Indazole-Based Compounds and Related Methods of Use

Abstract

This text describes bifunctional compounds that can be used as regulators of leucine-rich repeat kinase 2 (LRRK2). In particular, the heterobifunctional compounds of the present disclosure contain a moiety that binds to the cereblon E3 ubiquitin ligase at one end and a moiety that binds to LRRK2 at the other end, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of the target protein. The heterobifunctional compounds of the present disclosure exhibit a broad range of pharmacological activities related to the degradation / inhibition of the target protein. Treat or prevent diseases or disorders caused by abnormal regulation of the target protein with the compounds and compositions of the present disclosure.

Description

[0001] Cross - Reference to Related Applications

[0002] This disclosure claims the benefit and priority of U.S. Provisional Application No. 62 / 992,952, filed on March 21, 2020, titled "INDAZOLE BASED COMPOUNDS AND ASSOCIATED METHODS OF USE", which is incorporated herein by reference in its entirety for all purposes.

[0003] Incorporation by Reference

[0004] All cited references are hereby incorporated by reference in their entirety, including U.S. Patent Application Serial No. 14 / 686,640, filed on April 14, 2015, and published as U.S. Patent Application Publication No. 2015 / 0291562; and U.S. Patent Application Serial No. 14 / 792,414, filed on July 6, 2015, and published as U.S. Patent Application Publication No. 2016 / 0058872; and U.S. Patent Application Serial No. 15 / 953,108, filed on April 13, 2018, and published as U.S. Patent Application Publication No. 2018 / 0228907; and U.S. Patent Application Publication No. 2016 / 0009689A1, filed on September 2, 2015; and U.S. Patent Application Publication No. 2016 / 0200722A1, filed on February 18, 2016. Field of the Invention

[0005] The present invention provides heterobifunctional compounds comprising a target protein - binding moiety and an E3 ubiquitin ligase - binding moiety and related methods of use. The bifunctional compounds can be used as regulators of the targeted ubiquitination of leucine - rich repeat kinase 2 (LRRK2), which is then degraded and / or inhibited. Background Art

[0006] Most small - molecule drugs bind enzymes or receptors in tight and well - defined pockets. On the other hand, protein - protein interactions are notoriously difficult to target with small molecules due to their large contact surfaces, shallow grooves, or flat interfaces. E3 ubiquitin ligases (hundreds of which are known in humans) confer substrate - specific ubiquitination, and thus, due to their specificity for certain protein substrates, they are more attractive therapeutic targets than general proteasome inhibitors. The development of E3 ligase ligands has proven challenging, in part because they must disrupt protein - protein interactions. However, recent developments have provided specific ligands that bind to these ligases. For example, since the discovery of the first small - molecule E3 ligase inhibitor nutlin, additional compounds that target E3 ligases have been reported.

[0007] Cereblon is a protein encoded by the CRBN gene in humans. CRBN orthologs are highly conserved from plants to humans, underscoring its physiological importance. Cereblon forms an E3 ubiquitin ligase complex with regulators of damaged DNA binding protein 1 (DDB1), Cullin-4A (CUL4A), and Cullin 1 (ROC1). This complex ubiquitinates many other proteins. Through mechanisms that are not fully elucidated, the ubiquitination of target proteins by cereblon leads to elevated levels of fibroblast growth factor 8 (FGF8) and fibroblast growth factor 10 (FGF10). FGF8 in turn regulates many developmental processes, such as limb and otic vesicle formation. The end result is that this ubiquitin ligase complex is important for limb growth within the embryo. In the absence of cereblon, DDB1 forms a complex with DDB2, which functions as a DNA damage binding protein.

[0008] Bifunctional compounds, such as those described in U.S. Patent Application Publications 2015 / 0291562 and 2014 / 0356322 (incorporated herein by reference), serve to recruit endogenous proteins to an E3 ubiquitin ligase for ubiquitination and subsequent degradation in the proteasomal degradation pathway. In particular, the publications cited above describe bifunctional or proteolysis targeting chimeric protein degrader compounds that can be used as regulators of the targeted ubiquitination of a variety of polypeptides and proteins, which are then degraded and / or inhibited by the bifunctional compounds.

[0009] Leucine-rich repeat kinase 2 (LRRK2) is a member of the leucine-rich repeat kinase family and is a large multidomain protein with an N-terminal armadillo domain, ankyrin repeats, leucine-rich repeat (LRR) domains, tandem Roc-type GTPase domains, a kinase domain containing a DFG-like motif, and a C-terminal WD40 domain. The LRRK2 protein has 2527 amino acids and a molecular weight of 280 kDa. The catalytic activity of LRRK2 is associated with the kinase and GTPase domains, and the active form of LRRK2 is a heterodimer (Greggio E et al.: The Parkinson disease-associated leucine-rich repeat kinase 2 (LRRK2) is a dimer that undergoes intramolecular autophosphorylation. J Biol Chem 2008, 283:16906-16914). GTP binding is essential for kinase activity, and mutations that prevent GTP binding have been shown to abolish LRRK2 kinase activity (Ito G et al.: GTP binding is essential to the protein kinase activity of LRRK2, a causative gene product for familial Parkinson’s disease. Biochemistry 2007, 46:1380-1388). The only validated physiological substrates (other than LRRK2 itself) are a subset of low molecular weight G proteins, including Rab8a and Rab10, which are involved in regulating vesicle trafficking and endosomal function as well as trafficking on the cytoskeletal network (Steger M et al.: Phosphoproteomics reveals that Parkinson’s disease kinase LRRK2 regulates a subset of Rab GTPases. Elife 2016, 5.e12813). LRRK2 is most highly expressed in immune cells (neutrophils, monocytes, and B cells), lung, and kidney, and is expressed at lower levels in the brain (where it is expressed in dopaminergic neurons of the substantia nigra) (West AB et al.: Differential LRRK2 expression in the cortex, striatum, and substantia nigra in transgenic and nontransgenic rodents. J Comp Neurol 2014, 522:2465-2480).

[0010] There are several major gain-of-function pathogenic and characteristic mutations in LRRK2, which are located in the Roco domain (N1437H, R1441G / C / H, Y1699C) to enable GTP hydrolysis, or in the kinase domain (G2019S and I2020T). G2019S is the most common LRRK2 mutation associated with Parkinson's disease (PD), a progressive neurodegenerative disorder characterized by resting tremor, rigidity, bradykinesia (decreased movement), and postural instability. The histological features of PD include neurodegeneration of dopaminergic neurons in the substantia nigra pars compacta and intracellular inclusions called Lewy bodies and neurites composed of aggregated forms of α-synuclein. G2019S is associated with 1%-2% of all PD patients and results in a two-fold increase in kinase activity in vitro (West AB et al: Parkinson’s diseaseassociated mutations inleucine-rich repeat kinase 2augment kinase activity.Proc Natl Acad Sci U S A2005,102:16842-16847), and a four-fold increase in autophosphorylation at Ser1292 (Sheng Z et al: Ser1292autophosphorylation is an indicator of LRRK2 kinase activity and contributesto the cellular effects of PD mutations.Sci Transl Med 2012,4:164ra161). The G2019S and I2020T mutations are located within the DFG motif (DYGI in the case of LRRK2), which is common to all kinases and controls catalytic activity. These mutations are thought to disrupt the inactive conformation and thus increase catalytic activity (Schmidt SH et al: Thedynamic switch mechanism that leads to activation of LRRK2 is embedded in theDFGpsi motif in the kinase domain.Proc Natl Acad Sci USA 2019,116:14979-14988).Several of the above-mentioned Parkinson's disease-related mutations (R1441C / G, Y1699C, and I2020T) inhibit the phosphorylation of LRRK2 at Ser910 and Ser935, subsequently reducing the association of LRRK2 with 14-3-3 proteins, which is thought to represent the inactive form of LRRK2 (Nichols J et al: 14-3-3 binding to LRRK2 is disrupted by multiple Parkinson’s disease associated mutations and regulates cytoplasmic localisation. Biochem J 2010, 430:393-404).

[0011] In addition, LRRK2 is associated with autosomal-dominant PD through mutations in a region of chromosome 12 called PARK8, which are related to the LRRK2 gene (Funayama M et al: A new locus for Parkinson’s disease (PARK8) maps to chromosome 12p11.2-q13.1. Ann Neurol 2002, 51:296-301; Zimprich A et al: Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 2004, 44:601-607; Paisan-Ruiz C et al: Cloning of the gene containing mutations that cause PARK8-linked Parkinson’s disease. Neuron 2004, 44:595-600). LRRK2 was first described as being related to autosomal-dominant Parkinson's disease in 1978, tracing back to a family in Japan (Nukada H et al: [A big family of paralysis agitans (author’s transl)]. Rinsho Shinkeigaku 1978, 18:627-634). The most common pathogenic LRRK2 mutation (G2019S) occurs in 4%-8% of familial PD cases and 1%-3% of sporadic PD cases. In addition, the G2019S mutation is common in PD patients of selected ancestries, with 30-40% of North African Berber patients and 14% of Jewish patients carrying this mutation.

[0012] LRRK2 kinase inhibitors have been proposed to have potential for treating mutation-driven PD (where LRRK2 activity is increased), such as G2019S, and idiopathic PD (where LRRK2 activity is increased) (Chen J et al.: Leucine-rich repeat kinase 2 in Parkinson’s disease: updated from pathogenesis to potential therapeutic target. Eur Neurol 2018, 79:256-265; Alessi DR et al.: LRRK2 kinase in Parkinson’s disease. Science 2018, 360:36-37; Di Maio R et al.: LRRK2 activation in idiopathic Parkinson’s disease. Sci Transl Med 2018, 10). Several therapeutic agents are entering clinical trials, including LRRK2 kinase inhibitors that will directly affect the phosphorylation of downstream targets, and oligonucleotides (ASOs) that are directly infused into the CNS to block the translation of the LRRK2 protein and thus reduce LRRK2 protein levels.

[0013] Lewy bodies are the major histological hallmark of PD. Lewy bodies are mainly composed of aggregates of α-synuclein, and mutations in α-synuclein that increase this aggregation also increase the risk of developing PD (Meade RM et al.: Alpha-synuclein structure and Parkinson’s disease lessons and emerging principles. Mol Neurodegener 2019, 14:29-29). Depletion of LRRK2 with ASO (Zhao HT et al.: LRRK2 antisense oligonucleotides ameliorate a-synuclein inclusion formation in a Parkinson’s disease mouse model. Molecular therapy. Nucleic acids 2017, 8:508-519) and genomic deletion of LRRK2 have been shown to reduce α-synuclein-mediated pathologies in a PD mouse model (Lin X et al.: Leucine-rich repeat kinase 2 regulates the progression of neuropathology induced by Parkinson’s-disease-related mutant alpha-synuclein. Neuron 2009, 64:807-827). Mutations that increase LRRK2 activity, such as G2019S, increase the aggregation of α-synuclein in neurons and in a PD mouse model. This increase is reversed by LRRK2 kinase inhibitors (Volpicelli-Daley LA et al. G2019S-LRRK2 Expression Augments α-Synuclein Sequestration into Inclusions in Neurons. J Neurosci. July 13, 2016; 36(28):7415-27. doi:10.1523 / JNEUROSCI.3642-15.2016). There is some evidence that the G2019S mutant form of LRRK2 is resistant to inhibition by kinase inhibitors in the CNS, which may reduce its disease-modifying effects (Kelly K et al. The G2019S mutation in LRRK2 imparts resiliency to kinase inhibition. Exp Neurol. 2018 Nov; 309:1-13).Although Lewy bodies are also present in the majority of PD cases at autopsy, they are absent in a large number of PD cases associated with the LRRK2 G2019S mutation (Kalia LV et al.: Clinical correlations with Lewy body pathology in LRRK2-related Parkinson disease. JAMA neurol 2015, 72: 100-105). In addition to Lewy bodies being a common feature of PD, Tau pathology is also a major feature at autopsy in LRRK2 mutation carriers (Henderson MX et al.: Alzheimer’s disease tau is a prominent pathology in LRRK2 Parkinson’s disease. Acta Neuropathol Commun 2019, 7. 183-183). In one study, Tau pathology was observed in 100% of LRRK2 mutation carriers, thus highlighting LRRK2 as an important target linking PD to Tau pathology in the context of PD, although the genetic causality is not as strong as that between LRRK2 and primary tauopathies such as progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) (Ross OA et al. (2006) Lrrk2 R1441 substitution and progressive supranuclear palsy. Neuropathol Appl Neurobiol 32(1): 23-25; Sanchez-Contreras M et al. (2017) Study of LRRK2 variation in tauopathy: progressive supranuclear palsy and corticobasal degeneration. Mov Disord 32(1): 115-123). Common variation at the LRRK2 locus has recently been reported as a genetic determinant of survival in PSP (Jabbari E et al., Common variation at the LRRK2 locus is associated with survival in the primary tauopathy progressive supranuclear palsy. bioRxiv 2020.02.04.932335; doi: https: / / doi.org / 10.1101 / 2020.02.04.932335).It has been reported that the increased expression of LRRK2 in PSP obtained through expression quantitative trait locus (eQTL) analysis may lead to a pro-inflammatory state induced by reactive microglia, which drives the persistent accumulation of misfolded Tau protein and clinical disease progression. Functional variants of LRRK2 are also associated with Crohn's Disease and leprosy type-1 inflammatory responses (Hui KY et al. Functional variants in the LRRK2 gene confer shared effects on risk for Crohn's disease and Parkinson's disease. Sci Transl Med. January 10, 2018; 10(423). pii: eaai7795. doi: 10.1126 / scitranslmed.aai7795; Fava et al. Pleiotropic effects for Parkin and LRRK2 in leprosy type-1 reactions and Parkinson's disease. Proc Natl Acad Sci U S A. July 30, 2019; 116(31):15616-15624. doi: 10.1073 / pnas.1901805116. Epub July 15, 2019).

[0014] LRRK2 is highly expressed in the immune system in neutrophils, monocytes, macrophages, and brain microglia and is a regulator of the intrinsic regulation of microglial activation and lysosomal degradation processes (Ma et al. Genetic comorbidities in Parkinson's disease. Hum Mol Genet. February 1, 2014; 23(3):831-41. doi:10.1093 / hmg / ddt465. Epub September 20, 2013, which is reviewed in Schapansky et al. The complex relationships between microglia, alpha-synuclein, and LRRK2 in Parkinson's disease. Neuroscience. August 27, 2015; 302:74-88. doi:10.1016 / j.neuroscience.2014.09.049. Epub October 2, 2014). Prolonging the activation of these immune cells through the PD disease process or mutations in LRRK2 may increase neuroinflammation and lead to a greater risk of developing PD and / or Tauopathies. Treatment with anti-TNF agents reduced the risk of developing PD in patients with inflammatory bowel disease by 78% (Peter I et al.: Anti-tumor necrosis factor therapy and incidence of Parkinson disease among patients with inflammatory bowel disease. JAMA Neurol 2018), thus demonstrating the close link between inflammation and PD. In addition to PD, LRRK2 is associated with other diseases such as cancer, leprosy, and Crohn's disease (Lewis PA, Manzoni C. LRRK2 and human disease: a complicated question or a question of complexes? (2012). Sci Signal. 5(207), pe2).

[0015] There is a continuing need in the art for effective treatments for LRRK2-related diseases and disorders such as idiopathic PD, LRRK2 mutation-related PD (e.g., PD associated with one or more LRRK2 activating mutations), primary tauopathies (e.g., progressive supranuclear palsy (PSP) or corticobasal degeneration (CBD)), Lewy body dementia, Crohn's disease, leprosy (e.g., leprosy with a type 1 inflammatory response), and / or neuroinflammation. SUMMARY OF THE INVENTION

[0016] The present disclosure describes heterobifunctional compounds for recruiting leucine-rich repeat kinase 2 (LRRK2) to an E3 ubiquitin ligase for targeted ubiquitination and subsequent proteasomal degradation, and methods of making and using the heterobifunctional compounds. In addition, this specification provides methods of treating or ameliorating a disease condition, such as an LRRK2-related disease or disorder, e.g., an accumulation or overactivity of LRRK2 protein or a mutant LRRK2 protein or a misfolded LRRK2 protein, or an α-synuclein aggregation or accumulation, or a Tau aggregation or accumulation, or idiopathic PD, or LRRK2 mutation-related PD (e.g., PD associated with one or more LRRK2 activating mutations), or primary tauopathies (e.g., progressive supranuclear palsy (PSP) or corticobasal degeneration (CBD)), or Lewy body dementia, or Crohn's disease, or leprosy (e.g., leprosy with a type 1 inflammatory response), or neuroinflammation, using an effective amount of a compound of the present disclosure.

[0017] Thus, in one aspect, the present disclosure provides a heterobifunctional compound comprising an E3 ubiquitin ligase binding moiety (i.e., a ligand of an E3 ubiquitin ligase (“ULM” group)) and a moiety that binds to LRRK2 or a mutant form thereof (i.e., a protein targeting moiety or “PTM” group, i.e., a ligand that targets LRRK2 or “LTM” group), such that the LRRK2 protein is thereby positioned near the ubiquitin ligase to effect ubiquitination and subsequent degradation (and / or inhibition) of the LRRK2 protein. In a preferred embodiment, the ULM (ubiquitination ligase binding moiety) is a cereblon E3 ubiquitin ligase binding moiety (CLM). For example, the structure of the bifunctional compound can be described as:

[0018]

[0019] The respective positions of the PTM and ULM moieties (e.g., CLM), and their numbers as shown herein, are provided only by way of example and are not intended to limit the compounds in any way. As will be understood by those skilled in the art, bifunctional compounds as described herein can be synthesized such that the number and position of the respective functional moieties can be varied as needed.

[0020] In certain embodiments, the bifunctional compound further comprises a chemical linker (“L”). In this instance, the structure of the bifunctional compound can be described as:

[0021]

[0022] Wherein PTM is the LRRK2 targeting moiety (LTM), L is a linker, such as a bond or chemical linking group that couples the PTM to the ULM, and ULM is the cereblon E3 ubiquitin ligase binding moiety (CLM).

[0023] For example, the structure of a bifunctional compound can be described as:

[0024]

[0025] Wherein: PTM is the LRRK2 targeting moiety (LTM); "L" is a linker (such as a bond or chemical linking group) that couples the PTM to the CLM; and CLM is the cereblon E3 ubiquitin ligase binding moiety that binds to cereblon.

[0026] In certain embodiments, the compounds described herein comprise multiple independently selected ULMs, multiple PTMs, multiple chemical linkers, or combinations thereof.

[0027] In any aspect or embodiment described herein, the PTM is a small molecule that binds LRRK2 or a mutant thereof. In any aspect or embodiment described herein, the PTM is a small molecule that binds LRRK2. In any aspect or embodiment described herein, the PTM is a small molecule that binds wild-type LRRK2 protein and LRRK2 mutants (such as LRRK2 mutants comprising one or more mutations selected from G2019S, I2020T, N1437H, R1441G / C / H, and Y1699C). In any aspect or embodiment described herein, the PTM is a small molecule that binds wild-type LRRK2 protein and LRRK2 mutants (such as, but not limited to, G2019S, I2020T, N1437H, R1441G / C / H, Y1699C, or combinations thereof). In any aspect or embodiment described herein, the small molecule binds LRRK2 as described herein.

[0028] In one embodiment, the CLM comprises a chemical group derived from an imide, thioimide, amide, or thioamide. In certain embodiments, the chemical group is phthalimido, or an analogue or derivative thereof. In one embodiment, the CLM is selected from thalidomide, lenalidomide, pomalidomide, analogues thereof, isosteres thereof, and derivatives thereof. Other contemplated CLMs are described in U.S. Patent Application Publication No. 2015 / 0291562, which is incorporated herein by reference in its entirety.

[0029] In certain embodiments, "L" is a bond. In additional embodiments, linker "L" is a linker having a number of straight-chain non-hydrogen atoms in the range of 1 to 20. Linker "L" can include, but is not limited to, one or more functional groups such as ethers, amides, alkanes, alkenes, alkynes, ketones, hydroxyl groups, formic acid, thioethers, sulfoxides, and sulfones. The linker can include aromatic, heteroaromatic, cyclic, bicyclic, or tricyclic moieties. Halogen (such as Cl, F, Br, and I) substitution can be included in the linker. In the case of fluorine substitution, single or multiple fluorines can be included.

[0030] In certain embodiments, CLM is a derivative of piperidine-2,6-dione, wherein the piperidine-2,6-dione can be substituted at the 3-position, and the 3-substitution can be a bicyclic heteroarene, which is linked as a C-N bond or a C-C bond. Examples of CLM can be, but are not limited to, pomalidomide, lenalidomide, thalidomide, and their analogs.

[0031] In another aspect, the present specification provides a therapeutic composition comprising an effective amount of a compound as described herein or a salt form thereof, and a pharmaceutically acceptable carrier. The therapeutic composition can be used to trigger targeted degradation and / or inhibition of LRRK2 or a mutant form thereof in a patient or subject (e.g., an animal such as a human), and can be used to treat or ameliorate one or more disease states, disorders, or symptoms in the patient or subject that are causally related to LRRK2 or a mutant form thereof, and this treatment is accomplished by degrading or inhibiting the LRRK2 protein or a mutant form thereof, or controlling or reducing the protein level of the LRRK2 protein or a mutant form thereof. In certain embodiments, the therapeutic composition described herein can be used to effect degradation of LRRK2 or a mutant form thereof to treat or ameliorate diseases such as, for example, LRRK2 accumulation or hyperreactivity, α-synuclein aggregation or accumulation, Tau aggregation or accumulation, idiopathic PD, LRRK2 mutation-related PD (e.g., PD associated with one or more LRRK2 activating mutations), primary tauopathies (e.g., progressive supranuclear palsy (PSP) or corticobasal degeneration (CBD)), Lewy body dementia, Crohn's disease, leprosy (e.g., leprosy with a type 1 inflammatory response), and / or neuroinflammation.

[0032] In yet another aspect, the present disclosure provides a method of ubiquitinating LRRK2 or a mutant form thereof in a cell. In certain embodiments, the method comprises administering a heterobifunctional compound as described herein, the compound comprising a PTM that binds to LRRK2 or a mutant form thereof, and a CLM, which are preferably linked by a chemical linker moiety as described herein, to effect degradation of the LRRK2 protein or a mutant form thereof. Without wishing to be bound by theory, the inventors believe that, according to the present invention, when the wild-type or mutant LRRK2 protein is placed in proximity to an E3 ubiquitin ligase by using a heterobifunctional compound, polyubiquitination of the wild-type or mutant LRRK2 protein will occur, thereby triggering subsequent degradation of the LRRK2 or mutant protein via the proteasome pathway and controlling or reducing the level of the LRRK2 protein in a cell (such as a cell of a subject in need of such treatment). Control or reduction of the level of the LRRK2 protein or a mutant form thereof provided by the present disclosure provides treatment of an LRRK2 causally related disease state, disorder, or related symptoms, such as by modulating the amount of the LRRK2 protein or a mutant form thereof in the cells of a subject.

[0033] In yet another aspect, the present specification provides a method for treating or ameliorating a disease, disorder, or a symptom thereof causally related to LRRK2 or a mutant form thereof in a subject or patient (e.g., an animal such as a human), the method comprising administering to a subject in need thereof a composition comprising an effective amount (e.g., a therapeutically effective amount) of a heterobifunctional compound as described herein or a salt form thereof and a pharmaceutically acceptable carrier, wherein the composition effectively treats or ameliorates the disease or condition or a symptom thereof in the subject.

[0034] In another aspect, the present specification provides a method for identifying the effect of degrading the LRRK2 protein in a biological system using a compound according to the present disclosure.

[0035] In another aspect, the present specification provides methods and intermediates for preparing the heterobifunctional compounds of the present disclosure that are capable of targeting ubiquitination and degradation of the LRRK2 protein in a cell (e.g., in vivo or in vitro). BRIEF DESCRIPTION OF THE DRAWINGS

[0036] The drawings, which are incorporated in and constitute a part of this specification, illustrate several embodiments of the present disclosure and, together with the description, serve to explain the principles of the present disclosure. The drawings are only for the purpose of illustrating the embodiments of the present disclosure and should not be construed as limiting the present disclosure. Additional objects, features, and advantages of the present disclosure will become apparent from the following detailed description in conjunction with the drawings that illustrate illustrative embodiments of the present disclosure.

[0037] Figure 1A and Figure 1B . Illustration of the general principle of a heterobifunctional protein degradation compound. Figure 1A. Exemplary xenobiotic function protein degradation compounds comprise a protein targeting moiety (PTM; dark shaded rectangle), a ubiquitin ligase binding moiety (ULM; light shaded triangle), and optionally a linker moiety (L; black line) that couples the PTM to the ULM. Figure 1B Illustrates the functional use of the heterobifunctional protein degradation compounds (commercially known as protein degrader compounds) described herein. Briefly, the ULM (triangle) recognizes and binds to a specific E3 ubiquitin ligase, while the PTM (large rectangle) binds and recruits the target protein, bringing it in close proximity to the E3 ubiquitin ligase. Typically, the E3 ubiquitin ligase is complexed with an E2 ubiquitin-conjugating protein (E2) and, either alone or through the E2 protein, catalyzes the attachment of multiple ubiquitin molecules (black circles) to lysines on the target protein via isopeptide bonds. The polyubiquitinated protein (far right) is thus targeted for degradation by the cell's proteasome machinery. Detailed Description

[0038] Described herein are compounds, compositions, and methods related to the surprising discovery that once an E3 ubiquitin ligase and the LRRK2 protein are placed in close proximity by a bifunctional compound that binds the E3 ubiquitin ligase and the LRRK2 protein, the E3 ubiquitin ligase (e.g., the cereblon E3 ubiquitin ligase) ubiquitinates the LRRK2 protein or a mutant form thereof. Accordingly, the present disclosure provides compounds and compositions comprising an E3 ubiquitin ligase binding moiety ("ULM") coupled to a protein targeting moiety ("PTM") that targets the LRRK2 protein via a bond or chemical linking group (L), which results in ubiquitination of the LRRK2 protein and degradation of the LRRK2 protein by the proteasome (see Figure 1).

[0039] In one aspect, the present specification provides compounds in which the PTM binds to the LRRK2 protein and / or a mutant form thereof. The present disclosure also provides libraries of compositions and their use in effecting targeted degradation of the LRRK2 protein in cells.

[0040] In some aspects, the present disclosure provides heterobifunctional compounds comprising a ligand, such as a small molecule ligand (i.e., having a molecular weight of less than 2,000, 1,000, 500, or 200 daltons), that is capable of binding to an E3 ubiquitin ligase, such as cereblon. The compounds also comprise a small molecule moiety capable of binding to the LRRK2 protein or a mutant form thereof in such a manner that the LRRK2 protein or a mutant form thereof is positioned near the ubiquitin ligase to effect ubiquitination and degradation (and / or inhibition) of the LRRK2 protein or a mutant form thereof. "Small molecule" means, in addition to the above, that the molecule is non-peptidyl, i.e., it is not considered a peptide, e.g., it contains fewer than 4, 3, or 2 amino acid residues. According to the present specification, each of the PTM, ULM, and heterobifunctional molecule is a small molecule.

[0041] As used throughout the specification, the term "LRRK2" is intended to include both wild-type LRRK2 and mutant forms thereof, such as LRRK2 mutant proteins comprising one or more mutations selected from G2019S, I2020T, N1437H, R1441G / C / H, and Y1699C, unless specifically indicated to the contrary.

[0042] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The terms used in this specification are for the purpose of describing particular embodiments only and are not intended to limit the disclosure.

[0043] When providing a numerical range, it is to be understood that each intermediate value between the upper and lower limits of the range (each intermediate value reaching one-tenth of the lower limit unit, such as in the case of a group containing multiple carbon atoms, providing the number of carbon atoms per such atom falling within the range) and any other stated or intermediate value in the stated range is covered by the present disclosure. The upper and lower limits of these smaller ranges may independently be included in these smaller ranges and are also covered by the present disclosure, subject to any specific excluded limit values within the range. Where the range includes one or both of the limit values, ranges excluding one or both of the included limit values are also included in the present disclosure.

[0044] The following terms are used to describe the present disclosure. Where a term is not specifically defined herein, the ordinary skilled artisan who applies the term in the context of describing the present invention provides the meaning recognized in the art for the term.

[0045] Unless the context clearly indicates otherwise, as used in this specification and the appended claims, the articles "a" and "an" are used herein to refer to one or more than one (i.e., at least one) grammatical object of the article. For example, unless otherwise indicated, "an element" means one element or more than one element.

[0046] In the claims and the above specification, all transitional phrases, such as "comprising", "including", "carrying", "having", "containing", "involving", "holding", "composed of", etc., shall be understood to be open-ended, i.e., meaning including but not limited to. As described in Section 2111.03 of the Manual of Patent Examining Procedure of the United States Patent and Trademark Office, only the transitional phrases "consisting of" and "consisting essentially of" shall be closed or semi-closed transitional phrases, respectively.

[0047] It should also be understood that, unless the context indicates otherwise, in certain methods or processes described herein that include more than one step or action, the order of the steps or actions of the method is not necessarily limited to the order in which the steps or actions of the method are recited.

[0048] The terms "co-administration" and "co-administering" or "combination therapy" refer to simultaneous administration (administering two or more therapeutic agents simultaneously) and time-variable administration (administering one or more therapeutic agents at a time different from the administration of one or more additional therapeutic agents), provided that two or more therapeutic agents are present in the patient's body to some extent (preferably in an effective amount) simultaneously. In certain preferred aspects, one or more of the heterobifunctional compounds described herein are co-administered with at least one additional bioactive agent, such as an anti-cancer agent. In particularly preferred aspects, co-administration of such compounds results in synergistic activity and / or therapy, such as, for example, anti-cancer activity.

[0049] Unless otherwise indicated, as used herein, the term "compound" refers to any specific heterobifunctional compound disclosed herein, its pharmaceutically acceptable salts and solvates, and, where applicable, deuterated forms of any of the foregoing molecules. Envisioned deuterated compounds are those in which one or more of the hydrogen atoms contained in the pharmaceutical molecule have been replaced with deuterium. Such deuterated compounds preferably have one or more improved pharmacokinetic or pharmacodynamic properties (e.g., longer half-life) compared to the equivalent "non-deuterated" compound.

[0050] The term "ubiquitin ligase" refers to a family of proteins that facilitate the transfer of one or more ubiquitins to a specific substrate protein. The goal of adding chains of several ubiquitins (polyubiquitination) is to target the substrate protein for degradation. For example, cereblon is an E3 ubiquitin ligase that, either alone or in combination with an E2 ubiquitin-conjugating enzyme, can ultimately result in the attachment of a chain of four ubiquitins to a lysine residue on the target protein, thereby targeting the protein for degradation by the proteasome. Ubiquitin ligases are involved in polyubiquitination such that the first ubiquitin is attached to a lysine on the target protein; the second ubiquitin is attached to the first ubiquitin; the third ubiquitin is attached to the second ubiquitin, and the fourth ubiquitin is attached to the third ubiquitin. Such polyubiquitination marks the protein for degradation by the proteasome.

[0051] The terms "patient" or "subject" are used throughout the specification to describe an animal, preferably a human or domestic animal, to which treatment (including prophylactic treatment) with a composition according to the present disclosure is provided. For treating a disease, disorder, or condition specific to a particular animal, such as a human patient, the term "patient" refers to that particular animal, including domestic animals (such as dogs or cats) or farm animals (such as horses, cows, sheep, etc.). Generally, in the present disclosure, the terms "patient" and "subject" refer to a human patient, unless otherwise stated or implied by the context in which the term is used.

[0052] The terms "effective" and "therapeutically effective" are used to describe an amount of a compound or composition that, when used in the context of its intended use, either as a single dose or more preferably as multiple doses in the context of a treatment regimen, produces an intended result, such as an improvement in a disease or disorder, or an improvement or reduction in one or more symptoms associated with the disease or disorder. The terms "effective" and "therapeutically effective" encompass all other "effective amount" or "effective concentration" terms described or used otherwise in this application.

[0053] Compounds and Compositions

[0054] In one aspect, the present specification provides heterobifunctional compounds that include an E3 ubiquitin ligase binding moiety (“ULM”), namely a cereblon E3 ubiquitin ligase binding moiety (“CLM”). The CLM is covalently coupled to a protein targeting moiety (PTM) that binds to a protein, with said coupling being directly through a bond or through a chemical linker group (L) according to the following structure:

[0055] (A) PTM-L-CLM

[0056] wherein L is a bond or a chemical linker group, and PTM is a protein targeting moiety that binds to the protein LRRK2 or a mutant form thereof (such as G2019S), and wherein PTM is an LRRK2 targeting moiety (LTM). The term CLM includes all cereblon binding moieties.

[0057] In any aspect or embodiment, the CLM exhibits a half-maximal inhibitory concentration (IC 50 ) of less than about 200 μM for an E3 ubiquitin ligase (such as, the cereblon E3 ubiquitin ligase). The IC 50 can be determined according to any suitable method known in the art (such as, fluorescence polarization assay).

[0058] In certain embodiments, the heterobifunctional compounds described herein exhibit an IC 50 or a half-maximal degradation concentration (DC 50 ) of less than about 100, 50, 10, 1, 0.5, 0.1, 0.05, 0.01, 0.005, 0.001 mM, or less than about 100, 50, 10, 1, 0.5, 0.1, 0.05, 0.01, 0.005, 0.001 μM, or less than about 100, 50, 10, 1, 0.5, 0.1, 0.05, 0.01, 0.005, 0.001 nM, or less than about 100, 50, 10, 1, 0.5, 0.1, 0.05, 0.01, 0.005, 0.001 pM.

[0059] The term “alkyl” as used herein shall refer to a straight-chain, branched-chain, or cyclic fully saturated hydrocarbon group, preferably C 1 -C 10 alkyl, preferably C 1 -C 6 alkyl, or more preferably C 1 -C 3An alkyl group, which may optionally be substituted by any suitable one or more functional groups. Examples of alkyl groups are methyl, ethyl, n-butyl, sec-butyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, isopropyl, 2-methylpropyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclopentylethyl, cyclohexylethyl, and cyclohexyl, etc. In certain embodiments, the alkyl group is terminated with a halogen group (At, Br, Cl, F or I).

[0060] The term "alkenyl" refers to a straight-chain, branched-chain or cyclic C containing at least one C═C bond 2 -C 10 (preferably C 2 -C 6 ) hydrocarbon group.

[0061] The term "alkynyl" refers to a straight-chain, branched-chain or cyclic C containing at least one C≡C 2 -C 10 (preferably C 2 -C 6 ) hydrocarbon group.

[0062] The term "alkylene" when used refers to a -(CH 2 ) n - group (n is usually an integer from 0 to 6), which may optionally be substituted. When substituted, the alkylene group is preferably substituted by a C 1 -C 6 alkyl group (including cyclopropyl or tert-butyl) on one or more methylene groups, but may also be substituted by one or more halogen groups, preferably 1 to 3 halogen groups or one or two hydroxyl groups, O-(C 1 -C 6 ) alkyl group or an amino acid side chain as further disclosed herein. In certain embodiments, the alkylene group may be substituted by a carbamate or an alkoxy group (or other suitable functional group), and the carbamate or alkoxy group (or other suitable functional group) may be further substituted by a polyethylene glycol chain (1 to 10, preferably 1 to 6, or more preferably 1 to 4 ethylene glycol units), and the polyethylene glycol chain (preferably but not limited to the distal end of the polyethylene glycol chain) is substituted by an alkyl chain, and the alkyl chain is substituted by a single halogen group (preferably a chlorine group). In other embodiments, the alkylene group (such as a methylene group) may be substituted by an amino acid side chain group, such as a natural or unnatural amino acid side chain group, such as alanine, β-alanine, arginine, asparagine, aspartic acid, cysteine, cystine, glutamic acid, glutamine, glycine, phenylalanine, histidine, isoleucine, lysine, leucine, methionine, proline, serine, threonine, valine, tryptophan or tyrosine.

[0063] The term "unsubstituted" shall mean substituted only by hydrogen atoms. Containing C 0The carbon atom range means that carbon is absent and replaced by H. Thus, C 0 -C 6 The carbon atom range includes carbon atoms of 1, 2, 3, 4, 5, and 6, and for C 0 , H replaces carbon.

[0064] The term "substituted" or "optionally substituted" shall mean the presence of one or more substituents (independently up to five substituents, preferably up to three substituents, more preferably 1 or 2 substituents on a moiety in the compounds according to the present disclosure, and may include substituents that can themselves be further substituted) at any position of carbon (or nitrogen) on the molecule in the context, independently (i.e., when more than one substitution occurs, each substituent is selected independently of the other substituent), and includes possible substituents: hydroxyl, thiol, carboxyl, cyano (C≡N), nitro (NO 2 ), halogen (preferably 1, 2, or 3 halogens, especially on an alkyl group, especially a methyl group such as trifluoromethyl), alkyl (preferably C 1 -C 10 , more preferably C 1 -C 6 ), aryl (especially phenyl and substituted phenyl, such as benzyl or benzoyl), alkoxy (preferably C 1 -C 6 alkyl or aryl, including phenyl and substituted phenyl), thioether (preferably C 1 -C 6 alkyl or aryl), acyl (preferably C 1 -C 6 acyl), ester or thioester (preferably C 1 -C 6 alkyl or aryl, including alkylene esters (such that it is attached to the alkylene, rather than preferably being substituted on the ester functional group by C 1 -C 6 alkyl or aryl)), halogen (preferably F or Cl), amine (including five- or six-membered cyclic alkylene amines, also including C 1 -C 6 alkylamine or C 1 -C 6 dialkylamine, where the alkyl group can be substituted by one or two hydroxyl groups) or optionally substituted -N(C 0 -C 6 alkyl)C(O)(OC 1 -C 6 alkyl) group (which can optionally be substituted by a polyethylene glycol chain, and the polyethylene glycol chain is further bonded to an alkyl group containing a single halogen, preferably a chlorine substituent), hydrazine, amido group, which are preferably substituted by one or two C 1 -C 6 alkyl (including optionally being substituted by one or two C1 -C 6 alkyl-substituted formamide), alkanol (preferably C 1 -C 6 alkyl or aryl), or alkanoic acid (preferably C 1 -C 6 alkyl or aryl). The substituents according to the present disclosure may include, for example, -SiR 1 R 2 R 3 group, where each of R 1 and R 2 is as further described herein, and R 3 is H or C 1 -C 6 alkyl, preferably R 1 、R 2 、R 3 together are C 1 -C 3 alkyl (including isopropyl or tert-butyl). Each of the above groups may be directly attached to the substituted moiety, or alternatively, the substituent may be attached to the substituted moiety (preferably in the case of an aryl or heteroaryl moiety) through an optionally substituted -(CH 2 ) m- or alternatively an optionally substituted -(OCH 2 ) m -, -(OCH 2 CH 2 ) m - or -(CH 2 CH 2 O) m - group (which may be substituted by any one or more of the above substituents). The alkylene -(CH 2 ) m - or -(CH 2 ) n - group or other chains such as an ethylene glycol chain, as described above, may be substituted at any position on the chain. Preferred substituents on the alkylene include halogen or C 1 -C 6 (preferably C 1 -C 3 ) alkyl, which may optionally be substituted by one or two hydroxyl groups, one or two ether groups (OC 1 -C 6 group), up to three halogen groups (preferably F), or the side chain of an amino acid as further described herein and an optionally substituted amide (preferably the formamide substituted as described above) or a carbamate group (usually having one or two C 0 -C 6an alkyl substituent, wherein the group may be further substituted) substituted. In certain embodiments, the alkylene group (usually a single methylene group) is substituted by one or two optionally substituted C 1 -C 6 alkyl group, preferably C 1 -C 4 alkyl group, most commonly methyl or O-methyl, or the side chain of an amino acid as described elsewhere herein. In the present disclosure, a moiety in a molecule may be optionally substituted with up to five substituents, preferably up to three substituents. Most commonly, in the present disclosure, the substituted moiety is substituted with one or two substituents.

[0065] The term "substituted" (each substituent being independent of any other substituent) as used in the context herein shall also refer to C 1 -C 6 alkyl group, C 1 -C 6 alkoxy group, halogen, amide group, formamido group, sulfone, including sulfonamide, ketone group, carboxyl group, C 1 -C 6 ester (oxidized ester or carbonyl ester), C 1 -C 6 ketone group, carbamate -OC(O)-NR 1 R 2 or -N(R 1 )-C(O)-OR 1 、nitro group, cyano group and amine (specifically including C 1 -C 6 alkylene -NR 1 R 2 、mono- or di-C 1 -C 6 alkyl-substituted amine, which may be optionally substituted with one or two hydroxyl groups). Unless otherwise indicated in the context, each of these groups contains 1 to 6 carbon atoms. In certain embodiments, preferred substituents will include, for example, -NH-, -NHC(O)-, -O-, =O, -(CH 2 ) m -(wherein m and n are 1, 2, 3, 4, 5 or 6 in the context), -S-, -S(O)-, SO 2 -, or -NH-C(O)-NH-, -(CH 2 ) n OH, -(CH 2 ) n SH, -(CH 2 ) n COOH, C 1 -C 6 alkyl group, -(CH 2 ) nO-(C 1 -C 6 alkyl), -(CH 2 ) n C(O)-(C 1 -C 6 alkyl), -(CH 2 ) n OC(O)-(C 1 -C 6 alkyl), -(CH 2 ) n C(O)O-(C 1 -C 6 alkyl), -(CH 2 ) n NHC(O)-R 1 , -(CH 2 ) n C(O)-NR 1 R 2 , -(OCH 2 ) n OH, -(CH 2 O) n COOH, C 1 -C 6 alkyl, -(OCH 2 ) n O-(C 1 -C 6 alkyl), -(CH 2 O) n C(O)-(C 1 -C 6 alkyl), -(OCH 2 ) n NHC(O)-R 1 , -(CH 2 O) n C(O)-NR 1 R 2 , -S(O) 2 -R S , -S(O)-R S (R S is C 1 -C 6 alkyl or -(CH 2 ) m -NR 1 R 2 , NO 2 , CN or a halogen (F, Cl, Br, I, preferably F or Cl), depending on the context in which the substituent is used. R 1 and R 2 are each independently H or C in the context1 -C 6 alkyl (which may optionally be substituted by one or two hydroxyl groups or up to three halogen groups (preferably fluorine)). The term "substituted" in the chemical context of the defined compounds and the substituents used should also mean an optionally substituted aryl or heteroaryl or an optionally substituted heterocyclic group, as further described herein. The alkylene group may also be substituted as further disclosed herein, preferably by an optionally substituted C 1 -C 6 alkyl (methyl, ethyl or hydroxymethyl or hydroxyethyl is preferred, thus providing a chiral center), the side chain of an amino acid group as further described herein, an amide group as described above, or a carbamate group OC(O)-NR 1 R 2 group (wherein R 1 and R 2 are as further described herein), but many other groups may also be used as substituents. The various optionally substituted moieties may be substituted by 3 or more substituents, preferably not more than 3 substituents and preferably by 1 or 2 substituents. It should be noted that in a compound where substitution is required at a particular position in the molecule (mainly because of valence) but the substitution is not specified, the substituent is interpreted or understood as H, unless the context of the substitution indicates otherwise.

[0066] The term "aryl" or "aromatic", as used herein, refers to a substituted (as further described herein) or unsubstituted monovalent aromatic group having a single ring (e.g., benzene, phenyl, benzyl, or a 5-, 6-, 7- or 8-membered ring) or fused rings (e.g., naphthyl, anthryl, phenanthryl, a 10- to 16-membered ring, etc.), and can be bonded at any available stable position on one or more rings or as otherwise indicated in the presented chemical structure to a compound according to the present disclosure. In context, other examples of aryl can include heteroaromatic ring systems, "heteroaryl" groups having one or more nitrogen, oxygen or sulfur atoms in the ring (monocyclic) (such as imidazole, furyl, pyrrole, furyl, thiophene, thiazole, pyridine, pyrimidine, pyrazine, triazole, oxazole) or fused ring systems (such as indole, quinoline, indolizine, aza-indolizine, benzofuran, etc.), which can be optionally substituted as described above. Mentioned heteroaryl includes nitrogen-containing heteroaryl, such as pyrrole, pyridine, pyridone, pyridazine, pyrimidine, pyrazine, pyrazole, imidazole, triazole, triazine, tetrazole, indole, isoindole, indolizine, aza-indolizine, purine, indazole, quinoline, dihydroquinoline, tetrahydroquinoline, isoquinoline, dihydroisoquinoline, tetrahydroisoquinoline, quinazine, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, imidazopyridine, imidazotriazine, pyrazinopyridazine, acridine, phenanthridine, carbazole, carbazoline, pyrimidine, phenanthroline, phenanthrene, oxadiazole, benzimidazole, pyrrolopyridine, pyrrolopyrimidine and pyridopyrimidine; sulfur-containing aromatic heterocycles, such as thiophene and benzothiophene; oxygen-containing aromatic heterocycles, such as furan, pyran, cyclopentapyran, benzofuran and isobenzofuran; and aromatic heterocycles containing two or more heteroatoms selected from nitrogen, sulfur and oxygen, such as thiazole, thiadiazole, isothiazole, benzoxazole, benzothiazole, benzothiadiazole, phenothiazine, isoxazole, furan, phenoxazine, pyrazolooxazole, imidazothiazole, thiophenofuran, furanopyrrole, pyridazine, furanopyridine, furanopyrimidine, thiophenopyrimidine and oxazole, etc., all of which can be optionally substituted.

[0067] The term "substituted aryl" refers to an aromatic carbocyclic group consisting of at least one aromatic ring or multiple fused rings, wherein at least one ring is aromatic and one or more rings are substituted with one or more substituents. For example, an aryl can contain one or more substituents selected from: -(CH 2 ) n OH, -(CH 2 ) n -O-(C 1 -C 6 )alkyl, -(CH 2 ) n -O-(CH 2 ) n -(C 1 -C 6 )alkyl, -(CH2 ) n -C(O)(C 0 -C 6 )alkyl, -(CH 2 ) n -C(O)O(C 0 -C 6 )alkyl, -(CH 2 ) n -OC(O)(C 0 -C 6 )alkyl, amine, mono- or di-(C 1 -C 6 alkyl)amine, wherein the alkyl on the amine is optionally substituted with: 1 or 2 hydroxyl groups or up to three halo groups (preferably F, Cl) groups, OH, COOH, C 1 -C 6 alkyl (preferably CH 3 ), CF 3 , OMe, OCF 3 , NO 2 , or a CN group (each of which can be substituted at the ortho, meta, and / or para positions of the benzene ring, preferably the para position), an optionally substituted phenyl group (the phenyl group itself is preferably connected to the PTM group through a linker group, including the ULM group), and / or F, Cl, OH, COOH, CH 3 , CF 3 , OMe, OCF 3 , NO 2 or a CN group (at the ortho, meta, and / or para positions of the benzene ring, preferably the para position), an optionally substituted naphthyl group, an optionally substituted heteroaryl group (preferably an optionally substituted isoxazole, including a methyl-substituted isoxazole), an optionally substituted oxazole (including a methyl-substituted oxazole), an optionally substituted thiazole (including a methyl-substituted thiazole), an optionally substituted isothiazole (including a methyl-substituted isothiazole), an optionally substituted pyrrole (including a methyl-substituted pyrrole), an optionally substituted imidazole (including a methylimidazole), an optionally substituted benzimidazole or methoxybenzylimidazole, an optionally substituted oxime oxazole or methyl oxime oxazole, an optionally substituted diazole group (including a methyl diazole group), an optionally substituted triazole group (including a methyl-substituted triazole group), an optionally substituted pyridine group (including a halo group (preferably F) or a methyl-substituted pyridine group or an oxypyridine group) (wherein the pyridine group is connected to the phenyl through oxygen), an optionally substituted furan, an optionally substituted benzofuran, an optionally substituted dihydrobenzofuran, an optionally substituted indole, indolizine or azaindolizine (2, 3 or 4-azaindolizine), an optionally substituted quinoline, and combinations thereof.

[0068] "Carboxyl" means the group --C(O)OR, where R is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, and the meanings of these general substituents are the same as the definitions of the corresponding groups defined herein.

[0069] The term "heteroaryl / hetaryl" can mean but is not limited to 5-16 membered heteroaryl (e.g., 5, 6, 7 or 8 membered monocyclic or 10-16 membered heteroaryl with multiple fused rings), optionally substituted quinoline (which can be attached to the pharmacophore or substituted on any carbon atom within the quinoline ring), optionally substituted indole (including dihydroindole), optionally substituted indolizine, optionally substituted azaindolizine (2, 3 or 4-azaindolizine), optionally substituted benzimidazole, benzodiazole, benzofuran, optionally substituted imidazole, optionally substituted isoxazole, optionally substituted oxazole (preferably methyl substituted), optionally substituted dazole, optionally substituted triazole, tetrazole, optionally substituted benzofuran, optionally substituted thiophene, optionally substituted thiazole (preferably methyl and / or mercapto substituted), optionally substituted isothiazole, optionally substituted triazole (preferably substituted with methyl, triisopropylsilyl, optionally substituted -(CH 2 ) m -O-C 1 -C 6 alkyl or optionally substituted -(CH 2 ) m -C(O)-O-C 1 -C 6 alkyl substituted 1,2,3-triazole), optionally substituted pyridine (2, 3 or 4-pyridine) or a group according to the following chemical structure:

[0070]

[0071] wherein:

[0072] S c is CHR SS 、NR URE or O;

[0073] R HET is H, CN, NO 2 、halogen (preferably Cl or F), optionally substituted C 1 -C 6 alkyl (preferably substituted with one or two hydroxyl groups or at most three halogen groups (e.g., CF 3 ), optionally substituted O(C 1 -C 6 alkyl) (preferably substituted with one or two hydroxyl groups or at most three halogen groups) or optionally substituted alkynyl-C≡CR a , where R ais H or C 1 -C 6 alkyl (preferably C 1 -C 3 alkyl);

[0074] R SS is H, CN, NO 2 , halo group (preferably F or Cl), optionally substituted C 1 -C 6 alkyl (preferably substituted by one or two hydroxyl groups or at most three halo groups), optionally substituted O-(C 1 -C 6 alkyl) (preferably substituted by one or two hydroxyl groups or at most three halo groups) or optionally substituted -C(O)(C 1 -C 6 alkyl) (preferably substituted by one or two hydroxyl groups or at most three halo groups);

[0075] R URE is H, C 1 -C 6 alkyl (preferably H or C 1 -C 3 alkyl) or -C(O)(C 1 -C 6 alkyl), wherein each of said groups is optionally substituted by one or two hydroxyl groups or at most three halogens (preferably fluorine groups), or an optionally substituted heterocycle (such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted), and

[0076] Y C is N or C-R YC , wherein R YC is H, OH, CN, NO 2 , halo group (preferably Cl or F), optionally substituted C 1 -C 6 alkyl (preferably substituted by one or two hydroxyl groups or at most three halo groups (e.g., CF 3 )) substituted), optionally substituted O(C 1 -C 6 alkyl) (preferably substituted by one or two hydroxyl groups or at most three halo groups) or optionally substituted alkynyl -C≡C-R a , wherein R a is H or C 1 -C 6 alkyl (preferably C 1 -C 3 alkyl).

[0077] The terms "aralkyl" and "heteroaralkyl" refer to groups containing an aryl or, respectively, a heteroaryl as defined above, as well as an alkyl and / or heteroalkyl and / or carbocyclic and / or heterocyclic alkyl ring system.

[0078] As used herein, the term "aralkyl" refers to an aryl as defined above attached to an alkyl as defined above. The aralkyl is attached to the parent moiety through an alkyl, where the alkyl has 1 to 6 carbon atoms. The aryl in the aralkyl may be substituted as defined above.

[0079] The term "heterocycle" refers to a cyclic group containing at least one heteroatom such as N, O or S, and may be aromatic (heteroaryl) or non-aromatic. Thus, the heteroaryl moiety is subsumed within the definition of heterocycle, depending on the context of its use. Exemplary heteroaryls are described above.

[0080] Exemplary heterocycles include: azetidinyl, benzimidazolyl, 1,4-benzodioxanyl, 1,3-benzodioxazolyl, benzoxazolyl, benzothiazolyl, benzothienyl, dihydroimidazolyl, dihydropyranyl, dihydrofuranyl, dioxolanyl, dioxolyl, ethyleneurea, 1,3-dioxolane, 1,3-dioxane, 1,4-dioxane, furanyl, homopiperidinyl, imidazolyl, imidazolinyl, imidazolidinyl, indolinyl, indolyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolyl, morpholinyl, naphthyridinyl, oxazolidinyl, oxazolyl, pyridone, 2-pyrrolidone, pyridine, piperazinyl, N-methylpiperazinyl, piperidinyl, phthalimide, succinimide, pyrazinyl, pyrazolinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydroquinoline, thiazolidinyl, thiazolyl, thienyl, tetrahydrothiophene, oxane, oxetanyl, oxathiolanyl, thiane, etc.

[0081] The heterocyclic group may be optionally substituted by a member selected from the group consisting of: alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxy, keto, thione, carboxyl, carboxyalkyl, thioaryloxy, thioheteraryloxy, thioheteracyloxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocycle, heteracyloxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl, oxo group (=O), and -SO2-heteroaryl. Such heterocyclic groups may have a single ring or multiple fused rings. Examples of azacyclic and heteroaryl groups include, but are not limited to, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinazoline, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, dihydroindole, morpholino, piperidinyl, tetrahydrofuranyl, etc., and heterocycles containing N-alkoxy-nitrogen. The term "heterocycle" also includes bicyclic groups in which any heterocycle is fused to a benzene ring or a cyclohexane ring or another heterocycle (e.g., indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, etc.).

[0082] The term "cycloalkyl" may mean, but is by no means limited to, a monovalent group derived from a monocyclic or polycyclic alkyl or cycloalkane as defined herein, e.g., a saturated monocyclic hydrocarbon group having three to twenty carbon atoms in the ring, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. The term "substituted cycloalkyl" may mean, but is by no means limited to, a monocyclic or polycyclic alkyl and is substituted by one or more substituents such as amino, halogen, alkyl, substituted alkyl, carbonyloxy, carbonylthio, aryl, nitro, mercapto, or sulfo group, and the meanings of these general substituents are the same as the definitions of the corresponding groups defined in this legend.

[0083] "Heterocycloalkyl" refers to a monocyclic or polycyclic alkyl group in which at least one ring carbon atom of its cyclic structure is replaced by a heteroatom selected from the group consisting of N, O, S, or P. "Substituted heterocycloalkyl" refers to a monocyclic or polycyclic alkyl in which at least one ring carbon atom of its cyclic structure is replaced by a heteroatom selected from the group consisting of N, O, S, or P, and the group contains one or more substituents selected from the group consisting of: halogen, alkyl, substituted alkyl, carbonyloxy, carbonylthio, aryl, nitro, mercapto, or sulfo group, and the meanings of these general substituent groups are the same as the definitions of the corresponding groups defined in this legend.

[0084] The term "hydrocarbyl" shall mean a compound containing carbon and hydrogen, and which may be fully saturated, partially unsaturated or aromatic, and includes aryl, alkyl, alkenyl and alkynyl.

[0085] The term "independently" is used herein to indicate that variables applied independently vary independently among the various applications.

[0086] The term "lower alkyl" means methyl, ethyl or propyl.

[0087] The term "lower alkoxy" means methoxy, ethoxy or propoxy.

[0088] Exemplary CLM

[0089] New Imide Compounds

[0090] In one aspect, the present specification provides CLMs that can be used to bind and recruit cereblon. In certain embodiments, the CLM is selected from the group consisting of the following chemical structures:

[0091]

[0092]

[0093] Wherein:

[0094] W of formulas (a1) to (e) [e.g., (a1), (a2), (a3), (a4), (b), (c), (d1), (d2) and (e)] is independently selected from the groups CH 2 , O, CHR, C=O, SO 2 , NH, N, optionally substituted cyclopropyl, optionally substituted cyclobutyl and N-alkyl;

[0095] W of formulas (a1) to (e) 3 is selected from C or N;

[0096] X of formulas (a1) to (e) is independently selected from the groups absent, O, S and CH 2 ;

[0097] Y of formulas (a1) to (e) is independently selected from the groups CH 2 , -C=CR', NH, N-alkyl, N-aryl, N-heteroaryl, N-cycloalkyl, N-heterocyclic, O and S;

[0098] Z of formulas (a1) to (e) is independently selected from the groups absent, O and S or CH 2 , except that both X and Z cannot be CH 2 or absent;

[0099] In formulas (a1) to (e), G and G’ are independently selected from the group consisting of H, optionally substituted straight-chain or branched alkyl, OH, R’OCOOR, R’OCONRR”, CH optionally substituted by R’, 2 -heterocyclic group, and benzyl optionally substituted by R’;

[0100] In formulas (a1) to (e), Q1 - Q4 represent carbon C or N substituted by a group independently selected from H, R, N, or N-oxide;

[0101] In formulas (a1) to (e), A is independently selected from the group consisting of H, optionally substituted straight-chain or branched alkyl, cycloalkyl, Cl, and F;

[0102] In formulas (a1) to (e), n represents an integer from 1 to 10 (e.g., 1 - 4, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10);

[0103] R in formulas (a1) to (e) includes but is not limited to: H, -C(=O)R’ (e.g., carboxyl), -CONR’R” (e.g., amide group), -OR’ (e.g., OH), -NR’R” (e.g., amine group), -SR’, -SO 2 R’, -SO 2 NR’R”, -CR’R”-,-CR’NR’R”-,-(CR’O) n’ R”, optionally substituted heterocyclic group, optionally substituted aryl (e.g., optionally substituted C5 - C7 aryl), optionally substituted alkyl-aryl (e.g., alkyl-aryl containing at least one of optionally substituted C1 - C6 alkyl, optionally substituted C5 - C7 aryl, or a combination thereof), optionally substituted heteroaryl, optionally substituted alkyl (e.g., C1 - C6 straight-chain or branched alkyl optionally substituted by one or more halogens, cycloalkyl (e.g., C3 - C6 cycloalkyl), or aryl (e.g., C5 - C7 aryl)), optionally substituted alkoxy (e.g., methoxy, ethoxy, butoxy, propoxy, pentyloxy, or hexyloxy; wherein the alkoxy can be substituted by one or more halogens, alkyl, haloalkyl, fluoroalkyl, cycloalkyl (e.g., C3 - C6 cycloalkyl), or aryl (e.g., C5 - C7 aryl)), optionally substituted cycloalkyl, optionally substituted heterocyclic group, -P(O)(OR’)R”, -P(O)R’R”, -OP(O)(OR’)R”, -OP(O)R’R”, -Cl, -F, -Br, -I, -CF 3 ,-CN,-NR’SO 2 NR’R”, -NR’CONR’R”, -CONR’COR”, -NR’C(=N - CN)NR’R”, -C(=N - CN)NR’R”, -NR’C(=N - CN)R”, -NR’C(=C - NO2 )NR’R”, -SO 2 NR’COR”, -NO 2 , -CO 2 R’, -C(C=N-OR’)R”, -CR’=CR’R”, -CCR’, -S(C=O)(C=N-R’)R”, -SF 5 and -OCF 3 , wherein at least one of W, X, Y, Z, G, G’, R, R’, R”, Q1-Q4 or A is modified to covalently link to a PTM, a chemical linking group (L), a ULM, a CLM, or a combination thereof;

[0104] Each of x, y, and z in formulas (a1) to (e) is independently 0, 1, 2, 3, 4, 5, or 6;

[0105] R’ and R” in formulas (a1) to (e) are independently selected from H, optionally substituted straight-chain or branched-chain alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, -C(=O)R, optionally substituted heterocyclic group;

[0106] n' in formulas (a1) to (e) is an integer from 1 to 10 (e.g., 1-4, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10);

[0107] represents a single bond or a double bond; and

[0108] in formulas (a1) to (e) represents a bond that can be stereospecific ((R) or (S)) or non-stereospecific.

[0109] In any aspect or embodiment described herein, the CLM comprises a chemical structure selected from the group consisting of:

[0110]

[0111]

[0112] wherein:

[0113] W in formulas (a1) to (e)[e.g., (a1), (a2), (a3), (a4), (b), (c), (d1), (d2), and (e)] is independently selected from the group CH 2 , O, CHR, C=O, SO 2 , NH, N, optionally substituted cyclopropyl, optionally substituted cyclobutyl, and N-alkyl;

[0114] W in formulas (a1) to (e) 3 is selected from C or N;

[0115] X in formulas (a1) to (e) is independently selected from the groups O, S and CH 2 ;

[0116] Y in formulas (a1) to (e) is independently selected from the groups CH 2 , -C=CR’, NH, N-alkyl, N-aryl, N-heteroaryl, N-cycloalkyl, N-heterocyclic group, O and S;

[0117] Z in formulas (a1) to (e) is independently selected from the groups O and S or CH2, provided that both X and Z cannot be CH 2 or both are absent;

[0118] G and G’ in formulas (a1) to (e) are independently selected from the groups H, optionally substituted straight-chain or branched-chain alkyl, OH, R’OCOOR, R’OCONRR”, CH 2 -heterocyclic group and benzyl optionally substituted by R’;

[0119] Q1-Q4 in formulas (a1) to (e) represent carbon C or N substituted by a group independently selected from H, R, N or N-oxide;

[0120] A in formulas (a1) to (e) is independently selected from the groups H, optionally substituted straight-chain or branched-chain alkyl, cycloalkyl, Cl and F;

[0121] n in formulas (a1) to (e) represents an integer from 1 to 10 (for example, 1-4, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10);

[0122] R in formulas (a1) to (e) includes but is not limited to: H, -C(=O)R’ (for example, carboxyl), -CONR’R” (for example, amide group), -OR’ (for example, OH), -NR’R” (for example, amine group), -SR’, -SO2R’, -SO2NR’R”, -CR’R”-,-CR’NR’R”-(-CR’O) n’R”, an optionally substituted aryl (e.g., an optionally substituted C5-C7 aryl), an optionally substituted alkyl-aryl (e.g., an alkyl-aryl comprising at least one of an optionally substituted C1-C6 alkyl, an optionally substituted C5-C7 aryl, or a combination thereof), an optionally substituted heteroaryl, an optionally substituted straight or branched alkyl (e.g., a C1-C6 straight or branched alkyl optionally substituted by one or more halogens, cycloalkyl (e.g., C3-C6 cycloalkyl), or aryl (e.g., C5-C7 aryl)), an optionally substituted alkoxy (e.g., methoxy, ethoxy, butoxy, propoxy, pentyloxy, or hexyloxy; wherein the alkoxy may be substituted by one or more halogens, alkyls, haloalkyls, fluoroalkyls, cycloalkyls (e.g., C3-C6 cycloalkyl), or aryls (e.g., C5-C7 aryl)), an optionally substituted cycloalkyl, an optionally substituted heterocyclic group, -P(O)(OR’)R”, -P(O)R’R”, -OP(O)(OR’)R”, -OP(O)R’R”, -Cl, -F, -Br, -I, -CF3, -CN, -NR’SO2NR’R”, -NR’CONR’R”, -CONR’COR”, -NR’C(=N-CN)NR’R”, -C(=N-CN)NR’R”, -NR’C(=N-CN)R”, -NR’C(=C-NO2)NR’R”, -SO2NR’COR”, -NO2, -CO2R’, -C(C=N-OR’)R”, -CR’=CR’R”, -CCR’, -S(C=O)(C=N-R’)R”, -SF5, and -OCF3, wherein at least one of W, X, Y, Z, G, G’, R, R’, R”, Q1-Q4, or A is covalently linked (directly or indirectly, e.g., through a functional group or atom such as O, S, N) to a PTM, a chemical linking group (L), a ULM, a CLM, or a combination thereof;

[0123] Each of x, y, and z in formulas (a1) to (e) is independently 0, 1, 2, 3, 4, 5, or 6;

[0124] R’ and R” in formulas (a1) to (e) are independently selected from a bond, H, an optionally substituted straight or branched alkyl, an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocycle, -C(=O)R, and an optionally substituted heterocyclic group;

[0125] n' in formulas (a1) to (e) is an integer from 1 to 10 (e.g., 1 to 4, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10); and

[0126] In formulas (a) to (f), The bond may be stereospecific ((R) or (S)) or non-stereospecific.

[0127] In any aspect or embodiment described herein, the CLM or ULM is selected from the structures of formula (g):

[0128]

[0129] Wherein:

[0130] W in formula (g) is independently selected from the groups CH 2 , O, C═O, NH, and N-alkyl;

[0131] A in formula (g) is selected from H, methyl, or an optionally substituted straight-chain or branched alkyl;

[0132] n is an integer from 1 to 4;

[0133] R in formula (g) is independently selected from H, O, OH, N, NH, NH 2 , -Cl, -F, -Br, -I, methyl, an optionally substituted straight-chain or branched alkyl (e.g., an optionally substituted straight-chain or branched C1-C6 alkyl), an optionally substituted straight-chain or branched alkoxy (e.g., an optionally substituted straight-chain or branched C1-C6 alkoxy), -alkyl-aryl (e.g., -alkyl-aryl containing at least one of C1-C6 alkyl, C4-C7 aryl, or a combination thereof), aryl (e.g., C5-C7 aryl), amine, amide, or carboxyl), wherein at least one R or W is modified to covalently link to a PTM, a chemical linking group (L), a ULM, a CLM, or a combination thereof; and

[0134] The in formula (g) represents a bond that can be stereospecific ((R) or (S)) or non-stereospecific.

[0135] In any aspect or embodiment described herein, the CLM or ULM is selected from the group consisting of:

[0136]

[0137]

[0138] Wherein:

[0139] W is C═O or CH 2 ;

[0140] N* is a nitrogen atom covalently linked to a PTM or a linker, or a nitrogen atom shared with a PTM or a linker (e.g., a heteroatom shared with an optionally substituted heterocyclic group of the linker (L) or PTM); and

[0141] represents the point of attachment of the CLM or ULM to the linker (L) or PTM.

[0142] In any aspect or embodiment described herein, R is selected from: H, O, OH, N, NH, NH 2 , C1-C6 alkyl, C1-C6 alkoxy, -alkyl-aryl (e.g., -alkyl-aryl comprising at least one of C1-C6 alkyl, C4-C7 aryl, or a combination thereof), aryl (e.g., C5-C7 aryl), amine, amide, or carboxyl.

[0143] In any aspect or embodiment described herein, at least one R (e.g., an R group selected from H, O, OH, N, NH, NH 2 , C1-C6 alkyl, C1-C6 alkoxy, -alkyl-aryl (e.g., -alkyl-aryl comprising at least one of C1-C6 alkyl, C4-C7 aryl, or a combination thereof), aryl (e.g., C5-C7 aryl), amine, amide, or carboxyl) or W is modified to covalently link to a PTM, chemical linker group (L), ULM, CLM, or a combination thereof.

[0144] In any aspect or embodiment described herein, W, X, Y, Z, G, G’, R, R’, R”, Q1-Q4, and A of formulas (a) to (g) can be independently covalently coupled to a linker and / or a linker that connects one or more PTM, ULM, or CLM groups.

[0145] In any aspect or embodiment described herein, n is an integer from 1 to 4, and each R is an independently selected functional group or atom, such as O, OH, N, -Cl, -F, C1-C6 alkyl, C1-C6 alkoxy, -alkyl-aryl (e.g., -alkyl-aryl comprising at least one of C1-C6 alkyl, C4-C7 aryl, or a combination thereof), aryl (e.g., C5-C7 aryl), amine, amide, or carboxyl on the aryl or heteroaryl of CLM, and optionally, one of them is modified to covalently link to a PTM, chemical linker group (L), ULM, CLM, or a combination thereof.

[0146] More specifically, non-limiting examples of CLM include those shown below and those “hybrid” molecules generated by combinations of one or more different features shown in the following molecules, where at least one R or W is modified to covalently link to a PTM, chemical linking group (L), ULM, CLM, or a combination thereof.

[0147]

[0148]

[0149]

[0150]

[0151]

[0152]

[0153]

[0154]

[0155] In any aspect or embodiment described herein, the CLM comprises a chemical structure selected from the following groups:

[0156]

[0157]

[0158]

[0159]

[0160] Wherein:

[0161] W is independently selected from CH 2 , O, CHR, C=O, SO 2 , NH, N, optionally substituted cyclopropyl, optionally substituted cyclobutyl, and N-alkyl (e.g., CH 2 , CHR, C=O, SO 2 , NH, and N-alkyl);

[0162] Q 1 、Q 2 、Q 3 、Q 4 、Q 5 each independently represents a carbon C or N substituted by a group independently selected from R’, N, or N-oxide;

[0163] R 1 is selected from absent, H, OH, CN, C1-C3 alkyl, C=O;

[0164] R 2 is selected from absent, H, OH, CN, C1-C3 alkyl, CHF 2 , CF 3 , CHO, C(=O)NH 2 ;

[0165] R 3Selected from H, alkyl (e.g., C1-C6 or C1-C3 alkyl), substituted alkyl (e.g., substituted C1-C6 or C1-C3 alkyl), alkoxy (e.g., C1-C6 or C1-C3 alkoxy), substituted alkoxy (e.g., substituted C1-C6 or C1-C3 alkoxy);

[0166] R 4 Selected from H, alkyl, substituted alkyl;

[0167] R 5 and R 6 are each independently H, halogen, C(=O)R’, CN, OH, CF 3 ;

[0168] X is C, CH, C=O or N;

[0169] X 1 is C=O, N, CH or CH 2 ;

[0170] R’ is selected from H, halogen, amine, alkyl (e.g., C1-C3 alkyl), substituted alkyl (e.g., substituted C1-C3 alkyl), alkoxy (e.g., C1-C3 alkoxy), substituted alkoxy (e.g., substituted C1-C3 alkoxy), NR 2 R 3 , C(=O)OR 2 , optionally substituted phenyl;

[0171] n is 0-4;

[0172] is a single bond or a double bond; and

[0173] CLM is covalently linked to PTM, chemical linker group (L), ULM, CLM or a combination thereof.

[0174] In any aspect or embodiment described herein, CLM is covalently linked to PTM or chemical linker group (L) through an R group (such as R, R 1 , R 2 , R 3 , R 4 or R’), W, X, or Q group (such as Q 1 , Q 2 , Q 3 , Q 4 or Q 5 ).

[0175] In any aspect or embodiment described herein, CLM is covalently linked to PTM or chemical linker group (L) through W, X, R, R 1 , R 2 , R 3 , R4 , R 5 , R’, Q 1 , Q 2 , Q 3 , Q 4 and Q 5 are covalently linked to a PTM or a chemical linker group (L).

[0176] In any aspect or embodiment described herein, W, X, R 1 , R 2 , R 3 , R 4 , R’, Q 1 , Q 2 , Q 3 , Q 4 and Q 5 may be independently covalently coupled to a linker and / or a linker that is linked to one or more PTM, ULM or CLM groups.

[0177] More specifically, non-limiting examples of CLM include those shown below and “hybrid” molecules or compounds resulting from combining one or more features of the following compounds:

[0178]

[0179]

[0180]

[0181] Wherein:

[0182] W is independently selected from the groups CH 2 , CHR, C=O, SO 2 , NH and N-alkyl;

[0183] R 1 is selected from the groups absent, H, CH, CN, C1-C3 alkyl;

[0184] R 2 is H or C1-C3 alkyl;

[0185] R 3 is selected from H, alkyl, substituted alkyl, alkoxy, substituted alkoxy;

[0186] R 4 is methyl or ethyl;

[0187] R 5 is H or a halogen group;

[0188] R 6 is H or a halogen group;

[0189] n is an integer from 0 to 4;

[0190] R and R’ are independently H, a functional group or an atom (e.g., H, a halogen (e.g., -Cl or -F), an amine, a C1-C3 alkyl group, a C1-C3 alkoxy group, NR 2 R 3 or C(=O)OR 2 ); or a point of attachment of a PTM or a chemical linker group (L),

[0191] Q 1 and Q 2 are each independently C or N substituted with a group independently selected from H or a C1-C3 alkyl group; and

[0192] is a single bond or a double bond.

[0193] In any aspect or embodiment described herein, W, R 1 、R 2 、Q 1 、Q 2 、Q 3 、Q 4 、R and R’ can be independently covalently coupled to a linker and / or a linker attached to one or more PTM groups.

[0194] In any aspect or embodiment described herein, R 1 、R 2 、Q 1 、Q 2 、Q 3 、Q 4 、R and R’ can be independently covalently coupled to a linker and / or a linker attached to one or more PTM groups.

[0195] In any aspect or embodiment described herein, Q 1 、Q 2 、Q 3 、Q 4 、R and R’ can be independently covalently coupled to a linker and / or a linker attached to one or more PTM groups.

[0196] As will be apparent, in any aspect or embodiment described herein, R, R’, R”, R 1 、R 2 、R 3 、R 4 、R 5 and R 6 can be a bond.

[0197] In any aspect or embodiment described herein, R is a bond or is modified to covalently link to a linker group (L) or PTM or a combination thereof.

[0198] In any aspect or embodiment described herein, CLM is selected from:

[0199]

[0200]

[0201] wherein R’ is a halogen and R 1 as described herein.

[0202] In certain cases, “CLM” can be an imide that binds to the cereblon E3 ligase. These imides and linker attachment points can be, but are not limited to, one of the following structures:

[0203]

[0204]

[0205] In any aspect or embodiment described herein, ULM is selected from the group consisting of:

[0206]

[0207]

[0208] wherein:

[0209] of ULM represents the attachment point to the linker group or PTM;

[0210] N* is a nitrogen atom shared with the chemical linker group or PTM; and

[0211] W, Q 4 and Q 5 are each defined as described in any aspect or embodiment herein.

[0212] Exemplary Linkers

[0213] In certain embodiments, the compounds described herein comprise a PTM chemically linked to a ULM (e.g., CLM) via a chemical linker (L). In certain embodiments, the linker group L comprises one or more covalently linked structural units (e.g., -A L 1…… (A L ) q - or -(A L ) q -), where A L1 is a group coupled to PTM, and (A L ) q is a group coupled to ULM.

[0214] In any aspect or embodiment described herein, the connection of linker (L) to ULM (e.g., CLM) is a stable L-ULM connection. For example, in any aspect or embodiment described herein, when linker (L) and ULM are connected by a heteroatom (e.g., N, O, S), any additional heteroatoms (if present) are separated by at least one carbon atom (e.g., -CH 2 -), such as an acetal or acetalamine group. As a further example, in any aspect or embodiment described herein, when linker (L) and ULM are connected by a heteroatom, the heteroatom is not part of an ester.

[0215] In any aspect or embodiment described herein, linker group L is a bond or a chemical linker group represented by the formula -(A L ) q -, where A is a chemical moiety and q is an integer from 1 to 100 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79 or 80), and where L is covalently bonded to both PTM and ULM and provides binding of PTM to the protein target and binding of ULM to the E3 ubiquitin ligase to effect ubiquitination of the target protein.

[0216] In any aspect or embodiment described herein, linker group L is a bond or a chemical linker group represented by the formula -(A L ) q -, where A is a chemical moiety and q is an integer from 6 to 30 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25), and where L is covalently bonded to both PTM and ULM and is close enough to provide binding of PTM to the protein target and binding of ULM to the E3 ubiquitin ligase to result in ubiquitination of the target protein.

[0217] In any aspect or embodiment described herein, the linker group L is -(A L ) q -,in:

[0218] (A L ) q is a group that connects a ULM (e.g., a CLM) to a PTM (TTM);

[0219] The q of the linker is an integer greater than or equal to 1;

[0220] Each A L Independently selected from the group consisting of: a key, a CR L1 R L2 , O, S, SO, SO 2 NR L3 、SO 2 NR L3 ,SONR L3 ,CONR L3 NR L3 CONR L4 NR L3 SO 2 NR L4 ,CO,CR L1 =CR L2 、C≡C、SiR L1 R L2 、P(O)R L1 、P(O)OR L1 NR L3 C(=NCN)NR L4 NR L3 C(=NCN),NR L3 C(=CNO 2 )NR L4 , optionally 1-6 R L1 and / or R L2 C 3-11 Cycloalkyl, optionally substituted with 1-9 R L1 and / or R L2 C 5-13 Spirocycloalkyl, optionally substituted by 1-6 R L1 and / or R L2 C 3-11 Heterocyclic group, optionally substituted by 1-8 R L1 and / or R L2 C 5-13 Spiroheterocyclic group, optionally substituted by 1-6 R L1 and / or R L2 The aryl group is optionally substituted with 1 to 6 R L1 and / or RL2 Group-substituted heteroaryl, wherein R L1 or R L2 are each independently optionally linked to other groups to form an optionally 1-4 R L5 group-substituted cycloalkyl and / or heterocyclic moiety; and

[0221] R L1 、R L2 、R L3 、R L4 and R L5 are each independently H, halo, C 1-8 alkyl, OC 1-8 alkyl, SC 1-8 alkyl, NHC 1-8 alkyl, N(C 1-8 alkyl) 2 、C 3-11 cycloalkyl, aryl, heteroaryl, C 3-11 heterocyclic, OC 3-8 cycloalkyl, SC 3-8 cycloalkyl, NHC 3-8 cycloalkyl, N(C 3-8 cycloalkyl) 2 、N(C 3-8 cycloalkyl)(C 1-8 alkyl), OH, NH 2 、SH, SO 2 C 1-8 alkyl, P(O)(OC 1-8 alkyl)(C 1-8 alkyl), P(O)(OC 1-8 alkyl) 2 、CC-C 1-8 alkyl, CCH, CH=CH(C 1-8 alkyl), C(C 1-8 alkyl)=CH(C 1-8 alkyl), C(C 1-8 alkyl)=C(C 1-8 alkyl) 2 、Si(OH) 3 、Si(C 1-8 alkyl) 3 、Si(OH)(C 1-8 alkyl) 2 、COC 1-8 alkyl, CO 2 H, halogen, CN, CF 3 、CHF 2 、CH 2 F, NO 2 、SF 5 、SO2 NHC 1-8 Alkyl, SO 2 N(C 1-8 alkyl) 2 SONHC 1-8 Alkyl, SON(C 1-8 alkyl) 2 、CONHC 1-8 Alkyl, CON(C 1-8 alkyl) 2 、N(C 1-8 alkyl)CONH(C 1-8 Alkyl), N(C 1-8 alkyl)CON(C 1-8 alkyl) 2 NHCONH(C 1-8 alkyl), NHCON(C 1-8 alkyl) 2 NHCONH 2 、N(C 1-8 alkyl)SO 2 NH(C 1-8 Alkyl), N(C 1-8 alkyl)SO 2 N(C 1-8 alkyl) 2 NH SO 2 NH(C 1-8 alkyl), NH SO 2 N(C 1-8 alkyl) 2 or NH SO 2 NH 2 .

[0222] In certain embodiments, q is an integer greater than or equal to 1.

[0223] In any aspect or embodiment described herein, for example, when q of the linker is greater than 2, (A L ) q Is for A L 1 and (A L ) q A group wherein the linker couples the PTM to the ULM.

[0224] In any aspect or embodiment described herein, for example, when q of the linker is 2, A L 2 is connected to A L 1 and ULM's group.

[0225] In any aspect or embodiment described herein, for example, when q of the linker is 1, the structure of the linker group L is -A L 1 -, and A L 1 is a group that connects the ULM moiety to the PTM moiety.

[0226] In any aspect or embodiment described herein, the unit A of the linker (L) L comprises a group represented by a general structure selected from the group consisting of:

[0227] -NR(CH 2 ) n -(lower alkyl)-, -NR(CH 2 ) n -(lower alkoxy)-, -NR(CH 2 ) n -(lower alkoxy)-OCH 2 -, -NR(CH 2 ) n -(lower alkoxy)-(lower alkyl)-OCH 2 -, -NR(CH 2 ) n -(cycloalkyl)-(lower alkyl)-OCH 2 -, -NR(CH 2 ) n -(heterocycloalkyl)-, -NR(CH 2 CH 2 O) n -(lower alkyl)-O-CH 2 -, -NR(CH 2 CH 2 O) n -(heterocycloalkyl)-O-CH 2 -, -NR(CH 2 CH 2 O) n -aryl-O-CH 2 -, -NR(CH 2 CH 2 O) n -(heteroaryl)-O-CH 2 -, -NR(CH 2 CH 2 O) n -(cycloalkyl)-O-(heteroaryl)-O-CH 2 -, -NR(CH 2 CH 2 O) n -(cycloalkyl)-O-aryl-O-CH2 -, -NR(CH 2 CH 2 O) n -(lower alkyl)-NH-aryl-O-CH 2 -, -NR(CH 2 CH 2 O) n -(lower alkyl)-O-aryl-CH 2 , -NR(CH 2 CH 2 O) n -cycloalkyl-O-aryl-, -NR(CH 2 CH 2 O) n -cycloalkyl-O-(heteroaryl)l-, -NR(CH 2 CH 2 ) n -(cycloalkyl)-O-(heterocyclic group)-CH 2、 , -NR(CH 2 CH 2 ) n -(heterocyclic group)-(heterocyclic group)-CH 2 and -N(R1R2)-(heterocyclic group)-CH 2 ; wherein

[0228] n of the linker can be from 0 to 10;

[0229] R of the linker can be H or lower alkyl; and

[0230] R1 and R2 of the linker can form a ring with the connected N.

[0231] In any aspect or embodiment described herein, the linker (L) comprises an optionally substituted C 1 -C 50 alkyl (e.g., C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , C 20, C 21 , C 22 , C 23 , C 24 , C 25 , C 26 , C 27 , C 28 , C 29 , C 30 , C 31 , C 32 , C 33 , C 34 , C 35 , C 36 , C 37 , C 38 , C 39 , C 40 , C 41 , C 42 , C 43 , C 44 , C 45 , C 46 , C 47 , C 48 , C 49 or C 50 alkyl, and includes all implicit sub-ranges, such as C1-C10, C1-C20; C2-C10, C2-20; C10-C20, C10-C50, etc.), where each carbon is optionally and independently substituted or replaced by: (1) a heteroatom selected from N, O, S, P or Si atoms, having an appropriate number of hydrogens, substitutions or both to satisfy the valence, (2) an optionally substituted cycloalkyl or bicycloalkyl, (3) an optionally substituted heterocycloalkyl or bicycloheteroalkyl, (4) an optionally substituted aryl or biaryl, or (5) an optionally substituted heteroaryl or biaryl. In any aspect or embodiment described herein, the linker (L) does not have heteroatom-heteroatom bonding (e.g., no heteroatoms are covalently linked or adjacent).

[0232] In any aspect or embodiment described herein, the linker (L) includes an optionally substituted C 1 -C 50 alkyl (e.g., C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , C 12 , C 13 , C 14, C 15 , C 16 , C 17 , C 18 , C 19 , C 20 , C 21 , C 22 , C 23 , C 24 , C 25 , C 26 , C 27 , C 28 , C 29 , C 30 , C 31 , C 32 , C 33 , C 34 , C 35 , C 36 , C 37 , C 38 , C 39 , C 40 , C 41 , C 42 , C 43 , C 44 , C 45 , C 46 , C 47 , C 48 , C 49 or C 50 alkyl), wherein:

[0233] Each carbon is optionally substituted or replaced by: CR L1 R L2 , O, S, SO, SO 2 , NR L3 , SO 2 , NR L3 , SONR L3 , CONR L3 , NR L3 , CONR L4 , NR L3 , SO 2 , NR L4 , CO, CR L1 = CR L2 , C≡C, SiR L1 R L2 , P(O)R L1 , P(O)OR L1 , NR L3 , C(=NCN)NR L4 , NR L3 , C(=NCN), NR L3 , C(=CNO2 ) NR L4 , optionally substituted with 1 - 6 R L1 and / or R L2 groups, cycloalkyl, optionally substituted with 1 - 9 R 3-11 and / or R L1 groups, spirocycloalkyl, optionally substituted with 1 - 6 R L2 and / or R 5-13 groups, heterocyclic group, optionally substituted with 1 - 8 R L1 and / or R L2 groups, spiroheterocyclic group, optionally substituted with 1 - 6 R 3-11 and / or R L1 groups, aryl optionally substituted with 0 - 6 R L2 and / or R 5-13 groups, heteroaryl, where R L1 or R L2 are each independently optionally linked to other groups to form a cycloalkyl and / or heterocyclic group moiety optionally substituted with 1 - 4 R L1 groups; and L2 n 0> n 1> R L1 R L2 R L3 R L4 and R L5 are each independently H, halo, C 1-8 alkyl, OC 1-8 alkyl, SC 1-8 alkyl, NHC 1-8 alkyl, N(C 1-8 alkyl) 2 C 3-11 cycloalkyl, aryl, heteroaryl, C 3-11 heterocyclic group, OC 3-8 cycloalkyl, SC 3-8 cycloalkyl, NHC 3-8 cycloalkyl, N(C 3-8 cycloalkyl) 2 N(C 3-8 cycloalkyl)(C 1-8 alkyl), OH, NH 2 SH, SO 2 C 1-8 alkyl, P(O)(OC 1-8 alkyl)(C 1-8 alkyl), P(O)(OC 1-8 alkyl) 2 C 1-8 C 1-8 C 1-8 1-8 C - C1-8 alkyl, CCH, CH=CH(C 1-8 alkyl), C(C 1-8 alkyl)=CH(C 1-8 alkyl), C(C 1-8 alkyl)=C(C 1-8 alkyl) 2 , Si(OH) 3 , Si(C 1-8 alkyl) 3 , Si(OH)(C 1-8 alkyl) 2 , COC 1-8 alkyl, CO 2 H, halogen, CN, CF 3 , CHF 2 , CH 2 F, NO 2 , SF 5 , SO 2 NHC 1-8 alkyl, SO 2 N(C 1-8 alkyl) 2 , SONHC 1-8 alkyl, SON(C 1-8 alkyl) 2 , CONHC 1-8 alkyl, CON(C 1-8 alkyl) 2 , N(C 1-8 alkyl)CONH(C 1-8 alkyl), N(C 1-8 alkyl)CON(C 1-8 alkyl) 2 , NHCONH(C 1-8 alkyl), NHCON(C 1-8 alkyl) 2 , NHCONH 2 , N(C 1-8 alkyl)SO 2 NH(C 1-8 alkyl), N(C 1-8 alkyl)SO 2 N(C 1-8 alkyl) 2 , NH SO 2 NH(C 1-8 alkyl), NH SO 2 N(C 1-8 alkyl) 2 or NH SO 2 NH 2 .

[0235] In any aspect or embodiment described herein, the linker group is an optionally substituted C 1 -C 50 alkyl (e.g., C 1 、C 2 、C 3 、C 4 、C 5 、C 6 、C 7 、C 8 、C 9 、C 10 、C 11 、C 12 、C 13 、C 14 、C 15 、C 16 、C 17 、C 18 、C 19 、C 20 、C 21 、C 22 、C 23 、C 24 、C 25 、C 26 、C 27 、C 28 、C 29 、C 30 、C 31 、C 32 、C 33 、C 34 、C 35 、C 36 、C 37 、C 38 、C 39 、C 40 、C 41 、C 42 、C 43 、C 44 、C 45 、C 46 、C 47 、C 48 、C 49 or C 50alkyl, and includes all implicit sub-ranges, such as C1-C10, C1-C20; C2-C10, C2-20; C10-C20, C10-C50, etc.), where each carbon atom is optionally substituted or replaced by: an O, N, S, P or Si atom, having an appropriate number of hydrogens, substituents (e.g., OH, halo, alkyl, methyl, ethyl, haloalkyl, hydroxyalkyl, alkoxy, methoxy, etc.) or both to satisfy the valence; an optionally substituted aryl (e.g., optionally substituted C5 or C6 aryl) or bicyclic aryl (e.g., optionally substituted C5-C20 bicyclic heteroaryl); an optionally substituted heteroaryl (e.g., optionally substituted C5 or C6 heteroaryl) or bicyclic heteroaryl (e.g., an optionally substituted heteroaryl or bicyclic heteroaryl having one or more heteroatoms selected from N, O, S, P and Si, said heteroatoms having an appropriate number of hydrogens, substituents (e.g., OH, halo, alkyl, methyl, ethyl, haloalkyl, hydroxyalkyl, alkoxy, methoxy, etc.) or both to satisfy the valence); an optionally substituted C1-C6 alkyl; an optionally substituted C1-C6 alkenyl; an optionally substituted C1-C6 alkynyl; an optionally substituted cycloalkyl (e.g., optionally substituted C3-C7 cycloalkyl) or bicyclic cycloalkyl (e.g., optionally substituted C5-C20 bicyclic cycloalkyl); or an optionally substituted heterocycloalkyl (e.g., optionally substituted 3-, 4-, 5-, 6- or 7-membered heterocyclic group) or bicyclic heterocycloalkyl (e.g., an optionally substituted heterocycloalkyl bicyclic heterocycloalkyl having one or more heteroatoms selected from N, O, S, P or Si atoms, said heteroatoms having an appropriate number of hydrogens, substituents (e.g., OH, halo, alkyl, methyl, ethyl, haloalkyl, hydroxyalkyl, alkoxy, methoxy, etc.) or both to satisfy the valence). In any aspect or embodiment described herein, the optionally substituted alkyl linker is optionally substituted by one or more OH, halo, straight or branched C1-C6 alkyl (such as methyl or ethyl), straight or branched C1-C6 haloalkyl, straight or branched C1-C6 hydroxyalkyl, or straight or branched C1-C6 alkoxy (e.g., methoxy).

[0236] In any aspect or embodiment described herein, the linker (L) does not have heteroatom-heteroatom bonding (e.g., no heteroatoms are covalently linked or adjacent).

[0237] In any aspect or embodiment described herein, linker (L) includes from about 1 to about 50 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50) optionally substituted alkylene glycol units, where a carbon or oxygen may be substituted with a heteroatom selected from N, S, P, or Si atoms having a suitable number of hydrogens to satisfy valency.

[0238] In any aspect or embodiment described herein, unit A of linker (L) L comprises a structure selected from the group consisting of:

[0239]

[0240]

[0241]

[0242]

[0243] where N* is a nitrogen atom covalently linked to or shared with ULM or PTM.

[0244] In any aspect or embodiment described herein, unit A of linker (L) L comprises a structure selected from the group consisting of:

[0245]

[0246]

[0247]

[0248]

[0249] where:

[0250] N* is a nitrogen atom covalently linked to or shared with ULM or PTM; and

[0251] each of m, n, o, p, q, and r is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[0252] In any aspect or embodiment described herein, unit A of linker (L) L is selected from:

[0253]

[0254]

[0255]

[0256]

[0257] wherein N* is a nitrogen atom covalently linked to or shared with the ULM or PTM.

[0258] In any aspect or embodiment described herein, unit A of linker (L) L comprises a group represented by a general structure selected from the group consisting of:

[0259]

[0260]

[0261] and wherein,

[0262] m, n, o, p, q, and r of the linker are independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20;

[0263] when m, n, o, p, q, and r are zero, there are no N-O or O-O bonds,

[0264] X of the linker is H or F;

[0265]

[0266]

[0267]

[0268]

[0269]

[0270] wherein each n and m of the linker can independently be 0, 1, 2, 3, 4, 5, or 6.

[0271] In any aspect or embodiment described herein, unit A of linker (L) L is selected from the group consisting of:

[0272]

[0273]

[0274] where each m and n is independently selected from 0, 1, 2, 3, 4, 5 or 6.

[0275] In any aspect or embodiment described herein, unit A of joint (L) L is selected from the group consisting of:

[0276]

[0277]

[0278]

[0279]

[0280]

[0281]

[0282]

[0283]

[0284]

[0285]

[0286]

[0287]

[0288]

[0289]

[0290]

[0291]

[0292] where each m, n, o, p, q, r and s is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.

[0293] In any aspect or embodiment described herein, unit A of joint (L) LSelected from the group consisting of:

[0294]

[0295]

[0296]

[0297]

[0298]

[0299] In any aspect or embodiment described herein, the linker (L) comprises a structure selected from the structures shown below:

[0300]

[0301] Wherein:

[0302] W L1 and W L2 are each independently absent, a 4- to 8-membered ring having 0 to 4 heteroatoms, optionally substituted with R Q , each R Q is independently H, a halogen group, OH, CN, CF 3 , an optionally substituted straight-chain or branched C 1 -C 6 alkyl, an optionally substituted straight-chain or branched C 1 -C 6 alkoxy, or two R Q groups together with the atom to which they are attached form a 4- to 8-membered ring system having 0 to 4 heteroatoms;

[0303] Y L1 are each independently a bond; an optionally substituted straight-chain or branched C 1 -C 6 alkyl, and optionally one or more C atoms are replaced by O or NR YL1 ; an optionally substituted C 1 -C 6 alkene, and optionally one or more C atoms are replaced by O; an optionally substituted C 1 -C 6 alkyne, and optionally one or more C atoms are replaced by O; or an optionally substituted straight-chain or branched C 1 -C 6 alkoxy;

[0304] R YL1 is H, or an optionally substituted straight-chain or branched C 1-6 alkyl;

[0305] n is 0 - 10; and

[0306] Represents a connection point to PTM or ULM.

[0307] In any aspect or embodiment described herein, the linker (L) comprises a structure selected from the structures shown below:

[0308]

[0309] Wherein:

[0310] W L1 and W L2 are each independently absent, piperazine, piperidine, morpholine, optionally substituted with R Q substituted, each R Q is independently H, -Cl-, -F-, OH, CN, CF 3 , optionally substituted straight-chain or branched C 1 -C 6 alkyl (such as methyl, ethyl), optionally substituted straight-chain or branched C 1 -C 6 alkoxy (such as methoxy, ethoxy);

[0311] Y L1 are each independently a bond; optionally substituted straight-chain or branched C 1 -C 6 alkyl, and optionally one or more C atoms are replaced by O or NR YL1 substituted; optionally substituted C 1 -C 6 alkene, and optionally one or more C atoms are replaced by O; optionally substituted C 1 -C 6 alkyne, and optionally one or more C atoms are replaced by O; or optionally substituted straight-chain or branched C 1 -C 6 alkoxy;

[0312] R YL1 is H or optionally substituted straight-chain or branched C 1-6 alkyl (such as methyl, ethyl);

[0313] n is 0 - 10; and

[0314] Represents a connection point to PTM or ULM.

[0315] In any aspect or embodiment described herein, the linker (L) comprises a structure selected from the structures shown below:

[0316]

[0317] Wherein:

[0318] W L1 and W L2 each independently is absent; aryl; heteroaryl; ring; heterocycle; C 1-6 alkyl, and optionally one or more C atoms are replaced by O or NR YL1 ; C 1-6 alkene, and optionally one or more C atoms are replaced by O; C 1-6 alkyne, and optionally one or more C atoms are replaced by O; bicyclic; biaryl; diheteroaryl; or dicyclic, each optionally substituted by R Q substituted, each R Q independently is H, halo, OH, CN, CF 3 , hydroxy, nitro, C≡CH, C 2-6 alkenyl, C 2-6 alkynyl, optionally substituted straight-chain or branched C 1 -C 6 alkyl, optionally substituted straight-chain or branched C 1 -C 6 alkoxy, optionally substituted OC 1-3 alkyl (e.g., optionally substituted by 1 or more -F), OH, NH 2 , NR Y1 RY 2 , CN, or two R Q groups together with the atoms to which they are attached form a 4- to 8-membered ring system containing 0 to 4 heteroatoms;

[0319] Y L1 each independently is: a bond; NR YL1 ; O; S; NR YL2 ; CR YL1 R YL2 ; C=O; C=S; SO; SO 2 ; optionally substituted straight-chain or branched C 1 -C 6 alkyl, and optionally one or more C atoms are replaced by O; optionally substituted straight-chain or branched C 1 -C 6 alkoxy;

[0320] Q L is a 3- to 6-membered cycloaliphatic, bicyclic or aromatic ring having 0 to 4 heteroatoms, which is optionally bridged and optionally substituted by 0 to 6 R Q substituted, each R Q independently is H, optionally substituted straight-chain or branched C 1-6 alkyl (e.g., optionally substituted by 1 or more halo, C 1-6alkoxy-substituted), or two R Q groups together with the atoms to which they are attached form a 3- to 8-membered ring system containing 0 to 2 heteroatoms;

[0321] R YL1 and R YL2 are each independently: H; OH; optionally substituted straight-chain or branched C 1-6 alkyl (e.g., optionally substituted by 1 or more halo groups, C 1-6 alkoxy); or R 1 and R 2 groups together with the atoms to which they are attached form a 3- to 8-membered ring system containing 0 to 2 heteroatoms;

[0322] n is 0 to 10; and

[0323] represents the point of attachment to PTM or ULM.

[0324] In any aspect or embodiment described herein, the linker (L) comprises a structure selected from the structures shown below:

[0325]

[0326] wherein:

[0327] W L1 and W L2 are each independently absent; cyclohexane; cyclopentane; piperazine; piperidine; morpholine; C 1-6 alkyl, and optionally one or more C atoms are replaced by O or NR YL1 ; C 1-6 alkene, and optionally one or more C atoms are replaced by O; C 1-6 alkene, and optionally one or more C atoms are replaced by O; or C 1-6 alkyne, and optionally one or more C atoms are replaced by O, each optionally substituted by R Q where each R Q is independently H, -Cl, -F, OH, CN, CF 3 , hydroxy, optionally substituted straight-chain or branched C 1 -C 6 alkyl (e.g., methyl, ethyl) or optionally substituted straight-chain or branched C 1 -C 6 alkoxy;

[0328] Y L1 are each independently a bond; NR YL1 ; O; CR YL1 R YL2 ; C=O; optionally substituted straight-chain or branched C 1-C 6 alkyl, and optionally one or more C atoms are replaced by O or NR YL1 C; C 1-6 alkene, and optionally one or more C atoms are replaced by O; C 1-6 alkyne, and optionally one or more C atoms are replaced by O; or optionally substituted straight-chain or branched-chain C 1 -C 6 alkoxy;

[0329] Q L is a 3- to 6-membered heterocyclic, heterobicyclic or heteroaryl ring, which is optionally substituted by 0-6 R Q substituents, each R Q independently is H or optionally substituted straight-chain or branched-chain C 1-6 alkyl (for example, optionally substituted by 1 or more halogen groups, C 1-6 alkoxy);

[0330] R YL1 、R YL2 each independently is H, optionally substituted straight-chain or branched-chain C 1-6 alkyl (for example, methyl, ethyl, optionally substituted by 1 or more halogen groups, C 1-6 alkoxy);

[0331] n is 0-10; and

[0332] represents the point of attachment to PTM or ULM.

[0333] Exemplary PTM

[0334] In one aspect of the present disclosure, the PTM group (also referred to as the LTM group) binds to the target protein LRRK2 or a mutant form thereof.

[0335] The compositions described below illustrate members of the LRRK2-binding moiety that can be used according to the present invention. These binding moieties are preferably linked to the ubiquitin ligase-binding moiety (CLM) via a chemical linking group in order to present the LRRK2 protein (bound to the LTM) in the vicinity of the ubiquitin ligase for ubiquitination and subsequent degradation.

[0336] In certain instances, the term "target protein" is used to refer to the LRRK2 protein, which is a member of the leucine-rich repeat kinase family and is the target protein to be ubiquitinated and degraded. In other instances, the term "target protein" is used to refer to a mutant form of the LRRK2 protein, such as an LRRK protein having one or more mutations selected from the group consisting of G2019S, I2020T, N1437H, R1441G / C / H, and Y1699C.

[0337] The term "protein targeting moiety" or PTM is used to describe small molecules that bind to LRRK2 or mutant forms thereof, and can be used to target proteins for ubiquitination and degradation.

[0338] The compositions described herein illustrate the use of some of these PTMs.

[0339] In any aspect or embodiment described herein, the PTM is a small molecule that binds to LRRK2. For example, in any aspect or embodiment described herein, the PTM is represented by chemical structure PTM-IA or PTM-IB:

[0340]

[0341] wherein:

[0342] R 1 is selected from straight-chain or branched C1-C6 alkyl (e.g., isopropyl or tert-butyl), optionally substituted C3-C6 cycloalkyl (e.g., optionally substituted C3-C5 cycloalkyl, methylated C3-C5 cycloalkyl, or where the dashed line is the point of attachment to M of the PTM), straight-chain or branched C1-C6 haloalkyl (e.g., straight-chain or branched C1-C4 haloalkyl), optionally substituted C3-C6 halocycloalkyl (e.g., C3-C5 halocycloalkyl), optionally substituted alkyl nitrile (e.g., C1-C4 alkyl nitrile), optionally substituted C3-C6 cyclo nitrile (e.g., C3-C5 cyclo nitrile);

[0343] R 2 is selected from hydrogen, halogen (e.g., F, Cl or Br), C1-C3 alkyl or C1-C3 fluoroalkyl;

[0344] X 1 、X 2 、X 3 、X 4 、X 5 、X 6 and X 7 are each independently C, CH or N, where when it is CH, X 1 、X 2 and X 3 are each optionally substituted by R 2 ;

[0345] X 8 is CH, S or N;

[0346] M is CH 2 、NH or O;

[0347] is an optionally substituted 3- to 10-membered cycloalkyl or a heterocycloalkyl containing 1 to 4 (e.g., 1, 2, 3, or 4) heteroatoms selected from N, O, and S (e.g., optionally substituted with one or more (e.g., 1, 2, 3, or 4) substituents); and

[0348] of PTM represents the point of attachment to the linker (L) or ULM.

[0349] In any aspect or embodiment described herein, PTM is represented by chemical structures PTM-IIA, PTM-IIB, PTM-IIIA, and PTM-IIIB.

[0350]

[0351]

[0352] wherein:

[0353] R 1 is a straight-chain or branched C1-C6 alkyl (e.g., isopropyl or tert-butyl), an optionally substituted C3-C6 cycloalkyl (e.g., an optionally substituted C3-C5 cycloalkyl, a methylated C3-C5 cycloalkyl, or where the dashed line is the point of attachment to the M or oxygen atom of the PTM), a straight-chain or branched C1-C6 haloalkyl (e.g., a straight-chain or branched C1-C4 haloalkyl), an optionally substituted C3-C6 halocycloalkyl (e.g., a C3-C5 halocycloalkyl), an optionally substituted alkyl nitrile (e.g., a C1-C4 alkyl nitrile), an optionally substituted C3-C6 cyclo nitrile (e.g., a C3-C5 cyclo nitrile);

[0354] R 2 is hydrogen, a halogen (e.g., F, Cl, or Br), a C1-C3 alkyl, or a C1-C3 fluoroalkyl;

[0355] X 4 is CH or N;

[0356] M is CH 2 , NH, or O;

[0357] is an optionally substituted 3- to 10-membered heterocycloalkyl containing 1 to 4 (e.g., 1, 2, 3, or 4) heteroatoms selected from N, O, and S (e.g., optionally substituted with one or more (e.g., 1, 2, 3, or 4) substituents); and

[0358] of PTM represents the point of attachment to the chemical linker group or ULM.

[0359] In any aspect or embodiment described herein, including 1 - 4 substituents, each independently selected from halogen, OH, NH 2 , N(C1 - C3 alkyl) 2 , straight - chain or branched C1 - C4 alkyl (e.g., methyl or ethyl), straight - chain or branched C1 - C4 hydroxyalkyl, straight - chain or branched C1 - C4 alkoxy, and straight - chain or branched C1 - C4 haloalkyl).

[0360] In any aspect or embodiment described herein, PTM is covalently linked to L or ULM through an atom of the heterocycloalkyl or its substituent thereof.

[0361] In any aspect or embodiment described herein, is a 4 - 7 (e.g., 4, 5, 6, or 7) - membered cycloalkyl or a heterocycloalkyl containing 1 - 4 (e.g., 1, 2, 3, or 4) heteroatoms selected from N, O, and S, optionally substituted by one or more (e.g., 1, 2, 3, or 4) substituents, each substituent independently selected from halogen, OH, NH 2 , N(C1 - C3 alkyl) 2 , straight - chain or branched C1 - C4 alkyl, straight - chain or branched C1 - C4 hydroxyalkyl, straight - chain or branched C1 - C4 alkoxy, and straight - chain or branched C1 - C4 haloalkyl.

[0362] In any aspect or embodiment described herein, is a 4 - 7 (e.g., 5 or 6) - membered cycloalkyl or a heterocycloalkyl containing 1 - 4 (e.g., 1, 2, 3, or 4) heteroatoms selected from N, O, and S, the ring optionally substituted by one or more (e.g., 1, 2, 3, or 4) substituents, each substituent independently selected from straight - chain or branched C1 - C3 alkyl (e.g., methyl), straight - chain or branched C1 - C3 alkoxy (e.g., methoxy), and straight - chain or branched C1 - C3 haloalkyl.

[0363] In any aspect or embodiment described herein, is:

[0364] wherein:

[0365] R 3 and R 4 are each independently selected from H, halogen, OH, NH 2 , N(C1 - C3 alkyl) 2 , straight - chain or branched C1 - C4 alkyl, straight - chain or branched C1 - C4 hydroxyalkyl, straight - chain or branched C1 - C4 alkoxy, and straight - chain or branched C1 - C4 haloalkyl;

[0366] represents a point of attachment (i.e., a point of attachment to the 6-membered heteroaryl of the PTM); and

[0367] represents a point of attachment of the PTM to the L or ULM, and when absent, it can be attached to the L or ULM through an atom (e.g., carbon or nitrogen) of a 6-membered heterocycloalkyl, R 3 or R 4 is attached to the L or ULM.

[0368] In any aspect or embodiment described herein (such as but not limited to the aspects or embodiments in the foregoing paragraphs or the following paragraphs), it is:

[0369] In any aspect or embodiment described herein (such as but not limited to the aspects or embodiments in the foregoing paragraph), it is: In any aspect or embodiment described herein (such as but not limited to the aspects or embodiments in the foregoing paragraph), it is: In any aspect or embodiment described herein (such as but not limited to the aspects or embodiments in the foregoing paragraph), it is: In any aspect or embodiment described herein (such as but not limited to the aspects or embodiments in the foregoing paragraph), it is:

[0370] In any aspect or embodiment described herein, it is:

[0371] wherein:

[0372] R 3 is H or a straight-chain or branched C1-C3 alkyl (e.g., methyl or ethyl);

[0373] R 4 is H or a straight-chain or branched C1-C3 alkyl (e.g., methyl or ethyl);

[0374] represents a point of attachment (i.e., a point of attachment to the 6-membered heteroaryl of the PTM); and

[0375] Represents the connection point of PTM to L or ULM, and when absent, it can be connected to L or ULM through an atom of a 6 - membered heterocycloalkyl group (e.g., carbon or nitrogen of the 6 - membered heterocycloalkyl group), R 3 or R 4 connected to L or ULM.

[0376] In any aspect or embodiment described herein, selected from:

[0377] wherein R 3 and R 4 are defined as described in any aspect or embodiment herein.

[0378] In any aspect or embodiment described herein, selected from:

[0379] wherein:

[0380] R 3 and R 4 are defined as described in any aspect or embodiment herein; and

[0381] the heterocycloalkyl group is connected to L or PTM through an atom of the heterocycloalkyl group or its substituent (e.g., R 3 , R 4 or methyl).

[0382] In any aspect or embodiment described herein, PTM has the following chemical structure:

[0383]

[0384] wherein:

[0385] X 4 , R 1 , R 2 , R 3 and R 4 are defined as described in any aspect or embodiment herein; and

[0386] PTM is connected to L or ULM through an atom of the heterocycloalkyl A (e.g., carbon or nitrogen of the heterocycloalkyl group), R 3 or R 4 connected to L or ULM.

[0387] In any aspect or embodiment described herein, PTM has the following chemical structure:

[0388]

[0389]

[0390] Wherein:

[0391] X 4 , R 1 , R 2 , R 3 and R 4 are defined as described in any aspect or embodiment as described herein; and

[0392] The represents the connection point to L or ULM.

[0393] In any aspect or embodiment as described herein, R 1 is selected from optionally substituted C3-C5 cycloalkyl and straight-chain or branched C1-C4 alkyl.

[0394] In any aspect or embodiment as described herein, R 1 is Wherein: R 1a , R 1b and R 1C are each independently H or straight-chain or branched C1-C2 alkyl, each optionally substituted by one or more halogens or nitriles; or R 1a or R 1b together with the carbon to which they are attached form a C3-C6 cycloalkyl optionally substituted by one or more C1-C3 alkyl, nitrile or halogen.

[0395] In any aspect or embodiment as described herein, R 1 is Wherein: R 1a , R 1b and R 1C are each independently H or straight-chain or branched C1-C2 alkyl; or R 1a or R 1b together with the carbon to which they are attached form a C3-C6 cycloalkyl.

[0396] In any aspect or embodiment as described herein, PTM is selected from:

[0397]

[0398]

[0399] Wherein:

[0400] X, R 1a , R1b , R 1c , R 3 , R 4 and each of which is defined as described in any aspect or embodiment herein; and

[0401] L or ULM is connected through an atom of heteroalkyl A (e.g., carbon or nitrogen of heteroalkyl), R 3 or R 4 .

[0402] In any aspect or embodiment herein, PTM is selected from:

[0403]

[0404]

[0405] wherein:

[0406] X 4 , R 1a , R 1b , R 1c , R 3 and R 4 each of which is defined as described in any aspect or embodiment herein; and

[0407] The of PTM represents the point of attachment to L or ULM and is in the absence. In any aspect or embodiment herein, R 1 is selected from where the dashed line is the point of attachment to the M or oxygen atom of PTM.

[0408] In any aspect or embodiment herein, R 2 is H or F.

[0409] In any aspect or embodiment herein, PTM has the following chemical structure:

[0410]

[0411]

[0412] where the of PTM represents the point of attachment to the chemical linker group or ULM.

[0413] In any aspect or embodiment herein, PTM has the following chemical structure:

[0414]

[0415]

[0416]

[0417] Wherein the PTM is covalently linked to the L or ULM through an atom of the heterocyclic alkyl A or a substituent thereof.

[0418] In any aspect or embodiment described herein, the PTM has the following chemical structure:

[0419]

[0420]

[0421] Wherein represents the point of attachment to the L or ULM.

[0422] Therapeutic Compositions

[0423] The present invention also provides a pharmaceutical composition comprising a combination of a therapeutically effective amount of at least one bifunctional compound as described herein with a pharmaceutically acceptable carrier, additive, or excipient.

[0424] In another aspect, the present specification provides a therapeutic composition comprising an effective amount of a compound as described herein or a salt form thereof, and a pharmaceutically acceptable carrier, additive, or excipient, and optionally an additional bioactive agent. The therapeutic composition effects targeted protein degradation in a patient or subject (e.g., an animal such as a human), and can be used to treat or ameliorate a disease state or disorder that is modulated by degrading a target protein. In certain embodiments, the therapeutic composition as described herein can be used to effect protein degradation to treat or ameliorate an LRRK2-mediated inflammatory disease, autoimmune disease, or cancer. In certain additional embodiments, the disease is idiopathic PD, LRRK2 mutation-related PD (e.g., PD associated with one or more LRRK2 activating mutations), primary tauopathy (e.g., progressive supranuclear palsy (PSP) or corticobasal degeneration (CBD)), Lewy body dementia, Crohn's disease, leprosy (e.g., leprosy with a type 1 inflammatory response), and / or neuroinflammation.

[0425] In an alternative aspect, the present disclosure relates to a method for treating a disease state or ameliorating one or more symptoms of a disease or disorder in a subject in need thereof by degrading LRRK2 protein (e.g., wild-type LRRK2 protein or LRRK2 mutant protein (e.g., an LRRK2 mutant protein comprising one or more mutations selected from G2019S, I2020T, N1437H, R1441G / C / H, and Y1699C)), the method comprising administering to the patient or subject an effective amount (e.g., a therapeutically effective amount) of at least one compound as described herein, optionally in combination with a pharmaceutically acceptable carrier, additive, or excipient, and optionally co-administered with an additional bioactive agent, wherein the composition effectively treats or ameliorates the disease or disorder or one or more symptoms thereof in the subject. The methods according to the present disclosure can be used to treat certain disease states, disorders, or symptoms by administering an effective amount of at least one compound described herein, including inflammatory diseases, autoimmune diseases, or cancer. For example, the methods according to the present disclosure can be used to treat one or more of the following: Parkinson's disease (PD), idiopathic PD, LRRK2 mutation-related PD (e.g., PD associated with one or more LRRK2 activating mutations), primary tauopathies (e.g., progressive supranuclear palsy (PSP) or corticobasal degeneration (CBD)), Lewy body dementia, Crohn's disease, leprosy (e.g., leprosy with a type 1 inflammatory response), and neuroinflammation (such as neuroinflammation observed in Alzheimer's disease, PD, multiple sclerosis, traumatic brain injury, spinal cord injury, etc.).

[0426] The present disclosure also includes pharmaceutical compositions comprising a pharmaceutically acceptable salt of a compound as described herein, particularly acid or base addition salts. The acids used to prepare the pharmaceutically acceptable acid addition salts of the above compounds that can be used in accordance with this aspect are acids that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, glucuronate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate [i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)] and the like.

[0427] Pharmaceutically acceptable base addition salts can also be used to produce pharmaceutically acceptable salt forms of the compounds according to the present disclosure. Chemical bases that can be used as reagents for preparing pharmaceutically acceptable base salts of the compounds of the present invention are chemical bases that form non-toxic base salts with these compounds. Such non-toxic base salts include, but are not limited to, base salts derived from such pharmaceutically acceptable cations, such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium, zinc, and magnesium), ammonium or water-soluble amine addition salts (such as N-methylglucamine-(meglumine)), and other base salts of lower alkanolammonium and pharmaceutically acceptable organic amines, etc.

[0428] According to the present disclosure, the compounds described herein can be administered by oral, parenteral, or topical routes, either as a single dose or in divided doses. The range of administration of the active compound can range from continuous (intravenous infusion) to oral administration several times a day (e.g., Q.I.D.), and can include oral, topical, parenteral, intramuscular, intravenous, subcutaneous, transdermal (which may include a permeation enhancer), buccal, sublingual, intranasal, intraocular, intrathecal, vaginal, and suppository administration, as well as other routes of administration. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. Enteric-coated oral tablets can also be used to improve the bioavailability of the compound from the oral route of administration. The most effective dosage form will depend on the pharmacokinetics of the particular agent selected, as well as the type, location, and severity of the disease, disorder, or symptom, and the health status of the patient. The compounds according to the present disclosure can also be administered as sprays, mists, or aerosols for intranasal, intratracheal, or pulmonary administration. Accordingly, the present disclosure also relates to pharmaceutical compositions comprising an effective amount of the compounds described herein, optionally in combination with a pharmaceutically acceptable carrier, additive, or excipient. The compounds according to the present disclosure can be administered in immediate release, intermediate release, or sustained or controlled release forms. Sustained or controlled release forms are preferably administered orally, but also in suppositories and transdermal or other topical forms. Intramuscular injection of liposomal forms or depot preparations can also be used to control or maintain the release of the compound at the injection site.

[0429] The compositions described herein can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers and can also be administered in the form of controlled release formulations. Pharmaceutically acceptable carriers that can be used in these pharmaceutical compositions include, but are not limited to, ion exchange agents, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffering substances (such as phosphates, glycine), sorbic acid, potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon dioxide, magnesium trisilicate), polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polypropylene-block polymers, polyethylene glycol, and lanolin, and combinations thereof.

[0430] The sterile injectable form of the compositions described herein can be an aqueous or an oily suspension. These suspensions can be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are commonly employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be used, including synthetic mono- or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are suitable for the preparation of injectables, as are natural pharmaceutically acceptable oils such as olive oil or castor oil, especially in their polyoxylated forms. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as Ph.Helv or similar alcohols.

[0431] The pharmaceutical compositions described herein can be administered orally in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions or solutions. In the case of oral tablets, common carriers include lactose and corn starch, as well as other carriers known in the art. For oral administration in capsule form, useful diluents include lactose and corn starch. When an aqueous suspension is to be administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring, or coloring agents can also be added. Lubricants such as magnesium stearate are generally also added.

[0432] Optionally, the pharmaceutical compositions described herein can be administered rectally in the form of suppositories. These suppositories can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter, beeswax, and polyethylene glycol.

[0433] The pharmaceutical compositions as described herein can also be administered topically. For topical application, the pharmaceutical composition can be formulated as a transdermal patch, which can be a reservoir patch or a matrix patch, comprising a combination of the active compound with one or more carriers, buffers, absorption enhancers, and providing continuous administration for 1 day to two weeks.

[0434] Alternatively, the pharmaceutical compositions of the present disclosure can be formulated as a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of the present disclosure include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, and water.

[0435] Alternatively, the pharmaceutical compositions of the present disclosure can be formulated as a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0436] Alternatively, the pharmaceutical compositions of the present disclosure can be formulated for ophthalmic applications. For example, the pharmaceutical composition can be formulated as a micronized suspension in isotonic, pH-adjusted sterile saline, or preferably, as a solution in isotonic, pH-adjusted sterile saline with or without a preservative such as benzalkonium chloride. Optionally, for ophthalmic applications, the pharmaceutical composition can be formulated as an ointment such as petrolatum.

[0437] The pharmaceutical compositions as described herein can also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation, and can be prepared as a solution in physiological saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0438] The amount of the active pharmaceutical ingredient that can be combined with the carrier material to produce a single dosage form in the pharmaceutical compositions as described herein will vary depending on the condition of the subject and the disease, disorder, or symptom being treated, the particular mode of administration, and the circumstances of the subject. Preferably, the composition should be formulated to contain between about 0.05 mg and about 750 mg or more, more preferably about 1 mg to about 600 mg, and even more preferably about 10 mg to about 500 mg of the active ingredient, either alone or in combination with another compound according to the present disclosure.

[0439] It should also be understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity and bioavailability of the specific compound employed, age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the judgment of the treating physician, and the severity of the particular disease or disorder being treated.

[0440] A patient or subject in need of treatment with a compound according to the methods described herein can be treated by administering to the patient (subject) an effective amount of a compound according to the present disclosure, optionally in a pharmaceutically acceptable carrier or diluent, alone or in combination with another known therapeutic agent, depending on the pharmaceutically acceptable salts or solvates of the compounds according to the present disclosure.

[0441] In certain aspects, the active compound is combined with a pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver a therapeutically effective amount for the desired indication to the patient without causing an undue degree of severe toxic effects to the patient being treated. For all the disorders mentioned herein, the preferred dosage of the active compound is in the range of about 10 nanograms per kilogram (ng / kg) to 300 milligrams per kilogram (mg / kg), preferably 0.1 to 100 mg / kg per day, and more generally 0.5 to about 25 mg per kilogram of recipient / patient body weight per day. A typical topical dosage range will be 0.01 - 5% wt / wt in a suitable carrier.

[0442] In certain aspects, the compound is conveniently administered in any suitable unit dosage form, including but not limited to dosage forms containing less than 1 milligram (mg), 1 mg to 3000 mg, or 5 mg to 500 mg of the active ingredient per unit dosage form. An oral dosage of about 25 mg - 250 mg is usually convenient.

[0443] In certain aspects, it is preferred to administer the active ingredient to achieve a peak plasma concentration of the active compound of about 0.00001 - 30 millimolar (mM), preferably about 0.1 - 30 micromolar (μM). This can be achieved, for example, by intravenous injection of a solution or formulation of the active ingredient (optionally in saline or an aqueous medium), or by bolus administration of the active ingredient. Oral administration may also be suitable for producing an effective plasma concentration of the active agent.

[0444] The concentration of the active compound in the pharmaceutical composition will depend on the rate of absorption, distribution, inactivation, and excretion of the drug, as well as other factors known to those skilled in the art. It should be noted that the dosage values will also vary with the severity of the disorder to be alleviated. It should be further understood that for any particular subject, the specific dosage regimen should be adjusted over time according to individual needs and the professional judgment of the person administering or supervising the administration of the composition, and the concentration ranges set forth herein are only exemplary and are not intended to limit the scope or practice of the claimed composition. The active ingredient can be administered in one dose, or it can be divided into multiple smaller doses and administered at different time intervals.

[0445] Oral compositions will generally include an inert diluent or an edible carrier. They can be encapsulated in gelatin capsules or compressed into tablets. For purposes of oral therapeutic administration, the active compound or its prodrug derivatives can be combined with excipients and used in the form of tablets, lozenges, or capsules. Pharmaceutically compatible binders and / or adjuvant materials can be included as part of the composition.

[0446] Tablets, pills, capsules, lozenges, etc. can contain any of the following ingredients or compounds with similar properties: binders such as microcrystalline cellulose, tragacanth, or gelatin; excipients such as starch or lactose; disintegrants such as alginic acid, Primogel, or corn starch; lubricants such as magnesium stearate or Sterotes; glidants such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin; or flavoring agents such as peppermint, methyl salicylate, or orange flavoring. When the dosage unit form is a capsule, it can also contain a liquid carrier such as a fatty oil, in addition to the above types of materials. In addition, the dosage unit form can contain various other materials that modify the physical form of the dosage unit, such as coatings of sugar, shellac, or enteric solvents.

[0447] The active compound or its pharmaceutically acceptable salt can be administered as a component of elixirs, suspensions, syrups, wafers, chewing gums, etc. In addition to the active compound, syrups can also contain sucrose (as a sweetening agent) and certain preservatives, dyes, and coloring agents, as well as flavoring agents.

[0448] The active compound or its pharmaceutically acceptable salt can also be mixed with other active materials that do not impair the desired action, or with materials that supplement the desired action, such as anticancer agents as described herein, etc. In certain preferred aspects of the present disclosure, one or more compounds according to the present disclosure are co-administered with another bioactive agent, such as an anticancer agent or a wound healing agent, including antibiotics as further described herein.

[0449] Solutions or suspensions for parenteral, intradermal, subcutaneous, or topical administration may include the following components: a sterile diluent, such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol, or other synthetic solvents; an antibacterial agent, such as benzyl alcohol or methylparaben; an antioxidant, such as ascorbic acid or sodium bisulfite; a chelating agent, such as ethylenediaminetetraacetic acid; a buffer, such as acetate, citrate, or phosphate, and an agent for adjusting tonicity, such as sodium chloride or dextrose. Parenteral formulations may be enclosed in ampoules, disposable syringes, or multi-dose vials made of glass or plastic.

[0450] If administered intravenously, a preferred carrier is saline or phosphate-buffered saline (PBS).

[0451] In any aspect or embodiment, the active compound is prepared with a carrier that will prevent the rapid elimination of the compound from the body, such as a controlled release formulation comprising implants and microencapsulation delivery systems. Biodegradable biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid may be used. Methods for preparing such formulations will be apparent to those skilled in the art.

[0452] Liposome suspensions may also be a pharmaceutically acceptable carrier. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811, which is incorporated herein by reference in its entirety. For example, liposomal formulations can be prepared by dissolving appropriate one or more lipids (such as stearoyl phosphatidylethanolamine, stearoyl phosphatidylcholine, arachidoyl phosphatidylcholine, and cholesterol) in an inorganic solvent, followed by evaporation, leaving a dry lipid film on the surface of the container. An aqueous solution of the active compound is then introduced into the container. The container is then vortexed by hand to release the lipid material from the sides of the container and disperse the lipid aggregates, thereby forming a liposome suspension.

[0453] Therapeutic Methods

[0454] In another aspect, the present specification provides a method of treatment, the method of treatment comprising administering an effective amount of a compound or a salt form thereof as described herein, and a pharmaceutically acceptable carrier. The method of treatment can be used to effect protein degradation in a patient or subject in need thereof (e.g., an animal such as a human) for treating or ameliorating a disease state, disorder, or related symptoms that can be treated by targeted protein degradation.

[0455] As used herein, the terms "treat", "treating", "treatment" and the like refer to any action that provides a benefit to a patient to whom a compound of the invention can be administered, including treating any disease state, disorder or symptom associated with a protein to which a compound of the invention binds. Disease states or disorders that can be treated using the compounds according to the disclosure are set forth above, including cancer.

[0456] This specification provides methods of treatment for achieving targeted protein degradation for treating or ameliorating diseases such as Parkinson's disease (PD), primary tauopathies, Lewy body dementia, Crohn's disease, leprosy and / or neuroinflammation (such as described in In any aspect or embodiment, the disease is idiopathic PD, LRRK2 mutation-associated PD (e.g., PD associated with one or more LRRK2 activating mutations), PSP, CBD, leprosy with type 1 inflammatory response, Alzheimer's disease, PD, multiple sclerosis, traumatic brain injury and / or spinal cord injury. Thus, in another aspect, this specification provides methods for ubiquitinating / degrading a target protein in a cell. In certain embodiments, the method comprises administering a bifunctional compound of the invention. Control or reduction of the level of a specific protein in a subject's cells as provided by the present disclosure provides treatment of a disease state, disorder or symptom. In any aspect or embodiment, the method comprises administering an effective amount of a compound as described herein, optionally comprising a pharmaceutically acceptable excipient, carrier, adjuvant, another bioactive agent or a combination thereof.

[0457] In further embodiments, this specification provides methods for treating or ameliorating a disease, disorder or a symptom thereof in a subject or patient (e.g., an animal such as a human), the method comprising administering to a subject in need thereof a composition comprising an effective amount (e.g., a therapeutically effective amount) of a compound as described herein or a salt form thereof and a pharmaceutically acceptable excipient, carrier, adjuvant, another bioactive agent or a combination thereof, wherein the composition effectively treats or ameliorates the disease or disorder or a symptom thereof in the subject.

[0458] In another aspect, this specification provides methods for identifying the effect of degrading a target protein in a biological system using a compound according to the disclosure.

[0459] In another aspect, the present specification provides a method for preparing a molecule that can cause the degradation of intracellular LRRK2, the method comprising the steps of: (i) providing a small molecule that binds to LRRK2 or a mutant form thereof; (ii) providing an E3 ubiquitin ligase binding moiety (ULM), preferably CLM, such as thalidomide, pomalidomide, lenalidomide or analogues thereof; and (iii) covalently coupling the small molecule of step (i) to the ULM of step (ii) through a chemical linking group (L) to form a compound that binds to the cereblon E3 ubiquitin ligase and the LRRK2 protein and / or mutant form in cells, such that the cereblon E3 ubiquitin ligase approaches and ubiquitinates the bound LRRK2 protein, whereby the ubiquitinated LRRK2 is subsequently degraded.

[0460] In another aspect, the present specification provides a method for detecting whether a molecule can trigger the degradation of the LRRK2 protein in cells, the method comprising the steps of: (i) providing a molecule whose ability to trigger the degradation of the LRRK2 protein in cells is to be detected, the molecule having the following structure: CLM-L-PTM, wherein CLM is a cereblon E3 ubiquitin ligase binding moiety capable of binding to the cereblon E3 ubiquitin ligase in cells, the CLM being thalidomide, pomalidomide, lenalidomide or analogues thereof; PTM is a protein targeting moiety, which is a small molecule that binds to LRRK2 and / or its mutant LRRK form, the LRRK2 having at least one lysine residue that can be ubiquitinated by the cereblon E3 ubiquitin ligase that binds to this molecule; and L is a chemical linking group that covalently links CLM to PTM to form the molecule; (ii) incubating cells expressing the LRRK2 protein in the presence of the molecule of step (i); and (iii) detecting whether the LRRK2 protein in the cells is degraded.

[0461] In any aspect or embodiment described herein, the small molecule capable of binding to LRRK2 is a small molecule that binds to LRRK2. In certain embodiments, the small molecule that binds to LRRK2 is as described herein.

[0462] In another aspect of the treatment, the present disclosure provides a method of treating a human patient in need of such treatment for a disease state, disorder or symptom causally related to LRRK2 and / or a mutant form of LRRK2, expression, overexpression, mutation, aggregation, accumulation, misfolding or dysregulation, wherein degradation of the LRRK2 protein will produce a therapeutic effect in the patient, the method comprising administering to the patient an effective amount of a compound according to the present disclosure, optionally in combination with another bioactive agent.

[0463] In another aspect of the treatment, the present disclosure provides a method of treating a human patient in need of such treatment for a disease state, disorder or symptom causally related to α-synuclein expression, overexpression, mutation, aggregation, accumulation, misfolding or dysregulation, wherein degradation of the LRRK2 protein and / or its mutant forms will produce a therapeutic effect in the patient, the method comprising administering to the patient an effective amount of a compound according to the present disclosure, optionally in combination with another bioactive agent.

[0464] In another aspect of the treatment, the present disclosure provides a method of treating a human patient in need of such treatment for a disease state, disorder or symptom causally related to α-synuclein expression, overexpression, mutation, aggregation, misfolding or dysregulation, wherein degradation of the LRRK2 protein and / or its mutant forms will produce a therapeutic effect in the patient, the method comprising administering to the patient an effective amount of a compound according to the present disclosure, optionally in combination with another bioactive agent.

[0465] In another aspect of the treatment, the present disclosure provides a method of treating a human patient in need of such treatment for a disease state, disorder or symptom causally related to Tau expression, overexpression, mutation, aggregation, misfolding or dysregulation, wherein degradation of the LRRK2 protein and / or its mutant forms will produce a therapeutic effect in the patient, the method comprising administering to the patient an effective amount of a compound according to the present disclosure, optionally in combination with another bioactive agent.

[0466] The disease state, disorder or symptom may be caused by a microbial agent or other exogenous agent such as a virus, bacterium, fungus, protozoan or other microbe, or may be a disease state caused by the expression, overexpression, mutation, misfolding or dysregulation of a protein that results in the disease state, disorder or symptom.

[0467] In another aspect, the present disclosure provides a method of treating or ameliorating at least one symptom of a disease or disorder in a subject, the method comprising the steps of:

[0468] Providing a subject identified as having a symptom of a disease or disorder causally related to the expression, overexpression, mutation, misfolding or dysregulation of the LRRK2 protein and / or its mutant forms in the subject, and treating or ameliorating the symptom of the disease or disorder by degrading the LRRK2 protein and / or its mutant forms in the cells of the subject; and administering to the subject a therapeutically effective amount of a compound comprising a small molecule of the invention such that the LRRK2 protein and / or its mutant forms are degraded, thereby treating or ameliorating at least one symptom of the disease or disorder in the subject.

[0469] The term "disease state or disorder" is used to describe any disease state or disorder in which there is overexpression, mutation, misfolding or dysregulation of protein expression (e.g., an elevated amount of a protein expressed in a patient), and in which degradation of the LRRK2 protein and / or its mutant forms serves to lower or stabilize the level of the LRRK2 protein (mutated or not) in a patient in need thereof, providing beneficial treatment or symptom relief. In some cases, the disease state, disorder or symptom can be cured.

[0470] Disease states, disorders or symptoms that can be treated using the compounds according to the present disclosure include, for example, Parkinson's disease (PD), idiopathic PD, LRRK2 mutation-associated PD (e.g., PD associated with one or more LRRK2 activating mutations), primary tauopathies (e.g., progressive supranuclear palsy (PSP) or corticobasal degeneration (CBD)), dementia with Lewy bodies, Crohn's disease, leprosy (e.g., leprosy with a type 1 inflammatory response), and / or neuroinflammation (such as neuroinflammation observed in Alzheimer's disease, PD, multiple sclerosis, traumatic brain injury, spinal cord injury, etc.).

[0471] The term "bioactive agent" is used to describe an agent other than the compounds according to the present disclosure that is used in combination with the compounds of the invention as a bioactive agent to help achieve the desired treatment, inhibition, and / or prevention / control using the compounds of the invention. Preferred bioactive agents for use herein include those agents having a pharmacological activity similar to that of using or administering the compounds of the invention, and include, for example, anti-cancer agents, anti-viral agents, particularly including anti-HIV agents and anti-HCV agents, anti-bacterial agents, anti-fungal agents, etc.

[0472] The term "additional anti-autoimmune disease agent" is used to describe a therapeutic agent for an autoimmune disease that can be combined with the compounds according to the present disclosure to treat an autoimmune disease. These agents include, for example, infliximab, tofacitinib, baricitinib, secukinumab, adalimumab, etanercept, golimumab, certolizumab, anti-proliferative drugs (e.g., mycophenolate mofetil), and corticosteroids.

[0473] The term "pharmaceutically acceptable derivative" is used throughout the specification to describe any pharmaceutically acceptable prodrug form (such as esters, amides, and other prodrug groups) that directly or indirectly provides the compound of the invention or an active metabolite of the compound of the invention when administered to a patient.

[0474] Examples

[0475] Abbreviations

[0476] ACN Acetonitrile

[0477] AcOH Acetic acid

[0478] Boc tert-Butyloxycarbonyl

[0479] dba Dibenzylideneacetone

[0480] DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene

[0481] DCM Dichloromethane

[0482] DMA Dimethylacetamide

[0483] DME Dimethoxyethane

[0484] DMF Dimethylformamide

[0485] DMSO Dimethyl sulfoxide

[0486] DMAC / DMA Dimethylacetamide

[0487] DIEA N,N-Diisopropylethylamine

[0488] EDTA Ethylenediaminetetraacetic acid

[0489] EtOAc / EA Ethyl acetate

[0490] EtOH Ethanol

[0491] FA Formic acid

[0492] HPLC High performance liquid chromatography

[0493] Hz Hertz

[0494] IBX 2-Iodoxybenzoic acid

[0495] LAH Lithium aluminum hydride

[0496] LCMS Liquid chromatography / mass spectrometry

[0497] LiHMDS Lithium bis(trimethylsilyl)amide

[0498] MHz Megahertz

[0499] NBS N-Bromosuccinimide

[0500] NCS N-Chlorosuccinimide

[0501] NMR Nuclear magnetic resonance

[0502] NMP N-Methyl-2-pyrrolidone

[0503] MeOH Methanol

[0504] MPLC Medium pressure liquid chromatography

[0505] MTBE Methyl tert-butyl ether

[0506] PE Petroleum ether

[0507] Psi Pounds per square inch

[0508] RT or r.t. Room temperature

[0509] SFC Supercritical fluid chromatography

[0510] TEA Triethylamine

[0511] THF Tetrahydrofuran

[0512] TFA Trifluoroacetic acid

[0513] TLC Thin layer chromatography

[0514] TMS Trimethylsilyl

[0515] General Synthetic Methods

[0516] The synthesis implementation and optimization of the bifunctional molecules as described herein can be carried out in a stepwise or modular manner. For example, if no suitable ligand is immediately available, the identification of a compound that binds to a target protein (i.e., LRRK2) may involve high-throughput or medium-throughput screening activities. It is not uncommon for the initial ligand to require iterative design and optimization cycles to improve suboptimal aspects as identified through data from suitable in vitro and pharmacological and / or ADMET assays. Part of the optimization / SAR activity will be to probe positions where the ligand tolerates substitution and may be a suitable position for attaching the chemical linker groups mentioned earlier in this text. In cases where crystallographic or NMR structural data are available, these data can be used to focus this synthetic effort.

[0517] In a very similar manner, ligands for E3 ligases can be identified and optimized.

[0518] With PTMs and UMLs (e.g., CLMs), those skilled in the art can use known synthetic methods to combine them with or without one or more chemical linker groups. One or more chemical linker groups with a range of compositions, lengths, and flexibilities can be synthesized and functionalized such that the PTM and UML groups can be sequentially attached to the distal end of the linker. Thus, a library of bifunctional molecules can be realized and analyzed in in vitro and in vivo pharmacological and ADMET / PK studies. Like the PTM and UML groups, the final bifunctional molecules can be subjected to iterative design and optimization cycles in order to identify molecules with the desired properties.

[0519] In certain instances, a protecting group strategy and / or functional group interconversion (FGI) may be required to facilitate the preparation of the desired substance. Such chemical processes are well-known to synthetic organic chemists, and many of them can be found in texts such as “Greene's Protective Groups in Organic Synthesis” by Peter G.M. Wuts and Theodora W. Greene (Wiley) and “Organic Synthesis: The Disconnection Approach” by Stuart Warren and Paul Wyatt (Wiley).

[0520] Synthetic Procedures

[0521] General synthetic scheme

[0522] Scheme 1:

[0523]

[0524] Scheme 2:

[0525]

[0526] Scheme 3:

[0527]

[0528] Exemplary synthesis of intermediate 1, 2-(2,6-dioxo-3-piperidinyl)-5-hydroxy-isoindoline-1,3-dione

[0529] Step 1

[0530]

[0531] Sodium acetate (4.1 g, 49.4 mmol, 3.00 equiv) was added to a solution of 3-aminopiperidine-2,6-dione (4.1 g, 24.7 mmol, 1.50 equiv, HCl salt) in acetic acid (45 mL), and the mixture was then stirred at 25 °C for 1 h. 4-Hydroxyphthalic acid (3.0 g, 16.5 mmol, 1.00 equiv) was then added to the mixture and heated to 120 °C, and stirred for an additional 11 h. LCMS showed detection of the desired MS and the reaction was complete. The mixture was concentrated, then poured into water (20 mL), and then filtered. The crude product was purified by column chromatography (dichloromethane:methanol = 50:1 to 10:1) to afford 2-(2,6-dioxo-3-piperidinyl)-5-hydroxy-isoindoline-1,3-dione (3.9 g, 14.3 mmol, 86% yield) as a colorless solid.

[0532] Exemplary Synthesis of Intermediate 2,2-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-5-yl]oxyacetaldehyde

[0533] Step 1

[0534]

[0535] To a solution of 2-bromo-1,1-dimethoxy-ethane (3.22 g, 19.04 mmol, 2 equiv) in dimethylformamide (20 mL) was added potassium carbonate (3.95 g, 28.56 mmol, 3 equiv) and dimethyl 4-hydroxybenzene-1,2-dicarboxylate (2 g, 9.52 mmol, 1 equiv). The mixture was stirred at 100 °C for 3 h. LCMS indicated that the 4-hydroxybenzene-1,2-dicarboxylate was completely consumed and a new spot was formed. The reaction mixture was quenched with water (200 mL) at 25 °C and then extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (50 mL × 3), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 15:1 to 8:1). Dimethyl 4-(2,2-dimethoxyethoxy)benzene-1,2-dicarboxylate was obtained as a yellow oil (2.64 g, 8.85 mmol, 92% yield).

[0536] Step 2

[0537]

[0538] To a solution of dimethyl 4-(2,2-dimethoxyethoxy)benzene-1,2-dicarboxylate (2.64 g, 8.86 mmol, 1 equiv) in methanol (20 mL) was added sodium hydroxide (4 M, 4.43 mL, 2 equiv). The mixture was stirred at 40 °C for 12 h. The reaction mixture was quenched with hydrochloric acid (20 mL) at 20 °C, then diluted with water (100 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (50 mL × 3), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was used in the next step without further purification. 4-(2,2-Dimethoxyethoxy)phthalic acid was obtained as a yellow oil (2.2 g, 8.14 mmol, 91% yield).

[0539] Step 3

[0540]

[0541] To a solution of 4-(2,2-dimethoxyethoxy)phthalic acid (2.2 g, 8.14 mmol, 1 equiv) in pyridine (10 mL) was added 3-aminopiperidine-2,6-dione (2.01 g, 12.21 mmol, 1.5 equiv, hydrochloride). The mixture was stirred at 100 °C for 12 h. The reaction mixture was concentrated under reduced pressure to remove pyridine (10 mL). The residue was diluted with water (200 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (50 mL × 3), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 10:1 to 3:1). Compound 5-(2,2-dimethoxyethoxy)-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione was obtained as a yellow oil (1.6 g, 4.20 mmol, 51% yield, 95% purity).

[0542] Step 4

[0543]

[0544] To a solution of 5-(2,2-dimethoxyethoxy)-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione (192 mg, 0.53 mmol, 1 equiv) in tetrahydrofuran (10 mL) was added sulfuric acid (2 M, 10.6 mL, 40 equiv), and the mixture was stirred at 70 °C for 1 h. The reaction mixture was quenched by addition of sodium bicarbonate (5 mL) at 20 °C, followed by dilution with water (50 mL) and extraction with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (20 mL × 3), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was used in the next step without further purification. Compound 2-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-5-yl]oxyacetaldehyde was obtained as a white solid (160 mg, 0.50 mmol, 95% yield).

[0545] Exemplary synthesis of intermediate 2-[2-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-5-yl]oxyethoxy]ethyl 4-methylbenzenesulfonate

[0546] Step 1

[0547]

[0548] To a solution of 2-(2,6-dioxo-3-piperidinyl)-5-hydroxy-isoindoline-1,3-dione (300 mg, 1.09 mmol, 1 equiv) and 2-(2-hydroxyethoxy)ethyl 4-methylbenzenesulfonate (341 mg, 1.31 mmol, 1.2 equiv) in N,N-dimethylformamide (4 mL) was added potassium carbonate (302 mg, 2.19 mmol, 2 equiv). The mixture was stirred at 60 °C for 12 h. LCMS showed the reaction was complete. The mixture was diluted with water (10 mL) and extracted with dichloromethane (10 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (dichloromethane:methanol = 1:0 to 50:1) to give 2-(2,6-dioxo-3-piperidinyl)-5-[2-(2-hydroxyethoxy)ethoxy]isoindoline-1,3-dione (400 mg) as a yellow oil.

[0549] Step 2

[0550]

[0551] To a solution of 2-(2,6-dioxo-3-piperidinyl)-5-[2-(2-hydroxyethoxy)ethoxy]isoindoline-1,3-dione (400 mg, 1.10 mmol, 1 equiv) in dichloromethane (5 mL) was added p-toluenesulfonyl chloride (315 mg, 1.66 mmol, 1.5 equiv), 4-dimethylaminopyridine (13 mg, 0.11 mmol, 0.1 equiv) and triethylamine (335 mg, 3.31 mmol, 3 equiv). The mixture was stirred at 25 °C for 12 h. LCMS showed the reaction was complete. The mixture was diluted with water (10 mL) and extracted with dichloromethane (10 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative reverse-phase thin layer chromatography (dichloromethane:methanol = 20:1) to give 2-[2-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindolin-5-yl]oxyethoxy]ethyl 4-methylbenzenesulfonate (150 mg, 0.29 mmol, 26% yield) as a colorless oil.

[0552] The related intermediates 2-[2-[2-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-5-yl]oxyethoxy]ethoxy]ethyl 4-methylbenzenesulfonate, 2-[2-[2-[2-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-5-yl]oxyethoxy]ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate, and 2-[2-[2-[2-[2-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-5-yl]oxyethoxy]ethoxy]ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate were prepared in a manner similar to 2-[2-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-5-yl]oxyethoxy]ethyl 4-methylbenzenesulfonate.

[0553] Exemplary Synthesis of Exemplary Compound 1

[0554] Step 1

[0555]

[0556] At 0 °C under N 2 To a solution of 2-bromo-4-fluoro-1-nitrobenzene (16.78 g, 76.28 mmol, 1.1 eq) and 1-methylcyclopropanol (5 g, 69.34 mmol, 1 eq) in DMF (160 mL) was added NaH (4.16 g, 104.01 mmol, 60% in mineral oil, 1.5 eq) in one portion. The mixture was then heated to 20 °C and stirred for 4 h. TLC showed a new spot. The residue was poured into water (200 mL) and stirred for 10 min. The aqueous phase was extracted with ethyl acetate (3 x 300 mL). The combined organic phases were washed with brine (2 x 200 mL), dried over anhydrous Na 2 SO 4 and filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (100 - 200 mesh silica gel, 0 - 2% ethyl acetate in petroleum ether) to give 2-bromo-4-(1-methylcyclopropoxy)-1-nitrobenzene as a yellow oil (14.3 g, 52.56 mmol, 75.79% yield).

[0557] Step 2

[0558]

[0559] At 20 °C to 2-bromo-4-(1-methylcyclopropoxy)-1-nitrobenzene (14.3 g, 52.56 mmol, 1 eq), K 2 CO 3(14.53 g, 105.11 mmol, 2 eq.) and Cs 2 CO 3 To a mixture of 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborane (32.99 g, 131.39 mmol, 36.73 mL, 50% purity in EtOAc, 2.5 eq.) and Pd(PPh 3 ) 4 The mixture was stirred for 1 h at 40 ℃ for 2 h at 40 ℃ for 3 hours.Then the mixture was stirred for 1 h at 40 ℃ for 2 h at 40 ℃ for 3 hours.Then the mixture was stirred for 1 h at 40 ℃ for 2 h at 40 ℃ for 3 hours.Then the mixture was stirred for 1 h at 40 ℃ for 2 hours.The mixture was stirred for 1 h at 40 ℃ for 3 hours.Then the mixture was stirred for 2 h at 40 ℃ for 3 hours.Then the mixture was stirred for 1 h at 40 ℃ for 2 hours.Then the ...

[0560] Step 3

[0561]

[0562] At 20°C in N 2 10% Pd / C (4g, 5.31mmol, 0.1 equivalent) and ammonium formate (40.17g, 636.99mmol, 12 equivalents) were added once to a mixture of 2-methyl-4-(1-methylcyclopropyloxy)-1-nitro-benzene (11g, 53.08mmol, 1 equivalent) in EtOH (100mL). The mixture was stirred at 20°C for 2h to obtain a black mixture. TLC showed that the reaction was complete. The mixture was filtered through a silica gel pad, washed with EtOAc (3x 200mL) and concentrated in vacuo. The residue was purified by silica gel chromatography (0-10% ethyl acetate in petroleum ether) to obtain 2-methyl-4-(1-methylcyclopropyloxy)aniline (9.8g, crude product) in a red oil.

[0563] Step 4

[0564]

[0565] At 0°C in N 2 2-Methyl-4-(1-methylcyclopropyloxy)aniline (9.8 g, 55.29 mmol, 1 eq.) and Et 3A mixture of N (13.99 g, 138.23 mmol, 19.24 mL, 2.5 eq) in DCM (100 mL) was added Ac all at once 2 O (11.29 g, 110.58 mmol, 10.36 mL, 2 eq). The mixture was stirred at 0 °C for 30 min, then heated to 20 °C and stirred for 16 h. TLC showed that the reaction was complete. The reaction was quenched with saturated NaHCO 3 aqueous solution (30 mL) to adjust the pH = 7 - 8 and extracted with DCM (3 x 50 mL). The combined organic phases were washed with brine (3 × 50 mL), dried over anhydrous Na 2 SO 4 dried, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (20% - 40% ethyl acetate in petroleum ether) to give N-[2-methyl-4-(1-methylcyclopropoxy)phenyl]acetamide as a yellow oil (9.3 g, 42.41 mmol, 76.71% yield).

[0566] Step 5

[0567]

[0568] At 20 °C, KOAc (6.24 g, 63.62 mmol, 1.5 eq) and Ac were added to a solution of N-[2-methyl-4-(1-methylcyclopropoxy)phenyl]acetamide (9.3 g, 42.41 mmol, 1 eq) in toluene (100 mL) 2 O (19.92 g, 195.09 mmol, 18.27 mL, 4.6 eq). The solution was heated to 80 °C, and then 3-methylbutyl nitrite (19.87 g, 169.65 mmol, 22.84 mL, 4 eq) was added dropwise. After the addition, the mixture was stirred at 80 °C for 2 h. TLC showed that the reaction was complete. Then the reaction mixture was filtered, the wet filter cake was washed with EtOAc (70 mL), and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (silica gel 100 - 200 mesh, 0 - 10% ethyl acetate in petroleum ether) to give 1-[5-(1-methylcyclopropoxy)indazol-1-yl]ethanone as a yellow solid (8 g, crude).

[0569] Step 6

[0570]

[0571] At 20 °C, NH was added all at once to a mixture of 1-[5-(1-methylcyclopropoxy)indazol-1-yl]ethanone (8 g, 34.74 mmol, 1 eq) in MeOH (80 mL)3 (g / )MeOH (7M, 24.82 mL, 5 equiv). The mixture was stirred at 20 °C for 2 h to give a yellow solution. TLC showed the reaction was complete. The solution was concentrated in vacuo to give 5-(1-methylcyclopropoxy)-1H-indazole as a yellow solid (7.8 g, crude).

[0572] Step 7

[0573]

[0574] To a mixture of 5-(1-methylcyclopropoxy)-1H-indazole (7.8 g, 41.44 mmol, 1 equiv) in THF (80 mL) at 20 °C was added all at once N-dicyclohexylmethylamine (10.52 g, 53.87 mmol, 1.3 equiv) and SEM-Cl (8.29 g, 49.73 mmol, 8.80 mL, 1.2 equiv). The mixture was stirred at 20 °C for 16 h to give an orange solution. TLC showed the reaction was complete. The residue was poured into water (60 mL). The aqueous phase was extracted with ethyl acetate (3 x 50 mL). The combined organic phases were washed with brine (2 x 50 mL), dried over anhydrous Na 2 SO 4 and filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (silica gel 100 - 200 mesh, 0 - 10% ethyl acetate in petroleum ether) to give trimethyl-[2-[[5-(1-methylcyclopropoxy)indazol-2-yl]methoxy]ethyl]silane as a yellow oil (5.4 g, 16.96 mmol, 40.92% yield).

[0575] Step 8

[0576]

[0577] At -70 °C under N 2 to a mixture of trimethyl-[2-[[5-(1-methylcyclopropoxy)indazol-2-yl]methoxy]ethyl]silane (4.36 g, 13.70 mmol, 5.32e-1 equiv) in THF (6 mL) was added dropwise n-BuLi (2.5 M, 13.40 mL, 1.3 equiv). The mixture was then stirred at -20 °C for 1 h and at -70 °C was added dropwise ZnCl 2 solution (0.7 M, 55.20 mL, 1.5 equiv). The mixture was stirred at -40 °C for 1 h. 4,6-Dichloropyrimidine (4.22 g, 28.34 mmol, 1.1 equiv) and Pd(PPh 3 ) 4(1.49 g, 1.29 mmol, 0.05 eq) in a mixture of THF (4 mL) was stirred at 20 °C for 1 h and added to the solution. The cold bath was removed, and the mixture was stirred at 20 °C for 16 h to obtain a yellow solution. TLC showed residual starting material and the formation of some new spots. The residue was poured into water (10 mL). The aqueous phase was extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with brine (2 x 20 mL), dried over anhydrous Na 2 SO 4 dried, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (silica gel 100 - 200 mesh, 0 - 10% ethyl acetate in petroleum ether) to give 2-[[3-(6-chloropyrimidin-4-yl)-5-(1-methylcyclopropoxy)indazol-2-yl]methoxy]ethyl-trimethyl-silane as a yellow oil (2.9 g, crude).

[0578] Step 9

[0579]

[0580] To a mixture of 2-[[3-(6-chloropyrimidin-4-yl)-5-(1-methylcyclopropoxy)indazol-2-yl]methoxy]ethyl-trimethyl-silane (500 mg, 1.16 mmol, 1 eq) and tert-butyl (2S)-2-methylpiperazine-1-carboxylate (697.02 mg, 3.48 mmol, 3 eq) in DMSO (5 mL) was added Et 3 N (704.34 mg, 6.96 mmol, 968.82 μL, 6 eq) in one portion, and then the mixture was stirred at 100 °C for 1 h. TLC showed complete reaction. The mixture was cooled to 20 °C. The residue was poured into water (5 mL). The aqueous phase was extracted with ethyl acetate (3 x 5 mL). The combined organic phases were washed with brine (2 x 5 mL), dried over anhydrous Na 2 SO 4 dried, filtered and concentrated in vacuo to give tert-butyl (2S)-2-methyl-4-[6-[5-(1-methylcyclopropoxy)-2-(2-trimethylsilylethoxymethyl)indazol-3-yl]pyrimidin-4-yl]piperazine-1-carboxylate as a yellow oil (802 mg, crude).

[0581] Step 10

[0582]

[0583] At 25 °C, trifluoroacetic acid (TFA, 771.25 mg, 6.76 mmol, 500.81 μL, 5 eq) was added in one portion to a mixture of tert-butyl (2S)-2-methyl-4-[6-[5-[(1-methylcyclopropyl)methyl]-2-(2-trimethylsilylethoxymethyl)indazol-3-yl]pyrimidin-4-yl]piperazine-1-carboxylate (802 mg, 1.35 mmol, 1 eq) in DCM (5 mL). The mixture was stirred at 25 °C for 16 h. HCl (4 M, 338.20 μL, 1 eq) in MeOH (5 mL) was added at 25 °C, and then the mixture was heated to 60 °C and stirred for 0.5 h. LCMS showed that the reaction was complete. The mixture was cooled to 20 °C. The residue was poured into NaHCO 3 (5 mL) to adjust the pH to 7 - 8. The aqueous phase was extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with brine (2 x 10 mL), dried over anhydrous Na 2 SO 4 and filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (0 - 40% ethyl acetate in MeOH) to give 5-(1-methylcyclopropoxy)-3-[6-[(3S)-3-methylpiperazin-1-yl]pyrimidin-4-yl]-1H-indazole as a yellow solid (450 mg, 1.18 mmol, 87.41% yield, 95.77% purity).

[0584] Step 11

[0585]

[0586] A mixture of 5-(1-methylcyclopropoxy)-3-[6-[(3S)-3-methylpiperazin-1-yl]pyrimidin-4-yl]-1H-indazole (104.76 mg, 287.45 μmol, 1 eq), 2-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl]oxyacetaldehyde (100 mg, 316.19 μmol, 1.1 eq), NaOAc (70.74 mg, 862.34 μmol, 3 eq), CH 3 COOH (17.26 mg, 287.45 μmol, 16.44 μL, 1 eq) and NaBH 3 CN (36.13 mg, 574.89 μmol, 2 eq) in DMF (2 mL) was stirred at 25 °C for 1 h. LCMS showed that the reaction was complete. The mixture was cooled to 20 °C. The residue was poured into water (5 mL). The aqueous phase was extracted with ethyl acetate (3 x 5 mL). The combined organic phases were washed with brine (2 x 5 mL), dried over anhydrous Na 2 SO4 Dry, filter and concentrate in vacuo. Purify the residue by silica gel chromatography (silica gel 100 - 200 mesh, 0 - 10% ethyl acetate in MeOH). Further purify the mixture by preparative HPLC (column: YMC - Actus Triart C18 150*30mm*5um; mobile phase: [water (0.05% ammonia hydroxide v / v) - ACN]; B%: 48% - 68%, 10 min) to obtain 2-(2,6 - dioxo - 3 - piperidinyl)-5-[2-[(2S)-2 - methyl - 4-[6-[5-(1 - methylcyclopropoxy)-2H - indazol - 3 - yl]pyrimidin - 4 - yl]piperazin - 1 - yl]ethoxy]isoindoline - 1,3 - dione as a white solid (12.08 mg, 18.17 umol, 6.32% yield, 100% purity).

[0587] Exemplary Synthesis of Exemplary Compound 2

[0588] Step 1

[0589]

[0590] Add DIPEA (124.12 mg, 960.37 umol, 167.28 uL, 5 eq) in one portion to a mixture of 5-(1 - methylcyclopropoxy)-3-[6-[(3S)-3 - methylpiperazin - 1 - yl]pyrimidin - 4 - yl]-1H - indazole (70 mg, 192.07 umol, 1 eq), KI (63.77 mg, 384.15 umol, 2 eq) and 2-[2-[2-(2,6 - dioxo - 3 - piperidinyl)-1,3 - dioxoisoindolin - 5 - yl]oxyethoxy]ethyl 4 - methylbenzenesulfonate (99.21 mg, 192.07 umol, 1 eq) in ACN (2 mL). Stir the mixture at 100 °C for 16 h. Pour the residue into water (2 mL). Extract the aqueous phase with ethyl acetate (3 x 2 mL). Wash the combined organic phases with brine (2 x 2 mL), over anhydrous Na 2 SO 4Dry, filter and concentrate in vacuo. Purify the residue by silica gel chromatography (silica gel 100 - 200 mesh, 0 - 10% ethyl acetate in MeOH). Purify the crude product by preparative HPLC (column: YMC-Actus Triart C18 150*30mm*5um; mobile phase: [water (0.05% ammonia hydroxide v / v) - ACN]; B%: 45% - 65%, 10 min) to give 2-(2,6-dioxo-3-piperidinyl)-5-[2-[2-[(2S)-2-methyl-4-[6-[5-(1-methylcyclopropoxy)-1H-indazol-3-yl]pyrimidin-4-yl]piperazin-1-yl]ethoxy]ethoxy]isoindoline-1,3-dione as a white solid (11.63 mg, 16.41 μmol, 8.54% yield, 100% purity).

[0591] Prepare Exemplary Compounds 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 15, 16 and 19 in a manner similar to Exemplary Compound 2.

[0592] Exemplary Synthesis of Exemplary Compound 3

[0593] Step 1

[0594]

[0595] To a mixture of 5-(1-methylcyclopropoxy)-3-[6-[(3S)-3-methylpiperazin-1-yl]pyrimidin-4-yl]-1H-indazole (72.24 mg, 198.21 μmol, 1 equiv), KI (65.81 mg, 396.42 μmol, 2 equiv) and 2-[2-[2-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-5-yl]oxyethoxy]ethoxy]ethyl 4-methylbenzenesulfonate (100 mg, 178.39 μmol, 0.9 equiv) in ACN (2 mL) was added DIPEA (128.08 mg, 991.05 μmol, 172.62 μL, 5 equiv) in one portion. Stir the mixture at 100 °C for 16 h. Pour the residue into water (2 mL) and extract the aqueous phase with ethyl acetate (3 x 2 mL). Wash the combined organic phases with brine (2 x 2 mL), over anhydrous Na 2 SO 4Dry, filter and concentrate in vacuo. Purify the residue by silica gel chromatography (silica gel 100 - 200 mesh, 0 - 10% ethyl acetate in MeOH). Purify the crude product by preparative HPLC (column: YMC-Actus Triart C18 150*30mm*5um; mobile phase: [water (0.05% ammonia hydroxide v / v) - ACN]; B%: 45% - 65%, 10 min) to give 2-(2,6-dioxo-3-piperidinyl)-5-[2-[2-[2-[(2S)-2-methyl-4-[6-[5-(1-methylcyclopropoxy)-1H-indazol-3-yl]pyrimidin-4-yl]piperazin-1-yl]ethoxy]ethoxy]ethoxy]isoindoline-1,3-dione as a white solid (14.84 mg, 19.71 umol, 9.95% yield, 100% purity).

[0596] Exemplary synthesis of Exemplary Compound 4

[0597] Step 1

[0598]

[0599] To a mixture of 5-(1-methylcyclopropoxy)-3-[6-[(3S)-3-methylpiperazin-1-yl]pyrimidin-4-yl]-1H-indazole (66.97 mg, 183.77 umol, 1 equiv), KI (61.01 mg, 367.54 umol, 2 equiv) and 2-[2-[2-[2-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-5-yl]oxyethoxy]ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate (100 mg, 165.39 umol, 0.9 equiv) in MeCN (2 mL) was added DIPEA (118.75 mg, 918.84 umol, 160.04 uL, 5 equiv) in one portion. Stir the mixture at 100 °C for 16 h. Pour the residue into water (2 mL). Extract the aqueous phase with ethyl acetate (3 x 2 mL). Wash the combined organic phases with brine (2 x 2 mL), over anhydrous Na 2 SO 4Dry, filter and concentrate in vacuo. Purify the residue by silica gel chromatography (silica gel 100 - 200 mesh, 0 - 10% ethyl acetate in MeOH). Purify the crude product by preparative HPLC (column: YMC-Actus Triart C18 150*30mm*5um; mobile phase: [water (0.05% ammonia hydroxide v / v) - ACN]; B%: 45% - 65%, 10 min) to obtain 2-(2,6-dioxo-3-piperidinyl)-5-[2-[2-[2-[2-[(2S)-2-methyl-4-[6-[5-(1-methylcyclopropoxy)-1H-indazol-3-yl]pyrimidin-4-yl]piperazin-1-yl]ethoxy]ethoxy]ethoxy]ethoxy]isoindoline-1,3-dione as a white solid (5.1 mg, 6.23 umol, 3.39% yield, 97.275% purity).

[0600] Exemplary Synthesis of Exemplary Compound 5

[0601] Step 1

[0602]

[0603] Dissolve 5-(1-methylcyclopropoxy)-3-[6-[(3S)-3-methylpiperazin-1-yl]pyrimidin-4-yl]-1H-indazole (55.00 mg, 150.92 umol, 0.979 eq), 2-[2-[2-[2-[2-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-5-yl]oxyethoxy]ethoxy]ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate (100 mg, 154.16 umol, 1 eq), KI (51.18 mg, 308.32 umol, 2 eq) and DIPEA (99.62 mg, 770.80 umol, 134.26 uL, 5.00 eq) in CH 3The mixture in CN (2 mL) was stirred at 100 °C for 15 h. The mixture was diluted with water (10 mL) and extracted with dichloromethane (3 x 10 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was further purified by preparative HPLC (column: YMC-Actus Triart C18 150*30 mm*5 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 23%-63%, 11 min). Subsequently, the collected fractions were concentrated to remove most of the acetonitrile and lyophilized to give 2-(2,6-dioxo-3-piperidinyl)-5-[2-[2-[2-[2-[2-[(2S)-2-methyl-4-[6-[5-(1-methylcyclopropoxy)-1H-indazol-3-yl]pyrimidin-4-yl]piperazin-1-yl]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]isoindoline-1,3-dione as a red solid (10.1 mg, 11.41 μmol, 7.40% yield, 95% purity).

[0604] Exemplary synthesis of Exemplary Compound 6

[0605] Step 1

[0606]

[0607] To a mixture of 2-[[3-(6-chloropyrimidin-4-yl)-5-(1-methylcyclopropoxy)indazol-2-yl]methoxy]ethyl-trimethyl-silane (500 mg, 1.16 mmol, 1 equiv), (2S,6R)-tert-butyl 2,6-dimethylpiperazine-1-carboxylate (248.61 mg, 1.16 mmol, 1 equiv) in DMSO (5 mL) was added Et 3 N (352.17 mg, 3.48 mmol, 484.41 μL, 3 equiv) in one portion, and then the solution was stirred at 100 °C for 1 h. LCMS (EB16-35-P1A1) showed complete consumption of the starting material. The mixture was cooled to 20 °C. The residue was poured into water (5 mL). The mixture was extracted with ethyl acetate (3 x 5 mL). The combined organic phases were washed with brine (2 x 5 mL), dried over anhydrous Na 2 SO 4 and filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10 / 1 to 5 / 1) to give (2S,6R)-tert-butyl 2,6-dimethyl-4-[6-[5-(1-methylcyclopropoxy)-2-(2-trimethylsilylethoxymethyl)indazol-3-yl]pyrimidin-4-yl]piperazine-1-carboxylate as a yellow oil (811 mg, crude).

[0608] Step 2

[0609]

[0610] At 20 °C, HCl(g) / dioxane (4 M, 1.67 mL, 5 eq) was added in one portion to a mixture of tert-butyl (2S,6R)-2,6-dimethyl-4-[6-[5-(1-methylcyclopropoxy)-2-(2-trimethylsilylethoxymethyl)indazol-3-yl]pyrimidin-4-yl]piperazine-1-carboxylate (811 mg, 1.33 mmol, 1 eq) in MeOH (5 mL). The mixture was stirred at 65 °C for 0.5 h. LCMS showed that the reaction was complete. The mixture was cooled to 20 °C. The residue was poured into NaHCO 3 (10 mL) to adjust the pH to 7 - 8. The mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with brine (2 x 10 mL), dried over anhydrous Na 2 SO 4 dried, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (silica gel 100 - 200 mesh, 0 - 25% ethyl acetate in MeOH) to give 3-[6-[(3S,5R)-3,5-dimethylpiperazin-1-yl]pyrimidin-4-yl]-5-(1-methylcyclopropoxy)-1H-indazole as a yellow solid (400 mg, 978.01 μmol, 73.42% yield, 92.537% purity).

[0611] Step 3

[0612]

[0613] To a solution of 3-[6-[(3S,5R)-3,5-dimethylpiperazin-1-yl]pyrimidin-4-yl]-5-(1-methylcyclopropoxy)-1H-indazole (70 mg, 184.96 μmol, 1.1 eq) and 2-[2-[2-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-5-yl]oxyethoxy]ethoxy]ethyl 4-methylbenzenesulfonate (94.26 mg, 168.15 μmol, 1 eq) in MeCN (5 mL) was added DIPEA (108.66 mg, 840.73 μmol, 146.44 μL, 5 eq) and KI (55.82 mg, 336.29 μmol, 2 eq). The reaction mixture was stirred at 100 °C for 24 h. The residue was poured into water (5 mL). The aqueous phase was extracted with ethyl acetate (3 x 5 mL). The combined organic phases were washed with brine (2 x 5 mL), dried over anhydrous Na 2 SO4 Dry, filter and concentrate in vacuo. Purify the residue by silica gel chromatography (silica gel 100 - 200 mesh, 10 - 25% ethyl acetate in petroleum ether). Purify the crude product by reverse - phase HPLC (column: Agela DuraShell C18 250*25mm*10um; mobile phase: water (0.04% NH3H2O + 10 mM NH4HCO3) - ACN; B%: 45% - 75%, gradient time (min): 8 min; flow rate (ml / min): 25)), to obtain 5 - [2 - [2 - [2 - [(2S,6R) - 2,6 - dimethyl - 4 - [6 - [5 - (1 - methylcyclopropoxy) - 1H - indazol - 3 - yl]pyrimidin - 4 - yl]piperazin - 1 - yl]ethoxy]ethoxy]ethoxy] - 2 - (2,6 - dioxo - 3 - piperidinyl)isoindoline - 1,3 - dione as a yellow solid (10.09 mg, 12.98 umol, 7.72% yield, 98.681% purity).

[0614] Exemplary Synthesis of Exemplary Compound 7

[0615] Step 1

[0616]

[0617] Add DIPEA (124.18 mg, 960.82 umol, 167.36 uL, 5 eq) and KI (63.80 mg, 384.33 umol, 2 eq) to a solution of 3 - [6 - [(3S,5R) - 3,5 - dimethylpiperazin - 1 - yl]pyrimidin - 4 - yl] - 5 - (1 - methylcyclopropoxy) - 1H - indazole (80 mg, 211.38 umol, 1.1 eq) and 2 - [2 - [2 - [2 - [2 - (2,6 - dioxo - 3 - piperidinyl) - 1,3 - dioxoisoindolin - 5 - yl]oxyethoxy]ethoxy]ethoxy]ethyl 4 - methylbenzenesulfonate (116.19 mg, 192.16 umol, 1 eq) in MeCN (5 mL). Stir the reaction mixture at 100 °C for 24 h. Pour the residue into water (5 mL). Extract the aqueous phase with ethyl acetate (3 x 5 mL). Wash the combined organic phases with brine (2 x 5 mL), over anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo. Purify the residue by silica gel chromatography (silica gel 100 - 200 mesh, 10 - 25% ethyl acetate in petroleum ether). Purify the crude product by reverse - phase HPLC (column: Agela DuraShell C18 250*25mm*10um; mobile phase: water (0.04% NH 3 / H2 O + 10 mM NH 4 HCO 3 ) - ACN; B%: 45% - 75%, gradient time (min): 8 min; flow rate (ml / min): 25)), to obtain 5-[2-[2-[2-[2-[(2S,6R)-2,6-dimethyl-4-[6-[5-(1-methylcyclopropoxy)-1H-indazol-3-yl]pyrimidin-4-yl]piperazin-1-yl]ethoxy]ethoxy]ethoxy]ethoxy]-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione as a yellow solid (5.9 mg, 6.98 umol, 3.63% yield, 95.895% purity).

[0618] Exemplary synthesis of Exemplary Compound 8

[0619] Step 1

[0620]

[0621] To a mixture of 5-isopropoxy-3-[6-[(3S)-3-methylpiperazin-1-yl]pyrimidin-4-yl]-1H-indazole (160 mg, 453.99 umol, 1 equivalent) in MeCN (5 mL) was added 2-[2-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-5-yl]oxyethoxy]ethoxy methyl 4-methylbenzenesulfonate (347.37 mg, 635.58 umol, 1.4 equivalents), DIEA (293.37 mg, 2.27 mmol, 395.38 uL, 5 equivalents) and KI (602.90 mg, 3.63 mmol, 8 equivalents). The mixture was stirred at 95 °C for 12 hours to obtain a brown mixture. The mixture was cooled to room temperature and 20 mL of water was added to the reaction mixture. The resulting mixture was extracted with EtOAc (10 mL x 3). The combined extracts were washed with brine (10 mL), dried over anhydrous Na 2 SO 4 dried, filtered and the filtrate was concentrated under reduced pressure to obtain a residue (300 mg). The residue was purified by preparative HPLC (FA) to obtain 2-(2,6-dioxo-3-piperidinyl)-5-[2-[2-[2-[(2S)-4-[6-(5-isopropoxy-1H-indazol-3-yl)pyrimidin-4-yl]-2-methylpiperazin-1-yl]ethoxy]ethoxy]ethoxy]isoindoline-1,3-dione as a pink solid (104.3 mg, 137.94 umol, 30.38% yield, 97.97% purity).

[0622] Exemplary synthesis of Exemplary Compound 9

[0623] Step 1

[0624]

[0625] To a mixture of 5-isopropoxy-3-[6-[(3S)-3-methylpiperazin-1-yl]pyrimidin-4-yl]-1H-indazole (160 mg, 453.99 μmol, 1 equiv) in MeCN (8 mL) was added 2-[2-[2-[2-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-5-yl]oxyethoxy]ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate (384.29 mg, 635.58 μmol, 1.4 equiv), DIEA (293.37 mg, 2.27 mmol, 395.38 μL, 5 equiv), and KI (602.90 mg, 3.63 mmol, 8 equiv). The mixture was stirred at 95 °C for 12 h to give a brown mixture. The mixture was cooled to room temperature and water (20 mL) was added to the reaction mixture. The resulting mixture was extracted with EtOAc (10 mL x 3). The combined extracts were washed with brine (10 mL), dried over anhydrous Na 2 SO 4 2-(2,6-Dioxo-3-piperidinyl)-5-[2-[2-[2-[2-[(2S)-4-[6-(5-isopropoxy-1H-indazol-3-yl)pyrimidin-4-yl]-2-methylpiperazin-1-yl]ethoxy]ethoxy]ethoxy]ethoxy]isoindoline-1,3-dione (44.9 mg, 56.05 μmol, 12.35% yield, 97.98% purity) as a pink solid was obtained by purifying the residue by preparative HPLC (FA).

[0626] Exemplary Synthesis of Exemplary Compound 10

[0627] Step 1

[0628]

[0629] At 25 °C under N 2Downward 3-[6-[(3R,5S)-3,5-dimethylpiperazin-1-yl]pyrimidin-4-yl]-5-isopropoxy-1H-indazole (0.15 g, 409.32 μmol, 1 equivalent) and 2-[2-[2-[2-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-5-yl]oxyethoxy]ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate (296.98 mg, 491.19 μmol, 1.2 equivalents), DIEA (793.53 mg, 6.14 mmol, 1.07 mL, 15 equivalents) were added in one portion to a mixture of KI (1.02 g, 6.14 mmol, 15 equivalents) in MeCN (8 mL) and DMSO (2 mL). The mixture was stirred at 100 °C for 16 h. The reaction mixture was concentrated, cooled in an ice bath, and saturated NH 4 Cl was added to adjust the pH to 6. Saturated brine was added thereto, followed by extraction with ethyl acetate (50 mL x 2). The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by preparative TLC (silica gel, EA:MeOH = 10:1) to give 2-(2,6-dioxo-3-piperidinyl)-5-[2-[2-[2-[2-[(2R,6S)-4-[6-(5-isopropoxy-1H-indazol-3-yl)pyrimidin-4-yl]-2,6-dimethylpiperazin-1-yl]ethoxy]ethoxy]ethoxy]ethoxy]isoindoline-1,3-dione (8.5 mg, 10.19 μmol, 2.49% yield, 95.81% purity) as a pale yellow solid.

[0630] Exemplary synthesis of Exemplary Compound 11

[0631] Step 1

[0632]

[0633] At 25 °C, 2-iodopropane (8.24 g, 48.46 mmol, 4.85 mL, 1.3 equivalents) was added in one portion to a mixture of 1H-indazol-5-ol (5 g, 37.28 mmol, 1 equivalent) and Cs 2 CO 3 (18.22 g, 55.91 mmol, 1.5 equivalents) in DMF (50 mL). The mixture was stirred at 25 °C for 4 h. TLC (petroleum ether:ethyl acetate = 3:1, Rf = 0.58) showed complete reaction. The mixture was poured into water (50 mL), and the aqueous phase was extracted with ethyl acetate (60 mL * 3). The combined organic phases were washed with brine (20 mL * 2) and dried over anhydrous Na 2 SO 4Dry, filter and concentrate in vacuo to give a residue. Purify the residue by silica gel chromatography (petroleum ether / ethyl acetate = 3 / 1) to give 5-isopropoxy-1H-indazole as a pale yellow solid (4.1 g, 23.27 mmol, 62.42% yield).

[0634] Step 2

[0635]

[0636] At 25 °C under N 2 To a mixture of 5-isopropoxy-1H-indazole (4 g, 22.70 mmol, 1 equiv) in MeCN (80 mL) was added K 2 CO 3 (3.14 g, 22.70 mmol, 1 equiv) and I 2 (5.76 g, 22.70 mmol, 4.57 mL, 1 equiv) in one portion. Stir the mixture at 25 °C for 16 h. TLC (petroleum ether:ethyl acetate = 3:1) showed the reaction was complete. Dilute the mixture with brine (100 mL), and extract the aqueous phase with dichloromethane (100 mL × 3). Dry the combined organic phases over anhydrous Na 2 SO 4 dry, filter and concentrate in vacuo to give a residue. Purify the residue by silica gel chromatography (petroleum ether / ethyl acetate = 10 / 3) to give 3-iodo-5-isopropoxy-1H-indazole as a pale yellow oil (5.5 g, 18.21 mmol, 80.20% yield).

[0637] Step 3

[0638]

[0639] At 25 °C to a mixture of 3-iodo-5-isopropoxy-1H-indazole (5.5 g, 18.21 mmol, 1 equiv) in THF (100 mL) was added N-cyclohexyl-N-methyl-cyclohexanamine (4.62 g, 23.67 mmol, 5.02 mL, 1.3 equiv) and SEM-Cl (3.04 g, 18.21 mmol, 3.22 mL, 1 equiv) in one portion. Stir the mixture at 25 °C for 16 h to give an orange solution. TLC (petroleum ether:ethyl acetate = 20 / 1) showed the reaction was complete. Pour the residue into water (100 mL). Extract the aqueous phase with ethyl acetate (3 × 80 mL). Wash the combined organic phases with brine (2 × 20 mL), and dry over anhydrous Na 2 SO 4Dry, filter and concentrate in vacuo to obtain a residue. Purify the residue by silica gel chromatography (petroleum ether / ethyl acetate = 100 / 3) to obtain 2-[(3-iodo-5-isopropoxy-indazol-1-yl)methoxy]ethyl-trimethyl-silane as a pale yellow oil (7.4 g, 15.75 mmol, 86.47% yield, 92% purity).

[0640] Step 4

[0641]

[0642] At 25 °C under N 2 add K 3 PO 4 (14.53 g, 68.46 mmol, 4 equiv) and Pd(dppf)Cl 2 (2.50 g, 3.42 mmol, 0.2 equiv) in one portion to a mixture of 2-[(3-iodo-5-isopropoxy-indazol-1-yl)methoxy]ethyl-trimethyl-silane (7.4 g, 17.11 mmol, 1 equiv) and (2-fluoro-4-pyridyl)boronic acid (3.62 g, 25.67 mmol, 1.5 equiv) in dioxane (100 mL). Heat the mixture to 90 °C under N2 with stirring for 5 h. TLC (petroleum ether:ethyl acetate = 20 / 1) shows the reaction is complete. Cool the mixture to 25 °C and pour the residue into water (80 mL). Extract the aqueous phase with ethyl acetate (90 mL × 2). Wash the combined organic phases with brine (30 mL × 2), dry over anhydrous Na 2 SO 4 dry, filter and concentrate in vacuo to obtain a residue. Purify the residue by silica gel chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain 2-[[3-(2-fluoro-4-pyridyl)-5-isopropoxy-indazol-1-yl]methoxy]ethyl-trimethyl-silane as a pale yellow solid (5.96 g, 12.32 mmol, 71.98% yield, 83% purity).

[0643] Step 5

[0644]

[0645] 2-[[3-(2-Fluoro-4-pyridyl)-5-isopropoxy-indazol-1-yl]methoxy]ethyl-trimethyl-silane (300 mg, 747.11 μmol, 1 eq), tert-butyl (2S)-2-methylpiperazine-1-carboxylate (224.44 mg, 1.12 mmol, 1.5 eq) and DIEA (965.56 mg, 7.47 mmol, 1.30 mL, 10 eq) were taken up in DMSO (10 mL) in a microwave tube. The sealed tube was heated at 180 °C under microwave for 5 h. The mixture was cooled to 25 °C. The mixture was diluted with ethyl acetate (30 mL) and washed with brine (10 mL * 3), dried over anhydrous Na 2 SO 4 dried, filtered and concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (dichloromethane:methanol = 3 / 1) to give 2-[[5-isopropoxy-3-[2-[(3S)-3-methylpiperazin-1-yl]-4-pyridyl]indazol-1-yl]methoxy]ethyl-trimethyl-silane as a dark liquid (200 mg, 357.07 μmol, 47.79% yield, 86% purity).

[0646] Step 6

[0647]

[0648] A mixture of 2-[[5-isopropoxy-3-[2-[(3S)-3-methylpiperazin-1-yl]-4-pyridyl]indazol-1-yl]methoxy]ethyl-trimethyl-silane (200 mg, 415.19 μmol, 1 eq) and TFA (5 mL) was stirred at 25 °C for 1 h. The mixture was concentrated under reduced pressure at 60 °C to give a residue. The residue was purified by silica gel chromatography (dichloromethane / methanol = 100 / 5) to give 5-isopropoxy-3-[2-[(3S)-3-methylpiperazin-1-yl]-4-pyridyl]-1H-indazole as a dark oil (200 mg, 352.83 μmol, 84.98% yield, 62% purity).

[0649] Step 7

[0650]

[0651] At 25 °C, to a mixture of 5-isopropoxy-3-[2-[(3S)-3-methylpiperazin-1-yl]-4-pyridinyl]-1H-indazole (100 mg, 284.54 μmol, 1 equiv) and 2-[2-[2-[2-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-5-yl]oxyethoxy]ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate (206.45 mg, 341.45 μmol, 1.2 equiv) in CH 3 CN (3 mL) was added DIEA (367.74 mg, 2.85 mmol, 495.61 μL, 10 equiv) and KI (236.17 mg, 1.42 mmol, 5 equiv) in one portion. The mixture was stirred at 100 °C for 16 h. The mixture was poured into water (5 mL). The aqueous phase was extracted with ethyl acetate (15 mL × 3), and the combined organic phases were washed with brine (5 mL × 2), dried over anhydrous Na 2 SO 4 dried, filtered and concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 100*30 mm*5 μm; mobile phase: [water (0.05% HCl)-ACN]; B%: 15%-45%, 9 min) to give 2-(2,6-dioxo-3-piperidinyl)-5-[2-[2-[2-[2-[(2S)-4-[4-(5-isopropoxy-1H-indazol-3-yl)-2-pyridinyl]-2-methylpiperazin-1-yl]ethoxy]ethoxy]ethoxy]ethoxy]isoindoline-1,3-dione as a pale yellow solid (11.6 mg, 13.85 μmol, 4.87% yield, 93.6% purity).

[0652] Exemplary synthesis of Exemplary Compound 12

[0653] Step 1

[0654]

[0655] To a solution of 5-(1-methylcyclopropoxy)-1H-indazole (500 mg, 2.66 mmol, 1 equiv) in DMF (5 mL) was added KOH (558.89 mg, 9.96 mmol, 3.75 equiv) and I 2 (1.35 g, 5.31 mmol, 1.07 mL, 2 equiv). The mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched with saturated Na 2 SO 3(10 mL) was diluted and extracted with EtOAc (20 mL * 3). The combined organic layers were washed with brine (20 mL * 2) and dried over Na 2 SO 4 then filtered and concentrated under reduced pressure to give a residue. The crude product was purified by silica gel column chromatography (PE / EA = 0 to 10%) to give 3-iodo-5-(1-methylcyclopropoxy)-1H-indazole as a yellow solid (458 mg, 1.26 mmol, 47.53% yield, 86.592% purity).

[0656] Step 2

[0657]

[0658] To a mixture of 3-iodo-5-(1-methylcyclopropoxy)-1H-indazole (458 mg, 1.30 mmol, 1 equiv) in THF (20 mL) at 20 °C was added N-cyclohexyl-N-methylcyclohexanamine (760.45 mg, 3.89 mmol, 825.68 μL, 3 equiv) and SEM-Cl (432.69 mg, 2.60 mmol, 459.33 μL, 2 equiv) in one portion. The mixture was stirred at 20 °C for 3 h to give an orange suspension. TLC showed the reaction was complete. The residue was poured into water (10 mL). The aqueous phase was extracted with ethyl acetate (10 mL * 2). The combined organic phases were washed with brine (10 mL * 2) and dried over anhydrous Na 2 SO 4 then filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (silica gel 100 - 200 mesh, 0 - 10% ethyl acetate in petroleum ether) to give [3-iodo-5-(1-methylcyclopropoxy)indazol-1-yl]methanol as a yellow solid (300 mg, 706.09 μmol, 54.41% yield, 81% purity).

[0659] Step 3

[0660]

[0661] To a solution of (2S)-4-(4-bromo-2-pyridyl)-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (600 mg, 1.68 mmol, 1 equiv) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (641.51 mg, 2.53 mmol, 1.5 equiv) in 1,4-dioxane (8 mL) was added Pd(dppf)Cl 2(184.85 mg, 252.63 μmol, 0.15 equiv) and KOAc (495.87 mg, 5.05 mmol, 3 equiv). The mixture was stirred at 90 °C under N 2 for 1 h to give a brown solution. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (20 mL * 2), dried over Na 2 SO 4 and concentrated under reduced pressure to give [2-[(3S)-4-tert-butoxycarbonyl-3-methyl-piperazin-1-yl]-4-pyridyl]boronic acid as a brown gum (1.2 g, crude).

[0662] Step 4

[0663]

[0664] To a solution of [2-[(3S)-4-tert-butoxycarbonyl-3-methyl-piperazin-1-yl]-4-pyridyl]boronic acid (857.08 mg, 1.31 mmol, 1.5 equiv) and [3-iodo-5-(1-methylcyclopropoxy)-1H-indazol-1-yl]methanol (300.00 mg, 871.72 μmol, 1 equiv) in 1,4-dioxane (10 mL) and H 2 O (2 mL) was added Pd(dppf)Cl 2 (95.68 mg, 130.76 μmol, 0.15 equiv) and Na 2 CO 3 (277.18 mg, 2.62 mmol, 3 equiv). The mixture was stirred at 90 °C under N 2 for 1.5 h. The mixture was cooled to 20 °C and concentrated under reduced pressure. The residue was poured into water (10 mL) and the aqueous phase was extracted with ethyl acetate (10 mL * 3). The combined organic phases were washed with brine (10 mL * 2), dried over anhydrous Na 2 SO 4 and concentrated in vacuo. The residue was purified by silica gel chromatography (column height: 20 g, 100 - 200 mesh silica gel, 0 - 20% ethyl acetate in petroleum ether) to give tert-butyl (2S)-2-methyl-4-[4-[5-(1-methylcyclopropoxy)-1H-indazol-3-yl]-2-pyridyl]piperazine-1-carboxylate as a yellow oil (400 mg, crude).

[0665] Step 5

[0666]

[0667] At 20 °C, HCl / dioxane (4 M, 528.51 μL, 5 eq) was added in one portion to a mixture of tert-butyl (2S)-2-methyl-4-[4-[5-(1-methylcyclopropoxy)-2H-indazol-3-yl]-2-pyridinyl]piperazine-1-carboxylate (400 mg, 422.80 μmol, 1 eq) in MeOH (10 mL). The mixture was stirred at 65 °C for 0.5 h. TLC (EtOAc, Rf = 0.07) and LCMS showed that the reaction was complete. The mixture was cooled to 20 °C and the residue was poured into saturated NaHCO 3 aqueous solution (pH = 7 - 8). The aqueous phase was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with brine (20 mL × 2), dried over anhydrous Na 2 SO 4 and filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (100 - 200 mesh silica gel, 0 - 25% MeOH in DCM) to give 5-(1-methylcyclopropoxy)-3-[2-[(3S)-3-methylpiperazin-1-yl]-4-pyridinyl]-1H-indazole as a yellow solid (170 mg, 241.82 μmol, 57.19% yield, 51.7% purity).

[0668] Step 6

[0669]

[0670] To a solution of 5-(1-methylcyclopropoxy)-3-[2-[(3S)-3-methylpiperazin-1-yl]-4-pyridinyl]-1H-indazole (100 mg, 275.14 μmol, 1 eq) and 2-[2-[2-[2-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-5-yl]oxyethoxy]ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate (166.35 mg, 275.14 μmol, 1 eq) in MeCN (4 mL) was added KI (548.08 mg, 3.30 mmol, 12 eq) and DIPEA (426.71 mg, 3.30 mmol, 575.09 μL, 12 eq). The mixture was stirred at 90 °C for 12 h. The residue was poured into water (3 mL). The aqueous phase was extracted with ethyl acetate (3 mL × 2). The combined organic phases were washed with brine (3 mL), dried over anhydrous Na 2 SO 4Dry, filter and concentrate in vacuo. Purify the crude product by reverse-phase HPLC (column: Phenomenex Luna C18 100*30mm*5um; mobile phase: [water (0.225% FA)-ACN]; B%: 23%-53%, 9 min) to obtain 2-(2,6-dioxo-3-piperidinyl)-5-[2-[2-[2-[2-[(2S)-2-methyl-4-[4-[5-(1-methylcyclopropoxy)-1H-indazol-3-yl]-2-pyridinyl]piperazin-1-yl]ethoxy]ethoxy]ethoxy]ethoxy]isoindoline-1,3-dione as a yellow solid (12.5 mg, 15.14 umol, 5.50% yield, 96.4% purity).

[0671] Exemplary synthesis of Exemplary Compound 13

[0672] Step 1

[0673]

[0674] At 20 °C under N 2 To a mixture of 2-[2-[2-[2-[4-[(2,6-dioxo-3-piperidinyl)carbamoyl]-3-fluoro-phenoxy]ethoxy]ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate (162.07 mg, 271.65 umol, 1.1 eq) and 5-(1-methylcyclopropoxy)-3-[6-[(3S)-3-methylpiperazin-1-yl]pyrimidin-4-yl]-1H-indazole (90 mg, 246.95 umol, 1.00 eq) in MeCN (5 mL) was added KI (122.98 mg, 740.86 umol, 3 eq) and DIPEA (159.58 mg, 1.23 mmol, 215.07 uL, 5 eq) in one portion. Stir the mixture at 80 °C for 16 h. Cool the mixture to 20 °C and concentrate under reduced pressure at 20 °C. Pour the residue into water (5 mL). Extract the aqueous phase with ethyl acetate (3 x 5 mL). Wash the combined organic phases with brine (3 x 5 mL), over anhydrous Na 2 SO 4Dry, filter and concentrate under vacuum. Purify the crude product by reverse-phase HPLC (column: Welch Xtimate C18 150*30mm*5um; mobile phase: water (0.225% FA)-ACN; B%: 12%-42%, gradient time (min): 8 min; flow rate (ml / min): 25) to obtain N-(2,6-dioxo-3-piperidinyl)-2-fluoro-4-[2-[2-[2-[2-[(2S)-2-methyl-4-[6-[5-(1-methylcyclopropoxy)-1H-indazol-3-yl]pyrimidin-4-yl]piperazin-1-yl]ethoxy]ethoxy]ethoxy]ethoxy]benzamide as a red solid (23.23 mg, 28.98 umol, 11.73% yield, 98.399% purity).

[0675] Exemplary Synthesis of Exemplary Compound 14

[0676] Step 1

[0677]

[0678] Add a solution of NaNO 2 (3.83 g, 55.50 mmol, 1 equiv) in H 2 O (35 mL) to a mixture of 2-fluoro-5-methyl-phenol (7 g, 55.50 mmol, 1 equiv) in AcOH (15.2 mL) and H 2 SO 4 (2 mL) at 0 °C. Then stir the mixture at 0 °C for 1 h. Pour the reaction mixture into ice water (100 mL). Collect the precipitate by filtration and wash it subsequently with water (3 x 100 mL). Add the obtained solid portionwise to a mixture of HNO 3 (12 mL) and H 2 O (35 mL) with stirring. Stir the resulting suspension at 45 °C for 2 h. After cooling to room temperature, dilute the mixture with cold water (100 mL) and filter. Wash the solid with water (2 x 100 mL) and then dissolve it in ethyl acetate (100 mL). Wash the organic layer with brine (2 x 100 mL), dry over Na 2 SO 4 , filter and concentrate under reduced pressure to obtain 2-fluoro-5-methyl-4-nitro-phenol as a yellow solid (5.3 g, 30.35 mmol, 54.69% yield, 98% purity).

[0679] Step 2

[0680] ​​​​​​​​​​​​​​​​

[0681] At 20 °C in N 2 To a mixture of 2-fluoro-5-methyl-4-nitrophenol (5.3 g, 30.97 mmol, 1 equiv) and 2-iodopropane (10.53 g, 61.94 mmol, 6.19 mL, 2 equiv) in CH 3 CN (60 mL) was added K 2 CO 3 (8.56 g, 61.94 mmol, 2 equiv). The reaction mixture was stirred at 80 °C for 12 h. TLC (PE:EA = 10:1) indicated a major new spot with lower polarity. The reaction mixture was filtered and concentrated to give 1-fluoro-2-isopropoxy-4-methyl-5-nitrobenzene as a yellow solid (5 g, 23.45 mmol, 75.72% yield).

[0682] Step 3

[0683]

[0684] To a stirred solution of 1-fluoro-2-isopropoxy-4-methyl-5-nitrobenzene (5 g, 23.45 mmol, 1 equiv) in EtOH (120 mL) was added ammonium formate (16.27 g, 257.97 mmol, 11 equiv), followed by Pd / C (2.5 g, 23.45 mmol, 10% purity, 1.00 equiv). The reaction mixture was stirred at 20 °C for 4 h. The reaction mixture was filtered and concentrated in vacuo to give a residue. Dichloromethane (50 mL) was added to the residue and filtration was carried out. The filtrate was concentrated in vacuo to give 5-fluoro-4-isopropoxy-2-methylaniline as a brown oil (4.2 g, 20.63 mmol, 87.97% yield, 90% purity).

[0685] Step 4

[0686]

[0687] At 0 °C to a stirred solution of 5-fluoro-4-isopropoxy-2-methylaniline (4.2 g, 20.63 mmol, 1 equiv) in AcOH (40 mL) was added a solution of NaNO 2 (1.57 g, 22.69 mmol, 1.1 equiv) in H 2 O (5 mL). The reaction mixture was stirred at 20 °C for 16 h. The color of the reaction mixture changed from yellow to brown. The reaction mixture was concentrated in vacuo to give a residue. Saturated NaHCO 3A solution (40 mL) was used, and the mixture was extracted with EA (40 mL). The combined organic layers were washed with brine (40 mL) and dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (PE / EA = 100:20, 100:30) to give 6-fluoro-5-isopropoxy-1H-indazole as a brown oil (3.5 g, 18.02 mmol, 87.36% yield).

[0688] Step 5

[0689]

[0690] To a solution of 6-fluoro-5-isopropoxy-1H-indazole (1.4 g, 7.21 mmol, 1 equiv) in DMF (30 mL) was added KOH (1.52 g, 27.03 mmol, 3.75 equiv) and I 2 (3.66 g, 14.42 mmol, 2.90 mL, 2 equiv). The mixture was stirred at 25 °C for 3 h. The reaction mixture was diluted with saturated Na 2 S 2 O 3 (30 mL) and extracted with EtOAc (50 mL). The combined organic layers were washed with brine (50 mL) and dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The crude product was purified by silica gel column chromatography (0 to 10% ethyl acetate in petroleum ether) to give 6-fluoro-3-iodo-5-isopropoxy-1H-indazole as a yellow solid (1.62 g, 3.95 mmol, 54.76% yield, 78% purity).

[0691] Step 6

[0692]

[0693] To a solution of 6-fluoro-3-iodo-5-isopropoxy-1H-indazole (1.61 g, 5.03 mmol, 1 equiv) and 2-(chloromethoxy)ethyl-trimethyl-silane (838.61 mg, 5.03 mmol, 890.24 uL, 1 equiv) in THF (20 mL) was added N-cyclohexyl-N-methylcyclohexylamine (1.28 g, 6.54 mmol, 1.39 mL, 1.3 equiv). The mixture was stirred at 25 °C for 16 h. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (50 mL). The combined organic layers were washed with brine (30 mL) and dried over Na 2 SO4 Dry, filter and concentrate under reduced pressure to obtain a residue. Purify the crude product by silica gel column chromatography (0 to 5% ethyl acetate in petroleum ether) to obtain 2-[(6-fluoro-3-iodo-5-isopropoxy-indazol-1-yl)methoxy]ethyl-trimethyl-silane as a yellow oil (2.05 g, 4.23 mmol, 84.16% yield, 93% purity).

[0694] Step 7

[0695]

[0696] Add K to a solution of 4-bromo-2-fluoropyridine (1 g, 5.68 mmol, 1 equiv) and (2S)-tert-butyl 2-methylpiperazine-1-carboxylate (1.71 g, 8.52 mmol, 1.5 equiv) in DMSO (8 mL). 2 CO 3 (2.36 g, 17.05 mmol, 3 equiv). Stir the mixture at 100 °C for 4 h. Dilute the reaction mixture with water (50 mL) and extract with EtOAc (50 mL). Wash the combined organic layers with brine (50 mL), dry over Na 2 SO 4 dry, filter and concentrate under reduced pressure to obtain a residue. Purify the crude product by silica gel column chromatography (0 to 10% ethyl acetate in petroleum ether) to obtain (2S)-tert-butyl 4-(4-bromo-2-pyridyl)-2-methylpiperazine-1-carboxylate as a colorless oil (1.7 g, 4.68 mmol, 82.30% yield, 98% purity).

[0697] Step 8

[0698]

[0699] Add Pd(dppf)Cl to a solution of (2S)-tert-butyl 4-(4-bromo-2-pyridyl)-2-methylpiperazine-1-carboxylate (600 mg, 1.68 mmol, 1 equiv) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (641.51 mg, 2.53 mmol, 1.5 equiv) in 1,4-dioxane (8 mL). 2 (184.85 mg, 252.63 umol, 0.15 equiv) and KOAc (495.87 mg, 5.05 mmol, 3 equiv). Stir the mixture at 90 °C under N 2Stir for 1 hour. Dilute the reaction mixture with water (20 mL) and extract with EtOAc (30 mL). Wash the combined organic layers with 20 mL of brine and dry over Na 2 SO 4 to obtain tert-butyl (S)-2-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1-carboxylate (540 mg, 571.64 μmol, 33.94% yield) as a brown oil.

[0700] Step 9

[0701]

[0702] To a solution of tert-butyl (S)-2-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1-carboxylate (540 mg, 1.68 mmol, 1 equiv) and 2-[(6-fluoro-3-iodo-5-isopropoxy-indazol-1-yl)methoxy]ethyl-trimethyl-silane (1.14 g, 2.52 mmol, 1.5 equiv) in 1,4-dioxane (10 mL) and H 2 O (2 mL), add Pd(dppf)Cl 2 (184.53 mg, 252.20 μmol, 0.15 equiv) and Na 2 CO 3 (534.61 mg, 5.04 mmol, 3 equiv). Stir the mixture at 90 °C under N 2 for 2 hours. Dilute the reaction mixture with water (20 mL) and extract with EA (30 mL). Wash the combined organic layers with brine (20 mL) and dry over Na 2 SO 4 to obtain a residue. Purify the crude product by silica gel column chromatography (0 to 20% ethyl acetate in petroleum ether) to obtain tert-butyl (2S)-4-[4-[6-fluoro-5-isopropoxy-1-(2-trimethylsilylethoxymethyl)indazol-3-yl]-2-pyridinyl]-2-methyl-piperazine-1-carboxylate (1 g, 1.60 mmol, 95.19% yield, 96% purity) as a yellow oil.

[0703] Step 10

[0704]

[0705] To a solution of tert-butyl (2S)-4-[4-[6-fluoro-5-isopropoxy-1-(2-trimethylsilylethoxymethyl)-1H-indazol-3-yl]-2-pyridinyl]-2-methylpiperazine-1-carboxylate (1 g, 1.67 mmol, 1 equiv) in DCM (5 mL) was added TFA (1.54 g, 13.51 mmol, 1 mL, 8.10 equiv). The mixture was stirred at 25 °C for 6 h. Then NH 3 .H 2 O (701.14 mg, 5.00 mmol, 770.48 uL, 25% purity, 3 equiv) was added to the solution and the mixture was stirred for 2 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (30 mL). The combined organic layers were washed with brine (20 mL), dried over Na 2 SO 4 and filtered and concentrated under reduced pressure to afford 6-fluoro-5-isopropoxy-3-[2-[(3S)-3-methylpiperazin-1-yl]-4-pyridinyl]-1H-indazole as a yellow gum (590 mg, 1.39 mmol, 83.34% yield, 87% purity).

[0706] Step 11

[0707]

[0708] To a solution of 6-fluoro-5-isopropoxy-3-[2-[(3S)-3-methylpiperazin-1-yl]-4-pyridinyl]-1H-indazole (100 mg, 270.68 μmol, 1 equiv) and 2-[2-[2-[2-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl]oxyethoxy]ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate (163.66 mg, 270.68 μmol, 1 equiv) in CH 3 CN (2 mL) was added KI (539.21 mg, 3.25 mmol, 12 equiv) and DIEA (419.81 mg, 3.25 mmol, 565.78 μL, 12 equiv). The mixture was stirred at 90 °C for 12 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (30 mL). The combined organic layers were washed with brine (20 mL), dried over Na 2 SO 4Dry, filter and concentrate under reduced pressure to obtain a residue. Purify the residue by preparative HPLC (column: Phenomenex Luna C18 100*30mm*5um; mobile phase: [water (0.225% FA)-ACN]; B%: 0-26%; 12 min) to obtain 2-(2,6-dioxo-3-piperidinyl)-5-[2-[2-[2-[2-[(2S)-4-[4-(6-fluoro-5-isopropoxy-1H-indazol-3-yl)-2-pyridinyl]-2-methyl-piperazin-1-yl]ethoxy]ethoxy]ethoxy]ethoxy]isoindoline-1,3-dione as a white solid (24.3 mg, 29.74 umol, 10.99% yield, 98.14% purity).

[0709] Exemplary Synthesis of Exemplary Compound 15

[0710] Step 1

[0711]

[0712] A mixture of 2-[2-[2-[2-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-5-yl]oxyethoxy]ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate (280.82 mg, 464.45 umol, 1.5 equiv) and KI (770.99 mg, 4.64 mmol, 15 equiv) in DMSO (3 mL) was stirred at 50 °C under N 2 2. Then a solution of 6-fluoro-5-isopropoxy-3-[6-[(3S)-3-methylpiperazin-1-yl]pyrimidin-4-yl]-1H-indazole (150 mg, 309.63 umol, 1 equiv, TFA) and DIEA (600.27 mg, 4.64 mmol, 808.98 uL, 15 equiv) in CH 3 CN (3 mL) was added to the mixture. Then the mixture was stirred at 90 °C under N 2 2 for 16 h. Dilute the reaction mixture with water (20 mL) and extract with EA (30 mL). Wash the combined organic layers with brine (20 mL), over Na 2 SO 4Dry, filter and concentrate under reduced pressure to obtain a residue. Purify the residue by preparative TLC (PE:EA = 0:1) to obtain a crude product. Purify the crude product by preparative TLC (column: Phenomenex Luna C18 100*30mm*5um; conditions: water (0.225% FA)-ACN; start: B 16%, end: B 46%; gradient time: 9 min; 100% B hold time: 1 min; flow rate: 25 ml / min) to obtain 2-(2,6-dioxo-3-piperidinyl)-5-[2-[2-[2-[2-[(2S)-4-[6-(6-fluoro-5-isopropoxy-1H-indazol-3-yl)pyrimidin-4-yl]-2-methyl-piperazin-1-yl]ethoxy]ethoxy]ethoxy]ethoxy]isoindoline-1,3-dione as a white solid (15 mg, 18.68 umol, 6.03% yield, FA).

[0713] Exemplary synthesis of Exemplary Compound 16

[0714] Step 1

[0715]

[0716] At 20 °C under N 2 To a mixture of 1H-indazol-5-ol (1 g, 7.46 mmol, 1 equiv) in DCM (10 mL) was added imidazole (1.52 g, 22.37 mmol, 3 equiv) and TBSCl (1.69 g, 11.18 mmol, 1.37 mL, 1.5 equiv) in one portion. Stir the mixture at 20 °C for 2 h to obtain a brown solution. TLC (DCM:MeOH = 10:1, Rf = 0.23) showed the reaction was complete. Pour the residue into water (10 mL). Extract the aqueous phase with ethyl acetate (10 mL * 3). Wash the combined organic phases with brine (10 mL * 3), dry over anhydrous Na 2 SO 4 dry, filter and concentrate in vacuo. Purify the residue by silica gel chromatography (12 g, 30 mL / min, 100 - 200 mesh silica gel, 0 - 5% (10 min) MeOH in DCM) to obtain tert-butyl-(1H-indazol-5-yloxy)-dimethyl-silane as a yellow oil (1.5 g, 5.87 mmol, 78.73% yield, 97.2% purity).

[0717] Step 2

[0718]

[0719] At 20 °C under N 2A mixture of tert-butyl-(1H-indazol-5-yloxy)-dimethyl-silane (1.5 g, 6.04 mmol, 1 equiv) in THF (20 mL) was added N,N-dicyclohexylmethylamine (2.36 g, 12.08 mmol, 2.56 mL, 2 equiv) and SEM-Cl (2.01 g, 12.08 mmol, 2.14 mL, 2 equiv) in one portion. The mixture was stirred at 20 °C for 2 h to give a yellow suspension. TLC (PE:EtOAc = 3:1, Rf = 0.37) showed complete reaction. The residue was poured into water (20 mL). The aqueous phase was extracted with ethyl acetate (20 mL * 3). The combined organic phases were washed with brine (20 mL * 2), dried over anhydrous Na 2 SO 4 dried, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (column height: 40 g, 30 mL / min, 100 - 200 mesh silica gel, 0% ethyl acetate in petroleum ether (5 min), 1% ethyl acetate in petroleum ether (20 min)) to give tert-butyl-dimethyl-[1-(2-trimethylsilylethoxymethyl)indazol-5-yl]oxy-silane as a yellow oil (1.82 g, 4.81 mmol, 79.59% yield).

[0720] Step 3

[0721]

[0722] At -70 °C under N 2 To a mixture of tert-butyl-dimethyl-[1-(2-trimethylsilylethoxymethyl)indazol-5-yl]oxy-silane (1.82 g, 4.81 mmol, 1 equiv) in THF (5 mL) was added dropwise n-BuLi (2.5 M, 2.50 mL, 1.3 equiv). Then the mixture was stirred at -20 °C for 5 min and ZnCl 2 solution (1 M, 7.21 mL, 1.5 equiv) was added dropwise at -70 °C. The mixture was stirred at -40 °C for 10 min. 4,6-Dichloropyrimidine (787.67 mg, 5.29 mmol, 1.1 equiv) and Pd(PPh 3 ) 4(277.71 mg, 240.32 μmol, 0.05 eq) in THF (1 mL) was stirred at 20 °C for 30 min and added to the reaction. The cold bath was removed and the mixture was stirred at 20 °C for 2 h to give a yellow solution. TLC (PE:EtOAc = 10:1, Rf = 0.83) showed a new spot. The residue was poured into water (10 mL). The aqueous phase was extracted with ethyl acetate (20 mL * 3). The combined organic phases were washed with brine (20 mL * 2), dried over anhydrous Na 2 SO 4 dried, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (40 g, 35 mL / min, silica gel 100 - 200 mesh, 0 - 5% (30 min) ethyl acetate in petroleum ether) to give tert-butyl-[3-(6-chloropyrimidin-4-yl)-1-(2-trimethylsilylethoxymethyl)indazol-5-yl]oxy-dimethyl-silane as a yellow oil (1.18 g, 2.40 mmol, 49.98% yield).

[0723] Step 4

[0724]

[0725] At 20 °C under N 2 to a mixture of tert-butyl-[3-(6-chloropyrimidin-4-yl)-1-(2-trimethylsilylethoxymethyl)indazol-5-yl]oxy-dimethyl-silane (1.18 g, 2.40 mmol, 1 eq) in DCM (10 mL) was added TFA (3 g, 26.31 mmol, 1.95 mL, 10.95 eq) in one portion. The mixture was stirred at 20 °C for 1 h. Then NH 3 .H 2 O (2.55 g, 24.02 mmol, 2.80 mL, 33% purity, 10 eq) was added and the solution was stirred at 20 °C for 1 h. The solution was concentrated in vacuo. The crude product was dissolved in THF (5 mL), TBAF (1 M, 2.40 mL, 1 eq) was added, and the solution was stirred for 1 h to give a yellow solution. The aqueous phase was extracted with ethyl acetate (5 mL * 3). The combined organic phases were washed with brine (5 mL * 3), dried over anhydrous Na 2 SO 4 dried, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (column height: 12 g, 30 mL / min, 0 - 32% (18 min) ethyl acetate in petroleum ether, 32% (12 min) ethyl acetate in petroleum ether) to give 3-(6-chloropyrimidin-4-yl)-1H-indazol-5-ol as a yellow oil (140 mg, 567.60 μmol, 23.63% yield).

[0726] Step 5

[0727]

[0728] At 25 °C in N 2 To a mixture of 3-(6-chloropyrimidin-4-yl)-1H-indazol-5-ol (140 mg, 567.60 μmol, 1 equiv) in THF (5 mL) and DCM (5 mL) was added tert-butyl 2,2,2-trichloroacetimidate (744.15 mg, 3.41 mmol, 609.96 μL, 6 equiv) and BF 3 .Et 2 O (241.68 mg, 851.40 μmol, 210.15 μL, 50% purity, 1.5 equiv) in one portion. The mixture was stirred at 25 °C for 10 min to give a yellow solution. The residue was poured into water (5 mL) and stirred for 5 min. The aqueous phase was extracted with DCM (5 mL × 3). The combined organic phases were washed with brine (3 mL × 2), dried over anhydrous Na 2 SO 4 and filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (DCM:MeOH = 10:1, Rf = 0.38, 12 g, 30 mL / min, 100 - 200 mesh silica gel, 0 - 20% (10 min) ethyl acetate in petroleum ether, 20% (10 min) ethyl acetate in petroleum ether) to give 5-tert-butoxy-3-(6-chloropyrimidin-4-yl)-1H-indazole as a yellow solid (80 mg, 264.24 μmol, 46.55% yield).

[0729] Step 6

[0730]

[0731] To a mixture of 5-tert-butoxy-3-(6-chloropyrimidin-4-yl)-1H-indazole (200 mg, 660.59 μmol, 1 equiv), benzyl (2S)-2-methylpiperazine-1-carboxylate (154.77 mg, 660.59 μmol, 1 equiv) in DMSO (10 mL) was added Et 3N (200.54 mg, 1.98 mmol, 275.84 uL, 3 eq) was added, and the mixture was stirred at 100 °C for 1 h. TLC (PE:EtOAc = 5:1, Rf = 0.50) showed complete consumption of the starting material. The mixture was cooled to 20 °C, and the residue was then poured into water (10 mL). The aqueous phase was extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with brine (2 x 10 mL), dried over anhydrous Na 2 SO 4 dried, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (20 g, 40 mL / min, silica gel 100 - 200 mesh, 0 - 17% (3 min) ethyl acetate in petroleum ether, 17% (5 min) ethyl acetate in petroleum ether) to give (2S)-4-[6-(5-tert-butoxy-1H-indazol-3-yl)pyrimidin-4-yl]-2-methyl-piperazine-1-carboxylic acid benzyl ester as a yellow gum (230 mg, 450.27 μmol, 68.16% yield, 98% purity).

[0732] Step 7

[0733]

[0734] At 20 °C under N 2 to a mixture of (2S)-4-[6-(5-tert-butoxy-1H-indazol-3-yl)pyrimidin-4-yl]-2-methyl-piperazine-1-carboxylic acid benzyl ester (230 mg, 459.46 μmol, 1 eq) in EtOH (5 mL) was added Pd / C (100 mg, 459.46 μmol, 10% purity, 1 eq) in one portion. The suspension was degassed under vacuum and purged with H 2 several times. The mixture was stirred at 20 °C under H 2 (15 psi) for 1 h. The suspension was filtered through a pad of diatomaceous earth, and the pad was washed with EtOAc (3 x 50 mL) to give 5-tert-butoxy-3-[6-[(3S)-3-methylpiperazin-1-yl]pyrimidin-4-yl]-1H-indazole as a yellow gum (140 mg, 382.03 μmol, 83.15% yield). The crude product was used in the next step.

[0735] Step 8

[0736]

[0737] To a mixture of 5-tert-butoxy-3-[6-[(3S)-3-methylpiperazin-1-yl]pyrimidin-4-yl]-1H-indazole (140 mg, 382.03 μmol, 1 equiv), KI (317.09 mg, 1.91 mmol, 5 equiv) and 2-[2-[2-[2-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-5-yl]oxyethoxy]ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate (254.09 mg, 420.24 μmol, 1.1 equiv) in MeCN (5 mL) was added DIPEA (246.87 mg, 1.91 mmol, 332.71 μL, 5 equiv) in one portion. The mixture was stirred at 100 °C for 16 h. The residue was poured into water (5 mL). The aqueous phase was extracted with ethyl acetate (3 x 5 mL). The combined organic phases were washed with brine (2 x 5 mL), dried over anhydrous Na 2 SO 4 dried, filtered and concentrated in vacuo. The crude product was purified by reverse phase HPLC (column: Phenomenex luna C18 100*40 mm*3 μm; conditions: water (0.225% FA)-ACN; start B: 20 - 50; flow rate: 25 mL / min; gradient time: 8.5 min; 100% B hold time: 2 min). And the crude was purified by preparative TLC (DCM:MeOH = 10:1, Rf = 0.27) to give 5-[2-[2-[2-[2-[(2S)-4-[6-(5-tert-butoxy-1H-indazol-3-yl)pyrimidin-4-yl]-2-methylpiperazin-1-yl]ethoxy]ethoxy]ethoxy]ethoxy]-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione as a white solid (34.9 mg, 41.94 μmol, 10.98% yield, 96% purity).

[0738] Exemplary synthesis of Exemplary Compound 17

[0739] Step 1

[0740]

[0741] To a mixture of 2-(benzylamino)ethanol (17 g, 112.43 mmol, 15.89 mL, 1 equiv) and Et 3 N (11.38 g, 112.43 mmol, 15.65 mL, 1 equiv) in H 2The solution in O (200 mL) was heated to 105 °C. Ethyl (E)-4-bromobut-3-enoate (23.87 g, 123.67 mmol, 1.1 eq) was added dropwise and the reaction was heated at 105 °C for 16 h to give a red solution. The mixture was cooled to 20 °C and concentrated under reduced pressure at 20 °C. The residue was poured into NaOH (50 mL, 10%) and stirred for 5 min. The aqueous phase was extracted with ethyl acetate (100 mL * 3). The combined organic phases were washed with brine (100 mL * 2), dried over anhydrous Na 2 SO 4 dried, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (column height: 80 g, silica gel 100 - 200 mesh, 0 - 20% ethyl acetate in petroleum ether (30 min)) to give ethyl 2-(4-benzylmorpholin-2-yl)acetate (16 g, 60.76 mmol, 54.04% yield) as a yellow oil.

[0742] Step 2

[0743]

[0744] To a solution of ethyl 2-(4-benzylmorpholin-2-yl)acetate (5 g, 18.99 mmol, 1 eq) in THF (50 mL) was added LiAlH 4 (1.08 g, 28.48 mmol, 1.5 eq). After addition, the reaction mixture was stirred at 20 °C for 1 h. TLC (PE:EtOAc = 5:1, Rf = 0.18) showed the reaction was complete. The reaction mixture was quenched with water (5 mL), followed by addition of 15% aqueous sodium hydroxide (5 mL) and water (15 mL). The solid was removed by filtration. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (column height: 40 g, silica gel 100 - 200 mesh, 0 - 50% ethyl acetate in petroleum ether (20 min)) to give 2-(4-benzylmorpholin-2-yl)ethanol (2.73 g, 12.34 mmol, 64.97% yield) as a yellow oil.

[0745] Step 3

[0746]

[0747] At 0 °C under N 2A mixture of downward 2-[2-(2-hydroxyethoxy)ethoxy]ethanol (5 g, 33.29 mmol, 4.46 mL, 1 equivalent) in THF (50 mL) was added NaH (1.33 g, 33.29 mmol, 60% purity, 1 equivalent) in one portion. The mixture was stirred at 0 °C for 30 min, then (chloromethyl)benzene (3.79 g, 29.97 mmol, 3.45 mL, 0.9 equivalent) was added to the solution. Then the solution was heated to 25 °C and stirred for 16 h. The residue was poured into water (30 mL). The aqueous phase was extracted with ethyl acetate (30 mL * 3). The combined organic phases were washed with brine (30 mL * 2), dried over anhydrous Na 2 SO 4 dried, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (column height: 40 g, 100 - 200 mesh silica gel, 0 - 2% (10 min) MeOH in DCM, 2% (5 min) MeOH in DCM, 5% (15 min) MeOH in DCM) to give 2-[2-(2-benzyloxyethoxy)ethoxy]ethanol as a yellow oil (3 g, 12.48 mmol, 37.50% yield).

[0748] Step 4

[0749]

[0750] At 0 °C under N 2 To a mixture of 2-[2-(2-benzyloxyethoxy)ethoxy]ethanol (3 g, 12.48 mmol, 9.01 mL, 1 equivalent), Et 3 N (1.26 g, 12.48 mmol, 1.74 mL, 1 equivalent) and DMAP (1.53 g, 12.48 mmol, 1 equivalent) in DCM (20 mL) was added 4-methylbenzene-1-sulfonyl chloride (3.57 g, 18.73 mmol, 1.5 equivalents) in one portion. Then the reaction solution was warmed to 20 °C and stirred for 2 h to give a white suspension. TLC (MeOH:DCM = 10:1, Rf = 0.83) and LCMS showed the reaction was complete. The mixture was poured into HCl (2 M) to adjust the pH to 7 - 8. The aqueous phase was extracted with ethyl acetate (50 mL * 3). The combined organic phases were washed with brine (50 mL * 2), dried over anhydrous Na 2 SO 4Dry, filter and concentrate in vacuo. Purify the residue by silica gel chromatography (silica gel 100 - 200 mesh, 10 - 20% ethyl acetate in petroleum ether) to give 2-[2-(2-benzyloxyethoxy)ethoxy]ethyl 4-methylbenzenesulfonate as a yellow oil (3.14 g, 7.96 mmol, 63.76% yield).

[0751] Step 5

[0752]

[0753] At 0 °C under N 2 To a mixture of 2-(4-benzylmorpholin-2-yl)ethanol (1 g, 4.52 mmol, 1 equiv) in DMF (10 mL) was added portionwise NaH (542.26 mg, 13.56 mmol, 60% purity, 3 equiv) at once. The mixture was stirred at 20 °C for 30 min, then 2-[2-(2-benzyloxyethoxy)ethoxy]ethyl 4-methylbenzenesulfonate (1.78 g, 4.52 mmol, 1 equiv) was added to the solution. The mixture was stirred at 20 °C for 16 h. The residue was poured into water (10 mL). The aqueous phase was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with brine (10 mL × 2), dried over anhydrous Na 2 SO 4 dry, filtered and concentrated in vacuo. Purify the residue by silica gel chromatography (column height: 20 g, diameter: 100 mm, silica gel 100 - 200 mesh, 0 - 100% (60 min) ethyl acetate in petroleum ether) to give 4-benzyl-2-[2-[2-[2-(2-benzyloxyethoxy)ethoxy]ethoxy]ethyl]morpholine as a yellow oil (920 mg, 2.07 mmol, 45.90% yield).

[0754] Step 6

[0755]

[0756] Under N 2 To a solution of 4-benzyl-2-[2-[2-[2-(2-benzyloxyethoxy)ethoxy]ethoxy]ethyl]morpholine (920 mg, 2.07 mmol, 1 equiv) and Boc 2 O (905.31 mg, 4.15 mmol, 952.96 μL, 2 equiv) in MeOH (10 mL) was added Pd / C (100 mg, 2.07 mmol, 10% purity, 1 equiv). The suspension was degassed under vacuum and purged with H 2 several times. The mixture was stirred under H 2(45 psi) Stir at 50 °C for 4 h. TLC shows no starting material. Filter the suspension through a pad of diatomaceous earth or silica gel, and wash the pad or cake with EtOAc (50 mL * 3). Purify the residue by silica gel chromatography (column height: 20 g, 100 - 200 mesh silica gel, 0 - 10% MeOH in DCM) to obtain tert-butyl 2-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethyl]morpholine-4-carboxylate (684 mg, 1.88 mmol, 90.74% yield) as a colorless oil.

[0757] Step 7

[0758]

[0759] At 0 °C under N 2 To a mixture of tert-butyl 2-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethyl]morpholine-4-carboxylate (400 mg, 1.10 mmol, 1 equiv), Et 3 N (334.10 mg, 3.30 mmol, 459.56 uL, 3 equiv) and DMAP (134.46 mg, 1.10 mmol, 1 equiv) in DCM (10 mL), add 4-methylbenzenesulfonyl chloride (419.64 mg, 2.20 mmol, 2 equiv) in one portion. Stir the mixture at 0 °C for 2 h to obtain a white suspension. TLC (DCM:MeOH = 10:1, Rf = 0.54) and LCMS show complete reaction. Pour the residue into water (5 mL) and stir for 5 min. Extract the aqueous phase with DCM (5 mL * 3). Wash the combined organic phases with brine (5 mL * 2), dry over anhydrous Na 2 SO 4 dry, filter and concentrate in vacuo. Purify the residue by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100 - 200 mesh silica gel, 0 - 10% MeOH in DCM) and SFC {column: REGIS (s,s) WHELK-O1 (250 mm * 50 mm, 10 um); conditions: 0.1% NH3H2O IPA; start B: 20%; end B 20%; flow rate (ml / min): 70} to obtain enantiomer 1 (2* 1 )-tert-butyl 2-[2-[2-[2-[2-(p-toluenesulfonyloxy)ethoxy]ethoxy]ethoxy]ethyl]morpholine-4-carboxylate (148 mg, 234.51 umol, 21.31% yield, 82.019% purity) (Rt = 2.832 min, 148 mg) and enantiomer 2 (2* 2)-tert-Butyl 2-[2-[2-[2-[2-(p-toluenesulfonyloxy)ethoxy]ethoxy]ethoxy]ethyl]morpholine-4-carboxylate (146 mg, 259.63 μmol, 23.59% yield, 92.051% purity) (Rt = 3.004 min, 146 mg).

[0760] Step 8

[0761]

[0762] At 20 °C under N 2 to a mixture of enantiomer 1 (2* 1 )-tert-Butyl 2-[2-[2-[2-[2-(p-toluenesulfonyloxy)ethoxy]ethoxy]ethoxy]ethyl]morpholine-4-carboxylate (70 mg, 135.23 μmol, 1 equiv) and 2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindoline-1,3-dione (40.79 mg, 148.75 μmol, 1.1 equiv) in DMF (5 mL) was added K 2 CO 3 (37.38 mg, 270.46 μmol, 2 equiv) in one portion. The mixture was stirred at 65 °C for 1 h to give a green suspension. The mixture was cooled to 25 °C and concentrated under reduced pressure at 25 °C. The residue was poured into water (5 mL). The aqueous phase was extracted with ethyl acetate (5 mL * 3). The combined organic phases were washed with brine (5 mL * 3), dried over anhydrous Na 2 SO 4 and filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (column height: 12 g, 100 - 200 mesh silica gel, 0 - 100% (30 min) ethyl acetate in petroleum ether, 100% (10 min) ethyl acetate in petroleum ether) to give (2* 1 )-tert-Butyl 2-[2-[2-[2-[2-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl]oxyethoxy]ethoxy]ethoxy]ethyl]morpholine-4-carboxylate as a colorless gum (50 mg, 72.22 μmol, 53.40% yield, 89.5% purity).

[0763] Step 9

[0764]

[0765] At 25 °C under N 2 to (2* 1)-tert-Butyl 2-((2,6-dioxopiperidin-3-yl)-5-(2-(2-(2-(2-(2-(2-((2R)-morpholin-2-yl)ethoxy)ethoxy)ethoxy)ethoxy)isoindoline-1,3-dione (50 mg, 80.69 μmol, 1 equiv.) in DCM (5 mL) was added TFA (27.60 mg, 242.07 μmol, 17.92 μL, 3 equiv.) in one portion. The mixture was stirred at 25 °C for 30 min. TLC showed the reaction was complete. The reaction mixture was concentrated under reduced pressure to remove the solvent, giving 2-(2,6-dioxopiperidin-3-yl)-5-(2-(2-(2-(2-((2R)-morpholin-2-yl)ethoxy)ethoxy)ethoxy)ethoxy)isoindoline-1,3-dione as a yellow gum (50 mg, 71.72 μmol, 88.88% yield, 90.873% purity, TFA). 1 )-((2R)-morpholin-2-yl)ethoxy)ethoxy)ethoxy)ethoxy)isoindoline-1,3-dione (50 mg, 71.72 μmol, 88.88% yield, 90.873% purity, TFA).

[0766] Step 10

[0767]

[0768] At 20 °C under N 2 to a mixture of 3-(6-chloropyrimidin-4-yl)-5-(1-methylcyclopropoxy)-2H-indazole (26.11 mg, 86.81 μmol, 1.1 equiv.) and 2-(2,6-dioxopiperidin-3-yl)-5-(2-(2-(2-(2-((2R)-morpholin-2-yl)ethoxy)ethoxy)ethoxy)ethoxy)isoindoline-1,3-dione (50 mg, 78.92 μmol, 1 equiv., TFA) in DMSO (2 mL) was added DIPEA (20.40 mg, 157.84 μmol, 27.49 μL, 2 equiv.) in one portion. The mixture was stirred at 100 °C for 1 h. The aqueous phase was extracted with ethyl acetate (3 mL × 2). The combined organic phases were washed with brine (3 mL), dried over anhydrous Na 2 SO 4 dried, filtered and concentrated in vacuo. The crude product was purified by reverse-phase HPLC (column: Phenomenex Luna C18 100 × 30 mm × 5 μm; conditions: water (0.225% FA)-ACN; B: 23%-53%; 9 min), giving 2-(2,6-dioxopiperidin-3-yl)-5-(2-(2-(2-(2-((2R)-4-(6-(5-(1-methylcyclopropoxy)-2H-indazol-3-yl)pyrimidin-4-yl)morpholin-2-yl)ethoxy)ethoxy)ethoxy)ethoxy)isoindoline-1,3-dione as a yellow solid (7.6 mg, 9.21 μmol, 11.67% yield, 95% purity).

[0769] Exemplary Synthesis of Exemplary Compound 18

[0770] Step 1

[0771]

[0772] At 20 °C under N 2 to a mixture of tert-butyl (2* 2 )-2-[2-[2-[2-[2-(p-toluenesulfonyloxy)ethoxy]ethoxy]ethoxy]ethyl]morpholine-4-carboxylate (146 mg, 282.05 μmol, 1 equiv) and 2-(2,6-dioxo-3-piperidinyl)-5-hydroxy-isoindoline-1,3-dione (85.08 mg, 310.26 μmol, 1.1 equiv) in DMF (2 mL) was added K 2 CO 3 (77.97 mg, 564.11 μmol, 2 equiv) in one portion. The mixture was stirred at 70 °C for 2 h. The mixture was cooled to 25 °C and concentrated under reduced pressure at 25 °C. The residue was poured into water (5 mL). The aqueous phase was extracted with ethyl acetate (5 mL * 3). The combined organic phases were washed with brine (5 mL * 3), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (column height: 12 g, silica gel 100 - 200 mesh, 0 - 80% (20 min) ethyl acetate in petroleum ether, 80% (10 min) ethyl acetate in petroleum ether) to give tert-butyl (2* 2 )-2-[2-[2-[2-[2-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindolin-5-yl]oxyethoxy]ethoxy]ethoxy]ethyl]morpholine-4-carboxylate (118 mg, 190.43 μmol, 67.51% yield) as a colorless gum.

[0773] Step 2

[0774]

[0775] At 25 °C under N 2 to a mixture of (2* 2)-tert-Butyl 2-[2-[2-[2-[2-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl]oxyethoxy]ethoxy]ethoxy]ethoxy]morpholine-4-carboxylate (118 mg, 190.43 μmol, 1 equiv) was added in one portion to a mixture of TFA (21.71 mg, 190.43 μmol, 14.10 μL, 1 equiv) in DCM (5 mL). The mixture was stirred at 25 °C for 30 min. TLC showed consumption of the starting material. The reaction mixture was concentrated under reduced pressure to remove the solvent, giving 2-(2,6-dioxopiperidin-3-yl)-5-[2-[2-[2-[2-[(2* 2 )-morpholin-2-yl]ethoxy]ethoxy]ethoxy]ethoxy]isoindoline-1,3-dione (118 mg, 143.60 μmol, 75.41% yield, 77.102% purity, TFA).

[0776] Step 3

[0777]

[0778] At 20 °C under N 2 To a mixture of 2-[[3-(6-chloropyrimidin-4-yl)-5-(1-methylcyclopropoxy)indazol-2-yl]methoxy]ethyl-trimethyl-silane (107.68 mg, 249.83 μmol, 1.1 equiv) and 2-(2,6-dioxopiperidin-3-yl)-5-[2-[2-[2-[2-[(2* 2 )-morpholin-2-yl]ethoxy]ethoxy]ethoxy]ethoxy]isoindoline-1,3-dione (118 mg, 227.12 μmol, 1 equiv, TFA) in DMSO (2 mL) was added DIPEA (58.71 mg, 454.25 μmol, 79.12 μL, 2 equiv) in one portion. The mixture was stirred at 100 °C for 1 h, then HCl (4 M, 283.90 μL, 5 equiv) was added and the solution was stirred at 65 °C for 30 min. The aqueous phase was extracted with ethyl acetate (3 mL * 2). The combined organic phases were washed with brine (3 mL), dried over anhydrous Na 2 SO 4 dried, filtered and concentrated in vacuo. The crude product was purified by reverse-phase HPLC (column: Phenomenex Luna C18 100 * 30 mm * 5 μm; conditions: water (0.225% FA)-ACN; B%: 23%-53%; 9 min), giving 2-(2,6-dioxopiperidin-3-yl)-5-[2-[2-[2-[2-[(2* 2)-4-[6-[5-(1-Methylcyclopropoxy)-2H-indazol-3-yl]pyrimidin-4-yl]morpholin-2-yl]ethoxy]ethoxy]ethoxy]ethoxy]isoindoline-1,3-dione (43.1 mg, 53.17 μmol, 23.41% yield, 96.7% purity).

[0779] Total H count from HNMR data: 43

[0780] Exemplary synthesis of Exemplary Compound 19

[0781] Step 1

[0782]

[0783] To a solution of 4-hydroxyphthalic acid (256.24 mg, 1.41 mmol, 1 equiv) and 3-amino-3-methyl-piperidine-2,6-dione (200 mg, 1.41 mmol, 1 equiv) in HOAc (4 mL) was added NaOAc (346.24 mg, 4.22 mmol, 3 equiv). The reaction mixture was stirred at 120 °C under N 2 for 16 h. The reaction mixture was poured into H 2 O (10 mL * 2) and the residual water was removed by centrifugation to afford 5-hydroxy-2-(3-methyl-2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione as a white solid (114 mg, 355.93 μmol, 25.30% yield, 90% purity). The crude product was used directly in the next step.

[0784] Step 2

[0785]

[0786] To a solution of 2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate (165.35 mg, 474.58 μmol, 1.2 equiv) and 5-hydroxy-2-(3-methyl-2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione (114 mg, 395.48 μmol, 1 equiv) in DMF (5 mL) was added K 2 CO 3(163.97 mg, 1.19 mmol, 3 eq). After addition, the reaction mixture was stirred at 70 °C for 2 h. The reaction mixture was filtered and then the filtrate was concentrated. The residue was purified by silica gel column chromatography (0 to 100% ethyl acetate in petroleum ether) to give 5-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]-2-(3-methyl-2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione as a colorless oil (180 mg, 313.91 μmol, 79.37% yield, 81% purity).

[0787] Step 3

[0788]

[0789] To a solution of 5-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]-2-(3-methyl-2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione (180 mg, 387.54 μmol, 1 eq) and 4-methylbenzenesulfonyl chloride (147.77 mg, 775.09 μmol, 2 eq) in DCM (3 mL) was added DMAP (4.73 mg, 38.75 μmol, 0.1 eq) and TEA (117.65 mg, 1.16 mmol, 161.82 μL, 3 eq). After addition, the mixture was stirred at 20 °C for 16 h. The filtrate was quenched with water (10 mL) and extracted with ethyl acetate (3 × 10 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC (silica gel, petroleum ether:ethyl acetate = 0:1, Rf = 0.43) to give 2-[2-[2-[2-[2-(3-methyl-2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-5-yl]oxyethoxy]ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate as a colorless solid (140 mg, 193.94 μmol, 50.04% yield, 85.70% purity).

[0790] Step 4

[0791]

[0792] To a solution of 2-[2-[2-[2-[2-(3-methyl-2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-5-yl]oxyethoxy]ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate (140 mg, 226.30 μmol, 1 equiv) and 5-(1-methylcyclopropoxy)-3-[6-[(3S)-3-methylpiperazin-1-yl]pyrimidin-4-yl]-1H-indazole (82.47 mg, 226.30 μmol, 1 equiv) in ACN (4 mL) was added KI (187.83 mg, 1.13 mmol, 5 equiv) and DIEA (146.24 mg, 1.13 mmol, 197.09 μL, 5 equiv). The mixture was stirred at 100 °C for 6 h. The reaction was cooled, water (10 mL) was added, and the mixture was extracted with ethyl acetate (3 x 10 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 100*30 mm*5 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 15%-45%, 9 min) to give 2-(3-methyl-2,6-dioxo-3-piperidinyl)-5-[2-[2-[2-[2-[(2S)-2-methyl-4-[6-[5-(1-methylcyclopropoxy)-1H-indazol-3-yl]pyrimidin-4-yl]piperazin-1-yl]ethoxy]ethoxy]ethoxy]ethoxy]isoindoline-1,3-dione as a red solid (11.1 mg, 13.58 μmol, 6.00% yield, 99.21% purity).

[0793] Exemplary synthesis of exemplary compound 20

[0794] Step 1

[0795]

[0796] To a solution of 5-fluoroisobenzofuran-1,3-dione (1 g, 6.02 mmol, 1 equiv) and 3-aminopiperidine-2,6-dione HCl salt (1.49 g, 9.03 mmol, 1.5 equiv) in CH 3 COOH (10 mL) was added KOAc (1.18 g, 12.04 mmol, 2 equiv). After addition, the reaction mixture was stirred at 120 °C for 12 h. The mixture was diluted with water (40 mL). The mixture was filtered and the cake was washed with water (100 mL) to give 2-(2,6-dioxo-3-piperidinyl)-5-fluoro-isoindoline-1,3-dione as a black solid (1.4 g, 5.07 mmol, 84.19% yield).

[0797] Step 2

[0798]

[0799] To a solution of 2-(2,6-dioxo-3-piperidinyl)-5-fluoro-isoindoline-1,3-dione (1.15 g, 4.16 mmol, 1 equiv) and tert-butyl piperazine-1-carboxylate (852.97 mg, 4.58 mmol, 1.1 equiv) in NMP (10 mL) was added DIEA (1.61 g, 12.49 mmol, 2.18 mL, 3 equiv). The sealed tube was heated at 140 °C under microwave for 2 h. The mixture was combined with batch EB12-30-P1, diluted with water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic phases were washed with saturated brine (2 x 30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0 to 50% ethyl acetate in petroleum ether) to give tert-butyl 4-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-5-yl]piperazine-1-carboxylate as a yellow solid (1.4 g, 3.16 mmol, 76.00% yield). Based on EB12-30 (905.08 umol starting material) and EB12-32 (4.16 mmol starting material), the average yield was 62.49%.

[0800] Step 3

[0801]

[0802] To a solution of tert-butyl 4-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-5-yl]piperazine-1-carboxylate (1.2 g, 2.71 mmol, 1 equiv) in MeOH (10 mL) was added HCl / dioxane (4 M, 2.00 mL, 2.95 equiv). After addition, the reaction solution was stirred at 65 °C for 1 h. The reaction solution was combined with batch EB12-34-P1. The mixture was concentrated under reduced pressure to give 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindoline-1,3-dione hydrochloride as a yellow solid (1.1 g, crude). Based on EB12-34 (452.01 umol starting material) and EB12-35 (2.71 mmol starting material), the average yield was 91.04%.

[0803] Step 4

[0804]

[0805] A solution of KOH (2.21 g, 39.46 mmol, 2 eq) in ethylene glycol (3.67 g, 59.17 mmol, 3.31 mL, 5 eq) was stirred at 115 °C. After the potassium hydroxide had dissolved, 2-bromo-1,1-dimethoxy-ethane (2 g, 11.83 mmol, 1.39 mL, 1 eq) was added dropwise over 5 minutes and the reaction mixture was stirred for 20 h. TLC (ethyl acetate:petroleum ether = 1:1) showed a new spot. The mixture was then cooled to room temperature (20 °C) and diluted with water (40 mL) and then extracted with dichloromethane (3 x 20 mL). The organic layer was washed with brine (3 x 20 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0 to 50% ethyl acetate in petroleum ether) to give 2-(2,2-dimethoxyethoxy)ethanol as a pale yellow oil (200 mg, 1.33 mmol, 11.25% yield).

[0806] Step 5

[0807]

[0808] To a solution of 2-(2,2-dimethoxyethoxy)ethanol (200 mg, 1.33 mmol, 1 eq) and 4-methylbenzenesulfonyl chloride (507.81 mg, 2.66 mmol, 2 eq) in DCM (3 mL) was added TEA (269.53 mg, 2.66 mmol, 370.74 uL, 2 eq). After addition, the reaction solution was stirred at 20 °C for 16 h. TLC (petroleum ether:ethyl acetate = 1:1) showed consumption of the starting material and TLC (petroleum ether:ethyl acetate = 5:1) showed a new spot. The reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (3 x 10 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0 to 30% ethyl acetate in petroleum ether) to give 2-(2,2-dimethoxyethoxy)ethyl 4-methylbenzenesulfonate as a pale yellow oil (350 mg, 1.15 mmol, 86.35% yield).

[0809] Step 6

[0810]

[0811] To a solution of 5-(1-methylcyclopropoxy)-3-[6-[(3S)-3-methylpiperazin-1-yl]pyrimidin-4-yl]-1H-indazole (100 mg, 274.39 μmol, 1 equiv) and 2-(2,2-dimethoxyethoxy)ethyl 4-methylbenzenesulfonate (83.51 mg, 274.39 μmol, 1 equiv) in CH 3 CN (3 mL) was added KI (227.75 mg, 1.37 mmol, 5 equiv) and DIEA (70.93 mg, 548.78 μmol, 95.59 μL, 2 equiv). After addition, the reaction mixture was stirred at 90 °C for 12 h. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0 to 10% methanol in dichloromethane) to give 3-[6-[(3S)-4-[2-(2,2-dimethoxyethoxy)ethyl]-3-methyl-piperazin-1-yl]pyrimidin-4-yl]-5-(1-methylcyclopropoxy)-1H-indazole as a yellow oil (80 mg, 146.60 μmol, 53.43% yield, 91% purity).

[0812] Step 7

[0813]

[0814] To a solution of 3-[6-[(3S)-4-[2-(2,2-dimethoxyethoxy)ethyl]-3-methyl-piperazin-1-yl]pyrimidin-4-yl]-5-(1-methylcyclopropoxy)-1H-indazole (80 mg, 161.10 μmol, 1 equiv) in THF (3 mL) was added H 2 SO 4 (2 M, 3.22 mL, 40 equiv). After addition, the reaction solution was stirred at 70 °C for 1 h. The reaction solution was quenched with saturated NaHCO 3 (pH = 7). The resulting mixture was extracted with ethyl acetate (3 x 10 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give 2-[2-[(2S)-2-methyl-4-[6-[5-(1-methylcyclopropoxy)-1H-indazol-3-yl]pyrimidin-4-yl]piperazin-1-yl]ethoxy]acetaldehyde as a yellow solid (60 mg, 118.53 μmol, 73.58% yield, 89% purity). The crude product was used directly.

[0815] Step 8

[0816]

[0817] To a solution of 2-[2-[(2S)-2-methyl-4-[6-[5-(1-methylcyclopropoxy)-1H-indazol-3-yl]pyrimidin-4-yl]piperazin-1-yl]ethoxy]acetaldehyde (60 mg, 133.18 μmol, 1 equiv) and 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindoline-1,3-dione hydrochloride (50.45 mg, 133.18 μmol, 1 equiv) in DMF (3 mL) was added NaOAc (32.77 mg, 399.53 μmol, 3 equiv), HOAc (8.00 mg, 133.18 μmol, 7.62 μL, 1 equiv) and NaBH 3 CN (16.74 mg, 266.35 μmol, 2 equiv). After addition, the reaction mixture was stirred at 20 °C for 16 h. The filtrate was purified by preparative HPLC (column: Agela DuraShell C18 150*25 mm*5 μm; mobile phase: [water (0.04% NH 3 H 2 O + 10 mM NH 4 HCO 3 )-ACN]; B%: 40% - 70%, 8 min) to give 2-(2,6-dioxo-3-piperidinyl)-5-[4-[2-[2-[(2S)-2-methyl-4-[6-[5-(1-methylcyclopropoxy)-1H-indazol-3-yl]pyrimidin-4-yl]piperazin-1-yl]ethoxy]ethyl]piperazin-1-yl]isoindoline-1,3-dione as a yellow solid (15.8 mg, 20.13 μmol, 15.12% yield, 99% purity).

[0818] Exemplary Synthesis of Exemplary Compound 21

[0819] Step 1

[0820]

[0821] At 20 °C under N 2 to 3-[6-[(3R,5S)-3,5-dimethylpiperazin-1-yl]pyrimidin-4-yl]-5-(1-methylcyclopropoxy)-1H-indazole (100 mg, 264.22 μmol, 1 equiv) and 2-(2,2-dimethoxyethoxy)ethyl 4-methylbenzenesulfonate (80.42 mg, 264.22 μmol, 1 equiv) in CH 3KI (43.86 mg, 264.22 μmol, 1 equiv) and DIPEA (34.15 mg, 264.22 μmol, 46.02 μL, 1 equiv) were added to the mixture in CN (3 mL) in one portion. Subsequently, the reaction mixture was heated to 100 °C and stirred for 24 h to obtain a brown suspension. The suspension was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (silica gel 100 - 200 mesh, 0 - 10% MeOH in DCM) to afford 3-[6-[(3R,5S)-4-[2-(2,2-dimethoxyethoxy)ethyl]-3,5-dimethyl-piperazin-1-yl]pyrimidin-4-yl]-5-(1-methylcyclopropoxy)-1H-indazole as a yellow solid (110 mg, crude).

[0822] Step 2

[0823]

[0824] At 20 °C under N 2 H 2 SO 4 (2 M, 4.31 mL, 40 equiv) was added to a solution of 3-[6-[(3R,5S)-4-[2-(2,2-dimethoxyethoxy)ethyl]-3,5-dimethyl-piperazin-1-yl]pyrimidin-4-yl]-5-(1-methylcyclopropoxy)-1H-indazole (110 mg, 215.42 μmol, 1 equiv) in THF (5 mL) in one portion. Subsequently, the solution was heated to 70 °C and stirred for 1 h to obtain a yellow solution. TLC (DCM:MeOH = 10:1, Rf = 0.06) indicated complete reaction. The solution was cooled to 20 °C. The solution was poured into water (5 mL) and NaHCO 3 to adjust the pH to 7 - 8. The aqueous phase was extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with brine (2 x 10 mL), dried over anhydrous Na 2 SO 4 and filtered and concentrated in vacuo to afford 2-[2-[(2R,6S)-2,6-dimethyl-4-[6-[5-(1-methylcyclopropoxy)-1H-indazol-3-yl]pyrimidin-4-yl]piperazin-1-yl]ethoxy]acetaldehyde as a yellow solid (50 mg, 75.72 μmol, 35.15% yield, 70.353% purity).

[0825] Step 3

[0826]

[0827] To a mixture of 2-[2-[(2R,6S)-2,6-dimethyl-4-[6-[5-(1-methylcyclopropoxy)-1H-indazol-3-yl]pyrimidin-4-yl]piperazin-1-yl]ethoxy]acetaldehyde (50 mg, 107.63 μmol, 1 equiv) and 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindoline-1,3-dione hydrochloride (81.54 mg, 215.26 μmol, 2 equiv) in DMF (2 mL) was added NaOAc (26.49 mg, 322.89 μmol, 3 equiv) and acetic acid (3.23 mg, 53.81 μmol, 3.08 μL, 0.5 equiv). The mixture was stirred at 25 °C for 0.5 h. Then NaBH 3 CN (13.53 mg, 215.26 μmol, 2 equiv) was added to the mixture. The mixture was stirred at 20 °C for 16 h. The starting materials were completely consumed and the desired compound was detected by LCMS. The residue was filtered and the filtrate was purified directly by preparative HPLC (column: Agela DuraShell C18 150*25 mm*5 μm; mobile phase: water (0.04% NH3H2O + 10 mM NH4HCO3)-ACN; B%: 50%-80%, gradient time (min): 8 min; flow rate (ml / min): 25), to give 5-[4-[2-[2-[(2R,6S)-2,6-dimethyl-4-[6-[5-(1-methylcyclopropoxy)-1H-indazol-3-yl]pyrimidin-4-yl]piperazin-1-yl]ethoxy]ethyl]piperazin-1-yl]-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione (16.4 mg, 20.74 μmol, 19.27% yield, 100% purity) as a yellow solid.

[0828] Exemplary synthesis of Exemplary Compound 22

[0829] Step 1

[0830]

[0831] To 5-isopropoxy-3-[6-[(3S)-3-methylpiperazin-1-yl]pyrimidin-4-yl]-1H-indazole (320 mg, 822.85 μmol, 1 equiv, HCl salt) and 2-(2,2-diethoxyethoxy)ethyl 4-methylbenzenesulfonate (328.23 mg, 987.42 μmol, 1.2 equiv) in CH 3To the solution in CN (6 mL), KI (1.37 g, 8.23 mmol, 10 equiv) and DIEA (1.06 g, 8.23 mmol, 1.43 mL, 10 equiv) were added. The mixture was stirred at 90 °C for 18 h. Several new peaks were shown on LC-MS, and about 41% of the desired compound was detected. The reaction mixture was diluted with water (20 mL) and extracted with EA (30 mL). The combined organic layers were washed with brine (20 mL), dried over Na 2 SO 4 dried, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by silica gel column chromatography (MeOH in DCM = 0 to 10%), to give 3-[6-[(3S)-4-[2-(2,2-diethoxyethoxy)ethyl]-3-methyl-piperazin-1-yl]pyrimidin-4-yl]-5-isopropoxy-1H-indazole as a yellow oil (250 mg, 419.40 μmol, 50.97% yield, 86% purity).

[0832] Step 2

[0833]

[0834] To a solution of 3-[6-[(3S)-4-[2-(2,2-diethoxyethoxy)ethyl]-3-methyl-piperazin-1-yl]pyrimidin-4-yl]-5-isopropoxy-1H-indazole (125 mg, 243.83 μmol, 1 equiv) in THF (1 mL), H 2 SO 4 (2 M, 1.25 mL, 10.25 equiv) was added. The mixture was stirred at 70 °C for 1 h. TLC indicated that the reactant was consumed and a major new spot with higher polarity was detected. The reaction mixture was diluted with saturated NaHCO 3 (20 mL) and extracted with EA (30 mL). The combined organic layers were washed with brine (20 mL), dried over Na 2 SO 4 dried, filtered and concentrated under reduced pressure to give 2-[2-[(2S)-4-[6-(5-isopropoxy-1H-indazol-3-yl)pyrimidin-4-yl]-2-methyl-piperazin-1-yl]ethoxy]acetaldehyde as a light yellow solid (100 mg, 207.52 μmol, 85.11% yield, 91% purity).

[0835] Step 3

[0836]

[0837] To a solution of 2-[2-[(2S)-4-[6-(5-isopropoxy-1H-indazol-3-yl)pyrimidin-4-yl]-2-methylpiperazin-1-yl]ethoxy]acetaldehyde (100 mg, 228.04 μmol, 1 equiv) and 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindoline-1,3-dione 2,2,2-trifluoroacetate (104.07 mg, 228.04 μmol, 1 equiv) in DCE (3 mL) was added NaOAc (56.12 mg, 684.12 μmol, 3 equiv), HOAc (13.69 mg, 228.04 μmol, 13.04 μL, 1 equiv) and NaBH 3 CN (42.99 mg, 684.12 μmol, 3 equiv). The mixture was stirred at 25 °C for 18 h. LC-MS (EB134-92-P1C) showed consumption of the reactant 1. Several new peaks were shown on the LC-MS and about 86% of the desired compound was detected. The reaction solution was filtered to remove insoluble materials. The reaction solution was purified by preparative HPLC (FA conditions: column: Phenomenex Luna C18 100*30 mm*5 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 5%-35%, 18 min) to give 2-(2,6-dioxo-3-piperidinyl)-5-[4-[2-[2-[(2S)-4-[6-(5-isopropoxy-1H-indazol-3-yl)pyrimidin-4-yl]-2-methylpiperazin-1-yl]ethoxy]ethyl]piperazin-1-yl]isoindoline-1,3-dione as a yellow solid (27.70 mg, 34.88 μmol, 15.29% yield, 96.3% purity).

[0838] Exemplary synthesis of exemplary compound 23

[0839] Step 1

[0840]

[0841] To a solution of (3S)-tert-butyl 3-methylpiperazine-1-carboxylate (3.5 g, 17.48 mmol, 1 equiv) and 4-bromobutan-1-ol (3.34 g, 17.48 mmol, 1 equiv) in THF (10 mL) was added K 2 CO 3 (7.25 g, 52.43 mmol, 3 equiv). Then the mixture was at 60 °C under N 2Stir the mixture at a lower temperature for 16 hours. TLC (dichloromethane:methanol = 10:1, Rf = 0.2) shows new reaction spots. Filter the reaction mixture and then concentrate the filtrate. Purify the crude product by flash silica gel chromatography (0 - 10% methanol in dichloromethane) to obtain tert-butyl (3S)-4-(4-hydroxybutyl)-3-methylpiperazine-1-carboxylate (4 g, 14.69 mmol, 84.03% yield) as a colorless liquid.

[0842] Step 2

[0843]

[0844] Cool a solution of oxalyl chloride (512.58 mg, 4.04 mmol, 353.51 μL, 1.1 eq) in DCM (10 mL) to -60 °C under a dry nitrogen atmosphere. Dropwise add a solution of DMSO (717.13 mg, 9.18 mmol, 717.13 μL, 2.5 eq) in DCM (10 mL), and then stir the mixture at -60 °C for 15 min. Next, dropwise add a solution of tert-butyl (3R)-4-(4-hydroxybutyl)-3-methylpiperazine-1-carboxylate (1 g, 3.67 mmol, 1 eq) in DCM (10 mL), and stir the mixture at -60 °C for 45 min. Subsequently, add TEA (1.11 g, 11.01 mmol, 1.53 mL, 3 eq), and warm the mixture to -60 °C and maintain for 1 hour. TLC (dichloromethane:methanol = 10:1, Rf = 0.4) shows new spots. Filter the reaction mixture and use the filtrate directly in the next step. The solution of crude tert-butyl (3S)-3-methyl-4-(4-oxobutyl)piperazine-1-carboxylate (990 mg) in DCM is a colorless liquid and is used directly in the next step.

[0845] Step 3

[0846]

[0847] Add NaOAc (270.70 mg, 3.30 mmol, 3 eq) to a solution of 2-(2,6-dioxo-3-piperidinyl)-5-piperazin-1-ylisoindoline-1,3-dione (500 mg, 1.10 mmol, 1 eq, TFA) and tert-butyl (3S)-3-methyl-4-(4-oxobutyl)piperazine-1-carboxylate (446.11 mg, 1.65 mmol, 1.5 eq) in DCM (15 mL) and MeOH (15 mL), and stir the mixture at 20 °C for 20 min. Then add HOAc (6.61 mg, 110.00 μmol, 6.29 μL, 0.1 eq) and NaBH3 CN (691.24 mg, 11.00 mmol, 10 eq) was added to the solution and stirred at 20 °C for 2 h. TLC (dichloromethane:methanol = 10:1, Rf = 0.01) showed complete reaction. The reaction mixture was poured into H 2 O (20 mL). The mixture was extracted with ethyl acetate (30 mL * 3). The organic phase was washed with brine (20 mL), dried over anhydrous Na 2 SO 4 and concentrated in vacuo to give a residue. The residue was purified by silica gel column chromatography (0 - 20% methanol in dichloromethane) to give tert-butyl (3S)-4-[4-[4-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-5-yl]piperazin-1-yl]butyl]-3-methylpiperazine-1-carboxylate as a yellow gum (600 mg, 703.85 μmol, 63.99% yield, 70% purity).

[0848] Step 4

[0849]

[0850] TFA (3.08 g, 27.01 mmol, 2 mL, 80.59 eq) was added to a solution of tert-butyl (3S)-4-[4-[4-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-5-yl]piperazin-1-yl]butyl]-3-methylpiperazine-1-carboxylate (200 mg, 335.17 μmol, 1 eq) in DCM (4 mL), and the mixture was stirred at 15 °C for 1 h. TLC (dichloromethane:methanol = 5:1, Rf = 0.01) showed complete reaction. The reaction mixture was concentrated in vacuo to give 2-(2,6-dioxo-3-piperidinyl)-5-[4-[4-[(2S)-2-methylpiperazin-1-yl]butyl]piperazin-1-yl]isoindoline-1,3-dione as a yellow gum (200 mg, crude, TFA).

[0851] Step 5

[0852]

[0853] To a solution of 2-(2,6-dioxo-3-piperidinyl)-5-[4-[4-[(2S)-2-methylpiperazin-1-yl]butyl]piperazin-1-yl]isoindoline-1,3-dione (200 mg, 327.53 μmol, 1 equiv., TFA) and 3-(6-chloropyrimidin-4-yl)-5-isopropoxy-1H-indazole (66.20 mg, 229.27 μmol, 0.7 equiv.) in DMSO (5 mL) was added DIEA (211.66 mg, 1.64 mmol, 285.25 μL, 5 equiv.). The mixture was then stirred at 100 °C under N 2 for 2 h. The reaction mixture was poured into H 2 2O (10 mL). The mixture was extracted with ethyl acetate (10 mL × 3). The aqueous phase was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 100*40 mm*3 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 12% - 42%, 10 min) to give 2-(2,6-dioxo-3-piperidinyl)-5-[4-[4-[(2S)-4-[6-(5-isopropoxy-1H-indazol-3-yl)pyrimidin-4-yl]-2-methylpiperazin-1-yl]butyl]piperazin-1-yl]isoindoline-1,3-dione as a yellow solid (7.9 mg, 10.35 μmol, 3.16% yield, 98.07% purity).

[0854] Exemplary synthesis of Exemplary Compound 24

[0855] Step 1

[0856]

[0857] At 20 °C under N 2 to a solution of 5-(1-methylcyclopropoxy)-3-[6-[(3S)-3-methylpiperazin-1-yl]pyrimidin-4-yl]-1H-indazole (100 mg, 274.39 μmol, 1 equiv.) and tert-butyl 4-formylpiperidine-1-carboxylate (117.04 mg, 548.78 μmol, 2 equiv.) in DMF (2 mL) was added CH 3 3COOH (823.89 μg, 13.72 μmol, 7.85e -1 -5 μL, 0.05 equiv.) and NaOAc (45.02 mg, 548.78 μmol, 2 equiv.). The solution was stirred at 20 °C for 5 h. Then NaBH 3CN (34.49 mg, 548.78 μmol, 2 equivalents) and the solution was stirred for 1 h to obtain a pale yellow solution. The residue was poured into water (5 mL) and stirred for 5 min. The aqueous phase was extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with brine (2 x 5 mL), dried over anhydrous Na 2 SO 4 dried, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (100 - 200 mesh silica gel, 50 - 80% ethyl acetate in petroleum ether) to give tert-butyl 4-[[(2S)-2-methyl-4-[6-[5-(1-methylcyclopropoxy)-1H-indazol-3-yl]pyrimidin-4-yl]piperazin-1-yl]methyl]piperidine-1-carboxylate (110 mg, 172.72 μmol, 62.95% yield, 88.199% purity) as a yellow oil.

[0858] Step 2

[0859]

[0860] At 20 °C under N 2 2, trifluoroacetic acid (TFA) (66.99 mg, 587.48 μmol, 43.50 μL, 3 equivalents) was added in one portion to a mixture of tert-butyl 4-[[(2S)-2-methyl-4-[6-[5-(1-methylcyclopropoxy)-1H-indazol-3-yl]pyrimidin-4-yl]piperazin-1-yl]methyl]piperidine-1-carboxylate (110 mg, 195.83 μmol, 1 equivalent) in DCM (5 mL). The mixture was stirred at 20 °C for 1 h. The residue was poured into NaHCO 3 (5 mL) to adjust the pH to 7 - 8. The aqueous phase was extracted with ethyl acetate (3 x 5 mL). The combined organic phases were washed with brine (3 x 5 mL), dried over anhydrous Na 2 SO 4 dried, filtered and concentrated in vacuo to give the crude product (150 mg). The crude product was purified by silica gel chromatography (100 - 200 mesh silica gel, 0 - 100% MeOH in EtOAc) to give 5-(1-methylcyclopropoxy)-3-[6-[(3S)-3-methyl-4-(piperidin-4-ylmethyl)piperazin-1-yl]pyrimidin-4-yl]-1H-indazole (100 mg, crude) as a yellow gum.

[0861] Step 3

[0862]

[0863] To a mixture of 2-(2,6-dioxo-3-piperidinyl)-5-fluoro-isoindoline-1,3-dione (100 mg, 362.03 μmol, 1 equiv) and 4-piperidinemethanol (83.39 mg, 724.06 μmol, 2 equiv) in DMSO (2 mL) was added DIEA (140.37 mg, 1.09 mmol, 189.18 μL, 3 equiv) in one portion. The mixture was stirred at 100 °C for 3 h. TLC (DCM:MeOH = 10:1, Rf = 0.36) showed complete reaction. The mixture was cooled to 20 °C. The residue was poured into NaHCO 3 (10 mL) to adjust the pH to 7 - 8. The aqueous phase was extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with brine (2 x 10 mL), dried over anhydrous Na 2 SO 4 dried, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (100 - 200 mesh silica gel, 0 - 10% MeOH in DCM) to give 2-(2,6-dioxo-3-piperidinyl)-5-[4-(hydroxymethyl)-1-piperidinyl]isoindoline-1,3-dione as a yellow gum (120 mg, 283.18 μmol, 78.22% yield, 87.640% purity).

[0864] Step 4

[0865]

[0866] At 0 °C under N 2 2 to a solution of 2-(2,6-dioxo-3-piperidinyl)-5-[4-(hydroxymethyl)-1-piperidinyl]isoindoline-1,3-dione (120 mg, 323.11 μmol, 1 equiv) and TEA (98.09 mg, 969.34 μmol, 134.92 μL, 3 equiv) in DCM (5 mL) was added TsCl (27.35 mg, 387.74 μmol, 1.2 equiv) in one portion. The mixture was stirred at 20 °C for 20 h to give a yellow solution. TLC (DCM:MeOH = 10:1, Rf = 0.45) showed complete reaction. The residue was poured into water (5 mL). The aqueous phase was extracted with ethyl acetate (3 x 5 mL). The combined organic phases were washed with brine (2 x 5 mL), dried over anhydrous Na 2 SO 4Dry, filter and concentrate in vacuo. The residue was purified by silica gel chromatography (silica gel 100 - 200 mesh, 0 - 50% ethyl acetate in petroleum ether (5 min), 50 - 100% ethyl acetate in petroleum ether (10 min)) to give [1-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-5-yl]-4-piperidinyl] methyl 4-methylbenzenesulfonate as a yellow solid (160 mg, 228.91 μmol, 70.85% yield, 75.194% purity).

[0867] Step 5

[0868]

[0869] At 20 °C under N 2 To a solution of 5-(1-methylcyclopropoxy)-3-[6-[(3S)-3-methyl-4-(4-piperidinylmethyl)piperazin-1-yl]pyrimidin-4-yl]-1H-indazole (100 mg, 216.64 μmol, 1 equiv) and [1-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-5-yl]-4-piperidinyl] methyl 4-methylbenzenesulfonate (159.40 mg, 303.29 μmol, 1.4 equiv) in MeCN (5 mL) was added KI (179.81 mg, 1.08 mmol, 5 equiv) and DIPEA (84.00 mg, 649.91 μmol, 113.20 μL, 3 equiv) in one portion. The solution was stirred at 80 °C for 16 h. The residue was poured into water (5 mL) and stirred for 5 min. The aqueous phase was extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with brine (2 x 5 mL), dried over anhydrous Na 2 SO 4 dried, filtered and concentrated in vacuo to give 200 mg of the crude product. The crude product was purified by preparative HPLC (column: Welch Xtimate C18 150*30 mm*5 μm; mobile phase: water (0.225% FA)-ACN; B%: 10% - 40%, gradient time (min): 8 min; flow rate (ml / min): 25) to give 2-(2,6-dioxo-3-piperidinyl)-5-[4-[[4-[[(2S)-2-methyl-4-[6-[5-(1-methylcyclopropoxy)-1H-indazol-3-yl]pyrimidin-4-yl]piperazin-1-yl]methyl]-1-piperidinyl]methyl]-1-piperidinyl]isoindoline-1,3-dione as a yellow solid (53.77 mg, 65.33 μmol, 30.15% yield, 99.013% purity).

[0870] Exemplary Synthesis of Exemplary Compound 25

[0871] Step 1

[0872]

[0873] At 0 °C under nitrogen, NaH (516.69 mg, 12.92 mmol, 60% purity in oil, 1.3 equiv) was added portionwise to a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (2 g, 9.94 mmol, 1 equiv) in THF (20 mL). After the evolution of hydrogen ceased, ethyl 2-bromoacetate (3.32 g, 19.87 mmol, 2.20 mL, 2 equiv) was added dropwise. The resulting mixture was stirred at 0 °C for 2 h. TLC (petroleum ether:ethyl acetate = 5:1) showed two new spots. The reaction mixture was quenched with an aqueous NH 4 Cl solution (20 mL) and extracted with ethyl acetate (3 x 20 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0 to 20% ethyl acetate in petroleum ether) to give tert-butyl 4-(2-ethoxy-2-oxo-ethoxy)piperidine-1-carboxylate (800 mg, 2.78 mmol, 28.02% yield) as a colorless oil.

[0874] Step 2

[0875]

[0876] At 0 °C, LiAlH 4 (158.50 mg, 4.18 mmol, 1.5 equiv) was added to a solution of tert-butyl 4-(2-ethoxy-2-oxo-ethoxy)piperidine-1-carboxylate (800 mg, 2.78 mmol, 1 equiv) in THF (10 mL). After the addition, the reaction mixture was stirred at 20 °C for 2 h. TLC (petroleum ether:ethyl acetate = 1:1) showed that the starting material was consumed and new spots were formed. The reaction mixture was quenched by adding water (0.5 mL), followed by 15% aqueous NaOH solution (0.5 mL) and water (1.5 mL). The solid was removed by filtration. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0 to 50% ethyl acetate in petroleum ether) to give tert-butyl 4-(2-hydroxyethoxy)piperidine-1-carboxylate (400 mg, 1.63 mmol, 58.57% yield) as a colorless oil.

[0877] Step 3

[0878]

[0879] To a solution of tert-butyl 4-(2-hydroxyethoxy)piperidine-1-carboxylate (400 mg, 1.63 mmol, 1 equiv) in DCM (2 mL) at 20 °C was added 4-methylbenzenesulfonyl chloride (621.72 mg, 3.26 mmol, 2 equiv) and TEA (329.99 mg, 3.26 mmol, 453.91 μL, 2 equiv). After addition, the reaction solution was stirred at 20 °C for 16 h. TLC (petroleum ether:ethyl acetate = 3:1) showed two major spots. The reaction solution was diluted with water (10 mL) and extracted with dichloromethane (3 x 10 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0 to 30% ethyl acetate in petroleum ether) to give tert-butyl 4-[2-(p-toluenesulfonyloxy)ethoxy]piperidine-1-carboxylate as a colorless oil (490 mg, 1.23 mmol, 75.22% yield, 100% purity).

[0880] Step 4

[0881]

[0882] To a solution of tert-butyl 4-[2-(p-toluenesulfonyloxy)ethoxy]piperidine-1-carboxylate (131.54 mg, 329.27 μmol, 1 equiv) and 5-(1-methylcyclopropoxy)-3-[6-[(3S)-3-methylpiperazin-1-yl]pyrimidin-4-yl]-1H-indazole (120 mg, 329.27 μmol, 1 equiv) in CH 3 CN (3 mL) was added KI (273.30 mg, 1.65 mmol, 5 equiv) and DIEA (127.67 mg, 987.81 μmol, 172.06 μL, 3 equiv). After addition, the reaction mixture was stirred at 90 °C for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0 to 5% methanol in dichloromethane) to give tert-butyl 4-[2-[(2S)-2-methyl-4-[6-[5-(1-methylcyclopropoxy)-1H-indazol-3-yl]pyrimidin-4-yl]piperazin-1-yl]ethoxy]piperidine-1-carboxylate as a yellow gum (130 mg, 204.31 μmol, 62.05% yield, 93% purity).

[0883] Step 5

[0884]

[0885] To a solution of tert-butyl 4-[2-[(2S)-2-methyl-4-[6-[5-(1-methylcyclopropoxy)-1H-indazol-3-yl]pyrimidin-4-yl]piperazin-1-yl]ethoxy]piperidine-1-carboxylate (130 mg, 219.69 μmol, 1 equiv) in DCM (2 mL) was added HCl / dioxane (4 M, 549.23 μL, 10 equiv). After addition, the reaction mixture was stirred at 20 °C for 30 min. TLC (dichloromethane:methanol = 10:1) showed consumption of the starting material. The reaction mixture was concentrated under reduced pressure to afford 5-(1-methylcyclopropoxy)-3-[6-[(3S)-3-methyl-4-[2-(4-piperidyloxy)ethyl]piperazin-1-yl]pyrimidin-4-yl]-1H-indazole (108 mg, 206.50 μmol, 94.00%).

[0886] Step 6

[0887]

[0888] To a solution of 5-(1-methylcyclopropoxy)-3-[6-[(3S)-3-methyl-4-[2-(4-piperidyloxy)ethyl]piperazin-1-yl]pyrimidin-4-yl]-1H-indazole (105.23 mg, 214.05 μmol, 1.25 equiv) and methyl 4-methylbenzenesulfonate [1-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-5-yl]-4-piperidinyl] ester (90 mg, 171.24 μmol, 1 equiv) in CH 3 CN (5 mL) was added KI (142.13 mg, 856.21 μmol, 5 equiv) and DIEA (177.05 mg, 1.37 mmol, 238.62 μL, 8 equiv). After addition, the reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Welch Xtimate C18 150*25mm*5um; mobile phase: [water (0.225% FA)-ACN]; B%: 5%-35%, 8 min) to afford 2-(2,6-dioxo-3-piperidinyl)-5-[4-[[4-[2-[(2S)-2-methyl-4-[6-[5-(1-methylcyclopropoxy)-1H-indazol-3-yl]pyrimidin-4-yl]piperazin-1-yl]ethoxy]-1-piperidinyl]methyl]-1-piperidinyl]isoindoline-1,3-dione as a yellow solid (12.5 mg, 14.50 μmol, 8.47% yield, 98% purity).

[0889] Exemplary Synthesis of Exemplary Compound 26

[0890] Step 1

[0891]

[0892] To a solution of (3S)-Benzyl 3-methylpiperazine-1-carboxylate (500 mg, 2.13 mmol, 1 equiv) and tert-Butyl 4-(2-chloroethyl)piperazine-1-carboxylate (637.02 mg, 2.56 mmol, 1.2 equiv) in CH 3 CN (1 mL) was added DIEA (827.44 mg, 6.40 mmol, 1.12 mL, 3 equiv). The mixture was stirred at 80 °C for 32 h. The reaction mixture was concentrated under reduced pressure to remove the solvent. The crude product was purified by silica gel column chromatography (DCM in MeOH = 0 to 3%) to give (3S)-Benzyl 4-[2-(4-tert-butoxycarbonylpiperazin-1-yl)ethyl]-3-methylpiperazine-1-carboxylate as a brown gum (460 mg, 1.03 mmol, 48.27% yield).

[0893] Step 2

[0894]

[0895] Under N 2 to a solution of (3S)-Benzyl 4-[2-(4-tert-butoxycarbonylpiperazin-1-yl)ethyl]-3-methylpiperazine-1-carboxylate (460 mg, 1.03 mmol, 1 equiv) in MeOH (5 mL) was added Pd / C (200 mg, 2.06 mmol, 10% purity, 2 equiv). The suspension was degassed under vacuum and purged with H 2 several times. The mixture was stirred at 25 °C under H 2 (15 psi) for 2 h. TLC indicated no residual reactant and detected one major new spot of higher polarity. The reaction mixture was filtered and the filtrate was concentrated to give tert-Butyl 4-[2-[(2S)-2-methylpiperazin-1-yl]ethyl]piperazine-1-carboxylate as a pale yellow oil (290 mg, 928.15 μmol, 90.11% yield).

[0896] Step 3

[0897]

[0898] To a solution of tert-butyl 4-[2-[(2S)-2-methylpiperazin-1-yl]ethyl]piperazine-1-carboxylate (290 mg, 928.15 μmol, 1 equiv) and 2-[[3-(6-chloropyrimidin-4-yl)-5-isopropoxy-indazol-1-yl]methoxy]ethyl-trimethyl-silane (388.89 mg, 928.15 μmol, 1 equiv) in DMSO (3 mL) was added DIEA (359.87 mg, 2.78 mmol, 485.00 μL, 3 equiv). The mixture was stirred at 100 °C for 2 h. LC-MS (EB134-185-P1A) showed no residual reactant 1. Several new peaks were shown on the LC-MS, and about 64% of the desired compound was detected. The reaction mixture was diluted with water (20 mL) and extracted with EA (30 mL). The combined organic layers were washed with brine (20 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The crude product was purified by silica gel column chromatography (DCM in MeOH = 0 to 3%) to give tert-butyl 4-[2-[(2S)-4-[6-[5-isopropoxy-1-(2-trimethylsilylethoxymethyl)indazol-3-yl]pyrimidin-4-yl]-2-methyl-piperazin-1-yl]ethyl]piperazine-1-carboxylate as a brown gum (590 mg, 812.44 μmol, 87.53% yield, 95.7% purity).

[0899] Step 4

[0900]

[0901] To a solution of tert-butyl 4-[2-[(2S)-4-[6-[5-isopropoxy-1-(2-trimethylsilylethoxymethyl)indazol-3-yl]pyrimidin-4-yl]-2-methyl-piperazin-1-yl]ethyl]piperazine-1-carboxylate (350 mg, 503.61 μmol, 1 equiv) in DCM (3 mL) was added TFA (7.19 g, 63.03 mmol, 4.67 mL, 125.15 equiv). The mixture was stirred at 25 °C for 16 h. Then NH 3 .H 2 O (211.79 mg, 1.51 mmol, 232.74 μL, 25% purity, 3 equiv) was added to the solution and the mixture was stirred for 2 h. LC-MS (EB134-187-P1B) showed no residual reactant. Several new peaks were shown on the LC-MS, and about 97% of the desired compound was detected. The reaction mixture was diluted with water (20 mL) and extracted with EA (30 mL). The combined organic layers were washed with brine (20 mL), dried over Na2 SO 4 Dry, filter and concentrate under reduced pressure to obtain 5-isopropoxy-3-[6-[(3S)-3-methyl-4-(2-piperazin-1-ylethyl)piperazin-1-yl]pyrimidin-4-yl]-1H-indazole as a yellow gum (150 mg, 313.17 μmol, 62.18% yield, 97% purity).

[0902] Step 5

[0903]

[0904] To a solution of 5-isopropoxy-3-[6-[(3S)-3-methyl-4-(2-piperazin-1-ylethyl)piperazin-1-yl]pyrimidin-4-yl]-1H-indazole (150 mg, 322.85 μmol, 1 equiv) and methyl [1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl]piperidin-4-yl] 4-methylbenzenesulfonate (169.68 mg, 322.85 μmol, 1 equiv) in CH 3 CN (5 mL) was added KI (428.76 mg, 2.58 mmol, 8 equiv) and DIEA (333.81 mg, 2.58 mmol, 449.88 μL, 8 equiv). The mixture was stirred at 80 °C for 16 h. LC-MS (EB134-190-P1D2) showed no residual reactant 1. Several new peaks were shown on LC-MS and about 56% of the desired compound was detected. The reaction mixture was diluted with water (20 mL) and extracted with EA (30 mL). The combined organic layers were washed with brine (20 mL), dried over Na 2 SO 4 dried, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 100*30 mm*5 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 10%-40%; 11 min) to obtain 2-(2,6-dioxopiperidin-3-yl)-5-[4-[[4-[2-[(2S)-4-[6-(5-isopropoxy-1H-indazol-3-yl)pyrimidin-4-yl]-2-methylpiperazin-1-yl]ethyl]piperazin-1-yl]methyl]-1-piperidinyl]isoindoline-1,3-dione as a yellow solid (47 mg, 55.39 μmol, 17.16% yield, 96.4% purity).

[0905] Exemplary synthesis of Exemplary Compound 27

[0906] Step 1

[0907]

[0908] At 25 °C in N 2 To a solution of tert-butyl 4-(2-chloroethyl)piperazine-1-carboxylate (1 g, 4.02 mmol, 1 equiv) and 4-(dimethoxymethyl)piperidine (960.16 mg, 6.03 mmol, 1.5 equiv) in EtOH (30 mL) and water (4 mL) was added NaHCO 3 (1.01 g, 12.06 mmol, 469.07 uL, 3 equiv). The reaction mixture was then heated to 80 °C and stirred for 5 h to give a white suspension. TLC (dichloromethane:methanol = 10:1) showed complete reaction. The mixture was concentrated in vacuo and the residue was taken up in water (30 mL). The aqueous phase was extracted with ethyl acetate (30 mL * 3). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na 2 SO 4 dried, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100 - 200 mesh silica gel, dichloromethane:methanol = 100 / 1, 5 / 1) to give tert-butyl 4-[2-[4-(dimethoxymethyl)-1-piperidinyl]ethyl]piperazine-1-carboxylate as a yellow oil (900 mg, 2.42 mmol, 60.26% yield).

[0909] Step 2

[0910]

[0911] To a solution of tert-butyl 4-[2-[4-(dimethoxymethyl)-1-piperidinyl]ethyl]piperazine-1-carboxylate (800 mg, 2.15 mmol, 1 equiv) in THF (5 mL) at 25 °C was added HCl (2 M, 5 mL, 4.64 equiv), and the reaction mixture was then stirred at 50 °C for 2 h to give a grey-yellow solution. TLC (dichloromethane:methanol = 10:1) showed complete reaction. The residue was adjusted to pH = 8 with NaHCO 3 and the mixture was then poured into water (25 mL). The aqueous phase was extracted with ethyl acetate (25 mL * 2). The combined organic phases were washed with brine (30 mL * 2), dried over anhydrous Na 2 SO 4 dried, filtered and concentrated in vacuo to give tert-butyl 4-[2-(4-formyl-1-piperidinyl)ethyl]piperazine-1-carboxylate as a grey-yellow oil (420 mg, crude).

[0912] Step 3

[0913]

[0914] To a solution of 2-(2,6-dioxo-3-piperidinyl)-5-piperazin-1-yl-isoindoline-1,3-dione (601.45 mg, 1.55 mmol, 1.2 eq, FA) and NaOAc (423.47 mg, 5.16 mmol, 4 eq) in DCM (5 mL) and MeOH (5 mL) at 25 °C, the reaction was then stirred at 25 °C for 1 h, then 4-[2-(4-formyl-1-piperidinyl)ethyl]piperazine-1-carboxylic acid tert-butyl ester (420 mg, 1.29 mmol, 1 eq) was added and stirred for 1 h, then acetic acid (193.75 mg, 3.23 mmol, 184.52 uL, 2.5 eq) and sodium cyanoborohydride (162.20 mg, 2.58 mmol, 2 eq) were stirred at 25 °C for 1 h, then the reaction mixture was stirred at 25 °C for 14 h to obtain a yellow solution. TLC (dichloromethane:methanol = 10:1) showed the detection of a new spot. The residue was poured into ice water (w / w = 1 / 1) (35 mL). The aqueous phase was extracted with ethyl acetate (35 mL * 2). Then the aqueous phase was lyophilized to obtain a yellow solid. The solid was washed with MeOH / DCM (1 / 1, 40 mL) to obtain a yellow suspension. The suspension was filtered and concentrated in vacuo to obtain a yellow oil. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100 - 200 mesh silica gel, dichloromethane:methanol = 100 / 1, 5 / 1) to obtain tert-butyl 4-[2-[4-[[4-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-5-yl]piperazin-1-yl]methyl]-1-piperidinyl]ethyl]piperazine-1-carboxylate as a yellow oil (320 mg, 490.95 μmol, 38.04% yield).

[0915] Step 4

[0916]

[0917] To a solution of tert-butyl 4-[2-[4-[[4-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-5-yl]piperazin-1-yl]methyl]-1-piperidinyl]ethyl]piperazine-1-carboxylate (320 mg, 490.95 μmol, 1 equiv) in DCM (10 mL) at 25 °C was added TFA (3.08 g, 27.01 mmol, 2 mL, 55.02 equiv). Subsequently, the reaction mixture was stirred at 25 °C for 0.5 h to afford a yellow solution. TLC (dichloromethane:methanol = 10:1) showed consumption of the starting material and formation of a new spot. The reaction mixture was concentrated in vacuo to give 2-(2,6-dioxo-3-piperidinyl)-5-[4-[[1-(2-piperazin-1-ylethyl)-4-piperidinyl]methyl]piperazin-1-yl]isoindoline-1,3-dione (480 mg, 395.33 μmol, 80.52% yield, 83% purity, 4TFA) as a yellow solid.

[0918] Step 5

[0919]

[0920] To a solution of 2-(2,6-dioxo-3-piperidinyl)-5-[4-[[1-(2-piperazin-1-ylethyl)-4-piperidinyl]methyl]piperazin-1-yl]isoindoline-1,3-dione (160 mg, 158.77 μmol, 1 equiv, 4TFA) and 3-(6-chloropyrimidin-4-yl)-5-isopropoxy-1H-indazole (45.84 mg, 158.77 μmol, 1 equiv) in DMSO (10 mL) at 25 °C was added DIEA (102.60 mg, 793.83 μmol, 138.27 μL, 5 equiv). Subsequently, the reaction mixture was stirred at 25 °C for 30 min and then at 80 °C for 1.5 h to afford a yellow solution. The residue was poured into ice water (30 mL). The aqueous phase was extracted with ethyl acetate (25 mL × 2). The combined organic phases were washed with brine (30 mL × 2) and dried over anhydrous Na 2 SO 4Dry, filter and concentrate in vacuo. Purify the residue by preparative HPLC (column: Phenomenex Luna C18 100*30mm*5um, mobile phase: water (0.225% FA)-ACN); B%: 5%-35%; 9 min), to give 2-(2,6-dioxo-3-piperidinyl)-5-[4-[[1-[2-[4-[6-(5-isopropoxy-1H-indazol-3-yl)pyrimidin-4-yl]piperazin-1-yl]ethyl]-4-piperidinyl]methyl]piperazin-1-yl]isoindoline-1,3-dione as a yellow solid (6.8 mg, 8.42 umol, 5.31% yield, 99.6% purity).

[0921] Exemplary synthesis of Exemplary Compound 28

[0922] Step 1

[0923]

[0924] Add DIEA (102.60 mg, 793.83 umol, 138.27 uL, 5 eq) to a solution of 2-(2,6-dioxo-3-piperidinyl)-5-[4-[[1-(2-piperazin-1-ylethyl)-4-piperidinyl]methyl]piperazin-1-yl]isoindoline-1,3-dione (160 mg, 158.77 umol, 1 eq, 4TFA) and 3-(6-chloropyrimidin-4-yl)-5-(1-methylcyclopropoxy)-1H-indazole (47.75 mg, 158.77 umol, 1 eq) in DMSO (5 mL) at 25 °C and stir for 30 min, then stir the reaction mixture at 80 °C for 1.5 h to obtain a yellow solution. Pour the residue into water (35 mL). Extract the aqueous phase with ethyl acetate (30 mL * 2). Wash the combined organic phases with brine (35 mL * 2), dry over anhydrous Na 2 SO 4 Dry, filter and concentrate in vacuo. Purify the residue by preparative HPLC (column: Phenomenex Luna C18 100*30mm*5um, mobile phase: water (0.225% FA)-ACN); B%: 5%-35%; 9 min), to give 2-(2,6-dioxo-3-piperidinyl)-5-[4-[[1-[2-[4-[6-[5-(1-methylcyclopropoxy)-1H-indazol-3-yl]pyrimidin-4-yl]piperazin-1-yl]ethyl]-4-piperidinyl]methyl]piperazin-1-yl]isoindoline-1,3-dione as a yellow solid (7.0 mg, 8.56 umol, 5.39% yield, 99.8% purity).

[0925] Exemplary Synthesis of Exemplary Compound 29

[0926] Step 1

[0927]

[0928] HOAc (7.69 mg, 128.04 μmol, 7.32 μL, 0.1 eq) was added to a solution of (3S)-benzyl 3-methylpiperazine-1-carboxylate (300 mg, 1.28 mmol, 1 eq) and 2-chloroacetaldehyde (753.84 mg, 3.84 mmol, 617.90 μL, 3 eq) in DCM (5 mL) and MeOH (5 mL). The mixture was then stirred at 25 °C for 20 min. Then NaBH 3 CN (241.39 mg, 3.84 mmol, 3 eq) was added to the solution and the reaction was stirred at 25 °C for 1 h. TLC (petroleum ether:ethyl acetate = 1:1, Rf = 0.5) showed the reaction was complete. The reaction mixture was poured into H 2 O (10 mL). The mixture was extracted with ethyl acetate (20 mL * 3). The organic phase was washed with brine (20 mL), dried over anhydrous Na 2 SO 4 and concentrated in vacuo to give a residue. The residue was purified by silica gel column chromatography (0 - 100% ethyl acetate in petroleum ether) to give (3S)-benzyl 4-(2-chloroethyl)-3-methylpiperazine-1-carboxylate as a colorless oil (180 mg, 606.49 μmol, 47.37% yield).

[0929] Step 2

[0930]

[0931] (3S)-benzyl 4-(2-chloroethyl)-3-methylpiperazine-1-carboxylate (180 mg, 606.49 μmol, 1 eq) and 4-(dimethoxymethyl)piperidine (144.85 mg, 909.73 μmol, 1.5 eq) were dissolved in EtOH (5 mL) and water (0.5 mL), then NaHCO 3 (101.90 mg, 1.21 mmol, 47.17 μL, 2 eq) was added to the reaction and the mixture was stirred at 80 °C for 5 h. TLC (dichloromethane:methanol = 10:1, Rf = 0.4) indicated the reaction was complete. The reaction mixture was poured into H 2 O (20 mL). The mixture was extracted with ethyl acetate (20 mL * 2). The organic phase was washed with brine (15 mL * 3), dried over anhydrous Na 2 SO4 It was dried and concentrated in vacuo to give a residue. The residue was purified by preparative TLC (10% methanol in dichloromethane, Rf = 0.4) to give (3S)-4-[2-[4-(dimethoxymethyl)-1-piperidinyl]ethyl]-3-methyl-piperazine-1-carboxylic acid benzyl ester as a colorless oil (165 mg, 393.27 μmol, 64.84% yield).

[0932] Step 3

[0933]

[0934] A solution of (3S)-4-[2-[4-(dimethoxymethyl)-1-piperidinyl]ethyl]-3-methyl-piperazine-1-carboxylic acid benzyl ester (65 mg, 154.93 μmol, 1 equiv) in THF (2 mL) and H 2 SO 4 (2 M, 2 mL, 25.82 equiv) was stirred at 70 °C for 1 h. TLC (dichloromethane:methanol = 10:1, Rf = 0.2) showed consumption of the starting material. The reaction mixture was poured into H 2 O (20 mL) and basified to pH = 8 with aqueous NaHCO 3 . The mixture was extracted with ethyl acetate (20 mL × 5) and dried over anhydrous Na 2 SO 4 and concentrated in vacuo to give (3S)-4-[2-(4-formyl-1-piperidinyl)ethyl]-3-methyl-piperazine-1-carboxylic acid benzyl ester as a colorless oil (57 mg, crude).

[0935] Step 4

[0936]

[0937] To a solution of (3S)-4-[2-(4-formyl-1-piperidinyl)ethyl]-3-methyl-piperazine-1-carboxylic acid benzyl ester (57 mg, 152.62 μmol, 1 equiv) and 2-(2,6-dioxo-3-piperidinyl)-5-piperazin-1-yl-isoindoline-1,3-dione (69.65 mg, 152.62 μmol, 1 equiv, TFA) in DCE (3 mL) and MeOH (0.5 mL) was added NaOAc (54.81 mg, 668.11 μmol, 4.38 equiv), and the mixture was stirred at 25 °C for 20 min. Then HOAc (916.49 μg, 15.26 μmol, 8.73e-1 μL, 0.1 equiv) was added to the mixture and stirred at 25 °C for 20 min. Then NaBH 3CN (54.81 mg, 872.15 μmol, 5.71 eq) was added to the solution and stirred at 25 °C for 16 h. TLC (dichloromethane:methanol = 10:1, Rf = 0.2) indicated complete reaction. The reaction mixture was poured into H 2 O (20 mL). The mixture was extracted with ethyl acetate (20 mL × 2). The organic phase was washed with brine (15 mL × 3), dried over anhydrous Na 2 SO 4 and concentrated in vacuo to give a residue. The residue was purified by preparative TLC (10% methanol in dichloromethane, Rf = 0.2) to give (3S)-4-[2-[4-[[4-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-5-yl]piperazin-1-yl]methyl]-1-piperidinyl]ethyl]-3-methyl-piperazine-1-carboxylic acid benzyl ester as a white solid (60 mg, 68.59 μmol, 44.94% yield, 80% purity).

[0938] Step 5

[0939]

[0940] A mixture of (3S)-4-[2-[4-[[4-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-5-yl]piperazin-1-yl]methyl]-1-piperidinyl]ethyl]-3-methyl-piperazine-1-carboxylic acid benzyl ester (60 mg, 85.73 μmol, 1 eq) in TFA (4.62 g, 40.52 mmol, 3 mL, 472.60 eq) was stirred at 70 °C for 8 h. TLC (dichloromethane:methanol = 10:1, Rf = 0.01) indicated complete reaction. The reaction mixture was concentrated in vacuo to give 2-(2,6-dioxo-3-piperidinyl)-5-[4-[[1-[2-[(2S)-2-methylpiperazin-1-yl]ethyl]-4-piperidinyl]methyl]piperazin-1-yl]isoindoline-1,3-dione as a yellow solid (48 mg, crude, TFA).

[0941] Step 6

[0942]

[0943] Dissolve 2-(2,6-dioxo-3-piperidinyl)-5-[4-[[1-[2-[(2S)-2-methylpiperazin-1-yl]ethyl]-4-piperidinyl]methyl]piperazin-1-yl]isoindoline-1,3-dione (48 mg, 70.62 μmol, 1 eq., TFA) and 3-(6-chloropyrimidin-4-yl)-5-(1-methylcyclopropoxy)-1H-indazole (21.24 mg, 70.62 μmol, 1 eq.) in DMSO (5 mL), then add DIEA (91.27 mg, 706.16 μmol, 123.00 μL, 10 eq.) to the reaction. Stir the reaction at 80 °C for 8 h. Pour the reaction mixture into H 2 O (20 mL). Extract the mixture with ethyl acetate (20 mL * 2). Wash the organic phase with brine (15 mL * 3), dry over anhydrous Na 2 SO 4 and concentrate in vacuo to give a residue. Purify the residue by preparative HPLC (Phenomenex Luna C18 100 * 30 mm * 5 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 23% - 53%, 9 min) to give 2-(2,6-dioxo-3-piperidinyl)-5-[4-[[1-[2-[(2S)-2-methyl-4-[6-[5-(1-methylcyclopropoxy)-1H-indazol-3-yl]pyrimidin-4-yl]piperazin-1-yl]ethyl]-4-piperidinyl]methyl]piperazin-1-yl]isoindoline-1,3-dione as a yellow solid (8.4 mg, 9.78 μmol, 13.85% yield, 96.64% purity).

[0944] Exemplary Synthesis of Exemplary Compound 30

[0945] Step 1

[0946]

[0947] Add DIEA (228.46 mg, 1.77 mmol, 307.90 μL, 10 eq.) to a solution of 2-(2,6-dioxo-3-piperidinyl)-5-[4-[[1-[2-[(2S)-2-methylpiperazin-1-yl]ethyl]-4-piperidinyl]methyl]piperazin-1-yl]isoindoline-1,3-dione (100 mg, 176.77 μmol, 1 eq.) and 3-(6-chloropyrimidin-4-yl)-5-isopropoxy-1H-indazole (51.04 mg, 176.77 μmol, 1 eq.) in DMSO (3 mL). Stir the reaction mixture at 80 °C under N 2Stir the mixture at lower temperature for 6 h. Quench the reaction mixture with water (10 mL) and extract with ethyl acetate (3 × 10 mL). Dry the organic layer over sodium sulfate and concentrate under reduced pressure. Purify the residue by preparative HPLC (column: Phenomenex Luna C18 100 × 30 mm × 5 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 12% - 42%, 9 min) to obtain 2-(2,6-dioxo-3-piperidinyl)-5-[4-[[1-[2-[(2S)-4-[6-(5-isopropoxy-1H-indazol-3-yl)pyrimidin-4-yl]-2-methyl-piperazin-1-yl]ethyl]-4-piperidinyl]methyl]piperazin-1-yl]isoindoline-1,3-dione as a yellow solid (32.1 mg, 39.00 μmol, 22.06% yield, 99.38% purity).

[0948] Exemplary synthesis of Exemplary Compound 31

[0949] Step 1

[0950]

[0951] Add HOAc (14.47 mg, 240.97 μmol, 13.78 μL, 1 equiv) and (3S)-4-[2-(4-formyl-1-piperidinyl)ethyl]-3-methyl-piperazine-1-carboxylic acid benzyl ester (90 mg, 240.97 μmol, 1 equiv) to a solution of 3-(1-oxo-5-piperazin-1-yl-isoindolin-2-yl)piperidine-2,6-dione (118.69 mg, 361.46 μmol, 1.5 equiv) and NaOAc (59.30 mg, 722.91 μmol, 3 equiv) in DCE (8 mL) and MeOH (2 mL). Stir the reaction mixture at 25 °C for 1 h. Then add NaBH 3 CN (30.29 mg, 481.94 μmol, 2 equiv). After addition, stir the reaction mixture at 25 °C for 16 h. Dilute the reaction solution with water (15 mL) and extract with ethyl acetate (3 × 10 mL). Wash the organic layer with brine (20 mL), dry over sodium sulfate and concentrate under reduced pressure. Purify the residue by preparative TLC (chloromethane:methanol = 7:1, Rf = 0.1) to obtain (3S)-4-[2-[4-[[4-[2-(2,6-dioxo-3-piperidinyl)-1-oxo-isoindolin-5-yl]piperazin-1-yl]methyl]-1-piperidinyl]ethyl]-3-methyl-piperazine-1-carboxylic acid benzyl ester as a colorless gum (70 mg, 85.32 μmol, 35.41% yield, 83.6% purity).

[0952] Step 2

[0953]

[0954] A mixture of benzyl (3S)-4-[2-[4-[[4-[2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl]piperazin-1-yl]methyl]-1-piperidinyl]ethyl]-3-methylpiperazine-1-carboxylate (70 mg, 102.06 μmol, 1 equiv) and TFA (3 mL) was stirred at 80 °C for 2 h. The reaction solution was concentrated under reduced pressure to give 3-[5-[4-[[1-[2-[(2S)-2-methylpiperazin-1-yl]ethyl]-4-piperidinyl]methyl]piperazin-1-yl]-1-oxoisoindolin-2-yl]piperidine-2,6-dione (110 mg, crude, TFA) as a brown gum. The crude product was used directly.

[0955] Step 3

[0956]

[0957] To a solution of 3-[5-[4-[[1-[2-[(2S)-2-methylpiperazin-1-yl]ethyl]-4-piperidinyl]methyl]piperazin-1-yl]-1-oxoisoindolin-2-yl]piperidine-2,6-dione (103.76 mg, 155.85 μmol, 1.5 equiv, TFA) and 3-(6-chloropyrimidin-4-yl)-5-isopropoxy-1H-indazole (30 mg, 103.90 μmol, 1 equiv) in DMSO (3 mL) was added DIEA (94.00 mg, 727.32 μmol, 126.69 μL, 7 equiv). After addition, the reaction was stirred at 100 °C for 4 h to give a brown solution. The reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (3 x 10 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 100*30mm*5um; mobile phase: [water (0.225% FA)-ACN]; B%: 5%-35%; 9 min) to give 3-[5-[4-[[1-[2-[(2S)-4-[6-(5-isopropoxy-1H-indazol-3-yl)pyrimidin-4-yl]-2-methylpiperazin-1-yl]ethyl]-4-piperidinyl]methyl]piperazin-1-yl]-1-oxoisoindolin-2-yl]piperidine-2,6-dione (9.1 mg, 11.32 μmol, 10.89% yield, 100% purity) as a yellow solid.

[0958] Exemplary Synthesis of Exemplary Compound 32

[0959] Step 1

[0960]

[0961] At 0 °C in N 2 To a mixture of 2-bromoethanol (9 g, 72.02 mmol, 5.11 mL, 1 equiv) and DHP (9.09 g, 108.03 mmol, 9.88 mL, 1.5 equiv) in DCM (100 mL) was added PPTS (1.81 g, 7.20 mmol, 0.1 equiv) in one portion. The mixture was stirred at 20 °C for 16 h. TLC (DCM:MeOH = 10:1, Rf = 0.77) showed complete reaction. The residue was poured into water (50 mL) and stirred for 10 min. The aqueous phase was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with brine (50 mL × 3), dried over anhydrous Na 2 SO 4 2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (40 g, 0-10% (10 mL) ethyl acetate in petroleum ether) to give tert-butyl 3-(2-tetrahydropyran-2-yloxyethoxy)azetidine-1-carboxylate (12 g, 57.39 mmol, 79.69% yield) as a yellow oil.

[0962] Step 2

[0963]

[0964] At 0 °C, to a mixture of NaH (2.31 g, 57.73 mmol, 60% purity, 2 equiv) in DMF (20 mL) was added tert-butyl 3-hydroxyazetidine-1-carboxylate (5 g, 28.87 mmol, 1 equiv) in DMF (20 mL). The mixture was stirred at 25 °C for 0.5 h, then 2-(2-bromoethoxy)tetrahydropyran (6.64 g, 31.75 mmol, 4.81 mL, 1.1 equiv) in DMF (20 mL) was added to the reaction mixture at 0 °C. The mixture was stirred at 20 °C for 16 h to give a brown mixture. TLC (DCM:MeOH = 10:1, Rf = 0.56) showed a new spot. The residue was poured into water (50 mL). The aqueous phase was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with brine (50 mL × 2), dried over anhydrous Na 2 SO 4Dry, filter and concentrate in vacuo. Purify the residue by silica gel chromatography (45 g, 30 mL / min, 0 - 50% (15 min) ethyl acetate in petroleum ether) to afford tert-butyl 3-(2-tetrahydropyran-2-yloxyethoxy)azetidine-1-carboxylate as a yellow oil (6.6 g, 21.90 mmol, 75.86% yield).

[0965] Step 3

[0966]

[0967] At 20 °C under N 2 add TsOH (3.43 g, 19.91 mmol, 1 equiv) in one portion to a mixture of tert-butyl 3-(2-tetrahydropyran-2-yloxyethoxy)azetidine-1-carboxylate (6 g, 19.91 mmol, 1 equiv) in MeOH (60 mL). Stir the mixture at 20 °C for 1 h. TLC (petroleum ether:ethyl acetate = 2:3, Rf = 0.30) shows the reaction is complete. Add H 2 O (30 mL) to the reaction mixture and extract the mixture with EtOAc (30 mL * 3). Wash the combined extracts with saturated NaHCO 3 (30 mL * 2, aqueous solution), brine (30 mL), dry over anhydrous Na 2 SO 4 dry, filter and concentrate the filtrate under reduced pressure. Purify the residue by silica gel chromatography (40 g, 30 mL / min, 0 - 100% (30 min) ethyl acetate in petroleum ether) to afford tert-butyl 3-(2-hydroxyethoxy)azetidine-1-carboxylate as a yellow oil (1.5 g, 6.90 mmol, 34.68% yield).

[0968] Step 4

[0969]

[0970] At 0 °C, tosyl chloride (TosCl, 1.97 g, 10.36 mmol, 1.5 eq) was added to a mixture of tert-butyl 3-(2-hydroxyethoxy)azetidine-1-carboxylate (1.5 g, 6.90 mmol, 1 eq), triethylamine (TEA, 1.75 g, 17.26 mmol, 2.40 mL, 2.5 eq), and 4-dimethylaminopyridine (DMAP, 253.04 mg, 2.07 mmol, 0.3 eq) in dichloromethane (DCM, 15 mL). The mixture was stirred at 20 °C for 2 h to give a brown mixture. TLC (petroleum ether:ethyl acetate = 1:1, Rf = 0.56) indicated complete reaction. Most of the DCM was removed under reduced pressure to give a residue. The residue was dissolved in ethyl acetate (EtOAc, 30 mL), and the resulting mixture was washed with water (10 mL × 2), saturated NaHCO 3 (10 mL × 2, aqueous solution), brine (10 mL), dried over anhydrous Na 2 SO 4 , filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (20 g, 0 - 15% (10 min) ethyl acetate in petroleum ether, 15% (5 min) ethyl acetate in petroleum ether) to give tert-butyl 3-[2-(p-toluenesulfonyloxy)ethoxy]azetidine-1-carboxylate as a yellow oil (2.3 g, 6.19 mmol, 89.69% yield).

[0971] Step 5

[0972]

[0973] To a mixture of 2-(2,6-dioxo-3-piperidinyl)-5-hydroxyisoindoline-1,3-dione (1.55 g, 5.65 mmol, 1 eq) in N,N-dimethylformamide (DMF, 20 mL) were added Na 2 CO 3 (1.20 g, 11.31 mmol, 2 eq) and tert-butyl 3-[2-(p-toluenesulfonyloxy)ethoxy]azetidine-1-carboxylate (2.1 g, 5.65 mmol, 1 eq). The mixture was stirred at 70 °C for 16 h to give a yellow mixture. The reaction mixture was cooled to room temperature and added to aqueous HCl solution (100 mL, 2%, v / v) at 0 °C, and the resulting mixture was extracted with ethyl acetate (EtOAc, 30 mL × 3). The combined extracts were washed with water (30 mL), brine (30 mL), dried over anhydrous Na 2 SO 4Dry, filter and concentrate the filtrate under reduced pressure to obtain a residue. Purify the residue by flash silica gel chromatography (DCM:MeOH = 10:1, Rf = 0.31, 80 g, 0 - 50% (30 min) ethyl acetate in petroleum ether, 50% (60 min) ethyl acetate in petroleum ether) to obtain tert-butyl 3-[2-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-5-yl]oxyethoxy]azetidine-1-carboxylate as a white gum (1.8 g, 3.80 mmol, 67.24% yield).

[0974] Step 6

[0975]

[0976] Add TFA (866.94 mg, 7.60 mmol, 562.95 μL, 3 equiv) in one portion to a mixture of tert-butyl 3-[2-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-5-yl]oxyethoxy]azetidine-1-carboxylate (1.2 g, 2.53 mmol, 1 equiv) in DCM (10 mL) at 20 °C under N2. Stir the mixture at 20 °C for 30 min. TLC shows the reaction is complete. Concentrate the mixture under reduced pressure to obtain 5-[2-(azetidin-3-yloxy)ethoxy]-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione as a colorless gum (2 g, crude).

[0977] Step 7

[0978]

[0979] Add NaOAc (2.20 g, 26.78 mmol, 5 equiv) and NaBH 3CN (1.01 g, 16.07 mmol, 3 eq.). The mixture was then stirred at 20 °C for 30 min. Then HOAc (321.67 mg, 5.36 mmol, 306.36 μL, 1 eq.) was added to the solution and stirred at 20 °C for 1 h. TLC (DCM:MeOH = 10:1, Rf = 0.29) showed a new spot. The residue was poured into water (10 mL). The aqueous phase was extracted with ethyl acetate (10 mL * 3). The combined organic phases were washed with brine (10 mL * 2), dried over anhydrous Na 2 SO 4 dried, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (20 g, 30 mL / min, 0 - 5% (10 min) MeOH in DCM, 5% (10 min) MeOH in DCM) to give 5-[2-[1-(2-chloroethyl)azetidin-3-yl]oxyethoxy]-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione as a yellow gum (700 mg, 1.61 mmol, 29.98% yield).

[0980] Step 8

[0981]

[0982] At 20 °C under N 2 2 to a mixture of tert-butyl (3S)-3-methylpiperazine-1-carboxylate (229.75 mg, 1.15 mmol, 2 eq.) and 5-[2-[1-(2-chloroethyl)azetidin-3-yl]oxyethoxy]-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione (250 mg, 573.58 μmol, 1 eq.) in MeCN (5 mL) was added KI (476.07 mg, 2.87 mmol, 5 eq.) and DIPEA (370.65 mg, 2.87 mmol, 499.53 μL, 5 eq.) in one portion. The mixture was stirred at 80 °C for 16 h. The residue was poured into water (5 mL). The aqueous phase was extracted with ethyl acetate (5 mL * 3). The combined organic phases were washed with brine (5 mL * 2), dried over anhydrous Na 2 SO 4Dry, filter and concentrate in vacuo. Purify the residue by silica gel chromatography (0 - 100% (30 min) ethyl acetate in petroleum ether) to give tert-butyl (3S)-4-[2-[3-[2-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-5-yl]oxyethoxy]azetidin-1-yl]ethyl]-3-methylpiperazine-1-carboxylate (200 mg, 333.51 μmol, 58.15% yield) as a yellow solid.

[0983] Step 9

[0984]

[0985] At 20 °C under N 2 To a mixture of tert-butyl (3S)-4-[2-[3-[2-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-5-yl]oxyethoxy]azetidin-1-yl]ethyl]-3-methylpiperazine-1-carboxylate (200 mg, 333.51 μmol, 1 equiv) in DCM (5 mL) was added TFA (114.09 mg, 1.00 mmol, 74.08 μL, 3 equiv) in one portion. The mixture was stirred at 20 °C for 30 min. The solution was concentrated in vacuo to give 2-(2,6-dioxo-3-piperidinyl)-5-[2-[1-[2-[(2S)-2-methylpiperazin-1-yl]ethyl]azetidin-3-yl]oxyethoxy]isoindoline-1,3-dione (130 mg, 166.55 μmol, 49.94% yield, 64% purity) as a colorless gum.

[0986] Step 10

[0987]

[0988] Dissolve 3-(6-chloropyrimidin-4-yl)-5-isopropoxy-2H-indazole (60.11 mg, 208.18 μmol, 0.8 equiv) and 2-(2,6-dioxo-3-piperidinyl)-5-[2-[1-[2-[(2S)-2-methylpiperazin-1-yl]ethyl]azetidin-3-yl]oxyethoxy]isoindoline-1,3-dione (130 mg, 260.23 μmol, 1 equiv) in DMSO (5 mL), then at 20 °C under N 2DIPEA (100.90 mg, 780.69 μmol, 135.98 μL, 3 eq) was added below. The solution was stirred at 100 °C for 2 h to obtain a yellow solution. The mixture was cooled to 20 °C and concentrated under reduced pressure at 20 °C. The residue was poured into water (10 mL). The aqueous phase was extracted with ethyl acetate (10 mL * 3). The combined organic phases were washed with brine (10 mL * 3), dried over anhydrous Na 2 SO 4 dried, filtered and concentrated in vacuo. The crude product was purified by reverse-phase HPLC (column: Phenomenex luna C18 150 * 25 mm * 10 μm; conditions: water (0.2% FA)-ACN; start B: 20; end B: 40; flow rate: 25 mL / min; gradient time: 20 min; hold time at 100% B: 4 min) to give 2-(2,6-dioxo-3-piperidinyl)-5-[2-[1-[2-[(2S)-4-[6-(5-isopropoxy-1H-indazol-3-yl)pyrimidin-4-yl]-2-methyl-piperazin-1-yl]ethyl]azetidin-3-yl]oxyethoxy]isoindoline-1,3-dione as a white solid (26.3 mg, 34.98 μmol, 13.44% yield, 100% purity).

[0989] Exemplary synthesis of Exemplary Compound 33

[0990] Step 1

[0991]

[0992] To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (2 g, 9.94 mmol, 1 eq) in THF (20 mL) was added portionwise NaH (516.69 mg, 12.92 mmol, 60% purity in oil, 1.3 eq) at 0 °C under nitrogen. After the evolution of hydrogen ceased, ethyl 2-bromoacetate (3.32 g, 19.87 mmol, 2.20 mL, 2 eq) was added dropwise. The resulting mixture was stirred at 0 °C for 2 h. TLC (petroleum ether:ethyl acetate = 5:1) showed two new spots. The reaction mixture was quenched with aqueous NH 4 Cl (20 mL) and extracted with ethyl acetate (3 x 20 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0 to 20% ethyl acetate in petroleum ether) to give tert-butyl 4-(2-ethoxy-2-oxo-ethoxy)piperidine-1-carboxylate as a colorless oil (800 mg, 2.78 mmol, 28.02% yield).

[0993] Step 2

[0994]

[0995] At 0 °C, LiAlH 4 (158.50 mg, 4.18 mmol, 1.5 equiv) was added to a solution of tert-butyl 4-(2-ethoxy-2-oxo-ethoxy)piperidine-1-carboxylate (800 mg, 2.78 mmol, 1 equiv) in THF (10 mL). After the addition, the reaction mixture was stirred at 20 °C for 2 h. TLC (petroleum ether:ethyl acetate = 1:1) showed that the starting material was consumed and a new spot was formed. The reaction mixture was quenched by adding water (0.5 mL), followed by 15% aqueous NaOH solution (0.5 mL) and water (1.5 mL). The solid was removed by filtration. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0 to 50% ethyl acetate in petroleum ether) to give tert-butyl 4-(2-hydroxyethoxy)piperidine-1-carboxylate (400 mg, 1.63 mmol, 58.57% yield) as a colorless oil.

[0996] Step 3

[0997]

[0998] At 20 °C, 4-methylbenzenesulfonyl chloride (621.72 mg, 3.26 mmol, 2 equiv) and TEA (329.99 mg, 3.26 mmol, 453.91 μL, 2 equiv) were added to a solution of tert-butyl 4-(2-hydroxyethoxy)piperidine-1-carboxylate (400 mg, 1.63 mmol, 1 equiv) in DCM (2 mL). After the addition, the reaction solution was stirred at 20 °C for 16 h. TLC (petroleum ether:ethyl acetate = 3:1) showed two main spots. The reaction solution was diluted with water (10 mL) and extracted with dichloromethane (3 x 10 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0 to 30% ethyl acetate in petroleum ether) to give tert-butyl 4-[2-(p-toluenesulfonyloxy)ethoxy]piperidine-1-carboxylate (490 mg, 1.23 mmol, 75.22% yield, 100% purity) as a colorless oil.

[0999] Step 4

[1000]

[1001] To a solution of tert-butyl 4-[2-((4-methylphenyl)sulfonyloxy)ethoxy]piperidine-1-carboxylate (131.54 mg, 329.27 μmol, 1 equiv) and 5-(1-methylcyclopropoxy)-3-[6-[(3S)-3-methylpiperazin-1-yl]pyrimidin-4-yl]-1H-indazole (120 mg, 329.27 μmol, 1 equiv) in CH 3 CN (3 mL) was added KI (273.30 mg, 1.65 mmol, 5 equiv) and DIEA (127.67 mg, 987.81 μmol, 172.06 μL, 3 equiv). After addition, the reaction mixture was stirred at 90 °C for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0 to 5% methanol in dichloromethane) to give tert-butyl 4-[2-[(2S)-2-methyl-4-[6-[5-(1-methylcyclopropoxy)-1H-indazol-3-yl]pyrimidin-4-yl]piperazin-1-yl]ethoxy]piperidine-1-carboxylate as a yellow gum (130 mg, 204.31 μmol, 62.05% yield, 93% purity).

[1002] Step 5

[1003]

[1004] At 20 °C to a solution of tert-butyl 4-[2-[(2S)-2-methyl-4-[6-[5-(1-methylcyclopropoxy)-1H-indazol-3-yl]pyrimidin-4-yl]piperazin-1-yl]ethoxy]piperidine-1-carboxylate (130 mg, 219.69 μmol, 1 equiv) in DCM (2 mL) was added HCl / dioxane (4 M, 549.23 μL, 10 equiv). After addition, the reaction mixture was stirred at 20 °C for 30 min. TLC (dichloromethane:methanol = 10:1) showed consumption of the starting material. The reaction mixture was concentrated under reduced pressure to give 5-(1-methylcyclopropoxy)-3-[6-[(3S)-3-methyl-4-[2-(4-piperidyloxy)ethyl]piperazin-1-yl]pyrimidin-4-yl]-1H-indazole as a yellow solid (108 mg, 206.50 μmol, 94.00% yield, 94% purity). The crude product was used directly.

[1005] Step 6

[1006]

[1007] To a solution of 5-(1-methylcyclopropoxy)-3-[6-[(3S)-3-methyl-4-[2-(4-piperidyloxy)ethyl]piperazin-1-yl]pyrimidin-4-yl]-1H-indazole (105.23 mg, 214.05 μmol, 1.25 equiv) and [1-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-5-yl]-4-piperidinyl]methyl 4-methylbenzenesulfonate (90 mg, 171.24 μmol, 1 equiv) in CH 3 CN (5 mL) was added KI (142.13 mg, 856.21 μmol, 5 equiv) and DIEA (177.05 mg, 1.37 mmol, 238.62 μL, 8 equiv). After addition, the reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Welch Xtimate C18 150*25mm*5um; mobile phase: [water (0.225% FA)-ACN]; B%: 5%-35%, 8 min) to give 2-(2,6-dioxo-3-piperidinyl)-5-[4-[[4-[2-[(2S)-2-methyl-4-[6-[5-(1-methylcyclopropoxy)-1H-indazol-3-yl]pyrimidin-4-yl]piperazin-1-yl]ethoxy]-1-piperidinyl]methyl]-1-piperidinyl]isoindoline-1,3-dione (12.5 mg, 14.50 μmol, 8.47% yield, 98% purity) as a yellow solid.

[1008] Exemplary synthesis of Exemplary Compound 34

[1009] Step 1

[1010]

[1011] 3-Butyn-1-ol (1 g, 14.27 mmol, 1.08 mL, 1 equiv) and 2-bromo-1,1-diethoxy-ethane (2.81 g, 14.27 mmol, 2.15 mL, 1 equiv) were dissolved in anhydrous DMF (10 mL), and then NaH (684.77 mg, 17.12 mmol, 60% purity, 1.2 equiv) was added portionwise at 0 °C. The mixture was then stirred at 0 °C for 3 h. TLC (petroleum ether:ethyl acetate = 5:1, Rf = 0.2) showed a new spot for the reaction. The reaction was quenched with an aqueous solution of NH 4 Cl (10 mL) and extracted with ethyl acetate (3*20 mL). The combined organic phases were washed with water and passed through Na 2SO 4 Dry and concentrate in vacuo to give a residue. Purify the residue by silica gel column chromatography (0 - 20% ethyl acetate in petroleum ether) to afford 4-(2,2 - diethoxyethoxy)but - 1 - yne as a colorless oil (600 mg, 3.22 mmol, 22.58% yield).

[1012] Step 2

[1013]

[1014] Add 4-(2,2 - diethoxyethoxy)but - 1 - yne (600 mg, 3.22 mmol, 1 equiv) and THF (10 mL) to a flame - dried 100 mL three - necked round - bottom flask equipped with an argon inlet adapter, septum, and stir bar via syringe. Cool the solution in a dry ice / acetone bath at - 78 °C (bath temperature) and add n - BuLi (2.5 M, 1.55 mL, 1.2 equiv) dropwise via syringe, turning the reaction brown. Stir the reaction at - 78 °C for 30 min and add DMF (470.95 mg, 6.44 mmol, 495.73 μL, 2 equiv) dropwise via syringe, turning the reaction colorless. Stir the reaction at - 78 °C for 30 min, then warm to 25 °C and stir for 2 h. TLC (petroleum ether:ethyl acetate = 2:1, Rf = 0.1) shows a new spot. Add the reaction to a cold solution of ethyl acetate (10 mL) and 10% KH 2 PO 4 (10 mL) and stir for 30 min. Separate the aqueous layer, wash the organic layer with brine (20 mL), dry over magnesium sulfate, gravity filter, and concentrate under reduced pressure to afford 5-(2,2 - diethoxyethoxy)pent - 2 - ynal as a yellow oil (350 mg, crude).

[1015] Step 3

[1016]

[1017] Add NaOAc (53.92 mg, 657.36 μmol, 3 equiv) and HOAc (2.63 mg, 43.82 μmol, 2.51 μL, 0.2 equiv) to a solution of 2-(2,6 - dioxo - 3 - piperidinyl)-5 - piperazin - 1 - yl - isoindoline - 1,3 - dione (100 mg, 219.12 μmol, 1 equiv, TFA) and 5-(2,2 - diethoxyethoxy)pent - 2 - ynal (93.90 mg, 438.24 μmol, 2 equiv) in DCE (5 mL) and MeOH (1 mL). Then stir the mixture at 20 °C for 30 min. Then add NaBH3 CN (41.31 mg, 657.36 μmol, 3 eq) and the solution was stirred at 20 °C for 2 h. TLC (dichloromethane:methanol = 10:1, Rf = 0.37) showed consumption of the starting material. The reaction mixture was poured into H 2 O (10 mL). The mixture was extracted with ethyl acetate (20 mL * 5). The organic phase was washed with brine (20 mL), dried over anhydrous Na 2 SO 4 and concentrated in vacuo to give a residue. The residue was purified by preparative TLC (10% methanol in dichloromethane) to give 5-[4-[5-(2,2 - diethoxyethoxy)pent-2-ynyl]piperazin-1-yl]-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione as a yellow solid (120 mg, 188.68 μmol, 86.11% yield, 85% purity).

[1018] Step 4

[1019]

[1020] To a solution of 5-[4-[5-(2,2 - diethoxyethoxy)pent-2-ynyl]piperazin-1-yl]-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione (95 mg, 175.73 μmol, 1 eq) in THF (2 mL) was added H 2 SO 4 (2 M, 2 mL, 86.50 eq). The mixture was then stirred at 65 °C for 1 h. TLC (dichloromethane:methanol = 10:1, Rf = 0.37) showed consumption of the starting material. The reaction mixture was poured into H 2 O (2 mL) and basified to pH = 8 with aqueous NaHCO 3 . The mixture was extracted with ethyl acetate (15 mL * 5), dried over anhydrous Na 2 SO 4 and concentrated in vacuo to give 2-[5-[4-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-5-yl]piperazin-1-yl]pent-3-ynoxy]acetaldehyde as a yellow solid (80 mg, crude).

[1021] Step 5

[1022]

[1023] To a solution of 5-isopropoxy-3-[6-[(3S)-3-methylpiperazin-1-yl]pyrimidin-4-yl]-1H-indazole (100 mg, 283.74 μmol, 1 equiv) and 2-[5-[4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl]piperazin-1-yl]pent-3-ynoxy]acetaldehyde (80.00 mg, 171.50 μmol, 6.04e-1 equiv) in DCE (5 mL) and MeOH (2 mL) was added NaOAc (69.83 mg, 851.23 μmol, 3 equiv) and HOAc (3.41 mg, 56.75 μmol, 3.25 μL, 0.2 equiv). The mixture was then stirred at 25 °C for 60 min. Then NaBH 3 CN (53.49 mg, 851.23 μmol, 3 equiv) was added and the solution was stirred at 25 °C for 16 h. TLC (dichloromethane:methanol = 10:1, Rf = 0.37) showed starting materials of the reactants. The reaction mixture was poured into H 2 O (10 mL). The mixture was extracted with ethyl acetate (20 mL * 5). The organic phase was washed with brine (20 mL), dried over anhydrous Na 2 SO 4 and concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (Phenomenex Luna C18 100 * 30 mm * 5 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 8%-38%, 9 min) to give 2-(2,6-dioxopiperidin-3-yl)-5-[4-[5-[2-[(2S)-4-[6-(5-isopropoxy-1H-indazol-3-yl)pyrimidin-4-yl]-2-methylpiperazin-1-yl]ethoxy]pent-2-ynyl]piperazin-1-yl]isoindoline-1,3-dione as a yellow solid (19.4 mg, 23.60 μmol, 8.32% yield, 97.68% purity).

[1024] Exemplary Synthesis of Exemplary Compound 35

[1025] Step 1

[1026]

[1027] To a solution of tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (200 mg, 1.01 mmol, 1 equiv) and 2-chloroacetaldehyde (593.89 mg, 3.03 mmol, 486.80 μL, 3 equiv) in DCM (5 mL) and MeOH (5 mL) was added NaOAc (165.51 mg, 2.02 mmol, 2 equiv) and HOAc (6.06 mg, 100.88 μmol, 5.77 μL, 0.1 equiv). The mixture was then stirred at 20 °C for 20 min. Then NaBH 3 CN (190.18 mg, 3.03 mmol, 3 equiv) was added to the solution and the mixture was stirred at 20 °C for 16 h. TLC (petroleum ether:ethyl acetate = 1:1, Rf = 0.5) showed the reaction was complete. The reaction mixture was poured into H 2 O (20 mL). The mixture was extracted with ethyl acetate (30 mL × 3). The organic phase was washed with brine (20 mL), dried over anhydrous Na 2 SO 4 and concentrated in vacuo to give a residue. The residue was purified by silica gel column chromatography (0 - 100% ethyl acetate in petroleum ether) to give tert-butyl 6-(2-chloroethyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate as a colorless oil (165 mg, 632.77 μmol, 62.73% yield).

[1028] Step 2

[1029]

[1030] tert-Butyl 6-(2-chloroethyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (81.39 mg, 312.12 μmol, 1 equiv) and 5-isopropoxy-3-[6-[(3S)-3-methylpiperazin-1-yl]pyrimidin-4-yl]-1H-indazole (110 mg, 312.12 μmol, 1 equiv) were dissolved in anhydrous CH 3 CN (10 mL), then KI (777.17 mg, 4.68 mmol, 15 equiv) and DIEA (605.07 mg, 4.68 mmol, 815.46 μL, 15 equiv) were added to the reaction. The reaction was stirred at 100 °C for 16 h. The reaction mixture was poured into H 2 O (20 mL). The mixture was extracted with ethyl acetate (20 mL × 2). The organic phase was washed with brine (15 mL × 3), dried over anhydrous Na 2 SO 4Dry and concentrate in vacuo to give a residue. Purify the residue by preparative TLC (10% methanol in dichloromethane, Rf = 0.2) to give tert-butyl 6-[2-[(2S)-4-[6-(5-isopropoxy-1H-indazol-3-yl)pyrimidin-4-yl]-2-methylpiperazin-1-yl]ethyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate as a white solid (124 mg, 154.80 μmol, 49.60% yield).

[1031] Step 3

[1032]

[1033] Dissolve tert-butyl 6-[2-[(2S)-4-[6-(5-isopropoxy-1H-indazol-3-yl)pyrimidin-4-yl]-2-methylpiperazin-1-yl]ethyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (124 mg, 215.00 μmol, 1 equiv) in DCM (3 mL) and TFA (3.08 g, 27.01 mmol, 2 mL, 125.63 equiv). Stir the reaction at 25 °C for 1 h. TLC (dichloromethane:methanol = 10:1, Rf = 0.01) indicates complete reaction. Concentrate the reaction mixture in vacuo to give 3-[6-[(3S)-4-[2-(2,6-diazaspiro[3.3]heptan-2-yl)ethyl]-3-methylpiperazin-1-yl]pyrimidin-4-yl]-5-isopropoxy-1H-indazole as a yellow gum (126 mg, crude, TFA). Use the crude product directly in the next step.

[1034] Step 4

[1035]

[1036] To a solution of 2-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-5-yl]oxyacetaldehyde (67.47 mg, 213.33 μmol, 1 equiv) and 3-[6-[(3S)-4-[2-(2,6-diazaspiro[3.3]heptan-2-yl)ethyl]-3-methylpiperazin-1-yl]pyrimidin-4-yl]-5-isopropoxy-1H-indazole (126 mg, 213.33 μmol, 1 equiv, TFA) in DCE (5 mL) and MeOH (1 mL) was added NaOAc (52.50 mg, 639.99 μmol, 3 equiv), and the mixture was stirred at 25 °C for 20 min. Then HOAc (1.28 mg, 21.33 μmol, 1.22 μL, 0.1 equiv) was added to the mixture and stirred at 25 °C for 20 min. Then NaBH 3 CN (53.62 mg, 853.31 μmol, 4 equiv) was added to the solution and the mixture was stirred at 25 °C for 16 h. The reaction mixture was poured into H 2 O (20 mL). The mixture was extracted with ethyl acetate (20 mL × 2). The organic phase was washed with brine (15 mL × 3), dried over anhydrous Na 2 SO 4 and concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (Phenomenex Luna C18 100×30 mm×5 μm: [water (0.225% FA)-ACN]; B%: 5%-35%, 9 min) to give 2-(2,6-dioxo-3-piperidinyl)-5-[2-[6-[2-[(2S)-4-[6-(5-isopropoxy-1H-indazol-3-yl)pyrimidin-4-yl]-2-methylpiperazin-1-yl]ethyl]-2,6-diazaspiro[3.3]heptan-2-yl]ethoxy]isoindoline-1,3-dione as a yellow solid (14.7 mg, 17.35 μmol, 8.13% yield, 97.1% purity, FA).

[1037] Exemplary synthesis of Exemplary Compound 36

[1038] Step 1

[1039]

[1040] At 0 °C under N 2 to N-(3-hydroxypropyl)-N-methyl-carbamic acid tert-butyl ester (500 mg, 2.64 mmol, 1 equiv), DMAP (322.77 mg, 2.64 mmol, 1 equiv) and Et 3A mixture of N (267.34 mg, 2.64 mmol, 367.73 μL, 1 equiv) in DCM (5 mL) was added 4-methylbenzene-1-sulfonyl chloride (503.69 mg, 2.64 mmol, 1 equiv) in one portion. The mixture was stirred at 20 °C for 1 h to obtain a white suspension. The residue was poured into water (5 mL). The aqueous phase was extracted with ethyl acetate (5 mL * 3). The combined organic phases we...

Claims

1. A compound having the following chemical structure: PTM-L-CLM, or a pharmaceutically acceptable salt thereof, wherein: (a) said CLM is (1) CLM represented by the following chemical structure: wherein: W is selected from: CH 2 , O, CHR, C═O, SO 2 , NH, N, optionally substituted cyclopropyl, optionally substituted cyclobutyl, and N—C 1 —C 6 alkyl; W 3 is C or N; Each X is independently selected from: absent, O, S, and CH 2 ; Y is selected from: CH 2 , -C=CR’, NH, N-C 1 -C 6 -alkyl, N-5- to 16-membered aryl, N-5- to 16-membered heteroaryl, N-C 3 -C 20 -cycloalkyl, N-heterocyclic group, O and S, wherein the heterocyclic group is selected from azetidinyl, dihydroimidazolyl, dihydropyranyl, dihydrofuranyl, dioxalanyl, dioxolanyl, ethylenourea, homopiperidinyl, morpholinyl, piperazinyl, N-methylpiperazinyl, piperidinyl, phthalimido, succinimido, tetrahydrofuranyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydrothienyl, oxalanyl, oxetanyl, oxathiolanyl and thiolanyl; Z is selected from: absent, O, S, and CH 2 ; G and G' are independently selected from: H, optionally substituted C 1 -C 6 -alkyl, OH, R'OCOOR, R'OCONRR", CH optionally substituted by R' 2 -heterocyclic group, and benzyl optionally substituted by R', wherein the heterocyclic group is selected from azetidinyl, dihydroimidazolyl, dihydropyranyl, dihydrofuranyl, dioxalanyl, dioxolanyl, ethyleneurea, homopiperidinyl, morpholinyl, piperazinyl, N-methylpiperazinyl, piperidinyl, phthalimido, succinimido, tetrahydrofuranyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydrothienyl, oxalanyl, oxetanyl, oxathiolanyl and thiolanyl; Q 1 、Q 2 、Q 3 and Q 4 are each independently C or N substituted by a group independently selected from H, R, N or N-oxide; A is selected from H, optionally substituted C 1 -C 6 -alkyl, C 3 -C 20 -cycloalkyl, Cl, and F; n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; R is selected from H, -CONR’R”, -C(=O)R’, -OR’, -NR’R”, -SR’, -SO 2 R’, -SO 2 NR’R”, -CR’R”-, -CR’NR’R”-, (-CR’O) n’ R”, optionally substituted heterocyclic group, 5- to 16-membered aryl group, optionally substituted C 1 -C 6 alkyl-5- to 16-membered aryl group, 5- to 16-membered heteroaryl group, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy, -P(O)(OR’)R”, -P(O)R’R”, -OP(O)(OR’)R”, -OP(O)R’R”, -Cl, -F, -Br, -I, -CF 3 , -CN, -NR’SO 2 NR’R”, -NR’CONR’R”, -CONR’COR”, -NR’C(=N-CN)NR’R”, -C(=N-CN)NR’R”, -NR’C(=N-CN)R”, -NR’C(=C-NO 2 )NR’R”, -SO 2 NR’COR”, -NO 2 , -CO 2 R’, -C(C=N-OR’)R”, -CR’=CR’R”, -CCR’, -S(C=O)(C=N-R’)R”, -SF 5 and -OCF 3 , wherein at least one R or W is modified to be covalently linked to the PTM or the L, and wherein the heterocyclic group is selected from azetidinyl, dihydroimidazolyl, dihydropyranyl, dihydrofuranyl, dioxolanyl, dioxolyl, ethylenourea, homopiperidinyl, morpholinyl, piperazinyl, N-methylpiperazinyl, piperidinyl, phthalimido, succinimido, tetrahydrofuranyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydrothienyl, oxolanyl, oxetanyl, oxathiolanyl, and thiolanyl; each of x, y and z is independently 0, 1, 2, 3, 4, 5 or 6; R’ and R” are independently selected from the group consisting of: H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 20 cycloalkyl, optionally substituted 5- to 16-membered aryl, optionally substituted 5- to 16-membered heteroaryl, and optionally substituted heterocyclic group, wherein the heterocyclic group is selected from azetidinyl, dihydroimidazolyl, dihydropyranyl, dihydrofuranyl, dioxalanyl, dioxolanyl, ethyleneurea, homopiperidinyl, morpholinyl, piperazinyl, N-methylpiperazinyl, piperidinyl, phthalimido, succinimido, tetrahydrofuranyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydrothienyl, oxalanyl, oxetanyl, oxathiolanyl, and thiolanyl; n' is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; represents a single bond or a double bond; and represented as a stereotactic or non-stereotactic key; or (2) CLM represented by the following chemical structure: wherein: W is selected from: CH 2 , O, CHR, C=O, SO 2 , NH, N, optionally substituted cyclopropyl, optionally substituted cyclobutyl and N-C 1 -C 6 alkyl; Q 1 、Q 2 、Q 3 、Q 4 、Q 5 each independently represents C or N substituted by a group independently selected from R', N or N-oxide; R 1 selected from absent, H, OH, CN, C 1 -C 3 -alkyl and C=O; R 2 Selected from absent, H, OH, CN, C 1 -C 3 -alkyl, CHF 2 , CF 3 , CHO, C(=O)NH 2 ; R 3 Selected from H, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy and substituted C 1 -C 6 alkoxy; R 4 Selected from H, C 1 -C 6 alkyl and substituted C 1 -C 6 alkyl; R 5 and R 6 each independently is H, halogen, C(=O)R', CN, OH or CF 3 ; X is C, CH, C=O or N; X 1 is C=O, N, CH or CH 2 ; R’ is selected from H, halogen, C 1 -C 6 -alkyl, substituted C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, substituted C 1 -C 6 -alkoxy, NR 2 R 3 , C(=O)OR 2 and optionally substituted phenyl; n is 0, 1, 2, 3 or 4; is a single bond or a double bond; and said CLM is covalently linked to said L; (b) said PTM is represented by the following chemical structure: wherein: R 1 is C 1 -C 6 alkyl, optionally substituted C 3 -C 6 cycloalkyl, C 1 -C 6 haloalkyl, optionally substituted C 3 -C 6 halocycloalkyl, optionally substituted C 1 -C 6 alkyl nitrile, optionally substituted C 3 -C 6 cyclonitrile; R 2 is hydrogen, halogen, C 1 -C 3 -alkyl or C 1 -C 3 -fluoroalkyl; X 1 , X 2 , X 3 , X 4 , X 5 , X 6 and X 7 are each independently CH or N, wherein when CH, X 1 , X 2 and X 3 Each optionally R 2 replace; X 8 is CH, S, or N; M is CH 2 , NH or O; is a 3- to 10-membered cycloalkyl or heterocyclic group each optionally substituted with 1, 2, 3 or 4 substituents, wherein the heterocyclic group is selected from azetidinyl, dihydroimidazolyl, dihydropyranyl, dihydrofuranyl, dioxalanyl, dioxolanyl, ethyleneurea, homopiperidinyl, morpholinyl, piperazinyl, N-methylpiperazinyl, piperidinyl, phthalimido, succinimido, tetrahydrofuranyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydrothienyl, oxalanyl, oxetanyl, oxathiolanyl and thiolanyl; and The represents a connection point with the (c) said L is: wherein: W L1 and W L2 each independently is absent; a 5- to 16-membered aryl; a 5- to 16-membered heteroaryl; a 5- to 20-membered cycloalkyl; a heterocyclic group; C 1-6 alkyl, and optionally one or more C atoms are replaced by O; C 1-6 alkene, and optionally one or more C atoms are replaced by O; C 1-6 alkyne, and optionally one or more C atoms are replaced by O; a 10- to 16-membered biaryl; or a 10- to 16-membered diheteroaryl, each optionally substituted by R Q substituted, each R Q independently is H, a halogen group, OH, CN, CF 3 , a hydroxyl group, a nitro group, C≡CH, C 2-6 alkenyl, C 2-6 alkynyl, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy, OC 1-3 alkyl optionally substituted by one or more -F, OH, NH 2 , NR Y1 R Y2 R, CN, or two R Q groups together with the atoms to which they are attached form a 4- to 8-membered ring system containing 0-4 heteroatoms, wherein the heterocyclic group is selected from azetidinyl, dihydroimidazolyl, dihydropyranyl, dihydrofuranyl, dioxalanyl, dioxolanyl, ethylenourea, homopiperidinyl, morpholinyl, piperazinyl, N-methylpiperazinyl, piperidinyl, phthalimido, succinimido, tetrahydrofuranyl, tetrahydropyranyl, tetrahydroquinolinyl, tetrahydrothiophenyl, oxalanyl, oxetanyl, oxathiolanyl, and thiolanyl; Each Y L1 is independently a key; NR YL1 ; O; S; NR YL2 ; CR YL1 R YL2 ; C=O; C=S; SO; SO 2 ; optionally substituted C 1 -C 6 alkoxy; or optionally substituted C 1 -C 6 alkyl, wherein one or more C atoms are optionally replaced by O; Q L is a 3- to 6-membered alicyclic or 3- to 6-membered aromatic ring having 0 to 4 heteroatoms, which is optionally bridged and optionally substituted with 1 to 6 R Q substituents, each R Q independently being H, a straight-chain or branched C 1-6 alkyl optionally substituted with one or more halo groups or C 1-6 alkoxy groups, or two R Q groups together with the atoms to which they are attached form a 3- to 8-membered ring system containing 0 to 2 heteroatoms; R YL1 and R YL2 each independently is H; OH; C optionally substituted with one or more halogen groups or C 1-6 alkoxy-substituted C 1-6 alkyl; or R YL1 and R YL2 together with the atoms to which they are attached form a 3- to 8-membered ring system containing 0 to 2 heteroatoms; n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; and Indicates a connection point to the PTM or the CLM; and wherein the term "optionally substituted" means that the group is substituted by one or more substituents selected from hydroxyl, mercapto, carboxyl, cyano, nitro, halogen, C 1 -C 10 -alkyl, 5- to 16-membered aryl, C 1 -C 6 -alkoxy, C 1 -C 6 -thioether, C 1 -C 6 -acyl, C 1 -C 6 -ester, C 1 -C 6 -thioester, NH 2 -C 1 -C 6 -alkylamine, C 1 -C 6 -dialkylamine, -N(C 0 -C 6 -alkyl)C(O)(OC 1 -C 6 -alkyl), hydrazine, amido, C 1- C 6 -alkanol or C 1 -C 6 -substituents of alkanoic acid, and wherein said heteroaryl contains one nitrogen, oxygen or sulfur atom or contains 2 or more heteroatoms selected from nitrogen, sulfur and oxygen.

2. The compound according to claim 1, wherein said CLM is:

3. The compound according to claim 1, wherein said CLM is:

4. The compound according to claim 1, wherein said PTM is: wherein the represents the connection point with the L.

5. The compound according to claim 1, wherein: (1) including 1 - 4 substituents, each independently selected from halogen, OH, NH 2 , N(C 1 -C 3 alkyl), 2 C 1 -C 4 alkyl, C 1 -C 4 hydroxyalkyl, C 1 -C 4 alkoxy and C 1 -C 4 haloalkyl; (2) Yes Wherein: R 3 and R 4 each independently selected from H, halogen, OH, NH 2 , N(C 1 -C 3 alkyl) 2 , C 1 -C 4 alkyl, C 1 -C 4 hydroxyalkyl, C 1 -C 4 alkoxy and C 1 -C 4 haloalkyl; Indicates connection point; and Denotes the point of attachment to said L, and when absent, said Is attached to said L via a ring atom of ring A or via R 3 Or R 4 Is attached to said L; or (3) their combination.

6. The compound according to claim 1, wherein: (a) Selected from: Wherein: R 3 is H or C 1 -C 3 alkyl; R 4 is H or C 1 -C 3 alkyl; representation connection point; and represents the point of attachment to said L, and when absent, said is attached to said L via a ring atom of ring A or via R 3 or R 4 ; (b)R 1 is wherein: R 1a , R 1b and R 1C are each independently H or C 1 -C 2 alkyl optionally substituted by one or more halogens or nitriles; or R 1a or R 1b together with the carbon to which they are attached form a C 1 -C 3 cycloalkyl optionally substituted by one or more C 3 -C 6 alkyl, nitriles or halogens; (c)R 2 is H or F; or (d) their combination.

7. The compound according to claim 1, wherein or is: Ring A is attached to said L or said PTM via a ring atom of ring A or an atom of its substituent.

8. The compound according to claim 1, wherein said PTM is:

9. The compound according to claim 1, wherein said PTM is: wherein: represents the connection site with said L; and each PTM is coupled to at least one L.

10. The compound according to claim 1, wherein said L is: wherein: N* is a nitrogen atom covalently linked to said CLM or said PTM; and each of m, n, o, p, q and r is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.

11. The compound according to claim 1, wherein (a) said CLM is: wherein: The represents a connection point with the N* is a nitrogen atom shared with said L or said PTM; (b) said PTM is: wherein the PTM is covalently linked to the L through a ring atom of ring A or a substituent thereof; (c) said L is: wherein N* is a nitrogen atom covalently linked to the CLM or the PTM; or (d) their combination.

12. A compound, wherein said compound is:

13. A pharmaceutical composition comprising the compound according to any one of claims 1-12 and a pharmaceutically acceptable carrier.

14. The pharmaceutical composition according to claim 13, wherein said composition further comprises an additional bioactive agent.

15. The pharmaceutical composition according to claim 14, wherein said additional bioactive agent is an anti-inflammatory agent, a chemotherapeutic agent or an immunomodulatory agent.

16. Use of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one compound according to any one of claims 1-12 in the manufacture of a medicament for the treatment of a disease or disorder or symptom causally related to LRRK2.

17. Use according to claim 16, wherein the disease or disorder causally related to LRRK2 is selected from idiopathic Parkinson's disease (PD), PD related to LRRK2 mutation, primary tauopathy, dementia with Lewy bodies, Crohn's disease, leprosy, neuroinflammation, and combinations thereof.

18. Use of a compound according to any one of claims 1-12 in the preparation of a medicament for the treatment of a disease or disorder related to LRRK2.

19. Use according to claim 18, wherein the disease or disorder related to LRRK2 is selected from idiopathic Parkinson's disease (PD), PD related to LRRK2 mutation, primary tauopathy, dementia with Lewy bodies, Crohn's disease, leprosy, neuroinflammation, and combinations thereof.

20. Use of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one compound according to any one of claims 1-12 in the preparation of a medicament for the treatment of Parkinson's disease (PD).

21. Use of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one compound according to any one of claims 1-12 in the preparation of a medicament for the treatment of supranuclear palsy.

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