Indazole based compounds and associated methods of use

Abstract

To provide compounds for effective treatment of diseases and disorders related to LRRK2, which are idiopathic PD, LRRK2 mutation associated PD (e.g., PD associated with one or more LRRK2 activated mutations), primary tauopathy (e.g., progressive supranuclear palsy (PSP) or corticobasal degeneration (CBD)), Lewy body dementia, Crohn's disease, Hansen's disease (e.g., Hansen's disease associated with type 1 inflammatory reactions), and / or neuroinflammation, for example.SOLUTION: Provided are bifunctional compounds useful as modulators of leucine-rich repeat kinase 2 (LRRK2). Particularly, the hetero-bifunctional compounds of the present disclosure contain on one end a moiety that binds to the cereblon E3 ubiquitin ligase and on the other end a moiety which binds LRRK2, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The hetero-bifunctional compounds of the present disclosure exhibit a broad range of pharmacological activities associated with degradation / inhibition of target protein. Diseases or disorders that result from aberrant regulation of the target protein are treated or prevented with compounds and compositions of the present disclosure.SELECTED DRAWING: None

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This disclosure claims the benefit of and priority to U.S. Provisional Patent Application No. 62 / 992,952, entitled INDAZOLE-BASED COMPOUNDS AND RELATED METHODS OF USE, filed March 21, 2020, which is incorporated by reference in its entirety for all purposes.

[0002] Incorporation by Reference All references cited are incorporated herein by reference in their entirety, including U.S. Patent Application No. 14 / 686,640, filed April 14, 2015, published as U.S. Patent Application Publication No. 2015 / 0291562; and U.S. Patent Application No. 14 / 792,414, filed July 6, 2015, published as U.S. Patent Application Publication No. 2016 / 0058872; and U.S. Patent Application No. 15 / 953,108, filed April 13, 2018, published as U.S. Patent Application Publication No. 2018 / 0228907; and U.S. Patent Application Publication No. 2016 / 0009689A1, filed September 2, 2015; and U.S. Patent Application Publication No. 2016 / 0200722A1, filed February 18, 2016. The present invention provides heterobifunctional compounds comprising a target protein binding portion and an E3 ubiquitin ligase binding portion, and related methods of use. The bifunctional compounds are useful as modulators of targeted ubiquitination of leucine-rich repeat kinase 2 (LRRK2), which is then degraded and / or inhibited. [Background technology]

[0003] Most small molecule drugs bind enzymes or receptors in tight, well-defined pockets. Protein-protein interactions, on the other hand, are notoriously difficult to target using small molecules because they involve broad contact surfaces and shallow grooves or flat interfaces. E3 ubiquitin ligases (hundreds are known in humans) are more attractive therapeutic targets than general proteasome inhibitors because of their specificity for specific protein substrates, which confer substrate specificity to ubiquitination. Development of ligands for E3 ligases has proven difficult, in part, due to the fact that protein-protein interactions must be blocked. However, recent developments have provided specific ligands that bind to these ligases. For example, since the discovery of nutlin, the first small molecule E3 ligase inhibitor, additional compounds targeting E3 ligases have been reported.

[0004] Cereblon is a protein that in humans is encoded by the CRBN gene. Orthologues of CRBN are highly conserved from plants to humans, strongly suggesting its physiological importance. Cereblon forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB1), cullin 4A (CUL4A), and cullin regulatory factor 1 (ROC1). This complex ubiquitinates numerous other proteins. Ubiquitination of target proteins by cereblon through a mechanism that has yet to be fully elucidated leads to increased levels of fibroblast growth factor 8 (FGF8) and fibroblast growth factor 10 (FGF10). FGF8 then regulates numerous developmental processes such as limb and otocyst formation. As a final result, this ubiquitin ligase complex is important for limb growth in the embryo. In the absence of cereblon, DDB1 forms a complex with DDB2, which functions as a DNA damage binding protein.

[0005] Bifunctional compounds such as those described in U.S. Patent Application Publication Nos. 2015 / 0291562 and 2014 / 0356322 (herein incorporated by reference) function to recruit endogenous proteins to E3 ubiquitin ligases for ubiquitination and subsequent degradation in the proteasomal degradation pathway. In particular, the above-cited publications describe bifunctional or proteolysis-inducing chimeric (PROTAC®) proteolytic compounds that find utility as modulators of targeted ubiquitination of various polypeptides and proteins, which are then degraded and / or inhibited by the bifunctional compounds.

[0006] Leucine-rich repeat kinase 2 (LRRK2) is a member of the leucine-rich repeat kinase family and is a large multi-domain protein with an N-terminal armadillo domain, an ancrine repeat region, a leucine-rich repeat (LRR) domain, tandem Roco-type GTPase domains, a DFG-like motif-containing kinase domain, 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 domain and the GTPase domain, and LRRK2 is a heterodimer in its active form (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 block GTP binding have been shown to impair 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 physiological substrates identified (other than LRRK2 itself) are a subset of small G proteins, including Rab8a and Rab10, which are involved in regulating vesicular 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 expression levels are highest in immune cells (neutrophils, monocytes and B cells), lungs and kidneys, with lower levels in the brain and dopaminergic neurons in 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).

[0007] LRRK2 has several dominant, gain-of-function, pathogenic and characteristic mutations located either in the Roco domain (N1437H, R1441G / C / H, Y1699C) affecting 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, muscle rigidity, decreased movement (bradykinesia), and impaired postural stability. Histological hallmarks of PD include neurodegeneration of dopaminergic neurons in the substantia nigra pars compacta, as well as intracellular inclusions called Lewy bodies and neurites composed of aggregates of alpha-synuclein protein. G2019S is associated with 1-2% of all PD patients and causes a 2-fold increase in kinase activity in vitro (West AB, et al.: Parkinson's disease associated mutations in leucine-rich repeat kinase 2 augment kinase activity. Proc Natl Acad Sci USA 2005,102:16842-16847) and a 4-fold increase in autophosphorylation at Ser1292 (Sheng Z, et al.: Ser1292 autophosphorylation is an indicator of LRRK2 kinase activity and contributes to the cellular effects of PD mutations. Sci Transl Med 2012,4:164ra161). The G2019S and I2020T mutations are within the DFG motif (DYGI in the case of LRRK2) common to all kinases and control catalytic activity. These mutations are thought to increase catalytic activity by disrupting the inactive conformation (Schmidt SH, et al.:The dynamic switch mechanism that leads to activation of LRRK2 is embedded in the DFGpsi motif in the kinase domain.Proc Natl Acad Sci USA 2019,116:14979-14988).Some of the Parkinson's disease-associated mutations mentioned above (R1441C / G, Y1699C, and I2020T) suppress phosphorylation of LRRK2 at Ser910 and Ser935, resulting in reduced association of LRRK2 with 14-3-3 proteins, which are thought to represent inactive forms 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).

[0008] Furthermore, LRRK2 is associated with autosomal dominant PD due to mutations in a region of chromosome 12 called PARK8, which is 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 linked to autosomal dominant Parkinson's disease in 1978 and was followed up in a Japanese family (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 ancestry, with 30-40% of North African Berbers and 14% of Jewish patients carrying this mutation.

[0009] LRRK2 kinase inhibitors have been proposed as a potential treatment for PD caused by mutations such as G2019S that increase LRRK2 activity, and for idiopathic PD in which 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 have advanced to the clinic, including LRRK2 kinase inhibitors that directly affect phosphorylation of downstream targets and oligonucleotides (ASOs) that are injected directly into the CNS and reduce LRRK2 protein levels by blocking translation of the LRRK2 protein.

[0010] Lewy bodies are the main histological feature of PD. They are composed mainly of alpha-synuclein aggregates, and mutations in alpha-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 by 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 alpha-synuclein-mediated pathology in mouse models of PD (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 alpha-synuclein aggregation in neurons and mouse models of PD. This increase was reversed by an LRRK2 kinase inhibitor (Volpicelli-Daley LA, et al. G2019S-LRRK2 Expression Augments α-Synuclein Sequestration into Inclusions in Neurons. J Neurosci. 2016 Jul 13;36(28):7415-27. doi:10.1523 / JNEUROSCI.3642-15.2016).There is some evidence to suggest that the G2019S mutant form of LRRK2 is resistant to inhibition by kinase inhibitors in the CNS, potentially reducing their disease-modifying effects (Kelly K,et al.The G2019S mutation in LRRK2 imparts resiliency to kinase inhibition.Exp Neurol.2018 Nov;309:1-13).Most cases of PD also have Lewy bodies on postmortem examination, but many of the LRRK2 G2019S mutations associated with PD cases do not have Lewy bodies (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, a common feature of PD, tau pathology is also a prominent feature of LRRK2 mutation carriers postmortem (Henderson MX,et al.:Alzheimer's disease tau is a prominent pathology in LRRK2 Parkinson's disease.Acta Neuropathol Commun 2019,7.183-183).Although the genetic causal link between LRRK2 and primary tauopathies such as supranuclear palsy (PSP) or corticobasal degeneration (CBD) is not strong, one study found that tau pathology was observed in 100% of LRRK2 mutation carriers, highlighting LRRK2 as a key target linking PD and tau pathology in the context of PD (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). A common mutation at the LRRK2 locus was recently reported as a genetic determinant of PSP survival (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 increased expression of LRRK2 in PSP by expression quantitative trait loci (eQTL) analysis may result in a reactive microglia-induced inflammatory state, thereby driving the continued accumulation of misfolded tau protein and clinical disease progression.Functional variants in LRRK2 have also been associated with type 1 inflammatory responses in Crohn's disease and leprosy (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.2018 Jan 10;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 US A.2019 Jul 30;116(31):15616-15624.doi:10.1073 / pnas.1901805116.Epub 2019 Jul 15). LRRK2 is highly expressed in neutrophils, monocytes and macrophages of the immune system, as well as in brain microglia, and is a modulator of microglial activation and endogenous regulation of lysosomal degradative processes (Ma et al. Genetic comorbidities in Parkinson's disease. Hum Mol Genet. 2014 Feb 1;23(3):831-41. doi:10.1093 / hmg / ddt465. Epub 2013 Sep 20, reviewed in Schapansky et al The complex relationships between microglia,alpha-synuclein,and LRRK2 in Parkinson's disease. Neuroscience. 2015 Aug 27;302:74-88. doi:10.1016 / j.neuroscience.2014.09.049. Epub 2014 Oct 2). Prolonged activation of these immune cells through the PD disease process or mutations in LRRK2 may increase neuroinflammation and increase the risk of developing PD and / or tau pathology. Treatment with anti-TNF agents reduces the risk of developing PD by 78% in patients with inflammatory bowel disease (Peter I,et al.:Anti-tumor necrosis factor therapy and incidence of Parkinson disease among patients with inflammatory bowel disease.JAMA Neurol 2018), suggesting a strong link between inflammation and PD. In addition to PD, LRRK2 has also been implicated in 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). [Prior art documents] [Patent documents]

[0011] [Patent Document 1] US Patent Application Publication No. 2015 / 0291562 [Patent Document 2] US Patent Application Publication No. 2014 / 0356322 Summary of the Invention [Problem to be solved by the invention]

[0012] There is a continuing need in the art for effective treatments for LRRK2-related diseases and disorders, such as idiopathic PD, LRRK2 mutation-associated PD (e.g., PD associated with one or more LRRK2 activating mutations), primary tauopathy (e.g., supranuclear palsy (PSP) or corticobasal degeneration (CBD)), dementia with Lewy bodies, Crohn's disease, leprosy (e.g., leprosy with type 1 inflammatory response), and / or neuroinflammation. [Means for solving the problem]

[0013] The present disclosure describes heterobifunctional compounds that function to recruit leucine-rich repeat kinase 2 (LRRK2) to E3 ubiquitin ligase for targeted ubiquitination and subsequent proteasomal degradation, as well as methods of making and using the same. In addition, the present disclosure provides a method of using an effective amount of the compounds of the present disclosure for treating or alleviating a disease state, such as a disease or disorder associated with LRRK2, for example, accumulation or hyperactivity of LRRK2 protein or mutant LRRK2 protein or misfolded LRRK2 protein, or aggregation or accumulation of alpha-synuclein, or aggregation or accumulation of tau, or idiopathic PD, or LRRK2 mutation-associated PD (e.g., PD associated with one or more LRRK2 activating mutations), or primary tauopathy (e.g., supranuclear palsy (PSP) or corticobasal degeneration (CBD)), or dementia with Lewy bodies, or Crohn's disease, or leprosy (e.g., leprosy with type 1 inflammatory response), or neuroinflammation.

[0014] Thus, in one aspect, the disclosure provides heterobifunctional compounds that include an E3 ubiquitin ligase binding moiety (i.e., a ligand for 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 LRRK2 targeting ligand or "LTM" group), thereby positioning the LRRK2 protein in proximity to the ubiquitin ligase, resulting in 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 represented as follows: [ka]

[0015] The respective positions of the PTM and ULM moieties (e.g., CLM) exemplified herein, as well as their numbers, are provided by way of example only and are not intended to limit the compounds in any way. As will be appreciated by one of skill in the art, the bifunctional compounds described herein can be synthesized such that the number and position of each functional moiety can be varied as desired.

[0016] In certain embodiments, the bifunctional compound further comprises a chemical linker ("L"). In this example, the structure of the bifunctional compound can be represented as follows: [ka] where PTM is a LRRK2 targeting moiety (LTM), L is a linker, e.g., a bond or chemical linking group, that couples the PTM to the ULM, and ULM is a cereblon E3 ubiquitin ligase binding moiety (CLM).

[0017] For example, the structure of a bifunctional compound can be represented as follows: [ka] where the PTM is a LRRK2 targeting moiety (LTM), "L" is a linker (e.g., a bond or chemical linking group) that couples the PTM to the CLM, and the CLM is a cereblon E3 ubiquitin ligase binding moiety that binds to cereblon.

[0018] In certain embodiments, the compounds described herein comprise multiple independently selected ULMs, multiple PTMs, multiple chemical linkers, or combinations thereof.

[0019] In any of the aspects or embodiments described herein, the PTM is a small molecule that binds to LRRK2 or a mutant thereof. In any of the aspects or embodiments described herein, the PTM is a small molecule that binds to LRRK2. In any of the aspects or embodiments described herein, the PTM is a small molecule that binds to both LRRK2 wild-type protein and an LRRK2 mutant, such as an LRRK2 mutant comprising one or more mutations selected from G2019S, I2020T, N1437H, R1441G / C / H, and Y1699C. In any of the aspects or embodiments described herein, the PTM is a small molecule that binds to both LRRK2 wild-type protein and an LRRK2 mutant, such as, but not limited to, G2019S, I2020T, N1437H, R1441G / C / H, Y1699C, or a combination thereof. In any of the aspects or embodiments described herein, the small molecule binds to LRRK2 as described herein.

[0020] In embodiments, the CLM comprises a chemical group derived from an imide, a thioimide, an amide, or a thioamide. In certain embodiments, the chemical group is a phthalimide group, or an analog or derivative thereof. In certain embodiments, the CLM is selected from thalidomide, lenalidomide, pomalidomide, analogs 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.

[0021] In certain embodiments, "L" is a bond. In additional embodiments, the linker "L" is a linear connector with a number of non-hydrogen atoms ranging from 1 to 20. The connector "L" may contain one or more functional groups, such as, but not limited to, ether, amide, alkane, alkene, alkyne, ketone, hydroxyl, carboxylic acid, thioether, sulfoxide, and sulfone. The linker may contain aromatic, heteroaromatic, cyclic, bicyclic, or tricyclic moieties. The linker may include substitution with halogens, such as Cl, F, Br, and I. In the case of fluorine substitution, it may include one or more fluorines.

[0022] In certain embodiments, the CLM is a derivative of piperidine-2,6-dione, where the piperidine-2,6-dione can be substituted at the 3-position, and the 3-substitution can be a bicyclic heteroaromatic ring containing a C-N or C-C bond linkage. Examples of CLMs can be, but are not limited to, pomalidomide, lenalidomide, and thalidomide and analogs thereof.

[0023] In a further aspect, the present disclosure provides a therapeutic composition comprising an effective amount of a compound or a salt form thereof described herein and a pharma- ceutically acceptable carrier.The therapeutic composition can be used to induce targeted degradation of LRRK2 or its mutants and / or inhibition of LRRK2 or its mutants in a patient or subject, for example, an animal such as a human, and can be used to treat or alleviate one or more disease states, conditions, or symptoms causally related to LRRK2 or its mutants, which treatment is achieved by degradation or inhibition of LRRK2 protein or its mutants, or by controlling or reducing LRRK2 protein level or its mutants protein level in a patient or subject. In certain embodiments, the therapeutic compositions described herein may be used to effect degradation of LRRK2 or mutant forms thereof for the treatment or alleviation of diseases such as, for example, LRRK2 accumulation or hyperactivity, alpha-synuclein aggregation or accumulation, tau aggregation or accumulation, idiopathic PD, LRRK2 mutation-associated PD (e.g., PD associated with one or more LRRK2 activating mutations), primary tauopathy (e.g., supranuclear palsy (PSP) or corticobasal degeneration (CBD)), dementia with Lewy bodies, Crohn's disease, leprosy (e.g., leprosy with type 1 inflammatory response), and / or neuroinflammation.

[0024] 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 includes administering a heterobifunctional compound described herein that includes a PTM that binds to LRRK2 or a mutant form thereof and a CLM, preferably linked via a chemical linker moiety as described herein, to cause degradation of the LRRK2 protein or a mutant form thereof. Without wishing to be limited by theory, the inventors believe that, in accordance with the present invention, polyubiquitination occurs when an LRRK2 wild-type or mutant protein is placed in close proximity to an E3 ubiquitin ligase through the use of a heterobifunctional compound, thereby inducing subsequent degradation of the LRRK2 or mutant protein via the proteasome pathway and control or reduction of the LRRK2 protein level in a cell, such as a cell of a subject in need of such treatment. The control or reduction of the level of the LRRK2 protein or a mutant form thereof provided by the present disclosure provides for the treatment of a disease state, condition, or associated symptom causally linked to LRRK2, which is modulated by a reduction in the amount of the LRRK2 protein or a mutant form thereof in the cell of the subject.

[0025] In yet another aspect, the description provides a method for treating or alleviating a disease, condition, or symptom thereof causally associated with LRRK2 or a mutated form thereof in a subject or patient, e.g., an animal such as a human, comprising administering to a subject in need thereof a composition comprising an effective amount, e.g., a therapeutically effective amount, of a heterobifunctional compound described herein, or a salt form thereof, and a pharma- ceutically acceptable carrier, wherein the composition is effective to treat or alleviate the disease, disorder, or symptom thereof in the subject.

[0026] In another aspect, the present description provides methods for determining the effect of degradation of LRRK2 protein in a biological system using compounds according to the present disclosure.

[0027] In another aspect, the present specification provides processes and intermediates for producing the heterobifunctional compounds of the present disclosure that are capable of targeted ubiquitination and degradation of LRRK2 protein in a cell (e.g., in vivo or in vitro).

[0028] The accompanying drawings, which are incorporated in and form 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 embodiments of the present disclosure and are not to be construed as limiting the present disclosure. Further objects, features and advantages of the present disclosure will become apparent from the following detailed description taken in conjunction with the accompanying drawings showing exemplary embodiments of the present disclosure. [Brief description of the drawings]

[0029] [Figure 1] Illustrative general principle of heterobifunctional proteolytic compounds. A. An exemplary heterobifunctional proteolytic compound includes 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. B. Shows the functional use of the heterobifunctional proteolytic compounds described herein (commercially known as PROTAC® proteolytic compounds). Briefly, the ULM (triangle) recognizes and binds a specific E3 ubiquitin ligase, and the PTM (large rectangle) binds to the target protein and recruits it into close proximity to the E3 ubiquitin ligase. Typically, the E3 ubiquitin ligase complexes with an E2 ubiquitin-binding protein (E2) and catalyzes the attachment of multiple ubiquitin molecules (black circles) via isopeptide bonds to lysines on the target protein, either alone or through the E2 protein. This targets the polyubiquitinated protein (far right) for degradation by the cell's proteosome machinery. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0030] Described herein are compounds, compositions, and methods relating to the surprising discovery that when an E3 ubiquitin ligase (e.g., cereblon E3 ubiquitin ligase) and an LRRK2 protein are brought into close proximity via a bifunctional compound that binds to both the E3 ubiquitin ligase and the LRRK2 protein, the E3 ubiquitin ligase ubiquitinates the LRRK2 protein or a mutant form thereof. Accordingly, the present disclosure provides compounds and compositions that include an E3 ubiquitin ligase binding moiety ("ULM") conjugated or linked by a chemical linking group (L) to a protein targeting moiety ("PTM") that targets the LRRK2 protein, resulting in ubiquitination of the LRRK2 protein and resulting in degradation of the LRRK2 protein by the proteasome (see FIG. 1).

[0031] In one aspect, the present disclosure provides compounds in which the PTM binds to the LRRK2 protein and / or mutant forms thereof. The present disclosure also provides a library of compositions and uses thereof that effect targeted degradation of the LRRK2 protein in cells.

[0032] In certain embodiments, the present disclosure provides heterobifunctional compounds that include a ligand capable of binding to an E3 ubiquitin ligase, such as cereblon, e.g., a small molecule ligand (i.e., having a molecular weight of less than 2,000, 1,000, 500, or 200 daltons). The compound also includes a small molecule moiety capable of binding to an LRRK2 protein or mutant form thereof, such that the LRRK2 protein or mutant form is placed in close proximity to the ubiquitin ligase, resulting in ubiquitination and degradation (and / or inhibition) of the LRRK2 protein or mutant form. By "small molecule" we further mean that the molecule is non-peptidyl, i.e., not considered a peptide, e.g., contains less 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.

[0033] The term "LRRK2," as used throughout this specification, unless clearly stated to the contrary, is intended to include both wild-type LRRK2 and mutant forms, e.g., LRRK2 mutant proteins containing one or more mutations selected from G2019S, I2020T, N1437H, R1441G / C / H, and Y1699C.

[0034] 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 description are for the purpose of describing particular embodiments only and are not intended to be limiting of the disclosure.

[0035] Where a range of values ​​is provided, unless the context clearly dictates otherwise (such as in the case of a group containing a certain number of carbon atoms where each number of carbon atoms falling within the range is provided), it is understood that each value between the upper and lower limit of that range, to the tenth of the unit of the lower limit, and any other stated or intervening value in that stated range, is encompassed within the disclosure. The upper and lower limits of these narrower ranges may independently be included in the narrower range, and are also encompassed within the disclosure, if any particular limit in the stated range is excluded. When a stated range includes one or both of the limits, ranges excluding one or both of those included limits are also included in the disclosure.

[0036] The following terms are used to describe this disclosure. If a term is not expressly defined herein, the term is given its art-recognized meaning by one of ordinary skill in the art applying the term in the context of its use in describing this disclosure.

[0037] As used in this specification and the appended claims, the articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article, unless the context clearly indicates otherwise. By way of example, "an element" means one element or more than one element, unless otherwise specified.

[0038] In the claims and the above specification, transitional phrases such as "comprising," "including," "carrying," "having," "containing," "involving," "holding," "composed of," and the like, are all to be understood to be open-ended, i.e., to mean including, but not limited to. Only the transitional phrases "consisting of" and "consisting essentially of" shall be closed or semi-closed transitional phrases, respectively, as set forth in the United States Patent Office Manual of Patent Examining Procedures, Section 2111.03.

[0039] It is also to be understood that in a particular method or process that includes more than one step or act described herein, the order of the method steps or acts is not necessarily limited to the order in which the method steps or acts are recited, unless the context indicates otherwise.

[0040] The terms "co-administration" and "administered simultaneously" or "combination therapy" refer to both simultaneous administration (administration of two or more therapeutic agents at the same time) and staggered administration (administration of one or more therapeutic agents at a different time than administration of an additional therapeutic agent or agents), so long as the two or more therapeutic agents are present in the patient at the same time, to some extent, preferably in effective amounts. In certain preferred embodiments, one or more of the heterobifunctional compounds described herein are administered together with at least one additional bioactive agent, e.g., an anti-cancer agent. In particularly preferred embodiments, the co-administration of such compounds results in synergistic activity and / or treatment, e.g., anti-cancer activity.

[0041] The term "compound" as used herein refers to any specific heterobifunctional compound disclosed herein, its pharma- ceutically acceptable salts and solvates, and, if applicable, deuterated forms of any of the above molecules, unless otherwise specified. Contemplated deuterated compounds are those in which one or more of the hydrogen atoms contained in the drug molecule are 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.

[0042] The term "ubiquitin ligase" refers to a family of proteins that facilitate the transfer of one or more ubiquitins to a specific substrate protein. Once several ubiquitin chains have been added (polyubiquitination), the substrate protein is targeted for degradation. For example, cereblon is an E3 ubiquitin ligase that, alone or in combination with an E2 ubiquitin-conjugating enzyme, can ultimately result in the addition of four ubiquitin chains to lysine residues on a target protein, thereby targeting the protein for degradation by the proteasome. Ubiquitin ligases are involved in polyubiquitination, where one ubiquitin is attached to a lysine on the target protein, a second ubiquitin is attached to the first, a third to the second, and a fourth to the third. Such polyubiquitination marks the protein for degradation by the proteasome.

[0043] The terms "patient" or "subject" are used throughout the present specification to describe an animal, preferably a human or a domestic animal, to which treatment, including prophylactic treatment, with a composition according to the present disclosure is provided. With respect to treatment of a disease, condition, or symptom specific to a particular animal, such as a human patient, the term "patient" refers to the particular animal, including domestic animals, such as dogs or cats, or livestock animals, such as horses, cows, sheep, etc. In general, in this 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.

[0044] The terms "effective" and "therapeutically effective," when used within the context of their intended use, are used to describe an amount of a compound or composition that, either in a single dose, or more preferably after multiple doses within the context of a treatment regimen, produces an intended result, such as amelioration of a disease or condition, or alleviation or relief of one or more symptoms associated with a disease or condition. The terms "effective" and "therapeutically effective" include all other "effective amount" or "effective concentration" terms as otherwise described or used in this application.

[0045] Compounds and Compositions

[0046] In one aspect, the present disclosure provides heterobifunctional compounds that include an E3 ubiquitin ligase binding moiety ("ULM") that is a cereblon E3 ubiquitin ligase binding moiety ("CLM"). The CLM is covalently attached to a protein targeting moiety (PTM) that binds to a protein according to the following structure, where the coupling is direct by bond or via a chemical linking group (L): (A) PTM-L-CLM where L is a bond or chemical linking group and PTM is a protein targeting moiety that binds to the protein LRRK2 or a mutant form thereof, such as G2019S, where the PTM is a LRRK2 targeting moiety (LTM). The term CLM includes all cereblon binding moieties.

[0047] In any of the aspects or embodiments, the CLM has a half maximal inhibitory concentration (IC) for an E3 ubiquitin ligase (e.g., cereblon E3 ubiquitin ligase) of less than about 200 μM. 50 ) is shown. 50 can be determined according to any suitable method known in the art, for example, a fluorescence polarization assay.

[0048] In certain embodiments, the heterobifunctional compounds described herein have an IC 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. 50 or 50% cleavage concentration (DC 50 ) is shown.

[0049] The term "alkyl" refers, within its context, to a straight-chain, branched-chain or cyclic fully saturated hydrocarbon radical, preferably 1 -C 10 , preferably C 1 -C 6 or more preferably, C 1 -C 3 and optionally substituted with any suitable functional group or 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, among others. In certain embodiments, the alkyl group is end-capped with a halogen group (At, Br, Cl, F, or I).

[0050] The term "alkenyl" refers to any straight, branched or cyclic C alkyl group containing at least one C=C bond. 2 -C 10 (Preferably, C 2 -C 6 ) refers to a hydrocarbon radical.

[0051] The term "alkynyl" refers to any straight, branched or cyclic C alkyl group containing at least one C≡C bond. 2 -C 10 (Preferably, C 2 -C 6 ) refers to a hydrocarbon radical.

[0052] The term "alkylene", when used, refers to -(CH 2 ) n - group, where n is generally an integer from 0 to 6, which may be optionally substituted. When substituted, the alkylene group preferably has one or more of the methylene groups replaced by C 1 -C 6substituted with an alkyl group (including a cyclopropyl group or a t-butyl group), one or more halo groups, preferably 1 to 3 halo groups or 1 or 2 hydroxyl groups, O—(C 1 -C 6 In certain embodiments, the alkylene (e.g., methylene) group may be substituted with an amino acid side chain, such as a side chain of a natural or unnatural amino acid, e.g., 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. In certain embodiments, the alkylene (e.g., methylene) group may be substituted with a urethane or alkoxy group (or other suitable functional group), which may be further substituted with a polyethylene glycol chain (1-10, preferably 1-6, or more preferably 1-4 ethylene glycol units), which is substituted with an alkyl chain substituted with one halogen group, preferably a chlorine group (preferably, but not limited to, at the distal end of the polyethylene glycol chain). In yet other embodiments, the alkylene (e.g., methylene) group may be substituted with an amino acid side chain group, such as a side chain group of a natural or unnatural amino acid, e.g., 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.

[0053] The term "unsubstituted" is intended to mean substituted with only hydrogen atoms. 0 The range of carbon atoms including means that the carbon is absent and replaced with H. That is, C 0 -C 6 The range of carbon atoms for C includes 1, 2, 3, 4, 5 and 6 carbon atoms. 0 In the case of , H is present in place of carbon.

[0054] The term "substituted" or "optionally substituted" is intended to mean one or more substituents (independently up to five substituents, preferably up to three substituents, more preferably one or two substituents, on a moiety in a compound according to the present disclosure, which may themselves include further substituted substituents) independently (i.e., when two or more substituents are present, each substituent is selected independently of the other substituents) at a carbon (or nitrogen) anywhere in the molecule within the context, possible substituents being hydroxyl, thiol, carboxyl, cyano (C≡N), nitro (NO 2 ), halogen (preferably 1, 2 or 3 halogens, especially on the alkyl, especially on the methyl group, e.g. trifluoromethyl), alkyl group (preferably C 1 -C 10、 More preferably, C 1 -C 6 ), aryl (especially phenyl and substituted phenyl, e.g., benzyl or benzoyl), alkoxy groups (preferably C 1 -C 6 alkyl or aryl, including phenyl and substituted phenyl), thioethers (preferably C 1 -C 6 alkyl or aryl), acyl (preferably C 1 -C 6 acyl), alkylene ester (wherein the bond is on the alkylene group rather than the ester functionality, the ester functionality being preferably 1 -C 6 esters or thioesters (preferably C 1 -C 6 alkyl or aryl), halogen (preferably F or Cl), amines (including 5- or 6-membered cyclic alkylene amines, C 1 -C 6 Alkylamine or C 1 -C 6 Further included are dialkylamines, where the alkyl group may be substituted with one or two hydroxyl groups) or optionally substituted -N(C 0 -C 6Alkyl)C(O)(OC 1 -C 6 alkyl) groups (optionally substituted with a polyethylene glycol chain, which is further bonded to an alkyl group containing one halogen, preferably chlorine, substituent), hydrazine, amide, preferably one or two C 1 -C 6 Independently substituted with alkyl groups (optionally one or two C 1 -C 6 Alkanols (preferably C 1 -C 6 alkyl or aryl), or alkanoic acid (preferably C 1 -C 6 Substituents according to the present disclosure include, for example, -SiR 1 R 2 R 3 group (in the formula, R 1 and R 2 Each of the above is described separately herein, and R 3 is H or C 1 -C 6 is an alkyl group, preferably R 1 , R 2 , R 3 Both are C 1 -C 3 and alkyl groups, including isopropyl or t-butyl groups. Each of the above groups may be directly linked to the moiety to be substituted, or alternatively, the substituent may be an optionally substituted -(CH 2 ) m -or alternatively optionally substituted -(OCH 2 ) m -, -(OCH 2 CH 2 ) m -or-(CH 2 CH 2 O) mThe alkylene group -(CH 2 ) m -or-(CH 2 ) n - groups or other chains such as ethylene glycol chains may be substituted anywhere on the chain. Preferred substituents on the alkylene group include halogen or C 1 -C 6 (Preferably, C 1 -C 3 ) alkyl groups, which optionally contain one or two hydroxyl groups, one or two ether groups (OC 1 -C 6 groups), up to three halo groups (preferably F), or the side chains of amino acids as otherwise described herein and optionally substituted amide (preferably carboxamide, substituted as above) or urethane groups (often one or two C 0 -C 6 In certain embodiments, the alkylene group (often a single methylene group) can be substituted with one or two optionally substituted C 1 -C 6 Alkyl groups, preferably C 1 -C 4 Substituted with alkyl group, most often methyl or O-methyl group or the side chain of amino acid described elsewhere herein.In the present disclosure, a moiety in a molecule can be optionally substituted with up to 5 substituents, preferably up to 3 substituents.In many cases, in the present disclosure, a substituted moiety is substituted with 1 or 2 substituents.

[0055] The term "substituted," where each substituent is independent of any other substituent, within the context in which it is used, includes 1 -C 6 Alkyl, C 1 -C 6Alkoxy, halogen, amide, carboxamide, sulfone (including sulfonamide), keto, carboxy, C 1 -C 6 Esters (oxyesters or carbonylesters), C 1 -C 6 Keto, urethane-OC(O)-NR 1 R 2 or -N(R 1 )-C(O)-OR 1 , nitro, cyano and amine (especially C 1 -C 6 Alkylene-NR 1 R 2 , mono or di-C 1 -C 6 "Amino groups" refers to alkyl substituted amines, which may be optionally substituted with one or two hydroxyl groups. Each of these groups contains from 1 to 6 carbon atoms, unless otherwise specified, within the context. In certain embodiments, preferred substituents 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, -(CH 2 ) n O-(C 1 -C 6 alkyl), -(CH 2 ) n C(O)-(C 1 -C 6 alkyl), -(CH 2 ) n O.C.(O)-(C 1 -C 6 alkyl), -(CH 2 ) nC(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 (which is the base of 2 , CN or halogen (F, Cl, Br, I, preferably F or Cl). 1 and R 2 respectively, H or C, depending on the context. 1 -C 6The term "substituted" is also intended to mean, within the chemical context of the defined compound and the substituents used, an optionally substituted aryl or heteroaryl group or an optionally substituted heterocyclic group, as described elsewhere herein. The alkylene group is also preferably an optionally substituted 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 40 -C 41 -C 42 1 -C 6 an alkyl group (preferably methyl, ethyl or hydroxymethyl or hydroxyethyl, so that a chiral center results), the side chain of an amino acid group as described elsewhere herein, an amide group as described herein above, or a urethane group OC(O)-NR 1 R 2 group (in the formula, R 1 and R 2 may be substituted with H, as described elsewhere herein), although many other groups may be used as substituents. The various optionally substituted moieties may be substituted with three or more substituents, preferably no more than three, and preferably one or two. It should be noted that in the case of compounds where molecular substitution at a particular position is required (principally for valence reasons) but no substitution is indicated, the substituent is to be interpreted or understood to be H, unless otherwise indicated in the context of the substitution.

[0056] The term "aryl" or "aromatic," in context, refers to a substituted (as otherwise described herein) or unsubstituted monovalent aromatic radical (e.g., a 5- to 16-membered ring) having a single ring (e.g., benzene, phenyl, benzyl, or a 5-, 6-, 7-, or 8-membered ring) or fused rings (e.g., naphthyl, anthracenyl, phenanthrenyl, 10- to 16-membered rings, etc.) and may be attached to a compound according to the present disclosure at any available stable position on the ring(s) or as otherwise shown in the chemical structures provided. Other examples of aryl groups, in context, include "heteroaryl" groups having one or more nitrogen, oxygen, or sulfur atoms in a ring (single ring) that are heterocyclic aromatic ring systems, such as imidazole, furyl, pyrrole, furanyl, thienes, thiazoles, pyridines, pyrimidines, pyrazines, triazoles, oxazoles, or fused ring systems, such as indole, quinoline, indolizine, azaindolizine, benzofurazan, and the like, which may be optionally substituted as described above.Heteroaryl groups which may be mentioned are, inter alia, nitrogen-containing heteroaryl groups, such as pyrrole, pyridine, pyridone, pyridazine, pyrimidine, pyrazine, pyrazole, imidazole, triazole, triazine, tetrazole, indole, isoindole, indolizine, azaindolizine, purine, indazole, quinoline, dihydroquinoline, tetrahydroquinoline, isoquinoline, dihydroisoquinoline, tetrahydroisoquinoline, quinolizine, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, imidazopyridine, imidazotriazine, pyrazinopyridazine, acridine, phenanthridine, carbazole, carbazoline, pyrimidine, phenanthroline, phenacene, oxadiazole, benzoyl 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, thiadizole, isothiazole, benzoxazole, benzothiazole, benzothiadiazole, phenothiazine, isoxazole, furazan, phenoxazine, pyrazoloxazole, imidazothiazole, thienofuran, furopyrrole, pyridooxazine, furopyridine, furopyrimidine, thienopyrimidine and oxazole, all of which may be optionally substituted.

[0057] The term "substituted aryl" refers to an aromatic carbocyclic group consisting of at least one aromatic ring or multiple fused rings in which at least one ring is aromatic, where the ring(s) is substituted with one or more substituents. For example, an aryl group can be -(CH 2 ) n OH, -(CH 2 ) n -O-(C 1 -C 6 ) alkyl, -(CH 2 ) n -O-(CH 2 ) n -(C1 -C 6 ) alkyl, -(CH 2 ) 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)amines (wherein the alkyl groups on the amine are optionally substituted with one or two hydroxyl groups or up to three halo (preferably F, Cl) groups), OH, COOH, C 1 -C 6 Alkyl, preferably CH 3 , C.F. 3 , OMe, OCF 3 , NO 2 or CN groups (each of which may be substituted at the ortho, meta and / or para positions of the phenyl ring, preferably para), an optionally substituted phenyl group (the phenyl group itself is preferably connected via a linker group to a PTM group, including a ULM group), and / or F, Cl, OH, COOH, CH 3 , C.F. 3 , OMe, OCF 3 , NO 2or CN groups (ortho, meta and / or para positions of the phenyl ring, preferably para), a naphthyl group which may be optionally substituted, an optionally substituted heteroaryl, 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 methyl imidazole, an optionally substituted benzimidazole or methoxybenzylimidazole, an optionally substituted optionally substituted oxoimidazole or methyloxoimidazole, optionally substituted diazole groups including methyldiazole groups, optionally substituted triazole groups including methyl substituted triazole groups, optionally substituted pyridine groups including halo (preferably F) or methyl substituted pyridine or oxapyridine groups (wherein the pyridine group is linked to the phenyl group by an oxygen), optionally substituted furan, optionally substituted benzofuran, optionally substituted dihydrobenzofuran, optionally substituted indole, indolizine or azaindolizine (2-, 3-, or 4-azaindolizine), optionally substituted quinoline, and combinations thereof.

[0058] "Carboxyl" refers to the group --C(O)OR, where R is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl, where these generic substituents have the same meaning as in the definitions of the corresponding groups defined herein.

[0059] The term "heteroaryl" or "hetaryl" refers to 5-16 membered heteroaryl (e.g., 10-16 membered heteroaryl having 5, 6, 7, or 8 membered single or multiple fused rings), optionally substituted quinoline (which may be attached to the pharmacophore or substituted at 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, benzoxofumab, and the like. oran, optionally substituted imidazole, optionally substituted isoxazole, optionally substituted oxazole (preferably methyl substituted), optionally substituted diazole, optionally substituted triazole, tetrazole, optionally substituted benzofuran, optionally substituted thiophene, optionally substituted thiazole (preferably methyl and / or thiol substituted), optionally substituted isothiazole, optionally substituted triazole (preferably methyl group, triisopropylsilyl group, optionally substituted -(CH 2 ) m -OC 1 -C 6 Alkyl group or optionally substituted -(CH 2 ) m -C(O)-OC 1 -C 6 This may mean, but is not limited to, a 1,2,3-triazole substituted with an alkyl group), an optionally substituted pyridine (2, 3, or 4-pyridine) or a structure according to the following chemical structure: [ka] During the ceremony, S c is CHR SS , N.R. URE , or O, R HET H, CN, NO 2, halo (preferably Cl or F), optionally substituted C 1 -C 6 Alkyl (preferably containing one or two hydroxyl groups or up to three halo groups (e.g., CF 3 substituted with O(C 1 -C 6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or an optionally substituted acetylenic group -C≡CR a (In the formula, R a is H or C 1 -C 6 Alkyl (preferably C 1 -C 3 alkyl) R SS H, CN, NO 2 , halo (preferably F or Cl), optionally substituted C 1 -C 6 Alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups), optionally substituted O—(C 1 -C 6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or optionally substituted -C(O)(C 1 -C 6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups); R URE , H, C 1 -C 6 Alkyl (preferably H or C 1 -C 3 alkyl) or -C(O)(C 1 -C 6alkyl), each of which is optionally substituted with one or two hydroxyl groups or up to 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; Y C is N or CR YC where R YC H, OH, CN, NO 2 , halo (preferably Cl or F), optionally substituted C 1 -C 6 Alkyl (preferably containing one or two hydroxyl groups or up to three halo groups (e.g., CF 3 substituted with O(C 1 -C 6 alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or an optionally substituted acetylenic group -C≡CR a (In the formula, R a is H or C 1 -C 6 Alkyl groups (preferably C 1 -C 3 (alkyl).

[0060] The terms "aralkyl" and "heteroarylalkyl" refer to groups containing both aryl or heteroaryl, and alkyl and / or heteroalkyl and / or carbocyclic and / or heterocycloalkyl ring systems, respectively, in accordance with the definitions above.

[0061] The term "arylalkyl" as used herein refers to an aryl group, as defined above, appended to an alkyl group, as defined above. An arylalkyl group is attached to a parent moiety via an alkyl group, where the alkyl group is 1 to 6 carbon atoms. The aryl group in the arylalkyl group may be substituted as defined above.

[0062] The term "heterocycle" refers to a cyclic group that contains at least one heteroatom, such as N, O, or S, and may be aromatic (heteroaryl) or non-aromatic. Thus, heteroaryl moieties are included in the definition of heterocycle, depending on the context in which it is used. Exemplary heteroaryl groups are described above.

[0063] Exemplary heterocyclic rings include, among others, azetidinyl, benzimidazolyl, 1,4-benzodioxanyl, 1,3-benzodioxolyl, benzoxazolyl, benzothiazolyl, benzothienyl, dihydroimidazolyl, dihydropyranyl, dihydrofuranyl, dioxanyl, dioxolanyl, ethyleneurea, 1,3-dioxolane, 1,3-dioxane, 1,4-dioxane, furyl, homopiperidinyl, imidazolyl, imidazolinyl, imidazolidinyl, indolinyl, indolyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isooct ... Examples of such aryl groups include xazolidinyl, 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, and thiane.

[0064] Heterocyclic groups can be optionally substituted with 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, hydroxyl, keto, thioketo, carboxy, carboxyalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SOaryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl, oxo (=O), and -SO2-heteroaryl. Such heterocyclic groups can have a single ring or multiple condensed rings. Examples of nitrogen heterocycles and heteroaryls include, but are not limited to, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, morpholino, piperidinyl, tetrahydrofuranyl, and the like, and N-alkoxy nitrogen-containing heterocycles. The term "heterocyclic" also includes bicyclic groups in which any of the heterocyclic rings is fused to a benzene or cyclohexane ring or to another heterocyclic ring (eg, indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, etc.).

[0065] The term "cycloalkyl" may refer to, but is not limited to, a monocyclic or polycyclic alkyl group or a monovalent group derived from a cycloalkane as defined herein, for example, a saturated monocyclic hydrocarbon group having 3 to 20 carbon atoms in the ring, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. The term "substituted cycloalkyl" may refer to, but is not limited to, a monocyclic or polycyclic alkyl group substituted with one or more substituents, for example, amino, halogen, alkyl, substituted alkyl, carbyloxy, carbylmercapto, aryl, nitro, mercapto, or sulfo, while these common substituents have the same meaning as the definition of the corresponding group defined in this description.

[0066] "Heterocycloalkyl" refers to a monocyclic or polycyclic alkyl group in which at least one ring carbon atom of the cyclic structure is replaced with a heteroatom selected from the group consisting of N, O, S, or P. "Substituted heterocycloalkyl" refers to a monocyclic or polycyclic alkyl group in which at least one ring carbon atom of the cyclic structure is replaced with a heteroatom selected from the group consisting of N, O, S, or P, and contains one or more substituents selected from the group consisting of halogen, alkyl, substituted alkyl, carbyloxy, carbylmercapto, aryl, nitro, mercapto, or sulfo, while these common substituents have the same meaning as the definition of the corresponding group defined in this Description.

[0067] The term "hydrocarbyl" is intended to mean a compound that contains carbon and hydrogen and may be fully saturated, partially unsaturated or aromatic, and includes aryl, alkyl, alkenyl, and alkynyl groups.

[0068] The term "independently" is used herein to indicate that a variable that is independently applied varies independently from application to application.

[0069] The term "lower alkyl" refers to methyl, ethyl or propyl.

[0070] The term "lower alkoxy" refers to methoxy, ethoxy or propoxy.

[0071] Exemplary CLM

[0072] New imide compounds

[0073] In one aspect, the present disclosure provides a CLM useful for binding to and recruiting cereblon. In certain embodiments, the CLM is selected from the group consisting of the following chemical structures: [ka] [ka] (In the formula, In formulas (a1) to (e) [e.g., (a1), (a2), (a3), (a4), (b), (c), (d1), (d2), and (e)], W is CH 2 , O, CHR, C=O, SO 2 , NH, N, optionally substituted cyclopropyl, optionally substituted cyclobutyl, and N-alkyl; W in formulas (a1) to (e) 3 is selected from C or N, X in formulae (a1) to (e) is absent, O, S, or CH 2 are independently selected from the group Y in formulas (a1) to (e) is CH 2 , -C=CR', NH, N-alkyl, N-aryl, N-heteroaryl, N-cycloalkyl, N-heterocyclyl, O, and S; Z in formulae (a1) to (e) is absent, O, and S or CH 2 where X and Z are independently selected from the group 2 or cannot be absent, G and G' in formulae (a1) to (e) are each independently H, optionally substituted linear or branched alkyl, OH, R'OCOOR, R'OCONRR'', CH optionally substituted with R'. 2 -heterocyclyl, and benzyl optionally substituted with R'; Q1 to Q4 in formulae (a1) to (e) represent a carbon C or N substituted with a group independently selected from H, R, N or N-oxide; A in formulae (a1) to (e) is independently selected from the group consisting of H, optionally substituted linear or branched alkyl, cycloalkyl, Cl and F; In formulae (a1) to (e), n represents an integer of 1 to 10 (e.g., 1 to 4, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10); R in formulae (a1) to (e) is, but is not limited to, H, -C(=O)R' (e.g., a carboxy group), -CONR'R'' (e.g., an amide group), -OR' (e.g., OH), -NR'R'' (e.g., an amine group), -SR', -SO 2 R', -SO 2 NR'R'', -CR'R''-, -CR'NR'R''-, (-CR'O) n’R″, optionally substituted heterocyclyl, optionally substituted aryl (e.g., optionally substituted C5-C7 aryl), optionally substituted alkyl-aryl (e.g., alkyl-aryl comprising at least one of optionally substituted C1-C6 alkyl, optionally substituted C5-C7 aryl, or combinations thereof), optionally substituted heteroaryl, optionally substituted alkyl (e.g., optionally substituted with one or more halogen, cycloalkyl (e.g., C3-C6 cycloalkyl), or aryl (e.g., C5-C7 aryl). C1-C6 straight or branched alkyl), optionally substituted alkoxyl groups (e.g., methoxy, ethoxy, butoxy, propoxy, pentoxy, or hexoxy; where the alkoxyl can be substituted with one or more halogen, alkyl, haloalkoxy, fluoroalkyl, cycloalkyl (e.g., C3-C6 cycloalkyl), or aryl (e.g., C5-C7 aryl), optionally substituted cycloalkyl, optionally substituted heterocyclyl, -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 W, X, Y, Z, G, G', R, R', R'', Q1-Q4, or A is modified to covalently bond to a PTM, a chemical linker (L), a ULM, a CLM, or a combination thereof; Each of x, y, and z in formulae (a1) to (e) is independently 0, 1, 2, 3, 4, 5, or 6; R′ and R″ in formulae (a1) through (e) are independently selected from H, optionally substituted linear or branched alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, —C(═O)R, and optionally substituted heterocyclyl; In formulae (a1) to (e), n' is an integer from 1 to 10 (e.g., 1 to 4, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10); [ka] represents a single or double bond, Formulas (a1) to (e) [ka] represents a bond which may be stereospecific ((R) or (S)) or non-stereospecific).

[0074] In any aspect or embodiment described herein, the CLM comprises a chemical structure selected from the group consisting of: [ka] [ka] (In the formula, In formulas (a1) to (e) [e.g., (a1), (a2), (a3), (a4), (b), (c), (d1), (d2), and (e)], W is CH 2 , O, CHR, C=O, SO 2 , NH, N, optionally substituted cyclopropyl, optionally substituted cyclobutyl, and N-alkyl; W in formulas (a1) to (e) 3 is selected from C or N, X in formulae (a1) to (e) is absent, O, S, or CH2 are independently selected from the group Y in formulas (a1) to (e) is CH 2 , -C=CR', NH, N-alkyl, N-aryl, N-hetaryl, N-cycloalkyl, N-heterocyclyl, O, and S; Z in formulae (a1)-(e) is independently selected from the group consisting of O, S or CH2, with the proviso that both X and Z are CH 2 or cannot be absent, G and G' in formulae (a1) to (e) are each independently H, optionally substituted linear or branched alkyl, OH, R'OCOOR, R'OCONRR'', CH optionally substituted with R'. 2 -heterocyclyl, and benzyl optionally substituted with R'; Q1 to Q4 in formulae (a1) to (e) represent a carbon C or N substituted with a group independently selected from H, R, N or N-oxide; A in formulae (a1) to (e) is independently selected from the group consisting of H, optionally substituted linear or branched alkyl, cycloalkyl, Cl and F; In formulae (a1) to (e), n represents an integer of 1 to 10 (e.g., 1 to 4, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10); R in formulae (a1) to (e) is, but is not limited to, H, -C(=O)R' (e.g., a carboxy group), -CONR'R'' (e.g., an amide group), -OR' (e.g., OH), -NR'R'' (e.g., an amine group), -SR', -SOR', -SOR', -SOR'R'', -CR'R''-, -CR'NR'R''-, (-CR'O) n’R″, optionally substituted aryl (e.g., optionally substituted C5-C7 aryl), optionally substituted alkyl-aryl (e.g., alkyl-aryl including at least one of optionally substituted C1-C6 alkyl, optionally substituted C5-C7 aryl, or combinations thereof), optionally substituted hetaryl, optionally substituted straight or branched alkyl (e.g., C1-C6 straight or branched alkyl optionally substituted with one or more halogens, cycloalkyls (e.g., C3-C6 cycloalkyl), or aryls (e.g., C5-C7 aryl)), optionally substituted alkoxyl groups (e.g., methoxy, ethoxy, butoxy, propoxy, pentoxy, or hexoxy; where the alkoxyl is substituted with one or more halogens, alkyls, haloalkoxy, fluoroalkyls, cycloalkyls (e.g., C3-C6 cycloalkyl), or aryls (e.g., C5-C7 aryl). optionally substituted cycloalkyl, optionally substituted heterocyclyl, -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)N R'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 bonded (directly or indirectly, e.g., via a functional group or an atom such as O, S, N, etc.) to a PTM, a chemical linker (L), a ULM, a CLM, or a combination thereof; Each of x, y, and z in formulae (a1) to (e) is independently 0, 1, 2, 3, 4, 5, or 6; R′ and R″ in formulae (a1)-(e) are independently selected from a bond, H, optionally substituted linear or branched alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, —C(═O)R, and optionally substituted heterocyclyl; In formulae (a1) to (e), n' is an integer from 1 to 10 (e.g., 1 to 4, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10); Formulas (a) to (f) [ka] represents a bond which may be stereospecific ((R) or (S)) or non-stereospecific).

[0075] In any aspect or embodiment described herein, the CLM or ULM is selected from the structure of formula (g): [ka] , (In the formula, W in formula (g) is CH 2 , O, C═O, NH, and N-alkyl; A in formula (g) is selected from H, methyl, or optionally substituted linear or branched alkyl; n is an integer from 1 to 4, R in formula (g) is H, O, OH, N, NH, NH 2, -Cl, -F, -Br, -I, methyl, optionally substituted linear or branched alkyl (e.g., optionally substituted linear or branched C1-C6 alkyl), optionally substituted linear or branched alkoxy (e.g., optionally substituted linear or branched C1-C6 alkoxy), -alkyl-aryl (e.g., -alkyl-aryl comprising at least one of C1-C6 alkyl, C4-C7 aryl, or combinations thereof), aryl (e.g., C5-C7 aryl), amine, amide, or carboxy), where at least one R or W is modified to covalently bond to a PTM, a chemical linking group (L), a ULM, a CLM, or combinations thereof; In formula (g), [ka] represents a bond which may be stereospecific ((R) or (S)) or non-stereospecific).

[0076] In any aspect or embodiment described herein, the CLM or ULM is selected from the group consisting of: [ka] (In the formula, W is C=O or CH 2 and N* is a nitrogen atom covalently linked to or shared with a PTM or linker (L) (e.g., a heteroatom shared with an optionally substituted heterosilyl of a linker (L) or a PTM); [ka] indicates the attachment point of the CLM or ULM to the linker (L) or PTM).

[0077] In any aspect or embodiment described herein, R is 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 combinations thereof), aryl (e.g., C5-C7 aryl), amine, amide, or carboxy).

[0078] In any aspect or embodiment described herein, at least one R (e.g., 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 combinations thereof), aryl (e.g., C5-C7 aryl), amine, amide, or carboxy), or W is modified to covalently attach to a PTM, a chemical linker group (L), a ULM, a CLM, or combinations thereof.

[0079] In any aspect or embodiment described herein, W, X, Y, Z, G, G', R, R', R'', Q1-Q4, and A of formulas (a)-(g) can be independently covalently attached to a linker and / or a linker attached to one or more PTM groups, ULM groups, or CLM groups.

[0080] In any of the aspects or embodiments described herein, n on the aryl or heteroaryl of the CLM 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 combinations thereof), aryl (e.g., C5-C7 aryl), amine, amide, or carboxy, optionally one of which is modified to covalently attach to a PTM, a chemical linker group (L), a ULM, a CLM, or combinations thereof.

[0081] More specifically, non-limiting examples of CLMs include those shown below and "hybrid" molecules resulting from a combination of one or more of the various features shown in the molecules below, where at least one R or W is modified to covalently attach to a PTM, a chemical linker (L), a ULM, a CLM, or combinations thereof. [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0082] In any aspect or embodiment described herein, the CLM comprises a chemical structure selected from the following group: [ka] [ka] [ka] [ka] (In the formula, W is CH 2 , O, CHR, C=O, SO 2, NH, N, optionally substituted cyclopropyl groups, optionally substituted cyclobutyl groups, and N-alkyl (e.g., CH 2 , CHR, C=O, SO 2 , NH, and N-alkyl); Q 1 , Q 2 , Q 3 , Q 4 , Q 5 represents a carbon C or N, each independently substituted with a group independently selected from R′, N, or N-oxide; R 1 is selected from absent, H, OH, CN, C1-C3 alkyl, C=O; R 2 is absent, H, OH, CN, C1-C3 alkyl, CHF 2 , C.F. 3 , CHO, C(=O)NH 2 is selected from the group R 3 is selected 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 alkoxyl), substituted alkoxy (e.g., substituted C1-C6 or C1-C3 alkoxyl); R 4 is selected from H, alkyl, and substituted alkyl; R 5 and R 6 are each independently H, halogen, C(=O)R', CN, OH, or CF 3 and X is C, CH, C=O, or N; X 1 is C=O, N, CH, or CH 2 and R' is H, halogen, amine, alkyl (e.g., C1-C3 alkyl), substituted alkyl (e.g., substituted C1-C3 alkyl), alkoxy (e.g., C1-C3 alkoxyl), substituted alkoxy (e.g., substituted C1-C3 alkoxyl), NR 2 R 3 , C(=O)OR2 , optionally substituted phenyl; n is 0 to 4; [ka] is a single or double bond, The CLM is covalently attached to a PTM, a chemical linker group (L), a ULM, a CLM, or a combination thereof.

[0083] In any aspect or embodiment described herein, the CLM may be selected from the group R, R 1 , R 2 , R 3 , R 4 or R', W, X, or Q groups (Q 1 , Q 2 , Q 3 , Q 4 , or Q 5 etc.) to a PTM or chemical linker group (L).

[0084] In any aspect or embodiment described herein, the CLM is selected from the group consisting of W, X, R, R 1 , R 2 , R 3 , R 4 , R 5 , R', Q 1 , Q 2 , Q 3 , Q 4 , and Q 5 is covalently attached to a PTM or chemical linker group (L) via

[0085] 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 can be independently covalently attached to a linker and / or a linker attached to one or more PTM groups, ULM groups, CLM groups.

[0086] More specifically, non-limiting examples of CLMs include those shown below, as well as "hybrid" molecules or compounds that result from combining features of one or more of the following compounds: [ka] [ka] [ka] (In the formula, W is CH 2 , CHR, C=O, SO 2 , NH, and N-alkyl; R 1 is selected from the group consisting of absent, H, CH, CN, C1-C3 alkyl; R 2 is H or C1-C3 alkyl, R 3 is selected from H, alkyl, substituted alkyl, alkoxy, and substituted alkoxy; R 4 is methyl or ethyl, R 5 is H or halo, R 6 is H or halo, n is an integer from 0 to 4, R and R' are independently H, a functional group or atom (e.g., H, halogen (e.g., -Cl or -F), amine, C1-C3 alkyl, C1-C3 alkyl, C1-C3 alkoxyl, NR 2 R 3 , or C(=O)OR 2 ); or a point of attachment for a PTM or chemical linker group (L); Q 1 and Q 2 are each independently C or N substituted with a group independently selected from H or C1-C3 alkyl; [ka] is a single or double bond).

[0087] In any aspect or embodiment described herein, W, R 1 , R 2 , Q 1 , Q 2 , Q 3 , Q 4 , R, and R' can independently be covalently attached to a linker and / or a linker that is attached to one or more PTM groups.

[0088] In any aspect or embodiment described herein, R 1 , R 2 , Q 1 , Q 2 , Q 3 , Q 4 , R, and R' can independently be covalently attached to a linker and / or a linker that is attached to one or more PTM groups.

[0089] In any aspect or embodiment described herein, Q 1 , Q 2 , Q 3 , Q 4 , R, and R' can independently be covalently attached to a linker and / or a linker that is attached to one or more PTM groups.

[0090] As will be readily apparent, in any aspect or embodiment described herein, the R, R′, R″, R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 may be a bond.

[0091] In any aspect or embodiment described herein, R is a bond or is modified to be covalently attached to a linker group (L) or a PTM, or a combination thereof.

[0092] In any aspect or embodiment described herein, the CLM is selected from: [ka] [ka] (Wherein, R' is a halogen and R 1 is as described herein).

[0093] In certain cases, the "CLM" can be an imide that binds to cereblon E3 ligase. These imides and linker attachment points can be, but are not limited to, any of the following structures: [ka] [ka]

[0094] In any aspect or embodiment described herein, the ULM is selected from the group consisting of: [ka] [ka] (In the formula, ULM [ka] indicates the point of attachment to a linker group or PTM, N* is a nitrogen atom shared with a chemical linker group or a PTM; W, Q 4 , and Q 5 are each defined as described in any aspect or embodiment described herein).

[0095] Exemplary Linkers In certain embodiments, the compounds described herein include a PTM chemically linked to a ULM (e.g., a CLM) via a chemical linker (L). In certain embodiments, the linker group L comprises one or more covalently connected structural units (e.g., -A L 1… (A L ) q -or- (A L ) q -), wherein A L 1 is a group attached to the PTM, L ) q is a group attached to ULM.

[0096] In any aspect or embodiment described herein, the linker (L) to a ULM (e.g., CLM) connection is a stable L-ULM connection. For example, in any aspect or embodiment described herein, when the linker (L) and ULM are connected via a heteroatom (e.g., N, O, S), any additional heteroatom, if present, must be at least a carbon atom (e.g., -CH 2 -), for example, an acetal or aminal group. By way of further example, in any aspect or embodiment described herein, when the linker (L) and the ULM are connected via a heteroatom, the heteroatom is not part of an ester.

[0097] In any aspect or embodiment described herein, the linker group L is a bond or a group of 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), where L is covalently attached to both the PTM and ULM and provides conjugation of the PTM to the protein target and the ULM to the E3 ubiquitin ligase to effect ubiquitination of the target protein.

[0098] In any aspect or embodiment described herein, the linker group L is a bond or a group of the formula -(A L ) q -, where A is a chemical moiety, q is an integer between 6 and 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 L is covalently attached to both the PTM and the ULM, providing for linkage of the PTM to the protein target and linkage of the ULM to an E3 ubiquitin ligase in sufficient proximity to effect ubiquitination of the target protein.

[0099] In any aspect or embodiment described herein, the linker group L is -(A L ) q - in which (A L ) q is a group connecting a ULM (e.g., CLM) to a PTM (TTM); The q of the linker is an integer of 1 or more, Each A L is a bond, CR L1 R L2 , O, S, SO, SO 2 , N.R.L3 , S.O. 2 NR L3 ,SONR L3 ,CONR L3 , N.R. L3 CONR L4 , N.R. L3 SO 2 NR L4 , CO, CR L1 =CR L2 , C≡C, SiR L1 R L2 , P(O)R L1 , P(O)OR L1 , N.R. L3 C(=NCN)NR L4 , N.R. L3 C(=NCN), NR L3 C(=CNO 2 )NR L4 , 1 to 6 R L1 Group and / or R L2 C optionally substituted with a group 3-11 Cycloalkyl, 1 to 9 R L1 Group and / or R L2 C optionally substituted with a group 5-13 Spirocycloalkyl, 1 to 6 R L1 Group and / or R L2 C optionally substituted with a group 3-11 Heterocyclyl, 1 to 8 R L1 Group and / or R L2 C optionally substituted with a group 5-13 Spiroheterocyclyl, 1 to 6 R L1 Group and / or R L2 aryl optionally substituted with a group, and 1 to 6 R L1 Group and / or R L2 heteroaryl, optionally substituted with a aryl group, L1 or R L2 each independently represents, optionally linked to other groups, 1 to 4 R L5 forming a cycloalkyl and / or heterocyclyl moiety optionally substituted with a group, R L1 , R L2 , RL3 , R L4 and R L5 are each independently H, halo, or 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 Heterocyclyl, 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.C.-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 , C.H. 2 F, NO 2 ,SCIENCE FICTION 5 , S.O. 2 NHC 1-8 Alkyl, SO 2 N(C 1-8 Alkyl) 2 ,SONHC1-8 Alkyl, SON(C 1-8 Alkyl) 2 , CONH.C. 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 , N.H.C.O.N. 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 , NHSO 2 NH(C 1-8 alkyl), NH SO 2 N(C 1-8 Alkyl) 2 , or NHSO 2 NH 2 It is.

[0100] In certain embodiments, q is an integer of 1 or greater.

[0101] In any aspect or embodiment described herein, for example, when the linker q is greater than 2, (A L ) q A L 1 and (A L ) q and the linker is a group that attaches the PTM to the ULM.

[0102] In any aspect or embodiment described herein, for example, when q of the linker is 2, A L 2 A L 1 and a group connecting to ULM.

[0103] In any aspect or embodiment described herein, for example, when the linker q is 1, the structure of the linker group L is -A L 1 - and A L 1 is the group connecting the ULM moiety to the PTM moiety.

[0104] In any aspect or embodiment described herein, A of the linker (L) L The units include groups represented by a general structure selected from the group consisting of: -NR(CH 2 ) n -(lower alkyl)-, -NR(CH 2 ) n -(lower alkoxyl)-, -NR(CH 2 ) n -(lower alkoxy)-OCH 2 -, -NR(CH 2 ) n -(lower alkoxyl)-(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 2O) n -(cycloalkyl)-O-(heteroaryl)-O-CH 2 -, -NR(CH 2 CH 2 O) n -(cycloalkyl)-O-aryl-O-CH 2 -, -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-(heterocyclyl)-CH 2、 -NR(CH 2 CH 2 ) n -(heterocyclyl)-(heterocyclyl)-CH 2 and -N(R1R2)-(heterocyclyl)-CH 2 (In the formula, n of the linker can be 0 to 10; R of the linker can be H or lower alkyl; The linkers R1 and R2 can form a ring together with the N to which they are connected).

[0105] In any aspect or embodiment described herein, the linker (L) is an optionally substituted C 1 -C 50 Alkyl (e.g., C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C7 ,W 8 ,W 9 ,W 10 ,W 11 ,W 12 ,W 13 ,W 14 ,W 15 ,W 16 ,W 17 ,W 18 ,W 19 ,W 20 ,W 21 ,W 22 ,W 23 ,W 24 ,W 25 ,W 26 ,W 27 ,W 28 ,W 29 ,W 30 ,W 31 ,W 32 ,W 33 ,W 34 ,W 35 ,W 36 ,W 37 ,W 38 ,W 39 ,W 40 ,W 41 ,W 42 ,W 43 ,W 44 ,W 45 ,W 46 ,W 47 ,W 48 ,W 49 、またはC 50alkyl, and all suggested subranges, e.g., C1-C10, C1-C20; C2-C10, C2-20; C10-C20, C10-C50, etc.), where each carbon is optionally independently substituted or replaced with (1) a heteroatom selected from N, O, S, P, or Si atoms, with the appropriate number of hydrogens, substitutions, or both to satisfy the valences, (2) an optionally substituted cycloalkyl or bicyclic cycloalkyl, (3) an optionally substituted heterocycloalkyl or bicyclic heterocycloalkyl, (4) an optionally substituted aryl or bicyclic aryl, or (5) an optionally substituted heteroaryl or bicyclic heteroaryl. In any aspect or embodiment described herein, the linker (L) does not have interheteroatom bonds (e.g., the heteroatoms are not covalently linked or adjacently positioned).

[0106] In any aspect or embodiment described herein, the linker (L) 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 50 alkyl), where Each carbon may optionally independently be selected from the group consisting of CR L1 R L2 , O, S, SO, SO 2 , N.R. L3 , S.O. 2 NR L3 ,SONR L3 ,CONR L3 , N.R. L3 CONR L4 , N.R. L3 SO 2 NR L4 , CO, CR L1 =CR L2 , C≡C, SiR L1 R L2 , P(O)R L1 , P(O)OR L1 , N.R. L3 C(=NCN)NR L4 , N.R. L3 C(=NCN), NR L3 C(=CNO 2 )NR L4 , 1 to 6 R L1 Group and / or R L2 C optionally substituted with a group 3-11 Cycloalkyl, 1 to 9 R L1 Group and / or R L2 C optionally substituted with a group 5-13 Spirocycloalkyl, 1 to 6 R L1 Group and / or R L2 C optionally substituted with a group 3-11Heterocyclyl, 1 to 8 R L1 Group and / or R L2 C optionally substituted with a group 5-13 Spiroheterocyclyl, 1 to 6 R L1 Group and / or R L2 aryl optionally substituted with a group, or 0 to 6 R L1 Group and / or R L2 substituted or substituted with heteroaryl optionally substituted with a group, wherein R L1 or R L2 each independently represents, optionally linked to other groups, 1 to 4 R L5 forming a cycloalkyl and / or heterocyclyl moiety optionally substituted with a group, R L1 , R L2 , R L3 , R L4 and R L5 are each independently H, halo, or 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 Heterocyclyl, 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.C.-C. 1-8 Alkyl, CCH, CH=CH(C 1-8 alkyl), C(C 1-8 Alkyl)=CH(C1-8 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 , C.H. 2 F, NO 2 ,SCIENCE FICTION 5 , S.O. 2 NHC 1-8 Alkyl, SO 2 N(C 1-8 Alkyl) 2 ,SONHC 1-8 Alkyl, SON(C 1-8 Alkyl) 2 , CONH.C. 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 , N.H.C.O.N. 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 , NHSO 2 NH(C 1-8 alkyl), NH SO 2 N(C 1-8 Alkyl) 2 , or NHSO 2 NH 2 It is.

[0107] In any aspect or embodiment described herein, the linker group may optionally be 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 50substituted with alkyl, and all suggested subranges, e.g., C1-C10, C1-C20; C2-C10, C2-20; C10-C20, C10-C50, etc.), where each carbon atom is optionally substituted with an O, N, S, P, or Si atom having the appropriate number of hydrogen, substitutions (e.g., OH, halo, alkyl, methyl, ethyl, haloalkyl, hydroxyalkyl, alkoxy, methoxy, etc.), or both, to satisfy the valence; optionally substituted aryl (e.g., optionally substituted C optionally substituted C5 or C6 heteroaryl) or bicyclic heteroaryl (e.g., an optionally substituted C5-C20 bicyclic heteroaryl); optionally substituted heteroaryl (e.g., an optionally substituted C5 or C6 heteroaryl) or bicyclic heteroaryl (e.g., one selected from N, O, S, P, and Si with an appropriate number of hydrogens, substitutions (e.g., OH, halo, alkyl, methyl, ethyl, haloalkyl, hydroxyalkyl, alkoxy, methoxy, etc.), or both to satisfy valences; optionally substituted C-C alkyl; optionally substituted C-C alkenyl; optionally substituted C-C alkynyl; optionally substituted cycloalkyl (e.g., optionally substituted C-C cycloalkyl) or bicyclic cycloalkyl (e.g., optionally substituted C-C bicyclic cycloalkyl); or optionally substituted heterocycloalkyl (e.g., an optionally substituted 3-, 4-, 5-, 6-, or 7-membered heterocyclic group) or bicyclic heteroalkyl (e.g., an optionally substituted heterocycloalkyl bicyclic heteroalkyl having one or more heteroatoms selected from N, O, S, P, or Si atoms with an appropriate number of hydrogen, substitutions (e.g., OH, halo, alkyl, methyl, ethyl, haloalkyl, hydroxyalkyl, alkoxy, methoxy, etc.), or both to satisfy valences).In any aspect or embodiment described herein, the optionally substituted alkyl linker is optionally substituted with one or more OH, halo, straight or branched chain C1-C6 alkyl (such as methyl or ethyl), straight or branched chain C1-C6 haloalkyl, straight or branched chain C1-C6 hydroxyalkyl, or straight or branched chain C1-C6 alkoxy (e.g., methoxy).

[0108] In any aspect or embodiment described herein, the linker (L) has no inter-heteroatom bonds (e.g., the heteroatoms are not covalently linked or adjacently positioned).

[0109] In any aspect or embodiment described herein, the linker (L) comprises 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 carbon or oxygen may be substituted with a heteroatom selected from N, S, P, or Si atoms, including the appropriate number of hydrogens to satisfy valences.

[0110] In any aspect or embodiment described herein, A of the linker (L) L The units include a structure selected from the group consisting of: [ka] [ka] [ka] [ka] [ka] (wherein N* is a nitrogen atom covalently linked to or shared with a ULM or PTM).

[0111] In any aspect or embodiment described herein, A of the linker (L) L The units include a structure selected from the group consisting of: [ka] [ka] [ka] [ka] (In the formula, N* is a nitrogen atom covalently linked to or shared with a ULM or PTM; Each 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.

[0112] In any aspect or embodiment described herein, A of the linker (L) L The units are selected from the following: [ka] [ka] [ka] [ka] [ka] (wherein N* is a nitrogen atom covalently linked to or shared with a ULM or PTM).

[0113] In any aspect or embodiment described herein, A of the linker (L) L The units include groups represented by a general structure selected from the group consisting of: [ka] (In the formula, the linker's m, n, o, p, q, and r are independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; When m, n, o, p, q, and r are zero, the NO or OO bond is absent; X in the linker is H or F. [ka] [ka] [ka] [ka] [ka] wherein each n and m of the linker can independently be 0, 1, 2, 3, 4, 5, or 6.

[0114] In any aspect or embodiment described herein, A of the linker (L) L The units are selected from the group consisting of: [ka] [ka] wherein each m and n is independently selected from 0, 1, 2, 3, 4, 5, or 6.

[0115] In any aspect or embodiment described herein, A of the linker (L) L The units are selected from the group consisting of: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] wherein 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.

[0116] In any aspect or embodiment described herein, A of the linker (L) L The units are selected from the group consisting of: [ka] [ka] [ka] [ka] [ka]

[0117] In any aspect or embodiment described herein, the linker (L) comprises a structure selected from the structures shown below: [ka] (In the formula, W L1 and W L2 are each independently an absent or 4-8 membered ring containing 0-4 heteroatoms, and these are R Q and each R Q are independently H, halo, OH, CN, CF 3 , optionally substituted straight or branched chain C 1 -C 6 Alkyl, optionally substituted straight or branched chain C 1 -C 6 Alkoxy, or two R Qgroups formed together with the atom to which they are attached are 4-8 membered ring systems containing 0-4 heteroatoms; Y L1 each independently represents a bond, an optionally substituted straight or branched chain C 1 -C 6 Alkyl and optionally one or more C atoms are O or NR YL1 Replaced by, optionally replaced by C 1 -C 6 Alkenes and optionally one or more C atoms replaced by O, optionally substituted C 1 -C 6 Alkynes and optionally one or more C atoms replaced by O or optionally substituted linear or branched C 1 -C 6 is an alkoxy; R YL1 is H or optionally substituted straight or branched chain C 1-6 is alkyl, n is 0 to 10; [ka] indicates the attachment point to PTM or ULM).

[0118] In any aspect or embodiment described herein, the linker (L) comprises a structure selected from the structures shown below: [ka] (In the formula, W L1 and W L2 are each independently absent, piperazine, piperidine, or morpholine, and R Q and each R Q are independently H, -Cl-, -F-, OH, CN, CF 3 , optionally substituted linear or branched C 1 -C 6Alkyl (e.g., methyl, ethyl), optionally substituted straight or branched chain C 1 -C 6 alkoxy (e.g., methoxy, ethoxy); Y L1 each independently represents a bond, an optionally substituted straight or branched chain C 1 -C 6 Alkyl and optionally one or more C atoms are O or NR YL1 Replaced by, optionally replaced by C 1 -C 6 Alkenes and optionally one or more C atoms replaced by O, optionally substituted C 1 -C 6 Alkynes and optionally one or more C atoms replaced by O or optionally substituted linear or branched C 1 -C 6 is an alkoxy; R YL1 is H or optionally substituted straight or branched chain C 1-6 alkyl (e.g., methyl, ethyl); n is 0 to 10; [ka] indicates the attachment point to PTM or ULM).

[0119] In any aspect or embodiment described herein, the linker (L) comprises a structure selected from the structures shown below: [ka] (In the formula, W L1 and W L2 are each independently absent, aryl, heteroaryl, a ring, a heterocycle, C 1-6 Alkyl and optionally one or more C atoms are O or NR YL1 Replaced by, C 1-6Alkenes, optionally with one or more C atoms replaced by O, C 1-6 alkynes and optionally one or more C atoms replaced by O, bicyclic, biaryl, biheteroaryl, or biheterocyclic rings, each of which is represented by R Q and each R Q H, halo, OH, CN, CF 3 , Hydroxyl, Nitro, C≡CH, C 2-6 Alkenyl, C 2-6 Alkynyl, optionally substituted straight or branched chain C 1 -C 6 Alkyl, optionally substituted straight or branched chain C 1 -C 6 Alkoxy, optionally substituted OC 1-3 Alkyl (e.g., optionally substituted with one or more -F), OH, NH 2 , N.R. Y1 R Y2 , CN, or two R Q groups formed together with the atom to which they are attached are 4-8 membered ring systems containing 0-4 heteroatoms; Y L1 each independently represents a bond, NR YL1 ,O.S.,NR. YL2 , C.R. YL1 R YL2 , C=O, C=S, SO, SO 2 , optionally substituted linear or branched C 1 -C 6 Alkyl and optionally one or more C atoms replaced by O; optionally substituted linear or branched C 1 -C 6 is an alkoxy; Q L is a 3-6 membered alicyclic, bicyclic or aromatic ring containing 0-4 heteroatoms, which is optionally bridged and has 0-6 R Q and each R Q are independently H, optionally substituted straight or branched chain C 1-6Alkyl (e.g., optionally substituted with one or more halo, C 1-6 alkoxyl), or two R Q groups formed together with the atom to which they are attached are 3-8 membered ring systems containing 0-2 heteroatoms; R YL1 , R YL2 each independently represents H, OH, optionally substituted straight or branched chain C 1-6 Alkyl (e.g., optionally substituted with one or more halo, C 1-6 alkoxyl), or R 1 , R 2 are taken together with the atom to which they are attached to form a 3-8 membered ring system containing 0-2 heteroatoms; n is 0 to 10; [ka] indicates the attachment point to PTM or ULM).

[0120] In any aspect or embodiment described herein, the linker (L) comprises a structure selected from the structures shown below: [ka] (In the formula, 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 O or NR YL1 Replaced by, C 1-6 Alkenes, optionally with one or more C atoms replaced by O, C 1-6 Alkenes, optionally with one or more C atoms replaced by O, or C 1-6 Alkynes and optionally one or more C atoms replaced by O, each of which is R Q and each R Qare independently H, -Cl, -F, OH, CN, CF 3 , hydroxyl, optionally substituted straight or branched chain C 1 -C 6 Alkyl (e.g., methyl, ethyl) or optionally substituted straight or branched chain C 1 -C 6 is an alkoxy; Y L1 each independently represents a bond, NR YL1 , O., C.R. YL1 R YL2 , C=O, optionally substituted straight or branched chain C 1 -C 6 Alkyl and optionally one or more C atoms are O or NR YL1 Replaced by, C 1-6 Alkenes, optionally with one or more C atoms replaced by O, C 1-6 Alkynes and optionally one or more C atoms replaced by O or optionally substituted linear or branched C 1 -C 6 is an alkoxy; Q L is a 3-6 membered heterocyclic, heterobicyclic, or heteroaryl ring; Q and each R Q are independently H or optionally substituted straight or branched chain C 1-6 Alkyl (e.g., optionally substituted with one or more halo, C 1-6 alkoxyl), R YL1 , R YL2 each independently represents H, optionally substituted straight or branched chain C 1-6 Alkyl (e.g., methyl, ethyl, optionally substituted with one or more halo, C 1-6 alkoxyl), n is 0 to 10; [ka] indicates the attachment point to PTM or ULM).

[0121] Exemplary PTMs In one embodiment of the present disclosure, the PTM group (also referred to as an LTM group) binds to a target protein, LRRK2 or a mutated form thereof.

[0122] The compositions described below are illustrative of members of the LRRK2 binding moieties that can be used in accordance with the present invention. These binding moieties are linked, preferably via a chemical linking group, to a ubiquitin ligase binding moiety (CLM) to present the LRRK2 protein (to which the LTM binds) in proximity to the ubiquitin ligase for ubiquitination and subsequent degradation.

[0123] In certain contexts, the term "target protein" is used to refer to the LRRK2 protein, a member of the leucine-rich repeat kinase family, which is a target protein to be ubiquitinated and degraded. In other contexts, the term "target protein" is used to refer to mutant forms 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.

[0124] The term "protein targeting moiety" or PTM is used to describe a small molecule that binds to LRRK2 or a mutant form thereof, and can be used to target the protein for ubiquitination and degradation.

[0125] The compositions described herein exemplify the uses of some of these PTMs.

[0126] 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 the chemical structure PTM-IA or PTM-IB: [ka] (In the formula, R 1 is a straight or branched chain 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 [ka] (wherein the dashed line is the point of attachment of the PTM to M), a straight or branched C1-C6 haloalkyl (e.g., a straight or branched C1-C4 haloalkyl), an optionally substituted C3-C6 halocycloalkyl (e.g., a C3-C5 halocycloalkyl), an optionally substituted alkylnitrile (e.g., a C1-C4 alkylnitrile), an optionally substituted C3-C6 cyclonitrile (e.g., a C3-C5 cyclonitrile); R 2 is selected from hydrogen, halogen (e.g., F, Cl, or Br), C1-C3 alkyl, or C1-C3 fluoroalkyl; X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , and X 7 are each independently C, CH, or N, where X 1 , X 2 , and X 3 are CH, R 2 Optionally replaced by X 8 is CH, S, or N; M is CH 2 , NH, or O; [ka] is an optionally substituted 3-10 membered cycloalkyl or heterocycloalkyl (e.g., optionally substituted with one or more (e.g., 1, 2, 3, or 4) substituents) containing 1-4 (e.g., 1, 2, 3, or 4) heteroatoms selected from N, O, and S; PTM [ka] indicates the point of attachment to the linker (L) or ULM).

[0127] In any aspect or embodiment described herein, the PTMs are represented by chemical structures PTM-IIA, PTM-IIB, PTM-IIIA, and PTM-IIIB. [ka] (In the formula, R 1 is a straight or branched chain 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 [ka] (wherein the dashed line is the point of attachment to M or the oxygen atom of the PTM), a straight or branched chain C1-C6 haloalkyl (e.g., a straight or branched chain C1-C4 haloalkyl), an optionally substituted C3-C6 halocycloalkyl (e.g., a C3-C5 halocycloalkyl), an optionally substituted alkylnitrile (e.g., a C1-C4 alkylnitrile), an optionally substituted C3-C6 cyclonitrile (e.g., a C3-C5 cyclonitrile); R 2 is hydrogen, halogen (e.g., F, Cl, or Br), C1-C3 alkyl, or C1-C3 fluoroalkyl; X 4 is CH or N, M is CH2 , NH, or O; [ka] is an optionally substituted 3-10 membered heterocycloalkyl (e.g., optionally substituted with one or more (e.g., 1, 2, 3, or 4) substitutions) containing 1-4 (e.g., 1, 2, 3, or 4) heteroatoms selected from N, O, and S; PTM [ka] indicates the chemical linker group or point of attachment to ULM).

[0128] In any aspect or embodiment described herein, [ka] contains 1 to 4 substituents, each independently being halogen, OH, NH 2 , N(C1-C3 alkyl) 2 , straight or branched chain C1-C4 alkyl (e.g., methyl or ethyl), straight or branched chain C1-C4 hydroxyalkyl, straight or branched chain C1-C4 alkoxy, and straight or branched chain C1-C4 haloalkyl).

[0129] In any aspect or embodiment described herein, the PTM is [ka] is covalently linked to L or ULM via an atom or substituent of the heterocycloalkyl of.

[0130] In any aspect or embodiment described herein, [ka] is a 4-7 membered (e.g., 4, 5, 6, or 7 membered) cycloalkyl or heterocycloalkyl containing 1-4 (e.g., 1, 2, 3, or 4) heteroatoms selected from N, O, and S, which are optionally substituted with one or more (e.g., 1, 2, 3, or 4) substituents, each independently selected from halogen, OH, NH 2 , N(C1-C3 alkyl) 2 , straight or branched chain C1-C4 alkyl, straight or branched chain C1-C4 hydroxyalkyl, straight or branched chain C1-C4 alkoxy, and straight or branched chain C1-C4 haloalkyl.

[0131] In any aspect or embodiment described herein, [ka] is a 4-7 membered (e.g., 5 or 6 membered) cycloalkyl or heterocycloalkyl containing 1-4 (e.g., 1, 2, 3, or 4) heteroatoms selected from N, O, and S, the ring being optionally substituted with one or more (e.g., 1, 2, 3, or 4) substituents each independently selected from straight or branched chain C1-C3 alkyl (e.g., methyl), straight or branched chain C1-C3 alkoxy (e.g., methoxy), and straight or branched chain C1-C3 haloalkyl.

[0132] In any aspect or embodiment described herein, [ka] is: [ka] (In the formula, R 3 and R 4 are each independently H, halogen, OH, or NH 2 , N(C1-C3 alkyl) 2, linear or branched C1-C4 alkyl, linear or branched C1-C4 hydroxyalkyl, linear or branched C1-C4 alkoxy, and linear or branched C1-C4 haloalkyl; [ka] teeth, [ka] (i.e., the point of attachment of the PTM to the 6-membered heteroaryl); [ka] indicates the attachment point of PTM to L or ULM, and if not present, [ka] represents an atom (e.g., carbon or nitrogen) of a 6-membered heterocycloalkyl, R 3 , or R 4 (which may be linked to L or ULM via

[0133] In any aspect or embodiment described herein, including but not limited to, in the preceding or following paragraphs: [ka] teeth, [ka] In any aspect or embodiment described herein, including but not limited to, in the preceding paragraph: [ka] teeth, [ka] In any aspect or embodiment described herein, including but not limited to, in the preceding paragraph: [ka] teeth, [ka] It is. In any aspect or embodiment described herein, including but not limited to, in the preceding paragraph: [ka] teeth, [ka] In any aspect or embodiment described herein, including but not limited to, in the preceding paragraph: [ka] teeth, [ka] It is.

[0134] In any aspect or embodiment described herein, [ka] is: [ka] (In the formula, R 3 is H or a straight or branched C1-C3 alkyl (e.g., methyl or ethyl); R 4 is H or a straight or branched C1-C3 alkyl (e.g., methyl or ethyl); [ka] teeth, [ka] (i.e., the point of attachment of the PTM to the 6-membered heteroaryl); [ka] indicates the attachment point of PTM to L or ULM, and if not present, [ka] represents an atom of a 6-membered heterocycloalkyl (e.g., a carbon or nitrogen of a 6-membered heterocycloalkyl), R 3 , or R 4 (which may be linked to L or ULM via

[0135] In any aspect or embodiment described herein, [ka] is selected from: [ka] [ka] (In the formula, R 3 and R 4 is defined as set forth in any aspect or embodiment described herein).

[0136] In any aspect or embodiment described herein, [ka] is selected from: [ka] [ka] (In the formula, R 3 and R 4is defined as set forth in any aspect or embodiment described herein; Heterocycloalkyl can be any atom or any substituent of heterocycloalkyl, such as R 3 , R 4 , or methyl group) to L or PTM).

[0137] In any aspect or embodiment described herein, the PTM has the following chemical structure: [ka] (In the formula, X 4 , R 1 , R 2 , R 3 and R 4 is defined as set forth in any aspect or embodiment described herein; PTM is an atom of the heterocycloalkyl A (e.g., a carbon or nitrogen of a heterocycloalkyl), R 3 , or R 4 (connected to L or ULM via

[0138] In any aspect or embodiment described herein, the PTM has the following chemical structure: [ka] (In the formula, X 4 , R 1 , R 2 , R 3 and R 4 is defined as set forth in any aspect or embodiment described herein; PTM [ka] indicates the point of attachment to L or ULM).

[0139] In any aspect or embodiment described herein, R1 is selected from optionally substituted C3-C5 cycloalkyl and straight or branched C1-C4 alkyl.

[0140] In any aspect or embodiment described herein, R 1 teeth, [ka] where R 1a , R 1b , and R 1C are each independently H or a straight or branched chain C1-C2 alkyl, each optionally substituted with one or more halogen or nitrile groups, or R 1a or R 1b together with the carbons to which they are attached form a C3-C6 cycloalkyl optionally substituted with one or more C1-C3 alkyl, nitrile groups, or halogens.

[0141] In any aspect or embodiment described herein, R 1 teeth, [ka] where R 1a , R 1b , and R 1C are each independently H or a straight or branched C1-C2 alkyl group, or R 1a or R 1b together with the carbons to which they are attached form a C3-C6 cycloalkyl.

[0142] In any aspect or embodiment described herein, the PTM is selected from: [ka] , (In the formula, X, R 1a , R 1b , R 1c , R3 , R 4 , and [ka] each of which is defined as set forth in any aspect or embodiment described herein; L or ULM is an atom of the heterocycloalkyl A (e.g., a carbon or nitrogen of the heterocycloalkyl), R 3 , or R 4 (connected via ).

[0143] In any aspect or embodiment described herein, the PTM is selected from: [ka] (In the formula, X 4 , R 1a , R 1b , R 1c , R 3 , and R 4 each of which is defined as set forth in any aspect or embodiment described herein; PTM [ka] indicates the point of attachment to L or ULM, and when absent.

[0144] In any aspect or embodiment described herein, R 1 teeth, [ka] where the dashed line is the point of attachment to the M or oxygen atom of the PTM.

[0145] In any aspect or embodiment described herein, R 2 is H or F.

[0146] In any aspect or embodiment described herein, the PTM has the following chemical structure: [ka] [ka] [ka] (Wherein, PTM [ka] indicates the chemical linker group or point of attachment to ULM).

[0147] In any embodiment of the aspects described herein, the PTM has the following chemical structure: [ka] [ka] where PTM is covalently linked to L or ULM via an atom of heterocycloalkyl A or a substituent thereof.

[0148] In any aspect or embodiment described herein, the PTM has the following chemical structure: [ka] [ka] [ka] (In the formula, [ka] indicates the point of attachment to L or ULM).

[0149] therapeutic composition The present invention further provides pharmaceutical compositions comprising a therapeutically effective amount of at least one bifunctional compound described herein in combination with a pharma- ceutically acceptable carrier, excipient or vehicle.

[0150] In a further aspect, the present disclosure provides a therapeutic composition comprising an effective amount of a compound described herein or a salt form thereof, a pharma- ceutically acceptable carrier, additive or excipient, and optionally an additional bioactive agent. The therapeutic composition provides targeted protein degradation in a patient or subject, e.g., an animal, such as a human, and can be used to treat or alleviate a disease state or condition regulated by the degradation of the targeted protein. In certain embodiments, the therapeutic composition described herein can be used to provide protein degradation for the treatment or alleviation of LRRK2-mediated inflammatory disease, autoimmune disease, or cancer. In certain additional embodiments, the disease is idiopathic PD, LRRK2 mutation-associated PD (e.g., PD associated with one or more LRRK2 activating mutations), primary tauopathy (e.g., supranuclear palsy (PSP) or corticobasal degeneration (CBD)), Lewy body dementia, Crohn's disease, leprosy (e.g., leprosy with type 1 inflammatory response), and / or neuroinflammation.

[0151] In an alternative aspect, the disclosure provides a method for treating a pathology or alleviating one or more symptoms of a disease or condition in a subject in need thereof by degrading an LRRK2 protein (e.g., a wild-type LRRK2 protein or an LRRK2 mutant protein (e.g., an LRRK2 mutant protein comprising one or more mutations selected from G2019S, I2020T, N1437H, R1441G / C / H, and Y1699C), comprising administering to the patient or subject an effective amount, e.g., a therapeutically effective amount, of at least one compound described herein, optionally in combination with a pharma- ceutically acceptable carrier, excipient, or vehicle, optionally co-administered with an additional bioactive agent, wherein the composition is adapted to treat the disease or disorder of the subject or one or more symptoms thereof. The present disclosure relates to a method that is effective in treating or alleviating a condition, comprising administering an effective amount of at least one compound described herein. The method according to the present disclosure can be used to treat certain disease states, conditions or symptoms, including inflammatory diseases, autoimmune diseases, or cancer. For example, the method according to the present disclosure can be used to treat one or more of Parkinson's disease (PD), idiopathic PD, LRRK2 mutation-associated PD (e.g., PD associated with one or more LRRK2 activating mutations), primary tauopathy (e.g., supranuclear palsy (PSP) or corticobasal degeneration (CBD)), Lewy body dementia, Crohn's disease, leprosy (e.g., leprosy with type 1 inflammatory response), and neuroinflammation (such as observed in Alzheimer's disease, PD, multiple sclerosis, traumatic brain injury, spinal cord injury, etc.).

[0152] The present disclosure further includes pharmaceutical compositions comprising pharma- ceutically acceptable salts of the compounds described herein, particularly acid or base addition salts.The acids used to prepare the pharma- ceutically acceptable acid addition salts of the compounds described above that are useful according to this embodiment are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, hydrogen sulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e., 1,1'-methylene-bis-(2-hydroxy-3 naphthoate)] salts, among many others.

[0153] Pharmaceutically acceptable base addition salts can also be used to generate pharma-ceutically acceptable salt forms of the compounds according to the present disclosure. Chemical bases that can be used as reagents to prepare pharma-ceutically acceptable base salts of the compounds are those that form non-toxic base salts with the compounds. Such non-toxic base salts include, but are not limited to, those derived from such pharmacologically 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 pharma-ceutically acceptable lower alkanolammonium and other base salts of organic amines.

[0154] The compounds described herein may be administered in single or divided doses by oral, parenteral or topical routes in accordance with the present disclosure. Administration of the active compounds may range from continuous administration (intravenous drip) to multiple oral doses per day (e.g., QID) and may include oral, topical, parenteral, intramuscular, intravenous, subcutaneous transdermal (which may include a penetration enhancer), buccal, sublingual, intranasal, intraocular, intrathecal, vaginal, and suppository administration, among other routes of administration. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. Enteric coated oral tablets may also be used to improve the bioavailability of the compounds from oral routes of administration. The most effective dosage form will depend on the pharmacokinetics of the particular agent selected, as well as the type, site, and severity of the disease, condition, or symptom, and the health status of the patient. Administration of the compounds according to the present disclosure as sprays, mist or aerosols for nasal, intratracheal or pulmonary administration may also be used.Therefore, the present disclosure also relates to pharmaceutical compositions comprising an effective amount of the compounds described herein, optionally in combination with pharma-ceutically acceptable carriers, additives or excipients.The compounds according to the present disclosure may be administered in immediate release, intermediate release, or sustained or controlled release forms.The sustained or controlled release forms are preferably administered orally, but may also be suppositories and transdermal or other topical forms.Intramuscular injection in liposomal form or depot formulation may also be used to control or sustain the release of the compounds at the injection site.

[0155] The compositions described herein can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers, and can be administered in controlled release formulations.The pharmaceutically acceptable carriers that can be used in these pharmaceutical compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as prolamin sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose syrup, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, wax, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat, and combinations thereof.

[0156] Sterile injectable forms of the compositions described herein may be aqueous or oily suspensions. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, such as 1,3-butanediol solutions. Acceptable vehicles and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any non-irritating fixed oil may be used, including synthetic mono- or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectable preparations, as are natural pharma-ceutically acceptable oils such as olive oil or castor oil, especially their polyoxyethylated forms. These oily solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as Ph.Helv or similar alcohols.

[0157] The pharmaceutical compositions described herein may be orally administered in any orally acceptable dosage form, including, but not limited to, capsules, tablets, aqueous suspensions or liquids.For oral tablets, commonly used carriers include lactose and corn starch, among others known in the art.For oral administration in capsules, useful diluents include lactose and corn starch.When oral aqueous suspensions are required, the active ingredient may be combined with emulsifying and suspending agents.Also, if desired, some sweeteners, flavorings or colorings may be added.Lubricants such as magnesium stearate are also typically added.

[0158] Alternatively, the pharmaceutical compositions described herein can be administered in the form of suppositories for rectal administration. These can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, thereby melting in the rectum and releasing the drug. Such materials include cocoa butter, beeswax, and polyethylene glycols.

[0159] The pharmaceutical composition described herein may be administered locally.For topical application, the pharmaceutical composition can be formulated into a transdermal patch, and can be either a reservoir patch or a matrix patch that contains active compound in combination with one or more carriers, buffers, absorption enhancers, and provides continuous administration for 1 day to 2 weeks.

[0160] Alternatively, the pharmaceutical composition of the present disclosure can be formulated into a suitable ointment, which contains the active ingredient suspended or dispersed in one or more carriers.The carrier for topical administration of the compound of the present disclosure includes but is not limited to mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.

[0161] Alternatively, the pharmaceutical compositions of the present disclosure can be formulated into a suitable lotion or cream containing the active ingredient suspended or dispersed in one or more pharma- ceutically acceptable carriers, including, but not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl aryl, 2-octyldodecanol, benzyl alcohol and water.

[0162] Alternatively, the pharmaceutical composition of the present disclosure can be formulated for ophthalmic use.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 preservatives such as benzylalkonium chloride.Alternatively, for ophthalmic use, the pharmaceutical composition can be formulated into an ointment such as petrolatum.

[0163] The pharmaceutical compositions described herein can also be administered by nasal aerosol or inhalation.Such compositions can be prepared according to the techniques well known in the art of pharmaceutical formulations, and can be prepared as a solution in saline, utilizing benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0164] The amount of active pharmaceutical ingredient in the pharmaceutical compositions described herein that can be combined with a carrier material to produce a single dosage form will vary depending on the condition of the subject, and the disease, condition or symptom being treated, the particular mode of administration, and the condition of the subject. Preferably, the compositions should be formulated to contain about 0.05 milligrams to about 750 milligrams or more, more preferably about 1 milligram to about 600 milligrams, and even more preferably about 10 milligrams to about 500 milligrams of active ingredient, alone or in combination with another compound according to the present disclosure.

[0165] It is also to be understood that the specific dosage and treatment regimen for any particular patient will vary depending on a variety of factors, including the activity and bioavailability of the particular compound employed, age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease or condition being treated.

[0166] A patient or subject in need of therapy using 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, depending on its pharma- ceutically acceptable salt or solvate, optionally in a pharma- ceutically acceptable carrier or diluent, either alone or in combination with another known therapeutic agent.

[0167] In certain embodiments, the active compound is combined with a pharma- ceutically acceptable carrier or diluent in an amount sufficient to deliver to the patient a therapeutically effective amount for the desired indication without causing undue serious toxic effects to the patient being treated. Preferred doses of the active compound for all of the conditions mentioned herein are 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, more commonly 0.5 to about 25 mg per kilogram of recipient / patient body weight per day. Typical topical dosages will be in the range of 0.01 to 5% wt / wt in a suitable carrier.

[0168] In certain embodiments, the compounds are conveniently administered in any suitable unit dosage form, for example, but not limited to, a dosage form containing less than 1 milligram (mg), between 1 mg and 3000 mg, or between 5 mg and 500 mg of active ingredient per unit dosage form. In many cases, an oral dosage of about 25 mg to 250 mg is convenient.

[0169] In certain embodiments, the active ingredient is preferably administered 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 aqueous media, or by administration as a bolus of the active ingredient. Oral administration can also be suitable to provide effective plasma concentrations of the active agent.

[0170] The concentration of the active compound in the drug composition depends on the absorption, distribution, inactivation, and excretion rate of the drug, as well as other factors known to those skilled in the art. It should also be noted that the dosage value will also vary with the severity of the condition to be alleviated. For any particular subject, the specific dosage regimen should be adjusted over time according to the individual need and the professional judgment of the person administering or directing the administration of the composition, and it should further be understood that the concentration ranges described herein are merely exemplary and are not intended to limit the scope or practice of the claimed compositions. The active ingredient may be administered at once or may be divided into several smaller doses to be administered at various time intervals.

[0171] Oral compositions generally include an inert diluent or an edible carrier. Oral compositions may be enclosed in gelatin capsules or compressed into tablets. To administer oral therapeutics, the active compound or its prodrug derivatives may be incorporated with excipients and used in the form of tablets, troches, or capsules. Pharmaceutically compatible binding agents, and / or adjuvant materials may be included as part of the composition.

[0172] Tablets, pills, capsules, lozenges, etc. can contain any of the following ingredients, or compounds of similar nature: binders such as microcrystalline cellulose, gum tragacanth, or gelatin; excipients such as starch or lactose; dispersants such as alginic acid, Primogel, or corn starch; lubricants such as magnesium stearate or Sterotes; glidants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavorings such as peppermint, methyl salicylate, or orange flavoring. When the unit dosage form is a capsule, it can contain liquid carriers such as fatty oils in addition to the above types of materials. In addition, the unit dosage form can contain various other materials that modify the physical form of the dosage form, for example, sugar coating, shellac, or enteric agents.

[0173] The active compound or its pharma- ceutically acceptable salt can be administered as a component of an elixir, suspension, syrup, wafer, chewing gum, etc. A syrup may contain, in addition to the active compound, sucrose as a sweetening agent and may also contain certain preservatives, dyes and colorings and flavors.

[0174] Active compound or its pharmaceutically acceptable salt can also be mixed with other active materials that do not impair the desired action, or materials that supplement the desired action, such as, among others, anticancer agents described herein.In certain preferred embodiments of the present disclosure, one or more compounds according to the present disclosure are co-administered with another bioactive agent, such as, for example, anticancer agents or wound healing agents, including antibiotics, as described elsewhere herein.

[0175] Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application can include the following components: a sterile diluent such as water for injection, saline, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methylparabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates, and phosphates, and agents for the adjustment of isotonicity such as sodium chloride or dextrose. Parenteral preparations can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

[0176] If administered intravenously, preferred carriers are saline or phosphate buffered saline (PBS).

[0177] In any aspect or embodiment, the active compound is prepared with a carrier that protects the compound against rapid excretion from the body, such as controlled release formulations, including implants and microencapsulated delivery systems.Biodegradable biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters and polylactic acid can be used.The method of preparing such formulations will be clear to those skilled in the art.

[0178] Liposomal suspensions can also be pharma- ceutically acceptable carriers. Liposomal suspensions can be prepared according to methods known to those skilled in the art, such as those 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 as follows: suitable lipid(s) (such as stearoyl phosphatidylethanolamine, stearoyl phosphatidylcholine, aracadyl phosphatidylcholine, and cholesterol) are dissolved in an inorganic solvent, which is then evaporated, leaving a thin film of dry lipid on the container surface. An aqueous solution of active compound is then placed in the container. The container is then rotated by hand to allow lipid material to escape from the sides of the container and disperse lipid aggregates, forming a liposomal suspension.

[0179] Treatment method

[0180] In an additional aspect, the present disclosure provides a method of treatment comprising administering an effective amount of a compound described herein, or a salt form thereof, and a pharma- ceutically acceptable carrier, the method of treatment being useful for effecting protein degradation in a patient or subject in need thereof, e.g., an animal, such as a human, to treat or alleviate a disease state, condition, or associated symptom that can be treated by targeted protein degradation.

[0181] The terms "treat", "treating", and "treatment", as used herein, refer to any action that benefits a patient to which the compounds may be administered, including the treatment of any disease state, condition, or symptom associated with the protein to which the compounds bind. Disease states or conditions, including cancer, that may be treated using compounds according to the present disclosure are described above.

[0182] The present disclosure provides a therapeutic method for effecting degradation of a protein of interest for the treatment or alleviation of a disease, such as Parkinson's disease (PD), primary tauopathy, dementia with Lewy bodies, Crohn's disease, leprosy, and / or neuroinflammation (such as observed). 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, the present disclosure provides a method for ubiquitinating / degrading a target protein in a cell. In certain embodiments, the method includes administering a bifunctional compound of the present invention. The control or reduction of a specific protein level in a subject's cells provided by the present disclosure results in the treatment of a disease state, condition, or symptom. In any aspect or embodiment, the method includes administering an effective amount of a compound described herein, optionally including a pharma- ceutically acceptable excipient, carrier, adjuvant, another bioactive agent, or a combination thereof.

[0183] In additional embodiments, the present specification provides a method for treating or alleviating a disease, disorder, or a symptom thereof in a subject or patient, e.g., an animal such as a human, comprising administering to a subject in need thereof an effective amount, e.g., a therapeutically effective amount, of a composition comprising a compound described herein, or a salt form thereof, and a pharma- ceutically acceptable excipient, carrier, adjuvant, another bioactive agent, or a combination thereof, wherein the composition is effective to treat or alleviate the disease or disorder, or a symptom thereof, in the subject.

[0184] In another aspect, the present description provides methods for determining the effect of degradation of a protein of interest in a biological system using compounds according to the present disclosure.

[0185] In another aspect, the present disclosure provides a process for producing a molecule capable of causing degradation of LRRK2 in a cell, comprising the steps of: (i) providing a small molecule that binds to LRRK2 or a mutated form thereof; (ii) providing an E3 ubiquitin ligase binding moiety (ULM), preferably a CLM, such as thalidomide, pomalidomide, lenalidomide or an analog thereof; and (iii) covalently attaching the small molecule of step (i) to the ULM of step (ii) via a chemical linking group (L) to form a compound that binds to both cereblon E3 ubiquitin ligase and LRRK2 protein and / or mutant form in a cell, thereby bringing cereblon E3 ubiquitin ligase into proximity with the compound and ubiquitinating the LRRK2 protein bound to the compound, thereby degrading the ubiquitinated LRRK2.

[0186] In another aspect, the present disclosure provides a method for detecting whether a molecule is capable of inducing degradation of LRRK2 protein in a cell, the method comprising the steps of: (i) providing a molecule to be detected for its ability to induce degradation of LRRK2 protein in a cell, the molecule comprising the following structure: CLM-L-PTM, wherein CLM is a cereblon E3 ubiquitin ligase binding moiety capable of binding to cereblon E3 ubiquitin ligase in the cell, CLM is thalidomide, pomalidomide, lenalidomide, or an analog thereof, and the PTM is an LRR The method includes the steps of (ii) providing a protein targeting moiety that is a small molecule that binds to LRRK2 and / or its mutant LRRK forms, wherein the LRRK2 has at least one lysine residue capable of ubiquitination by cereblon E3 ubiquitin ligase bound to a CLM of the molecule, and L is a chemical linking group that covalently links the CLM to the PTM to form the molecule; (ii) incubating a cell expressing an LRRK2 protein in the presence of the molecule of step (i); and (iii) detecting whether the LRRK2 protein in the cell has been degraded.

[0187] In any of the aspects or embodiments 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.

[0188] In another aspect of such treatment, the disclosure provides a method of treating a human patient in need of such treatment for a disease state, condition, or symptom causally associated with expression, overexpression, mutation, aggregation, accumulation, misfolding or dysfunction of LRRK2 and / or mutant forms of LRRK2, where degradation of the LRRK2 protein provides a therapeutic effect in the patient, the method comprising administering to the patient an effective amount of a compound according to the disclosure, optionally in combination with another bioactive agent.

[0189] In another aspect of such treatment, the disclosure provides a method of treating a human patient in need of such treatment for a disease state, condition, or symptom causally associated with expression, overexpression, mutation, aggregation, accumulation, misfolding or dysfunction of alpha-synuclein, where degradation of LRRK2 protein and / or mutant forms thereof provides a therapeutic effect in the patient, the method comprising administering to the patient an effective amount of a compound according to the disclosure, optionally in combination with another bioactive agent.

[0190] In another aspect of such treatment, the disclosure provides a method of treating a human patient in need of such treatment for a disease state, condition, or symptom causally associated with expression, overexpression, mutation, aggregation, misfolding, or dysfunction of alpha-synuclein, where degradation of LRRK2 protein and / or mutant forms thereof provides a therapeutic effect in the patient, the method comprising administering to the patient an effective amount of a compound according to the disclosure, optionally in combination with another bioactive agent.

[0191] In another aspect of such treatment, the present disclosure provides a method of treating a human patient in need of such treatment for a disease state, condition, or symptom causally associated with expression, overexpression, mutation, aggregation, misfolding, or dysfunction of Tau, where degradation of LRRK2 protein and / or mutant forms thereof provides 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.

[0192] The disease state, condition, or symptom may be caused by a microbial or other foreign agent, such as a virus, bacteria, fungus, protozoa, or other microorganism, or may be a disease state caused by the expression, overexpression, mutation, misfolding, or dysfunction of a protein that results in the disease state, condition, or symptom.

[0193] In another aspect, the disclosure provides a method of treating or alleviating at least one symptom of a disease or condition in a subject, comprising the steps of providing a subject identified as having a symptom of a disease or condition causally associated with expression, overexpression, mutation, misfolding, or dysfunction of LRRK2 protein and / or mutant forms thereof in the subject, wherein the symptom of the disease or condition is treated or alleviated by degrading the LRRK2 protein and / or mutant forms thereof in cells of the subject, and administering to the subject a therapeutically effective amount of a compound, including a small molecule of the invention, such that the LRRK2 protein and / or mutant forms thereof are degraded, thereby treating or alleviating at least one symptom of the disease or condition in the subject.

[0194] The term "disease state or condition" is used to describe any disease state or condition in which a protein is expressed, overexpressed, mutated, misfolded, or dysfunctional (e.g., an increase in the amount of protein expressed in a patient) and degradation of the LRRK2 protein and / or mutant forms thereof in a patient results in a reduction or stabilization of the level of LRRK2 protein (whether mutant or not), thereby providing beneficial therapy or relief of symptoms to a patient in need thereof. In certain cases, the disease state, condition, or symptom may be cured.

[0195] Disease states, conditions, or symptoms that may be treated using 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 activating LRRK2 mutations), primary tauopathy (e.g., 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 that observed in Alzheimer's disease, PD, multiple sclerosis, traumatic brain injury, spinal cord injury, etc.).

[0196] The term "biologically active agent" is used to describe an agent other than a compound according to the present disclosure that is used in combination with the present compounds as an agent having biological activity that supplements the intended therapeutic, inhibitory and / or prophylactic effects for which the present compounds are used. Preferred biologically active agents for use herein include those that have pharmacological activity similar to that of the use or administration of the present compounds, such as anti-cancer agents, anti-viral agents, particularly anti-HIV and anti-HCV agents, anti-bacterial agents, anti-fungal agents, and the like.

[0197] The term "additional anti-autoimmune disease agent" is used to describe anti-autoimmune disease therapeutic agents that may be combined with compounds according to the present disclosure to treat autoimmune diseases. These agents include, for example, infliximab, tofacitinib, baricitinib, secukinumab, adalimumab, etanercept, golimumab, certolizumab pepol, antiproliferative drugs (e.g., mycophenolate mofetil), and corticosteroids.

[0198] The term "pharmaceutically acceptable derivative" is used throughout this specification to describe any pharmaceutically acceptable prodrug form (such as esters, amides, other prodrug groups, etc.) that, upon administration to a patient, directly or indirectly provides the compound or an active metabolite of the compound. EXAMPLES

[0199] Abbreviation ACN Acetonitrile AcOH Acetic acid Boc tert-butoxycarbonyl dba Dibenzylideneacetone DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene DCM Dichloromethane DMA Dimethylacetamide DME Dimethoxyethane DMF Dimethylformamide DMSO Dimethyl sulfoxide DMAC / DMA Dimethylacetamide DIEA N,N-Diisopropylethylamine EDTA Ethylenediaminetetraacetic acid EtOAc / EA Ethyl acetate EtOH Ethanol FA Formic Acid HPLC High Performance Liquid Chromatography Hz Hertz IBX 2-Iodoxybenzoic acid LAH Lithium Aluminum Hydride LCMS Liquid Chromatography / Mass Spectrometry LiHMDS Lithium bis(trimethylsilyl)amide MHz Megahertz NBS N-Bromosuccinimide NCS N-chlorosuccinimide NMR nuclear magnetic resonance NMP N-Methyl-2-pyrrolidone MeOH Methanol MPLC Medium Pressure Liquid Chromatography MTBE Methyl tert-butyl ether PE Petroleum Ether Psi pounds per square inch RT or rt Room temperature SFC Supercritical Fluid Chromatography TEA Triethylamine THF Tetrahydrofuran TFA Trifluoroacetic acid TLC Thin Layer Chromatography TMS Trimethylsilyl

[0200] General synthetic approach

[0201] The synthesis and optimization of the bifunctional molecules described herein may be approached in a stepwise or modular manner. For example, in identifying compounds that bind to a target protein, i.e., LRRK2, high or medium throughput screening experiments can be performed if suitable ligands are not immediately available. It is not uncommon that initial ligands require repeated design and optimization cycles to improve suboptimal points identified by data obtained from suitable in vitro and pharmacological and / or ADMET assays. Part of the optimization / SAR experiments will be to search for positions in the ligand that tolerate substitutions and positions that may be suitable for attaching the chemical linking groups mentioned earlier in this specification. If crystallographic or NMR structural data is available, they can be used to focus such synthesis efforts.

[0202] Thus, in a similar manner, ligands for E3 ligases can be identified and optimized.

[0203] With the PTMs and ULMs (e.g., CLMs) at hand, one of skill in the art can use known synthetic methods for their combinations with or without chemical linking group(s). The chemical linking group(s) can be synthesized in a variety of compositions, lengths and flexibility and functionalized to allow sequential attachment of the PTM and ULM groups to the distal ends of the linker. In this way, a library of bifunctional molecules can be realized and profiled in in vitro and in vivo pharmacological and ADMET / PK studies. As with the PTM and ULM groups, the final bifunctional molecules can undergo repeated cycles of design and optimization to identify molecules with desired properties.

[0204] In some cases, protecting group strategies and / or functional group transformations (FGI) may be required to facilitate the preparation of the desired materials. Such chemical processes are well known to organic synthetic chemists, and many can be found in texts such as "Greene's Protective Groups in Organic Synthesis" Peter GMWuts and Theodora W. Greene (Wiley), and "Organic Synthesis: The Disconnection Approach" Stuart Warren and Paul Wyatt (Wiley).

[0205] Synthesis procedure

[0206] General synthesis scheme [ka]

[0207] Exemplary Synthesis of Intermediate 1,2-(2,6-Dioxo-3-piperidyl)-5-hydroxy-isoindoline-1,3-dione Step 1 [ka] 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) was added sodium acetate (4.1 g, 49.4 mmol, 3.00 equiv.) 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 the desired MS and the reaction was complete. The mixture was concentrated and 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 give 2-(2,6-dioxo-3-piperidyl)-5-hydroxy-isoindoline-1,3-dione (3.9 g, 14.3 mmol, 86% yield) as a colorless solid.

[0208] Exemplary Synthesis of Intermediate 2, 2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]oxyacetaldehyde Step 1 [ka] 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 showed that 4-hydroxybenzene-1,2-dicarboxylic acid was completely consumed and one new spot was formed. The reaction mixture was quenched with 200 mL of water at 25 °C and then extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 15:1 to 8:1). The compound dimethyl 4-(2,2-dimethoxyethoxy)benzene-1,2-dicarboxylate (2.64 g, 8.85 mmol, 92% yield) was obtained as a yellow oil. Step 2 [ka] To a solution of dimethyl 4-(2,2-dimethoxyethoxy)benzene-1,2-dicarboxylate (2.64 g, 8.86 mmol, 1 equiv.) in methyl alcohol (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 20 mL of hydrochloric acid at 20° C., then diluted with 100 mL of water and extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine (50 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was used in the next step without further purification. Compound 4-(2,2-dimethoxyethoxy)phthalic acid (2.2 g, 8.14 mmol, 91% yield) was obtained as a yellow oil. Step 3 [ka] 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 salt). 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 200 mL of water and extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine (50 mL×3), dried over anhydrous sodium 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). The compound 5-(2,2-dimethoxyethoxy)-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (1.6 g, 4.20 mmol, 51% yield, 95% purity) was obtained as a yellow oil. Step 4 [ka] To a solution of 5-(2,2-dimethoxyethoxy)-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (192 mg, 0.53 mmol, 1 equiv.) in tetrahydrofuran (10 mL), sulfuric acid (2 M, 10.6 mL, 40 equiv.) was added and the mixture was stirred at 70° C. for 1 h. The reaction mixture was quenched by the addition of 5 mL of sodium bicarbonate at 20° C., then diluted with 50 mL of water and extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with brine (20 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was used in the next step without further purification. The compound 2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]oxyacetaldehyde (160 mg, 0.50 mmol, 95% yield) was obtained as a white solid.

[0209] Exemplary Synthesis of Intermediate 3, 2-[2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]oxyethoxy]ethyl 4-methylbenzenesulfonate Step 1 [ka] To a solution of 2-(2,6-dioxo-3-piperidyl)-5-hydroxy-isoindoline-1,3-dione (300 mg, 1.09 mmol, 1 eq.) and 2-(2-hydroxyethoxy)ethyl 4-methylbenzenesulfonate (341 mg, 1.31 mmol, 1.2 eq.) in N,N-dimethylformamide (4 mL) was added potassium carbonate (302 mg, 2.19 mmol, 2 eq.). 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×3). The combined organic layers were washed with brine (20 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by column chromatography (dichloromethane:methanol=1:0 to 50:1) to give 2-(2,6-dioxo-3-piperidyl)-5-[2-(2-hydroxyethoxy)ethoxy]isoindoline-1,3-dione (400 mg) as a yellow oil. Step 2 [ka] To a solution of 2-(2,6-dioxo-3-piperidyl)-5-[2-(2-hydroxyethoxy)ethoxy]isoindoline-1,3-dione (400 mg, 1.10 mmol, 1 equiv.) in dichloromethane (5 mL) was added paratoluenesulfonyl 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×3). The combined organic layers were washed with brine (20 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by preparative reverse-phase thin-layer chromatography (dichloromethane:methanol=20:1) to give 2-[2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]oxyethoxy]ethyl 4-methylbenzenesulfonate (150 mg, 0.29 mmol, 26% yield) as a colorless oil.

[0210] The related intermediates 2-[2-[2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]oxyethoxy]ethoxy]ethyl 4-methylbenzenesulfonate, 2-[2-[2-[2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]oxyethoxy]ethoxy]ethyl 4-methylbenzenesulfonate, and 2-[2-[2-[2-[2-[2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]oxyethoxy]ethoxy]ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate was prepared in a similar manner as 2-[2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]oxyethoxy]ethyl 4-methylbenzenesulfonate.

[0211] Exemplary Synthesis of Exemplary Compound 1 Step 1 [ka] To a solution of 2-bromo-4-fluoro-1-nitro-benzene (16.78 g, 76.28 mmol, 1.1 equiv.) and 1-methylcyclopropanol (5 g, 69.34 mmol, 1 equiv.) in DMF (160 mL), NaH (4.16 g, 104.01 mmol, 60% in mineral oil, 1.5 equiv.) was added 2 The mixture was added in one portion at 0° C. under reduced pressure. The mixture was then heated to 20° C. and stirred for 4 h. TLC showed several new spots. The residue was poured into water (200 mL) and stirred for 10 min. The aqueous phase was extracted with ethyl acetate (3×300 mL). The combined organic phase was washed with brine (2×200 mL) and diluted with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (100-200 mesh silica gel, 0-2% ethyl acetate / petroleum ether) to give 2-bromo-4-(1-methylcyclopropoxy)-1-nitro-benzene (14.3 g, 52.56 mmol, 75.79% yield) as a yellow oil. Step 2 [ka] 2-Bromo-4-(1-methylcyclopropoxy)-1-nitro-benzene (14.3 g, 52.56 mmol, 1 equiv.) in 1,4-dioxane (100 mL), K 2 CO 3 (14.53 g, 105.11 mmol, 2 equiv.) and Cs 2 CO 3 (17.12 g, 52.56 mmol, 1 equiv.) was treated with 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (32.99 g, 131.39 mmol, 36.73 mL, 50% purity in EtOAc, 2.5 equiv.) and Pd(PPh 3 ) 4(6.07 g, 5.26 mmol, 0.1 equiv)) was added at 20° C., then heated to 100° C. and stirred for 16 h to give a yellow solution. TLC showed the reaction was complete. The reaction was cooled to 20° C. and concentrated under vacuum. To the residue was added PE:EtOAc (10:1, 100 mL) and the mixture was filtered through a pad of silica. The filter pad was washed with petroleum ether:EtOAc (10:1, 1000 mL) solvent. The residue was purified by silica gel chromatography (100-200 mesh silica gel, 0-1% ethyl acetate / petroleum ether) to give 2-methyl-4-(1-methylcyclopropoxy)-1-nitro-benzene (11 g, crude) as a yellow oil. Step 3 [ka] To a mixture of 2-methyl-4-(1-methylcyclopropoxy)-1-nitro-benzene (11 g, 53.08 mmol, 1 equiv.) in EtOH (100 mL), 10% Pd / C (4 g, 5.31 mmol, 0.1 equiv.) and ammonium formate (40.17 g, 636.99 mmol, 12 equiv.) were added with N 2 The mixture was added in one portion at 20° C. under reduced pressure. The mixture was stirred at 20° C. for 2 h to give a black mixture. TLC showed the reaction was complete. The mixture was filtered through a pad of silica gel, washed with EtOAc (3×200 mL) and concentrated in vacuo. The residue was purified by silica gel chromatography (0-10% ethyl acetate / petroleum ether) to give 2-methyl-4-(1-methylcyclopropoxy)aniline (9.8 g, crude) as a red oil. Step 4 [ka] 2-Methyl-4-(1-methylcyclopropoxy)aniline (9.8 g, 55.29 mmol, 1 equiv.) in DCM (100 mL) and Et 3 To a mixture of N (13.99 g, 138.23 mmol, 19.24 mL, 2.5 equiv.) was added Ac 2 O (11.29 g, 110.58 mmol, 10.36 mL, 2 equiv.)2 The mixture was stirred at 0° C. for 30 min, then heated to 20° C. and stirred for 16 h. TLC showed the reaction was complete. The reaction was diluted with NaHCO 3 (30 mL) to adjust pH = 7-8 and extracted with DCM (3 x 50 mL). The combined organic phase was washed with brine (3 x 50 mL) and diluted with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (20-40% ethyl acetate / petroleum ether) to give N-[2-methyl-4-(1-methylcyclopropoxy)phenyl]acetamide (9.3 g, 42.41 mmol, 76.71% yield) as a yellow oil. Step 5 [ka] To a solution of N-[2-methyl-4-(1-methylcyclopropoxy)phenyl]acetamide (9.3 g, 42.41 mmol, 1 equiv.) in toluene (100 mL) was added KOAc (6.24 g, 63.62 mmol, 1.5 equiv.) and Ac 2 HO (19.92 g, 195.09 mmol, 18.27 mL, 4.6 equiv) was added at 20 °C, the solution was heated to 80 °C, and then 3-methylbutyl nitrite (19.87 g, 169.65 mmol, 22.84 mL, 4 equiv) was added dropwise. After the addition, the mixture was stirred at 80 °C for 2 h. TLC showed the reaction was complete. The reaction was then filtered, the wet cake was washed with EtOAc (70 mL), and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (100-200 mesh silica gel, 0-10% ethyl acetate / petroleum ether) to give 1-[5-(1-methylcyclopropoxy)indazol-1-yl]ethanone (8 g, crude) as a yellow solid. Step 6 [ka] To a mixture of 1-[5-(1-methylcyclopropoxy)indazol-1-yl]ethanone (8 g, 34.74 mmol, 1 equiv) in MeOH (80 mL) was added NH 3 (g / )MeOH (7M, 24.82 mL, 5 equiv.) was added in one portion at 20° C. 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 (7.8 g, crude) as a yellow solid. Step 7 [ka] To a mixture of 5-(1-methylcyclopropoxy)-1H-indazole (7.8 g, 41.44 mmol, 1 equiv.) in THF (80 mL) was added 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.) in one portion at 20° C. 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 (3×50 mL). The combined organic phase was washed with brine (2×50 mL) and anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (100-200 mesh silica gel, 0-10% ethyl acetate / petroleum ether) to give trimethyl-[2-[[5-(1-methylcyclopropoxy)indazol-2-yl]methoxy]ethyl]silane (5.4 g, 16.96 mmol, 40.92% yield) as a yellow oil. Step 8 [ka] To a mixture of trimethyl-[2-[[5-(1-methylcyclopropoxy)indazol-2-yl]methoxy]ethyl]silane (4.36 g, 13.70 mmol, 5.32 e-1 equiv.) in THF (6 mL), n-BuLi (2.5 M, 13.40 mL, 1.3 equiv.) was added2 The mixture was then stirred at -20°C for 1 hour, and ZnCl 2 (0.7 M, 55.20 mL, 1.5 equiv.) was added dropwise at -70° C. The mixture was stirred at -40° C. for 1 h. A solution of 4,6-dichloropyrimidine (4.22 g, 28.34 mmol, 1.1 equiv.) and Pd(PPh 3 ) 4 A mixture of (1.49 g, 1.29 mmol, 0.05 equiv) 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 give a yellow solution. TLC showed starting material remaining while some new spots formed. The residue was poured into water (10 mL). The aqueous phase was extracted with ethyl acetate (3×20 mL). The combined organic phase was washed with brine (2×20 mL) and anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (100-200 mesh silica gel, 0-10% ethyl acetate / petroleum ether) to give 2-[[3-(6-chloropyrimidin-4-yl)-5-(1-methylcyclopropoxy)indazol-2-yl]methoxy]ethyl-trimethyl-silane (2.9 g, crude) as a yellow oil. Step 9 [ka] 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.) and tert-butyl (2S)-2-methylpiperazine-1-carboxylate (697.02 mg, 3.48 mmol, 3 equiv.) in DMSO (5 mL) was added Et 3N (704.34 mg, 6.96 mmol, 968.82 uL, 6 equiv) was added in one portion and then the mixture was stirred at 100° C. for 1 h. TLC showed 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 (3×5 mL). The combined organic phase was washed with brine (2×5 mL) and anhydrous Na 2 SO 4 Drying at 40° C., filtering and concentrating in vacuo afforded tert-butyl (2S)-2-methyl-4-[6-[5-(1-methylcyclopropoxy)-2-(2-trimethylsilylethoxymethyl)indazol-3-yl]pyrimidin-4-yl]piperazine-1-carboxylate (802 mg, crude) as a yellow oil. Step 10 [ka] 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 equiv) in DCM (5 mL) was added TFA (771.25 mg, 6.76 mmol, 500.81 uL, 5 equiv) in one portion at 25° C. The mixture was stirred at 25° C. for 16 h. HCl (4 M, 338.20 uL, 1 equiv) in MeOH (5 mL) was added at 25° C., then heated to 60° C. and stirred for 0.5 h. LCMS showed the reaction was complete. The mixture was cooled to 20° C. The residue was purified by distillation with NaHCO 3 (5 mL) and adjusted to pH = 7-8. The aqueous phase was extracted with ethyl acetate (3 x 10 mL). The combined organic phase was washed with brine (2 x 10 mL) and anhydrous Na 2 SO 4The residue was purified by silica gel chromatography (0-40% ethyl acetate / MeOH) to give 5-(1-methylcyclopropoxy)-3-[6-[(3S)-3-methylpiperazin-1-yl]pyrimidin-4-yl]-1H-indazole (450 mg, 1.18 mmol, 87.41% yield, 95.77% purity) as a yellow solid. Step 11 [ka] 5-(1-Methylcyclopropoxy)-3-[6-[(3S)-3-methylpiperazin-1-yl]pyrimidin-4-yl]-1H-indazole (104.76 mg, 287.45 umol, 1 equiv.), 2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]oxyacetaldehyde (100 mg, 316.19 umol, 1.1 equiv.), NaOAc (70.74 mg, 862.34 umol, 3 equiv.), CH 3 COOH (17.26 mg, 287.45 umol, 16.44 uL, 1 equiv.) and NaBH 3 A mixture of CN (36.13 mg, 574.89 umol, 2 eq) was stirred at 25° C. for 1 h. LCMS showed 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 (3×5 mL). The combined organic phase was washed with brine (2×5 mL) and washed with anhydrous Na 2 SO 4The mixture was dried over 1000 ml, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (100-200 mesh silica gel, 0-10% ethyl acetate / MeOH). The mixture was further purified by preparative HPLC (column: YMC-Actus Triart C18 150*30mm*5um; mobile phase: [water (0.05% ammonium hydroxide v / v)-ACN]; B%: 48%-68%, 10 min) to give 2-(2,6-dioxo-3-piperidyl)-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 (12.08mg, 18.17umol, yield 6.32%, purity 100%) as a white solid.

[0212] Exemplary Synthesis of Exemplary Compound 2 Step 1 [ka] 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 equiv), KI (63.77 mg, 384.15 umol, 2 equiv) and 2-[2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]oxyethoxy]ethyl 4-methylbenzenesulfonate (99.21 mg, 192.07 umol, 1 equiv) in ACN (2 mL) was added DIPEA (124.12 mg, 960.37 umol, 167.28 uL, 5 equiv) in one portion. The mixture was stirred at 100° C. for 16 hours. The residue was poured into water (2 mL). The aqueous phase was extracted with ethyl acetate (3×2 mL). The combined organic phase was washed with brine (2×2 mL) and anhydrous Na 2 SO 4The mixture was dried at 40° C., filtered and concentrated in vacuo, and the residue was purified by silica gel chromatography (100-200 mesh silica gel, 0-10% ethyl acetate / MeOH). The crude product was purified by preparative HPLC (column: YMC-Actus Triart C18 150*30mm*5um; mobile phase: [water (0.05% ammonium hydroxide v / v)-ACN]; B%: 45%~65%, 10min) to give 2-(2,6-dioxo-3-piperidyl)-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 (11.63mg, 16.41umol, yield 8.54%, purity 100%) as a white solid. Exemplary compounds 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 15, 16, and 19 were prepared in a similar manner to exemplary compound 2.

[0213] Exemplary Synthesis of Exemplary Compound 3 Step 1 [ka] To a mixture of 5-(1-methylcyclopropoxy)-3-[6-[(3S)-3-methylpiperazin-1-yl]pyrimidin-4-yl]-1H-indazole (72.24 mg, 198.21 umol, 1 equiv), KI (65.81 mg, 396.42 umol, 2 equiv) and 2-[2-[2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]oxyethoxy]ethoxy]ethyl 4-methylbenzenesulfonate (100 mg, 178.39 umol, 0.9 equiv) in ACN (2 mL) was added DIPEA (128.08 mg, 991.05 umol, 172.62 uL, 5 equiv) in one portion. The mixture was stirred at 100° C. for 16 h. The residue was poured into water (2 mL) and the aqueous phase was extracted with ethyl acetate (3×2 mL). The combined organic phase was washed with brine (2×2 mL) and anhydrous Na 2 SO 4The mixture was dried at 40° C., filtered and concentrated in vacuo, and the residue was purified by silica gel chromatography (100-200 mesh silica gel, 0-10% ethyl acetate / MeOH). The crude product was purified by preparative HPLC (column: YMC-Actus Triart C18 150*30mm*5um; mobile phase: [water (0.05% ammonium hydroxide v / v)-ACN]; B%: 45%~65%, 10min) to give 2-(2,6-dioxo-3-piperidyl)-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 (14.84mg, 19.71umol, yield 9.95%, purity 100%) as a white solid.

[0214] Exemplary Synthesis of Exemplary Compound 4 Step 1 [ka] 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-piperidyl)-1,3-dioxo-isoindolin-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. The mixture was stirred at 100° C. for 16 hours. The residue was poured into water (2 mL). The aqueous phase was extracted with ethyl acetate (3×2 mL). The combined organic phase was washed with brine (2×2 mL) and anhydrous Na 2 SO 4The mixture was dried at 40° C., filtered and concentrated in vacuo, and the residue was purified by silica gel chromatography (100-200 mesh silica gel, 0-10% ethyl acetate / MeOH). The crude product was purified by preparative HPLC (column: YMC-Actus Triart C18 150*30mm*5um; mobile phase: [water (0.05% ammonium hydroxide v / v)-ACN]; B%: 45%~65%, 10min) to give 2-(2,6-dioxo-3-piperidyl)-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 (5.1mg, 6.23umol, yield 3.39%, purity 97.275%) as a white solid.

[0215] Exemplary Synthesis of Exemplary Compound 5 Step 1 [ka] CH 35-(1-Methylcyclopropoxy)-3-[6-[(3S)-3-methylpiperazin-1-yl]pyrimidin-4-yl]-1H-indazole (55.00 mg, 150.92 umol, 0.979 equiv.), 4-methylbenzenesulfonic acid 2-[2-[2-[2-[2-[2-(2,6-dioxo-3-piperidyl)-1, A mixture of 3-dioxo-isoindolin-5-yl]oxyethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl (100mg, 154.16umol, 1eq), KI (51.18mg, 308.32umol, 2eq) and DIPEA (99.62mg, 770.80umol, 134.26uL, 5.00eq) was stirred at 100°C for 15h. The mixture was diluted with water (10mL) and extracted with dichloromethane (3x10mL). 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*30mm*5um; mobile phase: [water (0.225%FA)-ACN]; B%: 23%~63%, 11min). The collected fractions were then concentrated to remove most of the acetonitrile and lyophilized to give 2-(2,6-dioxo-3-piperidyl)-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 (10.1 mg, 11.41 umol, 7.40% yield, 95% purity) as a red solid.

[0216] Exemplary Synthesis of Exemplary Compound 6 Step 1 [ka] 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 uL, 3 equiv) was added in one portion and then the solution was stirred at 100° C. for 1 h. LCMS (EB16-35-P1A1) showed that the starting material was completely consumed. The mixture was cooled to 20° C. The residue was poured into water (5 mL). The mixture was extracted with ethyl acetate (3×5 mL). The combined organic phase was washed with brine (2×5 mL) and anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate=10 / 1 to 5 / 1) to give 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, crude) as a yellow oil. Step 2 [ka] 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 equiv.) in MeOH (5 mL) was added HCl(g) / dioxane (4 M, 1.67 mL, 5 equiv.) in one portion at 20° C. The mixture was stirred at 65° C. for 0.5 h. LCMS indicated the reaction was complete. The mixture was cooled to 20° C. The residue was purified by hexanes extraction with NaHCO 3(10 mL) and adjusted to pH = 7-8. The mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic phase was washed with brine (2 x 10 mL) and anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (100-200 mesh silica gel, 0-25% ethyl acetate / MeOH) to give 3-[6-[(3S,5R)-3,5-dimethylpiperazin-1-yl]pyrimidin-4-yl]-5-(1-methylcyclopropoxy)-1H-indazole (400 mg, 978.01 umol, 73.42% yield, 92.537% purity) as a yellow solid. Step 3 [ka] 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 umol, 1.1 eq) and 2-[2-[2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]oxyethoxy]ethoxy]ethyl 4-methylbenzenesulfonate (94.26 mg, 168.15 umol, 1 eq) in MeCN (5 mL) was added DIPEA (108.66 mg, 840.73 umol, 146.44 uL, 5 eq) and KI (55.82 mg, 336.29 umol, 2 eq). The reaction mixture was stirred at 100° C. for 24 hours. The residue was poured into water (5 mL). The aqueous phase was extracted with ethyl acetate (3×5 mL). The combined organic phase was washed with brine (2×5 mL) and anhydrous Na 2 SO 4The mixture was dried over 100°C, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (100-200 mesh silica gel, 10-25% ethyl acetate / petroleum ether). The crude product was purified by reverse phase HPLC (column: Agela DuraShell C18 250*25mm*10um; mobile phase: water (0.04% NH3H2O+10mM Purification by NH4HCO3)-ACN; B%: 45%-75%, gradient time (min): 8 min; flow rate (ml / min): 25)) gave 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-piperidyl)isoindoline-1,3-dione (10.09 mg, 12.98 umol, 7.72% yield, 98.681% purity) as a yellow solid.

[0217] Exemplary Synthesis of Exemplary Compound 7 Step 1 [ka] 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 equiv) and 2-[2-[2-[2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]oxyethoxy]ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate (116.19 mg, 192.16 umol, 1 equiv) in MeCN (5 mL) was added DIPEA (124.18 mg, 960.82 umol, 167.36 uL, 5 equiv) and KI (63.80 mg, 384.33 umol, 2 equiv). 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 (3×5 mL). The combined organic phase was washed with brine (2×5 mL) and diluted with anhydrous Na 2 SO 4The mixture was dried over 100° C., filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (100-200 mesh silica gel, 10-25% ethyl acetate / petroleum ether). The crude product was purified by reverse phase HPLC (column: Agela DuraShell C18 250*25mm*10um; mobile phase: water (0.04% NH 3 / H 2 O + 10 mM NH 4 HCO 3 )-ACN; B%: 45%-75%, gradient time (min): 8 min; flow rate (ml / min): 25)) to give 5-[2-[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]ethoxy]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (5.9 mg, 6.98 umol, yield 3.63%, purity 95.895%) as a yellow solid.

[0218] Exemplary Synthesis of Exemplary Compound 8 Step 1 [ka] To a mixture of 5-isopropoxy-3-[6-[(3S)-3-methylpiperazin-1-yl]pyrimidin-4-yl]-1H-indazole (160 mg, 453.99 umol, 1 eq) in MeCN (5 mL) was added 2-[2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]oxyethoxy]ethoxymethyl 4-methylbenzenesulfonate (347.37 mg, 635.58 umol, 1.4 eq), DIEA (293.37 mg, 2.27 mmol, 395.38 uL, 5 eq) and KI (602.90 mg, 3.63 mmol, 8 eq). The mixture was stirred at 95° C. for 12 hours to give 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×3). The combined extracts were washed with brine (10 mL) and anhydrous Na 2 SO4 The mixture was dried at 40° C., filtered, and the filtrate was concentrated under reduced pressure to give a residue (300 mg). The residue was purified by preparative HPLC (FA) to give 2-(2,6-dioxo-3-piperidyl)-5-[2-[2-[2-[(2S)-4-[6-(5-isopropoxy-1H-indazol-3-yl)pyrimidin-4-yl]-2-methyl-piperazin-1-yl]ethoxy]ethoxy]ethoxy]isoindoline-1,3-dione (104.3 mg, 137.94 umol, 30.38% yield, 97.97% purity) as a pink solid.

[0219] Exemplary Synthesis of Exemplary Compound 9 Step 1 [ka] To a mixture of 5-isopropoxy-3-[6-[(3S)-3-methylpiperazin-1-yl]pyrimidin-4-yl]-1H-indazole (160 mg, 453.99 umol, 1 eq) in MeCN (8 mL) was added 2-[2-[2-[2-[2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]oxyethoxy]ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate (384.29 mg, 635.58 umol, 1.4 eq), DIEA (293.37 mg, 2.27 mmol, 395.38 uL, 5 eq) and KI (602.90 mg, 3.63 mmol, 8 eq). The mixture was stirred at 95° C. for 12 hours 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×3). The combined extracts were washed with brine (10 mL) and anhydrous Na 2 SO 4The mixture was dried at 40° C., filtered, and the filtrate was concentrated under reduced pressure to give a residue (320 mg). The residue was purified by preparative HPLC (FA) to give 2-(2,6-dioxo-3-piperidyl)-5-[2-[2-[2-[2-[(2S)-4-[6-(5-isopropoxy-1H-indazol-3-yl)pyrimidin-4-yl]-2-methyl-piperazin-1-yl]ethoxy]ethoxy]ethoxy]ethoxy]isoindoline-1,3-dione (44.9 mg, 56.05 umol, 12.35% yield, 97.98% purity) as a pink solid.

[0220] Exemplary Synthesis of Exemplary Compound 10 Step 1 [ka] To a mixture of 3-[6-[(3R,5S)-3,5-dimethylpiperazin-1-yl]pyrimidin-4-yl]-5-isopropoxy-1H-indazole (0.15 g, 409.32 μmol, 1 equiv.) and 2-[2-[2-[2-[2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]oxyethoxy]ethoxy]ethyl 4-methylbenzenesulfonate (296.98 mg, 491.19 μmol, 1.2 equiv.), DIEA (793.53 mg, 6.14 mmol, 1.07 mL, 15 equiv.) in MeCN (8 mL) and DMSO (2 mL), KI (1.02 g, 6.14 mmol, 15 equiv.) was added N 2 The mixture was stirred at 100° C. for 16 h. The reaction mixture was concentrated, cooled in an ice bath, and saturated NH 4The pH was adjusted to 6 by adding Cl. It was added with saturated brine, 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-piperidyl)-5-[2-[2-[2-[2-[(2R,6S)-4-[6-(5-isopropoxy-1H-indazol-3-yl)pyrimidin-4-yl]-2,6-dimethyl-piperazin-1-yl]ethoxy]ethoxy]ethoxy]ethoxy]isoindoline-1,3-dione (8.5 mg, 10.19 μmol, yield 2.49%, purity 95.81%) as a light yellow solid.

[0221] Exemplary Synthesis of Exemplary Compound 11 Step 1 [ka] 1H-Indazol-5-ol (5 g, 37.28 mmol, 1 equiv.) and Cs in DMF (50 mL) 2 CO 3 To a mixture of (18.22g, 55.91mmol, 1.5eq) was added 2-iodopropane (8.24g, 48.46mmol, 4.85mL, 1.3eq) in one portion at 25°C. The mixture was stirred at 25°C for 4 hours. TLC (petroleum ether:ethyl acetate=3:1, Rf=0.58) showed the reaction was complete. The mixture was poured into water (50mL) and the aqueous phase was extracted with ethyl acetate (60mL*3). The combined organic phase was washed with brine (20mL*2) and diluted with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered, and concentrated in vacuo to give a residue, which was purified by silica gel chromatography (petroleum ether / ethyl acetate=3 / 1) to give 5-isopropoxy-1H-indazole (4.1 g, 23.27 mmol, 62.42% yield) as a light yellow solid. Step 2 [ka] To a mixture of 5-isopropoxy-1H-indazole (4 g, 22.70 mmol, 1 equiv) in MeCN (80 mL), 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.) 2 The mixture was stirred at 25°C for 16 hours. TLC (petroleum ether:ethyl acetate=3:1) showed the reaction was complete. The mixture was diluted with brine (100mL) and the aqueous phase was extracted with dichloromethane (100mL*3). The combined organic phase was washed with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated in vacuo to give a residue which was purified by silica gel chromatography (petroleum ether / ethyl acetate=10 / 3) to give 3-iodo-5-isopropoxy-1H-indazole (5.5 g, 18.21 mmol, 80.20% yield) as a light yellow oil. Step 3 [ka] 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 at 25° C. The mixture was stirred at 25° C. for 16 h to give an orange solution. TLC (petroleum ether:ethyl acetate=20 / 1) showed the reaction was complete. The residue was poured into water (100 mL). The aqueous phase was extracted with ethyl acetate (3×80 mL). The combined organic phase was washed with brine (2×20 mL) and diluted with anhydrous Na 2 SO 4The mixture was dried at 40° C., filtered and concentrated in vacuo to give a residue, which was purified by silica gel chromatography (petroleum ether / ethyl acetate=100 / 3) to give 2-[(3-iodo-5-isopropoxy-indazol-1-yl)methoxy]ethyl-trimethyl-silane (7.4 g, 15.75 mmol, 86.47% yield, 92% purity) as a pale yellow oil. Step 4 [ka] 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), was added 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.) was dissolved in N 2 The mixture was heated to 90°C with stirring under N2 for 5 h. TLC (petroleum ether:ethyl acetate=20 / 1) showed the reaction was complete. The mixture was cooled to 25°C and the residue was poured into water (80 mL). The aqueous phase was extracted with ethyl acetate (90 mL*2). The combined organic phase was washed with brine (30 mL*2) and diluted with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered, and concentrated in vacuo to give a residue, which was purified by silica gel chromatography (petroleum ether / ethyl acetate=10 / 1) to give 2-[[3-(2-fluoro-4-pyridyl)-5-isopropoxy-indazol-1-yl]methoxy]ethyl-trimethyl-silane (5.96 g, 12.32 mmol, 71.98% yield, 83% purity) as a pale yellow solid. Step 5 [ka] 2-[[3-(2-fluoro-4-pyridyl)-5-isopropoxy-indazol-1-yl]methoxy]ethyl-trimethyl-silane (300 mg, 747.11 umol, 1 eq.), (2S)-tert-butyl 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 placed in DMSO (10 mL) in a microwave tube. The sealed tube was heated at 180° C. for 5 h under microwave. The mixture was cooled to 25° C. The mixture was diluted with ethyl acetate (30 mL), washed with brine (10 mL*3) and purified by anhydrous NaCl. 2 SO 4 The mixture was dried at 40° C., filtered, and concentrated under vacuum 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 (200 mg, 357.07 umol, 47.79% yield, 86% purity) as a dark liquid. Step 6 [ka] 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 umol, 1 eq.) and TFA (5 mL) was stirred at 25° C. for 1 hour. 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 (200 mg, 352.83 umol, 84.98% yield, 62% purity) as a dark oil. Step 7 [ka] CH 3To a mixture of 5-isopropoxy-3-[2-[(3S)-3-methylpiperazin-1-yl]-4-pyridyl]-1H-indazole (100 mg, 284.54 umol, 1 eq) and 2-[2-[2-[2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]oxyethoxy]ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate (206.45 mg, 341.45 umol, 1.2 eq) in CN (3 mL) was added DIEA (367.74 mg, 2.85 mmol, 495.61 uL, 10 eq) and KI (236.17 mg, 1.42 mmol, 5 eq) in one portion at 25° C. 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 phase was washed with brine (5 mL*2) and anhydrous Na 2 SO 4 The residue was purified by preparative HPLC (column: Phenomenex Luna C18 100*30mm*5um; mobile phase: [water (0.05% HCl)-ACN]; B%: 15%-45%, 9 min) to obtain 2-(2,6-dioxo-3-piperidyl)-5-[2-[2-[2-[2-[(2S)-4-[4-(5-isopropoxy-1H-indazol-3-yl)-2-pyridyl]-2-methyl-piperazin-1-yl]ethoxy]ethoxy]ethoxy]ethoxy]isoindoline-1,3-dione (11.6mg, 13.85umol, yield 4.87%, purity 93.6%) as a light yellow solid.

[0222] Exemplary Synthesis of Exemplary Compound 12 Step 1 [ka] To a solution of 5-(1-methylcyclopropoxy)-1H-indazole (500 mg, 2.66 mmol, 1 equiv.) in DMF (5 mL), KOH (558.89 mg, 9.96 mmol, 3.75 equiv.) and I 2 (1.35 g, 5.31 mmol, 1.07 mL, 2 equiv.) was added. The mixture was stirred at 25° C. for 2 h. The reaction mixture was diluted with saturated Na2 SO 3 (10 mL) and extracted with EtOAc (20 mL*3). The combined organic layer was washed with brine (20 mL*2) and 2 SO 4 The mixture was dried at 40° C., filtered, and concentrated under reduced pressure to give a residue. The crude product was purified by column chromatography on silica gel (PE / EA=0-10%) to give 3-iodo-5-(1-methylcyclopropoxy)-1H-indazole (458 mg, 1.26 mmol, 47.53% yield, 86.592% purity) as a yellow solid. Step 2 [ka] To a mixture of 3-iodo-5-(1-methylcyclopropoxy)-1H-indazole (458 mg, 1.30 mmol, 1 equiv) in THF (20 mL) was added N-cyclohexyl-N-methyl-cyclohexanamine (760.45 mg, 3.89 mmol, 825.68 uL, 3 equiv) and SEM-Cl (432.69 mg, 2.60 mmol, 459.33 uL, 2 equiv) in one portion at 20° C. 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 phase was washed with brine (10 mL*2) and anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (100-200 mesh silica gel, 0-10% ethyl acetate / petroleum ether) to give [3-iodo-5-(1-methylcyclopropoxy)indazol-1-yl]methanol (300 mg, 706.09 umol, 54.41% yield, 81% purity) as a yellow solid. Step 3 [ka] To a solution of (2S)-tert-butyl 4-(4-bromo-2-pyridyl)-2-methyl-piperazine-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) was added Pd(dppf)Cl 2 (184.85 mg, 252.63 umol, 0.15 equiv) and KOAc (495.87 mg, 5.05 mmol, 3 equiv). The mixture was diluted with N 2 The mixture was stirred at 90° C. for 1 h under reduced pressure to give a brown solution. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (20 mL*2) and diluted with Na 2 SO 4 It was dried at 40° C., filtered and concentrated under reduced pressure to give [2-[(3S)-4-tert-butoxycarbonyl-3-methyl-piperazin-1-yl]-4-pyridyl]boronic acid (1.2 g, crude) as a brown gum. Step 4 [ka] 1,4-Dioxane (10 mL) and H 2 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)indazol-1-yl]methanol (300.00 mg, 871.72 umol, 1 equiv.) in 2 mL of O was added Pd(dppf)Cl 2 (95.68mg, 130.76umol, 0.15eq) and Na 2 CO 3 (277.18 mg, 2.62 mmol, 3 equiv.) was added. The mixture was diluted with N 2The mixture was stirred at 90°C for 1.5 hours under reduced pressure. The mixture was cooled to 20°C and concentrated under reduced pressure. The residue was poured into water (10mL) and the aqueous phase was extracted with ethyl acetate (10mL*3). The combined organic phase was washed with brine (10mL*2) and diluted with anhydrous Na 2 SO 4 The residue was purified by silica gel chromatography (column height: 20 g, 100-200 mesh silica gel, 0-20% ethyl acetate / petroleum ether) to give tert-butyl (2S)-2-methyl-4-[4-[5-(1-methylcyclopropoxy)-1H-indazol-3-yl]-2-pyridyl]piperazine-1-carboxylate (400 mg, crude) as a yellow oil. Step 5 [ka] To a mixture of tert-butyl (2S)-2-methyl-4-[4-[5-(1-methylcyclopropoxy)-2H-indazol-3-yl]-2-pyridyl]piperazine-1-carboxylate (400 mg, 422.80 umol, 1 eq) in MeOH (10 mL) was added HCl / dioxane (4M, 528.51 uL, 5 eq) in one portion at 20° C. The mixture was stirred at 65° C. for 0.5 h. TLC (EtOAc, Rf=0.07) and LCMS indicated the reaction was complete. The mixture was cooled to 20° C. and the residue was dissolved in saturated NaHCO 3 The aqueous phase was extracted with ethyl acetate (20 mL*3). The combined organic phase was washed with brine (20 mL*2) and anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (100-200 mesh silica gel, 0-25% MeOH / DCM) to give 5-(1-methylcyclopropoxy)-3-[2-[(3S)-3-methylpiperazin-1-yl]-4-pyridyl]-1H-indazole (170 mg, 241.82 umol, 57.19% yield, 51.7% purity) as a yellow solid. Step 6 [ka] To a solution of 5-(1-methylcyclopropoxy)-3-[2-[(3S)-3-methylpiperazin-1-yl]-4-pyridyl]-1H-indazole (100 mg, 275.14 umol, 1 eq.) and 2-[2-[2-[2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]oxyethoxy]ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate (166.35 mg, 275.14 umol, 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 uL, 12 eq.). The mixture was stirred at 90° C. for 12 hours. The residue was poured into water (3 mL). The aqueous phase was extracted with ethyl acetate (3 mL*2). The combined organic phase was washed with brine (3 mL) and anhydrous Na 2 SO 4 The crude product was purified by reverse phase HPLC (column: Phenomenex Luna C18 100*30mm*5um; mobile phase: [water (0.225% FA)-ACN]; B%: 23%~53%, 9min) to give 2-(2,6-dioxo-3-piperidyl)-5-[2-[2-[2-[2-[(2S)-2-methyl-4-[4-[5-(1-methylcyclopropoxy)-1H-indazol-3-yl]-2-pyridyl]piperazin-1-yl]ethoxy]ethoxy]ethoxy]ethoxy]isoindoline-1,3-dione (12.5mg, 15.14umol, yield 5.50%, purity 96.4%) as a yellow solid.

[0223] Exemplary Synthesis of Exemplary Compound 13 Step 1 [ka] To a mixture of 2-[2-[2-[2-[4-[(2,6-dioxo-3-piperidyl)carbamoyl]-3-fluoro-phenoxy]ethoxy]ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate (162.07mg, 271.65umol, 1.1eq) and 5-(1-methylcyclopropoxy)-3-[6-[(3S)-3-methylpiperazin-1-yl]pyrimidin-4-yl]-1H-indazole (90mg, 246.95umol, 1.00eq) in MeCN (5mL) was added KI (122.98mg, 740.86umol, 3eq) and DIPEA (159.58mg, 1.23mmol, 215.07uL, 5eq). 2 The mixture was stirred at 80° C. for 16 h. The mixture was cooled to 20° C. and concentrated under reduced pressure at 20° C. The residue was poured into water (5 mL). The aqueous phase was extracted with ethyl acetate (3×5 mL). The combined organic phase was washed with brine (3×5 mL) and diluted with anhydrous Na 2 SO 4 The crude product was purified by reverse phase HPLC (column: Welch Xtimate C18 150*30mm*5um; mobile phase: water (0.225% FA)-ACN; B%: 12%-42%, gradient time (min): 8min; flow rate (ml / min): 25) to give N-(2,6-dioxo-3-piperidyl)-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 (23.23mg, 28.98umol, yield 11.73%, purity 98.399%) as a red solid.

[0224] Exemplary Synthesis of Exemplary Compound 14 Step 1 [ka] AcOH (15.2 mL) and H 2 SO 4To a mixture of 2-fluoro-5-methyl-phenol (7 g, 55.50 mmol, 1 equiv.) in 1 mL of H 2 NaNO in O (35 mL) 2 (3.83 g, 55.50 mmol, 1 equiv.) was added at 0° C. The mixture was then stirred at 0° C. for 1 h. The reaction mixture was poured into ice water (100 mL). The precipitate was collected by filtration and subsequently washed with water (3×100 mL). The resulting solid was dissolved in HNO 3 (12 mL) and H 2 The mixture was added dropwise with stirring to a mixture of 2×200 mL of 1H2O (35 mL). The resulting suspension was stirred at 45° C. for 2 h. After cooling to room temperature, the mixture was diluted with cold water (100 mL) and filtered. The solid was washed with water (2×100 mL) and then dissolved in ethyl acetate (100 mL). The organic layer was washed with brine (2×100 mL) and diluted with Na 2 SO 4 Drying at rt, filtration and concentration under reduced pressure gave 2-fluoro-5-methyl-4-nitro-phenol (5.3 g, 30.35 mmol, 54.69% yield, 98% purity) as a yellow solid. Step 2 [ka] CH 3 To a mixture of 2-fluoro-5-methyl-4-nitro-phenol (5.3 g, 30.97 mmol, 1 equiv.) and 2-iodopropane (10.53 g, 61.94 mmol, 6.19 mL, 2 equiv.) in CN (60 mL) was added K 2 CO 3 (8.56 g, 61.94 mmol, 2 equiv.) was reacted with N 2 The mixture was added at 20° C. under reduced pressure. The reaction mixture was stirred at 80° C. for 12 h. TLC (PE:EA=10:1) showed one major new spot with low polarity. The reaction mixture was filtered and concentrated to give 1-fluoro-2-isopropoxy-4-methyl-5-nitro-benzene (5 g, 23.45 mmol, 75.72% yield) as a yellow solid. Step 3 [ka] To a stirred solution of 1-fluoro-2-isopropoxy-4-methyl-5-nitro-benzene (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 filtered. The filtrate was concentrated in vacuo to give 5-fluoro-4-isopropoxy-2-methyl-aniline (4.2 g, 20.63 mmol, 87.97% yield, 90% purity) as a brown oil. Step 4 [ka] To a stirred solution of 5-fluoro-4-isopropoxy-2-methyl-aniline (4.2 g, 20.63 mmol, 1 equiv) in AcOH (40 mL) was added H 2 NaNO in O (5 mL) 2 (1.57 g, 22.69 mmol, 1.1 equiv) was added at 0° C. 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 3 Solution (40 mL) was added and the mixture was extracted with EA (40 mL). The combined organic layers were washed with 40 mL of brine and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel (PE / EA=100:20, 100:30) to give 6-fluoro-5-isopropoxy-1H-indazole (3.5 g, 18.02 mmol, 87.36% yield) as a brown oil. Step 5 [ka] 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.) was added. 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 2 SO 4 The mixture was dried at 40° C., filtered, and concentrated under reduced pressure to give a residue. The crude product was purified by column chromatography on silica gel (0-10% ethyl acetate / petroleum ether) to give 6-fluoro-3-iodo-5-isopropoxy-1H-indazole (1.62 g, 3.95 mmol, 54.76% yield, 78% purity) as a yellow solid. Step 6 [ka] 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-methylcyclohexanamine (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 diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered, and concentrated under reduced pressure to give a residue. The crude product was purified by column chromatography on silica gel (0-5% ethyl acetate / petroleum ether) to give 2-[(6-fluoro-3-iodo-5-isopropoxy-indazol-1-yl)methoxy]ethyl-trimethyl-silane (2.05 g, 4.23 mmol, 84.16% yield, 93% purity) as a yellow oil. Step 7 [ka] To a solution of 4-bromo-2-fluoro-pyridine (1 g, 5.68 mmol, 1 equiv.) and tert-butyl (2S)-2-methylpiperazine-1-carboxylate (1.71 g, 8.52 mmol, 1.5 equiv.) in DMSO (8 mL), was added K 2 CO 3 (2.36 g, 17.05 mmol, 3 equiv.) was added. The mixture was stirred at 100° C. for 4 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL). The combined organic layers were washed with brine (50 mL) and extracted with Na 2 SO 4 The mixture was dried at 40° C., filtered, and concentrated under reduced pressure to give a residue. The crude product was purified by column chromatography on silica gel (0-10% ethyl acetate / petroleum ether) to give tert-butyl (2S)-4-(4-bromo-2-pyridyl)-2-methyl-piperazine-1-carboxylate (1.7 g, 4.68 mmol, 82.30% yield, 98% purity) as a colorless oil. Step 8 [ka] To a solution of (2S)-tert-butyl 4-(4-bromo-2-pyridyl)-2-methyl-piperazine-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) was added Pd(dppf)Cl 2 (184.85 mg, 252.63 umol, 0.15 equiv) and KOAc (495.87 mg, 5.05 mmol, 3 equiv). The mixture was diluted with N 2 The mixture was stirred at 90° C. for 1 h under reduced pressure. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (30 mL). The combined organic layers were washed with 20 mL of brine and diluted with Na 2 SO 4Drying at 40° C., filtering and concentrating under reduced pressure afforded (S)-tert-butyl 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 umol, 33.94% yield) as a brown oil. Step 9 [ka] 1,4-Dioxane (10 mL) and H 2 To a solution of (S)-tert-butyl 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 2 mL of O was added Pd(dppf)Cl 2 (184.53mg, 252.20umol, 0.15eq) and Na 2 CO 3 (534.61 mg, 5.04 mmol, 3 equiv.) was added. The mixture was diluted with N 2 The mixture was stirred at 90° C. for 2 h under reduced pressure. 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) and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered, and concentrated under reduced pressure to give a residue. The crude product was purified by column chromatography on silica gel (0-20% ethyl acetate / petroleum ether) to give tert-butyl (2S)-4-[4-[6-fluoro-5-isopropoxy-1-(2-trimethylsilylethoxymethyl)indazol-3-yl]-2-pyridyl]-2-methyl-piperazine-1-carboxylate (1 g, 1.60 mmol, 95.19% yield, 96% purity) as a yellow oil. Step 10 [ka] To a solution of tert-butyl (2S)-4-[4-[6-fluoro-5-isopropoxy-1-(2-trimethylsilylethoxymethyl)indazol-3-yl]-2-pyridyl]-2-methyl-piperazine-1-carboxylate (1 g, 1.67 mmol, 1 eq.) in DCM (5 mL) was added TFA (1.54 g, 13.51 mmol, 1 mL, 8.10 eq.). 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) and extracted with Na 2 SO 4 Drying at 40° C., filtering and concentrating under reduced pressure gave 6-fluoro-5-isopropoxy-3-[2-[(3S)-3-methylpiperazin-1-yl]-4-pyridyl]-1H-indazole (590 mg, 1.39 mmol, 83.34% yield, 87% purity) as a yellow gum. Step 11 [ka] CH 3 To a solution of 6-fluoro-5-isopropoxy-3-[2-[(3S)-3-methylpiperazin-1-yl]-4-pyridyl]-1H-indazole (100 mg, 270.68 umol, 1 eq.) and 2-[2-[2-[2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]oxyethoxy]ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate (163.66 mg, 270.68 umol, 1 eq.) in CN (2 mL) was added KI (539.21 mg, 3.25 mmol, 12 eq.) and DIEA (419.81 mg, 3.25 mmol, 565.78 uL, 12 eq.). The mixture was stirred at 90° C. for 12 hours. 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) and diluted with Na 2 SO 4The residue was purified 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-piperidyl)-5-[2-[2-[2-[2-[(2S)-4-[4-(6-fluoro-5-isopropoxy-1H-indazol-3-yl)-2-pyridyl]-2-methyl-piperazin-1-yl]ethoxy]ethoxy]ethoxy]ethoxy]isoindoline-1,3-dione (24.3mg, 29.74umol, yield 10.99%, purity 98.14%) as a white solid.

[0225] Exemplary Synthesis of Exemplary Compound 15 Step 1 [ka] A mixture of 2-[2-[2-[2-[2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-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 reacted with 100 mL of N 2 The mixture was stirred at 50°C for 0.5 hours under reduced pressure. 3 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 eq, TFA) and DIEA (600.27 mg, 4.64 mmol, 808.98 uL, 15 eq) in CN (3 mL) was added to the mixture. The mixture was then cooled to 5° C. with 5% CO. 2 The mixture was stirred at 90° C. for 16 h under reduced pressure. 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) and diluted with Na 2 SO 4The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give a residue, which was purified by preparative TLC (PE:EA=0:1) to give the crude product. The crude product was purified by preparative TLC (column: Phenomenex Luna C18 100*30mm*5um; condition: water (0.225% FA)-ACN; start: B16%, end: B46%; gradient time: 9min; 100%B hold time: 1min; flow rate: 25ml / min) to give 2-(2,6-dioxo-3-piperidyl)-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 (15mg, 18.68umol, yield 6.03%, FA) as a white solid.

[0226] Exemplary Synthesis of Exemplary Compound 16 Step 1 [ka] To a mixture of 1H-indazol-5-ol (1 g, 7.46 mmol, 1 equiv.) in DCM (10 mL), imidazole (1.52 g, 22.37 mmol, 3 equiv.) and TBSCl (1.69 g, 11.18 mmol, 1.37 mL, 1.5 equiv.) were added in N 2 The mixture was stirred at 20°C for 2 h to give a brown solution. TLC (DCM:MeOH=10:1, Rf=0.23) showed the reaction was complete. The residue was poured into water (10 mL). The aqueous phase was extracted with ethyl acetate (10 mL*3). The combined organic phase was washed with brine (10 mL*3) and diluted with anhydrous Na 2 SO 4 The residue was purified by silica gel chromatography (12 g, 30 mL / min, 100-200 mesh silica gel, 0-5% (10 min) MeOH / DCM) to give tert-butyl-(1H-indazol-5-yloxy)-dimethyl-silane (1.5 g, 5.87 mmol, 78.73% yield, 97.2% purity) as a yellow oil. Step 2 [ka] To a mixture of tert-butyl-(1H-indazol-5-yloxy)-dimethyl-silane (1.5 g, 6.04 mmol, 1 equiv.) in THF (20 mL), 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.) were added 2 The mixture was stirred at 20°C for 2 h to give a yellow suspension. TLC (PE:EtOAc=3:1, Rf=0.37) showed the reaction was complete. The residue was poured into water (20 mL). The aqueous phase was extracted with ethyl acetate (20 mL*3). The combined organic phase was washed with brine (20 mL*2) and diluted with anhydrous Na 2 SO 4 The residue was purified by silica gel chromatography (column height: 40 g, 30 mL / min, 100-200 mesh silica gel, 0% (5 min) ethyl acetate / petroleum ether, 1% (20 min) ethyl acetate / petroleum ether) to give tert-butyl-dimethyl-[1-(2-trimethylsilylethoxymethyl)indazol-5-yl]oxy-silane (1.82 g, 4.81 mmol, 79.59% yield) as a yellow oil. Step 3 [ka] 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), n-BuLi (2.5 M, 2.50 mL, 1.3 equiv.) was added 2 The mixture was then stirred at -20°C for 5 min, and ZnCl 2(1M, 7.21 mL, 1.5 equiv.) was added dropwise at -70°C. The mixture was stirred at -40°C for 10 min. A solution of 4,6-dichloropyrimidine (787.67 mg, 5.29 mmol, 1.1 equiv.) and Pd(PPh 3 ) 4 (277.71mg, 240.32umol, 0.05eq) was stirred at 20℃ for 30min and added to the reaction. The cold bath was removed and the mixture was stirred at 20℃ for 2h to give a yellow solution. TLC (PE:EtOAc=10:1, Rf=0.83) showed one new spot. The residue was poured into water (10mL). The aqueous phase was extracted with ethyl acetate (20mL*3). The combined organic phase was washed with brine (20mL*2) and anhydrous Na 2 SO 4 The residue was purified by silica gel chromatography (40 g, 35 mL / min, 100-200 mesh silica gel, 0-5% (30 min) ethyl acetate / petroleum ether) to give tert-butyl-[3-(6-chloropyrimidin-4-yl)-1-(2-trimethylsilylethoxymethyl)indazol-5-yl]oxy-dimethyl-silane (1.18 g, 2.40 mmol, 49.98% yield) as a yellow oil. Step 4 [ka] 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 equiv.) in DCM (10 mL), TFA (3 g, 26.31 mmol, 1.95 mL, 10.95 equiv.) was added and N 2 The mixture was stirred at 20° C. for 1 h. Then, NH 3 .H 22.55 g, 24.02 mmol, 2.80 mL, 33% purity, 10 equiv. was added and the solution was stirred at 20° C. for 1 h. The solution was concentrated under vacuum. The crude was dissolved in THF (5 mL), TBAF (1 M, 2.40 mL, 1 equiv.) 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 phase was washed with brine (5 mL*3) and diluted with anhydrous Na 3 SO 4 The mixture was dried at 40° C., 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 / petroleum ether, 32% (12 min) ethyl acetate / petroleum ether) to give 3-(6-chloropyrimidin-4-yl)-1H-indazol-5-ol (140 mg, 567.60 umol, 23.63% yield) as a yellow oil. Step 5 [ka] To a mixture of 3-(6-chloropyrimidin-4-yl)-1H-indazol-5-ol (140 mg, 567.60 umol, 1 equiv) in THF (5 mL) and DCM (5 mL) was added tert-butyl 2,2,2-trichloroethanimidate (744.15 mg, 3.41 mmol, 609.96 uL, 6 equiv) and BF 3 .Et 2 O (241.68 mg, 851.40 umol, 210.15 uL, 50% purity, 1.5 equivalents) was dissolved in N 2 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 phase was washed with brine (3 mL*2) and diluted with anhydrous Na 2 SO 4The 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 / petroleum ether, 20% (10 min) ethyl acetate / petroleum ether) to give 5-tert-butoxy-3-(6-chloropyrimidin-4-yl)-1H-indazole (80 mg, 264.24 umol, 46.55% yield) as a yellow solid. Step 6 [ka] To a mixture of 5-tert-butoxy-3-(6-chloropyrimidin-4-yl)-1H-indazole (200 mg, 660.59 umol, 1 equiv.), (2S)-2-methylpiperazine-1-carboxylate (154.77 mg, 660.59 umol, 1 equiv.) in DMSO (10 mL) was added Et 3 N (200.54 mg, 1.98 mmol, 275.84 uL, 3 equiv) was added in one portion and then stirred at 100° C. for 1 h. TLC (PE:EtOAc=5:1, Rf=0.50) showed that the starting material was completely consumed. 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 (3×10 mL). The combined organic phase was washed with brine (2×10 mL) and anhydrous Na 2 SO 4 The residue was purified by silica gel chromatography (20 g, 40 mL / min, 100-200 mesh silica gel, 0-17% (3 min) ethyl acetate / petroleum ether, 17% (5 min) ethyl acetate / petroleum ether) to give benzyl (2S)-4-[6-(5-tert-butoxy-1H-indazol-3-yl)pyrimidin-4-yl]-2-methyl-piperazine-1-carboxylate (230 mg, 450.27 umol, 68.16% yield, 98% purity) as a yellow gum. Step 7 [ka] To a mixture of (2S)-benzyl 4-[6-(5-tert-butoxy-1H-indazol-3-yl)pyrimidin-4-yl]-2-methyl-piperazine-1-carboxylate (230 mg, 459.46 umol, 1 equiv.) in EtOH (5 mL), Pd / C (100 mg, 459.46 umol, 10% purity, 1 equiv.) was added 2 The suspension was degassed under vacuum and diluted with H 2 The mixture was purged with H 2 The mixture was stirred under (15 psi) at 20° C. for 1 h. The suspension was filtered through a pad of Celite and the pad was washed with EtOAc (3×50 mL) to give 5-tert-butoxy-3-[6-[(3S)-3-methylpiperazin-1-yl]pyrimidin-4-yl]-1H-indazole (140 mg, 382.03 umol, 83.15% yield) as a yellow gum. The crude product was used in the next step. Step 8 [ka] To a mixture of 5-tert-butoxy-3-[6-[(3S)-3-methylpiperazin-1-yl]pyrimidin-4-yl]-1H-indazole (140 mg, 382.03 umol, 1 equiv), KI (317.09 mg, 1.91 mmol, 5 equiv) and 2-[2-[2-[2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]oxyethoxy]ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate (254.09 mg, 420.24 umol, 1.1 equiv) in MeCN (5 mL) was added DIPEA (246.87 mg, 1.91 mmol, 332.71 uL, 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 (3×5 mL). The combined organic phase was washed with brine (2×5 mL) and anhydrous Na 2 SO 4It was dried at 40°C, filtered and concentrated under vacuum. The crude product was purified by reverse phase HPLC (column: Phenomenex luna C18 100*40mm*3um; condition: water (0.225% FA)-ACN; start B: 20-50; flow rate: 25mL / min; gradient time: 8.5min; 100%B retention time: 2min). 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-methyl-piperazin-1-yl]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (34.9 mg, 41.94 umol, 10.98% yield, 96% purity) as a white solid.

[0227] Exemplary Synthesis of Exemplary Compound 17 Step 1 [ka] H 2 2-(benzylamino)ethanol (17 g, 112.43 mmol, 15.89 mL, 1 equiv) in 2O (200 mL) and Et 3 A solution of N (11.38 g, 112.43 mmol, 15.65 mL, 1 equiv) was heated to 105° C. Ethyl (E)-4-bromobut-3-enoate (23.87 g, 123.67 mmol, 1.1 equiv) 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 phase was washed with brine (100 mL*2) and anhydrous Na 2 SO 4The mixture was dried at 40° C., filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (column height: 80 g, 100-200 mesh silica gel, 0-20% (30 min) ethyl acetate / petroleum ether) to give ethyl 2-(4-benzylmorpholin-2-yl)acetate (16 g, 60.76 mmol, 54.04% yield) as a yellow oil. Step 2 [ka] To a solution of ethyl 2-(4-benzylmorpholin-2-yl)acetate (5 g, 18.99 mmol, 1 equiv.) in THF (50 mL) was added LiAlH 4 (1.08 g, 28.48 mmol, 1.5 equiv) was added. After the 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), and then 15% aqueous sodium hydroxide solution (5 mL) and water (15 mL) were added. The solids were removed by filtration. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (column height: 40 g, 100-200 mesh silica gel, 0-50% (20 min) ethyl acetate / petroleum ether) to give 2-(4-benzylmorpholin-2-yl)ethanol (2.73 g, 12.34 mmol, 64.97% yield) as a yellow oil. Step 3 [ka] To a mixture of 2-[2-(2-hydroxyethoxy)ethoxy]ethanol (5 g, 33.29 mmol, 4.46 mL, 1 equiv.) in THF (50 mL), NaH (1.33 g, 33.29 mmol, 60% purity, 1 equiv.) was added in N 2The mixture was stirred at 0°C for 30 minutes, then (chloromethyl)benzene (3.79 g, 29.97 mmol, 3.45 mL, 0.9 equiv) was added to the solution. The solution was then heated to 25°C and stirred for 16 hours. The residue was poured into water (30 mL). The aqueous phase was extracted with ethyl acetate (30 mL*3). The combined organic phase was washed with brine (30 mL*2) and anhydrous Na 2 SO 4 The residue was purified by silica gel chromatography (column height: 40 g, 100-200 mesh silica gel, 0-2% (10 min) MeOH / DCM, 2% (5 min) MeOH / DCM, 5% (15 min) MeOH / DCM) to give 2-[2-(2-benzyloxyethoxy)ethoxy]ethanol (3 g, 12.48 mmol, 37.50% yield) as a yellow oil. Step 4 [ka] 2-[2-(2-benzyloxyethoxy)ethoxy]ethanol (3 g, 12.48 mmol, 9.01 mL, 1 equiv) in DCM (20 mL), Et 3 To a mixture of N (1.26 g, 12.48 mmol, 1.74 mL, 1 equiv.) and DMAP (1.53 g, 12.48 mmol, 1 equiv.), 4-methylbenzene-1-sulfonyl chloride (3.57 g, 18.73 mmol, 1.5 equiv.) was added to N 2 The mixture was poured into HCl (2M) and the pH was adjusted to 7-8. The aqueous phase was extracted with ethyl acetate (50mL*3). The combined organic phase was washed with brine (50mL*2) and diluted with anhydrous NaCl. 2 SO 4The mixture was dried at 40° C., filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (100-200 mesh silica gel, 10-20% ethyl acetate / petroleum ether) to give 2-[2-(2-benzyloxyethoxy)ethoxy]ethyl 4-methylbenzenesulfonate (3.14 g, 7.96 mmol, 63.76% yield) as a yellow oil. Step 5 [ka] To a mixture of 2-(4-benzylmorpholin-2-yl)ethanol (1 g, 4.52 mmol, 1 equiv.) in DMF (10 mL), NaH (542.26 mg, 13.56 mmol, 60% purity, 3 equiv.) was added 2 The mixture was stirred at 20°C for 30 minutes, and 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 hours. The residue was poured into water (10 mL). The aqueous phase was extracted with ethyl acetate (10 mL*3). The combined organic phase was washed with brine (10 mL*2) and diluted with anhydrous Na 2 SO 4 The residue was purified by silica gel chromatography (column height: 20 g, diameter: 100 mm, 100-200 mesh silica gel, 0-100% (60 min) ethyl acetate / petroleum ether) to give 4-benzyl-2-[2-[2-[2-(2-benzyloxyethoxy)ethoxy]ethoxy]ethyl]morpholine (920 mg, 2.07 mmol, 45.90% yield) as a yellow oil. Step 6 [ka] 4-Benzyl-2-[2-[2-[2-(2-benzyloxyethoxy)ethoxy]ethoxy]ethyl]morpholine (920 mg, 2.07 mmol, 1 equiv.) in MeOH (10 mL) and Boc 2To a solution of 2O (905.31 mg, 4.15 mmol, 952.96 uL, 2 equiv.), Pd / C (100 mg, 2.07 mmol, 10% purity, 1 equiv.) was added 2 The suspension was degassed under vacuum and H 2 The mixture was purged with H 2 The mixture was stirred at 50°C under (45 psi) for 4 h. TLC showed no starting material. The suspension was filtered through a Celite pad or silica gel, and the pad or filter cake was washed with EtOAc (50 mL*3). The residue was purified by silica gel chromatography (column height: 20 g, 100-200 mesh silica gel, 0-10% MeOH / DCM) to give 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. Step 7 [ka] tert-Butyl 2-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethyl]morpholine-4-carboxylate (400 mg, 1.10 mmol, 1 equiv.) in DCM (10 mL), Et 3 To a mixture of N (334.10 mg, 3.30 mmol, 459.56 uL, 3 equiv.) and DMAP (134.46 mg, 1.10 mmol, 1 equiv.), 4-methylbenzenesulfonyl chloride (419.64 mg, 2.20 mmol, 2 equiv.) was added to N 2 The mixture was stirred at 0° C. for 2 h to give a white suspension. TLC (DCM:MeOH=10:1, Rf=0.54) and LCMS showed the reaction was complete. 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 phase was washed with brine (5 mL*2) and diluted with anhydrous Na 2 SO 4The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, 0-10% MeOH / DCM) and SFC {column: REGIS(s,s)WHELK-O1 (250 mm*50 mm, 10 um); condition: 0.1% NH3H2O ​​PA; start B: 20%; end B 20%; flow rate (ml / min): 70)} to give enantiomer 1 of (2*1)-tert-butyl 2-[2-[2-[2-[2-(p-tolylsulfonyloxy)ethoxy]ethoxy]ethoxy]ethyl]morpholine-4-carboxylate (148 mg, 234.51 umol, yield 21.31%, purity 82.019%) (Rt=2.832 min). , 148 mg) as a colorless oil, and enantiomer 2 (2*2)-2-[2-[2-[2-[2-(p-tolylsulfonyloxy)ethoxy]ethoxy]ethoxy]ethyl]morpholine-4-carboxylate tert-butyl (146 mg, 259.63 umol, 23.59% yield, 92.051% purity) (Rt=3.004 min, 146 mg) was obtained as a colorless oil. Step 8 [ka] of enantiomer 1 (2*) in DMF (5 mL) 1 )-tert-butyl 2-[2-[2-[2-[2-(p-tolylsulfonyloxy)ethoxy]ethoxy]ethoxy]ethyl]morpholine-4-carboxylate (70 mg, 135.23 umol, 1 equiv.) and 2-(2,6-dioxo-3-piperidyl)-5-hydroxy-isoindoline-1,3-dione (40.79 mg, 148.75 umol, 1.1 equiv.) were added to a mixture of K 2 CO 3 (37.38mg, 270.46umol, 2eq.) 2 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 phase was washed with brine (5 mL*3) and diluted with anhydrous Na 2 SO4 The residue was purified by silica gel chromatography (column height: 12 g, 100-200 mesh silica gel, 0-100% (30 min) ethyl acetate / petroleum ether, 100% (10 min) ethyl acetate / petroleum ether) to give tert-butyl (2*1)-2-[2-[2-[2-[2-[2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]oxyethoxy]ethoxy]ethoxy]ethyl]morpholine-4-carboxylate (50 mg, 72.22 umol, 53.40% yield, 89.5% purity) as a colorless gum. Step 9 [ka] (2*) in DCM (5 mL) 1 To a mixture of tert-butyl 2-[2-[2-[2-[2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]oxyethoxy]ethoxy]ethoxy]ethyl]morpholine-4-carboxylate (50 mg, 80.69 umol, 1 equiv.), TFA (27.60 mg, 242.07 umol, 17.92 uL, 3 equiv.) was added to N 2 The mixture was added in one portion at 25° C. under reduced pressure. The mixture was stirred at 25° C. for 30 minutes. TLC indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure to remove the solvent to give 2-(2,6-dioxo-3-piperidyl)-5-[2-[2-[2-[2-[(2*1)-morpholin-2-yl]ethoxy]ethoxy]ethoxy]ethoxy]isoindoline-1,3-dione (50 mg, 71.72 umol, 88.88% yield, 90.873% purity, TFA) as a yellow gum. Step 10 [ka] To a mixture of 3-(6-chloropyrimidin-4-yl)-5-(1-methylcyclopropoxy)-2H-indazole (26.11 mg, 86.81 umol, 1.1 eq) and 2-(2,6-dioxo-3-piperidyl)-5-[2-[2-[2-[2-[(2R)-morpholin-2-yl]ethoxy]ethoxy]ethoxy]ethoxy]isoindoline-1,3-dione (50 mg, 78.92 umol, 1 eq, TFA) in DMSO (2 mL) was added DIPEA (20.40 mg, 157.84 umol, 27.49 uL, 2 eq) and N 2 The mixture was stirred at 100° C. for 1 hour. The aqueous phase was extracted with ethyl acetate (3 mL*2). The combined organic phase was washed with brine (3 mL) and diluted with anhydrous Na 2 SO 4 The crude product was purified by reverse phase HPLC (column: Phenomenex Luna C18 100*30mm*5um; condition: water (0.225% FA)-ACN; B: 23%~53%; 9 min) to give 2-(2,6-dioxo-3-piperidyl)-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 (7.6mg, 9.21umol, yield 11.67%, purity 95%) as a yellow solid.

[0228] Exemplary Synthesis of Exemplary Compound 18 Step 1 [ka] (2*) in DMF (2 mL) 2 )-tert-butyl 2-[2-[2-[2-[2-(p-tolylsulfonyloxy)ethoxy]ethoxy]ethoxy]ethyl]morpholine-4-carboxylate (146 mg, 282.05 umol, 1 eq.) and 2-(2,6-dioxo-3-piperidyl)-5-hydroxy-isoindoline-1,3-dione (85.08 mg, 310.26 umol, 1.1 eq.), 2CO 3 (77.97 mg, 564.11 umol, 2 equivalents) was added to N 2 The mixture was stirred at 70° C. for 2 hours. 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 phase was washed with brine (5 mL*3) and diluted with anhydrous Na 2 SO 4 The residue was purified by silica gel chromatography (column height: 12 g, 100-200 mesh silica gel, 0-80% (20 min) ethyl acetate / petroleum ether, 80% (10 min) ethyl acetate / petroleum ether) to give tert-butyl (2*2)-2-[2-[2-[2-[2-[2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]oxyethoxy]ethoxy]ethoxy]ethyl]morpholine-4-carboxylate (118 mg, 190.43 umol, 67.51% yield) as a colorless gum. Step 2 [ka] (2*) in DCM (5 mL) 2 To a mixture of tert-butyl 2-[2-[2-[2-[2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]oxyethoxy]ethoxy]ethoxy]ethyl]morpholine-4-carboxylate (118 mg, 190.43 umol, 1 equiv.), TFA (21.71 mg, 190.43 umol, 14.10 uL, 1 equiv.) was added to N 2 The mixture was added in one portion at 25° C. under reduced pressure. The mixture was stirred at 25° C. for 30 minutes. TLC indicated that the starting material had been consumed. The reaction mixture was concentrated under reduced pressure to remove the solvent to give 2-(2,6-dioxo-3-piperidyl)-5-[2-[2-[2-[2-[(2*2)-morpholin-2-yl]ethoxy]ethoxy]ethoxy]ethoxy]isoindoline-1,3-dione (118 mg, 143.60 umol, 75.41% yield, 77.102% purity, TFA) as a yellow gum. Step 3 [ka] A mixture of 2-[[3-(6-chloropyrimidin-4-yl)-5-(1-methylcyclopropoxy)indazol-2-yl]methoxy]ethyl-trimethyl-silane (107.68 mg, 249.83 umol, 1.1 equiv.) and 2-(2,6-dioxo-3-piperidyl)-5-[2-[2-[2-[2-[(2* 2 To a mixture of 1,3-dimethyl-2-(2-methyl-1,2-diphenyl)ethoxyethyl]ethoxyethyl]isoindoline-1,3-dione (118 mg, 227.12 umol, 1 equiv., TFA), DIPEA (58.71 mg, 454.25 umol, 79.12 uL, 2 equiv.) was added in a 10 mL flask. 2 The mixture was stirred at 100° C. for 1 h, then HCl (4M, 283.90 uL, 5 eq.) 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 phase was washed with brine (3 mL) and diluted with anhydrous Na 2 SO 4 The crude product was purified by reverse phase HPLC (column: Phenomenex Luna C18 100*30mm*5um; condition: water (0.225% FA)-ACN; B%: 23%~53%; 9 min) to give 2-(2,6-dioxo-3-piperidyl)-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 (43.1mg, 53.17umol, yield 23.41%, purity 96.7%) as a pink solid. Total H in HNMR data: 43

[0229] Exemplary Synthesis of Exemplary Compound 19 Step 1 [ka] 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 cooled to 5° C. for 2 hours at 37° C. for 3 hours. 2 The reaction mixture was stirred at 120° C. for 16 hours under H 2 Pour into O (10 mL*2) and remove residual water by centrifugation to give 5-hydroxy-2-(3-methyl-2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (114 mg, 355.93 umol, 25.30% yield, 90% purity) as a white solid. The crude product was used directly in the next step. Step 2 [ka] To a solution of 2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate (165.35 mg, 474.58 umol, 1.2 equiv.) and 5-hydroxy-2-(3-methyl-2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (114 mg, 395.48 umol, 1 equiv.) in DMF (5 mL) was added K 2 CO 3 (163.97 mg, 1.19 mmol, 3 equiv.) was added. After the addition, the reaction mixture was stirred at 70 °C for 2 h. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography (0-100% ethyl acetate / petroleum ether) to give 5-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]-2-(3-methyl-2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (180 mg, 313.91 umol, 79.37% yield, 81% purity) as a colorless oil. Step 3 [ka] To a solution of 5-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]-2-(3-methyl-2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (180 mg, 387.54 umol, 1 eq) and 4-methylbenzenesulfonyl chloride (147.77 mg, 775.09 umol, 2 eq) in DCM (3 mL) was added DMAP (4.73 mg, 38.75 umol, 0.1 eq) and TEA (117.65 mg, 1.16 mmol, 161.82 uL, 3 eq). After addition, the mixture was stirred at 20° C. for 16 hours. 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-piperidyl)-1,3-dioxo-isoindolin-5-yl]oxyethoxy]ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate (140 mg, 193.94 umol, yield 50.04%, purity 85.70%) as a colorless solid. Step 4 [ka] To a solution of 2-[2-[2-[2-[2-(3-methyl-2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]oxyethoxy]ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate (140 mg, 226.30 umol, 1 eq.) and 5-(1-methylcyclopropoxy)-3-[6-[(3S)-3-methylpiperazin-1-yl]pyrimidin-4-yl]-1H-indazole (82.47 mg, 226.30 umol, 1 eq.) in ACN (4 mL) was added KI (187.83 mg, 1.13 mmol, 5 eq.) and DIEA (146.24 mg, 1.13 mmol, 197.09 uL, 5 eq.). 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 (3×10 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%: 15%~45%, 9min) to give 2-(3-methyl-2,6-dioxo-3-piperidyl)-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 (11.1mg, 13.58umol, yield 6.00%, purity 99.21%) as a red solid.

[0230] Exemplary Synthesis of Exemplary Compound 20 Step 1 [ka] CH 3To 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 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 filtrate cake was washed with water (100 mL) to give 2-(2,6-dioxo-3-piperidyl)-5-fluoro-isoindoline-1,3-dione (1.4 g, 5.07 mmol, 84.19% yield) as a black solid. Step 2 [ka] To a solution of 2-(2,6-dioxo-3-piperidyl)-5-fluoro-isoindoline-1,3-dione (1.15 g, 4.16 mmol, 1 eq.) and tert-butyl piperazine-1-carboxylate (852.97 mg, 4.58 mmol, 1.1 eq.) in NMP (10 mL) was added DIEA (1.61 g, 12.49 mmol, 2.18 mL, 3 eq.). The sealed tube was heated in a microwave at 140° C. for 2 h. The mixture was combined with batch EB12-30-P1, diluted with water (50 mL) and extracted with ethyl acetate (2×50 mL). The combined organic phase was washed with saturated brine (2×30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-50% ethyl acetate / petroleum ether) to give tert-butyl 4-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]piperazine-1-carboxylate (1.4 g, 3.16 mmol, 76.00% yield) as a yellow solid. Based on EB12-30 (905.08 umol starting material) and EB12-32 (4.16 mmol starting material), the average yield is 62.49%. Step 3 [ka] To a solution of tert-butyl 4-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]piperazine-1-carboxylate (1.2 g, 2.71 mmol, 1 eq.) in MeOH (10 mL) was added HCl / dioxane (4 M, 2.00 mL, 2.95 eq.). 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 (1.1 g, crude) as a yellow solid. Based on EB12-34 (452.01 umol starting material) and EB12-35 (2.71 mmol starting material), the average yield is 91.04%. Step 4 [ka] A solution of KOH (2.21 g, 39.46 mmol, 2 equiv.) in ethylene glycol (3.67 g, 59.17 mmol, 3.31 mL, 5 equiv.) was stirred at 115° C. After dissolving potassium hydroxide, 2-bromo-1,1-dimethoxy-ethane (2 g, 11.83 mmol, 1.39 mL, 1 equiv.) was added dropwise over 5 min and the reaction mixture was stirred for 20 h. TLC (ethyl acetate:petroleum ether=1:1) showed one new spot. The mixture was then allowed to cool to room temperature (20° C.) and the whole was diluted with water (40 mL) and then extracted with dichloromethane (3×20 mL). The organic layer was washed with brine (3×20 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-50% ethyl acetate / petroleum ether) to give 2-(2,2-dimethoxyethoxy)ethanol (200 mg, 1.33 mmol, 11.25% yield) as a pale yellow oil. Step 5 [ka] To a solution of 2-(2,2-dimethoxyethoxy)ethanol (200 mg, 1.33 mmol, 1 equiv.) and 4-methylbenzenesulfonyl chloride (507.81 mg, 2.66 mmol, 2 equiv.) in DCM (3 mL) was added TEA (269.53 mg, 2.66 mmol, 370.74 uL, 2 equiv.). After the addition, the reaction solution was stirred at 20° C. for 16 h. TLC (petroleum ether:ethyl acetate=1:1) showed that the starting material was consumed, and TLC (petroleum ether:ethyl acetate=5:1) showed one new spot. The reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (3×10 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-30% ethyl acetate / petroleum ether) to give 2-(2,2-dimethoxyethoxy)ethyl 4-methylbenzenesulfonate (350 mg, 1.15 mmol, 86.35% yield) as a pale yellow oil. Step 6 [ka] CH 3To a solution of 5-(1-methylcyclopropoxy)-3-[6-[(3S)-3-methylpiperazin-1-yl]pyrimidin-4-yl]-1H-indazole (100 mg, 274.39 umol, 1 eq) and 2-(2,2-dimethoxyethoxy)ethyl 4-methylbenzenesulfonate (83.51 mg, 274.39 umol, 1 eq) in CN (3 mL) was added KI (227.75 mg, 1.37 mmol, 5 eq) and DIEA (70.93 mg, 548.78 umol, 95.59 uL, 2 eq). After addition, the reaction mixture was stirred at 90° C. for 12 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3×10 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-10% methanol / 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 (80 mg, 146.60 umol, 53.43% yield, 91% purity) as a yellow oil. Step 7 [ka] 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 umol, 1 equiv) in THF (3 mL) was added H 2 SO 4 (2M, 3.22 mL, 40 equiv.) was added. After the addition, the reaction solution was stirred at 70° C. for 1 h. The reaction solution was diluted with saturated NaHCO 3The mixture was quenched with ethyl acetate (pH=7). The resulting mixture was extracted with ethyl acetate (3×10 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 (60 mg, 118.53 umol, 73.58% yield, 89% purity) as a yellow solid. The crude product was used directly. Step 8 [ka] 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 umol, 1 equiv.) and 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindoline-1,3-dione hydrochloride (50.45 mg, 133.18 umol, 1 equiv.) in DMF (3 mL) was added NaOAc (32.77 mg, 399.53 umol, 3 equiv.), HOAc (8.00 mg, 133.18 umol, 7.62 uL, 1 equiv.) and NaBH 3 CN (16.74 mg, 266.35 umol, 2 equiv.) was added. After the 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 um; 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-piperidyl)-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 (15.8 mg, 20.13 umol, 15.12% yield, 99% purity) as a yellow solid.

[0231] Exemplary Synthesis of Exemplary Compound 21 Step 1 [ka] CH 3 To a mixture of 3-[6-[(3R,5S)-3,5-dimethylpiperazin-1-yl]pyrimidin-4-yl]-5-(1-methylcyclopropoxy)-1H-indazole (100 mg, 264.22 umol, 1 equiv.) and 2-(2,2-dimethoxyethoxy)ethyl 4-methylbenzenesulfonate (80.42 mg, 264.22 umol, 1 equiv.) in CN (3 mL) was added KI (43.86 mg, 264.22 umol, 1 equiv.) and DIPEA (34.15 mg, 264.22 umol, 46.02 uL, 1 equiv.) in N 2 The mixture was added in one portion at 20° C. under reduced pressure, then the reaction mixture was heated to 100° C. and stirred for 24 h to give a brown suspension. The suspension was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (100-200 mesh silica gel, 0-10% MeOH / DCM) to give 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, crude) as a yellow solid. Step 2 [ka] 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 umol, 1 equiv) in THF (5 mL) was added H 2 SO 4 (2M, 4.31mL, 40eq) 2The mixture was added in one portion at 20° C. under reduced pressure. The solution was then heated to 70° C. and stirred for 1 h to give a yellow solution. TLC (DCM:MeOH=10:1, Rf=0.06) showed the reaction was complete. The solution was cooled to 20° C. The solution was diluted with water (5 mL) and NaHCO 3 The pH was adjusted to 7-8. The aqueous phase was extracted with ethyl acetate (3×10 mL). The combined organic phase was washed with brine (2×10 mL) and anhydrous Na 2 SO 4 Drying at 40° C., filtering and concentrating in vacuo afforded 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, 75.72 umol, 35.15% yield, 70.353% purity) as a yellow solid. Step 3 [ka] 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 umol, 1 eq) and 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindoline-1,3-dione hydrochloride (81.54 mg, 215.26 umol, 2 eq) in DMF (2 mL) was added NaOAc (26.49 mg, 322.89 umol, 3 eq) and acetic acid (3.23 mg, 53.81 umol, 3.08 uL, 0.5 eq). The mixture was stirred at 25° C. for 0.5 h. Then, NaBH 3CN (13.53 mg, 215.26 umol, 2 eq) was added to the mixture. The mixture was stirred at 20°C for 16 h. The starting material was completely consumed and the desired compound was detected by LCMS. The residue was filtered and the filtrate was purified by preparative HPLC (column: Agela DuraShell C18 150*25mm*5um; mobile phase: water (0.04% NH3H2O+10 mM Direct purification by hexane distillation (NH4HCO3)-ACN; B%: 50%-80%, gradient time (min): 8 min; flow rate (ml / min): 25) gave 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-piperidyl)isoindoline-1,3-dione (16.4 mg, 20.74 umol, 19.27% ​​yield, 100% purity) as a yellow solid.

[0232] Exemplary Synthesis of Exemplary Compound 22 Step 1 [ka] CH 3 To a solution of 5-isopropoxy-3-[6-[(3S)-3-methylpiperazin-1-yl]pyrimidin-4-yl]-1H-indazole (320 mg, 822.85 umol, 1 eq, HCl salt) and 2-(2,2-diethoxyethoxy)ethyl 4-methylbenzenesulfonate (328.23 mg, 987.42 umol, 1.2 eq) in CN (6 mL) was added KI (1.37 g, 8.23 ​​mmol, 10 eq) and DIEA (1.06 g, 8.23 ​​mmol, 1.43 mL, 10 eq). The mixture was stirred at 90° C. for 18 h. LC-MS showed some new peaks 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) and concentrated with Na 2 SO 4The mixture was dried at 40° C., filtered, and concentrated under reduced pressure to give a residue. The crude product was purified by column chromatography on silica gel (DCM / MeOH=0-10%) to give 3-[6-[(3S)-4-[2-(2,2-diethoxyethoxy)ethyl]-3-methyl-piperazin-1-yl]pyrimidin-4-yl]-5-isopropoxy-1H-indazole (250 mg, 419.40 umol, 50.97% yield, 86% purity) as a yellow oil. Step 2 [ka] 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 umol, 1 equiv) in THF (1 mL) was added H 2 SO 4 (2M, 1.25 mL, 10.25 equiv.) was added. The mixture was stirred at 70° C. for 1 h. TLC showed that the reactants were consumed and one major new spot of greater polarity was detected. The reaction mixture was washed with saturated NaHCO 3 (20 mL) and extracted with EA (30 mL). The combined organic layers were washed with brine (20 mL) and 2 SO 4 Drying at 40° C., filtering, and concentrating under reduced pressure gave 2-[2-[(2S)-4-[6-(5-isopropoxy-1H-indazol-3-yl)pyrimidin-4-yl]-2-methyl-piperazin-1-yl]ethoxy]acetaldehyde (100 mg, 207.52 umol, 85.11% yield, 91% purity) as a pale yellow solid. Step 3 [ka] To a solution of 2-[2-[(2S)-4-[6-(5-isopropoxy-1H-indazol-3-yl)pyrimidin-4-yl]-2-methyl-piperazin-1-yl]ethoxy]acetaldehyde (100 mg, 228.04 umol, 1 equiv.) and 2,2,2-trifluoroacetic acid 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindoline-1,3-dione (104.07 mg, 228.04 umol, 1 equiv.) in DCE (3 mL), was added NaOAc (56.12 mg, 684.12 umol, 3 equiv.), HOAC (13.69 mg, 228.04 umol, 13.04 uL, 1 equiv.) and NaBH 3 CN (42.99 mg, 684.12 umol, 3 equiv.) was added. The mixture was stirred at 25° C. for 18 h. LC-MS (EB134-92-P1C) showed that reactant 1 was consumed. LC-MS showed some new peaks and about 86% of the desired compound was detected. The reaction solution was filtered to remove insoluble material. The reaction solution was purified by preparative HPLC (FA condition: column: Phenomenex Luna C18 100*30mm*5um; mobile phase: [water (0.225% FA)-ACN]; B%: 5%~35%, 18 min) to obtain 2-(2,6-dioxo-3-piperidyl)-5-[4-[2-[2-[(2S)-4-[6-(5-isopropoxy-1H-indazol-3-yl)pyrimidin-4-yl]-2-methyl-piperazin-1-yl]ethoxy]ethyl]piperazin-1-yl]isoindoline-1,3-dione (27.70mg, 34.88umol, yield 15.29%, purity 96.3%) as a yellow solid.

[0233] Exemplary Synthesis of Exemplary Compound 23 Step 1 [ka] To a solution of tert-butyl (3S)-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.) was added. The mixture was then diluted with N 2 The mixture was stirred at 60° C. for 16 h under reduced pressure. TLC (dichloromethane:methanol=10:1, Rf=0.2) showed several new spots of reaction. The reaction mixture was filtered and the filtrate was concentrated. The crude was purified by flash chromatography on silica (0-10% methanol / dichloromethane) to give tert-butyl (3S)-4-(4-hydroxybutyl)-3-methyl-piperazine-1-carboxylate (4 g, 14.69 mmol, 84.03% yield) as a colorless liquid. Step 2 [ka] A solution of oxalyl chloride (512.58 mg, 4.04 mmol, 353.51 uL, 1.1 equiv) in DCM (10 mL) was cooled to -60°C under an atmosphere of dry nitrogen. A solution of DMSO (717.13 mg, 9.18 mmol, 717.13 uL, 2.5 equiv) in DCM (10 mL) was added dropwise and the mixture was then stirred at -60°C for 15 min. Next, a solution of (3R)-tert-butyl 4-(4-hydroxybutyl)-3-methyl-piperazine-1-carboxylate (1 g, 3.67 mmol, 1 equiv) in DCM (10 mL) was added dropwise and the mixture was stirred at -60°C for 45 min. Then TEA (1.11 g, 11.01 mmol, 1.53 mL, 3 equiv) was added and the mixture was warmed to -60°C for 1 h. TLC (dichloromethane:methanol=10:1, Rf=0.4) showed one new spot. The reaction mixture was filtered and the filtrate was used directly in the next step. (3S)-tert-butyl 3-methyl-4-(4-oxobutyl)piperazine-1-carboxylate (990 mg, crude) in DCM solution was used directly in the next step as a colorless liquid. Step 3 [ka] To a solution of 2-(2,6-dioxo-3-piperidyl)-5-piperazin-1-yl-isoindoline-1,3-dione (500 mg, 1.10 mmol, 1 eq, TFA) and (3S)-3-methyl-4-(4-oxobutyl)piperazine-1-carboxylate tert-butyl (446.11 mg, 1.65 mmol, 1.5 eq) in DCM (15 mL) and MeOH (15 mL) was added NaOAc (270.70 mg, 3.30 mmol, 3 eq) and the mixture was stirred at 20° C. for 20 minutes. Then, HOAc (6.61 mg, 110.00 umol, 6.29 uL, 0.1 eq) and NaBH 3 CN (691.24 mg, 11.00 mmol, 10 equiv.) was added to the solution and stirred at 20° C. for 2 h. TLC (dichloromethane:methanol=10:1, Rf=0.01) showed the reaction was complete. The reaction mixture was diluted with H 2 The mixture was poured into 20 mL of ethyl acetate (30 mL*3). The organic phase was washed with brine (20 mL) and anhydrous Na 2 SO 4 The mixture was dried at 40° C. and concentrated in vacuo to give a residue which was purified by silica gel column chromatography (0-20% methanol / dichloromethane) to give tert-butyl (3S)-4-[4-[4-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]piperazin-1-yl]butyl]-3-methyl-piperazine-1-carboxylate (600 mg, 703.85 umol, 63.99% yield, 70% purity) as a yellow gum. Step 4 [ka] To a solution of (3S)-tert-butyl 4-[4-[4-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]piperazin-1-yl]butyl]-3-methyl-piperazine-1-carboxylate (200 mg, 335.17 umol, 1 eq) in DCM (4 mL) was added TFA (3.08 g, 27.01 mmol, 2 mL, 80.59 eq) and the mixture was stirred for 1 h at 15° C. TLC (dichloromethane:methanol=5:1, Rf=0.01) indicated completion of the reaction. The reaction mixture was concentrated in vacuo to give 2-(2,6-dioxo-3-piperidyl)-5-[4-[4-[(2S)-2-methylpiperazin-1-yl]butyl]piperazin-1-yl]isoindoline-1,3-dione (200 mg, crude, TFA) as a yellow gum. Step 5 [ka] To a solution of 2-(2,6-dioxo-3-piperidyl)-5-[4-[4-[(2S)-2-methylpiperazin-1-yl]butyl]piperazin-1-yl]isoindoline-1,3-dione (200 mg, 327.53 umol, 1 eq, TFA) and 3-(6-chloropyrimidin-4-yl)-5-isopropoxy-1H-indazole (66.20 mg, 229.27 umol, 0.7 eq) in DMSO (5 mL) was added DIEA (211.66 mg, 1.64 mmol, 285.25 uL, 5 eq). The mixture was then cooled to 5° C. with 5% CO.sub.2O. 2 The reaction mixture was stirred at 100° C. for 2 hours under H 2The mixture was poured into 2,6-dioxo-3-piperidyl)-5-[4-[4-[(2S)-4-[6-(5-isopropoxy-1H-indazol-3-yl)pyrimidin-4-yl]-2-methyl-piperazin-1-yl]butyl]piperazin-1-yl]isoindoline-1,3-dione (7.9 mg, 10.35 umol, yield 3.16%, purity 98.07%) as a yellow solid.

[0234] Exemplary Synthesis of Exemplary Compound 24 Step 1 [ka] To a solution of 5-(1-methylcyclopropoxy)-3-[6-[(3S)-3-methylpiperazin-1-yl]pyrimidin-4-yl]-1H-indazole (100 mg, 274.39 umol, 1 equiv.) and tert-butyl 4-formylpiperidine-1-carboxylate (117.04 mg, 548.78 umol, 2 equiv.) in DMF (2 mL) was added CH 3 COOH(823.89ug, 13.72umol, 7.85e -1 uL, 0.05 equiv.) and NaOAc (45.02 mg, 548.78 umol, 2 equiv.) were added to N 2 The solution was stirred at 20° C. for 5 hours. Then, NaBH 3 CN (34.49 mg, 548.78 umol, 2 equiv) was added and the solution was stirred for 1 h to give 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 (3×10 mL). The combined organic phase was washed with brine (2×5 mL) and anhydrous Na 2 SO 4The mixture was dried at 40° C., filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (100-200 mesh silica gel, 50-80% ethyl acetate / 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 umol, 62.95% yield, 88.199% purity) as a yellow oil. Step 2 [ka] 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 umol, 1 equiv) in DCM (5 mL) was added TFA (66.99 mg, 587.48 umol, 43.50 uL, 3 equiv) and N 2 The mixture was stirred at 20°C for 1 h. The residue was diluted with NaHCO 3 (5 mL) and adjusted to pH = 7-8. The aqueous phase was extracted with ethyl acetate (3 x 5 mL). The combined organic phase was washed with brine (3 x 5 mL) and anhydrous Na 2 SO 4 The mixture was dried at 40° C., 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 / EtOAc) to give 5-(1-methylcyclopropoxy)-3-[6-[(3S)-3-methyl-4-(4-piperidylmethyl)piperazin-1-yl]pyrimidin-4-yl]-1H-indazole (100 mg, crude) as a yellow gum. Step 3 [ka] To a mixture of 2-(2,6-dioxo-3-piperidyl)-5-fluoro-isoindoline-1,3-dione (100 mg, 362.03 umol, 1 eq.) and 4-piperidylmethanol (83.39 mg, 724.06 umol, 2 eq.) in DMSO (2 mL) was added DIEA (140.37 mg, 1.09 mmol, 189.18 uL, 3 eq.) in one portion at 20° C. The mixture was stirred at 100° C. for 3 h. TLC (DCM:MeOH=10:1, Rf=0.36) indicated the reaction was complete. The mixture was cooled to 20° C. The residue was dissolved in NaHCO 3 (10 mL) and adjusted to pH = 7-8. The aqueous phase was extracted with ethyl acetate (3 x 10 mL). The combined organic phase was washed with brine (2 x 10 mL) and anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (100-200 mesh silica gel, 0-10% MeOH / DCM) to give 2-(2,6-dioxo-3-piperidyl)-5-[4-(hydroxymethyl)-1-piperidyl]isoindoline-1,3-dione (120 mg, 283.18 umol, 78.22% yield, 87.640% purity) as a yellow gum. Step 4 [ka] To a solution of 2-(2,6-dioxo-3-piperidyl)-5-[4-(hydroxymethyl)-1-piperidyl]isoindoline-1,3-dione (120 mg, 323.11 umol, 1 equiv) and TEA (98.09 mg, 969.34 umol, 134.92 uL, 3 equiv) in DCM (5 mL), TsCl (27.35 mg, 387.74 umol, 1.2 equiv) was added and N 2 The mixture was stirred at 20° C. for 20 h to give a yellow solution. TLC (DCM:MeOH=10:1, Rf=0.45) showed the reaction was complete. The residue was poured into water (5 mL). The aqueous phase was extracted with ethyl acetate (3×5 mL). The combined organic phase was washed with brine (2×5 mL) and washed with anhydrous Na 2 SO 4The mixture was dried at 40° C., filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (100-200 mesh silica gel, 0-50% ethyl acetate / petroleum ether 5 min, 50-100% ethyl acetate / petroleum ether 10 min) to give [1-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]-4-piperidyl]methyl 4-methylbenzenesulfonate (160 mg, 228.91 umol, 70.85% yield, 75.194% purity) as a yellow solid. Step 5 [ka] To a solution of 5-(1-methylcyclopropoxy)-3-[6-[(3S)-3-methyl-4-(4-piperidylmethyl)piperazin-1-yl]pyrimidin-4-yl]-1H-indazole (100 mg, 216.64 umol, 1 eq) and [1-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]-4-piperidyl]methyl 4-methylbenzenesulfonate (159.40 mg, 303.29 umol, 1.4 eq) in MeCN (5 mL), KI (179.81 mg, 1.08 mmol, 5 eq) and DIPEA (84.00 mg, 649.91 umol, 113.20 uL, 3 eq) were added. 2 The mixture was added in one portion at 20° C. under reduced pressure. 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 (3×10 mL). The combined organic phase was washed with brine (2×5 mL) and diluted with anhydrous Na 2 SO 4It was dried at 40° C., filtered and concentrated in vacuo to give 200 mg of crude product. The crude product was purified by preparative HPLC (column: Welch Xtimate C18 150*30mm*5um; mobile phase: water (0.225% FA)-ACN; B%: 10%-40%, gradient time (min): 8min; flow rate (ml / min): 25) to give 2-(2,6-dioxo-3-piperidyl)-5-[4-[[4-[[(2S)-2-methyl-4-[6-[5-(1-methylcyclopropoxy)-1H-indazol-3-yl]pyrimidin-4-yl]piperazin-1-yl]methyl]-1-piperidyl]methyl]-1-piperidyl]isoindoline-1,3-dione (53.77mg, 65.33umol, yield 30.15%, purity 99.013%) as a yellow solid.

[0235] Exemplary Synthesis of Exemplary Compound 25 Step 1 [ka] To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (2 g, 9.94 mmol, 1 equiv) in THF (20 mL) was added NaH (516.69 mg, 12.92 mmol, 60% purity in oil, 1.3 equiv) in one portion under nitrogen at 0° C. When hydrogen gas evolution 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 purified with NH 4 It was quenched with aqueous Cl (20 mL) and extracted with ethyl acetate (3×20 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-20% ethyl acetate / 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. Step 2 [ka] 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) was added LiAlH 4 (158.50 mg, 4.18 mmol, 1.5 equiv) was added at 0° C. After the addition, the reaction mixture was stirred at 20° C. for 2 h. TLC (petroleum ether:ethyl acetate=1:1) showed consumption of starting material and formation of one new spot. The reaction mixture was quenched by addition of water (0.5 mL), followed by addition of 15% aqueous NaOH (0.5 mL) and water (1.5 mL). The solids were removed by filtration. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-50% ethyl acetate / petroleum ether) to give tert-butyl 4-(2-hydroxyethoxy)piperidine-1-carboxylate (400 mg, 1.63 mmol, 58.57% yield) as a colorless oil. Step 3 [ka] To a solution of tert-butyl 4-(2-hydroxyethoxy)piperidine-1-carboxylate (400 mg, 1.63 mmol, 1 equiv) in DCM (2 mL) was added 4-methylbenzenesulfonyl chloride (621.72 mg, 3.26 mmol, 2 equiv) and TEA (329.99 mg, 3.26 mmol, 453.91 uL, 2 equiv) at 20° C. 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 (3×10 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-30% ethyl acetate / petroleum ether) to give tert-butyl 4-[2-(p-tolylsulfonyloxy)ethoxy]piperidine-1-carboxylate (490 mg, 1.23 mmol, 75.22% yield, 100% purity) as a colorless oil. Step 4 [ka] CH 3 To a solution of tert-butyl 4-[2-(p-tolylsulfonyloxy)ethoxy]piperidine-1-carboxylate (131.54 mg, 329.27 umol, 1 eq) and 5-(1-methylcyclopropoxy)-3-[6-[(3S)-3-methylpiperazin-1-yl]pyrimidin-4-yl]-1H-indazole (120 mg, 329.27 umol, 1 eq) in CN (3 mL) was added KI (273.30 mg, 1.65 mmol, 5 eq) and DIEA (127.67 mg, 987.81 umol, 172.06 uL, 3 eq). After addition, the reaction mixture was stirred at 90° C. for 16 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3×10 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-5% methanol / 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 (130 mg, 204.31 umol, 62.05% yield, 93% purity) as a yellow gum. Step 5 [ka] 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 umol, 1 eq) in DCM (2 mL) was added HCl / dioxane (4 M, 549.23 uL, 10 eq) at 20° C. After addition, the reaction mixture was stirred at 20° C. for 30 min. TLC (dichloromethane:methanol=10:1) showed consumption of 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 (108 mg, 206.50 umol, 94.00%). Step 6 [ka] CH 3To 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 umol, 1.25 equiv) and [1-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]-4-piperidyl]methyl 4-methylbenzenesulfonate (90 mg, 171.24 umol, 1 equiv) in CN (5 mL) was added KI (142.13 mg, 856.21 umol, 5 equiv) and DIEA (177.05 mg, 1.37 mmol, 238.62 uL, 8 equiv). After the addition, the reaction mixture was stirred at 100° C. for 16 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3×10 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%, 8min) to give 2-(2,6-dioxo-3-piperidyl)-5-[4-[[4-[2-[(2S)-2-methyl-4-[6-[5-(1-methylcyclopropoxy)-1H-indazol-3-yl]pyrimidin-4-yl]piperazin-1-yl]ethoxy]-1-piperidyl]methyl]-1-piperidyl]isoindoline-1,3-dione (12.5mg, 14.50umol, yield 8.47%, purity 98%) as a yellow solid.

[0236] Exemplary Synthesis of Exemplary Compound 26 Step 1 [ka] CH 3To 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 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 column chromatography on silica gel (DCM / MeOH=0-3%) to give (3S)-4-[2-(4-tert-butoxycarbonylpiperazin-1-yl)ethyl]-3-methyl-piperazine-1-carboxylate (460 mg, 1.03 mmol, 48.27% yield) as a brown gum. Step 2 [ka] To a solution of (3S)-benzyl 4-[2-(4-tert-butoxycarbonylpiperazin-1-yl)ethyl]-3-methyl-piperazine-1-carboxylate (460 mg, 1.03 mmol, 1 equiv) in MeOH (5 mL) was added N 2 Pd / C (200 mg, 2.06 mmol, 10% purity, 2 equiv.) was added. The suspension was degassed under vacuum and diluted with H 2 The mixture was purged with H 2 The mixture was stirred at 25° C. under (15 psi) for 2 hours. TLC showed no reactant remaining and one major new spot of greater polarity was detected. 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 (290 mg, 928.15 umol, 90.11% yield) as a pale yellow oil. Step 3 [ka] To a solution of tert-butyl 4-[2-[(2S)-2-methylpiperazin-1-yl]ethyl]piperazine-1-carboxylate (290 mg, 928.15 umol, 1 eq.) and 2-[[3-(6-chloropyrimidin-4-yl)-5-isopropoxy-indazol-1-yl]methoxy]ethyl-trimethyl-silane (388.89 mg, 928.15 umol, 1 eq.) in DMSO (3 mL) was added DIEA (359.87 mg, 2.78 mmol, 485.00 uL, 3 eq.). The mixture was stirred at 100° C. for 2 hours. LC-MS (EB134-185-P1A) showed no reactant 1 remaining. LC-MS showed some new peaks 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) and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered, and concentrated under reduced pressure to give a residue. The crude product was purified by column chromatography on silica gel (DCM / MeOH=0-3%) 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 (590 mg, 812.44 umol, 87.53% yield, 95.7% purity) as a brown gum. Step 4 [ka] 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 umol, 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 22H2O (211.79 mg, 1.51 mmol, 232.74 uL, 25% purity, 3 equiv) was added to the solution and the mixture was stirred for 2 h. LC-MS (EB134-187-P1B) showed no reactant remaining. LC-MS showed some new peaks 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) and washed with NaCl. 2 SO 4 Drying at 40° C., filtering and concentrating under reduced pressure gave 5-isopropoxy-3-[6-[(3S)-3-methyl-4-(2-piperazin-1-ylethyl)piperazin-1-yl]pyrimidin-4-yl]-1H-indazole (150 mg, 313.17 umol, 62.18% yield, 97% purity) as a yellow gum. Step 5 [ka] CH 3 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 umol, 1 equiv.) and [1-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]-4-piperidyl]methyl 4-methylbenzenesulfonate (169.68 mg, 322.85 umol, 1 equiv.) in CN (5 mL) was added KI (428.76 mg, 2.58 mmol, 8 equiv.) and DIEA (333.81 mg, 2.58 mmol, 449.88 uL, 8 equiv.). The mixture was stirred at 80° C. for 16 h. LC-MS (EB134-190-P1D2) showed no remaining reactant 1. LC-MS showed some new peaks 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) and diluted with Na 2 SO 4The residue was purified by preparative HPLC (column: Phenomenex Luna C18 100*30mm*5um; mobile phase: [water (0.225% FA)-ACN]; B%: 10%~40%; 11 min) to obtain 2-(2,6-dioxo-3-piperidyl)-5-[4-[[4-[2-[(2S)-4-[6-(5-isopropoxy-1H-indazol-3-yl)pyrimidin-4-yl]-2-methyl-piperazin-1-yl]ethyl]piperazin-1-yl]methyl]-1-piperidyl]isoindoline-1,3-dione (47mg, 55.39umol, yield 17.16%, purity 96.4%) as a yellow solid.

[0237] Exemplary Synthesis of Exemplary Compound 27 Step 1 [ka] 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 (1.01g, 12.06mmol, 469.07uL, 3eq.) 2 The mixture was added under 25°C under reduced pressure. The reaction mixture was then heated to 80°C and stirred for 5 hours to give a white suspension. TLC (dichloromethane:methanol=10:1) showed the reaction was complete. The mixture was concentrated under vacuum and the residue was taken up in water (30mL). The aqueous phase was extracted with ethyl acetate (30mL*3). The combined organic phase was washed with brine (30mL) and diluted with anhydrous Na 2 SO 4The mixture was dried at 40° C., 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-piperidyl]ethyl]piperazine-1-carboxylate (900 mg, 2.42 mmol, 60.26% yield) as a yellow oil. Step 2 [ka] To a solution of tert-butyl 4-[2-[4-(dimethoxymethyl)-1-piperidyl]ethyl]piperazine-1-carboxylate (800 mg, 2.15 mmol, 1 equiv.) in THF (5 mL) was added HCl (2 M, 5 mL, 4.64 equiv.) at 25° C., and the reaction mixture was then stirred at 50° C. for 2 h to give an off-yellow solution. TLC (dichloromethane:methanol=10:1) showed the reaction was complete. The residue was dissolved in NaHCO 3 (s) was added to adjust pH=8, and then the mixture was poured into water (25 mL). The aqueous phase was extracted with ethyl acetate (25 mL*2). The combined organic phase was washed with brine (30 mL*2) and anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated in vacuo to give tert-butyl 4-[2-(4-formyl-1-piperidyl)ethyl]piperazine-1-carboxylate (420 mg, crude) as an off-yellow oil. Step 3 [ka] To a solution of 2-(2,6-dioxo-3-piperidyl)-5-piperazin-1-yl-isoindoline-1,3-dione (601.45 mg, 1.55 mmol, 1.2 equiv, FA) and NaOAc (423.47 mg, 5.16 mmol, 4 equiv) in DCM (5 mL) and MeOH (5 mL) at 25 °C, the reaction was then stirred for 1 h at 25 °C, and then 4-[2-(4-formyl-1-piperidyl)-2-(4-methyl-1-pyridine)-2-(2 ... tert-Butyl)ethyl]piperazine-1-carboxylate (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 added and stirred at 25°C for 1 h, then the reaction mixture was stirred at 25°C for 14 h to give a yellow solution. TLC (dichloromethane:methanol=10:1) showed 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). The aqueous phase was then lyophilized to give a yellow solid. The solid was washed with MeOH / DCM (1 / 1, 40 mL) to give a yellow suspension. The suspension was filtered and concentrated under vacuum to give 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 give tert-butyl 4-[2-[4-[[4-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]piperazin-1-yl]methyl]-1-piperidyl]ethyl]piperazine-1-carboxylate (320 mg, 490.95 umol, 38.04% yield) as a yellow oil. Step 4 [ka] To a solution of tert-butyl 4-[2-[4-[[4-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]piperazin-1-yl]methyl]-1-piperidyl]ethyl]piperazine-1-carboxylate (320 mg, 490.95 umol, 1 eq) in DCM (10 mL) was added TFA (3.08 g, 27.01 mmol, 2 mL, 55.02 eq) at 25° C., and the reaction mixture was then stirred at 25° C. for 0.5 h to give a yellow solution. TLC (dichloromethane:methanol=10:1) showed consumption of starting material and formation of one new spot. The reaction mixture was concentrated in vacuo to give 2-(2,6-dioxo-3-piperidyl)-5-[4-[[1-(2-piperazin-1-ylethyl)-4-piperidyl]methyl]piperazin-1-yl]isoindoline-1,3-dione (480 mg, 395.33 umol, 80.52% yield, 83% purity, 4TFA) as a yellow solid. Step 5 [ka] To a solution of 2-(2,6-dioxo-3-piperidyl)-5-[4-[[1-(2-piperazin-1-ylethyl)-4-piperidyl]methyl]piperazin-1-yl]isoindoline-1,3-dione (160 mg, 158.77 umol, 1 eq, 4TFA) and 3-(6-chloropyrimidin-4-yl)-5-isopropoxy-1H-indazole (45.84 mg, 158.77 umol, 1 eq) in DMSO (10 mL) was added DIEA (102.60 mg, 793.83 umol, 138.27 uL, 5 eq) at 25° C., then the reaction mixture was stirred at 25° C. for 30 minutes, then the reaction mixture was stirred at 80° C. for 1.5 hours to give 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 phase was washed with brine (30 mL*2) and anhydrous Na 2 SO 4The 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 2-(2,6-dioxo-3-piperidyl)-5-[4-[[1-[2-[4-[6-(5-isopropoxy-1H-indazol-3-yl)pyrimidin-4-yl]piperazin-1-yl]ethyl]-4-piperidyl]methyl]piperazin-1-yl]isoindoline-1,3-dione (6.8mg, 8.42umol, yield 5.31%, purity 99.6%) as a yellow solid.

[0238] Exemplary Synthesis of Exemplary Compound 28 Step 1 [ka] To a solution of 2-(2,6-dioxo-3-piperidyl)-5-[4-[[1-(2-piperazin-1-ylethyl)-4-piperidyl]methyl]piperazin-1-yl]isoindoline-1,3-dione (160 mg, 158.77 umol, 1 eq, 4 TFA) and 3-(6-chloropyrimidin-4-yl)-5-(1-methylcyclopropoxy)-1H-indazole (47.75 mg, 158.77 umol, 1 eq) in DMSO (5 mL) was added DIEA (102.60 mg, 793.83 umol, 138.27 uL, 5 eq) at 25° C. and stirred for 30 minutes, then the reaction mixture was stirred at 80° C. for 1.5 hours to give a yellow solution. The residue was poured into water (35 mL). The aqueous phase was extracted with ethyl acetate (30 mL*2). The combined organic phase was washed with brine (35 mL*2) and anhydrous Na 2 SO 4The residue was purified by preparative HPLC (column Phenomenex Luna C18 100*30mm*5um, mobile phase: water (0.225% FA)-ACN; B%: 5%~35%; 9min) to give 2-(2,6-dioxo-3-piperidyl)-5-[4-[[1-[2-[4-[6-[5-(1-methylcyclopropoxy)-1H-indazol-3-yl]pyrimidin-4-yl]piperazin-1-yl]ethyl]-4-piperidyl]methyl]piperazin-1-yl]isoindoline-1,3-dione (7.0mg, 8.56umol, yield 5.39%, purity 99.8%) as a yellow solid.

[0239] Exemplary Synthesis of Exemplary Compound 29 Step 1 [ka] To a solution of (3S)-benzyl 3-methylpiperazine-1-carboxylate (300 mg, 1.28 mmol, 1 equiv) and 2-chloroacetaldehyde (753.84 mg, 3.84 mmol, 617.90 uL, 3 equiv) in DCM (5 mL) and MeOH (5 mL) was added HOAc (7.69 mg, 128.04 umol, 7.32 uL, 0.1 equiv). The mixture was then stirred at 25° C. for 20 min. NaBH 3 CN (241.39 mg, 3.84 mmol, 3 equiv) 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 diluted with H 2 The mixture was poured into 200 mL of ethyl acetate (10 mL*3). The mixture was extracted with ethyl acetate (20 mL*3). The organic phase was washed with brine (20 mL) and anhydrous Na 2 SO 4 The mixture was dried at 40° C. and concentrated in vacuo to give a residue, which was purified by silica gel column chromatography (0-100% ethyl acetate / petroleum ether) to give (3S)-4-(2-chloroethyl)-3-methyl-piperazine-1-benzyl carboxylate (180 mg, 606.49 umol, 47.37% yield) as a colorless oil. Step 2 [ka] (3S)-benzyl 4-(2-chloroethyl)-3-methyl-piperazine-1-carboxylate (180 mg, 606.49 umol, 1 eq.) and 4-(dimethoxymethyl)piperidine (144.85 mg, 909.73 umol, 1.5 eq.) were dissolved in EtOH (5 mL) and water (0.5 mL) and then added NaHCO 3 (101.90 mg, 1.21 mmol, 47.17 uL, 2 equiv) was added to the reaction and stirred at 80° C. for 5 h. TLC (dichloromethane:methanol=10:1, Rf=0.4) showed the reaction was complete. The reaction mixture was diluted with H 2 The mixture was poured into 200 mL of ethyl acetate (20 mL*2). The mixture was extracted with ethyl acetate (20 mL*2). The organic phase was washed with brine (15 mL*3) and anhydrous Na 2 SO 4 The residue was dried at 40° C. and concentrated in vacuum to give a residue. The residue was purified by preparative TLC (10% methanol / dichloromethane, Rf=0.4) to give (3S)-4-[2-[4-(dimethoxymethyl)-1-piperidyl]ethyl]-3-methyl-piperazine-1-carboxylate benzyl (165 mg, 393.27 umol, 64.84% yield) as a colorless oil. Step 3 [ka] THF (2 mL) and H 2 SO 4 A solution of (3S)-benzyl 4-[2-[4-(dimethoxymethyl)-1-piperidyl]ethyl]-3-methyl-piperazine-1-carboxylate (65 mg, 154.93 umol, 1 eq) in (2M, 2 mL, 25.82 eq) was stirred at 70° C. for 1 h. TLC (dichloromethane:methanol=10:1, Rf=0.2) indicated consumption of starting material. The reaction mixture was diluted with H 2 Pour into 20 mL of NaHCO 3 The mixture was basified with aqueous solution of ethyl acetate (20 mL*5) and diluted with anhydrous Na 2 SO 4Drying at 40° C. and concentration in vacuo afforded (3S)-benzyl 4-[2-(4-formyl-1-piperidyl)ethyl]-3-methyl-piperazine-1-carboxylate (57 mg, crude) as a colorless oil. Step 4 [ka] To a solution of (3S)-4-[2-(4-formyl-1-piperidyl)ethyl]-3-methyl-piperazine-1-carboxylate benzyl (57 mg, 152.62 umol, 1 eq) and 2-(2,6-dioxo-3-piperidyl)-5-piperazin-1-yl-isoindoline-1,3-dione (69.65 mg, 152.62 umol, 1 eq, TFA) in DCE (3 mL) and MeOH (0.5 mL) was added NaOAc (54.81 mg, 668.11 umol, 4.38 eq) and the mixture was stirred at 25° C. for 20 minutes. Then HOAc (916.49 ug, 15.26 umol, 8.73e-1 uL, 0.1 eq) was added to the mixture and stirred at 25° C. for 20 minutes. Then NaBH 3 CN (54.81 mg, 872.15 umol, 5.71 equiv) was added to the solution and stirred at 25° C. for 16 h. TLC (dichloromethane:methanol=10:1, Rf=0.2) showed the reaction was complete. The reaction mixture was diluted with H 2 The mixture was poured into 200 mL of ethyl acetate (20 mL*2). The mixture was extracted with ethyl acetate (20 mL*2). The organic phase was washed with brine (15 mL*3) and anhydrous Na 2 SO 4 The residue was dried at 40° C. and concentrated under vacuum to give a residue. The residue was purified by preparative TLC (10% methanol / dichloromethane, Rf=0.2) to give (3S)-4-[2-[4-[[4-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]piperazin-1-yl]methyl]-1-piperidyl]ethyl]-3-methyl-piperazine-1-carboxylate benzyl (60 mg, 68.59 umol, 44.94% yield, 80% purity) as a white solid. Step 5 [ka] A mixture of (3S)-benzyl 4-[2-[4-[[4-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]piperazin-1-yl]methyl]-1-piperidyl]ethyl]-3-methyl-piperazine-1-carboxylate (60 mg, 85.73 umol, 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 the reaction was complete. The reaction mixture was concentrated in vacuo to give 2-(2,6-dioxo-3-piperidyl)-5-[4-[[1-[2-[(2S)-2-methylpiperazin-1-yl]ethyl]-4-piperidyl]methyl]piperazin-1-yl]isoindoline-1,3-dione (48 mg, crude, TFA) as a yellow solid. Step 6 [ka] 2-(2,6-Dioxo-3-piperidyl)-5-[4-[[1-[2-[(2S)-2-methylpiperazin-1-yl]ethyl]-4-piperidyl]methyl]piperazin-1-yl]isoindoline-1,3-dione (48 mg, 70.62 umol, 1 eq, TFA) and 3-(6-chloropyrimidin-4-yl)-5-(1-methylcyclopropoxy)-1H-indazole (21.24 mg, 70.62 umol, 1 eq) were dissolved in DMSO (5 mL) and then DIEA (91.27 mg, 706.16 umol, 123.00 uL, 10 eq) was added to the reaction. The reaction was stirred at 80° C. for 8 hours. The reaction mixture was diluted with H 2 The mixture was poured into 200 mL of ethyl acetate (20 mL*2). The mixture was extracted with ethyl acetate (20 mL*2). The organic phase was washed with brine (15 mL*3) and anhydrous Na 2 SO 4The residue was purified by preparative HPLC (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-piperidyl)-5-[4-[[1-[2-[(2S)-2-methyl-4-[6-[5-(1-methylcyclopropoxy)-1H-indazol-3-yl]pyrimidin-4-yl]piperazin-1-yl]ethyl]-4-piperidyl]methyl]piperazin-1-yl]isoindoline-1,3-dione (8.4mg, 9.78umol, yield 13.85%, purity 96.64%) as a yellow solid.

[0240] Exemplary Synthesis of Exemplary Compound 30 Step 1 [ka] To a solution of 2-(2,6-dioxo-3-piperidyl)-5-[4-[[1-[2-[(2S)-2-methylpiperazin-1-yl]ethyl]-4-piperidyl]methyl]piperazin-1-yl]isoindoline-1,3-dione (100 mg, 176.77 umol, 1 equiv) and 3-(6-chloropyrimidin-4-yl)-5-isopropoxy-1H-indazole (51.04 mg, 176.77 umol, 1 equiv) in DMSO (3 mL) was added DIEA (228.46 mg, 1.77 mmol, 307.90 uL, 10 equiv). The reaction mixture was cooled to 5° C. for 2 hours and cooled to 5° C. for 2 hours. 2The mixture was stirred at 80° C. for 6 hours under reduced pressure. 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 HPLC (column: Phenomenex Luna C18 100*30mm*5um; mobile phase: [water (0.225% FA)-ACN]; B%: 12%~42%, 9min) to give 2-(2,6-dioxo-3-piperidyl)-5-[4-[[1-[2-[(2S)-4-[6-(5-isopropoxy-1H-indazol-3-yl)pyrimidin-4-yl]-2-methyl-piperazin-1-yl]ethyl]-4-piperidyl]methyl]piperazin-1-yl]isoindoline-1,3-dione (32.1mg, 39.00umol, yield 22.06%, purity 99.38%) as a yellow solid.

[0241] Exemplary Synthesis of Exemplary Compound 31 Step 1 [ka] To a solution of 3-(1-oxo-5-piperazin-1-yl-isoindolin-2-yl)piperidine-2,6-dione (118.69 mg, 361.46 umol, 1.5 eq) and NaOAc (59.30 mg, 722.91 umol, 3 eq) in DCE (8 mL) and MeOH (2 mL) was added HOAc (14.47 mg, 240.97 umol, 13.78 uL, 1 eq) and (3S)-4-[2-(4-formyl-1-piperidyl)ethyl]-3-methyl-piperazine-1-benzyl carboxylate (90 mg, 240.97 umol, 1 eq). The reaction mixture was stirred at 25° C. for 1 h. Then, NaBH 3CN (30.29 mg, 481.94 umol, 2 equiv.) was added. After the addition, the reaction mixture was stirred at 25° C. for 16 h. The reaction solution was diluted with water (15 mL) and extracted with ethyl acetate (3×10 mL). The organic layer was washed with brine (20 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative TLC (chloromethane:methanol=7:1, Rf=0.1) to give (3S)-benzyl 4-[2-[4-[[4-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperazin-1-yl]methyl]-1-piperidyl]ethyl]-3-methyl-piperazine-1-carboxylate (70 mg, 85.32 umol, 35.41% yield, 83.6% purity) as a colorless gum. Step 2 [ka] A mixture of (3S)-4-[2-[4-[[4-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperazin-1-yl]methyl]-1-piperidyl]ethyl]-3-methyl-piperazine-1-carboxylate (70 mg, 102.06 umol, 1 eq) and TFA (3 mL) was stirred at 80° C. for 2 hours. The reaction solution was concentrated under reduced pressure to give 3-[5-[4-[[1-[2-[(2S)-2-methylpiperazin-1-yl]ethyl]-4-piperidyl]methyl]piperazin-1-yl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (110 mg, crude, TFA) as a brown gum. The crude product was used directly. Step 3 [ka] To a solution of 3-[5-[4-[[1-[2-[(2S)-2-methylpiperazin-1-yl]ethyl]-4-piperidyl]methyl]piperazin-1-yl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (103.76 mg, 155.85 umol, 1.5 eq, TFA) and 3-(6-chloropyrimidin-4-yl)-5-isopropoxy-1H-indazole (30 mg, 103.90 umol, 1 eq) in DMSO (3 mL) was added DIEA (94.00 mg, 727.32 umol, 126.69 uL, 7 eq). After addition, the reaction was stirred at 100° C. for 4 hours to give a brown solution. The reaction mixture was diluted with water (15 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 HPLC (column: Phenomenex Luna C18 100*30mm*5um; mobile phase: [water (0.225% FA)-ACN]; B%: 5%~35%; 9 min) to obtain 3-[5-[4-[[1-[2-[(2S)-4-[6-(5-isopropoxy-1H-indazol-3-yl)pyrimidin-4-yl]-2-methyl-piperazin-1-yl]ethyl]-4-piperidyl]methyl]piperazin-1-yl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (9.1mg, 11.32umol, yield 10.89%, purity 100%) as a yellow solid.

[0242] Exemplary Synthesis of Exemplary Compound 32 Step 1 [ka] 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.) 2The mixture was stirred at 20° C. for 16 h. TLC (DCM:MeOH=10:1, Rf=0.77) showed the reaction was complete. 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 phase was washed with brine (50 mL*3) and diluted with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (40 g, 0-10% (10 mL) ethyl acetate / 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. Step 2 [ka] 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) at 0° C. 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 that there was one new spot. The residue was poured into water (50 mL). The aqueous phase was extracted with ethyl acetate (50 mL*3). The combined organic phase was washed with brine (50 mL*2) and anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (45 g, 30 mL / min, 0-50% (15 min) ethyl acetate / petroleum ether) to give tert-butyl 3-(2-tetrahydropyran-2-yloxyethoxy)azetidine-1-carboxylate (6.6 g, 21.90 mmol, 75.86% yield) as a yellow oil. Step 3 [ka] 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), TsOH (3.43 g, 19.91 mmol, 1 equiv.) was added in N 2 The mixture was stirred at 20° C. for 1 hour. TLC (petroleum ether:ethyl acetate=2:3, Rf=0.30) showed the reaction was complete. 2 O (30 mL) was added to the reaction mixture, and the mixture was extracted with EtOAc (30 mL*3). The combined extracts were washed with saturated NaHCO 3 (30mL*2, aqueous solution), washed with brine (30mL), and anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (40 g, 30 mL / min, 0-100% ethyl acetate / petroleum ether (30 min)) to give tert-butyl 3-(2-hydroxyethoxy)azetidine-1-carboxylate (1.5 g, 6.90 mmol, 34.68% yield) as a yellow oil. Step 4 [ka] To a mixture of tert-butyl 3-(2-hydroxyethoxy)azetidine-1-carboxylate (1.5 g, 6.90 mmol, 1 eq.), TEA (1.75 g, 17.26 mmol, 2.40 mL, 2.5 eq.) and DMAP (253.04 mg, 2.07 mmol, 0.3 eq.) in DCM (15 mL), TosCl (1.97 g, 10.36 mmol, 1.5 eq.) was added at 0° C. 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) showed the reaction was complete. Most of the DCM was removed under reduced pressure to give a residue. The residue was dissolved in EtOAc (30 mL) and the resulting mixture was washed with water (10 mL*2), saturated NaHCO 3 (10mL*2, aqueous solution), washed with brine (10mL), and anhydrous Na2 SO 4 The mixture was dried at 40° C., filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (20 g, 0-15% (10 min) ethyl acetate / petroleum ether, 15% (5 min) ethyl acetate / petroleum ether) to give tert-butyl 3-[2-(p-tolylsulfonyloxy)ethoxy]azetidine-1-carboxylate (2.3 g, 6.19 mmol, 89.69% yield) as a yellow oil. Step 5 [ka] To a mixture of 2-(2,6-dioxo-3-piperidyl)-5-hydroxy-isoindoline-1,3-dione (1.55 g, 5.65 mmol, 1 equiv.) in DMF (20 mL) was added Na 2 CO 3 (1.20 g, 11.31 mmol, 2 equiv.) and tert-butyl 3-[2-(p-tolylsulfonyloxy)ethoxy]azetidine-1-carboxylate (2.1 g, 5.65 mmol, 1 equiv.) were added. The mixture was stirred at 70° C. for 16 h to give a yellow mixture. The reaction mixture was cooled to room temperature, and aqueous HCl (100 mL, 2%, v / v) was added at 0° C., and the resulting mixture was extracted with EtOAc (30 mL*3). The combined extracts were washed with water (30 mL), brine (30 mL), and anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered, and the filtrate was concentrated under reduced pressure to give a residue that was purified by flash silica gel chromatography (DCM:MeOH=10:1, Rf=0.31, 80 g, 0-50% (30 min) ethyl acetate / petroleum ether, 50% (60 min) ethyl acetate / petroleum ether) to give tert-butyl 3-[2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]oxyethoxy]azetidine-1-carboxylate (1.8 g, 3.80 mmol, 67.24% yield) as a white gum. Step 6 [ka] To a mixture of tert-butyl 3-[2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]oxyethoxy]azetidine-1-carboxylate (1.2 g, 2.53 mmol, 1 equiv.) in DCM (10 mL), TFA (866.94 mg, 7.60 mmol, 562.95 uL, 3 equiv.) was added N 2 The mixture was added in one portion at 20° C. under reduced pressure. The mixture was stirred at 20° C. for 30 min. TLC showed the reaction was complete. The mixture was concentrated under reduced pressure to give 5-[2-(azetidin-3-yloxy)ethoxy]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (2 g, crude) as a colorless gum. Step 7 [ka] To a solution of 5-[2-(azetidin-3-yloxy)ethoxy]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (2 g, 5.36 mmol, 1 equiv.) and 2-chloroacetaldehyde (3.15 g, 16.07 mmol, 2.58 mL, 3 equiv.) in DCE (10 mL) and MeOH (2 mL) was added NaOAc (2.20 g, 26.78 mmol, 5 equiv.) and NaBH 3 CN (1.01g, 16.07mmol, 3eq) was added. The mixture was then stirred at 20°C for 30 min. HOAc (321.67mg, 5.36mmol, 306.36uL, 1eq) was then added to the solution and stirred at 20°C for 1 h. TLC (DCM:MeOH=10:1, Rf=0.29) showed one new spot. The residue was poured into water (10mL). The aqueous phase was extracted with ethyl acetate (10mL*3). The combined organic phase was washed with brine (10mL*2) and anhydrous Na 2 SO 4The residue was purified by silica gel chromatography (20 g, 30 mL / min, 0-5% (10 min) MeOH / DCM, 5% (10 min) MeOH / DCM) to give 5-[2-[1-(2-chloroethyl)azetidin-3-yl]oxyethoxy]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (700 mg, 1.61 mmol, 29.98% yield) as a yellow gum. Step 8 [ka] To a mixture of tert-butyl (3S)-3-methylpiperazine-1-carboxylate (229.75mg, 1.15mmol, 2eq) and 5-[2-[1-(2-chloroethyl)azetidin-3-yl]oxyethoxy]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (250mg, 573.58umol, 1eq) in MeCN (5mL) was added KI (476.07mg, 2.87mmol, 5eq) and DIPEA (370.65mg, 2.87mmol, 499.53uL, 5eq) and N 2 The mixture was stirred at 80° C. for 16 hours. The residue was poured into water (5 mL). The aqueous phase was extracted with ethyl acetate (5 mL*3). The combined organic phase was washed with brine (5 mL*2) and diluted with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (0-100% (30 min) ethyl acetate / petroleum ether) to give tert-butyl (3S)-4-[2-[3-[2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]oxyethoxy]azetidin-1-yl]ethyl]-3-methyl-piperazine-1-carboxylate (200 mg, 333.51 umol, 58.15% yield) as a yellow solid. Step 9 [ka] To a mixture of (3S)-tert-butyl 4-[2-[3-[2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]oxyethoxy]azetidin-1-yl]ethyl]-3-methyl-piperazine-1-carboxylate (200 mg, 333.51 umol, 1 equiv.) in DCM (5 mL), TFA (114.09 mg, 1.00 mmol, 74.08 uL, 3 equiv.) was added and N 2 The mixture was added in one portion at 20° C. under reduced pressure. The mixture was stirred at 20° C. for 30 minutes. The solution was concentrated in vacuo to give 2-(2,6-dioxo-3-piperidyl)-5-[2-[1-[2-[(2S)-2-methylpiperazin-1-yl]ethyl]azetidin-3-yl]oxyethoxy]isoindoline-1,3-dione (130 mg, 166.55 umol, 49.94% yield, 64% purity) as a colorless gum. Step 10 [ka] 3-(6-chloropyrimidin-4-yl)-5-isopropoxy-2H-indazole (60.11 mg, 208.18 umol, 0.8 equiv.) and 2-(2,6-dioxo-3-piperidyl)-5-[2-[1-[2-[(2S)-2-methylpiperazin-1-yl]ethyl]azetidin-3-yl]oxyethoxy]isoindoline-1,3-dione (130 mg, 260.23 umol, 1 equiv.) were dissolved in DMSO (5 mL) and then DIPEA (100.90 mg, 780.69 umol, 135.98 uL, 3 equiv.) was added to the N 2 The mixture was added under reduced pressure at 20°C. The solution was stirred at 100°C for 2 hours to give a yellow solution. The mixture was cooled to 20°C and concentrated under reduced pressure at 20°C. The residue was poured into water (10mL). The aqueous phase was extracted with ethyl acetate (10mL*3). The combined organic phase was washed with brine (10mL*3) and diluted with anhydrous Na 2 SO 4The crude product was purified by reverse phase HPLC (column: Phenomenex luna C18 150*25mm*10um; condition: water (0.2% FA)-ACN; start B: 20; end B: 40; flow rate: 25mL / min; gradient time: 20min; 100% B retention time: 4min) to give 2-(2,6-dioxo-3-piperidyl)-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 (26.3mg, 34.98umol, yield 13.44%, purity 100%) as a white solid.

[0243] Exemplary Synthesis of Exemplary Compound 33 Step 1 [ka] To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (2 g, 9.94 mmol, 1 equiv) in THF (20 mL) was added NaH (516.69 mg, 12.92 mmol, 60% purity in oil, 1.3 equiv) in one portion under nitrogen at 0° C. When hydrogen gas evolution 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 purified with NH 4 It was quenched with aqueous Cl (20 mL) and extracted with ethyl acetate (3×20 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-20% ethyl acetate / 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. Step 2 [ka] 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) was added LiAlH 4 (158.50 mg, 4.18 mmol, 1.5 equiv) was added at 0° C. After the addition, the reaction mixture was stirred at 20° C. for 2 h. TLC (petroleum ether:ethyl acetate=1:1) showed consumption of starting material and formation of one new spot. The reaction mixture was quenched by addition of water (0.5 mL), followed by addition of 15% aqueous NaOH (0.5 mL) and water (1.5 mL). The solids were removed by filtration. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-50% ethyl acetate / petroleum ether) to give tert-butyl 4-(2-hydroxyethoxy)piperidine-1-carboxylate (400 mg, 1.63 mmol, 58.57% yield) as a colorless oil. Step 3 [ka] To a solution of tert-butyl 4-(2-hydroxyethoxy)piperidine-1-carboxylate (400 mg, 1.63 mmol, 1 equiv) in DCM (2 mL) was added 4-methylbenzenesulfonyl chloride (621.72 mg, 3.26 mmol, 2 equiv) and TEA (329.99 mg, 3.26 mmol, 453.91 uL, 2 equiv) at 20° C. 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 (3×10 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-30% ethyl acetate / petroleum ether) to give tert-butyl 4-[2-(p-tolylsulfonyloxy)ethoxy]piperidine-1-carboxylate (490 mg, 1.23 mmol, 75.22% yield, 100% purity) as a colorless oil. Step 4 [ka] CH 3 To a solution of tert-butyl 4-[2-(p-tolylsulfonyloxy)ethoxy]piperidine-1-carboxylate (131.54 mg, 329.27 umol, 1 eq) and 5-(1-methylcyclopropoxy)-3-[6-[(3S)-3-methylpiperazin-1-yl]pyrimidin-4-yl]-1H-indazole (120 mg, 329.27 umol, 1 eq) in CN (3 mL) was added KI (273.30 mg, 1.65 mmol, 5 eq) and DIEA (127.67 mg, 987.81 umol, 172.06 uL, 3 eq). After addition, the reaction mixture was stirred at 90° C. for 16 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3×10 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-5% methanol / 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 (130 mg, 204.31 umol, 62.05% yield, 93% purity) as a yellow gum. Step 5 [ka] 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 umol, 1 eq) in DCM (2 mL) was added HCl / dioxane (4 M, 549.23 uL, 10 eq) at 20° C. After addition, the reaction mixture was stirred at 20° C. for 30 min. TLC (dichloromethane:methanol=10:1) showed consumption of 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 (108 mg, 206.50 umol, 94.00% yield, 94% purity) as a yellow solid. The crude product was used directly. Step 6 [ka] CH 3To 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 umol, 1.25 equiv) and [1-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]-4-piperidyl]methyl 4-methylbenzenesulfonate (90 mg, 171.24 umol, 1 equiv) in CN (5 mL) was added KI (142.13 mg, 856.21 umol, 5 equiv) and DIEA (177.05 mg, 1.37 mmol, 238.62 uL, 8 equiv). After the addition, the reaction mixture was stirred at 100° C. for 16 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3×10 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%, 8min) to give 2-(2,6-dioxo-3-piperidyl)-5-[4-[[4-[2-[(2S)-2-methyl-4-[6-[5-(1-methylcyclopropoxy)-1H-indazol-3-yl]pyrimidin-4-yl]piperazin-1-yl]ethoxy]-1-piperidyl]methyl]-1-piperidyl]isoindoline-1,3-dione (12.5mg, 14.50umol, yield 8.47%, purity 98%) as a yellow solid.

[0244] Exemplary Synthesis of Exemplary Compound 34 Step 1 [ka] But-3-yn-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 dry DMF (10 mL), and then NaH (684.77 mg, 17.12 mmol, 60% purity, 1.2 equiv.) was added in portions 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 of reaction. The reaction was purified by NH 4 The mixture was quenched with aqueous Cl (10 mL) and extracted with ethyl acetate (3*20 mL). The combined organic phase was washed with water and 2 SO 4 The mixture was dried at 40° C. and concentrated in vacuo to give a residue which was purified by silica gel column chromatography (0-20% ethyl acetate / petroleum ether) to give 4-(2,2-diethoxyethoxy)but-1-yne (600 mg, 3.22 mmol, 22.58% yield) as a colorless oil. Step 2 [ka] To a flame dried 3-neck 100 mL round bottom flask equipped with an argon inlet adapter, septum, and stir bar was added 4-(2,2-diethoxyethoxy)but-1-yne (600 mg, 3.22 mmol, 1 equiv) and THF (10 mL) via syringe. The solution was cooled to -78°C (bath temperature) in a dry ice / acetone bath and n-BuLi (2.5 M, 1.55 mL, 1.2 equiv) was added dropwise via syringe, turning the reaction brown. The reaction was stirred at -78°C for 30 minutes and DMF (470.95 mg, 6.44 mmol, 495.73 uL, 2 equiv) was added dropwise via syringe, turning the reaction colorless. The reaction was stirred at -78°C for 30 minutes and then warmed to 25°C and stirred for 2 hours. TLC (petroleum ether:ethyl acetate=2:1, Rf=0.1) showed one new spot. The reaction was diluted with ethyl acetate (10 mL) and 10% KH 2 PO 4(10 mL) and stirred for 30 min. The aqueous layer was separated and the organic layer was washed with brine (20 mL), dried over magnesium sulfate, gravity filtered and concentrated under reduced pressure to give 5-(2,2-diethoxyethoxy)pent-2-ynal (350 mg, crude) as a yellow oil. Step 3 [ka] To a solution of 2-(2,6-dioxo-3-piperidyl)-5-piperazin-1-yl-isoindoline-1,3-dione (100 mg, 219.12 umol, 1 eq, TFA) and 5-(2,2-diethoxyethoxy)pent-2-ynal (93.90 mg, 438.24 umol, 2 eq) in DCE (5 mL) and MeOH (1 mL) was added NaOAc (53.92 mg, 657.36 umol, 3 eq) and HOAc (2.63 mg, 43.82 umol, 2.51 uL, 0.2 eq). The mixture was then stirred at 20° C. for 30 minutes. NaBH 3 CN (41.31 mg, 657.36 umol, 3 equiv) was added and the solution was stirred at 20° C. for 2 h. TLC (dichloromethane:methanol=10:1, Rf=0.37) indicated consumption of starting material. The reaction mixture was diluted with H 2 The mixture was poured into 200 mL of ethyl acetate (10 mL*5). The mixture was extracted with ethyl acetate (20 mL*5). The organic phase was washed with brine (20 mL) and anhydrous Na 2 SO 4 The mixture was dried at 40° C. and concentrated in vacuo to give a residue, which was purified by preparative TLC (10% methanol / dichloromethane) to give 5-[4-[5-(2,2-diethoxyethoxy)pent-2-ynyl]piperazin-1-yl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (120 mg, 188.68 umol, 86.11% yield, 85% purity) as a yellow solid. Step 4 [ka] To a solution of 5-[4-[5-(2,2-diethoxyethoxy)pent-2-ynyl]piperazin-1-yl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (95 mg, 175.73 umol, 1 equiv) in THF (2 mL) was added H 2 SO 4 (2M, 2 mL, 86.50 equiv.) was added. The mixture was then stirred at 65° C. for 1 h. TLC (dichloromethane:methanol=10:1, Rf=0.37) showed consumption of starting material. The reaction mixture was diluted with H 2 Pour into 2 mL of O and add NaHCO 3 The mixture was basified with aqueous solution of ethyl acetate (15 mL*5) and diluted with anhydrous Na 2 SO 4 Drying in vacuo afforded 2-[5-[4-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]piperazin-1-yl]pent-3-ynoxy]acetaldehyde (80 mg, crude) as a yellow solid. Step 5 [ka] To a solution of 5-isopropoxy-3-[6-[(3S)-3-methylpiperazin-1-yl]pyrimidin-4-yl]-1H-indazole (100 mg, 283.74 umol, 1 eq.) and 2-[5-[4-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]piperazin-1-yl]pent-3-ynoxy]acetaldehyde (80.00 mg, 171.50 umol, 6.04e-1 eq.) in DCE (5 mL) and MeOH (2 mL), NaOAc (69.83 mg, 851.23 umol, 3 eq.) and HOAc (3.41 mg, 56.75 umol, 3.25 uL, 0.2 eq.) were added. The mixture was then stirred at 25° C. for 60 min. Next, NaBH 3 CN (53.49 mg, 851.23 umol, 3 equiv) was added and the solution was stirred at 25° C. for 16 h. TLC (dichloromethane:methanol=10:1, Rf=0.37) showed no starting material. The reaction mixture was diluted with H 2The mixture was poured into 200 mL of ethyl acetate (10 mL*5). The mixture was extracted with ethyl acetate (20 mL*5). The organic phase was washed with brine (20 mL) and anhydrous Na 2 SO 4 The residue was purified by preparative HPLC (Phenomenex Luna C18 100*30mm*5um; mobile phase: [water (0.225% FA)-ACN]; B%: 8%-38%, 9 min) to give 2-(2,6-dioxo-3-piperidyl)-5-[4-[5-[2-[(2S)-4-[6-(5-isopropoxy-1H-indazol-3-yl)pyrimidin-4-yl]-2-methyl-piperazin-1-yl]ethoxy]pent-2-ynyl]piperazin-1-yl]isoindoline-1,3-dione (19.4mg, 23.60umol, yield 8.32%, purity 97.68%) as a yellow solid.

[0245] Exemplary Synthesis of Exemplary Compound 35 Step 1 [ka] To a solution of tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (200 mg, 1.01 mmol, 1 eq) and 2-chloroacetaldehyde (593.89 mg, 3.03 mmol, 486.80 uL, 3 eq) in DCM (5 mL) and MeOH (5 mL) was added NaOAc (165.51 mg, 2.02 mmol, 2 eq) and HOAc (6.06 mg, 100.88 umol, 5.77 uL, 0.1 eq). The mixture was then stirred at 20° C. for 20 minutes. 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 diluted with H 2 The mixture was poured into 20 mL of ethyl acetate (30 mL*3). The organic phase was washed with brine (20 mL) and anhydrous Na 2 SO 4The mixture was dried at 40° C. and concentrated in vacuo to give a residue, which was purified by silica gel column chromatography (0-100% ethyl acetate / petroleum ether) to give tert-butyl 6-(2-chloroethyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (165 mg, 632.77 umol, 62.73% yield) as a colorless oil. Step 2 [ka] tert-Butyl 6-(2-chloroethyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (81.39 mg, 312.12 umol, 1 equiv) and 5-isopropoxy-3-[6-[(3S)-3-methylpiperazin-1-yl]pyrimidin-4-yl]-1H-indazole (110 mg, 312.12 umol, 1 equiv) were dissolved in dry CH3CN (10 mL) and then KI (777.17 mg, 4.68 mmol, 15 equiv) and DIEA (605.07 mg, 4.68 mmol, 815.46 uL, 15 equiv) were added to the reaction. The reaction was stirred at 100° C. for 16 hours. The reaction mixture was diluted with H 2 The mixture was poured into 200 mL of ethyl acetate (20 mL*2). The mixture was extracted with ethyl acetate (20 mL*2). The organic phase was washed with brine (15 mL*3) and anhydrous Na 2 SO 4 The residue was dried at 40° C. and concentrated under vacuum to give a residue. The residue was purified by preparative TLC (10% methanol / dichloromethane, Rf=0.2) to give tert-butyl 6-[2-[(2S)-4-[6-(5-isopropoxy-1H-indazol-3-yl)pyrimidin-4-yl]-2-methyl-piperazin-1-yl]ethyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (124 mg, 154.80 umol, 49.60% yield) as a white solid. Step 3 [ka] 6-[2-[(2S)-4-[6-(5-isopropoxy-1H-indazol-3-yl)pyrimidin-4-yl]-2-methyl-piperazin-1-yl]ethyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate tert-butyl (124 mg, 215.00 umol, 1 eq) was dissolved in DCM (3 mL) and TFA (3.08 g, 27.01 mmol, 2 mL, 125.63 eq). The reaction was stirred at 25° C. for 1 h. TLC (dichloromethane:methanol=10:1, Rf=0.01) showed the reaction was complete. The reaction mixture was concentrated in vacuo to give 3-[6-[(3S)-4-[2-(2,6-diazaspiro[3.3]heptan-2-yl)ethyl]-3-methyl-piperazin-1-yl]pyrimidin-4-yl]-5-isopropoxy-1H-indazole (126 mg, crude, TFA) as a yellow gum. The crude product was used directly in the next step. Step 4 [ka] To a solution of 2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]oxyacetaldehyde (67.47 mg, 213.33 umol, 1 equiv.) and 3-[6-[(3S)-4-[2-(2,6-diazaspiro[3.3]heptan-2-yl)ethyl]-3-methyl-piperazin-1-yl]pyrimidin-4-yl]-5-isopropoxy-1H-indazole (126 mg, 213.33 umol, 1 equiv., TFA) in DCE (5 mL) and MeOH (1 mL), NaOAc (52.50 mg, 639.99 umol, 3 equiv.) was added and the mixture was stirred at 25° C. for 20 min. Then, HOAc (1.28 mg, 21.33 umol, 1.22 uL, 0.1 equiv) was added to the mixture and stirred at 25° C. for 20 minutes. Then, NaBH 3 CN (53.62 mg, 853.31 umol, 4 equiv) was added to the solution and the mixture was stirred at 25° C. for 16 h. The reaction mixture was 2 The mixture was poured into 200 mL of ethyl acetate (20 mL*2). The mixture was extracted with ethyl acetate (20 mL*2). The organic phase was washed with brine (15 mL*3) and anhydrous Na 2 SO4 The residue was purified by preparative HPLC (Phenomenex Luna C18 100*30mm*5um: [water (0.225% FA)-ACN]; B%: 5%-35%, 9 min) to give 2-(2,6-dioxo-3-piperidyl)-5-[2-[6-[2-[(2S)-4-[6-(5-isopropoxy-1H-indazol-3-yl)pyrimidin-4-yl]-2-methyl-piperazin-1-yl]ethyl]-2,6-diazaspiro[3.3]heptan-2-yl]ethoxy]isoindoline-1,3-dione (14.7mg, 17.35umol, yield 8.13%, purity 97.1%, FA) as a yellow solid.

[0246] Exemplary Synthesis of Exemplary Compound 36 Step 1 [ka] tert-Butyl N-(3-hydroxypropyl)-N-methyl-carbamate (500 mg, 2.64 mmol, 1 equiv.), DMAP (322.77 mg, 2.64 mmol, 1 equiv.) and Et 3 To a mixture of N (267.34 mg, 2.64 mmol, 367.73 uL, 1 equiv.), 4-methylbenzene-1-sulfonyl chloride (503.69 mg, 2.64 mmol, 1 equiv.) was added N 2 The mixture was stirred at 20°C for 1 h to give 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 phase was washed with brine (5 mL*2) and diluted with anhydrous Na 2 SO 4 The residue was purified by silica gel chromatography (column height: 12 g, 100-200 mesh silica gel, 0-20% (10 min) ethyl acetate / petroleum ether, 20% (5 min) ethyl acetate / petroleum ether) to give 3-[tert-butoxycarbonyl(methyl)amino]propyl 4-methylbenzenesulfonate (670 mg, 1.95 mmol, 73.84% yield) as a colorless oil. Step 2 [ka] To a mixture of 3-[tert-butoxycarbonyl(methyl)amino]propyl 4-methylbenzenesulfonate (670 mg, 1.95 mmol, 1 equiv) and 2-(2,6-dioxo-3-piperidyl)-5-piperazin-1-yl-isoindoline-1,3-dione (890.32 mg, 2.60 mmol, 1.33 equiv) in MeCN (5 mL) was added KI (1.62 g, 9.75 mmol, 5 equiv) and DIPEA (1.26 g, 9.75 mmol, 1.70 mL, 5 equiv) in N 2 The mixture was stirred at 80° C. for 16 hours. 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 phase was washed with brine (10 mL*3) and diluted with anhydrous Na 2 SO 4 The residue was purified by silica gel chromatography (column height: 40 g, 100-200 mesh silica gel, 0-100% ethyl acetate / petroleum ether) to give tert-butyl N-[3-[4-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]piperazin-1-yl]propyl]-N-methyl-carbamate (1 g, crude) as a yellow solid. Step 3 [ka] To a mixture of tert-butyl N-[3-[4-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]piperazin-1-yl]propyl]-N-methyl-carbamate (1 g, 1.95 mmol, 1 equiv.) in DCM (5 mL), TFA (222.01 mg, 1.95 mmol, 144.16 uL, 1 equiv.) was added to the N 2 The mixture was stirred at 20°C for 30 min. The residue was diluted with NaHCO 3The combined organic phase was washed with brine (5 mL*2) and poured into anhydrous NaCl (pH=7-8). The aqueous phase wa...

Claims

[Claim 1] The invention described herein.

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