4.29 mmol) and Pearlman catalyst (1.14 g, 1.07 mmol) in methanol (20 mL) and tetrahydrofuran (30 mL) was hydrogenated at 50°C (1 atm) for 7 hours. The mixture was cooled to room temperature, filtered through a Celite filter, and washed with methanol (3 x 50 mL) and tetrahydrofuran (3 x 50 mL). The filtrate was concentrated under reduced pressure to give the title compound (1.85 g, 98%) as a solid, which was used in the next step without further purification. MS (ESI) [M+H]+ 438.2. 1 H NMR (400 MHz, CDCl3) δ 7.99 (s, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.18 (s, 1H), 7.02 (d, J = 8.3 Hz, 1H), 4.34 (t, J = 5.9Hz, 1H), 4.04 (s, 3H), 3.09 - 2.98 (m, 1H), 2.77 - 2.66 (m, 1H), 2.63 - 2.51(m, 1H), 2.47 (s, 3H), 2.44 - 2.36 (m, 1H), 2.26 (s, 3H), 1.68 (s, 9H).

[0618] Step 70.3: Synthesis of 3-[6-(3,5-dimethyl-1H-pyrazol-4-yl)-1-methyl-indazole-3-yl]piperidine-2,6-dione hydrochloride. To a solution of 4-[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-6-yl]-3,5-dimethyl-pyrazol-1-carboxylic acid tert-butyl ester (1.8 g, 4.11 mmol) in 1,4-dioxane (10 mL), 4N in 1,4-dioxane and HCl (5.14 mL, 20.6 mmol) were added, and the mixture was stirred at room temperature for 16 hours. The volatiles were evaporated under reduced pressure. Ethyl acetate (10 mL) was added, and the resulting precipitate was collected by filtration, washed with ethyl acetate (3 x 10 mL), and then dried under vacuum to give the title compound (1.45 g, quantitative) as a solid, which was used in the next step without further purification. MS (ESI) [M+H]+ 338.2. 1 ¹H NMR (500 MHz, DMSO-d⁶) δ 10.91 (s, 1H), 7.78 (dd, J = 8.3, 0.4 Hz, 1H), 7.57 (s, 1H), 7.11 (dd, J = 8.4, 1.3 Hz, 1H), 4.41 (dd, J = 10.0, 5.1 Hz, 1H), 4.02 (s, 3H), 2.75 - 2.59 (m, 2H), 2.44 - 2.36 (m, 1H), 2.36 (s, 6H), 2.24 - 2.16 (m, 1H). Note: Exchangeable protons are not visible.

[0619] Step 70.4: Synthesis of 2-[[6-[[5-chloro-2-[4-[[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazol-6-yl]methyl]piperazin-1-yl]pyrimidin-4-yl]amino]-1-methyl-2-oxo-3-quinolinyl]oxy]-N-methyl-acetamide. To a mixture of 3-[6-(3,5-dimethyl-1H-pyrazol-4-yl)-1-methyl-indazole-3-yl]piperidin-2,6-dione hydrochloride (40 mg, 0.11 mmol) and 2-[[6-[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]-1-methyl-2-oxo-3-quinolinyl]oxy]-N-methyl-acetamide (41.9 mg, 0.11 mmol, intermediate 22), N-methyl-2-pyrrolidone (0.25 mL) was added, and the mixture was heated to 160°C for 1 hour, then cooled to room temperature. The crude reaction mixture was purified by preparative HPLC (BEH column, C18) using a gradient elution of 28-38% acetonitrile and 10 mM ammonium formate to give the title compound (32.5 mg, 40%) as a solid. MS (ESI) [M+H]+ 709.3. 1 H NMR (500 MHz, DMSO-d6) δ 8.52 (s, 1H), 8.32 (s, 1H), 8.10 (d, J = 2.4 Hz, 1H), 7.92 (d, J = 4.4Hz, 1H), 7.80 - 7.76 (m, 1H), 7.76 - 7.73 4.00 (s, 3H), 3.68 (s, 3H), 2.73 - 2.61 (m, 2H), 2.56 (d, J = 4.7 Hz, 3H), 2.44 - 2.38 (m, 1H), 2.36 (s, 3H), 2.24 (s, 3H), 2.22 - 2.16 (m, 1H). Note: Exchangeable protons are not visible.

[0620] Example 71. 2-[[6-[[5-chloro-2-[4-[3-(2,4-dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]oxy-1-piperidinyl]pyrimidin-4-yl]amino]-1-methyl-2-oxo-3-quinolinyl]oxy]-N-methyl-acetamide.

[0621]

[0622] Step 71.1: Synthesis of tert-butyl 4-[3-(2,4-dioxohexahydropyrimidin-1-yl)-1-methyl-indazole-6-yl]oxypiperidine-1-carboxylic acid. A mixture of [3-(2,4-dioxohexahydropyrimidin-1-yl)-1-methyl-indazole-6-yl]boronic acid (100 mg, 0.35 mmol, intermediate 9), tert-butyl 4-hydroxypiperidine-1-carboxylic acid (140 mg, 0.69 mmol), copper(II) acetate (139 mg, 0.69 mmol), 4-dimethylaminopyridine (21 mg, 0.17 mmol), and 3 Å MS (350 mg) in 1,2-dichloroethane (7 mL) was heated to 50°C for 24 hours under an O2 atmosphere (1 atm). The mixture was filtered through a Celite filter and washed with a 1:1 mixture of acetonitrile and methanol (3 x 5 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by reversed-phase chromatography (C18) using a gradient elution of 10–100% acetonitrile and 10 mM ammonium formate to give the title compound (42 mg, 27%) as a solid. MS (ESI) [M+H]+ 444.3. 1 ¹H NMR (400 MHz, DMSO-d⁶) δ 7.51 (d, J = 8.7 Hz, 1H), 7.13 (s, 1H), 6.76 (dd, J = 8.9, 1.7 Hz, 1H), 4.70 (s, 1H), 3.92 (s, 3H), 3.96 - 3.85 (m, 2H), 3.71 - 3.64 (m, 2H), 3.26 - 3.18 (m, 2H), 2.74 (t, J = 6.5 Hz, 2H), 2.01 - 1.90 (m, 2H), 1.62 - 1.51 (m, 2H), 1.41 (s, 9H). Note: One exchangeable proton is not shown.

[0623] Step 71.2: Synthesis of 1-[1-methyl-6-(4-piperidinoxy)indazol-3-yl]hexahydropyrimidine-2,4-dione hydrochloride. A solution of 4-[3-(2,4-dioxohexahydropyrimidine-1-yl)-1-methyl-indazol-6-yl]oxypiperidin-1-carboxylic acid tert-butyl ester (42 mg, 0.09 mmol) in 1,4-dioxane (5 mL) was added to a solution of 4N HCl in 1,4-dioxane (0.24 mL, 0.95 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 to give the title compound (33 mg, 92%) as a solid, which was used in the next step without further purification. MS (ESI) [M+H]+ 344.2.

[0624] Step 71.3: Synthesis of 2-[[6-[[5-chloro-2-[4-[3-(2,4-dioxohexahydropyrimidin-1-yl)-1-methyl-indazol-6-yl]oxy-1-piperidinyl]pyrimidin-4-yl]amino]-1-methyl-2-oxo-3-quinolinyl]oxy]-N-methyl-acetamide. To a mixture of 2-[[6-[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]-1-methyl-2-oxo-3-quinolinyl]oxy]-N-methyl-acetamide (30 mg, 80 µmol, intermediate i-22) in DMSO (1 mL), 1-[1-methyl-6-(4-piperidinyloxy)indazol-3-yl]hexahydropyrimidin-2,4-dione (33 mg, 0.10 mmol) and diisopropylethylamine (0.17 mL, 0.96 mmol) were added 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 elution of 41-51% acetonitrile and 10 mM ammonium formate in aqueous solution to give the title compound (20.7 mg, 30%) as a solid. MS (ESI) [M+H]+ 715.3. 1H NMR (400MHz, DMSO-d6) δ 10.53 (s, 1H), 8.88 (s, 1H), 8.07 (s, 1H), 7.93 (d, J = 4.6Hz, 1H), 7.90 (d, J = 2.3 Hz, 1H), 7.77 (dd, J = 9.1, 2.4 Hz, 1H), 7.51 (d, J= 8.9 Hz, 1H), 7.47 (d, J = 9.2 Hz, 1H), 7.15 (d, J = 1.7 Hz, 1H), 7.11 (s,1H), 6.76 (dd, J = 8.9, 2.0 Hz, 1H), 4.84 - 4.74 (m, 1H), 4.56 (s, 2H), 4.13- 4.03 (m, 2H), 3.92 (d, J = 2.0 Hz, 3H), 3.92 - 3.88 (m, 2H), 3.66 (s, 3H), 3.52 (t, J = 9.6 Hz, 2H), 2.74 (t, J = 6.7 Hz, 2H), 2.60 (d, J = 4.6 Hz, 3H), 2.08 - 1.98 (m, 2H), 1.70 - 1.60 (m, 2H).

[0625] Example 72. 2-[[6-[[5-chloro-2-[4-[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazol-7-yl]oxy-1-piperidinyl]pyrimidin-4-yl]amino]-1-methyl-2-oxo-3-quinolinyl]oxy]-N-methyl-acetamide

[0626]

[0627] Step 72.1: Synthesis of 7-bromo-3-iodo-1-methyl-indazole. Iodine (13 g, 51 mmol) and potassium hydroxide (2.8 g, 50.8 mmol) were added sequentially to a solution of 7-bromo-1H-indazole (5 g, 25 mmol) in N,N-dimethylformamide (25 mL) at 0°C. The reaction mixture was warmed to room temperature for 18 hours and then cooled to 0°C. Water (50 mL) and a saturated sodium sulfite solution (50 mL) were added, and the resulting precipitate was collected by filtration, washed with water (3 x 10 mL), and then dried under vacuum to give the title compound (7.8 g, 95%) as a solid, which was used in the next step without further purification. MS (ESI) [M+H]+ 322.6. 1H NMR (400 MHz, DMSO-d6) δ 13.94 (s, 1H), 7.70 (dd, J = 7.4, 0.7 Hz, 1H), 7.47 (dd, J = 8.1, 0.7 Hz, 1H), 7.15 (dd, J = 8.0,7.5 Hz, 1H).

[0628] Step 72.2: Synthesis of 7-bromo-3-iodo-1H-indazole. Sodium hydride (1.7 g, 43 mmol) was added to a solution of 7-bromo-3-iodo-1H-indazole (7.8 g, 24 mmol) in N,N-dimethylformamide (25 mL) at 0°C, and the reaction mixture was stirred for 30 min. Iodomethane (1.6 mL, 26 mmol) was added, and the mixture was warmed to room temperature for 2 h. The mixture was cooled to 0°C, water (100 mL) was added, and the precipitate was collected by filtration, washed with water (2 x 50 mL), and then dried under vacuum. The residue was purified by silica gel column chromatography using a gradient elution of ethyl acetate from 0-100% in hexane to give the title compound (6.1 g, 75%) as a solid. MS (ESI) [M+H]+ 336.9. 1 H NMR (400 MHz, DMSO-d6) δ 7.73 (dd, J = 7.4, 0.9 Hz, 1H), 7.46 (dd, J = 8.1, 0.9 Hz, 1H), 7.13 (dd, J = 8.1, 7.5 Hz, 1H), 4.35 (s, 3H).

[0629] Step 72.3: Synthesis of 7-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole. A mixture of 7-bromo-3-iodo-1-methyl-indazole (1.5 g, 4.5 mmol), 2,6-dibenzyloxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyridine (2.8 g, 6.7 mmol), tetrakis(triphenylphosphine)palladium(0) (514 mg, 0.45 mmol), and tripotassium phosphate (2.8 g, 13.4 mmol) in 1,4-dioxane (36 mL) and water (9 mL) was heated to 100°C for 3 hours, and then cooled to room temperature. Water (20 mL) and ethyl acetate (50 mL) were added, and the layers were separated. The organic layer was washed with saturated ammonium chloride solution (20 mL) and brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient elution of 5-50% ethyl acetate in hexane to give the title compound (1.1 g, 49%) as a solid. MS (ESI) [M+H]+ 50 1.2. 1 H NMR (400 MHz, DMSO-d6) δ 7.87 (d, J = 8.1 Hz,1H), 7.66 (dd, J = 8.1, 0.8 Hz, 1H), 7.61 (dd, J = 7.4, 0.8 Hz, 1H), 7.50 -7.45 (m, 2H), 7.43 - 7.38 (m, 2H), 7.37 - 7.30 (m, 4H), 7.30 - 7.26 (m, 2H), 6.93 (dd, J = 8.1, 7.5 Hz, 1H), 6.60 (d, J = 8.1 Hz, 1H), 5.44 (s, 2H), 5.43 (s, 2H), 4.36 (s, 3H).

[0630] Step 72.4: Synthesis of 3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole-7-ol. A mixture of 7-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole (1.1 g, 2.2 mmol), tBuXPhos-Pd-G3 (93 mg, 0.11 mmol), and 1M potassium hydroxide (8.8 mL, 8.8 mmol) in 1,4-dioxane (20 mL) was heated to 100°C for 1 hour, then cooled to room temperature. Water (50 mL) and ethyl acetate (100 mL) were added, and the layers were separated. The organic layer was washed with saturated aqueous ammonium chloride solution (50 mL) and brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient elution of ethyl acetate from 0-100% in hexane to give the title compound (800 mg, 83%) as a semi-solid. MS (ESI) [M+H]+ 439.2. 1 H NMR (500 MHz, DMSO-d6) δ10.12 (s, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.47 (d, J = 7.1 Hz, 2H), 7.43 -7.37 (m, 2H), 7.37 - 7.32 (m, 3H), 7.31 - 7.23 (m, 3H), 7.04 (d, J = 8.1 Hz, 1H), 6.79 (app t, J = 7.8 Hz, 1H), 6.65 (d, J = 7.4 Hz, 1H), 6.57 (d, J = 8.0Hz, 1H), 5.43 (s, 2H), 5.41 (s, 2H), 4.25 (s, 3H).

[0631] Step 72.5: Synthesis of tert-butyl 4-[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole-7-yl]oxypiperidine-1-carboxylic acid. To a solution of 3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole-7-ol (800 mg, 1.8 mmol) in N,N-dimethylformamide (12 mL), tert-butyl 4-(p-toluenesulfonyloxy)piperidine-1-carboxylic acid (975 mg, 2.7 mmol) and cesium carbonate (1.2 g, 3.7 mmol) were added sequentially. The reaction mixture was heated to 60°C for 2 hours and then cooled to room temperature. Water (10 mL) and ethyl acetate (20 mL) were added, and the layers were separated. The organic layer was washed with saturated ammonium chloride solution (5 mL), water (3 x 5 mL), and brine (5 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient elution of ethyl acetate from 0-100% in hexane to give the title compound (800 mg, 70%) as a solid. MS (ESI) [M+H]+ 622.7. 1 H NMR (400 MHz, DMSO-d6) δ7.84 (d, J = 8.1 Hz, 1H), 7.47 (d, J = 7.0 Hz, 2H), 7.43 - 7.33 (m, 5H), 7.32- 7.24 (m, 3H), 7.17 (dd, J = 7.0, 1.8 Hz, 1H), 6.94 - 6.84 (m, 2H), 6.58 (d,J = 8.1 Hz, 1H), 5.43 (s, 2H), 5.42 (s, 2H), 4.82 - 4.74 (m, 1H), 4.26 (s,3H), 3.68 - 3.55 (m, 2H), 3.40 - 3.33 (m, 2H), 2.04 - 1.92 (m, 2H), 1.77 -1.66 (m, 2H), 1.41 (s, 9H).

[0632] Step 72.6: Synthesis of tert-butyl 4-[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-7-yl]oxypiperidin-1-carboxylic acid. A mixture of tert-butyl 4-[3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-indazole-7-yl]oxypiperidin-1-carboxylic acid (800 mg, 1.29 mmol) and Pearlman catalyst (200 mg, 25 wt% loading) in a mixture of ethanol (13 mL) and tetrahydrofuran (13 mL) was hydrogenated at 1 atm and 50°C for 3 h. The mixture was filtered through a Celite filter and washed with a mixture of acetonitrile and methanol (1:1, 3 x 20 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using a gradient elution of 0-10% methanol in dichloromethane to give the title compound (405 mg, 71%) as a solid. MS (ESI) [M+H]+ 443.2. 1 H NMR (400 MHz, DMSO-d6) δ 10.87 (s,1H), 7.21 (dd, J = 8.0, 0.7 Hz, 1H), 6.98 (app t, J = 7.8 Hz, 1H), 6.91 (d, J= 7.4 Hz, 1H), 4.83 - 4.75 (m, 1H), 4.31 (dd, J = 9.8, 5.1 Hz, 1H), 4.18 (s,3H), 3.66 - 3.56 (m, 2H), 3.40 - 3.33 (m, 2H), 2.73 - 2.55 (m, 2H), 2.38 -2.27 (m, 1H), 2.21 - 2.11 (m, 1H), 2.03 - 1.92 (m, 2H), 1.77 - 1.65 (m, 2H), 1.41 (s, 9H).

[0633] Step 72.7: Synthesis of 3-[1-methyl-7-(4-piperidinyloxy)indazole-3-yl]piperidine-2,6-dione hydrochloride. 4N HCl (2.3 mL, 9.2 mmol) in 1,4-dioxane was added to a solution of 4-[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-7-yl]oxypiperidine-1-carboxylic acid tert-butyl ester (405 mg, 0.92 mmol) in 1,4-dioxane (10 mL). The reaction mixture was heated to 100°C for 3 hours and then cooled to room temperature. The volatiles were evaporated under reduced pressure. Diethyl ether (10 mL) was added, and the resulting precipitate was collected by filtration, washed with diethyl ether (3 x 5 mL), and then dried under vacuum to give the title compound (340 mg, 96%) as a solid. MS (ESI) [M+H]+ 343.5. 1 H NMR (400 MHz, D2O)δ 7.28 (d, J = 7.8 Hz, 1H), 7.11 (app t, J = 7.5 Hz, 1H), 6.96 (d, J = 7.9Hz, 1H), 4.92 (br s, 1H), 4.43 (dd, J = 11.6, 4.8 Hz, 1H), 4.26 (s, 3H), 3.52- 3.39 (m, 2H), 3.38 - 3.24 (m, 2H), 2.89 - 2.72 (m, 2H), 2.53 - 2.40 (m,1H), 2.35 - 2.16 (m, 5H).

[0634] Step 72.8: Synthesis of 2-[[6-[[5-chloro-2-[4-[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazol-7-yl]oxy-1-piperidinyl]pyrimidin-4-yl]amino]-1-methyl-2-oxo-3-quinolinyl]oxy]-N-methyl-acetamide. To a suspension of 3-[1-methyl-7-(4-piperidinyloxy)inzol-3-yl]piperidine-2,6-dione hydrochloride (70 mg, 0.18 mmol) in dimethyl sulfoxide (1 mL), 2-[[6-[(5-chloro-2-fluoro-pyrimi...

Claims

1. Compounds of formula (I): ， Or its pharmaceutically acceptable salt, wherein: Ring A is a 4- to 12-membered nitrogen-containing heterocyclic group, a 5- to 12-membered carbocyclic group, a 5- to 6-membered nitrogen-containing heteroaryl group, or a phenylene group. or , or does not exist, where ring A, when it exists, is (R 10 ) x replace; Each R 10 Independently, it is a halogen, a C1-C6 alkyl, a C1-C6 alkoxy, a C1-C6 hydroxyalkyl, or a C1-C6 haloalkyl, or two Rs. 10 Together with the carbon atoms they are connected to, they form oxo groups; x is 0, 1, 2, 3 or 4; L 1 It is N(R) 11 ) or N(R 11 CH2C(O) or not present; R 11 It is hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, or C1-C6 haloalkyl; L 2 It is -(CH2) y N(R 12 )-、-O(CH2) y -、-N(R 12 )C(O)-、-C(O)N(R 12 (CH2) z -、-C(O)N(R 12 (CH2) z N(R 12 )-、-C(O)N(R 12 (CH2) z O-, -(CH2) z C(O)N(R 12 )- or (CH2) z Or it may not exist; Each R 12 It is independently hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 deuterated alkyl, or C1-C6 haloalkyl; y is 0 or 1; z is 1, 2, 3, 4 or 5; R 1 It is hydrogen or C1-C6 alkyl; R 2 It is a C1-C6 alkyl group; R 3 It is either halogen or cyano; R 4 yes , , , , , , , , , or ; X 1 It is C(R) 13 ) or N; X 2 X 3 and X 4 It is C(H); or X 2 and X 4 It is C(H), and X 3 It is N; or X 2 It is N, and X 3 and X 4 It is C(H); or X 2 and X 3 It is C(H), and X 4 It is N; R 13 It is hydrogen or C1-C6 alkyl; Each R 14 Halogens are independent of each other; R 52 It is hydrogen or C1-C6 alkyl; and p is 0, 1, 2 or 3.

2. The compound of claim 1, wherein ring A is a 4- to 6-membered monocyclic nitrogen-containing heterocyclic group, an 8- to 10-membered spirocyclic nitrogen-containing heterocyclic group, or an 8- to 10-membered fused bicyclic nitrogen-containing heterocyclic group.

3. The compound of claim 1, wherein ring A is piperidinyl, piperazineyl, azacyclobutane, pyrrolidine, 2,6-diazaspiro[3.4]octyl, 2,8-diazaspiro[4.5]decyl, 8-azabicyclo[3.2.1]octyl, octahydro-1H-pyrrolo[3,2-c]pyridinyl, cyclohexenyl, pyrazolyl, or Its being (R) 10 ) x Replacement; or ring A does not exist.

4. The compound of any one of claims 1-3, wherein each R 10 Independently halogen, C1-C6 alkyl or C1-C6 hydroxyalkyl, or two R 10 Together with the carbon atoms they are connected to, they form an oxo group; and x is 0, 1, or 2.

5. The compound of any one of claims 1-4, wherein L 1 It is N(R) 11 ); and R 11 It is hydrogen, C1-C6 alkyl, or C1-C6 hydroxyalkyl.

6. The compound of any one of claims 1-5, wherein L 1 It does not exist.

7. The compound of any one of claims 1-6, wherein L 2 It is -(CH2) y N(R 12 )-、-O(CH2) y -、-N(R 12 )C(O)-、-C(O)N(R 12 (CH2) z -、-C(O)N(R 12 (CH2) z N(R 12 )-、-C(O)N(R 12 (CH2) z O-、 -(CH2) z C(O)N(R 12 )- or (CH2) z And each R 12 It is independently hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl or C1-C6 deuterated alkyl.

8. The compound of any one of claims 1-6, wherein L 2 It is -N(H)-, -N(CH3)-, -N(CH2CH2OH)-, -CH2N(H)-, -CH2N(CH3)-, -CH2N(CD3)-, -O-, -OCH2-, -N(H)C(O)-, -C(O)N(H)CH2-, -C(O)N(H)CH2CH2N(H)-, -C(O)N(H)CH2CH2CH2N(H)-, -C(O)N(H)CH2CH2O-, -CH2C(O)N(H)- or -CH2- or does not exist.

9. The compound of any one of claims 1-8, wherein R 1 It is hydrogen or methyl; and R 2 It is a methyl group.

10. The compound of any one of claims 1-9, wherein R 4 yes: , , , , , , , , , , or .

11. The compound of any one of claims 1-10, wherein R 13 It is either hydrogen or methyl.

12. The compound of any one of claims 1-11, wherein R 14 It's fluorine.

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

14. A compound according to any one of claims 1-4 and 7-13, having formula (II): ， Or its pharmaceutically acceptable salt.

15. A compound according to any one of claims 1, 4, 5 and 9-12, having formula (III): ， Or its pharmaceutically acceptable salt.

16. A compound according to any one of claims 1-4 and 9-12, having formula (IV): ， Or its pharmaceutically acceptable salt.

17. The compounds in Table 1 or their pharmaceutically acceptable salts.

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

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

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

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