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-references to related applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 595,065, 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 salt, wherein the value of the variable (e.g., ring A, L) 1 L 2 Z 1 Z 2 R 1 R 2 R 4 As described in this article.

[0017] In another aspect, pharmaceutical compositions are provided comprising the compounds described herein (e.g., compounds of formulas (I)-(VI) 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)-(VI) 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, a method for treating cancer or autoimmune diseases in individuals in need is provided, the method comprising administering to the individual an effective amount of a compound described herein (e.g., a compound of formula (I)-(VI) or Table 1 or a pharmaceutically acceptable salt of any of the foregoing 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)-(VI) 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)-(VI) 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)-(VI) 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(Ra )C(O)R a -N(R) a S(O) t R a (where t is 1 or 2), -S(O) t OR a (where t is 1 or 2), -S(O) t R a (where t is 1 or 2) and -S(O) t N(R a )2 (where t is 1 or 2), where 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 bonded via oxygen atoms, wherein 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 or inorganic bases and organic acids or organic bases). Suitable pharmaceutically acceptable base addition salts of compounds include, but are not limited to, metal salts prepared from, for example, aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc, or organic salts prepared from, for example, 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.

[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] Z 1 It is C(R) 3 ), and Z 2 Is it N or Z? 1 It is N, and Z 2 It is C(R) 3 );

[0090] R 3 It is either halogen or cyano;

[0091] L 1 It is N(R) 11 (or does not exist;)

[0092] R 11 It is hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, or C1-C6 haloalkyl;

[0093] 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;

[0094] Each R 12 It is independently hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 deuterated alkyl, or C1-C6 haloalkyl;

[0095] y is 0 or 1;

[0096] z is 1, 2, 3, 4 or 5;

[0097] R 1 yes: , , , , , , , , , , , , , or ;

[0098] Z 3 It is C(H)2, C(H)(CH2CH2C(O)NR 1b R 1c ), C(H)(OCH2C(O)NR 1b R 1c ), N(CH2CH2C(O)NR 1b R 1c ), and Z 4 It is C(H)2; or

[0099] Z 3 It is C(H)2 or C(H)(CH2CH2C(O)NR 1b R 1c ), and Z 4 It is O;

[0100] Z 5 It is C(H)2, C(F)2, or C(H)(F);

[0101] R 1a It is hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl or -CH2CH2C(O)NR 1b R 1c ;

[0102] R 1b It is hydrogen or C1-C6 alkyl;

[0103] R 1c It is a C1-C6 alkyl group;

[0104] R 1d It is hydrogen or halogen;

[0105] R 1e It is -N(R) 1a )C(O)(C1-C6 alkyl), -N(R) 1a )C(O)NR 1b R 1c -CH2C(O)NR 1b R 1c 5 to 6-membered heteroaryl or ;

[0106] Z 6 It is C(H2), C(H)R 1a or N(R) 1a );

[0107] Z 7 Is it O or S?

[0108] R 2 It is hydrogen or fluorine;

[0109] R 3 It is either halogen or cyano;

[0110] R 4 yes , , , , , , , , , or ;

[0111] X 1 It is C(R) 13 ) or N;

[0112] 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;

[0113] R 13 It is hydrogen or C1-C6 alkyl.

[0114] Each R 14 Halogens are independent of each other;

[0115] R 52 It is hydrogen or C1-C6 alkyl; and

[0116] p is 0, 1, 2, or 3;

[0117] The condition is when R 4 yes At that time, R 1 no or .

[0118] In another respect, this paper provides compounds of formula (II):

[0119] ,

[0120] 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.

[0121] In another aspect, this paper provides compounds of formula (III):

[0122] ,

[0123] Or a pharmaceutically acceptable salt thereof, wherein the value of the variable (e.g., R) 1 R 2 R 3 R 4 R 10 R 11 (x) as described with respect to compounds of formula (I) or elsewhere herein.

[0124] In another aspect, this paper provides compounds of formula (IV):

[0125] ,

[0126] 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.

[0127] In another respect, this paper provides the compound formula (V):

[0128] ,

[0129] Or its pharmaceutically acceptable salt, wherein L 1 and L 2 One of them does not exist, and R 50 It is hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 deuterated alkyl, or C1-C6 haloalkyl. The values ​​of other variables (e.g., ring A, L) 1 L 2 R 2R 3 As described with respect to compounds of formula (I) or elsewhere herein. In some embodiments of formula (V), yes The value of the variable R 10 R 11 x is as described with respect to compounds of formula (I) or elsewhere herein. The values ​​of the remaining variables are as described with respect to compounds of formula (I) or elsewhere herein. In some embodiments of formula (V), the compound is not 3-(6-(4-((5-chloro-4-((1-(3-hydroxy-3-methylbutyl)-2-oxo-dihydroindole-6-yl)amino)pyrimidin-2-yl)amino)piperidin-1-yl)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione, 3-[6-[[1-[5-chloro-4-[[1-(3-hydroxy-3-methyl-butyl)-2-oxo-dihydroindole-6-yl]amino] [Pyrimidin-2-yl]-4-piperidinyl]amino]-1-methyl-indazole-3-yl]piperidin-2,6-dione, 3-(6-((1-(5-chloro-4-((1-(3-hydroxy-3-methylbutyl)-2-oxodihydroindole-6-yl)amino)pyrimidin-2-yl)piperidin-4-yl)(methyl)amino)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione, 3-(6-(4-((5-chloro-4-((1-(3-hydroxy-3-methylbutyl)-2-oxodihydroindole-6-yl)amino)pyrimidin-2-yl)(methyl)amino)piperidin-1-yl)-1-methyl-1H-indazole- 3-yl)piperidin-2,6-dione, 3-(6-(((3R,4R)-1-(5-chloro-4-((1-methyl-2-oxodihydroindole-6-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione, or 3-(6-(((3R,4R)-1-(5-chloro-4-((1-(3-hydroxy-3-methylbutyl)-2-oxodihydroindole-6-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione, or salts thereof.

[0130] In another respect, this paper provides compounds of formula (VI):

[0131] ,

[0132] Or a pharmaceutically acceptable salt thereof, wherein R 51 It is hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 deuterated alkyl, or C1-C6 haloalkyl (e.g., in some embodiments, C1-C6 alkyl, such as methyl); R 52It is hydrogen or a C1-C6 alkyl group (e.g., hydrogen or methyl in some embodiments); and R 53 It is hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, or C1-C6 haloalkyl (e.g., in some embodiments, hydrogen, C1-C6 alkyl, or C1-C6 alkoxy, such as hydrogen, methyl, or methoxy). The values ​​of the remaining variables (e.g., R) 2 R 3 R 13 As described with respect to compounds of formula (I) or elsewhere in this document.

[0133] In some embodiments, ring A is a 4- to 12-membered nitrogen-containing heterocyclic group or a 5- to 6-membered nitrogen-containing heteroaryl 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.

[0134] In some implementations, ring A is a 5- to 12-membered carbocyclic group or a phenylene group.

[0135] 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 Substitution. In some embodiments, ring A is piperidinyl, piperazineyl, 2,8-diazaspiro[4,5]decylene, phenylene, or... Its being (R) 10 ) x Replacement. 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.

[0136] In the alternative implementation, ring A does not exist.

[0137] 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 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 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.

[0138] 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.

[0139] In some implementations, L 1 It is N(R) 11 In some implementations, L 1 It does not exist.

[0140] 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 11 It is methyl. In some embodiments, R 11 It is a C1-C6 alkyl, C1-C6 hydroxyalkyl, or C1-C6 haloalkyl.

[0141] 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)-.

[0142] In the alternative implementation scheme, L 2 It does not exist.

[0143] In some implementations, each R 12 Independently hydrogen or C1-C6 alkyl. In one specific embodiment, each R 12Independently 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 Independently, it is a C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 deuterated alkyl, or C1-C6 haloalkyl. In some embodiments, 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 It can be hydrogen, methyl, hydroxyethyl, or -CD3 independently.

[0144] In some implementations, y is 0. In some implementations, y is 1.

[0145] 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.

[0146] In some implementation schemes, R 1 yes:

[0147] , , , , , , , , , , , , , , or In one specific implementation plan, R 1 yes:

[0148] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0149] In some implementation schemes, Z 3 It is C(H)2, C(H)(CH2CH2C(O)N(H)CH3) or N(CH2CH2C(O)N(H)CH3), and Z 4 It is C(H)2. In some implementations, Z 3 It is C(H)2 or C(H)(CH2CH2C(O)N(H)CH3), and Z 4 It is O.

[0150] In some implementation schemes, Z 5 It is C(H)2.

[0151] In some implementation schemes, R 1a It is hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 deuterated alkyl, or -CH2CH2C(O)NR 1b R 1c In some implementations, R 1a It is hydrogen, methyl, -CD3, hydroxymethyl, hydroxypentyl, or -CH2CH2C(O)N(H)CH3. In some embodiments, R 1a It is either hydrogen or methyl.

[0152] In some implementation schemes, R 1b It is hydrogen or methyl. In one specific implementation, R 1b It is hydrogen. In another specific implementation, R 1b It is a methyl group.

[0153] In some implementation schemes, R 1c It is a methyl group.

[0154] In some implementation schemes, R 1d It is either hydrogen or fluorine.

[0155] In some implementation schemes, R 1e It is -N(R) 1a )C(O)CH3、-N(R 1a )C(O)NR 1b R 1c -CH2C(O)NR 1b R 1c Imidazole, pyrazol, oxazol, isoxazol, thiazolyl, isothiazol, or .

[0156] In some implementation schemes, Z 6 It is C(H)2. In some implementations, Z 6 It is C(H)R 1a or N(R) 1a ).

[0157] In some implementation schemes, Z 7 It is O. In some implementations, Z 7 It is S.

[0158] In some implementation schemes, R 2 It is hydrogen.

[0159] 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.

[0160] In some implementation schemes, R 4 yes:

[0161] , , , , , , , , , , , , , , , or In one specific implementation plan, R 4 yes:

[0162] , , , , , , , , 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 .

[0163] In some implementation schemes, R 4 yes:

[0164] , , , , or In some implementations, R 4 yes:

[0165] , , , , , , , , , , 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 .

[0166] In some implementation schemes, X 2 X 3 and X 4 It is C(H). In some implementations, X 2 X 3 and X 4One 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.

[0167] In some implementation schemes, R 13 It is hydrogen or methyl. In one specific implementation, R 13 It is hydrogen.

[0168] In some implementation schemes, R 14 It's fluorine.

[0169] In some implementation schemes, R 50 It is hydrogen, C1-C6 alkyl, or C1-C6 hydroxyalkyl. In one specific embodiment, R 50 It is hydrogen, methyl, or hydroxypentyl.

[0170] In some implementation schemes, R 51 It is a C1-C6 alkyl group. In one specific embodiment, R 51 It is a methyl group.

[0171] 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.

[0172] In some implementation schemes, R 53 It is hydrogen, C1-C6 alkyl, or C1-C6 alkoxy. In one specific embodiment, R 53 It is hydrogen, methyl, or methoxy.

[0173] In some implementations, p is 0 or 1. In one specific implementation, p is 0. In another specific implementation, p is 1.

[0174] In another respect, this document provides compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein ring A is phenylene. Values ​​for the remaining variables are as described with respect to compounds of formula (I) or elsewhere herein.

[0175] 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 Z 3 Z 4 Z 5 Z 6 R 1 R 1a R 1b R 1c R 1d R 1e R 2 R 4 R 10 R 11 R 12 R 13 One or more.

[0176] 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), (IV), and (V), and are described equally, as if each description, variation, embodiment, or aspect were listed separately and individually for all chemical formulas.

[0177] 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.

[0178] Table 1.

[0179]

[0180]

[0181]

[0182]

[0183]

[0184]

[0185]

[0186]

[0187]

[0188]

[0189] Or its pharmaceutically acceptable salt.

[0190] In some embodiments, compounds selected from the following are provided:

[0191] , , ,

[0192] , ,

[0193] , or

[0194] ,

[0195] Or its pharmaceutically acceptable salt.

[0196] 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.

[0197] 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.

[0198] Process 1.

[0199]

[0200] Where R 1a R 1e R 2 and R 3 As stated in equation (I); X" is C, and R and R' are as R in equation (I). 1d and R 1e The stated, or X", is C or N, and R and R' together with the atoms in between form a monocyclic or polycyclic (e.g., bicyclic) ring, such as R in formula (I). 1 In the middle; LG2 and LG3 are independently leaving groups, such as F or Cl.

[0201] Process 2.

[0202]

[0203] Where x and R 10 R 11 and R 12 As described in formula (I); LG4 is a leaving group, such as Br or Cl; Y is H, C1-C6 alkyl, 6- or 7-membered heterocyclic group or Boc, wherein the heterocyclic group contains 1-3 heteroatoms selected from N, O and S; PG is a protecting group, such as Boc; X is CH, CH2, N, NH or NBoc; X' is CH, CH2, N or NH; As described for ring A of formula (I), such as a pentyl or 6-membered heterocyclic group; and Bn is benzyl.

[0204] Step 3.

[0205]

[0206] Where R 12 As stated in equation (I); PG 1 is a protecting group, such as Fmoc or Boc; LG4 is a leaving group, such as Br or Cl; and Y is H, C1-C6 alkyl, 6- or 7-membered heterocyclic group or Boc, wherein the heterocyclic group contains 1-3 heteroatoms selected from N, O and S.

[0207] Step 4.

[0208]

[0209]

[0210]

[0211] Where R 2 R 3 R 10 R 11 and R 13As defined in formula (I); LG3 is a leaving group, such as OTs, OMs, F, Cl or I; A is C or N; E is N, C (=O) or C (H); G is N, N (H), N (CH3), C (H), C (H)2, C (CH3), C (H)(CH3) or C (=O); and X", R and R' are as described in process 1.

[0212] As outlined in Process 1, compounds of formula (i-1) can be synthesized by coupling compound e (e.g., compounds e-1 to e-16) with compound f to form compounds of formula (i-1).

[0213] Procedure 2 provides two routes for the synthesis of compounds j' or m'. Indazole derivative g can be coupled with compound h to provide compound i. Deprotection and further reduction of compound i form compound j, which is optionally deprotected to form compound j'. Alternatively, indazole derivative g can be coupled with compound k to give compound l. Deprotection and further reduction of compound l form compound m, which is optionally deprotected with an amine to form compound m'.

[0214] Procedure 3 provides the synthesis of compound p'. Indazole derivative n can be coupled with compound h to give compound o, which is then deprotected to form compound p, and optionally subsequently deprotected to form compound p'.

[0215] Procedure 4 provides the synthesis of various compounds of formula (I) (e.g., formula (Ia), formula (Ib), etc.). The compound of formula (i-1) can be coupled with various compounds of formula (i-2) (e.g., compounds of formulas (i-2a) to (i-2l)) to obtain the compound of formula (I).

[0216] How to use

[0217] 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.

[0218] 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.

[0219] 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%.

[0220] 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.

[0221] 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.

[0222] 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%.

[0223] 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).

[0224] 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.

[0225] 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.

[0226] 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.

[0227] 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.

[0228] 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.

[0229] 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.

[0230] 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).

[0231] 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.

[0232] 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).

[0233] 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.

[0234] 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.

[0235] 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.

[0236] Pharmaceutical Compositions and Routes of Administration

[0237] 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.

[0238] 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.

[0239] 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.

[0240] 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.

[0241] 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.

[0242] 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.

[0243] 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.

[0244] 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.

[0245] 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.

[0246] 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.

[0247] 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.

[0248] 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.

[0249] Exemplary Implementation

[0250] Implementation Scheme 1. Compound of Formula (I):

[0251] ,

[0252] Or its pharmaceutically acceptable salt, wherein:

[0253] 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;

[0254] 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;

[0255] x is 0, 1, 2, 3 or 4;

[0256] Z 1 It is C(R) 3 ), and Z 2 Is it N or Z? 1 It is N, and Z 2 It is C(R) 3 );

[0257] R 3 It is either halogen or cyano;

[0258] L 1 It is N(R) 11 (or does not exist;)

[0259] R 11 It is hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, or C1-C6 haloalkyl;

[0260] 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;

[0261] Each R 12 It is independently hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 deuterated alkyl, or C1-C6 haloalkyl;

[0262] y is 0 or 1;

[0263] z is 1, 2, 3, 4 or 5;

[0264] R 1 yes: , , , , , , , , , , , , , or ;

[0265] Z 3 It is C(H)2, C(H)(CH2CH2C(O)NR 1b R 1c ), C(H)(OCH2C(O)NR 1b R 1c ), N(CH2CH2C(O)NR 1b R 1c ), and Z 4 It is C(H)2; or

[0266] Z 3 It is C(H)2 or C(H)(CH2CH2C(O)NR 1b R 1c ), and Z 4 It is O;

[0267] Z 5 It is C(H)2, C(F)2, or C(H)(F);

[0268] R 1a It is hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl or -CH2CH2C(O)NR 1b R 1c ;

[0269] R 1b It is hydrogen or C1-C6 alkyl;

[0270] R 1c It is a C1-C6 alkyl group;

[0271] R 1d It is hydrogen or halogen;

[0272] R 1e It is -N(R) 1a )C(O)(C1-C6 alkyl), -N(R) 1a )C(O)NR 1b R 1c -CH2C(O)NR 1b R 1c 5 to 6-membered heteroaryl or ;

[0273] Z 6 It is C(H2), C(H)R 1a or N(R) 1a );

[0274] Z 7 Is it O or S?

[0275] R 2 It is hydrogen or fluorine;

[0276] R 3 It is either halogen or cyano;

[0277] R 4 yes , , , , , , , , , or ;

[0278] X 1 It is C(R) 13 ) or N;

[0279] 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;

[0280] R 13 It is hydrogen or C1-C6 alkyl.

[0281] Each R 14 Halogens are independent of each other;

[0282] R 52 It is hydrogen or C1-C6 alkyl; and

[0283] p is 0, 1, 2, or 3;

[0284] The condition is when R 4 yes At that time, R 1 no or .

[0285] Implementation Scheme 2. The compound of Implementation Scheme 1, wherein ring A is a 4- to 12-membered nitrogen-containing heterocyclic group.

[0286] Implementation Scheme 3. The compound of Implementation Scheme 2, wherein ring A is a 4- to 6-membered monocyclic nitrogen-containing heterocyclic group or an 8- to 10-membered spirocyclic nitrogen-containing heterocyclic group.

[0287] Implementation Scheme 4. The compound of Implementation Scheme 1, wherein ring A is piperidinyl, piperazineyl, 2,8-diazaspiro[4,5]decylene, phenylene, or Its being (R) 10 ) x replace.

[0288] Implementation Scheme 5. The compound of Implementation Scheme 4, wherein ring A is (R 10 ) x Substituted piperidinyl group.

[0289] Implementation Scheme 6. The compound of Implementation Scheme 1, wherein ring A is absent.

[0290] Implementation Scheme 7. A compound of any one of Implementation Schemes 1-5, wherein R 10 It is a halogen, a C1-C6 alkyl, or a C1-C6 alkoxy.

[0291] Implementation Scheme 8. The compound of Implementation Scheme 7, wherein R 10 It is fluorine, methyl, or methoxy.

[0292] Implementation Scheme 9. A compound of any one of Implementation Schemes 1-8, wherein x is 0 or 1.

[0293] Implementation Scheme 10. A compound of any one of Implementation Schemes 1-9, wherein L 1 It is N(R) 11 ).

[0294] Implementation Scheme 11. A compound of any one of Implementation Schemes 1-10, wherein R 11 It is hydrogen or C1-C6 alkyl.

[0295] Implementation Scheme 12. The compound of Implementation Scheme 11, wherein R 11 It is either hydrogen or methyl.

[0296] Implementation Scheme 13. A compound of any one of Implementation Schemes 1-9, wherein L 1 It does not exist.

[0297] 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)- or -(CH2) z C(O)N(R 12 )-.

[0298] Implementation Scheme 15. The compound of Implementation Scheme 14, wherein L 2 It is (CH2) y N(R 12 ) or -O(CH2) y -

[0299] Implementation Scheme 16. A compound of any one of Implementation Schemes 1-15, wherein each R 12 It is independently hydrogen or C1-C6 alkyl.

[0300] Implementation Scheme 17. The compound of Implementation Scheme 16, wherein each R 12 It can be hydrogen or methyl on its own.

[0301] Implementation Scheme 18. A compound of any one of Implementation Schemes 1-17, where y is 0.

[0302] Implementation Scheme 19. A compound of any one of Implementation Schemes 1-17, wherein y is 1.

[0303] Implementation Scheme 20. A compound of any one of Implementation Schemes 1-18, wherein z is 1, 2 or 3.

[0304] Implementation Scheme 21. A compound of any one of Implementation Schemes 1-13, wherein L 2 It is -N(H)-, -N(CH3)-, -CH2N(H)-, -O-, -N(H)C(O)- or -CH2C(O)N(H)-.

[0305] Implementation Scheme 22. A compound of any one of Implementation Schemes 1-13, wherein L 2 It does not exist.

[0306] Implementation Scheme 23. A compound of any one of Implementation Schemes 1-22, wherein R 1 yes:

[0307] , , , , , , , , , , , , , , or .

[0308] Implementation Scheme 24. A compound of any one of Implementation Schemes 1-23, wherein Z 3 It is C(H)2, C(H)(CH2CH2C(O)N(H)CH3) or N(CH2CH2C(O)N(H)CH3), and Z 4 It is C(H)2.

[0309] Implementation Scheme 25. A compound of any one of Implementation Schemes 1-23, wherein Z 3 It is C(H)2 or C(H)(CH2CH2C(O)N(H)CH3), and Z 4 It is O.

[0310] Implementation Scheme 26. A compound of any one of Implementation Schemes 1-25, wherein Z 5 It is C(H)2.

[0311] Implementation Scheme 27. A compound of any one of Implementation Schemes 1-26, wherein R 1a It is hydrogen, methyl, -CD3, hydroxymethyl, hydroxypentyl or -CH2CH2C(O)N(H)CH3.

[0312] Implementation Scheme 28. A compound of any one of Implementation Schemes 1-27, wherein R 1b It is either hydrogen or methyl.

[0313] Implementation Scheme 29. A compound of any one of Implementation Schemes 1-28, wherein R 1c It is a methyl group.

[0314] Implementation Scheme 30. A compound of any one of Implementation Schemes 1-29, wherein R 1d It is either hydrogen or fluorine.

[0315] Implementation Scheme 31. A compound of any one of Implementation Schemes 1-30, wherein R 1e It is -N(R) 1a C(O)CH3、 -N(R 1a )C(O)NR 1b R 1c -CH2C(O)NR 1b R 1c Imidazole, pyrazol, oxazol, isoxazol, thiazolyl, isothiazol, or .

[0316] Implementation Scheme 32. A compound of any one of Implementation Schemes 1-23, wherein R 1 yes:

[0317] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0318] Implementation Scheme 33. A compound of any one of Implementation Schemes 1-32, wherein R 2 It is hydrogen.

[0319] Implementation Scheme 34. A compound of any one of Implementation Schemes 1-33, wherein R 3 It is either chlorine or cyanide.

[0320] Implementation Scheme 35. A compound of any one of Implementation Schemes 1-34, wherein R 4 yes:

[0321] , , , , , , , , , , , , , , , or .

[0322] Implementation Scheme 36. The compound of Implementation Scheme 35, wherein R 4 yes:

[0323] , , ,

[0324] , , , , , or .

[0325] Implementation Scheme 37. A compound of any one of Implementation Schemes 1-36, wherein X 2 X 3 and X 4 It is C(H).

[0326] Implementation Scheme 38. A compound of any one of Implementation Schemes 1-37, wherein R 13 It is either hydrogen or methyl.

[0327] Implementation Scheme 39. The compound of Implementation Scheme 38, wherein R 13 It is hydrogen.

[0328] Implementation Scheme 40. A compound of any one of Implementation Schemes 1-39, wherein R 14 It's fluorine.

[0329] Implementation Scheme 41. A compound of any one of Implementation Schemes 1-40, wherein R 52 It is either hydrogen or methyl.

[0330] Implementation Scheme 42. A compound of any one of Implementation Schemes 1-41, wherein p is 0 or 1.

[0331] Implementation Scheme 43. A compound of any one of Implementation Schemes 1-5, 7-9 and 14-42, having formula (II):

[0332] ,

[0333] Or its pharmaceutically acceptable salt.

[0334] Implementation Scheme 44. A compound of any one of Implementation Schemes 1, 7-12 and 23-42, having formula (III):

[0335] ,

[0336] Or its pharmaceutically acceptable salt.

[0337] Implementation Scheme 45. A compound of any one of Implementation Schemes 1-9 and 23-42, having formula (IV):

[0338] ,

[0339] Or its pharmaceutically acceptable salt.

[0340] Implementation Scheme 46. A compound of any one of Implementation Schemes 1, 33, 34, 38, 39 and 41, having formula (VI):

[0341] ,

[0342] Or its pharmaceutically acceptable salt, wherein:

[0343] R 51 It is hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 deuterated alkyl, or C1-C6 haloalkyl;

[0344] R 52 It is hydrogen or C1-C6 alkyl; and

[0345] R 53 It is hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, or C1-C6 haloalkyl.

[0346] Implementation Scheme 47. The compound of Implementation Scheme 46, wherein R 51 It is a C1-C6 alkyl group.

[0347] Implementation Scheme 48. The compound of Implementation Scheme 47, wherein R 51 It is a methyl group.

[0348] Implementation Scheme 49. A compound of any one of Implementation Schemes 46-48, wherein R 53 It is hydrogen, C1-C6 alkyl, or C1-C6 alkoxy.

[0349] Implementation Scheme 50. The compound of Implementation Scheme 49, wherein R 53 It is hydrogen, methyl, or methoxy.

[0350] Implementation scheme 51. The compounds in Table 1 or their pharmaceutically acceptable salts.

[0351] Implementation Scheme 52. The compound of Implementation Scheme 51, selected from:

[0352] , , ,

[0353] , ,

[0354] , ,or

[0355] ,

[0356] Or its pharmaceutically acceptable salt.

[0357] Implementation Scheme 53. A pharmaceutical composition comprising a compound of any one of Implementation Schemes 1-52 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0358] Implementation Scheme 54. 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 1-52 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of Implementation Scheme 53.

[0359] Implementation Scheme 55. 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 a compound of any one of Implementation Schemes 1-52 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Implementation Scheme 53.

[0360] Example

[0361] 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.

[0362] 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).

[0363] The following abbreviations may be relevant to this application.

[0364] abbreviation

[0365]

[0366]

[0367] Synthesis Examples

[0368] General Procedure 1: First SNAr reaction of pyrimidine.

[0369]

[0370] DIPEA (1.1 equivalents) was added to a mixture of 5-amino-1-methyldihydroindol-2-one (1 equivalent) in dry tetrahydrofuran at -40°C [0.4 M]. A solution of 5-chloro-2,4-difluoropyrimidine (1 equivalent) in dry tetrahydrofuran [1.5 M] was slowly added to the mixture, and the mixture was slowly warmed to room temperature. The reaction mixture was stirred at room temperature for 16 hours. After this time, the reaction mixture was filtered and washed with acetonitrile. The solid was dried under vacuum to give the title compound.

[0371] General Procedure 2: Buchwald coupling of amine with indazole CBM.

[0372]

[0373] A mixture of 6-bromo-3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-indazole 1a (1.1 equivalents), an amine (1.0 equivalent), Ruphos-Pd-G3 (0.20 equivalents), and NaOtBu (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 EtOAc. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using a gradient elution of 0-100% EtOAc in hexane to give the title compound.

[0374] General Procedure 3: Methylation of Amines

[0375]

[0376] NaH (4.4 equivalents) was added to a solution of amine (1.0 equivalent, 14.2 mmol) in DMF [0.15 M], and the mixture was stirred at 0°C for 1 hour. Iodomethane (2.8 equivalents) was added to the mixture at 0°C. The resulting reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was then quenched with water and extracted with EA. The extracts were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography, eluting with PE / EA (15:1) to give the title compound.

[0377] General Procedure 4: Reduce CBM with hydrogen.

[0378]

[0379] A mixture of an indazole intermediate (1.0 equivalent) and Pd / C (10 wt.% palladium; 40% by weight) in EtOH:THF (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 EtOH and THF. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using a gradient elution of 0-100% EtOAc in hexane to give the title compound.

[0380] General Procedure 5: Use HCl or TFA to deprotect BOC.

[0381]

[0382] 4N HCl (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 the title compound (quantitatively), as a solid, which was used in the next step without further purification.

[0383] General Procedure 6: SNAr reaction of modified TBM with CBM.

[0384]

[0385] 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.

[0386] Intermediate i-1

[0387]

[0388] Step i-1.1: Synthesis of 5-((5-chloro-2-fluoropyrimidin-4-yl)amino)-1-methyldihydroindole-2-one. DIPEA (2.37 mL, 13.6 mmol) was added to a solution of 5-amino-1-methyldihydroindole-2-one (2.0 g, 12.3 mmol) in tetrahydrofuran (32 mL) at -40°C. A solution of 5-chloro-2,4-difluoropyrimidin (1.86 g, 12.3 mmol) in dry tetrahydrofuran (8 mL) was slowly added to the above mixture, and the mixture was allowed to slowly warm to room temperature. The reaction mixture was stirred at room temperature for 16 hours. After this time, the reaction mixture was filtered and washed with acetonitrile (~50 mL). The solid was dried under vacuum to give the title compound as a brown solid. MS (ESI) [M+H] + 293.1.

[0389] Intermediate i-2.

[0390]

[0391] Step i-2.1: Synthesis of 6-bromo-3-iodo-1-methyl-indazole. NIS (25.58 g, 113.7 mmol) was added to a solution of 6-bromo-1-methyl-indazole (8.00 g, 37.9 mmol) in DMF (100 mL). The reaction mixture was heated to 150°C overnight 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+H]+336.90.

[0392] 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. LCMS showed complete consumption of the reactants and the desired product as the dominant mass spectra. The reaction mixture 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) to give the title compound (2.1 g, 4.20 mmol, 71% yield) as a pale yellow solid. MS (ES) [M+H]+500.3. 1 H NMR (400 MHz, DMSO-d6) δ 7.96 (s, 1H), 7.91 (d, J= 8.1 Hz, 1H), 7.62 (d, J= 8.7 Hz, 1H), 7.50 - 7.24 (m, 10H), 7.12 (dd, J= 8.7, 1.4 Hz, 1H), 6.60 (d, J= 8.1 Hz, 1H), 5.45 (s, 2H), 5.43 (s, 2H), 4.05 (s, 3H).

[0393] 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 Cs2CO3 (5.2 g, 15.99 mmol) in 1,4-dioxane (53.292 mL) was heated to 110°C for 28 hours and then cooled to room temperature. The mixture was filtered through a Celite filter and washed with EtOAc (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; 1H NMR (500MHz, 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).

[0394] 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 THF (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 MeOH:MeCN (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 (400MHz, 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, 5.2Hz, 1H), 3.93 - 3.86 (m, 2H), 3.81 (s, 3H), 2.96 (br, 2H), 2.60 (t, J = 7.0Hz, 2H), 2.30 - 2.20 (m, 1H), 2.18 - 2.11 (m, 1H), 1.94 (d, J = 11.0 Hz, 2H), 1.41 (s, 9H), 1.30 - 1.19 (m, 3H).

[0395] Step i-2.5: Synthesis of 3-[1-methyl-6-(4-piperidinylamino)indazole-3-yl]piperidine-2,6-dione hydrochloride. To a solution of tert-butyl 4-[[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-6-yl]amino]piperidine-1-carboxylic acid (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, 3 H), 1.72 (br s, 2 H).

[0396] Intermediate i-3.

[0397]

[0398] Step i-3.1: Synthesis of 6-bromo-3-iodo-1-methyl-indazole. NIS (25.58 g, 113.7 mmol) was added to a solution of 6-bromo-1-methyl-indazole (8.00 g, 37.9 mmol) in DMF (100 mL). The reaction mixture was heated to 150°C overnight 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+H] + 336.90.

[0399] Step i-3.2: 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, 17.8 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(ii) (0.43 g, 0.590 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. The reaction mixture 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 substance was purified by column chromatography (silica gel, gradient: 0-30% ethyl acetate in petroleum ether) to give the title compound (2.1 g, 4.20 mmol, 71% yield) as a pale yellow solid. MS (ES) [M+H + 500.3; 1 H NMR (400 MHz, DMSO-d6) δ 7.96 (s,1H), 7.91 (d, J= 8.1 Hz, 1H), 7.62 (d, J= 8.7 Hz, 1H), 7.50 - 7.24 (m, 10H),7.12 (dd, J= 8.7, 1.4 Hz, 1H), 6.60 (d, J= 8.1 Hz, 1H), 5.45 (s, 2H), 5.43(s, 2H), 4.05 (s, 3H).

[0400] Step i-3.3: 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-pyridyl)-1-methyl-indazole (1.92 g, 3.84 mmol), (3R,4R)-4-amino-3-methyl-piperidine-1-carboxylic acid tert-butyl ester (685 mg, 3.20 mmol), RuPhos Pd G3 (668.6 mg, 0.80 mmol), and Cs2CO3 (1.25 g, 3.84 mmol) in 1,4-dioxane (15 mL) was heated to 90°C for 20 hours. The mixture was cooled to room temperature, filtered through a Celite filter, and washed with EtOAc (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 EtOAc from 0-40% in hexane to give the title compound (1.37 g, 68%) as a solid. MS (ESI) [M+H] + 634.1; 1 H NMR (400 MHz, DMSO-d6) δ 7.86 (d, J = 8.1 Hz, 1H), 7.50 - 7.46 (m,1H), 7.46 - 7.25 (m, 10H), 6.54 (d, J = 8.1 Hz, 1H), 6.43 (d, J = 1.8 Hz,1H), 6.41 (d, J = 2.2 Hz, 1H), 5.70 (d, J = 8.9 Hz, 1H), 5.44 (s, 2H), 5.40(s, 2H), 3.97 - 3.89 (m, 2H), 3.88 (s, 3H), 3.24 - 3.14 (m, 1H), 2.99 - 2.87(m, 1H), 2.05 - 2.01 (m, 1H), 2.01 - 1.98 (m, 1H), 1.57 - 1.47 (m, 1H), 1.41(s, 9H), 1.17 - 1.08 (m, 1H), 0.93 (d, J = 6.5 Hz, 3H).

[0401] Step i-3.4: 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).

[0402] Step i-3.5: Synthesis of 3-(1-methyl-6-(((3R,4R)-3-methylpiperidin-4-yl)amino)-1H-indazol-3-yl)piperidin-2,6-dione hydrochloride. At 25°C, 4M HCl (35 mL) in dioxane was added to a solution of (3R,4R)-4-[[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazol-6-yl]amino]-3-methyl-piperidin-1-carboxylic acid tert-butyl ester (8.0 g, 17.6 mmol) in DCM (35 mL). After addition, the reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was filtered to give the title compound (8.0 g, 100% yield) as a creamy white solid. MS (ESI) [M+H]+356.2. 400 MHz MeOD δ: 8.04 (s, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.11 (d, J =8.8 Hz, 1H), 4.59-4.55 (m, 1H), 4.11 (s, 3H), 3.75-7.71 (m, 1H), 3.49-3.46(m,2H), 3.20-3.15 (m, 1H), 3.03 (s, 2H), 2.93-2.89 (m, 1H), 2.83-2.81 (m,2H), 2.52-2.48 (m, 1H), 2.40-2.35 (m, 1H), 2.30-2.26 (m, 1H), 2.20-2.15 (m,1H), 2.02 (s, 1H), 1.80-1.75 (m, 1H), 1.24-1.22 (m, 3H).

[0403] Example 1

[0404]

[0405] 5-(((1-((1-(5-chloro-4-((1-methyl-2-oxodihydroindole-5-yl)amino)pyrimidin-2-yl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isodihydroindole-1,3-dione

[0406] Step 1.1: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-((piperidin-4-ylmethyl)amino)isodihydroindole-1,3-dione hydrochloride. Decaborane (14) (244 mg, 2.00 mmol) was added to a solution of 5-amino-2-(2,6-dioxopiperidin-3-yl)isodihydroindole-1,3-dione (546 mg, 2.00 mmol), tert-butyl 4-formylpiperidin-1-carboxylate (853 mg, 4.00 mmol), and 1,4-dioxane (10 mL). The reaction mixture was stirred at 25°C for 15 hours. The mixture was filtered and purified by reversed-phase HPLC (10 to 100% acetonitrile in water (containing 0.1% formic acid)) to give the title compound (550 mg, 59%); LCMS m / z 371.2 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ ppm 6.79 (br d, J=8.44 Hz, 1 H), 6.23 (s, 1 H), 6.10 (br d, J=8.44 Hz,1 H), 4.26 (br dd, J=12.29, 4.83 Hz, 1 H), 2.85 - 2.89 (m, 2 H), 2.64 (br d,J=12.47 Hz, 1 H), 2.55 - 2.59 (m, 1 H), 2.42 (br d, J=6.36 Hz, 2 H), 2.21 (brt, J=12.47 Hz, 2 H), 2.00 - 2.12 (m, 1 H), 1.85 - 1.99 (m, 2 H), 1.16 - 1.34 (m, 4 H), 0.62 - 0.74 (m, 2H).

[0407] Step 1.2: Synthesis of tert-butyl 4-((4-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisodihydroindole-5-yl)amino)methyl)piperidin-1-yl)methyl)piperidin-1-carboxylic acid. Sodium triacetoxyborohydride (212 mg, 1.0 mmol) was added to a solution of 2-(2,6-dioxopiperidin-3-yl)-5-((piperidin-4-ylmethyl)amino)isodihydroindole-1,3-dione hydrochloride (203 mg, 0.5 mmol), tert-butyl 4-formylpiperidin-1-carboxylic acid (213 mg, 1.0 mmol), and DIPEA (78 mg, 0.6 mmol) in DMSO (2 mL) and DCM (1 mL) for 1 hour at room temperature. The crude material was purified by reversed-phase HPLC (10 to 100% acetonitrile in water (containing 0.1% formic acid)) to give the title compound (226 mg, 79% yield); LCMS m / z 568.2 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ ppm 11.05 (s, 1 H), 8.16 (s, 1 H), 7.55 (d, J=8.44 Hz, 1 H), 7.16 (t, J=5.56 Hz, 1 H), 6.96 (s, 1H), 6.87 (dd, , 2.78- 2.95 (m, 3 H), 2.54-2.76 (m, 3 H), 2.12 (br d, J=6.60 Hz, 2 H), 1.94 -2.04 (m, 1 H), 1.86 (br t, J=10.64 Hz, 2 H), 1.59 - 1.77 (m, 5 H), 1.48 -1.59 (m, 1 H), 1.38 (s, 9 H), 1.14 - 1.30 (m, 2 H), 0.83 - 1.00 (m, 2 H).

[0408] Step 1.3: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-(((1-(piperidin-4-ylmethyl)piperidin-4-yl)methyl)amino)isodihydroindole-1,3-dione hydrochloride. The title compound was synthesized using 4-((4-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisodihydroindole-5-yl)amino)methyl)piperidin-1-yl)methyl)piperidin-1-carboxylic acid tert-butyl ester as the starting material, according to General Procedure 4.

[0409] Step 1.4: Synthesis of 5-(((1-((1-(5-chloro-4-((1-methyl-2-oxodihydroindole-5-yl)amino)pyrimidin-2-yl)piperidin-4-yl)methyl)piperidin-4-yl)methyl)amino)-2-(2,6-dioxopiperidin-3-yl)isodihydroindole-1,3-dione)

[0410] The title compound was synthesized from 5-((5-chloro-2-fluoropyrimidin-4-yl)amino)-1-methyldihydroindole-2-one (8.7 mg, 0.030 mmol) and 2-(2,6-dioxopiperidin-3-yl)-5-(((1-(piperidin-4-ylmethyl)piperidin-4-yl)methyl)amino)isodihydroindole-1,3-dione hydrochloride (15 mg, 0.030 mmol) as starting materials according to General Procedure 6. The crude material was purified by reversed-phase HPLC (10 to 100% acetonitrile in water (containing 0.1% TFA)) to give the title compound (3.5 mg, 16%); LC-MS C 38 H 42 The theoretical value of ClN9O5 is 739.3, and the measured value is 740.2 [M+H]. + ; 1H NMR (500 MHz, DMSO-d6) δ ppm 11.06 (s, 1 H), 8.61 - 8.86 (m, 2 H), 8.01 (s, 1 H), 7.58 (d, J=8.44 Hz, 1 H), 7.52 (s, 1 H), 7.48 (dd, J=8.31, 1.96 Hz, 1 H), 7.17 - 7.30 (m, 1 H), 6.98 - 7.04 (m, 1 H), 6.88 - 6.96 (m, 2 H), 4.98 - 5.08 (m, 1 H), 4.40 - 4.48 (m, 2 H), 3.54 (s, 4 H), 3.19 - 3.29 (m, 1 H), 3.14 (br s, 2 H),2.78 - 2.97 (m, 7 H), 2.52 - 2.63 (m, 2 H), 1.89 - 2.15 (m, 4 H), 1.78 - 1.88(m, 1 H), 1.73 (br d, J=10.27 Hz, 2 H), 1.38 - 1.55 (m, 2 H), 1.00 - 1.20 (m, 2 H).

[0411] Example 2

[0412]

[0413] 3-(6-(((3R,4R)-1-(4-([1,2,4]triazolo[1,5-a]pyridin-6-ylamino)-5-chloropyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione

[0414] Step 2.1: Synthesis of N-(5-chloro-2-fluoropyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-amine. A mixture of [1,2,4]triazolo[1,5-a]pyridine-6-amine (111 mg, 0.830 mmol) and 5-chloro-2,4-difluoropyrimidin (100 mg, 0.664 mmol) was dissolved in NMP (2 mL) and treated with DIPEA (0.232 mL, 1.33 mmol). The vial was sealed and heated at 65°C for 16 hours. The reaction was cooled to room temperature and treated with water (~10 mL) with stirring until the product precipitated. The solid was filtered, washed with water, and dried to give the title compound (150 mg, 85% yield).

[0415] Step 2.2: Synthesis of 3-(6-(((3R,4R)-1-(4-([1,2,4]triazolo[1,5-a]pyridin-6-ylamino)-5-chloropyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione. The title compound was synthesized using N-(5-chloro-2-fluoropyrimidin-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-6-amine (25 mg, 0.094 mmol) and 3-(1-methyl-6-(((3R,4R)-3-methylpiperidin-4-yl)amino)-1H-indazole-3-yl)piperidin-2,6-dione HCl (37 mg, 0.094 mmol) as starting materials according to General Procedure 6. The crude material was purified by reversed-phase HPLC (10 to 100% acetonitrile in water (containing 0.1% TFA)) to give the title compound (3.5 mg, 16%); LCMS C 29 H 30 ClN 11 Theoretical O2 value: 599.2; Measured value: 601.2 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ ppm 10.82 (s, 1H),9.36 (br s, 1H), 9.10 (s, 1H), 8.44 (s,1H), 8.14 (s, 1H), 7.96 (dd, 1H, J=2.0, 9.5 Hz), 7.84 (d, 1H, J=9.5 Hz), 7.31 (d, 1H,J=8.8 Hz), 6.51 (dd, 1H, J=1.6, 8.8 Hz), 6.45 (s, 1H), 5.71 (d, 1H, J=8.9 Hz), 4.49 (brs, 2H), 4.18 (dd,1H, J=5.1, 8.7 Hz), 3.82 (s, 3H), 3.0-3.3 (m, 1H), 2.7-2.8 (m, 1H), 2.5-2.6(m, 2H), 2.1-2.3 (m, 4H), 1.6-1.7 (m, 1H), 1.1-1.3 (m, 1H), 1.01 (d, 3H, J=6.4 Hz).

[0416] Example 3

[0417]

[0418] 3-(6-(((3R,4R)-1-(5-chloro-4-((4-methoxyimidazo[1,2-a]quinolin-7-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione

[0419] Step 3.1: Synthesis of 3-methoxy-6-nitroquinoline-2(1H)-one. Ethanol (10 mL) was added to a solution containing 5-nitrodihydroindole-2,3-dione (1 g, 5.20 mmol) in DMF (10 mL), followed by the slow addition of TMS-diazomethane (7.81 mL, 15.6 mmol) over 10 minutes. The reaction mixture was stirred for 10 hours. An additional 0.5 equivalent of TMS-diazomethane was added, and stirring continued for 4 hours. The reaction mixture was then poured onto water / ice (~50 mL) and stirred for 30 minutes to obtain a fine solid, which was filtered, washed with water, and dried to give the title compound (670 mg, 3.04 mmol, 58.5% yield), m / z (221, M+H).

[0420] Step 3.2: Synthesis of 2-chloro-3-methoxy-6-nitroquinoline. POCl3 (2.75 mL, 29.5 mmol) was added in small, repeated additions to a solution containing 1.3 g (5.90 mmol) of 3-methoxy-6-nitroquinoline-2(1H)-one in DMF (10 mL) to prevent the reaction temperature from rising above 30°C. The reaction mixture was stirred for 1 hour, poured onto ice / water (~50 mL), stirred for 30 minutes, and the solid was filtered, washed, and dried to give the title compound (900 mg, 3.77 mmol, 63.9% yield), m / z (239, M+H).

[0421] Step 3.3: Synthesis of 3-methoxy-6-nitroquinoline-2-amine. Ammonium hydroxide (10 mL, 64.2 mmol) was added to a suspension containing 2-chloro-3-methoxy-6-nitroquinoline (750 mg, 3.14 mmol) in 2-propanol (10 mL). The container was sealed and heated at 75°C for 20 hours. The reaction was cooled to room temperature, most of the solvent was evaporated under a nitrogen stream, the solid was filtered, washed with water, and dried to give the title compound (500 mg, 2.281 mmol, 72.6% yield), m / z (220, M+H).

[0422] Step 3.4: Synthesis of 4-methoxy-7-nitroimidazo[1,2-a]quinoline. An aqueous solution of chloroacetaldehyde (0.358 mL, 2.28 mmol) was added to a suspension of 3-methoxy-6-nitroquinoline-2-amine (250 mg, 1.14 mmol) in 2-propanol (2.5 mL), followed by sodium bicarbonate (383 mg, 4.56 mmol). The vial was sealed and heated at 55°C for 14 hours. The reaction was cooled, the solid was filtered, washed with water, and dried to give the impure title compound (160 mg, 0.658 mmol, 57.7% yield), m / z (244, M+H). It was used without further purification.

[0423] Step 3.5: Synthesis of 4-methoxyimidazo[1,2-a]quinoline-7-amine. A solution containing 4-methoxy-7-nitroimidazo[1,2-a]quinoline (175 mg, 0.720 mmol) in MeOH:THF (10 mL) was purged with nitrogen, and a Pearlman catalyst (101 mg, 0.072 mmol) was added. The reaction mixture was purged with hydrogen, placed in a hydrogen-filled balloon, and stirred for 12 hours. The reaction mixture was then purged with nitrogen, filtered through a Celite filter, and the filter pad was rinsed with DCM. The filtrate was concentrated to give the title compound (74 mg, 0.347 mmol, 48% yield), m / z (214, M+H).

[0424] Step 3.6: Synthesis of N-(5-chloro-2-fluoropyrimidin-4-yl)-4-methoxyimidazo[1,2-a]quinoline-7-amine. The title compound was synthesized by reacting 4-methoxyimidazo[1,2-a]quinoline-7-amine (50 mg, 0.234 mmol) and 5-chloro-2,4-difluoropyrimidine (35 mg, 0.234 mmol) as starting materials at 70°C for 16 hours according to General Procedure 1. Water was added to the mixture, and the title compound (70 mg, 87% yield) was isolated by filtration of the resulting solid.

[0425] Step 3.7: Synthesis of 3-(6-(((3R,4R)-1-(5-chloro-4-((4-methoxyimidazo[1,2-a]quinoline-7-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione. The title compound was synthesized using N-(5-chloro-2-fluoropyrimidin-4-yl)-4-methoxyimidazo[1,2-a]quinoline-7-amine (70 mg, 0.204 mmol) and 3-(1-methyl-6-(((3R,4R)-3-methylpiperidin-4-yl)amino)-1H-indazole-3-yl)piperidin-2,6-dione HCl (96 mg, 0.244 mmol) as starting materials according to General Procedure 6. The crude material was purified by reversed-phase HPLC (10 to 100% acetonitrile in water (containing 0.1% TFA)) to give the title compound (16.5 mg, 12%); LC-MSC 35 H 35 ClN 10 Theoretical O3 value: 678.3; Measured value: 680.0 [M+H] + ; 1 H NMR (500 MHz, DMSO-d6) δ ppm10.82 (s, 1H), 8.98 (s, 1H), 8.58 (s, 1H), 8.1-8.2 (m, 3H), 7.80 (dd, 1H, J=2.3, 9.0 Hz), 7.53 (d, 1H, J=1.1 Hz), 7.31 (d, 1H, J=8.8 Hz), 6.89 (s, 1H), 6.51 (dd, 1H, J=1.6, 8.8 Hz), 6.45 (s, 1H), 5.70 (d, 1H, J=8.9 Hz), 4.52 (brd, 1H, J=12.2 Hz), 4.0-4.2 (m, 2H), 3.93 (s, 3H), 3.81 (s, 3H), 3.17 (d, 1H,J=4.5 Hz), 3.06 (br t, 1H, J=11.7 Hz), 2.7-2.8 (m, 1H), 2.5-2.7 (m, 2H), 2.1-2.3 (m, 2H), 1.6-1.7 (m, 1H), 1.1-1.3 (m, 1H), 0.99 (d, 3H, J=6.5 Hz).

[0426] Example 4

[0427]

[0428] 3-(5-(((3R,4R)-1-(5-chloro-4-((1-methyl-2-oxodihydroindole-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1H-indazol-1-yl)piperidin-2,6-dione

[0429] Step 4.1: Synthesis of 3-(5-bromo-1H-indazole-1-yl)piperidine-2,6-dione. 3-bromopiperidine-2,6-dione (7.31 g, 38.1 mmol) and sodium hydride (1.52 g, 38.1 mmol) were added to a solution of 5-bromo-1H-indazole (5 g, 25.4 mmol) in DMF (80 mL) at 0°C. The mixture was stirred overnight at room temperature, then diluted with water (100 mL) and extracted with EtOAc (2 x 50 mL). The combined organic compounds were washed with brine, dried over sodium sulfate, concentrated, and then purified by silica gel chromatography by elution with EtOAc in hexane from 0-100%. The title compound (1.04 g, 13%) was eluted first, followed by the elution of unwanted regioisomers.

[0430] Step 4.2: Synthesis of tert-butyl ester (3R,4R)-4-((1-(2,6-dioxopiperidin-3-yl)-1H-indazole-5-yl)amino)-3-methylpiperidin-1-carboxylic acid. A mixture of 3-(5-bromo-1H-indazole-1-yl)piperidin-2,6-dione (300 mg, 0.974 mmol), (3R,4R)-4-amino-3-methylpiperidin-1-carboxylic acid tert-butyl ester (417 mg, 1.95 mmol), 3Å molecular sieve (1x, by weight), RuPhos Pd G2 (151 mg, 0.195 mmol), and LiHMDS (5.84 mL, 5.84 mmol) in toluene (5 mL) was stirred at 80°C under a nitrogen atmosphere for 2 hours. After completion, the reaction mixture was filtered, and the filtrate was concentrated under vacuum. The compound was purified by reversed-phase preparative HPLC using a MeCN gradient elution from 0-100% in water. Fractions containing the target product were combined and concentrated to give the title compound (114 mg, 26%).

[0431] Step 4.3: Synthesis of 3-(5-(((3R,4R)-3-methylpiperidin-4-yl)amino)-1H-indazole-1-yl)piperidin-2,6-dione HCl. The title compound was synthesized using (3R,4R)-4-((1-(2,6-dioxopiperidin-3-yl)-1H-indazole-5-yl)amino)-3-methylpiperidin-1-carboxylic acid tert-butyl ester (116 mg, 0.263 mmol) as the starting material according to General Procedure 5.

[0432] Step 4.4: Synthesis of 3-(5-(((3R,4R)-1-(5-chloro-4-((1-methyl-2-oxodihydroindol-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1H-indazole-1-yl)piperidin-2,6-dione. The title compound was synthesized using 5-((5-chloro-2-fluoropyrimidin-4-yl)amino)-1-methyldihydroindol-2-one (70 mg, 0.238 mmol) and 3-(5-(((3R,4R)-3-methylpiperidin-4-yl)amino)-1H-indazole-1-yl)piperidin-2,6-dione, HCl (90 mg, 0.238 mmol) as starting materials according to General Procedure 6. The crude material was purified by reversed-phase HPLC (10 to 100% acetonitrile in water (containing 10 mM ammonium acetate)) to give the title compound (25.7 mg, 17%); LC-MS C 31 H 32 The theoretical value of ClN9O3 is 613.2, and the measured value is 614.7 [M+H]. + ; 1 H NMR (500 MHz, DMSO-d6) δ ppm 8.65 (s, 1 H) 8.02 (s, 1 H) 7.79 (s, 1 H) 7.44 - 7.67 (m, 2 H) 7.33 (d, J=9.06 Hz, 1 H) 6.90 -6.98 (m, 1 H) 6.87 (br d, J=8.94 Hz, 1 H) 6.74 (s, 1 H) 5.67 (dd, J=11.74,4.95 Hz, 1 H) 5.15 (br d, J=8.82 Hz, 1 H) 4.45 (br d, J=11.09 Hz, 2 H) 3.54(s, 3 H) 3.14-3.25 (m, 2 H) 3.11 (s, 3 H) 3.01 (br t, J=11.80 Hz, 1 H) 2.75- 2.90 (m, 1 H) 2.63 - 2.75 (m, 3 H) 2.14 - 2.37 (m, 1 H) 2.03 - 2.11 (m, 2H) 1.87 (s, 2 H) 1.53 - 1.67 (m, 1 H) 1.04 - 1.32 (m, 2 H) 1.00 (br d, J=6.20Hz, 3 H).

[0433] Example 5

[0434]

[0435] 2-((3R,4R)-4-((1-(2,6-dioxopiperidin-3-yl)-1H-indazol-5-yl)amino)-3-methylpiperidin-1-yl)-4-((1-methyl-2-oxodihydroindole-5-yl)amino)pyrimidin-5-carboxynitrile

[0436] Step 5.1: Synthesis of 2-chloro-4-[(1-methyl-2-oxo-dihydroindol-5-yl)amino]pyrimidine-5-carboxynitrile. The title compound was synthesized using 2,4-dichloropyrimidine-5-carboxynitrile as the starting material according to General Procedure 1.

[0437] Step 5.2: Synthesis of 2-((3R,4R)-4-((1-(2,6-dioxopiperidin-3-yl)-1H-indazole-5-yl)amino)-3-methylpiperidin-1-yl)-4-((1-methyl-2-oxodihydroindole-5-yl)amino)pyrimidine-5-carboxylonitrile. The title compound was synthesized using 2-chloro-4-((1-methyl-2-oxodihydroindole-5-yl)amino)pyrimidine-5-carboxylonitrile (10.5 mg, 0.035 mmol) and 3-(5-(((3R,4R)-3-methylpiperidin-4-yl)amino)-1H-indazole-1-yl)piperidin-2,6-dione, HCl (12 mg, 0.035 mmol) as starting materials according to General Procedure 6. The crude material was purified by reversed-phase HPLC (10 to 100% acetonitrile in water (containing 10 mM ammonium acetate)) to give the title compound (25.7 mg, 17%); LC-MS C 32 H 32 N 10 O3 theoretical value 604.3, measured value 605.2 [M+H] + ; 1 H NMR (500 MHz, CDCl3) δ ppm 8.30 (s, 1H), 7.98 (s, 1H), 7.89 (s, 1H), 7.41 (br s, 1H), 7.2-7.3 (m, 2H), 6.8-6.9 (m, 2H), 5.08 (t, 1H, J=2.7 Hz), 3.8-3.8 (m, 2H), 3.7-3.8 (m, 3H), 3.6-3.7 (m, 2H), 3.5-3.6 (m, 2H), 3.0-3.2 (m, 2H), 2.8-2.9 (m, 2H), 2.48 (br dd, 1H, J=3.5,12.9 Hz), 1.2-1.5 (m, 3H), 1.13 (br s, 3H).

[0438] Example 6

[0439]

[0440] 3-(5-((1-(5-chloro-4-((1-methyl-2-oxodihydroindole-5-yl)amino)pyrimidin-2-yl)piperidin-4-yl)amino)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-2,6-dione

[0441] Step 6.1: Synthesis of tert-butyl 4-[[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazol-5-yl]amino]piperidin-1-carboxylate. N,N-diisopropylethylamine (104 mg, 0.800 mmol) was added to a solution of tert-butyl 4-oxo-1-piperidincarboxylate (160 mg, 0.800 mmol), 3-(5-amino-3-methyl-2-oxo-benzimidazol-1-yl)piperidin-2,6-dione; hydrochloride (250 mg, 0.800 mmol), and decborane (14) (45.11 mg, 0.4000 mmol) in 1,4-dioxane (2 mL) and DMSO (2 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then filtered and purified by reversed-phase semi-preparative HPLC to give the title compound (185 mg, 50% yield).

[0442] Step 6.2: Synthesis of 3-[3-methyl-2-oxo-5-(4-piperidinylamino)benzimidazol-1-yl]piperidine-2,6-dione hydrochloride. The title compound was synthesized using 4-[[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazol-5-yl]amino]piperidine-1-carboxylic acid tert-butyl ester (180 mg, 0.39 mmol) as the starting material according to General Procedure 5.

[0443] Step 6.3: Synthesis of 3-(5-((1-(5-chloro-4-((1-methyl-2-oxodihydroindol-5-yl)amino)pyrimidin-2-yl)piperidin-4-yl)amino)-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-2,6-dione. The title compound was synthesized using 5-((5-chloro-2-fluoropyrimidin-4-yl)amino)-1-methyldihydroindol-2-one (15 mg, 0.051 mmol) and 3-[3-methyl-2-oxo-5-(4-piperidinylamino)benzimidazol-1-yl]piperidin-2,6-dione hydrochloride (20 mg, 0.051 mmol) as starting materials according to General Procedure 6. The crude material was purified by reversed-phase HPLC (10 to 100% acetonitrile in water (containing 0.1% formic acid)) to give the title compound (17 mg, 52%); LCMS C 31 H 32 The theoretical value of ClN9O4 is 629.2, and the measured value is 630.2 [M+H]. + ; 1 H NMR (500 MHz, DMSO-d6) δ ppm 11.04 (s, 1 H),8.64 (s, 1 H), 8.01 (s, 1 H), 7.47 - 7.56 (m, 2 H), 6.90 - 6.98 (m, 1 H),6.80 (d, J=8.44 Hz, 1 H), 6.46 (d, J=1.96 Hz, 1 H), 6.32 (dd, J=8.50, 2.02Hz, 1 H), 5.07 - 5.29 (m, 2 H), 4.35 (br d, J=12.84 Hz, 2 H), 3.54 (s, 2 H), 3.26 (s, 3 H), 3.10 (s, 3 H), 3.02 - 3.08 (m, 2 H), 2.83 - 2.94 (m, 1 H), 2.72 - 2.73 (m, 1 H), 2.55 - 2.72 (m, 1 H), 1.87 - 2.03 (m, 3 H), 1.20 - 1.32 (m, 2 H).

[0444] Example 7

[0445]

[0446] 3-(6-((1-(5-chloro-4-((1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)amino)pyrimidin-2-yl)piperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione

[0447] Step 7.1: Synthesis of 6-[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]-1-methyl-3,4-dihydroquinolin-2-one. The title compound was synthesized using 6-amino-3,4-dihydro-1-methyl-2(1H)-quinolinone as the starting material according to General Procedure 1.

[0448] Step 7.2: Synthesis of 3-(6-((1-(5-chloro-4-((1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)amino)pyrimidin-2-yl)piperidin-4-yl)amino)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione. The title compound was synthesized using 6-[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]-1-methyl-3,4-dihydroquinolin-2-one (30 mg, 0.099 mmol) and 3-[1-methyl-6-(4-piperidinylamino)indazole-3-yl]piperidin-2,6-dione hydrochloride (40 mg, 0.118 mmol) as starting materials according to General Procedure 6. The crude material was purified by reversed-phase HPLC (10 to 100% acetonitrile in water (containing 0.1% formic acid)) to give the title compound (40 mg, 63%); LCMS C 32 H 34 The theoretical value of ClN9O3 is 627.2, and the measured value is 628.0 [M+H]. + ; 1H NMR (400 MHz, DMSO-d6) δ ppm 10.76 (s, 1H), 8.92 (br s, 1H), 8.03 (s, 1H), 7.5-7.5 (m, 1H), 7.47 (d, 1H, J=8.8 Hz), 7.30 (d, 1H, J=8.4Hz), 7.00 (d, 1H, J=8.7 Hz), 6.49 (br d, 2H, J=9.0 Hz), 4.2-4.3 (m, 3H), 4.1-4.2 (m, 2H), 3.77 (s, 4H), 3.61 (br s, 1H), 3.1-3.2 (m, 5H), 2.76 (t, 2H, J=7.4 Hz), 2.5-2.6 (m, 2H), 2.5-2.5 (m, 1H), 2.1-2.2 (m, 1H), 1.9-2.1 (m, 4H), 1.3-1.4 (m, 2H).

[0449] Example 8

[0450]

[0451] 3-(6-(((R)-1-(5-chloro-4-((1-methyl-2-oxodihydroindole-5-yl)amino)pyrimidin-2-yl)piperidin-3-yl)oxy)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione

[0452] Step 8.1: Synthesis of (3R)-3-[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole-6-yl]oxypiperidine-1-carboxylic acid tert-butyl ester. 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole (250.2 mg, 0.500 mmol), quinine ring (61.15 mg, 0.550 mmol), 4,4'-di-tert-butyl-2,2'-dipyridyl (6.71 mg, 0.020 mmol), nickel(II) ethylene glycol dimethyl ether complex (5.49 mg, 0.020 mmol), and 200 μL of acetonitrile were added to a 2-dram vial equipped with a stir bar. In a separate 1-darabin vial, (4,4'-di-tert-butyl-2,2'-bipyridine)bis[3,5-difluoro-2-[5-trifluoromethyl-2-pyridinyl-κN)phenyl-κC]iridium(III) hexafluorophosphate (5.61 mg, 0.005 mmol) and 200 μL of MeCN were added. The solution was sonicated and added to the reaction vial. (R)-1-BOC-3-hydroxypiperidine (301 mg, 1.50 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 4 days without fan cooling (reaction temperature ~55°C). The reaction mixture was stirred at 1000 rpm. The reaction was stirred at room temperature for 3 days. LC-MS showed significant product formation. The reaction mixture was concentrated, loaded onto a SNAP 25G column, and purified by elution with 0-30% EA / / hexane to obtain the title compound.

[0453] Step 8.2: Synthesis of 3-[1-methyl-6-[[(3R)-3-piperidinyl]oxy]indazole-3-yl]piperidin-2,6-dione; hydrochloride. The title compound was synthesized using (3R)-3-[3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-indazole-6-yl]oxypiperidin-1-carboxylic acid tert-butyl ester as the starting material according to general procedures 4 and 5.

[0454] Step 8.3: Synthesis of 3-(6-(((R)-1-(5-chloro-4-((1-methyl-2-oxodihydroindole-5-yl)amino)pyrimidin-2-yl)piperidin-3-yl)oxy)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione. The title compound was synthesized using 5-[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]-1-methyl-dihydroindole-2-one (20 mg, 0.068 mmol) and 3-[1-methyl-6-[[rac-(3S)-3-piperidinyl]oxy]indazole-3-yl]piperidin-2,6-dione; hydrochloride (31 mg, 0.081 mmol) as starting materials according to General Procedure 6. The crude material was purified by reversed-phase HPLC (10 to 100% acetonitrile in water (containing 0.1% formic acid)) to give the title compound (21 mg, 47%); LCMS C 31 H 31 The theoretical value of ClN8O4 is 614.2, and the measured value is 615.0 [M+H]. + ; 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.7-11.0 (m, 1H), 8.5-8.8 (m,1H), 8.02 (d, 1H, J=0.9 Hz), 7.3-7.6 (m, 3H), 7.0-7.2 (m, 1H), 6.6-6.8 (m,1H), 4.4-4.6 (m, 1H), 4.2-4.4 (m, 2H), 3.9-4.1 (m, 1H), 3.7-3.9 (m, 3H), 3.3-3.4 (m, 2H), 3.32 (s, 5H), 2.9-3.0 (m, 2H), 2.6-2.7 (m, 2H), 2.3-2.4 (m, 1H), 2.1-2.2 (m, 2H), 1.7-1.9 (m, 2H), 1.5-1.6 (m, 1H).

[0455] Example 9

[0456]

[0457] 3-(6-((1-(5-chloro-4-((1-methyl-2-oxo-4-((2-(pyrimidin-2-yl)propane-2-yl)amino)-1,2-dihydroquinazolin-6-yl)amino)pyrimidin-2-yl)piperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione

[0458] Step 9.1: Synthesis of 6-nitro-1H-quinazoline-2,4-dione. Concentrated nitric acid (9.5 mL, 159 mmol) was added to a solution of 1H-quinazoline-2,4-dione (20.0 g, 123 mmol) in concentrated sulfuric acid (330.0 mL, 6.19 mol) at 0°C. The reaction mixture was slowly warmed to room temperature and stirred for 2 hours, then poured into ice-cold water (500 mL). After stirring for 30 minutes, the resulting precipitate was filtered and then dried in a vacuum oven at 55°C for 12 hours to give the title compound (23.1 g, 90%) as a solid.

[0459] Step 9.2: Synthesis of 2,4-dichloro-6-nitro-quinazoline. A solution of 10.0 g (48.3 mmol) of 6-nitro-1H-quinazoline-2,4-dione in POCl3 (60.0 mL, 642.0 mmol) was refluxed for 72 hours and then cooled to room temperature. The mixture was poured into ice-cold water and stirred for 1 hour. The resulting precipitate was filtered and dried in a vacuum oven at 55°C for 12 hours to give the title compound (9.77 g, 83%) as a solid. 1 H NMR (500 MHz, DMSO) δ 8.74 (d, J = 2.4 Hz, 1H), 8.56 (dd, J = 8.9, 2.7 Hz, 1H), 7.81 (d, J = 9.0 Hz, 1H).

[0460] Step 9.3: Synthesis of 2-chloro-N-(1-methyl-1-pyrimidin-2-yl-ethyl)-6-nitro-quinazoline-4-amine. 2-pyrimidin-2-ylpropyl-2-amine (2.47 g, 18.0 mmol) and TEA (9.6 mL, 68.8 mmol) were added sequentially to a solution of 2,4-dichloro-6-nitro-quinazoline (4.0 g, 16.4 mmol) in DMF (35.0 mL) at room temperature. The reaction mixture was heated to 80°C for 2 hours and then cooled to room temperature. The volatiles were evaporated under reduced pressure, and water was added. The precipitate was collected by filtration and then dried under vacuum to give the title compound (5.48 g, 97%) as a solid. 1¹H NMR (500 MHz, DMSO) δ 9.72 (d, J = 2.3 Hz, 1H), 9.48 (s, 1H), 8.72 (d, J = 4.8 Hz, 2H), 8.51 (d, J = 9.0 Hz, 1H), 7.73 (d, J = 9.3 Hz, 1H), 7.32 (t, J = 4.9 Hz, 1H), 1.85 (s, 6H), DMF and TEA present. MS (ESI) [M+H] + 345.2.

[0461] Step 9.4: Synthesis of 4-[(1-methyl-1-pyrimidin-2-yl-ethyl)amino]-6-nitro-1H-quinazolin-2-one. A solution of 2-chloro-N-(1-methyl-1-pyrimidin-2-yl-ethyl)-6-nitro-quinazolin-4-amine (5.50 g, 16.0 mmol) in acetic acid (143 mL) was heated to 70°C for 2 hours, then cooled to room temperature. The volatiles were evaporated under reduced pressure, and then slowly added to a saturated aqueous solution of NaHCO3 (100 mL). After stirring for 10 minutes, the precipitate was collected by filtration, washed with diethyl ether (10.0 mL), and dried under vacuum to give the title compound (3.93 g, 76%) as a solid. 1 H NMR (400MHz, DMSO) δ 11.14 (bs, 1H), 9.42 (d, J = 2.5 Hz, 1H), 8.74 (bs, 1H), 8.70 (d, J = 4.8 Hz, 2H), 8.37 (dd, J = 9.1, 2.3 Hz, 1H), 7.28 (t, J = 4.9 Hz, 1H), 7.20 (d, J = 9.1 Hz, 1H), 1.81 (s, 6H). MS (ESI) [M+H] + 327.2.

[0462] Step 9.5: Synthesis of 1-methyl-4-[(1-methyl-1-pyrimidin-2-yl-ethyl)amino]-6-nitro-quinazolin-2-one. NaH (60% dispersed in mineral oil, 235.0 mg, 6.13 mmol) was added to a solution of 4-[(1-methyl-1-pyrimidin-2-yl-ethyl)amino]-6-nitro-1H-quinazolin-2-one (2.0 g, 6.13 mmol) in DMF (48.0 mL). After stirring for 10 minutes, iodomethane (0.38 mL, 6.13 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. Water (500 mL) and ethyl acetate (500 mL) were added, and the layers were separated. The organic layer was washed with brine (500.0 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to give the title compound (1.98 g, 95%) as a solid, which was used in the next step without further purification. 1 H NMR (400 MHz, DMSO) δ 9.44 (d, J = 2.5 Hz, 1H), 8.81 (s,1H), 8.70 (d, J = 4.8 Hz, 2H), 8.46 (dd, J = 9.4, 2.5 Hz, 1H), 7.48 (d, J =9.4 Hz, 1H), 7.28 (t, J = 4.8 Hz, 1H), 3.40 (s, 3H), 1.81 (s, 6H).

[0463] Step 9.6: Synthesis of 6-amino-1-methyl-4-[(1-methyl-1-pyrimidin-2-yl-ethyl)amino]quinazolin-2-one. A mixture of 1-methyl-4-[(1-methyl-1-pyrimidin-2-yl-ethyl)amino]-6-nitro-quinazolin-2-one (1.98 g, 5.82 mmol) and 10% Pd / C (619.0 mg, 5.82 mmol) in a mixture of DMF (33.0 mL) and isopropanol (66.0 mL) was hydrogenated at room temperature for 7 hours under a hydrogen atmosphere. The mixture was filtered through a Celite filter and washed with acetonitrile. The filtrate was concentrated under reduced pressure to give the title compound (1.40 g, 78%) as a solid, which was used in the next step without further purification. MS (ESI) [M+H] + 311.3.

[0464] Step 9.7: Synthesis of 6-[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]-1-methyl-4-[(1-methyl-1-pyrimidin-2-yl-ethyl)amino]quinazolin-2-one. To a solution of 6-amino-1-methyl-4-[(1-methyl-1-pyrimidin-2-yl-ethyl)amino]quinazolin-2-one (1.40 g, 4.51 mmol) cooled to -15°C in 55.0 mL of DMF, 5-chloro-2,4-difluoro-pyrimidinium (0.52 mL, 5.41 mmol) and DIPEA (3.14 mL, 18.0 mmol) were added sequentially. The reaction mixture was slowly warmed to room temperature and stirred for 3 hours. The volatiles were evaporated under reduced pressure, and water (20.0 mL) was added. The precipitate was collected by filtration and purified by silica gel column chromatography using a gradient elution of 0-10% MeOH in DCM to give the title compound (704.0 mg, 35%) as a solid. 1 H NMR (500 MHz, DMSO) δ 9.81 (s, 1H), 8.73 (d, J = 4.8 Hz, 2H), 8.42 - 8.37 (m, 2H), 8.18 (s, 1H), 7.77 (dd, J = 9.0, 2.2 Hz, 1H), 7.37(d, J = 9.1 Hz, 1H), 7.31 (t, J = 4.8 Hz, 1H), 3.38 (s, 3H), 1.81 (s, 6H). MS(ESI) [M+H] + 441.2.

[0465] Step 9.8: Synthesis of 3-(6-((1-(5-chloro-4-((1-methyl-2-oxo-4-((2-(pyrimidin-2-yl)propane-2-yl)amino)-1,2-dihydroquinazolin-6-yl)amino)pyrimidin-2-yl)piperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione. The title compound was synthesized using 6-[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]-1-methyl-4-[(1-methyl-1-pyrimidin-2-yl-ethyl)amino]quinazolin-2-one (20 mg, 0.045 mmol) and 3-[1-methyl-6-(4-piperidinylamino)indazol-3-yl]piperidin-2,6-dione hydrochloride (17 mg, 0.050 mmol) as starting materials according to General Procedure 6. The crude material was purified by reversed-phase HPLC (10 to 100% acetonitrile in water (containing 0.1% formic acid)) to give the title compound (10 mg, 28%); LCMS C 38 H 40 ClN 13O3 theoretical value 761.3, measured value 762.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ ppm 10.84 (s, 1 H), 8.93 (s, 1 H), 8.58 (d, J=4.77 Hz, 3 H), 8.05 - 8.15 (m, 2 H), 7.78 (dd, J=9.05, 2.20 Hz, 1 H), 7.30 (dd, J=8.99, 4.34Hz, 2 H), 7.12 (t, J=4.89 Hz, 1 H), 6.50 (dd, J=8.74, 1.53 Hz, 1 H), 6.38 (d,J=1.10 Hz, 1 H), 5.74 (br s, 1 H), 4.39 (br d, J=12.47 Hz, 2 H), 4.19 (dd, J=8.68, 5.26 Hz, 1 H), 3.75 (s, 3 H), 3.56 - 3.58 (m, 1 H), 3.34 (s, 3 H), 3.13 (br t, J=11.13 Hz, 2 H), 2.58 - 2.65 (m, 2 H), 2.21 - 2.32 (m, 1 H), 2.11 -2.21 (m, 1 H), 2.02 (br d, J=10.27 Hz, 2 H), 1.73 (s, 6 H), 1.27 - 1.40 (m, 2H).

[0466] Example 10

[0467]

[0468] 3-(6-(((3S,4S)-1-(5-chloro-4-((1-methyl-2-oxo-4-((2-(pyrimidin-2-yl)propane-2-yl)amino)-1,2-dihydroquinazolin-6-yl)amino)pyrimidin-2-yl)-3-fluoropiperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione

[0469] Step 10.1: Synthesis of tert-butyl 3-(3S,4S)-4-[[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole-6-yl]amino]-3-fluoro-piperidine-1-carboxylic acid. The title compound was synthesized using 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole (500 mg, 1.0 mmol), (3S,4S)-4-amino-3-fluoro-piperidine-1-carboxylic acid tert-butyl ester (327 mg, 1.5 mmol), XPHOS Pd G3 (84.5 mg, 0.1 mmol), and cesium carbonate (651 mg, 2 mmol) as starting materials according to General Procedure 2. The crude material was purified by silica gel chromatography (0 to 50% ethyl acetate in hexane with 1% methanol additive) to give the title compound (566 mg, 88%).

[0470] Step 10.2: Synthesis of 3-(6-(((3S,4S)-1-(5-chloro-4-((1-methyl-2-oxo-4-((2-(pyrimidin-2-yl)propane-2-yl)amino)-1,2-dihydroquinazolin-6-yl)amino)pyrimidin-2-yl)-3-fluoropiperidin-4-yl)amino)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione. The title compound was synthesized using (3S,4S)-4-[[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole-6-yl]amino]-3-fluoro-piperidin-1-carboxylic acid tert-butyl ester as the starting material, according to general procedures 4, 5, and 6. The title compound was isolated by reversed-phase HPLC purification (43 mg, 79% yield). LC-MSC 38 H 39 ClFN 13 O3 theoretical value 779.3, measured value 780.0 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ ppm10.7-10.9 (m, 1H), 9.0-9.2 (m, 1H), 8.5-8.6 (m, 3H), 8.1-8.2 (m, 2H), 7.7-7.8(m, 1H), 7.2-7.4 (m, 2H), 7.1-7.2 (m, 1H), 6.5-6.6 (m, 1H), 6.4-6.5 (m, 1H), 4.6-4.6 (m, 1H), 4.5-4.5 (m, 1H), 4.2-4.4 (m, 2H), 4.2-4.2 (m, 1H), 4.0-4.1(m, 1H), 3.8-3.9 (m, 1H), 3.8-3.8 (m, 3H), 3.6-3.6 (m, 1H), 3.4-3.5 (m, 1H), 3.35 (s, 3H), 2.6-2.6 (m, 2H), 2.2-2.3 (m, 1H), 2.1-2.2 (m, 2H), 1.7-1.8 (m,6H), 1.4-1.5 (m,1H).

[0471] Example 11

[0472]

[0473] 1-(5-chloro-4-((1-(3-(methylamino)-3-oxopropyl)-1H-indol-6-yl)amino)pyrimidin-2-yl)-N-(3-(2,6-dioxopiridine-3-yl)-1-methyl-1H-indazol-6-yl)piperidine-4-carboxamide

[0474] Step 11.1: Synthesis of 3-(6-bromoindole-1-yl)-N-methylpropionamide. 6-Bromoindole (200 mg, 1.02 mmol) and sodium hydride (61.21 mg, 1.53 mmol) were added to a 2-duralam flask equipped with a stir bar. DMF (4.1 mL) was added, and the reaction mixture was stirred at room temperature for 1 hour. 3-Chloro-N-methylpropionamide (136.43 mg, 1.12 mmol) was added, and the mixture was stirred at room temperature overnight. LC-MS showed significant product formation. The reaction was quenched with water, extracted with ethyl acetate (3x), and the combined organic layers were washed with water (2x) and brine (1x). The organic layers were dried over magnesium sulfate, filtered, concentrated, and purified by silica gel chromatography (SNAP-25G, 20% EA in hexane) to give the title compound (210 mg, 73% yield).

[0475] Step 11.2: Synthesis of N-[1-[3-(methylamino)-3-oxopropyl]indol-6-yl]tert-butyl carbamate. 3-(6-bromoindol-1-yl)-N-methylpropionamide (279 mg, 0.990 mmol), tert-butyl carbamate (140 mg, 1.19 mmol), XPHOS (42.58 mg, 0.0900 mmol), cesium carbonate (485 mg, 1.49 mmol), tris(dibenzylacetone)dipalladium(O) (27 mg, 0.030 mmol), and 1,4-dioxane (3.97 mL) were added to a 2-duralumin vial and purged with nitrogen. The vials were sealed and stirred overnight at 80°C. LC-MS showed complete conversion to the product. The reaction mixture was diluted with DCM and water and extracted with DCM (3x). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. The residue was purified by elution using a SNAP 25G silica gel column with 0-100% ethyl acetate / hexane containing 10% methanol to give the title compound (146 mg, 46% yield).

[0476] Step 11.3: Synthesis of 3-(6-aminoindol-1-yl)-N-methylpropionamide. N-[1-[3-(methylamino)-3-oxopropyl]indol-6-yl]carbamate tert-butyl ester (100 mg, 0.3200 mmol) was reacted with 4 M HCl (4 mL) in dioxane. After 1 hour, the reaction mixture was concentrated, and the next step was directly carried out.

[0477] Step 11.4: Synthesis of 3-[6-[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]indol-1-yl]-N-methyl-propionamide. 3-(6-aminoindol-1-yl)-N-methyl-propionamide hydrochloride (183 mg, 0.720 mmol) and THF (7.2 mL) were added to a vial equipped with a stir bar and cooled to -40°C using a dry ice acetonitrile bath. N,N-diisopropylethylamine (0.14 mL, 0.79 mmol) and 5-chloro-2,4-difluoro-pyrimidinium (108 mg, 0.72 mmol) were added, and the reaction mixture was stirred overnight and slowly warmed to room temperature. The reaction mixture was concentrated, loaded onto a 25 G SNAP silica column, and purified by elution with a 0-100% gradient of 10% MeOH / EA in hexane. All product fractions were combined and concentrated to give the title compound (51 mg, 20% yield).

[0478] Step 11.5: Synthesis of 1-[5-chloro-4-[[1-[3-(methylamino)-3-oxopropyl]indol-6-yl]amino]pyrimidin-2-yl]piperidin-4-carboxylic acid. 3-[6-[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]indol-1-yl]-N-methylpropionamide (75 mg, 0.22 mmol), DIPEA (33 mg, 0.26 mmol), isoperidinic acid (33 mg, 0.26 mmol), and DMSO (0.43 mL) were added to a 2-duralumin vial equipped with a stir bar. The mixture was heated to 85°C and stirred for 6 hours. The crude product was purified by reversed-phase HPLC to give the title compound (52 mg, 52% yield).

[0479] Step 11.6: Synthesis of tert-butyl carbamate (3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazole-6-yl)carbamate. 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-1-methyl-1H-indazole (160 g, 320 mmol) was dissolved in 1,4-dioxane (1600 mL) and placed in a 3000 mL multi-necked round-bottom flask equipped with a reflux condenser. The mixture was mechanically stirred under nitrogen protection. Next, tert-butyl carbamate (56.2 g, 480 mmol) was added, followed by K₂CO₃ (133 g, 959 mmol). The mixture was purged for 5 minutes, then XPhos Pd G₂ (25.2 g, 32.0 mmol) was added, followed by another purging for 5 minutes. The mixture was then 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 using an ISCO rapid chromatography system on silica gel with petroleum ether / ethyl acetate (PE / EtOAc) as eluent to give the title compound (148 g, 275 mmol, 86% yield) as a white solid. MS (ESI) m / z 537.30 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ ppm 9.5 (s,1H), 7.89 - 7.91 (m, 1H), 7.28 - 7.54 (m, 12 H), 6.94 (d, 1 H), 6.58 (d, 1H), 5.41-5.45 (d, 4 H), 3.96 (s, 3 H), 1.50 (s, 9 H), 1.37 (s, 1H).

[0480] Step 11.7: Synthesis of tert-butyl (3-(2,6-dioxadiazin-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 THF (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 THF (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] + ; 1 H NMR (400 MHz, DMSO-d6) δppm 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, 2H) 2.13 - 2.37 (m, 2H), 1.36 (s, 9H).

[0481] Step 11.8: Synthesis of 3-(6-amino-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione, HCl salt. In a 2 L round-bottom flask, tert-butyl 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) with 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] + . 1H NMR (400 MHz, DMSO-d6) δ ppm 7.80 - 7.82 (d, 1 H), 7.53 (s, 1 H), 7.08 - 7.11 (d 1 H), 4.39- 4.43 (m, 1 H), 3.99 (s, 3 H), 2.50 - 2.73 (m, 2 H), 2.38 - 2.40 (m, 1 H), 2.18 - 2.36 (m, 1 H).

[0482] Step 11.9: Synthesis of 1-(5-chloro-4-((1-(3-(methylamino)-3-oxopropyl)-1H-indol-6-yl)amino)pyrimidin-2-yl)-N-(3-(2,6-dioxopiridine-3-yl)-1-methyl-1H-indazole-6-yl)piperidine-4-carboxamide. 1-[5-chloro-4-[[1-[3-(methylamino)-3-oxopropyl]indol-6-yl]amino]pyrimidin-2-yl]piperidin-4-carboxylic acid (25 mg, 0.050 mmol), 3-(6-amino-1-methyl-indazole-3-yl)piperidin-2,6-dione hydrochloride (18 mg, 0.060 mmol), HATU (26 mg, 0.070 mmol), N,N-diisopropylethylamine (0.02 mL, 0.12 mmol), and DMF (0.51 mL) were added to a 1-dallant vial equipped with a stir bar. The reaction was stirred overnight at 55°C. The crude product was purified by reversed-phase HPLC to give the title compound (18 mg, 46% yield); LCMS (ESI) m / z 697.2 [M+H] + . 1 H NMR(400 MHz, DMSO-d6) δ ppm 10.8-10.9 (m, 1H), 10.0-10.2 (m, 1H), 8.5-8.7 (m,1H), 8.05 (s, 3H), 7.7-7.9 (m, 1H), 7.5-7.6 (m, 1H), 7.4-7.5 (m, 1H), 7.2-7.3(m, 2H), 7.1-7.2 (m, 1H), 6.3-6.4 (m, 1H), 4.5-4.7 (m, 2H), 4.2-4.4 (m, 3H),3.90 (s, 3H), 2.9-3.0 (m, 2H), 2.6-2.7 (m, 3H), 2.5-2.6 (m, 2H), 2.3-2.4 (m,3H), 2.1-2.2 (m, 1H), 1.8-1.9 (m, 2H), 1.5-1.7 (m, 2H).

[0483] Example 12

[0484]

[0485] 3-(7-((5-chloro-2-(4-((3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)amino)piperidin-1-yl)pyrimidin-4-yl)amino)-4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-N-methylpropionamide

[0486] Step 12.1: Synthesis of (rac)-5-(benzyloxy)-2-bromo-5-oxovalerate. A suspension of 2-amino-5-(benzyloxy)-5-oxovalerate (3.0 g, 12.6 mmol) and sodium bromide (4.55 g, 44.2 mmol) in water (20 mL) was dissolved in 20 mL of 48% hydrobromic acid (2.86 mL, 25.3 mmol), resulting in a clear solution. The reaction was cooled to -10°C, and a solution of sodium nitrite (1.745 g, 25.3 mmol) in water (3 mL) was slowly added over 30 minutes. The reaction was stirred at 0°C for 2 hours and then allowed to cool slowly to room temperature overnight.

[0487] The mixture was then cooled to 0°C, and concentrated sulfuric acid (1.1 mL, 20.64 mmol) was added. The mixture was then extracted with Et₂O (2x). The combined organic compounds were washed with brine, dried over MgSO₄, and concentrated. The residue was purified by silica gel column chromatography (40 g, EtOAc / hexane = 0–50%) to give the title compound (2.45 g, 8.14 mmol, 64.3% yield) as a colorless oil. 1 ¹H NMR (499 MHz, chloroform-d) δ 7.47 - 7.33 (m, 5H), 5.16 (s, 2H), 4.44 (dd, J=8.5, 5.7 Hz, 1H), 2.69 - 2.56 (m, 2H), 2.52 - 2.42 (m, 1H), 2.40 - 2.29 (m, 1H).

[0488] Step 12.2: Synthesis of benzyl (rac)-4-bromo-5-chloro-5-oxovalerate. Oxaloyl chloride (1.42 mL, 16.3 mmol) and two drops of DMF were added to a solution of (S)-5-(benzyloxy)-2-bromo-5-oxovalerate (2.45 g, 8.14 mmol) in DCM (30 mL) cooled at 0°C. The mixture was then stirred at room temperature for 1 hour. The solution was concentrated with some toluene, and the residue was redistilled with toluene. The compound was then used in the next step without further purification.

[0489] Step 12.3: Synthesis of benzyl 3-(7-nitro-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propionate. A mixture of 2-amino-5-nitrophenol (1.25 g, 8.14 mmol) and K₂CO₃ (3.37 g, 24.4 mmol) in NMP (12 mL) was stirred for 30 min, cooled to 0°C, and a solution of (rac)-4-bromo-5-chloro-5-oxovalerate benzyl ester (2.60 g, 8.14 mmol) in NMP (5 mL) was added dropwise. The reaction mixture was stirred at room temperature over the entire weekend. The reaction mixture was cooled to 0°C, water was added, and the mixture was extracted with EtOAc (2x). The combined organic compounds were washed with brine, dried over MgSO₄, and concentrated. The residue was purified by silica gel chromatography (80 g, EtOAc / hexane = 0-60%) to give (rac)-3-(7-nitro-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)benzyl propionate (1.92 g, 5.39 mmol, 66.2% yield). 1 H NMR (500 MHz, CDCl3) δ 8.37 (br s, 1H), 7.93 (dd, J=8.6, 2.4 Hz, 1H), 7.86 (d, J=2.4 Hz, 1H), 7.45 - 7.32 (m, 5H), 6.90 (d, J=8.6 Hz, 1H), 5.17 (s, 2H), 4.75 (dd, J=8.4, 4.6 Hz, 1H), 2.69 (t, J=7.3 Hz, 2H), 2.45 (dtd, J=14.8, 7.6, 4.6Hz, 1H), 2.36 - 2.22 (m, 1H).

[0490] Step 12.4: Synthesis of (rac)-3-(4-methyl-7-nitro-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)benzyl propionate. K₂CO₃ (248 mg, 1.796 mmol) and MeI (0.084 mL, 1.347 mmol) were added to a solution of (rac)-3-(7-nitro-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)benzyl propionate (320 mg, 0.898 mmol) in DMF (6 mL). The mixture was stirred at room temperature for 3 hours, followed by purification by reversed-phase HPLC to give the title compound (298 mg, 90% yield).

[0491] Step 12.5: Synthesis of (rac)-3-(7-amino-4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propionic acid. Benzyl (4-methyl-7-nitro-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propionic acid (298 mg, 0.805 mmol) and 10% Pd-C (50 mg, 0.047 mmol) were purged with H2 in a mixture of EtOH (5 mL) and ethyl acetate (5 mL), and then stirred under an H2 balloon for 2 hours. After this time, the reaction was purged with nitrogen, and the catalyst was filtered off. The filtrate was concentrated to give the title compound (200 mg, 0.799 mmol, 99% yield).

[0492] Step 12.6: Synthesis of 3-(7-amino-4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-N-methylpropionamide. A mixture of 3-(7-amino-4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propionic acid (10 mg, 0.040 mmol), methylamine HCl (13 mg, 0.2 mmol), HATU (30.4 mg, 0.080 mmol), and TEA (0.017 mL, 0.12 mmol) in DMSO (1 mL) was stirred at room temperature for 30 min. The crude mixture was purified by reversed-phase HPLC to give the title compound (10.5 mg, 95% yield).

[0493] Step 12.7: Synthesis of 3-[7-[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]-4-methyl-3-oxo-1,4-benzoxazin-2-yl]-N-methyl-propionamide. DIEA (580 µL, 3.39 mmol) and 5-chloro-2,4-difluoro-pyrimidin (312 µL, 3.23 mmol) were added dropwise to a solution of 3-(7-amino-4-methyl-3-oxo-1,4-benzoxazin-2-yl)-N-methyl-propionamide (810 mg, 3.08 mmol) in a mixture of THF (30 mL) and DMF (10 mL) at -40°C. 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, washed with water and ether, and then dried under vacuum to give the title compound (1.07 g, 88%) as a solid. 1 HNMR (500 MHz, DMSO) δ 9.55 (s, 1H), 8.38 (d, J = 1.3 Hz, 1H), 7.79 (bs, 1H),7.34 - 7.29 (m, 2H), 7.17 (d, J = 9.4 Hz, 1H), 4.64 (dd, J = 8.4, 4.5 Hz, 1H), 3.29 (s, 3H), 2.55 (d, J = 4.6 Hz, 3H), 2.27 (t, J = 7.7 Hz, 2H), 2.12 -2.03 (m, 1H), 1.96 - 1.87 (m, 1H). MS (ESI) [M+H] + 394.2.

[0494] Step 12.8: Synthesis of 3-(7-((5-chloro-2-(4-((3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)amino)piperidin-1-yl)pyrimidin-4-yl)amino)-4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-N-methylpropionamide. The title compound was synthesized using 3-[7-[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]-4-methyl-3-oxo-1,4-benzoxazin-2-yl]-N-methylpropionamide (30 mg, 0.076 mmol) and 3-[1-methyl-6-(4-piperidinylamino)indazol-3-yl]piperidin-2,6-dione hydrochloride (35 mg, 0.091 mmol) as starting materials according to General Procedure 6. The crude material was purified by reversed-phase HPLC (10 to 100% acetonitrile in water (containing 0.1% formic acid)) to give the title compound (40 mg, 70%); LC-MS C35 H 39 ClN 10 O5 theoretical value 714.3, measured value 715.0 [M+H] + ; 1 HNMR (400 MHz, DMSO-d6) δ ppm 10.7-10.9 (m, 1H), 8.6-8.8 (m, 1H), 8.06 (s,1H), 7.7-7.8 (m, 1H), 7.4-7.5 (m, 2H), 7.3-7.3 (m, 1H), 7.1-7.1 (m, 1H), 6.5-6.6 (m, 1H), 6.4-6.5 (m, 1H), 5.7-5.8 (m, 1H), 4.6-4.7 (m, 1H), 4.3-4.5 (m,2H), 4.1-4.2 (m, 1H), 3.83 (s, 3H), 3.6-3.7 (m, 1H), 3.2-3.3 (m, 3H), 3.1-3.2(m, 2H), 2.9-3.0 (m, 1H), 2.6-2.6 (m, 2H), 2.4-2.5 (m, 1H), 2.2-2.3 (m, 3H),2.1-2.2 (m, 1H), 2.0-2.1 (m, 3H), 1.8-1.9 (m, 1H), 1.2-1.4 (m, 2H), 0.9-1.0 (m, 3H).

[0495] Example 13

[0496]

[0497] 3-(7-((5-chloro-2-(4-((3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)amino)piperidin-1-yl)pyrimidin-4-yl)amino)-3-oxo-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-N-methylpropionamide

[0498] Step 13.1: Synthesis of methyl 3-(7-nitro-3-oxo-1,4-benzoxazin-4-yl)propionate. K₂CO₃ (1.07 g, 7.73 mmol), methyl 3-bromopropionate (473 mg, 2.83 mmol), and KI (85.6 mg, 0.52 mmol) were added sequentially to a solution of 7-nitro-4H-1,4-benzoxazin-3-one (500 mg, 2.58 mmol) in DMF (10 mL). The reaction mixture was stirred overnight at room temperature, and volatiles were removed under reduced pressure. Water (20.0 mL) was slowly added, and the precipitate was collected by filtration, washed with diethyl ether (50 mL), and dried under vacuum to give the title compound (600.0 mg, 83%) as a solid. 1 H NMR (500 MHz, DMSO) δ 7.95 (dd, J = 9.0, 2.6 Hz, 1H), 7.81 (d,J = 2.6 Hz, 1H), 7.49 (d, J = 9.0 Hz, 1H), 4.79 (s, 2H), 4.28 - 4.11 (m, 2H), 3.59 (s, 3H), 2.72 - 2.58 (m, 2H).

[0499] Step 13.2: Synthesis of methyl 3-(7-amino-3-oxo-1,4-benzoxazin-4-yl)propionate. A mixture of methyl 3-(7-nitro-3-oxo-1,4-benzoxazin-4-yl)propionate (500.0 mg, 1.78 mmol) and 10% Pd / C (190 mg, 0.18 mmol) in DMF (20.0 mL) was hydrogenated at room temperature for 4 hours under a hydrogen atmosphere. The mixture was filtered through a Celite filter, and the filtrate was concentrated under reduced pressure to give the title compound (450.0 mg, 94%) as a solid, which was used in the next step without further purification. 1 H NMR (500 MHz, DMSO) δ 6.87 (d, J = 8.6 Hz, 1H), 6.26 (dd, J = 8.5, 2.4 Hz, 1H), 6.23 (d, J = 2.4 Hz, 1H), 5.02 (s, 2H), 4.47(s, 2H), 4.14 - 3.97 (m, 2H), 3.58 (s, 3H), 2.60 - 2.52 (m, 2H). MS (ESI) [M+H] + 251.1.

[0500] Step 13.3: Synthesis of 3-(7-amino-3-oxo-1,4-benzoxazin-4-yl)-N-methylpropionamide. Methyl 3-(7-amino-3-oxo-1,4-benzoxazin-4-yl)propionate (430.0 mg, 1.72 mmol) was added to a solution of MeNH2 (2.0 M, in methanol, 3.44 mL, 6.87 mmol). The reaction mixture was heated to 60°C overnight and then cooled to room temperature. The precipitate was collected by filtration, washed with MeOH (2 x 5.0 mL) and diethyl ether (20 mL), and then dried under vacuum to give the title compound (212.0 mg, 49%) as a solid. 1 H NMR (500 MHz, DMSO) δ 7.87 (s,1H), 6.86 (d, J = 8.6 Hz, 1H), 6.26 (dd, J = 8.6, 2.4 Hz, 1H), 6.22 (d, J =2.4 Hz, 1H), 5.00 (s, 2H), 4.47 (s, 2H), 4.09 - 3.87 (m, 2H), 2.55 (d, J =4.6 Hz, 3H), 2.38 - 2.27 (m, 2H).

[0501] Step 13.4: Synthesis of 3-[7-[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]-3-oxo-1,4-benzoxazin-4-yl]-N-methyl-propionamide. To a solution of 3-(7-amino-3-oxo-1,4-benzoxazin-4-yl)-N-methyl-propionamide (2.10 g, 8.42 mmol) cooled to -40°C in a mixture of THF (40 mL) and DMF (10 mL), 5-chloro-2,4-difluoro-pyrimidin (0.81 mL, 8.42 mmol) and DIPEA (1.59 mL, 9.27 mmol) were added sequentially. The reaction mixture was slowly warmed to room temperature and stirred for 24 hours. The volatiles were evaporated under reduced pressure. THF (50.0 mL) was slowly added, and the precipitate was collected by filtration, washed with THF (50.0 mL), and then dried under vacuum to give the title compound (2.24 g, 75%) as a solid. 1H NMR (500 MHz, DMSO) δ 9.55 (s, 1H), 8.38 (d, J = 1.1 Hz, 1H), 7.93 (d, J = 4.1 Hz, 1H), 7.39 - 7.27 (m, 2H), 7.23 (d, J = 8.7 Hz, 1H), 4.66(s, 2H), 4.17 - 3.98 (m, 2H), 2.57 (d, J = 4.6 Hz, 3H), 2.46 - 2.34 (m, 2H);. MS (ESI) [M+H] + 380.1.

[0502] Step 13.5: Synthesis of 3-(7-((5-chloro-2-(4-((3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)amino)piperidin-1-yl)pyrimidin-4-yl)amino)-3-oxo-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-N-methylpropionamide. 3-[1-methyl-6-(4-piperidinylamino)inzol-3-yl]piperidin-2,6-dione; hydrochloride (35.8 mg, 0.090 mmol), 3-[7-[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]-3-oxo-1,4-benzoxazin-4-yl]-N-methyl-propionamide (30 mg, 0.0800 mmol), N,N-diisopropylethylamine (0.03 mL, 0.1600 mmol), and DMSO (0.15 mL) were added to a 1-drylan bottle equipped with a stir bar and heated to 80°C overnight.

[0503] The reaction was cooled to room temperature, and water was added to precipitate the product. The resulting solid was filtered through a Buchner funnel and washed with water (3x) and MTBE (1x). The solid was dried overnight under vacuum at 45°C to give the title compound (45 mg, 0.061 mmol, 76% yield). LCMS m / z = 701 [M+H] + ; 1H NMR (DMSO-d6, 400 MHz) δ 10.75 (s, 1H),8.6-8.7 (m, 1H), 7.99 (s, 1H), 7.8-7.9 (m, 1H), 7.4-7.4 (m, 1H), 7.3-7.4 (m,1H), 7.2-7.3 (m, 1H), 7.0-7.1 (m, 1H), 6.40 (s, 2H), 5.6-5.8 (m, 1H), 4.53(s, 2H), 4.3-4.4 (m, 2H), 4.1-4.2 (m, 1H), 3.9-4.0 (m, 2H), 3.76 (s, 3H),3.5-3.7 (m, 1H), 3.0-3.2 (m, 2H), 2.5-2.6 (m, 2H), 2.47 (d, 3H, J=4.6 Hz), 2.3-2.3 (m, 2H), 2.1-2.2 (m, 1H), 2.0-2.1 (m, 1H), 1.9-2.0 (m, 2H), 1.2-1.4(m, 2H).

[0504] Example 14

[0505]

[0506] 2-(4-(5-chloro-4-((1-methyl-2-oxodihydroindole-5-yl)amino)pyrimidin-2-yl)piperazin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)acetamide

[0507] Step 14.1: Synthesis of 7-bromo-3-iodo-1H-indazole. Potassium hydroxide (11.39 g, 203.0 mmol, 2 equivalents) was added to a solution of 7-bromo-1H-indazole (20.0 g, 101 mmol, 1 equivalent) and iodine (51.53 g, 203.0 mmol, 2 equivalents) in dimethylformamide (500 mL) at 0°C. The mixture was stirred at 16°C for 12 hours. 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 washed with sodium sulfite (20 mL × 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The title compound was used directly in the next step without further purification. 1H NMR (400 MHz, DMSO-d6) 13.93 (s, 1 H), 7.64 - 7.79 (m, 1 H), 7.47 (d, J = 8.0 Hz, 1 H), 7.08 - 7.26 (m, 1 H).

[0508] Step 14.2: Synthesis of bromo-3-iodo-1-methyl-1H-indazole. Potassium tert-butoxide (22.73 g, 202.5 mmol, 2 equivalents) was added to a solution of 7-bromo-3-iodo-1H-indazole (32.7 g, 101 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 (28.75 g, 202.5 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. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel chromatography (2-67% ethyl acetate in petroleum ether) to give the title compound (21.24 g, 63.04 mmol, 62% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.66 (d, J = 7.6 Hz, 1 H), 7.40 (d, J = 8.0Hz, 1 H), 6.95 - 7.16 (m, 1 H), 4.31 (s, 3 H).

[0509] Step 14.3: Synthesis of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-7-bromo-1-methyl-1H-indazole. To a solution of 7-bromo-3-iodo-1-methyl-1H-indazole (5.00 g, 14.8 mmol, 1 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 (6.19 g, 14.8 mmol, 1 equivalent), (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (1.09 g, 1.48 mmol, 0.1 equivalent), and cesium carbonate (14.5 g, 44.5 mmol, 3 equivalent) were added. The mixture was stirred at 100°C for 12 hours. 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 title compound (4.24 g, 8.47 mmol, 57% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ7.86 (d, J = 8.0 Hz, 1 H), 7.57 - 7.69 (m, 2 H), 7.45 - 7.50 (m, 2 H), 7.25 -7.43 (m, 8 H), 6.93 (t, J = 7.6 Hz, 1 H), 6.60 (d, J = 8.0 Hz, 1 H), 5.43 (s, 4 H), 4.36 (s, 3 H).

[0510] Step 14.4: 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 (1.31 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, 16.7 g, 33.4 mmol, 1 equivalent), tert-butyl carbamate (3.91 g, 33.4 mmol, 1 equivalent), and cesium carbonate (21.75 g, 66.75 mmol, 2 equivalents) in dioxane (300 mL). The mixture was heated to 100°C and stirred for 16 hours. The solution was cooled to room temperature and filtered. The filtrate was concentrated, and the residue was purified by silica gel chromatography (1% to 12% ethyl acetate in petroleum ether solution) to give the title compound (6.60 g, 12.3 mmol, 37% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ = 7.85 (d, J = 8.0Hz, 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).

[0511] Step 14.5: Synthesis of tert-butyl carbamate (3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazole-7-yl)carbamate. Pd / C (1.00 g, 10% by weight) was added to a solution of tert-butyl carbamate (8.00 g, 14.9 mmol, 1 equivalent) in THF (150 mL). The mixture was stirred at 25°C for 24 hours under hydrogen (50 psi). The mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel chromatography (10% to 67% ethyl acetate in petroleum ether) to give the title compound (3.60 g, 10.0 mmol, 67% yield) as a yellow solid. 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).

[0512] Step 14.6: 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 (3.50 g, 9.77 mmol, 1 equivalent) was added to an aqueous solution of hydrogen chloride (12 M, 50 mL, 61.4 equivalent) at 0°C, and the mixture was stirred at 25°C for 2 hours. A clear yellow solution was obtained. This solution was poured into cold water (500 mL) at 0°C, and then lyophilized to give the title compound, which was used without further purification (2673 mg, 8.73 mmol, 89% yield, 96.2% purity, HCl salt). 1H NMR (400 MHz, DMSO-d6) δ = 10.91 (s, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.50 (d, J = 7.2 Hz, 1H), 7.15 (t, J = 7.6 Hz, 1H), 4.39-4.45 (m, 1H), 4.32 (s, 3H), 2.57-2.75 (m, 2H), 2.32-2.45 (m, 1H), 2.13-2.21 (m, 1H).

[0513] Step 14.7: Synthesis of tert-butyl 4-[2-[[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-7-yl]amino]-2-oxo-ethyl]piperazine-1-carboxylic acid. N,N-diisopropylethylamine (0.39 mL, 2.24 mmol) was added to a solution of 3-(7-amino-1-methyl-indazole-3-yl)piperidin-2,6-dione; hydrochloride (300 mg, 1.02 mmol) and 2-(4-(tert-butoxycarbonyl)piperazine-1-yl)acetic acid (273 mg, 1.12 mmol) in DMSO (2 mL). The reaction mixture was stirred at 80°C for 15 hours, followed by purification by reversed-phase HPLC to give the title compound (164 mg, 33% yield). 1 HNMR (400 MHz, DMSO-d6) δ ppm 10.90 (s, 1 H), 9.87 (s, 1 H), 7.58 (d, J=8.07Hz, 1 H), 7.29 (d, J=7.34 Hz, 1 H), 7.08 (t, J=7.64 Hz, 1 H), 4.38 (dd, J=10.21, 5.07 Hz, 1 H), 4.10 (s, 3 H), 3.41 (br s, 4 H), 3.23 (s, 2 H), 2.52 -2.77 (m, 3 H), 2.29 - 2.45 (m, 2 H), 2.11 - 2.23 (m, 1 H).

[0514] Step 14.8: Synthesis of N-[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-7-yl]-2-piperazin-1-yl-acetamide; hydrochloride. The title compound was synthesized using 4-[2-[[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-7-yl]amino]-2-oxo-ethyl]piperazin-1-carboxylic acid tert-butyl ester as the starting material, according to General Procedure 5.

[0515] Step 14.9: Synthesis of 2-(4-(5-chloro-4-((1-methyl-2-oxodihydroindol-5-yl)amino)pyrimidin-2-yl)piperazin-1-yl)-N-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazole-7-yl)acetamide. The title compound was synthesized using 5-[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]-1-methyl-dihydroindol-2-one (14.5 mg, 0.050 mmol) and N-[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-7-yl]-2-piperazin-1-yl-acetamide; hydrochloride (22 mg, 0.052 mmol) as starting materials according to General Procedure 6. The crude material was purified by reversed-phase HPLC (10 to 100% acetonitrile in water (containing 0.1% formic acid)) to give the title compound (10 mg, 29%); LCMS C 32 H 33 ClN 10 O4 theoretical value 656.2, measured value 657.0 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.90 (s, 1 H),9.91 (s, 1 H), 8.68 (s, 1 H), 8.02 (s, 1 H), 7.58 (d, J=7.82 Hz, 1 H), 7.53(s, 1 H), 7.46 - 7.51 (m, 1 H), 7.33 (d, J=7.21 Hz, 1 H), 7.08 (t, J=7.70 Hz, 1 H), 6.94 (d, J=8.44 Hz, 1 H), 4.38 (dd, J=9.96, 5.07 Hz, 1 H), 4.13 (s, 3H), 3.70 (br s, 4 H), 3.56 (s, 2 H), 3.24 (s, 2 H), 3.12 (s, 3 H), 2.68 -2.74 (m, 1 H), 2.56 - 2.65 (m, 5 H), 2.33 - 2.42 (m, 1 H), 2.12 - 2.21 (m, 1H).

[0516] Example 15

[0517]

[0518] 3-(7-((1-(5-chloro-4-((1-methyl-2-oxodihydroindole-5-yl)amino)pyrimidin-2-yl)piperidin-4-yl)(methyl)amino)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione

[0519] Step 15.4: Synthesis of 3-(7-((1-(5-chloro-4-((1-methyl-2-oxodihydroindol-5-yl)amino)pyrimidin-2-yl)piperidin-4-yl)(methyl)amino)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione. The title compound was synthesized using 5-[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]-1-methyl-dihydroindol-2-one (19 mg, 0.064 mmol) and 3-[1-methyl-7-[methyl(4-piperidinyl)amino]indazole-3-yl]piperidin-2,6-dione; hydrochloride (25 mg, 0.064 mmol) as starting materials according to General Procedure 6. The crude material was purified by reversed-phase HPLC (10 to 100% acetonitrile in water (containing 0.1% formic acid)) to give the title compound (40 mg, 70%); LCMS C 32 H 34 The theoretical value of ClN9O3 is 627.3, and the measured value is 628.0 [M+H]. + ; 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.88 (s, 1 H), 8.62 (s, 1 H), 7.98 (s, 1 H), 7.47 - 7.56 (m, 2 H), 7.42 (d, J=7.95 Hz, 1 H), 7.16 (d, J=7.09 Hz, 1 H), 7.04 (t, J=7.70 Hz, 1 H), 6.92 (d, J=9.05 Hz, 1 H), 4.38 -4.51 (m, 2 H), 4.34 (dd, J=9.72, 5.07 Hz, 1 H), 4.22 (s, 3 H), 3.53 (s, 2 H),3.20 - 3.29 (m, 1 H), 3.10 (s, 3 H), 2.77 - 2.95 (m, 2 H), 2.59 - 2.73 (m, 5H), 2.29 - 2.40 (m, 1 H), 2.12 - 2.23 (m, 1 H), 1.72 - 1.86 (m, 2 H), 1.41 -1.58 (m, 2 H).

[0520] Example 16

[0521]

[0522] 3-(5-(2-((5-chloro-4-((2-oxodihydroindole-5-yl)amino)pyrimidin-2-yl)amino)ethyl)-1-oxoisodihydroindole-2-yl)piperidin-2,6-dione

[0523] Step 16.1: Synthesis of 5-aminodihydroindole-2-one. A mixture of 2.67 g (15.0 mmol) of 5-nitrodihydroindole-2-one and 10% Pd / C (798.0 mg, 0.75 mmol) in ethyl acetate (40.0 mL) and methanol (70.0 mL) was shaken at room temperature for 1 h at 50 psi under hydrogen atmosphere in a Parr hydrogenator. The reaction mixture was filtered through a Celite filter and washed with methanol (2 x 10.0 mL). The filtrate was concentrated under reduced pressure to give the title compound (2.20 g, 99%) as a solid, which was used in the next step without further purification. MS (ESI) [M+H] + 148.8.

[0524] Step 16.2: Synthesis of 5-[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]dihydroindole-2-one. DIEA (1.32 mL, 7.70 mmol) and 5-chloro-2,4-difluoro-pyrimidinidine (1.05 g, 7.0 mol) were added sequentially to a solution of 5-aminodihydroindole-2-one (1.04 g, 7.00 mmol) cooled to -40 °C in THF (70.0 mL). After the addition was complete, the reaction was cooled to room temperature and stirred for 2 hours. The precipitate was collected by filtration, washed with THF (2.0 mL), and dried under vacuum to give the title compound (1.25 g, 64%) as a solid. The filtrate was concentrated under reduced pressure and ground in acetonitrile (10.0 mL). A precipitate was formed and collected by filtration, washed with acetonitrile (2.0 mL), and dried under vacuum to give the other title compound (350.0 mg, 18%) as a solid. 1 H NMR (500 MHz, DMSO) δ 10.40(s, 1H), 9.49 (s, 1H), 8.31 (d, J = 1.2 Hz, 1H), 7.35 (s, 1H), 7.27 (dd, J =8.3, 2.1 Hz, 1H), 6.82 (d, J = 8.3 Hz, 1H), 3.51 (s, 2H). MS (ESI) [M+H] + 279.0.

[0525] Step 16.3: Synthesis of 3-(5-allyl-1-oxo-isodihydroindol-2-yl)piperidine-2,6-dione. Allyltri-n-butyltin (990.0 µL, 3.19 mmol) and Pd(PPh3)2Cl2 (112.0 mg, 0.16 mmol) were added sequentially to a solution of 3-(5-bromo-1-oxo-isodihydroindol-2-yl)piperidine-2,6-dione (1.03 g, 3.19 mmol) in dry DMF (20.0 mL). The reaction mixture was degassed with nitrogen, sealed, heated to 90°C overnight, and then cooled to room temperature. Ethyl acetate (20.0 mL) and water (20.0 mL) were added, and the layers were separated. The organic layer was washed with water (20.0 mL) and brine (2 x 20.0 mL), then dried (MgSO4), filtered, and concentrated under reduced pressure. The substance was purified by silica gel chromatography using a 5% to 95% ethyl acetate / hexane gradient to give the title compound (0.600 g, 66%) as a solid. 1 H NMR (500 MHz, DMSO) δ 10.97 (s, 1H), 7.66 (d, J = 7.7 Hz, 1H), 7.43 (s, 1H), 7.34 (d, J = 7.2 Hz, 1H), 5.99 (ddt, J = 16.8, 10.0, 6.7 Hz, 1H), 5.16 - 5.06 (m,3H), 4.43 (d, J = 17.2 Hz, 1H), 4.30 (d, J = 17.2 Hz, 1H), 3.49 (d, J = 6.8Hz, 2H), 2.96 - 2.86 (m, 1H), 2.60 (d, J = 17.5 Hz, 1H), 2.39 (dd, J = 13.2,4.5 Hz, 1H), 2.03 - 1.96 (m, 1H).

[0526] Step 16.4: Synthesis of 3-[5-(2,3-dihydroxypropyl)-1-oxo-isodihydroindol-2-yl]piperidine-2,6-dione. NaHCO3 (88.6 mg, 1.06 mmol), NMO (1.14 g, 8.44 mmol), 2,6-rutidine (0.49 mL, 4.22 mmol), and OsO4 (21.5 mg, 0.08 mmol, 0.157 M, in water) were added sequentially to a solution of 3-(5-allyl-1-oxo-isodihydroindol-2-yl)piperidine-2,6-dione (600.0 mg, 2.11 mmol) in THF (6.0 mL) and water (3.0 mL), and the reaction mixture was stirred at room temperature for 8 hours. Solid Na₂SO₃ (2.39 g, 19.0 mmol) was added in portions, and the mixture was stirred for another 30 minutes. Volatile substances were removed under reduced pressure. The substance was lyophilized, dissolved in acetone, and then filtered to remove insoluble substances. The filtrate was concentrated under reduced pressure, and the substance was purified by reversed-phase chromatography (C18) with acetonitrile / 0.1% formic acid gradient (5-100%) to give the title compound (530.0 mg, 79%) as a solid. MS (ESI). [M+H] + 319.

[0527] Step 16.5: Synthesis of 2-[2-(2,6-dioxo-3-piperidinyl)-1-oxo-isodihydroindole-5-yl]acetaldehyde. NaIO4 (470.0 mg, 2.2 mmol) was added to a solution of 3-[5-(2,3-dihydroxypropyl)-1-oxo-isodihydroindole-2-yl]piperidin-2,6-dione (350.0 mg, 1.1 mmol) in a mixture of THF (7.0 mL) and water (7.0 mL), and the reaction mixture was stirred at room temperature for 2 hours. The mixture was extracted with DCM (3 x 20.0 mL), and the combined organic extracts were washed with brine (20.0 mL), dried (MgSO4), filtered, and concentrated under reduced pressure to give the title compound (220.0 mg, 70%) as a solid, which was used in the next step without further purification (220 mg, 70%). 1H NMR(500 MHz, DMSO) δ 11.04 (d, J = 9.4 Hz, 1H), 9.79 (t, J = 1.6 Hz, 1H), 7.77(d, J = 7.8 Hz, 1H), 7.54 (s, 1H), 7.44 (t, J = 7.9 Hz, 1H), 5.18 (dd, J =13.4, 5.2 Hz, 1H), 4.52 (d, J = 17.3 Hz, 1H), 4.38 (d, J = 17.3 Hz, 1H), 4.01(d, J = 1.3 Hz, 2H), 3.02 - 2.93 (m, 1H), 2.68 - 2.64 (m, 1H), 2.46 (dd, J =13.0, 4.5 Hz, 1H), 2.10 - 2.04 (m, 1H). MS (ESI) [M+H] + 287.4

[0528] Step 16.6: Synthesis of 3-[5-(2-hydroxyethyl)-1-oxo-isodihydroindol-2-yl]piperidine-2,6-dione. NaBH4 (58.1 mg, 1.54 mmol) was added to a solution of 2-[2-(2,6-dioxo-3-piperidinyl)-1-oxo-isodihydroindol-5-yl]acetaldehyde (440.0 mg, 1.54 mmol) in MeOH (5.0 mL) cooled to 0°C, and the reaction mixture was stirred for 1 hour. A saturated aqueous solution of NH4Cl (0.5 mL) was slowly added, and the mixture was stirred for 15 minutes. The volatiles were removed under reduced pressure, and the substance was lyophilized to give the title compound (400 mg, 90%) as a solid, which was used in the next step without further purification. MS (ESI) [M+H] + 289.3.

[0529] Step 16.7: Synthesis of 3-[5-(2-chloroethyl)-1-oxo-isodihydroindol-2-yl]piperidine-2,6-dione. DIPEA (0.40 mL, 2.30 mmol) and methanesulfonyl chloride (0.13 mL, 1.69 mmol) were added sequentially to a solution of 3-[5-(2-hydroxyethyl)-1-oxo-isodihydroindol-2-yl]piperidine-2,6-dione (443.0 mg, 1.54 mmol) in DMF (10.0 mL), and the reaction mixture was stirred overnight at room temperature. Further addition of DIPEA (0.4 mL, 2.3 mmol) and methanesulfonyl chloride (0.13 mL, 1.69 mmol) was added, and the reaction mixture was stirred for another day. Ethyl acetate (50.0 mL) and water (50.0 mL) were added, and the layers were separated. The aqueous layer was extracted with ethyl acetate (2 x 50.0 mL), and the combined organic layers were washed with brine (50.0 mL), dried (MgSO4), filtered, and concentrated under reduced pressure to give the title compound (440.0 mg, 93%), which was used in the next step without further purification. MS (ESI) [M+H + 307.3.

[0530] Step 16.8: Synthesis of 3-[5-(2-azidoethyl)-1-oxo-isodihydroindol-2-yl]piperidine-2,6-dione. NaI (1.2 g, 8.15 mmol) was added to a solution of 3-[5-(2-chloroethyl)-1-oxo-isodihydroindol-2-yl]piperidine-2,6-dione (250.0 mg, 0.82 mmol) in acetone (20.0 mL). The reaction was refluxed for 8 hours, then cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. Ethyl acetate (10.0 mL) and water (10.0 mL) were added, and the layers were separated. The organic layer was washed with water (2 x 10.0 mL), dried (MgSO4), filtered, and concentrated under reduced pressure to give 3-[5-(2-iodoethyl)-1-oxo-isodihydroindol-2-yl]piperidine-2,6-dione, which was used in the next step without further purification. NaN3 (371.0 mg, 5.71 mmol) was added to a solution of 3-[5-(2-iodoethyl)-1-oxo-isodihydroindol-2-yl]piperidine-2,6-dione in DMF (10.0 mL). The reaction mixture was stirred at room temperature for 18 hours. The organic layer was separated by adding ethyl acetate (20.0 mL) and water (30.0 mL), washed with water (30.0 mL), dried (MgSO4), filtered, and concentrated under reduced pressure to give the title compound (230.0 mg, 90%) as a solid, which was used in the next step without further purification. MS (ESI) [M+H] + 314.1

[0531] Step 16.9: Synthesis of 3-[5-(2-aminoethyl)-1-oxo-isodihydroindol-2-yl]piperidine-2,6-dione. 10% Pd / C (85.0 mg, 0.079 mmol) was added to a solution of 3-[5-(2-azidoethyl)-1-oxo-isodihydroindol-2-yl]piperidine-2,6-dione (100.0 mg, 0.32 mmol) in MeOH (10.0 mL), and the reaction mixture was degassed with H2 and stirred for 1 h under H2 atmosphere. The mixture was filtered through a Celite filter and washed with MeOH (2 x 10.0 mL). The filtrate was concentrated under reduced pressure to give the title compound 1h (90 mg, 98%) as a solid, which was used in the next step without further purification. MS (ESI) [M+H] + 288.4.

[0532] Step 16.10: Synthesis of 3-(5-(2-((5-chloro-4-((2-oxodihydroindol-5-yl)amino)pyrimidin-2-yl)amino)ethyl)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione. 5-[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]dihydroindol-2-one (25.2 mg, 0.09 mmol) and DIPEA (0.02 mL, 0.11 mmol) were added sequentially to a solution of 3-[5-(2-aminoethyl)-1-oxo-isodihydroindol-2-yl]piperidin-2,6-dione (26.0 mg, 0.09 mmol) in DMSO (1.0 mL). The reaction mixture was heated to 80°C for 45 minutes and then cooled to room temperature. The mixture was purified directly by reversed-phase chromatography (C18) with elution of acetonitrile / 0.1% formic acid gradient (22-28%) to give the title compound (5.0 mg, 10% yield) as a solid. 1 H NMR (500 MHz, DMSO) δ 10.97 (s, 1H), 10.39 (s, 1H), 7.95 (s, 1H), 7.60 (s, 1H), 7.46 (s, 1H), 7.40 (d, J = 7.8 Hz, 1H), 7.27 -7.20 (bs, 1H), 7.17 - 7.12 (m, 1H), 6.77 (s, 1H), 5.10 (dd, J = 13.3, 5.0 Hz,1H), 4.37 (d, J = 17.5 Hz, 1H), 4.26 (d, J = 16.9 Hz, 1H), 3.42 (s, 2H), 2.98- 2.76 (m, 3H), 2.63 (d, J = 17.2 Hz, 1H), 2.38 - 2.34 (m, 2H), 2.03 - 1.97(m, 1H); MS (ESI) [M+H] + 546.2.

[0533] Example 17

[0534]

[0535] 3-(5-((1-(5-chloro-4-((1-methyl-2-oxodihydroindole-5-yl)amino)pyrimidin-2-yl)piperidin-4-yl)amino)-1H-benzo[d][1,2,3]triazol-1-yl)piperidin-2,6-dione

[0536] Step 17.1: 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 DIPEA (50.0 mL) were added sequentially to a solution of 4-bromo-1-fluoro-2-nitro-benzene (19.0 g, 86.4 mmol) in DMF (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 aqueous solution of NH4Cl (500.0 mL) and EtOAc (500.0 mL) were added, and the layers were separated. The organic layer was washed with brine (200.0 mL), dried (Na₂SO₄), 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.

[0537] Step 17.2: Synthesis of tert-butyl 5-amino-4-(2-amino-4-bromo-anilino)-5-oxo-valerate. Zinc powder (47.0 g, 718.0 mmol) and NH4Cl (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 THF (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 THF (200 mL). The filtrate was concentrated under reduced pressure. The substance was purified by silica gel column chromatography using a gradient elution of 10-20% MeOH in DCM to give the title compound (28.1 g, 95%) as a solid. 1 H NMR (400MHz, 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). MS (ESI) [M+H] +374.2.

[0538] Step 17.3: Synthesis of tert-butyl 5-amino-4-(5-bromobenzotriazol-1-yl)-5-oxo-valerate. Tert-butyl nitrite (4.31 mL, 32.6 mmol) and acetic acid (1.83 mL, 32.05 mmol) were added sequentially to a solution of tert-butyl 5-amino-4-(2-amino-4-bromo-aniline)-5-oxo-valerate (5.97 g, 16.0 mmol) in MeCN (40.1 mL). The reaction mixture was stirred at room temperature for 1.5 h. Water (20.0 mL) and diethyl ether (20.0 mL) were added, and the layers were separated. The organic layer was dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The substance was purified by silica gel column chromatography using a gradient elution of 0-100% ethyl acetate in hexane to give the title compound (2.78 g, 44%) as a solid. 1 ¹H NMR (500 MHz, DMSO) δ 8.36 (s, 1H), 7.83 - 7.81 (m, 2H), 7.71 (d, J = 8.7 Hz, 1H), 7.52 (s, 1H), 5.62 - 5.60 (m, 1H), 2.21 - 2.15 (m, 1H), 2.10 - 2.04 (m, 1H), 1.33 (s, 9H). Note: Both protons are masked by the DMSO signal. MS (ESI) [M+H] + 383.1.

[0539] Step 17.4: Synthesis of N-[1-(2,6-dioxo-3-piperidinyl)benzotriazol-5-yl]carbamate tert-butyl ester. A mixture of tert-butyl 5-amino-4-(5-bromobenzotriazol-1-yl)-5-oxo-valerate (1.31 g, 3.42 mmol), tert-butyl carbamate (600 mg, 5.13 mmol), tBuXPhos-Pd-G3 (554.1 mg, 0.68 mmol), and NaOtBu (821.2 mg, 8.55 mmol) in 1,4-dioxane (33.0 mL) was heated to 50°C for 18 hours and then cooled to room temperature. Acetic acid (0.98 mL, 17.1 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. The volatiles were evaporated under reduced pressure. Acetonitrile (50.0 mL) was added, and the precipitate was collected by filtration and washed with acetonitrile (3 x 25.0 mL) and diethyl ether (3 x 25.0 mL). The substance was purified by reversed-phase chromatography (C18) using a gradient elution of 0-100% acetonitrile and water (containing 0.1 formic acid) to give the title compound (331.0 mg, 28%) as a solid. 1 ¹H NMR (400 MHz, DMSO) δ 9.58 (s, 1H), 8.16 (s, 1H), 7.70–7.68 (m, 1H), 7.56 (dd, J = 9.0, 1.7 Hz, 1H), 6.18–6.13 (m, 1H), 2.93–2.90 (m, 2H), 2.77–2.73 (m, 1H), 2.40–2.37 (m, 1H), 1.51 (s, 9H). Note: NH4+ in glutarimide was not observed. MS (ESI) [M+H] + 346.2.

[0540] Step 17.5: Synthesis of 3-(5-aminobenzotriazol-1-yl)piperidin-2,6-dione; hydrochloride. HCl (0.8 mL, 3.19 mmol) in 4N in 1,4-dioxane was added to a solution of N-[1-(2,6-dioxo-3-piperidinyl)benzotriazol-5-yl]carbamate (110.0 mg, 0.32 mmol) in DCM (2.0 mL). The reaction mixture was stirred at room temperature for 4 hours. The volatiles were evaporated under reduced pressure to give the title compound (90.0 mg, 99% yield) as a solid, which was used in the next step without further purification. 1H NMR (500 MHz, DMSO) δ 11.30 (s, 1H), 7.95 (s, 1H), 7.89 (d, J = 8.7 Hz, 1H), 7.48 (d, J = 7.8 Hz, 1H), 6.27 - 6.24 (m,1H), 4.09 (bs, 3H), 2.98 - 2.90 (m, 2H), 2.80 - 2.76 (m, 1H), 2.50 - 2.42 (m,1H). MS (ESI) [M+H] + 246.2.

[0541] Step 17.6: Synthesis of 4-[[1-(2,6-dioxo-3-piperidinyl)benzotriazol-5-yl]amino]piperidin-1-carboxylic acid tert-butyl ester. At room temperature, 4-oxopiperidin-1-carboxylic acid tert-butyl ester (151 mg, 0.76 mmol) and acetic acid (0.95 mL) were added sequentially to a solution of 3-(5-aminobenzotriazol-1-yl)piperidin-2,6-dione; hydrochloride (171 mg, 0.61 mmol) in DMSO (4.7 mL). The reaction mixture was stirred for 30 min, and then sodium triacetoxyborohydride (257 mg, 1.21 mmol) was added. The reaction mixture was stirred overnight at room temperature. Water was added, and the resulting precipitate was collected by filtration, washed with diethyl ether (5.0 mL), and then dried under vacuum to give the title compound (201 mg, 69% yield) as a solid, which was used in the next step without further purification. 1 HNMR(500 MHz, DMSO) δ 11.23 (s, 1H), 7.48 (d,J = 8.8 Hz, 1H), 6.98 (d, J = 8.9 Hz, 1H), 6.93 (s, 1H), 6.06 - 6.03 (m, 1H),5.73 (d, J = 6.9 Hz, 1H), 3.88 (d, J = 10.9 Hz, 2H), 3.50 (s, 1H), 2.94 -2.83 (m, 4H), 2.74 - 2.71 (m, 1H), 2.34 - 2.32 (m, 1H), 1.95 (d, J = 11.0 Hz, 2H), 1.41 (s, 9H), 1.28 -1.24 (m, 2H). MS (ESI) [M+H] + 429.3.

[0542] Step 17.7: Synthesis of 3-[5-[methyl(4-piperidinyl)amino]benzotriazol-1-yl]piperidin-2,6-dione; hydrochloride. To a solution of tert-butyl 4-[[1-(2,6-dioxo-3-piperidinyl)benzotriazol-5-yl]methyl-amino]piperidin-1-carboxylic acid (59.0 mg, 0.13 mmol) in 1,4-dioxane (0.80 mL), HCl in 1,4-dioxane (0.33 mL, 1.33 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. The volatiles were evaporated under reduced pressure to give the title compound (50.0 mg, 98.9%) as a solid, which was used in the next step without further purification. MS (ESI) [M+H] + 343.3.

[0543] Step 17.8: Synthesis of 3-(5-((1-(5-chloro-4-((1-methyl-2-oxodihydroindol-5-yl)amino)pyrimidin-2-yl)piperidin-4-yl)amino)-1H-benzo[d][1,2,3]triazol-1-yl)piperidin-2,6-dione. At room temperature, 5-[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]-1-methyl-dihydroindol-2-one (22.5 mg, 0.08 mmol) and DIPEA (0.07 mL, 0.38 mmol) were added sequentially to a solution of 3-[5-(4-piperidinylamino)benzotriazol-1-yl]piperidin-2,6-dione hydrochloride (35.0 mg, 0.10 mmol) in DMSO (1.25 mL). The reaction mixture was heated to 85°C for 2 hours and then cooled to room temperature. The substance was purified by preparative HPLC (BEH, C18) using a gradient elution of 36-56% acetonitrile and 10 mM ammonium formate in aqueous solution to give the title compound (18.0 mg, 30%) as a solid. 1H NMR (500 MHz, DMSO)δ 11.08 (s, 1H), 8.64 (s, 1H), 8.01 (s, 1H), 7.55 - 7.50 (m, 2H), 7.47 (d, J= 8.9 Hz, 1H), 6.98 (dd, J = 9.0, 1.9 Hz, 1H), 6.96 - 6.91 (m, 2H), 6.04 (dd,J = 12.5, 5.1 Hz, 1H), 5.71 (d, J = 8.1 Hz, 1H), 4.44 - 4.30 (m, 2H), 3.67 -3.56 (m, 1H), 3.55 (s, 2H), 3.17 - 3.11 (m, MS (ESI) [M+H] + 601.4.

[0544] Example 18

[0545]

[0546] 3-(6-(4-((5-chloro-4-((1-methyl-2-oxodihydroindole-5-yl)amino)pyrimidin-2-yl)amino)piperidin-1-yl)-1-methyl-1H-indole-3-yl)piperidin-2,6-dione

[0547] Step 18.1: Synthesis of 6-bromo-3-iodo-1-methyl-indole. Iodine (10.1 g, 40.0 mmol) was added to a solution of 6-bromo-1-methyl-indole (4.20 g, 20.0 mmol) in DMF (80 mL) at 0°C, followed by the addition of powdered KOH (2.24 g, 40.0 mmol) in portions over 10 minutes. The reaction mixture was cooled to room temperature for 3 hours and diluted with water (100 mL), saturated Na₂SO₃ solution (100 mL), and EtOAc (100 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (2 x 100 mL). The combined organic fractions were washed with saturated Na₂SO₃ solution (100 mL) and brine (100 mL), dried (Na₂SO₄), filtered, and concentrated under reduced pressure to give the title compound (6.51 g, 97%) as a solid. MS(ESI) [M+H]+ 334.8. 1 H NMR (500 MHz, DMSO-d6) δ 7.77 (d, J = 1.6 Hz, 1H), 7.57(s, 1H), 7.26 (dd, J = 8.4, 1.6 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 3.80 (s,3H).

[0548] Step 18.2: Synthesis of 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indole. Pd(PPh3)4 (57.8 mg, 0.0500 mmol) was added to a degassed mixture of 6-bromo-3-iodo-1-methyl-indole (168 mg, 0.500 mmol), 2,6-dibenzyloxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyridine (229 mg, 0.550 mmol, an intermediate provided by Celgene), K3PO4 (530 mg, 2.50 mmol), water (1.5 mL), and 1,4-dioxane (3 mL). The reaction vessel was sealed, and the reaction mixture was heated to 100 °C for 8 hours, then cooled to room temperature. EtOAc (50 mL) was added, and the layers were separated. The organic layer was dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 3% Et2O elution in hexane to give the title compound (111 mg, 44%) as a solid. MS (ESI) [M+H] + 499.1. 1 H NMR (500 MHz, DMSO-d6) δ 7.85 (d, J = 8.0Hz, 1H), 7.73 (d, J = 1.7 Hz, 1H), 7.58 (s, 1H), 7.54 (d, J = 8.5 Hz, 1H), 7.46 - 7.42 (m, 2H), 7.42 - 7.36 (m, 4H), 7.36 - 7.31 (m, 3H), 7.30 - 7.25(m, 1H), 7.14 (dd, J = 8.5, 1.8 Hz, 1H), 6.55 (d, J = 8.0 Hz, 1H), 5.43 (s,2H), 5.37 (s, 2H), 3.80 (s, 3H).

[0549] Step 18.3: Synthesis of N-[1-[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indole-6-yl]-4-piperidinyl] tert-butyl carbamate. At room temperature, tBuXPhos-Pd-G3 (74.5 mg, 90 µmol) was added to a degassed mixture of 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indole (440 mg, 0.880 mmol), N-(4-piperidinyl) tert-butyl carbamate (264 mg, 1.32 mmol), and tBuONa (127 mg, 1.32 mmol) in THF (4.4 mL). The reaction vessel was sealed, and the reaction mixture was heated to 80 °C for 18 hours, then cooled to room temperature, diluted with EtOAc (20 mL), and filtered through a Celite filter. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using a 10-50% EtOAc gradient elution in hexane to give the title compound (360 mg, 66%) as a solid. MS (ESI) [M+H + 618.6. 1 H NMR (500 MHz, DMSO-d6) δ 7.88 (d, J = 8.1 Hz, 1H), 7.48(d, J = 8.8 Hz, 1H), 7.45 - 7.39 (m, 5H), 7.39 - 7.35 (m, 2H), 7.35 - 7.32(m, 2H), 7.30 - 7.27 (m, 1H), 6.88 (d, J = 2.0 Hz, 1H), 6.86 (d, J = 7.5 Hz, 1H), 6.80 (dd, J = 8.9, 2.1 Hz, 1H), 6.53 (d, J = 8.0 Hz, 1H), 5.44 (s, 2H),5.35 (s, 2H), 3.72 (s, 3H), 3.65 - 3.56 (m, 2H), 3.38 (br s, 1H), 2.72 (t, J= 10.9 Hz, 2H), 1.88 - 1.79 (m, 2H), 1.61 - 1.49 (m, 2H), 1.40 (s, 9H).

[0550] Step 18.4: Synthesis of N-[1-[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indole-6-yl]-4-piperidinyl]tert-butyl carbamate. A mixture of N-[1-[3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-indole-6-yl]-4-piperidinyl]tert-butyl carbamate (360 mg, 0.580 mmol) and Pearlman catalyst (93.9 mg, 0.130 mmol) in EtOH (6 mL) and THF (6 mL) was hydrogenated at 50°C (1 atm) for 1 h. The reaction mixture was cooled to room temperature, filtered through a Celite filter, and washed with EtOH (2 x 10 mL). The filtrate was concentrated under reduced pressure to give the title compound (250 mg, 97%) as a solid, which was used in the next step without further purification. MS (ESI) [M+H) + 441.2.

[0551] Step 18.5: Synthesis of 3-[6-(4-amino-1-piperidinyl)-1-methyl-indol-3-yl]piperidin-2,6-dione hydrochloride. N-[1-[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indol-6-yl]-4-piperidinyl]carbamate tert-butyl ester (250 mg, 0.570 mmol) was added to a solution of 4N HCl in 1,4-dioxane (7 mL, 28 mmol) at room temperature, and the reaction mixture was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure, and the residue was ground in Et2O (20 mL), filtered, and dried under reduced pressure to give the title compound (200 mg, 93%) as a solid, which was used in the next step without further purification. MS (ESI) [M+H] + 341.2.

[0552] Step 18.6: Synthesis of 3-(6-(4-((5-chloro-4-((1-methyl-2-oxodihydroindol-5-yl)amino)pyrimidin-2-yl)amino)piperidin-1-yl)-1-methyl-1H-indol-3-yl)piperidin-2,6-dione. A mixture of 5-[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]-1-methyl-dihydroindol-2-one (43.9 mg, 0.150 mmol), 3-[6-(4-amino-1-piperidinyl)-1-methyl-indol-3-yl]piperidin-2,6-dione hydrochloride (62.1 mg, 0.170 mmol), and DIEA (100 µL, 0.750 mmol) in DMSO (1 mL) was degassed for 10 min by bubbling nitrogen. The reaction vessel was sealed, and the reaction mixture was heated to 90°C for 18 hours, then cooled to room temperature. The crude reaction mixture was purified by reversed-phase chromatography (C18) using a gradient elution of 10–80% MeCN and 10 mM ammonium formate in aqueous solution to give the title compound (10.5 mg, 10%) as a solid. MS (ESI) [M+H] + 613.3. 1 H NMR (500 MHz, acetic acid-d4) δ 8.12 (s, 1H), 7.78(d, J = 2.1 Hz, 1H), 7.72 (d, J = 8.7 Hz, 1H), 7.67 (d, J = 2.1 Hz, 1H), 7.62(dd, J = 8.4, 2.2 Hz, 1H), 7.38 (dd, J = 8.7, 2.1 Hz, 1H), 7.28 (s, 1H), 7.07(d, J = 8.4 Hz, 1H), 4.23 - 4.16 (m, 2H), 3.99 - 3.90 (m, 2H), 3.83 (s, 3H),3.75 - 3.67 (m, 2H), 3.26 (s, 3H), 2.85 - 2.78 (m, 2H), 2.52 - 2.45 (m, 2H), 2.45 - 2.38 (m, 1H), 2.38 - 2.32 (m, 1H), 2.32 - 2.24 (m, 2H), 1.43 - 1.37 (m, 2H). Note: The three exchangeable protons are not visible.

[0553] Example 19

[0554]

[0555] 3-(6-(4-(5-chloro-4-((1-(methyl-d3)-2-oxo-4-((2-(pyrimidin-2-yl)propane-2-yl)amino)-1,2-dihydroquinazolin-6-yl)amino)pyrimidin-2-yl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione

[0556] Step 19.1: Synthesis of 3-(1-methyl-6-piperazin-1-yl-indazole-3-yl)piperidine-2,6-dione; hydrochloride. The title compound was synthesized by reacting 6-bromo-3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-indazole, 1-boc-piperazine, 25 mol% RuPhos-Pd-G3 Cs2CO3 (1.2 equivalents), and 1,4-dioxane at 90°C in the first step according to general procedures 2, 4, and 5.

[0557] Step 19.2: Synthesis of 4-[(1-methyl-1-pyrimidin-2-yl-ethyl)amino]-6-nitro-1-(trideuterylmethyl)quinazolin-2-one. NaH (60% dispersed in mineral oil, 36.7 mg, 0.92 mmol) was added to a solution of 4-[(1-methyl-1-pyrimidin-2-yl-ethyl)amino]-6-nitro-1H-quinazolin-2-one (150.0 mg, 0.46 mmol) in DMF (5.0 mL) at room temperature. After stirring for 30 minutes, iodomethane-d3 (66.6 mg, 0.46 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. Water (10.0 mL) was added, and the resulting precipitate was collected by filtration and then dried under vacuum to give the title compound (148.0 mg, 93%) as a solid, which was used in the next step without further purification. 1 H NMR (500 MHz, DMSO) δ 9.44 (s, 1H), 8.81 (s, 1H), 8.70 (d, J = 4.5 Hz, 2H), 8.46 (d, J = 9.2 Hz, 1H), 7.47 (d, J = 9.3 Hz, 1H), 7.31 - 7.23 (m, 1H), 1.81 (s, 6H). MS (ESI) [M+H] + 344.3.

[0558] Step 19.3: Synthesis of 6-amino-4-[(1-methyl-1-pyrimidin-2-yl-ethyl)amino]-1-(trideutermethyl)quinazolin-2-one. A mixture of 4-[(1-methyl-1-pyrimidin-2-yl-ethyl)amino]-6-nitro-1-(trideutermethyl)quinazolin-2-one (148.0 mg, 0.43 mmol) and 10% Pd / C (45.8 mg, 0.04 mmol) in a mixture of ethanol (14.0 mL) and THF (14.0 mL) was hydrogenated at room temperature for 3 h under a hydrogen atmosphere. The reaction mixture was filtered through a Celite filter and washed with MeOH. The filtrate was concentrated under reduced pressure to give the title compound (130 mg, 96%) as a solid, which was used in the next step without further purification. MS (ESI) [M+H] + 314.3.

[0559] Step 19.4: Synthesis of 6-[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]-4-[(1-methyl-1-pyrimidin-2-yl-ethyl)amino]-1-(trideutermethyl)quinazolin-2-one. DIPEA (0.090 mL, 0.50 mmol) and 5-chloro-2,4-difluoro-pyrimidinium (62.4 mg, 0.41 mmol) were added sequentially to a solution of 6-amino-4-[(1-methyl-1-pyrimidin-2-yl-ethyl)amino]-1-(trideutermethyl)quinazolin-2-one (130.0 mg, 0.41 mmol) cooled to -40 °C in a mixture of THF (7.5 mL) and DMF (1.5 mL). The reaction was slowly cooled to room temperature and stirred for 18 hours. The volatiles were evaporated under reduced pressure. THF was added, and the resulting precipitate was collected by filtration, washed with THF, and then dried under vacuum to give the title compound (79.0 mg, 43%) as a solid, which was used in the next step without further purification. 1 H NMR (500 MHz, DMSO) δ 9.81 (s, 1H), 8.78 - 8.65 (m, 2H), 8.45 - 8.33 (m, 2H), 8.18 (s, 1H), 7.77 (d, J= 9.1 Hz, 1H), 7.37 (d, J= 9.0 Hz, 1H), 7.34 - 7.22 (m, 1H), 1.81 (s, 6H).

[0560] Step 19.5: Synthesis of 3-[6-[4-[5-chloro-4-[[4-[(1-methyl-1-pyrimidin-2-yl-ethyl)amino]-2-oxo-1-(trideuterylmethyl)quinazolin-6-yl]amino]pyrimidin-2-yl]piperazin-1-yl]-1-methyl-indazole-3-yl]piperidine-2,6-dione. To a solution of 6-[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]-4-[(1-methyl-1-pyrimidin-2-yl-ethyl)amino]-1-(trideuterylmethyl)quinazolin-2-one (37.0 mg, 0.08 mmol) in DMSO (1.0 mL), 3-(1-methyl-6-piperazin-1-yl-indazole-3-yl)piperidin-2,6-dione; hydrochloride (30.3 mg, 0.08 mmol); and DIEA (0.06 mL, 0.33 mmol) were added sequentially. The reaction mixture was heated to 80°C for 2 hours and then cooled to room temperature. Water was added, and the precipitate was collected by filtration, washed with diethyl ether (3 x 5.0 mL), and dried under vacuum to give the title compound (16.8 mg, 26%) as a solid. 1 H NMR (500 MHz, DMSO) δ 10.84 (s, 1H), 9.02 (s,1H), 8.73 (d, J = 4.8 Hz, 2H), 8.66 (d, J = 1.4 Hz, 1H), 8.18 (s, 1H), 8.12(s, 1H), 7.75 (dd, J = 9.1, 1.7 Hz, 1H), 7.47 (d, J = 8.9 Hz, 1H), 7.33 -7.26 (m, 2H), 6.85 (dd, J = 9.0, 0.8 Hz, 1H), 6.76 (s, 1H), 4.25 (dd, J =9.2, 5.1 Hz, 1H), 3.84 - 3.80 (m, 4H), 3.79 (s, 3H), 3.28 - 3.22 (m, 4H), 2.66 - 2.56 (m, 2H), 2.33 - 2.24 (m, 1H), 2.18 - 2.09 (m, 1H), 1.81 (s, 6H). MS (ESI) [M+H] + 751.4.

[0561] Example 20

[0562]

[0563] 3-[7-[[5-chloro-2-[4-[[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazol-6-yl]amino]-1-piperidinyl]pyrimidin-4-yl]amino]-3-oxo-4-(trideuterylmethyl)-1,4-benzoxazin-2-yl]-N-methyl-propionamide

[0564] Step 20.1: Synthesis of (2S)-2-bromo-5-methoxy-5-oxo-pentanoic acid. A solution of NaNO2 (3.05 g, 44.2 mmol) in H2O (25.0 mL) was added dropwise to a solution of (2S)-2-amino-5-methoxy-5-oxo-pentanoic acid (3.75 g, 23.3 mmol) and NaBr (6.58 g, 64.0 mmol) in 1.0 M HBr (140.0 mL) cooled to -5°C over a period of 30 minutes. The reaction mixture was stirred for 10 hours, followed by the dropwise addition of concentrated H2SO4 (2.50 mL). After stirring for 5 minutes, diethyl ether (150.0 mL) was added, and the layers were separated. The aqueous layer was extracted with diethyl ether (2 x 150.0 mL), and the combined organic extracts were washed with brine (100.0 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The substance was purified by silica gel column chromatography, eluting with an ethyl acetate / hexane gradient (0–70%) to give the title compound (750.0 mg, 14%) as an oil. 1 ¹H NMR (400 MHz, acetic acid) δ 4.49 (dd, J = 8.5, 5.8 Hz, 1H), 3.73 (s, 3H), 2.68 -2.52 (m, 2H), 2.49 - 2.39 (m, 1H), 2.36 - 2.23 (m, 1H).

[0565] Step 20.2: Synthesis of methyl 3-(7-nitro-3-oxo-4H-1,4-benzoxazin-2-yl)propionate. Oxaloyl chloride (707.0 µL, 8.35 mmol) was added to a solution of (2S)-2-bromo-5-methoxy-5-oxo-pentanoic acid (940.0 mg, 4.18 mmol) in THF (15.0 ml) cooled to 0°C. The reaction mixture was stirred at 0°C for 2 hours. The volatiles were removed under reduced pressure to give methyl (4S)-4-bromo-5-chloro-5-oxo-pentanoic acid. To a solution of methyl (4S)-4-bromo-5-chloro-5-oxovalerate in NMP (15.0 mL), 2-amino-5-nitrophenol (644 mg, 4.18 mmol) and K₂CO₃ (1.73 g, 12.5 mmol) were added sequentially. The reaction mixture was heated to 80°C for 2 hours and then cooled to room temperature. Water (25.0 mL), 5% citric acid (25.0 mL), and ethyl acetate (25.0 mL) were added, and the mixture was stirred for 5 minutes. The layers were then separated. The aqueous layer was extracted with ethyl acetate (2 x 25.0 mL), and the combined organic extracts were washed with brine (50.0 mL), dried (Na₂SO₄), filtered, and concentrated under reduced pressure. Ethyl acetate (10.0 mL) was added, and the precipitate was collected by filtration and dried under vacuum to give the title compound (650.0 mg, 56%) as a solid, which was used in the next step without further purification. 1 H NMR (400 MHz, DMSO) δ 11.34 (s, 1H), 7.92 (dd, J = 8.7, 2.5 Hz, 1H), 7.78 (d, J = 2.5 Hz, 1H), 7.07 (d, J = 8.7 Hz, 1H), 4.79 (dd, J = 8.6, 4.4Hz, 1H), 3.60 (s, 3H), 2.55 (t, J = 7.4 Hz, 2H), 2.21 - 2.10 (m, 1H), 2.07 -1.96 (m, 1H).

[0566] Step 20.3: Synthesis of methyl 3-[7-nitro-3-oxo-4-(trideutermethyl)-1,4-benzoxazin-2-yl]propionate. Iodomethane-d3 (240 µL, 3.85 mmol) was added to a mixture of methyl 3-(7-nitro-3-oxo-4H-1,4-benzoxazin-2-yl)propionate (900 mg, 3.21 mmol) and K2CO3 (1.33 g, 9.63 mmol) in MeCN (25 mL). The mixture was heated to 70°C and stirred for 4 hours. Water (50 mL) was added, and the resulting precipitate was collected by filtration, washed with Et2O (3 x 10 mL), and then dried under vacuum to give the title compound (700 mg, 73%) as a solid, which was used directly without further purification. 1 H NMR (500 MHz, DMSO-d6) δ 7.99 (dd, J = 8.9, 2.6Hz, 1H), 7.83 (d, J = 2.6 Hz, 1H), 7.37 (d, J = 8.9 Hz, 1H), 4.84 (dd, J =8.7, 4.5 Hz, 1H), 3.60 (s, 3H), 2.55 (t, J = 7.4 Hz, 2H), 2.21 - 2.10 (m,1H), 2.07 - 1.97 (m, 1H).

[0567] Step 20.4: Synthesis of 3-[7-amino-3-oxo-4-(trideutermethyl)-1,4-benzoxazin-2-yl]-N-methylpropionamide. A mixture of methyl 3-[7-nitro-3-oxo-4-(trideutermethyl)-1,4-benzoxazin-2-yl]propionate (700 mg, 2.35 mmol) and 10% Pd / C (251 mg, 0.240 mmol) in MeOH (20 mL) was hydrogenated at room temperature (1 atm) for 2 hours. The mixture was filtered through a Celite filter and washed with MeOH (2 x 25 mL). The filtrate was concentrated under reduced pressure to give a solid. Methylamine (4.39 mL, 35.3 mmol, 33% wt. in EtOH) was added to a solution of the crude intermediate in MeOH (15 mL) at room temperature, and the mixture was heated at 70°C for 16 hours, then cooled to room temperature. Volatile substances were removed under reduced pressure, and the residue was purified by reversed-phase chromatography (C18) using a gradient elution of 5–80% MeCN and 10 mM ammonium formate in aqueous solution to give a racemic mixture of the title compound. The two enantiomers were separated using a chiral SFC (LuxCel2) with isocratic elution using 55% isopropanol and 10 mM ammonium formate in aqueous solution to obtain the separated enantiomers. These separated enantiomers were used in subsequent steps.

[0568] Step 20.5: Synthesis of 3-[7-[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]-3-oxo-4-(trideutermethyl)-1,4-benzoxazin-2-yl]-N-methyl-propionamide. 5-chloro-2,4-difluoro-pyrimidin (78.6 mg, 0.520 mmol) was added dropwise to a solution of 3-[7-amino-3-oxo-4-(trideutermethyl)-1,4-benzoxazin-2-yl]-N-methyl-propionamide (139 mg, 0.520 mmol, first eluted isomer) and DIEA (109 µL, 0.630 mmol) in THF (5 mL) and DMF (1 mL) at -40°C. The mixture was then cooled to room temperature and stirred for 16 hours. The volatiles were evaporated under reduced pressure. Water (10 mL) was added, and the precipitate was collected by filtration, washed with water (2 x 10 mL), and then dried under vacuum to give the title compound (162 mg, 78%) as a solid, which was used directly without further purification. MS (ESI) [MH] - 395.3.

[0569] Step 20.6: Synthesis of 3-[7-[[5-chloro-2-[4-[[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazol-6-yl]amino]-1-piperidinyl]pyrimidin-4-yl]amino]-3-oxo-4-(trideutermethyl)-1,4-benzoxazin-2-yl]-N-methyl-propionamide. To a solution of 3-[7-[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]-3-oxo-4-(trideutermethyl)-1,4-benzoxazin-2-yl]-N-methyl-propionamide (65 mg, 0.160 mmol) in DMSO (2 mL), 3-[1-methyl-6-(4-piperidinylamino)indazol-3-yl]piperidine-2,6-dione dihydrochloride (55.9 mg, 0.160 mmol) and DIEA (114 µL, 0.66 mmol) were added sequentially. The mixture was heated to 80°C for 2 hours and then cooled to room temperature. Water (10 mL) was added, and the resulting precipitate was collected by filtration, washed with Et2O (3 x 5 mL), and dried under vacuum to give the diastereomer. Separation was performed using a chiral SFC (AD) followed by isocratic elution with 55% isopropanol and 10 mM ammonium formate aqueous solution to obtain the title compounds separated into individual diastereomers:

[0570]

[0571] The first diastereomer - MS (ESI) [M+H] + 718.4. 1H NMR (500 MHz, DMSO-d6) δ8.71 (s, 1H), 8.06 (s, 1H), 7.77 - 7.72 (m, 1H), 7.44 - 7.39 (m, 2H), 7.32(d, J = 8.8 Hz, 1H), 7.10 (d, J = 9.0 Hz, 1H), 6.52 (dd, J = 8.8, 1.7 Hz,1H), 6.46 (s, 1H), 5.78 (d, J = 7.9 Hz, 1H), 4.61 (dd, J = 8.9, 4.6 Hz, 1H), 4.46 - 4.36 (m, 2H), 4.18 (dd, J = 8.8, 5.2 Hz, 1H), 3.82 (s, 3H), 3.69 -3.59 (m, 1H), 3.16 (t, J = 11.3 Hz, 2H), 2.63 - 2.55 (m, 2H), 2.52 - 2.51 (m, 3H), 2.30 - 2.20 (m, 3H), 2.18 - 2.10 (m, 1H), 2.05 - 1.95 (m, 3H), 1.92 -1.81 (m, 1H), 1.39 - 1.28 (m, 2H). Note: Glutarimide signal is not visible.

[0572] The second diastereomer - MS (ESI) [M+H] + 718.4. 1H NMR (500 MHz, DMSO-d6) δ8.71 (s, 1H), 8.06 (s, 1H), 7.78 - 7.70 (m, 1H), 7.44 - 7.37 (m, 2H), 7.32(d, J = 8.7 Hz, 1H), 7.11 (d, J = 8.9 Hz, 1H), 6.51 (d, J = 8.8 Hz, 1H), 6.46(s, 1H), 5.78 (d, J = 8.5 Hz, 1H), 4.61 (dd, J = 8.8, 4.6 Hz, 1H), 4.41 (d, J= 12.1 Hz, 2H), 4.18 (dd, J = 8.8, 5.2 Hz, 1H), 3.82 (s, 3H), 3.69 - 3.60 (m, 1H), 3.16 (t, J = 11.3 Hz, 2H), 2.63 - 2.57 (m, 2H), 2.53 - 2.51 (m, 3H), 2.28 - 2.20 (m, 3H), 2.19 - 2.11 (m, 1H), 2.05 - 1.95 (m, 3H), 1.91 - 1.82 (m, 1H), 1.38 - 1.28 (m, 2H). Note: Glutarimide signal is not visible.

[0573] The third diastereomer - MS (ESI) [M+H] + 718.4. 1H NMR (500 MHz, DMSO-d6) δ10.81 (br s, 1H), 8.71 (s, 1H), 8.05 (s, 1H), 7.75 (d, J = 3.9 Hz, 1H), 7.45- 7.37 (m, 2H), 7.32 (d, J = 8.8 Hz, 1H), 7.10 (d, J = 8.3 Hz, 1H), 6.52 (d,J = 8.6 Hz, 1H), 6.46 (s, 1H), 5.78 (d, J = 7.0 Hz, 1H), 4.61 (dd, J = 8.6,4.6 Hz, 1H), 4.46 - 4.35 (m, 2H), 4.18 (dd, J = 8.5, 5.3 Hz, 1H), 3.82 (s,3H), 3.69 - 3.61 (m, 1H), 3.16 (t, J = 11.5 Hz, 2H), 2.65 - 2.56 (m, 2H),2.53 - 2.51 (m, 3H), 2.30 - 2.20 (m, 3H), 2.20 - 2.10 (m, 1H), 2.07 - 1.94 (m, 3H), 1.94 - 1.81 (m, 1H), 1.40 - 1.27 (m, 2H).

[0574] The fourth diastereomer - MS (ESI) [M+H] + 718.4. 1H NMR (500 MHz, DMSO-d6) δ8.71 (s, 1H), 8.05 (s, 1H), 7.78 - 7.71 (m, 1H), 7.44 - 7.38 (m, 2H), 7.32(d, J = 8.8 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 6.52 (d, J = 8.6 Hz, 1H), 6.46(s, 1H), 5.78 (d, J = 8.1 Hz, 1H), 4.61 (dd, J = 8.7, 4.5 Hz, 1H), 4.47 -4.36 (m, 2H), 4.18 (dd, J = 8.6, 5.1 Hz, 1H), 3.82 (s, 3H), 3.68 - 3.61 (m, 1H), 3.16 (t, J = 11.2 Hz, 2H), 2.65 - 2.56 (m, 2H), 2.53 - 2.51 (m, 3H), 2.24 (t, J = 7.6 Hz, 3H), 2.19 - 2.09 (m, 1H), 2.06 - 1.94 (m, 3H), 1.92 -1.81 (m, 1H), 1.41 - 1.26 (m, 2H). Note: Glutarimide signal is not visible.

[0575] Example 21

[0576]

[0577] 3-(5-(4-((5-chloro-4-((1-methyl-2-oxodihydroindole-5-yl)amino)pyrimidin-2-yl)(methyl)amino)piperidin-1-yl)-1H-benzo[d]imidazol-1-yl)piperidin-2,6-dione

[0578] Step 21.1: Synthesis of 2,6-Dibenzyloxypyridine-3-amine. Iron powder (8.3 g, 148 mmol) was added to a solution of 2,6-dibenzyloxy-3-nitropyridine (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 MeOH (200 mL), and the filtrate was concentrated under reduced pressure. EtOAc (500 mL) and a saturated aqueous solution of NaHCO3 (400 mL) were added, and the layers were separated. The organic layer was washed with water (400 mL) 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.

[0579] Step 21.2: Synthesis of 2,6-Dibenzyloxy-N-(4-bromo-2-nitro-phenyl)pyridine-3-amine. 1 M LiHMDS (68.6 mL, 68.6 mmol) in THF 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 THF (163 mL) at 0°C for 30 minutes. After the addition was complete, the reaction mixture was stirred at room temperature for 3 hours, then cooled to 0°C. A saturated aqueous solution of NH4Cl (150 mL) and EtOAc (300 mL) were added, and the layers were separated. The organic layer was washed with a saturated aqueous solution of NaHCO3 (150 mL), water (150 mL), and brine (150 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient elution of 0-50% EtOAc in hexane to give the title compound (8.7 g, 53%). 1 H NMR(400 MHz, CDCl3) δ 9.11 (s, 1H), 8.30 (d, J = 2.3 Hz, 1H), 7.47 (d, J = 8.4Hz, 1H), 7.42 - 7.26 (m, 8H), 7.26 - 7.24 (m, 2H), 7.23 (s, 1H), 6.70 (d, J =9.1 Hz, 1H), 6.42 (d, J = 8.3 Hz, 1H), 5.35 (s, 2H), 5.33 (s, 2H). MS (ESI) [M+H] + 508.2.

[0580] Step 21.3: Synthesis of 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 CaCl2 (3.8 g, 34 mmol) in EtOH (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 EtOAc (200 mL), and the filtrate was concentrated under reduced pressure. EtOAc (400 mL) and water (300 mL) were added, and the layers were separated. The organic layer was washed with brine (300 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (7.1 g, 87%) as an oil, which was used without further purification. MS (ESI) [M+H + 476.2.

[0581] Step 21.4: 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 0-100% EtOAc gradient elution to give the title compound (5.4 g, 87%) as a semi-solid. 1 H NMR (500 MHz, DMSO) δ 8.41(s, 1H), 8.13 (s, 1H), 7.95 (d, J = 8.3 Hz, 1H), 7.93 (d, J = 1.8 Hz, 1H),7.49 - 7.46 (m, 2H), 7.42 - 7.35 (m, 4H), 7.28 - 7.24 (m, 4H), 7.24 - 7.21(m, 1H), 6.67 (d, J = 8.3 Hz, 1H), 5.43 (s, 2H), 5.40 (s, 2H). MS (ESI) [M+H] + 487.2.

[0582] Step 21.5: 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), NaOtBu (296 mg, 3.1 mmol), and tBuXPhos-Pd-G3 (82 mg, 0.10 mmol) in THF (12.5 mL) was heated to 70°C for 18 hours and then cooled to room temperature. The mixture was filtered through Celite, washed with MeOH (20 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient elution of 0-100% EtOAc in hexane to give the title compound (284 mg, 45% yield) as an oil. 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 = 8.3 Hz, 1H), 5.42 (s, 2H), 5.40 (s, 2H), 3.66 (m, 2H), 3.30 - 3.27 (m, 1H), 2.73 - 2.68 (m, 2H), 2.71 (s, 3H), 1.88 - 1.79 (m, 2H), 1.67 - 1.59 (m, 2H), 1.41 (s, 9H). MS (ESI) [M+H] + 621.4.

[0583] Step 21.6: 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% Pd(OH)2 / C (42 mg, 0.06 mmol) in THF (6 mL) and EtOH (6 mL) was hydrogenated at 1 atm and 50°C for 5 h. The mixture was filtered through a Celite filter and washed with MeOH (3 x 10 mL). The filtrate was concentrated under reduced pressure to give the title compound 1d (192 mg) as a semi-solid, which was used in the next step without further purification. MS (ESI) [M+H]+ 442.3.

[0584] Step 21.7: 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.

[0585] Step 21.8: Synthesis of 3-[5-[4-[[5-chloro-4-[(1-methyl-2-oxo-dihydroindol-5-yl)amino]pyrimidin-2-yl]-methyl-amino]-1-piperidinyl]benzimidazol-1-yl]piperidin-2,6-dione. 5-[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]-1-methyl-dihydroindol-2-one (21 mg, 0.07 mmol) and DIEA (0.1 mL, 0.59 mmol) were added sequentially to a solution of 3-[5-[4-(methylamino)-1-piperidinyl]benzimidazol-1-yl]piperidin-2,6-dione hydrochloride (50 mg, 0.15 mmol) in DMSO (0.7 mL). The reaction mixture was heated to 80°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 35-45% MeCN and 10 mM ammonium formate in aqueous solution to give the title compound (4.8 mg, 10%) as a solid. MS (ESI) [M+H] + 614.3. 1 H NMR (500 MHz, DMSO-d6) δ 8.58 (s, 1H), 8.47 (s, 1H), 8.14 (s, 1H), 8.02 (s, 1H), 7.68 - 7.56 (m, 1H), 7.38 (d, J = 8.6 Hz, 1H), 7.18 (d, J = 2.3Hz, 1H), 7.05 - 7.00 (m, 1H), 6.94 (d, J = 8.4 Hz, 1H), 5.61 (dd, J = 13.4,5.3 Hz, 1H), 3.69 (d, J = 9.8 Hz, 2H), 3.54 (s, 2H), 3.30 - 3.26 (m, 3H),3.09 (s, 3H), 2.93 (s, 3H), 2.89 - 2.65 (m, 3H), 2.23 - 2.19 (m, 1H), 1.95 -1.87 (m, 2H), 1.71 - 1.65 (m, 2H). Note: No exchangeable protons were observed.

[0586] Example 22

[0587]

[0588] 3-(6-((5-chloro-2-(4-((3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)amino)piperidin-1-yl)pyrimidin-4-yl)amino)-1-methyl-2-oxo-1,4-dihydroquinazolin-3(2H)-yl)-N-methylpropionamide

[0589] Step 22.1: Synthesis of 2-(aminomethyl)-4-bromo-N-methylaniline. A solution of 1.0 M BH3 in THF (4.74 mL, 4.74 mmol) was added dropwise to a solution of 5-bromo-2-(methylamino)benzyl nitrile (500 mg, 2.37 mmol) cooled to 0°C in 20.0 mL of THF over a period of 10 minutes. After the addition was complete, the reaction mixture was stirred overnight at room temperature and then cooled to 0°C. An aqueous solution of HCl (6.0 M, 10.0 mL) was added, and the volatiles were evaporated under reduced pressure. The pH of the solution was adjusted to 10 using an aqueous solution of NaOH (1 M). DCM (100 mL) was added, and the layers were separated. The aqueous layer was extracted with DCM (2 x 100 mL), and the combined organic extracts were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (400 mg, 78%) as a solid. 1 H NMR (500 MHz, DMSO) δ 7.27 - 7.13 (m,2H), 6.42 (d, J = 8.5 Hz, 1H), 5.82 (d, J = 4.1 Hz, 1H), 3.60 (s, 2H), 2.70(d, J = 4.5 Hz, 3H), 1.83 (s, 2H).

[0590] Step 22.2: Synthesis of 6-bromo-1-methyl-3,4-dihydroquinazolin-2-one. CDI (1.96 g, 12.1 mmol) was added to a solution of 2-(aminomethyl)-4-bromo-N-methylaniline (2.0 g, 9.30 mmol) in THF (30.0 mL). The reaction mixture was refluxed for 18 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 0-20% MeOH gradient elution in DCM to give the title compound (2.10 g, 94%) as a solid. 1HNMR (500 MHz, DMSO) δ 7.40 (dd, J = 8.6, 2.4 Hz, 1H), 7.38 - 7.36 (m, 1H), 7.13 (s, 1H), 6.87 (d, J = 8.6 Hz, 1H), 4.36 - 4.19 (m, 2H), 3.12 (s, 3H). MS(ESI) [M+H] + 243.1.

[0591] Step 22.3: Synthesis of 3-(6-bromo-1-methyl-2-oxo-4H-quinazolin-3-yl)-N-methylpropionamide. KOH (105.0 mg, 1.87 mmol) and methyl-N-methylpropionamide (238 mg, 2.80 mmol) were added sequentially to a solution of 6-bromo-1-methyl-3,4-dihydroquinazolin-2-one (450 mg, 1.87 mmol) in 1,4-dioxane (5.6 mL) cooled to 0°C. The reaction mixture was stirred overnight at room temperature. Water (20 mL) and ethyl acetate (40 mL) were added, and the layers were separated. The aqueous layer was extracted with ethyl acetate (2 x 40.0 mL), and the combined organic extracts were washed with brine (50 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The substance was purified by silica gel column chromatography using a gradient elution of 0-20% MeOH in DCM to give the title compound (400 mg, 66%) as a solid. 1 H NMR (500 MHz, CDCl3) δ7.35 (dd, J = 8.6, 2.1 Hz, 1H), 7.18 (d, J = 1.7 Hz, 1H), 6.69 (d, J = 8.7Hz, 1H), 6.14 (s, 1H), 4.40 (s, 2H), 3.70 (t, J = 6.4 Hz, 2H), 3.25 (s, 3H), 2.77 (d, J = 4.8 Hz, 3H), 2.53 (t, J = 6.4 Hz, 2H).

[0592] Step 22.4: Synthesis of N-[1-methyl-3-[3-(methylamino)-3-oxo-propyl]-2-oxo-4H-quinazoline-6-yl] tert-butyl carbamate. A suspension of 3-(6-bromo-1-methyl-2-oxo-4H-quinazoline-3-yl)-N-methylpropionamide (325.0 mg, 1.0 mmol), tert-butyl carbamate (175.0 mg, 1.49 mmol), Cs₂CO₃ (649.0 mg, 1.99 mmol), Pd(OAc)₂ (22.4 mg, 0.10 mmol), and X-Phos (86.4 mg, 0.20 mmol) in 1,4-dioxane (27.0 mL) was degassed with nitrogen, and the resulting mixture was heated to 90°C for 24 hours and then cooled to room temperature. The reaction mixture was filtered through a Celite filter, washed with DCM (30 mL), and the filtrate was concentrated under reduced pressure. The substance was purified by silica gel column chromatography using a 0-20% MeOH gradient elution in DCM to give the title compound (320 mg, 89%) as a solid. 1 H NMR (500 MHz, CDCl3) δ 7.20 (s, 1H), 7.15 (d, J = 8.6 Hz, 1H), 6.74 (d, J = 8.7 Hz, 1H), 6.43 (s, 1H), 6.36 (s, 1H), 4.39 (s, 2H), 3.70 (t, J =6.5 Hz, 2H), 3.26 (s, 3H), 2.77 (d, J = 4.8 Hz, 3H), 2.54 (t, J = 6.4 Hz, 2H), 1.51 (s, 9H). MS (ESI) [M+H] + 363.3.

[0593] Step 22.5: Synthesis of [1-methyl-3-[3-(methylamino)-3-oxo-propyl]-2-oxo-4H-quinazolin-6-yl]ammonium; 2,2,2-trifluoroacetate. TFA (2.0 mL) was added to a solution of N-[1-methyl-3-[3-(methylamino)-3-oxo-propyl]-2-oxo-4H-quinazolin-6-yl]carbamate (320 mg, 0.88 mmol) cooled to 0°C in DCM (5.0 mL). The reaction mixture was stirred at room temperature for 4 hours. The volatiles were evaporated under reduced pressure to give the title compound (330 mg, 99%) as a solid, which was used in the next step without further purification. 1H NMR (400MHz, DMSO) δ 9.40 (bs, 3H), 7.84 (s, 1H), 7.18 (d, J = 8.6 Hz, 1H), 7.07 (s,1H), 6.98 (d, J = 8.6 Hz, 1H), 4.41 (s, 2H), 3.52 (t, J = 6.4 Hz, 2H), 3.17 (s, 3H), 2.57 - 2.52 (m, 3H), 2.36 (t, J = 6.2 Hz, 2H). MS (ESI) [M+H] + 263.2.

[0594] Step 22.6: Synthesis of 3-[6-[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]-1-methyl-2-oxo-4H-quinazoline-3-yl]-N-methyl-propionamide. 5-chloro-2,4-difluoro-pyrimidin (35.5 µL, 0.37 mmol) and DIEA (140.0 µL, 0.84 mmol) were added sequentially to a solution of [1-methyl-3-[3-(methylamino)-3-oxo-propyl]-2-oxo-4H-quinazoline-6-yl]ammonium; 2,2,2-trifluoroacetate (126 mg, 0.33 mmol) in a mixture of THF (5.0 mL) and DMF (1.0 mL). The reaction mixture was slowly warmed to room temperature and stirred for 24 hours. The volatiles were evaporated under reduced pressure. Diethyl ether (20.0 mL) was slowly added, forming a precipitate, which was collected by filtration, washed with diethyl ether (10.0 mL), and then dried under vacuum to give the title compound (82.0 mg, 62%) as a solid, which was used in the next step without further purification. 1 H NMR (500 MHz, DMSO) δ 9.54 (s, 1H), 8.35 (s, 1H), 7.85 (d, J =4.2 Hz, 1H), 7.42 (dd, J = 8.7, 2.4 Hz, 1H), 7.32 (d, J = 2.1 Hz, 1H), 6.95(d, J = 8.8 Hz, 1H), 4.40 (s, 2H), 3.54 (t, J = 7.1 Hz, 2H), 3.20 (s, 3H), 2.56 (d, J = 4.6 Hz, 3H), 2.38 (t, J = 7.1 Hz, 2H). MS (ESI) [M+H] + 393.4.

[0595] Step 22.7: Synthesis of 3-(6-((5-chloro-2-(4-((3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)amino)piperidin-1-yl)pyrimidin-4-yl)amino)-1-methyl-2-oxo-1,4-dihydroquinazolin-3(2H)-yl)-N-methylpropionamide. To a solution of 3-[6-[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]-1-methyl-2-oxo-4H-quinazolin-3-yl]-N-methyl-propionamide (30.0 mg, 76.0 µmol) in DMSO (1.0 mL), 3-[1-methyl-6-(4-piperidinylamino)indazol-3-yl]piperidin-2,6-dione; hydrochloride (31.1 mg, 80.0 µmol); and DIEA (33.3 µL, 190.0 µmol) were added sequentially. The reaction mixture was heated to 80°C overnight and then cooled to room temperature. The reaction mixture was purified directly by preparative HPLC (BEH, C18) using a gradient elution of 36-66% acetonitrile and 10 mM ammonium formate in aqueous solution to give the title compound (29 mg, 53%) as a solid. 1H NMR (500 MHz, DMSO) δ 10.79 (s, 1H), 8.66 (s,1H), 8.03 (s, 1H), 7.86 - 7.73 (m, 1H), 7.53 (dd, J = 8.8, 2.4 Hz, 1H), 7.50- 7.40 (m, 1H), 7.32 (d, J = 8.8 Hz, 1H), 6.88 (d, J = 8.9 Hz, 1H), 6.52 (dd,J = 8.8, 1.7 Hz, 1H), 6.46 (s, 1H), 5.78 (d, J = 8.1 Hz, 1H), 4.50 - 4.37 (m,2H), 4.36 (s, 2H), 4.18 (dd, J = 8.8, 5.1 Hz, 1H), 3.82 (s, 3H), 3.72 - 3.58 (m, 1H), 3.55 - 3.48 (m, 2H), 3.16 (s, 3H), 3.16 - 3.08 (m, 2H), 2.65 - 2.57 (m, 2H), 2.52 - 2.51 (m, 3H, masked by DMSO), 2.35 (t, J = 7.1 Hz, 2H), 2.31 -2.20 (m, 1H), 2.20 - 2.09 (m, 1H), 2.02 (d, J = 10.4 Hz, 2H), 1.40 - 1.27 (m, 2H). MS (ESI) [M+H) + 714.4.

[0596] Example 23

[0597]

[0598] 3-(6-((1-(5-chloro-4-((1-methyl-2-oxo-4-((2-(pyrimidin-2-yl)propane-2-yl)amino)-1,2-dihydroquinazolin-6-yl)amino)pyrimidin-2-yl)piperidin-4-yl)(methyl)amino)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione

[0599] Step 23.1: 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 Cs2CO3 (651 mg, 2 mmol) in 1,4-dioxane (5 mL) was heated to 90°C for 18 hours and then cooled to room temperature. The mixture was filtered through a Celite filter and washed with EtOAc (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 0-100% EtOAc in hexane to give the title compound (550 mg, 89%) as a solid. 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). MS (ESI) [M+H] + 620.5.

[0600] Step 23.2: 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 DMSO (3.6 mL) and acetic acid (0.9 mL), aqueous formaldehyde solution (0.13 mL, 1.8 mmol) and NaBH(OAc)3 (282 mg, 1.3 mmol) were added sequentially. The reaction mixture was stirred at room temperature for 1 hour. Water (10 mL) and EtOAc (25 mL) were added, and the layers were separated. The organic layer was washed with saturated NaHCO3 aqueous solution (5 mL), water (3 x 5 mL), and brine (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The substance was purified by silica gel column chromatography using a gradient elution of 0-100% EtOAc in hexane to give the title compound (467 mg, 83% yield) as a solid. 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). MS (ESI) [M+H] + 635.5.

[0601] Step 23.3: 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% Pd(OH)2 / C (117 mg, 25 wt%) in THF (7 mL) and EtOH (7 mL) was hydrogenated at 1 atm and 50°C for 2 hours. The mixture was filtered through Celite, washed with a mixture of MeCN and MeOH (1:1, 3 x 10 mL), and the filtrate was concentrated under reduced pressure. The substance was purified by silica gel column chromatography using a gradient elution of 0-20% MeOH in DCM to give the title compound (258 mg, 77%) as a solid. 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 = 1.9 Hz, 1H), 4.23 (dd, J = 9.0, 5.1 Hz, 1H), 4.09 -3.99 (m, 2H), 3.98 - 3.91 (m, 1H), 3.87 (s, 3H), 2.86 (br s, 2H), 2.76 (s,3H), 2.64 - 2.56 (m, 2H), 2.33 - 2.25 (m, 1H), 2.21 - 2.13 (m, 1H), 1.67 -1.54 (m, 4H), 1.41 (s, 9H). MS (ESI) [M+H] + 456.3.

[0602] Step 23.4: 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. Et2O (5 x mL) was added, and the precipitate was collected by filtration, washed with 1,4-dioxane (3 x 1 mL) and Et2O (10 x 2 mL), and then dried under vacuum to give the title compound (217 mg, 92%) as a solid. 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. MS (ESI) [M+H] + 356.2.

[0603] Step 23.5: Synthesis of 3-(6-((1-(5-chloro-4-((1-methyl-2-oxo-4-((2-(pyrimidin-2-yl)propane-2-yl)amino)-1,2-dihydroquinazolin-6-yl)amino)pyrimidin-2-yl)piperidin-4-yl)(methyl)amino)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione. To a solution of 3-[1-methyl-6-[methyl(4-piperidinyl)amino]indazol-3-yl]piperidin-2,6-dione (43.0 mg, 0.12 mmol) in DMSO (0.7 mL), 6-[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]-1-methyl-4-[(1-methyl-1-pyrimidin-2-yl-ethyl)amino]quinazolin-2-one (48.0 mg, 0.11 mmol) and DIPEA (0.08 mL, 0.48 mmol) were added sequentially. The reaction mixture was heated to 80°C for 12 hours and then cooled to room temperature. The mixture was purified by preparative HPLC (BEH, C18) using a gradient elution of 41-51% acetonitrile and 10 mM ammonium formate in aqueous solution to give the title compound (30.5 mg, 32%) as a solid. 1 H NMR (500 MHz, DMSO) δ10.84 (s, 1H), 8.93 (s, 1H), 8.57 (d, J = 4.4 Hz, 3H), 8.11 (s, 1H), 8.07 (s,1H), 7.75 (d, J = 9.0 Hz, 1H), 7.43 (d, J = 8.8 Hz, 1H), 7.29 (d, J = 8.5 Hz,1H), 7.16 - 7.10 (m, 1H), 6.84 (d, J = 8.6 Hz, 1H), 6.61 (s, 1H), 4.66 - 4.62(m, 2H), 4.28 - 4.21 (m, 1H), 4.03 - 3.97 (m, 1H), 3.82 (s, 3H), 3.30 (s, 3H, covered by water), 2.92 (t, J = 11.1 Hz, 2H), 2.71 (s, 3H), 2.65 - 2.59 (m, 2H), 2.33 - 2.24 (m, 1H), 2.21 - 2.12 (m, 1H), 1.75 (s, 6H), 1.71 - 1.60 (m, 4H). MS(ESI) [M+H] + 776.5.

[0604] Example 24

[0605]

[0606] 3-(6-(4-((5-chloro-4-((1-methyl-2-oxodihydroindole-5-yl)amino)pyrimidin-2-yl)(methyl)amino)phenyl)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione

[0607] Step 24.1: Synthesis of N-[4-[3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole-6-yl]phenyl]-N-methyl-carbamate tert-butyl ester. 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1-methyl-indazole (2.63 g, 5.26 mmol), [4-[tert-butoxycarbonyl(methyl)amino]phenyl]boronic acid (1.10 g, 4.38 mmol), Pd(dppf)Cl2 A mixture of DCM (0.18 g, 0.22 mmol) and K3PO4 (2.79 g, 13.1 mmol) in 1,4-dioxane (12 mL) and water (2 mL) was heated to 90°C for 3 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 0–40% EtOAc in hexane to give the title compound (2.93 g, 89%) as a solid. MS (ESI) [M+H] + 627.3.

[0608] Step 24.2: Synthesis of N-[4-[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-6-yl]phenyl]-N-methyl-carbamate tert-butyl ester. A mixture of N-[4-[3-(2,6-dibenzyloxy-3-pyridinyl)-1-methyl-indazole-6-yl]phenyl]-N-methyl-carbamate tert-butyl ester (3.0 g, 4.79 mmol) and Pd / C (1.27 g, 1.20 mmol) in EtOH (100 mL) and THF (100 mL) was stirred at 50°C for 8 hours under a hydrogen atmosphere (1 atm). The mixture was filtered through a Celite filter and washed with THF (200 mL) and MeOH (200 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using a gradient elution of 0-100% EtOAc in hexane to give the title compound (1.47 g, 68%) as a solid. MS (ESI) [M+H + 448.8.

[0609] Step 24.3: Synthesis of 3-[1-methyl-6-[4-(methylamino)phenyl]indazole-3-yl]piperidine-2,6-dione hydrochloride. HCl (4.10 mL, 16.4 mmol) in 1,4-dioxane was added to a solution of N-[4-[3-(2,6-dioxo-3-piperidinyl)-1-methyl-indazole-6-yl]phenyl]-N-methyl-carbamate tert-butyl ester (1.47 g, 3.28 mmol) in 1,4-dioxane (6 mL). The reaction mixture was stirred at room temperature for 16 hours, and the volatiles were evaporated under reduced pressure. Et₂O (20 mL) was added, and the resulting precipitate was collected by filtration, washed with Et₂O (3 x 10 mL), and then dried under vacuum to give the title compound (1.29 g, quantitative) as a solid. MS (ESI) [M+H] + 349.3. 1 H NMR (500 MHz, DMSO-d6) δ 10.90 (s, 1H), 7.89 (s, 1H), 7.89 (s, 1H), 7.87 (s, 1H), 7.79 (d,J = 8.5 Hz, 1H), 7.53 (s, 1H), 7.52 (s, 1H), 7.44 (dd, J = 8.5, 1.4 Hz, 1H), 4.40 (dd, J = 9.9, 5.0 Hz, 1H), 4.05 (s, 3H), 2.92 (s, 3H), 2.74 - 2.58 (m,2H), 2.44 - 2.34 (m, 1H), 2.20 (dq, J = 13.2, 5.3 Hz, 1H). Note: Exchangeable protons are not visible.

[0610] Step 24.4: Synthesis of 3-(6-(4-((5-chloro-4-((1-methyl-2-oxodihydroindole-5-yl)amino)pyrimidin-2-yl)(methyl)amino)phenyl)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione. A solution of 3-[1-methyl-6-[4-(methylamino)phenyl]indazole-3-yl]piperidin-2,6-dione hydrochloride (200 mg, 0.52 mmol) and 5-[(5-chloro-2-fluoro-pyrimidin-4-yl)amino]-1-methyl-dihydroindole-2-one (228 mg, 0.78 mmol) in NMP (2 mL) was replaced with N2 and then placed in a preheated oil bath at 160°C for 30 min. The crude reaction mixture was purified by reversed-phase chromatography (C18) using a gradient elution of 5–70% MeCN and water containing 0.1% formic acid to give the title compound (54.8 mg, 16%) as a solid. MS (ESI) [M+H] + 622.2. 1 H NMR (500 MHz, acetic acid-d4) δ 8.19 (s, 1H), 7.98 (s, 1H), 7.96 (s, 1H), 7.95 (s, 1H), 7.88 (s, 1H), 7.68 (s, 1H), 7.63 (dd, J= 8.6, 1.2 Hz, 1H), 7.60 (s, 1H), 7.60 - 7.58 (m, 2H), 6.90 (d, J = 8.4 Hz,1H), 4.67 (dd, J = 10.4, 5.2 Hz, 1H), 4.24 (s, 3H), 3.67 (s, 3H), 3.63 (s,2H), 3.20 (s, 3H), 3.09 - 3.01 (m, 1H), 3.01 - 2.92 (m, 1H), 2.77 - 2.67 (m, 1H), 2.57 - 2.49 (m, 1H).

[0611] Example 25

[0612]

[0613] 3-(6-(((3R,4R)-1-(5-chloro-4-((3-((S)-3-(hydroxymethyl)-2-oxopyrrolidine-1-yl)phenyl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione

[0614] Step 25.1: Synthesis of 1-(3-nitrophenyl)-2-oxopyrrolidine-3-carboxylic acid. In a microwave-safe vial, 3-nitroaniline (2,2841 mg, 20.57 mmol) was added to a stirred solution of 6,6-dimethyl-5,7-dioxane[2.5]octane-4,8-dione (1, 1000 mg, 5.88 mmol) in 7.0 mL of ethanol. The reaction mixture was irradiated in a microwave at 100°C for 10 min. The reactants were cooled to room temperature, and volatiles were removed by evaporation under vacuum. The crude residue was quenched with 10% NaOH solution (pH = 9–10) and stirred for 30 min, then washed with ethyl acetate (3 x 50 mL). The aqueous layer was then acidified with 1.5 N HCl and stirred at room temperature for 15 min. The solid precipitate was filtered off, the filter bed was washed with excess water, and dried under vacuum to give the title compound (537.1 mg, 2.146 mmol, 36.5% yield) as a yellow solid.

[0615] Step 25.2: Synthesis of methyl 1-(3-nitrophenyl)-2-oxopyrrolidine-3-carboxylate. Thionyl chloride (0.371 mL, 5.08 mmol) was added dropwise to a stirred solution of 1-(3-nitrophenyl)-2-oxopyrrolidine-3-carboxylic acid (636 mg, 2.54 mmol) in methanol (2.0 mL). The reaction mixture was heated to 80°C and stirred for 4 hours. The reaction mixture was cooled to room temperature, quenched with 10% sodium bicarbonate solution, and extracted in dichloromethane (3 x 25 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to give the title compound (470 mg, 1.581 mmol, 62.2% yield) as a yellow solid.

[0616] Step 25.3: Synthesis of methyl 1-(3-aminophenyl)-2-oxopyrrolidine-3-carboxylate. 10% Pd / C (300 mg, 0.282 mmol) was added to a stirred solution of methyl 1-(3-nitrophenyl)-2-oxopyrrolidine-3-carboxylate (470 mg, 1.581 mmol) in ethanol (2.0 mL) and THF (2.0 mL) under a nitrogen atmosphere at 25°C. The reaction mixture was stirred under a hydrogen atmosphere for 24 hours. The reaction mixture was filtered through a Celite filter, and the Celite pad was washed with ethanol (3 x 10 mL). The filtrate was evaporated under reduced pressure to give the title compound (400 mg, 1.537 mmol, 97% yield). The crude product was used in the next step without further purification.

[0617] Step 25.4: Synthesis of methyl 1-(3-((5-chloro-2-fluoropyrimidin-4-yl)amino)phenyl)-2-oxopyrrolidine-3-carboxylate. DIPEA (1.15 mL, 6.58 mmol) was added dropwise to a stirred solution of methyl 1-(3-aminophenyl)-2-oxopyrrolidine-3-carboxylate (425 mg, 1.65 mmol) and 5-chloro-2,4-difluoropyrimidine (6,297 mg, 1.975 mmol) in 10 mL of THF at -78°C under a nitrogen atmosphere. The reaction mixture was slowly warmed to 25°C and stirred for 16 hours. The reaction mixture was evaporated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography using ethyl acetate as the eluent to give the title compound (478 mg, 1.241 mmol, 75% yield) as a creamy white solid.

[0618] Step 25.5: Synthesis of 1-(3-(((5-chloro-2-fluoropyrimidin-4-yl)amino)phenyl)-3-(hydroxymethyl)pyrrolidine-2-one. Methyl 1-(3-(((5-chloro-2-fluoropyrimidin-4-yl)amino)phenyl)-2-oxopyrrolidine-3-carboxylate (238 mg, 0.618 mmol) was added to a stirred solution of sodium borohydride (46.8 mg, 1.236 mmol) and calcium chloride (137 mg, 1.236 mmol) in ethanol (15 mL). The reaction mixture was stirred at 0°C for 4 hours. The reaction mixture was quenched with water (5 mL) and evaporated under vacuum to remove ethanol. The concentrated reaction residue was extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with a saturated brine solution, dried over anhydrous sodium sulfate, filtered, and evaporated to give the crude product. The crude product was purified by silica gel rapid column chromatography using 70% ethyl acetate in petroleum ether as eluent to give a mixture of enantiomers of the title compound. This enantiomer mixture was further purified by SFC column chromatography to give the chiral pure title compound (peak 1 + peak 2) (104 mg, 0.308 mmol, 48.0%). SFC HPLC method: Rt 6.64 and 8.98 min; column: Chiralpak-IG (250 mm × 4.6 × 5 u); 0.2% ammonia in methanol solution 40 mmol / L; flow rate: 4.0 mL / min.

[0619] Step 25.6: Synthesis of 3-(6-(((3R,4R)-1-(5-chloro-4-((3-((S)-3-(hydroxymethyl)-2-oxopyrrolidone-1-yl)phenyl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione. 3-(1-methyl-6-((((3R,4R)-3-methylpiperidin-4-yl)amino)amino)-3-(hydroxymethyl)pyrrolidone-2-one (peak 1, step 25.5, 40 mg, 0.114 mmol) and DIPEA (0.062 mL, 0.353 mmol) were added to a stirred solution of 1-(3-((5-chloro-2-fluoropyrimidin-4-yl)amino)-1H-indazole-3-yl)piperidin-2,6-dione hydrochloride (43.7 mg, 0.088 mmol) and DIPEA (0.062 mL, 0.353 mmol) in DMSO (1.0 mL) at 25°C. The reaction mixture was heated to 80°C and stirred for 16 hours. The reaction mixture was cooled to room temperature and purified by preparative HPLC to give the title compound (20.31 mg, 0.030 mmol, 30.70% yield) as a pale pink solid. LCMS: 672.2 (M+H), Rt 2.140 min; 1 H NMR(400 MHz, DMSO-d6): δ 10.82 (s, 1H), 8.73 (s, 1H), 8.07 (s, 1H), 8.01 (s,1H), 7.45-7.40 (m, 2H), 7.31 (d, J = 7.60 Hz, 2H), 6.51 (d, J = 8.80 Hz, 1H), 6.44 (s, 1H), 5.71 (d, J = 8.40 Hz, 1H), 4.80 (s, 1H), 4.52 (s, 2H), 4.19-4.16 (m, 1H), 4.00 (s, 1H), 3.81 (s, 3H), 3.79-3.75 (m, 2H), 3.70-3.60 (m,2H), 3.03 (t, J = 12.80 Hz, 1H), 2.69-2.67 (m, 2H), 2.60 (s, 2H), 2.33-1.99(m, 5H), 1.58 (s, 1H), 1.24-1.18 (m, 1H), 0.95 (d, J = 6.40 Hz, 3H).

[0620] Example 26

[0621]

[0622] 3-(6-(((3R,4R)-1-(5-chloro-4-((3-((R)-3-(hydroxymethyl)-2-oxopyrrolidine-1-yl)phenyl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione

[0623] Step 26.1: Synthesis of 3-(6-(((3R,4R)-1-(5-chloro-4-((3-(((R)-3-(hydroxymethyl)-2-oxopyrrolidine-1-yl)phenyl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione. 3-(1-methyl-6-((((3R,4R)-3-methylpiperidin-4-yl)amino)-1H-indazole-3-yl)piperidin-2,6-dione hydrochloride (56 mg, 0.114 mmol) and DIPEA (0.062 mL, 0.353 mmol) were added to a stirred solution of 1-(3-((5-chloro-2-fluoropyrimidin-4-yl)amino)-1H-indazole-3-yl)piperidin-2,6-dione hydrochloride (56 mg, 0.114 mmol) and DIPEA (0.062 mL, 0.353 mmol) in DMSO (1.0 mL) at 25°C. The reaction mixture was heated to 80°C and stirred for 16 hours. The reaction mixture was cooled to room temperature and purified by preparative HPLC to give the title compound (20.31 mg, 0.030 mmol, 30.70% yield) as a pale pink solid. LCMS: 672.2 (M+H), Rt 2.140 min; 1H NMR(400 MHz, DMSO-d6): δ 10.83 (s, 1H), 8.73 (s, 1H), 8.07 (s, 1H), 7.99 (s,1H), 7.43 (t, J = 9.60 Hz, 2H), 7.31 (d, J = 8.00 Hz, 2H), 6.52 (d, J = 8.40Hz, 1H), 6.44 (s, 1H), 5.71 (d, J = 8.40 Hz, 1H), 4.79 (s, 1H), 4.52 (s, 2H),4.19-4.16 (m, 1H), 3.82 (s, 3H), 3.77 (t, J = 6.40 Hz, 2H), 3.65 (d, J =18.00 Hz, 2H), 3.38-3.15 (m, 2H), 3.03 (t, J = 12.00 Hz, 1H), 2.73-2.61 (m,3H), 2.33-2.01 (m, 5H), 1.59 (s, 1H), 1.24-1.18 (m, 1H), 0.96 (d, J = 6.00Hz, 3H).

[0624] Example 27

[0625]

[0626] 3-(5-(((3R,4R)-1-(5-chloro-4-((1-methyl-2-oxodihydroindole-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1H-indazol-1-yl)-3-methylpiperidin-2,6-dione

[0627] Step 27.1: Synthesis of 2-(5-bromo-1H-indazole-1-yl)propionitrile. 2-bromopropionitrile (2, 3.06 g, 22.84 mmol) and K₂CO₃ (4.21 g, 30.5 mmol) were added to a stirred solution of 5-bromo-1H-indazole (1, 3.0 g, 15.23 mmol) in DMF (20 mL) at 25°C under a nitrogen atmosphere. The reaction mixture was heated to 70°C and stirred for 16 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (150 mL), and washed with a saturated brine solution. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to give the crude compound. The crude compound was purified by silica gel rapid column chromatography using 5–10% ethyl acetate / petroleum ether to give the title compound (2.4 g, 9.31 mmol, 61.1% yield) as a creamy white solid.

[0628] Step 27.2: Synthesis of tert-butyl acrylate 4-(5-bromo-1H-indazol-1-yl)-4-cyanopentanoate. Tert-butyl acrylate 4 (0.717 g, 5.60 mmol), K₂CO₃ (0.928 g, 6.72 mmol), and benzyltriethylammonium chloride (0.127 g, 0.560 mmol) were added sequentially to a stirred solution of 2-(5-bromo-1H-indazol-1-yl)propionitrile (1.4 g, 5.60 mmol) in toluene (15 mL) at room temperature. The reaction mixture was heated to 70°C and stirred for 16 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (250 mL), and washed with a saturated brine solution. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to give the crude compound. The crude compound was purified by silica gel rapid column chromatography using elution with 10-45% ethyl acetate / petroleum ether to give the title compound (1.8 g, 4.38 mmol, 78% yield) as a creamy white solid.

[0629] Step 27.3: Synthesis of tert-butyl 4-(3R,4R)-4-((1-(5-(tert-butoxy)-2-cyano-5-oxopentane-2-yl)-1H-indazol-5-yl)amino)-3-methylpiperidin-1-carboxylic acid. Tert-butyl 4-(5-bromo-1H-indazol-1-yl)-4-cyanopentane (1 g, 2.64 mmol) and (3R,4R)-4-amino-3-methylpiperidin-1-carboxylic acid tert-butyl 6 (0.567 g, 2.64 mmol) were degassed in a stirred solution in toluene (10 mL) for 5 min. Then, NaOtBu (0.508 g, 5.29 mmol), Pd2dba3 (0.242 g, 0.264 mmol) and Cphos (0.346 g, 0.793 mmol) were added at 25°C. The reaction mixture was heated to 100°C and stirred for 12 hours. The mixture was quenched with water (100 mL) and diluted with ethyl acetate (50 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (2 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude residue was purified by silica gel rapid column chromatography using 65% ethyl acetate / petroleum ether to give the title compound (470 mg, 0.854 mmol, 32.3% yield) as a creamy white solid.

[0630] Step 27.4: Synthesis of 3-methyl-3-(5-((((3R,4R)-3-methylpiperidin-4-yl)amino)-1H-indazole-1-yl)piperidin-2,6-dione. Sulfuric acid (0.046 mL, 0.854 mmol) was added to a stirred solution of (3R,4R)-4-((1-(5-(tert-butoxy)-2-cyano-5-oxopentane-2-yl)-1H-indazole-5-yl)amino)-3-methylpiperidin-1-carboxylic acid tert-butyl ester (470 mg, 0.854 mmol) in acetic acid (8 mL). The reaction mixture was heated to 80°C and stirred for 12 hours. The reaction mixture was concentrated under reduced pressure, and the resulting crude mixture was poured into ethyl acetate (50 mL) and washed with a saturated brine solution (50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude title compound (220 mg, 0.390 mmol, 45.6% yield) as a black, viscous solid.

[0631] Step 27.5: Synthesis of 3-(5-(((3R,4R)-1-(5-chloro-4-((1-methyl-2-oxodihydroindol-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1H-indazole-1-yl)-3-methylpiperidin-2,6-dione. 5-((5-chloro-2-fluoropyrimidin-4-yl)amino)-1H-indazol-1-yl)piperidin-2,6-dione (150 mg, 0.270 mmol) and DIPEA (0.472 mL, 2.70 mmol) were added to a stirred solution of 3-methyl-3-(5-(((3R,4R)-3-methylpiperidin-4-yl)amino)-1-methyldihydroindole-2-one (84 mg, 0.270 mmol) and DIPEA (0.472 mL, 2.70 mmol) in DMSO (4 mL) at 25°C. The reaction mixture was heated to 80°C and stirred for 8 hours. The reaction mixture was cooled to room temperature and purified by preparative HPLC to give the title compound (47 mg, 27%). LCMS: 628.2 (M+H) + Rt 2.53 min; 1H NMR (400 MHz, DMSO-d6): δ11.15 (s, 1H), 9.15 (s, 1H), 8.11 (s, 1H), 7.87 (s, 1H), 7.42-7.54 (m,3H), 6.96 (d, J = 8.40 Hz, 2H), 4.34 (d, J = 12.40 Hz, 2H), 3.55 (s, 3H), 3.27 (d, J = 9.60 Hz, 1H), 3.11 (s, 3H), 3.04-3.08 (m, 1H), 2.75-2.81 (m,2H), 2.67-2.70 (m, 1H), 2.25 (q, J = 15.60 Hz, 2H), δ 1.99 (d, J = 10.80 Hz, 1H), 1.87 (s, 3H), 1.68 (s, 1H), 1.21-1.24 (m, 1H), 1.02 (d, J = 6.00 Hz, 3H).

[0632] Example 29

[0633]

[0634] 3-(6-(((3R,4R)-1-(5-chloro-4-((1-(3-hydroxy-3-methylbutyl)-1H-indol-6-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione

[0635] Step 29.1: Synthesis of 2-methyl-4-(6-nitro-1H-indole-1-yl)but-2-ol. Compound 3-hydroxy-3-methylbutyl 4-methylbenzenesulfonic acid (2, 5.97 g, 23.1 mmol) and cesium carbonate (15.07 g, 46.3 mmol) were added to a stirred solution of 6-nitro-1H-indole (2.5 g, 15.42 mmol) in DMF (30 mL) at 25°C. The reaction mixture was heated to 120°C for 16 hours. The reaction mixture was cooled to room temperature and quenched with ice-cold water. A solid precipitated. The solid was then separated by filtration to give the title compound (3.42 g, 13.46 mmol, 87% yield) as a brown oily liquid.

[0636] Step 29.2: Synthesis of 4-(6-amino-1H-indol-1-yl)-2-methylbut-2-ol. 10% Pd / C (1.648 g, 15.48 mmol) was added to a stirred solution of 2-methyl-4-(6-nitro-1H-indol-1-yl)but-2-ol (3.42 g, 12.9 mmol) in ethanol (5 mL) and THF (5 mL) under a nitrogen atmosphere at 25°C. The reaction mixture was stirred under a hydrogen atmosphere for 6 hours. The reaction mixture was filtered through a Celite filter, and the Celite pad was washed with 50% ethanol / THF (100 mL). The filtrate was concentrated under reduced pressure to give the title compound (2.38 g) as a green gelatinous solid. The crude product was used in the next step without further purification.

[0637] Step 29.3: Synthesis of 4-(6-((5-chloro-2-fluoropyrimidin-4-yl)amino)-1H-indol-1-yl)-2-methylbut-2-ol. A stirred solution of 4-(6-amino-1H-indol-1-yl)-2-methylbut-2-ol (2.38 g, 10.9 mmol) in THF (10 mL) was purged with nitrogen for 5 min. Then, 5-chloro-2,4-difluoropyrimidine (2.30 g, 15.3 mmol) and DIPEA (7.62 mL, 15.3 mmol) were added sequentially at -40°C. The reaction mixture was slowly warmed to 25°C and stirred for 12 h. The volatiles were evaporated to give the crude product. The crude residue was purified by silica gel rapid column chromatography with elution of 10-60% ethyl acetate / petroleum ether to give the title compound (2.96 g, 53% yield) as a yellow solid.

[0638] Step 29.4: Synthesis of 3-(6-(((3R,4R)-1-(5-chloro-4-((1-(3-hydroxy-3-methylbutyl)-1H-indol-6-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione. 3-(1-methyl-6-((((3R,4R)-3-methylpiperidin-4-yl)amino)-1H-indol-1-yl)-2-methylbut-2-ol (105 mg, 0.281 mmol) and DIPEA (0.221 mL, 1.265 mmol) were added to a stirred solution of 4-(6-((5-chloro-2-fluoropyrimidin-4-yl)amino)-1H-indazole-3-yl)piperidin-2,6-dione (150 mg, 0.316 mmol) and DIPEA (0.221 mL, 1.265 mmol) in DMSO (2.0 mL) at 25°C. The reaction mixture was heated to 80°C and stirred for 3 hours. The reaction mixture was cooled to room temperature and purified by preparative HPLC to give the title compound (29 mg, 0.042 mmol, 13% yield) as a creamy white solid. LCMS: 684.2 (M+H) + ; 1 H NMR (400 MHz, DMSO-d6): δ 10.82 (s, 1H), 8.67 (s, 1H),8.03 (s,1H), 7.74 (s,1H), 7.48 (d, J = 16.4 Hz, 1H), 7.31 - 7.28 (m, 3H),6.52 (dd, J = 1.6 Hz, 1H), 6.42 (s, 1H), 6.37 (d, J = 2.8 Hz, 1H), 5.7 (d, J= 9.2 Hz, 1H), 4.54 - 4.47 (m, 3H), 4.20 - 4.15 (m, 3H), 3.81 (s, 1H), 3.33(s, 2H), 3.06 (t, J=12 Hz, 1H), 2.68 - 2.65 (m, 1H), 2.62 - 2.58 (m, 1H), 2.34 - 2.33 (m, 1H), 2.26 - 2.22 (m, 2H), 1.86 (t, J = 8.4 Hz, 2H), 1.58 -1.57 (m, 1H), 1.15 (s, 6H), 0.95 (d, J= 6.4 Hz, 3H).

[0639] Example 30

[0640]

[0641] 3-(6-(((3R,4R)-1-(5-chloro-4-((1-(3-hydroxy-3-methylbutyl)-1H-indazol-6-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione

[0642] Step 30.1: Synthesis of 4-(6-((5-chloro-2-fluoropyrimidin-4-yl)amino)-1H-indazole-1-yl)-2-methylbut-2-ol. Similar to steps 1-3 of Example XX (above), the title compound was synthesized using 6-nitro-1H-indazole as the starting material in step 1.

[0643] Step 30.2: Synthesis of 3-(6-(((3R,4R)-1-(5-chloro-4-((1-(3-hydroxy-3-methylbutyl)-1H-indazole-6-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione. 3-(1-methyl-6-((((3R,4R)-3-methylpiperidin-4-yl)amino)-1H-indazol-1-yl)-2-methylbut-2-ol (105 mg, 0.281 mmol) and DIPEA (0.192 mL, 1.125 mmol) were added to a stirred solution of 4-(6-((5-chloro-2-fluoropyrimidin-4-yl)amino)-1H-indazol-3-yl)piperidin-2,6-dione (100 mg, 0.281 mmol) and DIPEA (0.192 mL, 1.125 mmol) in DMSO (2.0 mL) at 25°C. The reaction mixture was heated to 80°C and stirred for 3 hours. The reaction mixture was cooled to room temperature and purified by preparative HPLC to give the title compound (15 mg, 0.022 mmol, 7.7% yield) as a white solid. LCMS: 685.20 (M+H) + , 1H NMR (400 MHz, DMSO-d6): δ 10.82 (s, 1H), 8.86 (s, 1H), 8.10 (s, 1H), 7.97 (s, J = 7.2 Hz, 2H), 7.68 (d, J = 8.8 Hz, 1H), 7.44 (d, J= 8.8 Hz, 1H), 7.32 (d, J = 8.8 Hz, 1H), 6.52 (dd, J = 1.6 Hz, 1H), 6.42 (s,1H), 5.71 (d, J = 8.8 Hz, 1H), 4.56 (d, J = 12.4 Hz, 2H), 4.48 (s, 1H), 4.41(t, J = 8 Hz, 1H), 3.8 (s, 3H), 3.32 (brs, 1H), 3.11 (t, J = 12.4Hz, 1H), 2.75 - 2.66 (m, 1H), 2.58 - 2.52 (m, 2H), 2.29 - 2.21 (m, 1H), 2.16 - 2.09(m, 2H), 1.92 (t, J = 6.4 Hz, 2H), 1.59 (brs, 1H), 1.23 (d, J = 14 Hz, 1H), 1.14 (s, 6H), 0.97 (d, J = 6.4 Hz, 3H).

[0644] Example 31

[0645]

[0646] 3-(6-(((3R,4R)-1-(5-chloro-4-((1-(3-hydroxy-3-methylbutyl)-3-methyl-1H-indazol-6-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione

[0647] Step 31.1: Synthesis of 4-(6-((5-chloro-2-fluoropyrimidin-4-yl)amino)-3-methyl-1H-indazole-1-yl)-2-methylbut-2-ol. Similar to steps 1-3 of Example XX (above), the title compound was synthesized using 3-methyl-6-nitro-1H-indazole as the starting material in step 1.

[0648] Step 31.2: Synthesis of 3-(6-(((3R,4R)-1-(5-chloro-4-((1-(3-hydroxy-3-methylbutyl)-3-methyl-1H-indazole-6-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione. 3-(1-methyl-6-((((3R,4R)-3-methylpiperidin-4-yl)amino)-1H-indazol-1-yl)-2-methylbut-2-ol (200 mg, 0.440 mmol) and DIPEA (0.192 mL, 1.099 mmol) were added to a stirred solution of 4-(6-((5-chloro-2-fluoropyrimidin-4-yl)amino)-1H-indazol-3-yl)piperidin-2,6-dione (83 mg, 0.220 mmol) and DIPEA (0.192 mL, 1.099 mmol). The reaction mixture was heated to 90°C and stirred for 12 hours. The reaction mixture was cooled to room temperature and purified by preparative HPLC to give the title compound (64.14 mg, 0.0918 mmol, 39.7% yield) as a creamy white solid. LCMS: 699.20 (M+H) + , 1H NMR (400 MHz, DMSO-d6): δ 10.82 (s,1H), 8.84 (s, 1H), 8.10 (s, 1H), 7.89 (s, 1H), 7.61 (d, J = 8.40 Hz, 1H), 7.41 (d, J = 1.20 Hz, 1H), 7.38 (d, J = 1.20 Hz, 1H), 7.31 (d, J = 8.80 Hz,1H), 6.51 (dd, J = 1.60, 8.80 Hz, 1H), 6.43 (s, 1H), 5.68-5.70 (m, 1H), 4.54(d, J = 12.00 Hz, 2H), 4.30 (t, J = 2.80 Hz, 3H), 4.18 (q, J = 5.20 Hz, 1H), δ 3.82 (s, 3H), 3.09 (t, J = Hz, 1H), 2.75 (t, J = 12.80 Hz, 1H), 2.61(t, J =6.00 Hz, 1H), 2.44 (s, 3H), 2.23-2.27 (m, 1H), 2.10-2.17 (m, 2H), 1.87 (t, J= 8.00 Hz, 2H), 1.61-1.62 (m, 1H), 1.17-1.24 (m, 1H), 1.14 (s, 6H), 0.97 (d,J = 6.40 Hz, 3H).

[0649] Example 32

[0650]

[0651] 3-(6-(((3R,4R)-1-(5-chloro-4-((6-hydroxy-5-methylnaphthyl-2-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione

[0652] Step 32.1: Synthesis of 6-bromo-1-methylnaphthyl-2-ol. Bromine (0.651 mL, 12.64 mmol) in AcOH (6.0 mL) was added dropwise to a stirred solution of 1-methylnaphthyl-2-ol (2.0 g, 12.64 mmol) cooled to 10°C in AcOH (4.00 mL) under a nitrogen atmosphere, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was then treated with cold water (20 mL), and the resulting solid was filtered and dried to give the crude title compound (3.5 g, 11.90 mmol, 94% yield) as a slightly reddish powder.

[0653] Step 32.2: Synthesis of 6-bromo-2-((4-methoxybenzyl)oxy)-1-methylnaphthalene. NaH (32.6 mg, 0.816 mmol) was added to a stirred solution of 6-bromo-1-methylnaphthalene-2-ol (200 mg, 680 mmol) cooled to 0°C in DMF (2.0 mL) under a nitrogen atmosphere, and the mixture was stirred for 10 min. Then (chloromethyl)-4-methoxybenzene (160 mg, 1.020 mmol) was added to the reaction mixture, and the temperature was slowly lowered to 25°C. The reaction mixture was stirred for 1 h, treated with cold water (10 mL), and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel rapid column chromatography using 10–20% ethyl acetate / petroleum ether to give the title compound (150 mg, 0.323 mmol, 47% yield) as a creamy white solid.

[0654] Step 32.3: Synthesis of N-(6-((4-methoxybenzyl)oxy)-5-methylnaphthyl-2-yl)-1,1-diphenylmethyleneimine. A stirred solution of 6-bromo-2-((4-methoxybenzyl)oxy)-1-methylnaphthyl (550 mg, 1.386 mmol) and diphenylmethyleneimine (377 mg, 2.078 mmol) in toluene (20 mL) was added. The reaction mixture was purged with nitrogen for 15 min, followed by the addition of sodium tert-butoxide (399 mg, 4.16 mmol), BINAP (173 mg, 0.277 mmol), and Pd2(dba)3 (127 mg, 0.139 mmol). The reaction mixture was stirred at 100°C for 3 h. The reaction mixture was diluted with water and extracted with EtOAc (3 x 75 mL). The filtrate was concentrated under reduced pressure to obtain a crude residue, which was purified by silica gel rapid column chromatography using 5-10% ethyl acetate / petroleum ether to give the title compound (490 mg, 1.03 mmol, 74% yield) as a yellow liquid.

[0655] Step 32.4: Synthesis of 6-((4-methoxybenzyl)oxy)-5-methylnaphthyl-2-amine. N-(6-((4-methoxybenzyl)oxy)-5-methylnaphthyl-2-yl)-1,1-diphenylmethyleneimine (490 mg, 1.028 mmol) was added to a stirred solution of MeOH (15.0 mL). Sodium acetate (253 mg, 3.08 mmol) and hydroxylamine hydrochloride (214 mg, 3.08 mmol) were then added sequentially at 25°C. The reaction mixture was stirred at 25°C for 4 hours. The reaction mixture was diluted with water and extracted with DCM (3 x 50 mL). The organic layer was evaporated to give crude compound 6 (300 mg, 68% yield). This was used in the next step without further purification.

[0656] Step 32.5: Synthesis of 5-chloro-2-fluoro-N-(6-(((4-methoxybenzyl)oxy)-5-methylnaphthyl-2-yl)pyrimidine-4-amine. DIPEA (0.125 mL, 0.716 mmol) was added dropwise to a stirred solution of 6-((4-methoxybenzyl)oxy)-5-methylnaphthyl-2-amine (100 mg, 0.239 mmol) and 5-chloro-2,4-difluoropyrimidine (7, 46.7 mg, 0.310 mmol) in EtOH (4 mL) at -20°C under a nitrogen atmosphere. The reaction mixture was slowly warmed to 25°C and stirred for 16 hours. The reaction mixture was evaporated under reduced pressure to give a crude product. The crude product was purified by silica gel rapid column chromatography using 10-20% ethyl acetate / petroleum ether as eluent to give the title compound (80 mg, 73% yield) as a brown solid.

[0657] Step 32.6: Synthesis of 3-(6-(((3R,4R)-1-(5-chloro-4-((6-(((4-methoxybenzyl)oxy)-5-methylnaphth-2-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione. To a stirred solution of 5-chloro-2-fluoro-N-(6-(((4-methoxybenzyl)oxy)-5-methylnaphthyl-2-yl)pyrimidin-4-amine (80 mg, 0.176 mmol) in DMSO (1.0 mL), 3-(1-methyl-6-(((3R,4R)-3-methylpiperidin-4-yl)amino)-1H-indazol-3-yl)piperidin-2,6-dione, TFA (82 mg, 0.176 mmol), and DIPEA (0.123 mL, 0.702 mmol) were added. The reaction mixture was heated to 85°C and stirred for 4 hours. The reaction mixture was cooled to room temperature, diluted with water, filtered to obtain a solid, and dried to give the title compound (120 mg, 0.128 mmol, 73% yield) as a creamy white solid.

[0658] Step 32.7: Synthesis of 3-(6-(((3R,4R)-1-(5-chloro-4-((6-hydroxy-5-methylnaphthyl-2-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione. A solution of 3-(6-(((3R,4R)-1-(5-chloro-4-((6-(((4-methoxybenzyl)oxy)-5-methylnaphthyl-2-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione (80 mg, 0.085 mmol) in a stirred TFA (1.0 mL) was stirred at 70°C for 2 hours. The reaction mixture was then concentrated to obtain a crude compound, which was purified by preparative HPLC to give the title compound (28 mg, 50% yield) as a creamy white solid. LCMS: 639.2 (M+H) + , 1H NMR (400 MHz, DMSO-d6): δ 10.84 (s, 1H), 9.39 (s, 1H), 8.90 (s, 1H), 8.13 (s, 1H), 8.09 (s, 1H), 7.81 (d, J = 9.20 Hz, 1H), 7.72 (dd, J =2.00, 9.20 Hz, 1H), 7.49 (d, J = 8.80 Hz, 1H), 7.31 (d, J = 8.80 Hz, 1H), 7.14 (d, J = 8.80 Hz, 1H), 6.51 (dd, J = 1.60, 8.80 Hz, 1H), 6.45 (s, 1H),5.73 (d, J = 7.60 Hz, 1H), δ 4.52 (d, J = 11.20 Hz, 2H), 4.18 (q, J = 5.20Hz, 1H), 3.82 (s, 3H), 3.08 (t, J = 12.40 Hz, 1H), 2.68-2.77 (m, 1H), 2.59(t, J = 5.60 Hz, 3H), 2.40 (s, 3H), 2.23-2.28 (m, 1H), 2.08-2.18 (m, 3H), 1.63 (t, J = 4.40 Hz, 1H), 1.22 (d, J = 15.20 Hz, 1H), 0.97 (d, J = 6.40 Hz, 3H).

[0659] Example 33

[0660]

[0661] 2-(5-((5-chloro-2-((3R,4R)-4-((3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)amino)-3-methylpiperidin-1-yl)pyrimidin-4-yl)amino)-2-fluorophenyl)-N-methylacetamide

[0662] Step 33.1: Synthesis of 2-(2-fluoro-5-nitrophenyl)-N-methylacetamide. Under a nitrogen atmosphere, DIPEA (0.351 mL, 2.009 mmol) and HATU (286 mg, 0.753 mmol) were added to a stirred solution of 2-(2-fluoro-5-nitrophenyl)acetic acid (100 mg, 0.502 mmol) and methylamine hydrochloride (37.3 mg, 0.552 mmol) in DMF (2 mL). The reaction mixture was heated at 25 °C.o The mixture was stirred at C for 4 hours. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to give the crude compound. The crude product was purified by silica gel rapid column chromatography using 10–30% ethyl acetate / petroleum ether elution to give the title compound (60 mg, 0.249 mmol, 50% yield) as a creamy white solid.

[0663] Step 33.2: Synthesis of 2-(5-amino-2-fluorophenyl)-N-methylacetamide. Pd / C (30.1 mg, 0.283 mmol) was added to a stirred solution of 2-(2-fluoro-5-nitrophenyl)-N-methylacetamide (60 mg, 0.283 mmol) in ethanol (2 mL) under a nitrogen atmosphere at 25°C. The reaction mixture was stirred under a hydrogen atmosphere for 4 hours. The reaction mixture was filtered through a Celite filter, and the Celite pad was washed with ethanol (3 x 5 mL). The filtrate was evaporated under reduced pressure to give compound 3 (38 mg, 0.158 mmol, 56% yield) as a brown liquid. The crude product was used in the next step without further purification.

[0664] Step 33.3: Synthesis of 2-(5-((5-chloro-2-((3R,4R)-4-((3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)amino)-3-methylpiperidin-1-yl)pyrimidin-4-yl)amino)-2-fluorophenyl)-N-methylacetamide. The title compound was synthesized using 2-(5-amino-2-fluorophenyl)-N-methylacetamide (38 mg, 0.209 mmol) as the starting material according to General Procedures 1 and 6. LCMS: 648.2 (M+H) + , 1H NMR (400 MHz, DMSO-d6): δ 10.82(s, 1H), 9.16 (s, 1H), 8.13 (s, 1H), 7.96 (d, J = 4.40 Hz, 1H), 7.61-7.60 (m,1H), 7.59-7.59 (m, 1H), 7.51-7.50 (m, 1H), 7.48 (dd, J = 4.00, Hz, 1H), 7.33-7.23 (m, 1H), 7.17-7.10 (m, 1H), 6.54-6.45 (m, 2H), 4.38 (s, 2H), 4.20-4.16(m, 1H), 4.00 (s, 8H), 3.37 (d, J = 45.20 Hz, 2H), 3.08-2.77 (m, 1H), 2.74-2.67 (m, 1H), 2.63-2.61 (m, 1H), 2.59-2.56 (m, 2H), 2.51 (s, 3H), 2.33 (s,1H), 2.27-2.25 (m, 2H), 1.15-0.97 (m, 1H), 0.96 (d, J = Hz, 3H).

[0665] Example 34

[0666]

[0667] 3-(3-(((3R,4R)-1-(5-chloro-4-((1-methyl-2-oxodihydroindole-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)phenyl)piperidin-2,6-dione

[0668] Step 34.1: Synthesis of 2,6-bis(benzyloxy)-3-(3-bromophenyl)pyridine. 1-Bromo-3-iodobenzene (1.0 g, 3.53 mmol) and (2,6-bis(benzyloxy)pyridin-3-yl)boronic acid (0.829 g, 2.474 mmol), tripotassium phosphate (2.25 g, 10.60 mmol) were reacted in a stirred solution of 1,4-dioxane (30 mL):water (1.5 mL). The reactants were degassed for 10 minutes. Then, PdCl₂ (dppf) was added at 25°C. The mixture was stirred for 2 hours. The reaction mixture was filtered through a Celite bed and washed with ethyl acetate (50 mL). The combined filtrates were evaporated under reduced pressure to give the crude product. The crude residue was purified by silica gel column chromatography using 25% ethyl acetate in petroleum ether as the eluent to give the title compound (600 mg, 0.914 mmol, 25.9% yield) as a yellow solid.

[0669] Step 34.2: Synthesis of (3R,4R)-1-benzyl-N-(3-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-3-methylpiperidin-4-amine. Compound 6 (600 mg, 1.344 mmol), (3R,4R)-1-benzyl-3-methylpiperidin-4-amine (302 mg, 1.479 mmol), CPos (58.7 mg, 0.134 mmol), and sodium tert-butoxide (388 mg, 4.03 mmol) were added to toluene (12 mL) in a stirred solution. The reaction mixture was degassed for 10 min. Then Pd2(dba)3 (61.5 mg, 0.067 mmol) was added at 25°C. The reaction mixture was heated to 100°C and stirred for 16 h. The reaction mixture was filtered through a Celite bed and washed with ethyl acetate (50 mL). The combined filtrates were evaporated under reduced pressure to obtain the crude product. The crude residue was purified by silica gel rapid column chromatography using 25% ethyl acetate in petroleum ether as the eluent to give the title compound (500 mg, 0.668 mmol, 49.7% yield) as a yellow solid.

[0670] Step 34.3: Synthesis of 3-(3-(((3R,4R)-3-methylpiperidin-4-yl)amino)phenyl)piperidin-2,6-dione. TFA (0.068 mL, 0.878 mmol) and Pd(OH)₂ (246 mg, 1.755 mmol) were added to a stirred solution of (3R,4R)-1-benzyl-N-(3-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-3-methylpiperidin-4-amine (500 mg, 0.878 mmol) in a mixture of ethanol (2.0 mL) and THF (2.0 mL) at 25°C under a nitrogen atmosphere. The reaction mixture was stirred at 50°C for 4 hours at 4 atm hydrogen pressure. The reaction mixture was filtered through a Celite filter and the Celite pad was washed with ethanol (2 x 20 mL). The filtrate was evaporated under reduced pressure to give the title compound (300 mg, 0.871 mmol, 99% yield) as a black solid. The crude product was used in the next step without further purification.

[0671] Step 34.4: Synthesis of 3-(3-(((3R,4R)-1-(5-chloro-4-((1-methyl-2-oxodihydroindol-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)phenyl)piperidin-2,6-dione. At 25 o C10 was added to a stirred solution of 5-((5-chloro-2-fluoropyrimidin-4-yl)amino)-1-methyldihydroindole-2-one (291 mg, 0.995 mmol) in DMSO (3 mL) with 3-(3-(((3R,4R)-3-methylpiperidin-4-yl)amino)phenyl)piperidin-2,6-dione (300 mg, 0.995 mmol) and DIPEA (0.522 mL, 2.99 mmol). The reaction mixture was heated to 80°C and stirred for 4 hours. The reaction mixture was cooled to room temperature and purified by preparative HPLC to give the title compound (78 mg, 0.111 mmol, 11.16% yield) as a creamy white solid. LCMS: 575.2 (M+H) + , 1 H NMR (400 MHz, DMSO-d6): δ10.79 (s, 1H), 9.25 (s, 1H), 8.12 (s, 1H), 7.53-7.48 (m, 2H), 7.05-6.97 (m,2H), 6.53-0.47 (m, 2H), 6.37 (d, J = 7.20 Hz, 1H), 4.33-4.30 (m, 2H), 3.70-3.66 (m, 1H), 3.56 (s, 2H), 3.18-3.06 (m, 5H), 2.77-2.74 (m, 1H), 2.68-2.61(m, 1H), 2.52-2.50 (m, 2H), 2.13-2.09 (m, 3H), 2.02-1.99 (m, 1H), 1.59-1.58 (m, 1H), 0.96 (d, J = 6.00 Hz, 3H).

[0672] Example 35

[0673]

[0674] 3-(6-(((3R,4R)-1-(5-chloro-4-((3-(3-methyl-2-thioimidazolidine-1-yl)phenyl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione

[0675] Step 35.1: Synthesis of 1-methyl-3-(3-nitrophenyl)imidazolidine-2-thione. (The last sentence appears to be incomplete and possibly refers to a separate step.) o C. 2-(methylamino)ethanol-1-ol (0.417 g, 5.55 mmol) was added to a stirred solution of 1-isothiocyano-3-nitrobenzene (1.0 g, 5.55 mmol) in THF (10 mL). The reaction mixture was evaporated under reduced pressure to give a crude compound, which was ground with n-pentane to give the intermediate thiourea.

[0676] In 25 o C. Add NaOH aqueous solution (0.555 g, 13.87 mmol) to the above-mentioned crude thiourea solution in THF (5 mL) under stirring, and stir for 15 minutes. Then add a solution of p-toluenesulfonyl chloride (1.058 g, 5.55 mmol) in THF. Heat the reaction mixture at 25°C. o Stirring at C for 3 hours. Quenching the reaction mixture with water (25 mL) and extracting with ethyl acetate (3 x 20 mL). Drying the combined organic layers over anhydrous sodium sulfate, filtering, and evaporating under reduced pressure to give the crude compound. Purifying the crude product by silica gel rapid column chromatography with elution of 10-20% ethyl acetate in petroleum ether, yielding the title compound (220 mg, 0.896 mmol, 16.15% yield) as a brown solid.

[0677] Step 35.2: Synthesis of 1-(3-aminophenyl)-3-methylimidazolidine-2-thione. At 25... o C. Add stannous(II) chloride (278 mg, 1.467 mmol) to a stirred solution of 1-methyl-3-(3-nitrophenyl)imidazolidine-2-thione (120 mg, 0.489 mmol) in ethanol (3 mL). Heat the reaction mixture to 70 °C. o The reaction was carried out at C for 3 hours. After the reaction was complete, the mixture was cooled to room temperature, and the volatiles were evaporated under reduced pressure to obtain the crude compound. The crude product was purified by silica gel rapid column chromatography using 20-30% ethyl acetate in petroleum ether as elution to give the title compound (60 mg, 0.283 mmol, 57.9% yield) as a brown solid.

[0678] Step 35.3: Synthesis of 3-(6-(((3R,4R)-1-(5-chloro-4-((3-(3-methyl-2-thioimidazolidine-1-yl)phenyl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione. The title compound was synthesized using 1-(3-aminophenyl)-3-methylimidazolidine-2-thione (50 mg, 0.234 mmol) as the starting material according to general procedures 1 and 6. LCMS: 673.2 (M+H) + , 1 H NMR (400 MHz, DMSO-d6): δ10.84 (s, 1H), 8.78 (s, 1H), 8.08 (s, 1H), 7.95 (s, 1H), 7.51-7.48 (m, 1H),7.34-7.28 (m, 1H), 6.53-6.45 (m, 2H), 5.72 (d, J = 9.20 Hz, 2H), 4.51 (m,2H), 4.20-4.16 (m, 1H), 4.00-3.82 (m, 2H), 3.69 (s, 3H), 3.66-3.36 (m, 2H), 3.00 (m, 4H), 2.73-2.70 (m, 1H), 2.68-2.63 (m, 2H), 2.50-2.24 (m, 1H), 2.17-2.12 (m, 1H), 2.08-1.60 (m, 1H), 1.24-1.20 (m, 1H), 0.94 (d, J = Hz, 3H).

[0679] Example 36

[0680]

[0681] 3-(5-(((3R,4R)-1-(5-chloro-4-fluoro-6-((1-methyl-2-oxodihydroindole-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1H-indazol-1-yl)piperidin-2,6-dione

[0682] Step 36.1: Synthesis of 3-(5-bromo-1H-indazol-1-yl)piperidine-2,6-dione. At 0 o Sodium hydride (60.9 mg, 1.52 mmol) was added in portions to a stirred solution of 5-bromo-1H-indazole (100 mg, 0.508 mmol) in THF (0.5 mL). The reaction mixture was then heated at 0°C. oStir at C for 30 minutes. Then add 3-bromopiperidine-2,6-dione (195 mg, 1.01 mmol) at 0°C. Heat the reaction mixture to 25°C and stir for 16 hours. Quench the reaction mixture with water (5 mL) and dilute with ethyl acetate (5 mL). Separate the layers and extract the aqueous layer with ethyl acetate (2 x 5 mL). Dry the combined organic layers over anhydrous sodium sulfate, filter, and evaporate under reduced pressure to give the crude product. Purify the crude residue by silica gel rapid column chromatography with 25% ethyl acetate in petroleum ether to give the title compound (54 mg, 0.175 mmol, 34.5% yield) as a white solid.

[0683] Step 36.2: Synthesis of tert-butyl (3R,4R)-4-((1-(2,6-dioxopiperidin-3-yl)-1H-indazole-5-yl)amino)-3-methylpiperidin-1-carboxylic acid. Molecular sieve 4Å and LiHMDS (3.89 mL, 3.89 mmol) were added to a stirred solution of 3-(5-bromo-1H-indazole-1-yl)piperidin-2,6-dione (200 mg, 0.649 mmol) and (3R,4R)-4-amino-3-methylpiperidin-1-carboxylic acid tert-butyl ester (139 mg, 0.649 mmol) in 1,4-dioxane (5 mL). The reaction mixture was degassed for 10 min. Ruphos Pd G4 (55.2 mg, 0.065 mmol) was then added, and the mixture was degassed again for 2 minutes. The reaction mixture was heated to 80°C and stirred for 2 hours. The reaction mixture was cooled to 25°C, quenched with acetic acid, and the volatiles were evaporated under reduced pressure to give the crude product. The crude residue was purified by silica gel rapid column chromatography with elution of 5% methanol in DCM to give the title compound (30 mg, 0.050 mmol, 7.64% yield) as a yellow solid.

[0684] Step 36.3: Synthesis of the TFA salt of 3-(5-(((3R,4R)-3-methylpiperidin-4-yl)amino)-1H-indazole-1-yl)piperidin-2,6-dione. The title compound was synthesized using (3R,4R)-4-((1-(2,6-dioxopiperidin-3-yl)-1H-indazole-5-yl)amino)-3-methylpiperidin-1-carboxylic acid tert-butyl ester (90 mg, 0.204 mmol) as the starting material according to General Procedure 5.

[0685] Step 36.4: Synthesis of 5-((5-chloro-2,6-difluoropyrimidin-4-yl)amino)-1-methyldihydroindole-2-one. (The last sentence appears to be incomplete and possibly refers to a separate step.) oC. Under a nitrogen atmosphere, DIPEA (0.538 mL, 3.08 mmol) was added dropwise to a stirred solution of 5-amino-1-methyldihydroindole-2-one (500 mg, 3.08 mmol) and 5-chloro-2,4,6-trifluoropyrimidine (519 mg, 3.08 mmol) in acetonitrile (25 mL). The reaction mixture was then heated at 0°C. o Stirring at C for 2 hours. Quench the reaction mixture with water (10 mL) and dilute with DCM (3 x 25 mL). Dry the combined organic layers over anhydrous sodium sulfate, filter, and evaporate under reduced pressure to give compound 3 (550 mg, 1.593 mmol, 51.7% yield) as a creamy white solid. The crude product was used in the next step without further purification.

[0686] Step 36.5: Synthesis of 3-(5-(((3R,4R)-1-(5-chloro-4-fluoro-6-((1-methyl-2-oxodihydroindol-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1H-indazol-1-yl)piperidin-2,6-dione. In 0 o C10 was added to a stirred solution of 3-(5-(((3R,4R)-3-methylpiperidin-4-yl)amino)-1H-indazol-1-yl)piperidin-2,6-dione TFA salt (60 mg, 0.105 mmol) in DMSO (1.5 mL) with stirring. 5-((5-chloro-2,6-difluoropyrimidin-4-yl)amino)-1-methyldihydroindole-2-one (36.4 mg, 0.105 mmol) and DIPEA (0.092 mL, 0.527 mmol) were added. The reaction mixture was heated to 80°C and stirred for 3 hours. The reaction mixture was cooled to room temperature and purified by preparative HPLC to give the title compound (10.5 mg, 0.016 mmol, 15% yield). LCMS: 632.3 (M+H) + , 1H NMR (400MHz, DMSO-d6): δ 11.07 (s, 1H), 9.00 (s, 1H), 7.89 (br d, J = 4.0 Hz, 1H), 7.58-7.26 (m, 3H), 6.97-6.93 (m, 1H), 5.72 (br d, J = 6.5 Hz, 1H), 4.38-4.27(m, 2H), 3.54 (s, 2H), 3.31-3.22 (m, 1H), 3.14-3.07 (m, 3H), 3.02-2.95 (m,1H), 2.87-2.82 (m, 1H), 2.75-2.63 (m, 3H), 2.28-2.19 (m, 1H), 2.07-1.93 (m,1H), 1.71-1.59 (m, 1H), 1.26-1.15 (m, 1H), 1.09-0.97 (m, 3H).

[0687] Example 37

[0688]

[0689] 3-(5-(((3R,4R)-1-(5-chloro-4-((1-methyl-2-oxodihydroindole-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-3-methyl-1H-indazol-1-yl)piperidin-2,6-dione

[0690] Step 37.1: Synthesis of 3-(5-bromo-3-methyl-1H-indazole-1-yl)piperidine-2,6-dione. Sodium hydride (284 mg, 7.11 mmol) was added in portions to a stirred solution of 5-bromo-3-methyl-1H-indazole (500 mg, 2.369 mmol) in THF (10 mL) at 0°C. The reaction mixture was stirred at 0°C for 30 min. Then, 3-bromopiperidine-2,6-dione (682 mg, 3.55 mmol) was added at 0°C. The reaction mixture was warmed to 25°C and stirred for 16 h. The reaction mixture was quenched with water (25 mL) and diluted with ethyl acetate (25 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (2 x 25 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to give the crude product. The crude residue was purified by silica gel rapid column chromatography by elution with 25% ethyl acetate in petroleum ether to give the title compound (420 mg, 1.269 mmol, 54% yield) as a white solid.

[0691] Step 37.2: Synthesis of tert-butyl (3R,4R)-4-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazole-5-yl)amino)-3-methylpiperidin-1-carboxylic acid. Molecular sieve 4Å (451 mg, 1.02 mmol) and LiHMDS (4.10 mL, 4.10 mmol) were added to a stirred solution of 3-(5-bromo-3-methyl-1H-indazole-1-yl)piperidin-2,6-dione (220 mg, 0.683 mmol) and (3R,4R)-4-amino-3-methylpiperidin-1-carboxylic acid (146 mg, 0.683 mmol) in toluene (7 mL). The reaction mixture was degassed for 10 min. Then Ruphos Pd G2 (53.0 mg, 0.068 mmol) was added, and the mixture was degassed again for 2 minutes. The reaction mixture was heated to 80°C and stirred for 1 hour. The reaction mixture was cooled to 25°C, quenched with acetic acid (5 equivalents), and the volatiles were evaporated under reduced pressure to give the crude product. The crude residue was purified by silica gel rapid column chromatography with elution of 5% methanol in DCM to give the title compound (220 mg, 0.303 mmol, 44% yield) as a yellow solid.

[0692] Step 37.3: Synthesis of the TFA salt of 3-(3-methyl-5-(((3R,4R)-3-methylpiperidin-4-yl)amino)-1H-indazole-1-yl)piperidin-2,6-dione. TFA (0.554 mL, 7.19 mmol) was added dropwise to a stirred solution of (3R,4R)-4-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazole-5-yl)amino)-3-methylpiperidin-1-carboxylic acid tert-butyl ester (260 mg, 0.360 mmol) in DCM (5 mL) at 0°C under a nitrogen atmosphere. The resulting solution was stirred at 25°C for 3 hours. The volatiles were evaporated under reduced pressure and ground with diethyl ether to give the title compound (20 mg, 0.186 mmol, 52% yield) as a yellow solid. The crude product was used in the next step without further purification.

[0693] Step 37.4: Synthesis of 3-(5-(((3R,4R)-1-(5-chloro-4-((1-methyl-2-oxodihydroindol-5-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-3-methyl-1H-indazole-1-yl)piperidin-2,6-dione. 5-((5-chloro-2,6-difluoropyrimidin-4-yl)amino)-1H-indazol-1-yl)piperidin-2,6-dione TFA salt (120 mg, 0.186 mmol) was added to a stirred solution of 3-(3-methyl-5-(((3R,4R)-3-methylpiperidin-4-yl)amino)-1-methyldihydroindole-2-one (57.2 mg, 0.186 mmol) and DIPEA (0.162 mL, 0.928 mmol) in DMSO (3.0 mL). The reaction mixture was heated to 90°C and stirred for 7 hours. The reaction mixture was cooled to room temperature and purified by preparative HPLC to give the title compound (86 mg, 0.135 mmol, 72.8% yield) as a creamy white solid. LCMS: 628.3 (M+H) + , 1 H NMR (400 MHz, DMSO-d6): δ11.05 (s, 1H), 9.16 (s, 1H), 8.10 (s, 1H), 7.53-7.47 (m, 3H), 7.22 (bs, 2H), 6.98-6.95 (m, 1H), 5.67-5.66(m, 1H), 4.33 (d, J = 4.36 Hz, 2H), 3.51 (s, 2H), 3.39 (bs, 1H), 3.11 (s,3H), 3.00-2.94 (m, 1H), 2.86-2.67 (m, 4H), 2.49 (s, 3H), 2.24-2.20 (m, 1H),1.96, (bs, 1H), 1.73 (bs, 1H), 1.35-1.20 (m, 1H), 1.09-1.07 (m, 3H).

[0694] Example 38

[0695]

[0696] 3-(6-(((3R,4R)-1-(5-chloro-4-((3-hydroxyisoquinoline-7-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione

[0697] Step 38.1: Synthesis of 7-bromo-3-((4-methoxybenzyl)oxy)isoquinoline. Cs₂CO₃ (873 mg, 2.68 mmol) was added to a stirred solution of 7-bromoisoquinoline-3-ol (500 mg, 2.232 mmol) in DMF (8.0 mL) at 0°C under a nitrogen atmosphere, and the mixture was stirred for 10 min. 4-Methoxybenzyl chloride (0.365 mL, 2.68 mmol) was added to the reaction mixture, and the temperature was slowly lowered to 25°C. The reaction mixture was stirred for 4 h, treated with cold water (100 mL), and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude title compound (550 mg, 44% yield) as a yellow solid. This was used in the next step without further purification.

[0698] Step 38.2: Synthesis of N-(3-((4-methoxybenzyl)oxy)isoquinoline-7-yl)-1,1-diphenylmethyleneimine. A stirred solution of 7-bromo-3-((4-methoxybenzyl)oxy)isoquinoline (550 mg, 0.975 mmol) and diphenylmethyleneimine (265 mg, 1.462 mmol) in toluene (10 mL) was added. The reaction mixture was purged with nitrogen for 15 min, followed by the addition of sodium tert-butoxide (281 mg, 2.92 mmol), BINAP (121 mg, 0.195 mmol), and Pd2(dba)3 (89 mg, 0.097 mmol). The reaction mixture was stirred at 100°C for 3 h. The reaction mixture was diluted with water and extracted with EtOAc (3 x 75 mL). The filtrate was concentrated under reduced pressure to obtain a crude compound, which was purified by silica gel rapid column chromatography using 5-10% ethyl acetate / petroleum ether elution to give the title compound (400 mg, 0.675 mmol, 69% yield) as a yellow liquid.

[0699] Step 38.3: Synthesis of 3-((4-methoxybenzyl)oxy)isoquinoline-7-amine. N-(3-((4-methoxybenzyl)oxy)isoquinoline-7-yl)-1,1-diphenylmethyleneimine (450 mg, 0.860 mmol)) was added to a stirred solution in MeOH (10.0 mL). Sodium acetate (212 mg, 2.58 mmol) and hydroxylamine hydrochloride (179 mg, 2.58 mmol) were then added sequentially at 25°C. The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was diluted with water and extracted with DCM (3 x 50 mL). The organic layer was evaporated to give the crude title compound (360 mg, 74% yield). This was used in the next step without further purification.

[0700] Step 38.4: Synthesis of N-(5-chloro-2-fluoropyrimidin-4-yl)-3-((4-methoxybenzyl)oxy)isoquinoline-7-amine. At -20 o C. Under a nitrogen atmosphere, DIPEA (0.183 mL, 1.049 mmol) was added dropwise to a stirred solution of 3-((4-methoxybenzyl)oxy)isoquinoline-7-amine (100 mg, 0.350 mmol) and 5-chloro-2,4-difluoropyrimidine (79 mg, 0.524 mmol) in EtOH (4 mL). The reaction mixture was then slowly warmed to 25°C. o C, and stirred for 16 hours. The reaction mixture was evaporated under reduced pressure to obtain the crude product. The crude product was purified by silica gel rapid column chromatography using 30-50% ethyl acetate / petroleum ether as eluent to give the title compound (60 mg, 41% yield) as a brown solid.

[0701] Step 38.5: Synthesis of 3-(6-(((3R,4R)-1-(5-chloro-4-((3-(((4-methoxybenzyl)oxy)isoquinoline-7-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione. 3-(1-methyl-6-(((3R,4R)-3-methylpiperidin-4-yl)amino)-1H-indazol-3-yl)piperidin-2,6-dione, TFA (67.9 mg, 0.143 mmol), and DIPEA (0.100 mL, 0.572 mmol) were added to a stirred solution of N-(5-chloro-2-fluoropyrimidin-4-yl)-3-((4-methoxybenzyl)oxy)isoquinoline-7-amine (60 mg, 0.143 mmol) in DMSO (1.0 mL) at 25°C. The reaction mixture was heated to 85°C and stirred for 3 hours. The reaction mixture was cooled to room temperature, diluted with water, and the resulting solid was filtered and dried to give the title compound (105 mg, 0.136 mmol, 95% yield) as a creamy white solid.

[0702] Step 38.6: Synthesis of 3-(6-(((3R,4R)-1-(5-chloro-4-((3-hydroxyisoquinoline-7-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione. A solution of 3-(6-(((3R,4R)-1-(5-chloro-4-((3-(((4-methoxybenzyl)oxy)isoquinoline-7-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione (50 mg, 0.066 mmol) was stirred at 70°C for 3 hours in a stirred TFA (1.0 mL). The reaction mixture was then concentrated to obtain a crude compound, which was purified by grinding with diethyl ether (2 x 15 mL). The ether layer was decanted and dried under reduced pressure to give the title compound (46 mg, 90% yield) as a pale yellow solid. LCMS: 626.2 (M+H) + , 1 H NMR (400 MHz, DMSO-d6): δ10.84 (s, 1H), 9.25 (s, 1H), 8.85 (s, 1H), 8.23 ​​(s, 1H), 8.15 (s, 1H), 7.88(dd, J = 2.00, 9.00 Hz, 1H), 7.73 (d, J = 9.20 Hz, 1H), 7.32 (d, J = 8.80 Hz,1H), 6.96 (s, 1H), 6.52 (d, J = 8.80 Hz, 1H), 6.46 (s, 1H), 4.45 (s, 2H), 4.18 (q, J = 5.20 Hz, 2H), 3.36 (q, J = 6.40 Hz, 2H), 3.10 (s, 1H), 2.71 (d,J = 22.00 Hz, 2H), 2.62 (d, J = 9.20 Hz, 2H), 2.34 (d, J = 1.60 Hz, 1H), 2.10-2.24 (m, 3H), 1.26-1.24 (m, 1H), 1.10-1.08 (m, 2H), 0.97 (d, J = 6.80Hz, 3H).

[0703] Example 39

[0704]

[0705] 3-(6-(((3R,4R)-1-(5-chloro-4-((3-hydroxy-4-methylisoquinoline-7-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-indazole-3-yl)piperidin-2,6-dione

[0706] Step 39.1: Synthesis of (S)-N-(3-bromobenzyl)-2-hydroxypropionamide. 3-Bromophenyl)methylamine (3.0 g, 16.12 mmol) and methyl (S)-2-hydroxypropionate (1.679 g, 16.12 mmol) were charged into a sealed tube at 25°C. The reaction mixture was stirred at 130°C for 2 hours. The residue was azeotropically dried with toluene to give the title compound (4.0 g, 7.04 mmol, 43.7% yield) as a colorless oil.

[0707] Step 39.2: Synthesis of N-(3-bromobenzyl)-2-oxopropionamide. A stirred solution of (S)-N-(3-bromobenzyl)-2-hydroxypropionamide (4.0 g, 7.04 mmol) in DCM (40 mL) was cooled to 0°C. At 0°C, Dys-Martin reagent (2.99 g, 7.04 mmol) was added to the reaction mixture, and the mixture was stirred for 1 hour. The reaction mixture was quenched with a saturated NaHCO3 solution (30 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude compound. The crude residue was purified by silica gel rapid column chromatography using 15–25% ethyl acetate / petroleum ether as an eluent to the title compound (1.0 g, 21% yield) as a colorless oil.

[0708] Step 39.3: Synthesis of 7-bromo-4-methylisoquinoline-3(2H)-one. A stirred solution of N-(3-bromobenzyl)-2-oxopropionamide (1.0 g, 1.469 mmol) in THF (10 mL) was cooled to 0°C. Sulfuric acid (0.078 mL, 1.47 mmol) was added to the reaction mixture at 0°C, and the mixture was slowly warmed to room temperature and then stirred for 3 hours. The reaction mixture was diluted with ice-cold water, and the pH was adjusted by dropwise addition of an aqueous solution of ammonium hydroxide. The resulting bright yellow precipitate was collected by filtration, washed with water, and then dried under vacuum to give the title compound (0.8 g crude) as a yellow solid.

[0709] Step 39.4: Synthesis of 7-bromo-3-((4-methoxybenzyl)oxy)-4-methylisoquinoline. Cs₂CO₃ (468 mg, 1.436 mmol) was added to a stirred solution of 7-bromo-4-methylisoquinoline-3(2H)-one (300 mg, 1.197 mmol) in DMF (8.0 mL) at 0°C under a nitrogen atmosphere, and the mixture was stirred for 10 min. 4-Methoxybenzyl chloride (0.196 mL, 1.44 mmol) was added to the reaction mixture, and the temperature was slowly lowered to 25°C. The reaction mixture was stirred for 4 h, treated with cold water (100 mL), and extracted with ethyl acetate (3 x 75 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude compound. The crude product was ground with diethyl ether to give the title compound (300 mg, 21% yield) as a yellow solid.

[0710] Step 39.5: Synthesis of N-(3-((4-methoxybenzyl)oxy)-4-methylisoquinoline-7-yl)-1,1-diphenylmethyleneimine. A stirred solution of 7-bromo-3-((4-methoxybenzyl)oxy)-4-methylisoquinoline (300 mg) and diphenylmethyleneimine (228 mg, 1.26 mmol) in toluene (10 mL) was added. The reaction mixture was purged with nitrogen for 15 min, followed by the addition of NaOtBu (241 mg, 2.51 mmol), BINAP (104 mg, 0.167 mmol), and Pd2(dba)3 (77 mg, 0.084 mmol). The reaction mixture was stirred at 100°C for 3 h. The reaction mixture was diluted with cold water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel rapid column chromatography using 5-10% ethyl acetate / petroleum ether elution to give the title compound (140 mg, 27%) as a pale yellow solid.

[0711] Step 39.6: Synthesis of 3-((4-methoxybenzyl)oxy)-4-methylisoquinoline-7-amine. N-(3-((4-methoxybenzyl)oxy)-4-methylisoquinoline-7-yl)-1,1-diphenylmethyleneimine (140 mg, 0.104 mmol)) was added to a stirred solution in MeOH (5.0 mL). Sodium acetate (57.9 mg, 0.705 mmol) and hydroxylamine hydrochloride (49 mg, 0.705 mmol) were then added sequentially at 25°C. The reaction mixture was slowly cooled to 25°C and stirred for 4 hours. The reaction mixture was diluted with water and extracted with DCM (3 x 50 mL). The organic layer was evaporated, and the crude compound was purified by silica gel rapid column chromatography using 50-60% ethyl acetate / petroleum ether as a elution to the title compound (50 mg, 61%) as a brown solid.

[0712] Step 39.7: Synthesis of N-(5-chloro-2-fluoropyrimidin-4-yl)-3-((4-methoxybenzyl)oxy)-4-methylisoquinoline-7-amine. At -20 o DIPEA (0.025 mL, 0.144 mmol) was added dropwise to a stirred solution of 3-((4-methoxybenzyl)oxy)-4-methylisoquinoline-7-amine (50 mg, 0.144 mmol) and 5-chloro-2,4-difluoropyrimidine (21.7 mg, 0.144 mmol) in EtOH (2.0 mL) under a nitrogen atmosphere. The reaction mixture was then slowly warmed to 25°C. o C, and stirred for 16 hours. The reaction mixture was evaporated under reduced pressure to obtain the crude product. The crude product was purified by silica gel rapid column chromatography using 40% ethyl acetate / PE as the eluent to give the title compound (45 mg, 72% yield) as a yellow solid.

[0713] Step 39.8: Synthesis of 3-(6-(((3R,4R)-1-(5-chloro-4-((3-(((4-methoxybenzyl)oxy)-4-methylisoquinoline-7-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amino)-1-methyl-1H-indazol-3-yl)piperidin-2,6-dione. In 23 oIn a nitrogen atmosphere, C added dropwise DIPEA (0.054 mL, 0.311 mmol) to a stirred solution of N-(5-chloro-2-fluoropyrimidin-4-yl)-3-((4-methoxybenzyl)oxy)-4-methylisoquinoline-7-amine (45 mg, 0.104 mmol) and 3-(1-methyl-6-(((3R,4R)-3-methylpiperidin-4-yl)amino)-1H-indazol-3-yl)piperidin-2,6-dione, TFA (12, 49.2 mg, 0.104 mmol) in DMSO (1.0 mL). The reaction mixture was then slowly heated to 85°C. o C, and stir for 3 hours. Dilute the reaction mixture with water, filter the resulting solid to give the title compound (55 mg, 67% yield) as a creamy white solid.

[0714] Step 39.9: Synthesis of 3-(6-(((3R,4R)-1-(5-chloro-4-((3-hydroxy-4-methylisoquinoline-7-yl)amino)pyrimidin-2-yl)-3-methylpiperidin-4-yl)amin...

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; Z 1 It is C(R) 3 ), and Z 2 Is it N or Z? 1 It is N, and Z 2 It is C(R) 3 ); R 3 It is either halogen or cyano; L 1 It is N(R) 11 (or does not exist;) 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 yes: , , , , , , , , , , , , , or ; Z 3 It is C(H)2, C(H)(CH2CH2C(O)NR 1b R 1c ), C(H)(OCH2C(O)NR 1b R 1c ), N(CH2CH2C(O)NR 1b R 1c ), and Z 4 It is C(H)2; or Z 3 It is C(H)2 or C(H)(CH2CH2C(O)NR 1b R 1c ), and Z 4 It is O; Z 5 It is C(H)2, C(F)2, or C(H)(F); R 1a It is hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 deuterated alkyl, C1-C6 haloalkyl or -CH2CH2C(O)NR 1b R 1c ; R 1b It is hydrogen or C1-C6 alkyl; R 1c It is a C1-C6 alkyl group; R 1d It is hydrogen or halogen; R 1e It is -N(R) 1a )C(O)(C1-C6 alkyl), -N(R) 1a )C(O)NR 1b R 1c -CH2C(O)NR 1b R 1c 5 to 6-membered heteroaryl or ; Z 6 It is C(H2), C(H)R 1a or N(R) 1a ); Z 7 Is it O or S? R 2 It is hydrogen or fluorine; 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; The condition is when R 4 yes At that time, R 1 no or .

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

3. The compound of claim 1, wherein ring A is piperidinyl, piperazineyl, 2,8-diazaspiro[4.5]decylene, phenylene, or... And ring A is (R) 10 ) x replace.

4. The compound of any one of claims 1-3, wherein R 10 It is fluorine, methyl, or methoxy; and x is 0 or 1.

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

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)- or -(CH2) z C(O)N(R 12 )-; and each R 12 It is independently hydrogen or C1-C6 alkyl.

8. The compound of any one of claims 1-7, wherein z is 1, 2 or 3.

9. The compound of any one of claims 1-6, wherein L 2 It is -N(H)-, -N(CH3)-, -CH2N(H)-, -O-, -N(H)C(O)- or -CH2C(O)N(H)-, or L 2 It does not exist.

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

11. The compound of any one of claims 1-10, wherein R 2 It is hydrogen; and R 3 It is either chlorine or cyanide.

12. The compound of any one of claims 1-11, wherein R 4 yes: , , , , , , , , or ; X 2 X 3 and X 4 It is C(H); R 13 It is hydrogen or methyl; R 14 It is fluorine; R 52 It is hydrogen or methyl; and p is 0 or 1.

13. A compound according to any one of claims 1-4 and 7-12, having formula (II): ， Or its pharmaceutically acceptable salt.

14. A compound according to any one of claims 1, 4, 5 and 10-12, having formula (III): ， Or its pharmaceutically acceptable salt.

15. The compound of claim 1 or 11, having formula (VI): ， Or its pharmaceutically acceptable salt, wherein: R 51 It is hydrogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 deuterated alkyl, or C1-C6 haloalkyl; R 52 It is hydrogen or C1-C6 alkyl; and R 53 It is hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, or C1-C6 haloalkyl.

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

17. The compound of claim 16, wherein the compound is selected from: 、 、 、 、 、 , or ， Or its pharmaceutically acceptable salt.

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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