Indazole-based compounds and related methods of use

Abstract

Described herein are bifunctional compounds useful as modulators of leucine-rich repeat kinase 2 (LRRK2). In particular, the disclosed heterobifunctional compounds contain a moiety that binds to cereblon E3 ubiquitin ligase at one end and a moiety that binds to LRRK2 at the other end, thereby placing the target protein in close proximity to the ubiquitin ligase, resulting in degradation (and inhibition) of the target protein. The disclosed heterobifunctional compounds exhibit a wide range of pharmacological activities related to target protein degradation / inhibition. Diseases or disorders resulting from aberrant regulation of target proteins are treated or prevented by the disclosed compounds and compositions.

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 herein 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 No. 2015 / 0291562; and U.S. Patent Application No. 14 / 792,414, filed July 6, 2015, published as U.S. Patent Application No. 2016 / 0058872; and U.S. Patent Application No. 15 / 953,108, filed April 13, 2018, published as U.S. Patent Application No. 2018 / 0228907; and U.S. Patent Application No. 2016 / 0009689A1, filed September 2, 2015; and U.S. Patent Application No. 2016 / 0200722A1, filed February 18, 2016. The present invention provides heterobifunctional compounds comprising a target protein-binding moiety and an E3 ubiquitin ligase-binding moiety, and related methods of use. The bifunctional compounds 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 to 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 large contact surfaces, shallow grooves, or flat interfaces. E3 ubiquitin ligases (hundreds of which are known in humans) confer substrate specificity to ubiquitination and therefore are more attractive therapeutic targets than general proteasome inhibitors due to their specificity for specific protein substrates. Development of ligands for E3 ligases has proven challenging, 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 encoded by the CRBN gene in humans. CRBN orthologs 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 regulatory element of cullin 1 (ROC1). This complex ubiquitinates numerous other proteins. Cereblon ubiquitination of target proteins, through a mechanism that is not yet fully understood, 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 otic vesicle formation. Ultimately, this ubiquitin ligase complex is critical for limb development 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 (incorporated herein 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-directing 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), a member of the leucine-rich repeat kinase family, is a large multidomain protein containing 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 consists of 2,527 amino acids and a molecular weight of 280 kDa. The catalytic activity of LRRK2 is associated with the kinase and GTPase domains, 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 inhibit 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 identified physiological substrates (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 along 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 expression levels in the brain and dopaminergic neurons of the substantia nigra (West AB, et al.: Differential LRRK2 expression in the cortex, striatum, and substantia nigra in transgenic and nontransgenic rodents. J Comp Neurol 2014,522:2465-2480).

[0007] LRRK2 has several dominant, gain-of-function, pathogenic, and characteristic mutations located either in the Roco domain (N1437H, R1441G / C / H, Y1699C), which affect 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 mutation, which is associated with 1-2% of all PD patients, causes a two-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 four-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 located within the DFG motif (DYGI in the case of LRRK2), which is common to all kinases and regulates catalytic activity. These mutations are thought to enhance 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 localization. Biochem J 2010, 430:393-404).

[0008] Furthermore, LRRK2 is associated with autosomal dominant Parkinson's disease (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 associated with autosomal dominant Parkinson's disease in 1978, when a Japanese family was investigated (Nukada H, et al.: [A large 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, as well as for idiopathic PD (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 the phosphorylation of downstream targets and oligonucleotides (ASOs) that are injected directly into the CNS to reduce LRRK2 protein levels by blocking LRRK2 translation.

[0010] Lewy bodies are the primary histological feature of PD. They are primarily composed 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 ASOs (Zhao HT, et al.: LRRK2 antisense oligonucleotides ameliorate α-synuclein inclusion formation in a Parkinson's disease mouse model. Molecular therapy. Nucleic acids 2017, 8:508-519) and genomic deletion of LRRK2 have been shown to reduce α-synuclein-mediated 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 α-synuclein. Neuron 2009, 64:807-827). Mutations that increase LRRK2 activity, such as G2019S, increase α-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).Some evidence suggests that the G2019S mutant form of LRRK2 is resistant to kinase inhibitor inhibition in the CNS, potentially reducing its disease-modifying effects (Kelly K, et al. The G2019S mutation in LRRK2 imparts resiliency to kinase inhibition. Exp Neurol. 2018 Nov;309:1-13). While Lewy bodies are also present in most cases of PD on postmortem examination, many LRRK2 G2019S mutation-associated PD cases do not have Lewy bodies (Kalia LV, et al. Clinical correlates 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 one study found that tau pathology was observed in 100% of LRRK2 mutation carriers, and thus the genetic causal relationship between LRRK2 and primary tauopathies such as supranuclear palsy (PSP) or corticobasal degeneration (CBD) is not strong, LRRK2 has been highlighted 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 has recently been reported as a genetic determinant of survival in PSP (Jabbari E, et al., Common variation at the LRRK2 locus is associated with survival in the primary tauopathy progressive supranuclear palsy. bioRxiv 2020.02.04.932335; doi:https: / / doi.org / 10.1101 / 2020.02.04.932335). Expression quantitative trait locus (eQTL) analysis has shown that increased expression of LRRK2 in PSP may result in a reactive microglia-induced inflammatory state, which in turn drives 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 degradation 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, as 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 during the PD disease process or via LRRK2 mutations can increase neuroinflammation and increase the risk of developing PD and / or tau pathology. Treatment with anti-TNF agents reduces the risk of PD by 78% in patients with inflammatory bowel disease (Peter I, et al.: Anti-tumor necrosis factor therapy and incidence of Parkinson's 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] U.S. Patent Application Publication No. 2015 / 0291562 [Patent Document 2] U.S. 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 activating LRRK2 mutations), primary tauopathies (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 for making and using the same. Additionally, the present disclosure provides methods of using an effective amount of a compound of the present disclosure for the treatment or alleviation of a disease state, such as a disease or disorder associated with LRRK2, e.g., accumulation or hyperactivity of LRRK2 protein, 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 a type 1 inflammatory response), or neuroinflammation.

[0014] Thus, in one aspect, the present 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., an LRRK2 targeting ligand or "LTM" group), thereby placing 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) and their numbers exemplified herein 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 ULM, and ULM is a cereblon E3 ubiquitin ligase binding moiety (CLM).

[0017] For example, the structure of the bifunctional compound can be represented as follows: [ka] where PTM is an LRRK2 targeting moiety (LTM), "L" is a linker (e.g., a bond or chemical linking group) that couples the PTM to the CLM, and 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 the 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 the 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 the LRRK2 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 having 1 to 20 non-hydrogen atoms. 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. Fluorine substitution may include one or more fluorines.

[0022] In certain embodiments, the CLM is a derivative of piperidine-2,6-dione, wherein the piperidine-2,6-dione can be substituted at the 3-position, and the 3-substitution can be a bicyclic heteroaromatic ring containing a C-N or C-C bond linkage. Examples of the CLM 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 described herein or a salt form thereof and a pharmaceutically acceptable carrier. The therapeutic composition can be used to induce targeted degradation of LRRK2 or a mutant form thereof and / or inhibit LRRK2 or a mutant form thereof 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 associated with LRRK2 or a mutant form thereof, wherein the treatment is achieved by degradation or inhibition of LRRK2 protein or a mutant form thereof, or by regulating or reducing the protein level of LRRK2 or a mutant form thereof 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 a type 1 inflammatory response), and / or neuroinflammation.

[0024] In yet another aspect, the present disclosure provides a method for ubiquitinating LRRK2 or a mutant form thereof in a cell. In certain embodiments, the method includes administering a heterobifunctional compound described herein comprising a PTM that binds to LRRK2 or a mutant form thereof and a CLM, preferably linked via a chemical linker moiety described herein, to cause degradation of the LRRK2 protein or 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 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 controlling or reducing LRRK2 protein levels in cells, such as cells of a subject in need of such treatment. The control or reduction in the level of LRRK2 protein or a mutant form thereof provided by the present disclosure provides for the treatment of disease states, conditions, or associated symptoms causally linked to LRRK2, which are modulated by reducing the amount of LRRK2 protein or a mutant form thereof in the subject's cells.

[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 mutant 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 pharmaceutically 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 the LRRK2 protein in a biological system using compounds according to the present disclosure.

[0027] In another aspect, the description 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 explanation of the drawings]

[0029] [Figure 1] Illustrative illustration of the general principle of heterobifunctional proteolytic compounds. A. An exemplary heterobifunctional proteolytic compound includes a protein targeting moiety (PTM; darkly shaded rectangle), a ubiquitin ligase-binding moiety (ULM; lightly shaded triangle), and, optionally, a linker moiety (L; black line) that couples the PTM to the ULM. B. Illustrated is the functional use of the heterobifunctional proteolytic compounds described herein (commercially known as PROTAC® proteolytic compounds). Briefly, the ULM (triangle) recognizes and binds to a specific E3 ubiquitin ligase, and the PTM (large rectangle) binds to the target protein and recruits it into proximity with the E3 ubiquitin ligase. Typically, the E3 ubiquitin ligase complexes with an E2 ubiquitin-binding protein (E2) and, either alone or via the E2 protein, catalyzes the attachment of multiple ubiquitin molecules (black circles) via isopeptide bonds to lysines on the target protein. This targets the polyubiquitinated protein (far right) for degradation by the cell's proteasome machinery. DETAILED DESCRIPTION OF THE INVENTION

[0030] Described herein are compounds, compositions, and methods related to the surprising discovery that when an E3 ubiquitin ligase (e.g., cereblon E3 ubiquitin ligase) and the 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 comprise 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 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 result in 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 that can bind to an LRRK2 protein or mutant form thereof such that the LRRK2 protein or mutant form is positioned in proximity to the ubiquitin ligase, resulting in ubiquitination and degradation (and / or inhibition) of the LRRK2 protein or mutant form. "Small molecule" further means that the molecule is nonpeptidyl, i.e., not considered a peptide, e.g., contains fewer than 4, 3, or 2 amino acid residues. According to the present specification, each of the PTM, ULM, and heterobifunctional molecule is a small molecule.

[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 carbon atom number 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 within that stated range, is encompassed within the disclosure. The upper and lower limits of these narrower ranges may independently be included in the narrower ranges, and are also encompassed within the disclosure, provided that any specific limit in the stated range is excluded. When the 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, all transitional phrases such as "comprising," "including," "carrying," "having," "containing," "involving," "holding," "composed of," and the like, shall 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 defined in the United States Patent Office Manual of Patent Examining Procedures, Section 2111.03.

[0039] It should also be understood that, in any particular method or process described herein that includes more than one step or act, 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 otherwise dictates.

[0040] The terms "co-administration" and "administering 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 one or more additional therapeutic 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 with at least one additional bioactive agent, e.g., an anti-cancer agent. In particularly preferred embodiments, co-administration of such compounds results in synergistic activity and / or treatment, e.g., anti-cancer activity.

[0041] The term "compound," as used herein, unless otherwise specified, refers to any specific heterobifunctional compound disclosed herein, its pharmaceutically acceptable salts and solvates, and, where applicable, deuterated forms of any of the above molecules. Contemplated deuterated compounds are those in which one or more of the hydrogen atoms contained in the drug molecule have been replaced with deuterium. Such deuterated compounds preferably have one or more improved pharmacokinetic or pharmacodynamic properties (e.g., longer half-life) compared to the equivalent "non-deuterated" compound.

[0042] The term "ubiquitin ligase" refers to a family of proteins that facilitate the transfer of one or more ubiquitin chains to a specific substrate protein. The addition of several ubiquitin chains (polyubiquitination) targets the substrate protein 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 the target protein, thereby targeting the protein for degradation by the proteasome. Ubiquitin ligases are involved in polyubiquitination, where one ubiquitin chain is attached to a lysine residue on the target protein, followed by a second ubiquitin chain attached to the first, a third ubiquitin chain attached to the second, and a fourth ubiquitin chain attached to the third. This polyubiquitination marks the protein for degradation by the proteasome.

[0043] The terms "patient" or "subject" are used throughout this specification to describe an animal, preferably a human or domestic animal, to which treatment, including prophylactic treatment, with a composition according to the present disclosure is provided. 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. Generally, in this disclosure, the terms "patient" and "subject" refer to a human patient unless otherwise stated or suggested by the context in which the terms are 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 terms "effective amount" or "effective concentration" 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, either directly by a bond or via a chemical linking group (L) according to the following structure: (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, e.g., G2019S, where PTM is an 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) against an E3 ubiquitin ligase (e.g., cereblon E3 ubiquitin ligase) of less than about 200 μM. 50 ) indicates IC 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 C-C 10 , preferably C1-C6, or more preferably C1-C3 alkyl groups, 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 a straight, branched or cyclic C-C alkyl group containing at least one C=C bond. 10 (Preferably C2-C6) refers to a hydrocarbon radical.

[0051] The term "alkynyl" refers to a C-C alkyl group that is straight, branched, or cyclic and contains at least one C≡C bond. 10 (Preferably C2-C6) refers to a hydrocarbon radical.

[0052] The term "alkylene," when used, refers to -(CH) nn refers to an - group (n is generally an integer from 0 to 6), which may be optionally substituted. When substituted, the alkylene group preferably has one or more methylene groups substituted with a C1-C6 alkyl group (including a cyclopropyl group or a t-butyl group), but may also be substituted with one or more halo groups, preferably 1 to 3 halo groups or 1 or 2 hydroxyl groups, an O-(C1-C6 alkyl) group, or an amino acid side chain as otherwise disclosed herein. In certain embodiments, the alkylene group may be substituted with a urethane group or an alkoxy group (or other suitable functional group), which may be further substituted with a polyethylene glycol chain (1 to 10, preferably 1 to 6, or more preferably 1 to 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 the 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. A range of carbon atoms that includes C0 means that the carbon is absent and replaced with H. That is, a range of carbon atoms that is C0-C6 includes 1, 2, 3, 4, 5, and 6 carbon atoms, with H replacing the carbon in the case of C0.

[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 substituents which may be further substituted), independently (i.e., when two or more substituents are present, each substituent is selected independently of the other substituents) on a carbon (or nitrogen) anywhere in the molecule within the context, possible substituents being hydroxyl, thiol, carboxyl, cyano (C≡N), nitro (NO), halogen (preferably one, two or three halogens, especially on alkyl, especially on methyl groups, e.g., trifluoromethyl), alkyl groups (preferably C1-C 10、More preferably, the alkyl group is selected from the group consisting of C1-C6 alkyl, C1-C6 dialkyl, C1-C6 alkyl aryl, C1-C6 dialkyl ... Further examples include alkylamines, where the alkyl group is optionally substituted with one or two hydroxyl groups) or an optionally substituted —N(C0-C6 alkyl)C(O)(O—C1-C6 alkyl) group (optionally substituted with a polyethylene glycol chain, which is further bonded to an alkyl group containing one halogen, preferably chlorine, substituent); hydrazines; amides, preferably independently substituted with one or two C1-C6 alkyl groups (including carboxamides optionally substituted with one or two C1-C6 alkyl groups); alkanols (preferably C1-C6 alkyl or aryl); or alkanoic acids (preferably C1-C6 alkyl or aryl). Substituents according to the present disclosure can include, for example, -SiR1R2R3 groups, where each of R1 and R2 is described elsewhere herein and R3 is H or a C1-C6 alkyl group, preferably R1, R2, and R3 are all C1-C3 alkyl groups (including isopropyl or t-butyl groups). Each of the above groups can be directly linked to the moiety being substituted, or the substituent can be an optionally substituted -(CH2) m -or alternatively optionally substituted -(OCH2) m -, -(OCH2CH2) m -or- (CH2CH2O) mThe alkylene group -(CH) as specified above may be linked to the substituted moiety (preferably in the case of an aryl or heteroaryl moiety) via a - group, which may be substituted with any one or more of the above substituents. m -or-(CH2) 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 C1-C6 (preferably C1-C3) alkyl groups, which may optionally be substituted with one or two hydroxyl groups, one or two ether groups (O-C1-C6 groups), up to three halo groups (preferably F), or the side chains of amino acids described elsewhere herein and optionally substituted amide (preferably carboxamido substituted as described above) or urethane groups (often having one or two C0-C6 alkyl substituents, which group(s) may be further substituted). In certain embodiments, the alkylene group (often a single methylene group) is substituted with one or two optionally substituted C1-C6 alkyl groups, preferably C1-C4 alkyl groups, most often methyl or O-methyl groups, or the side chains of amino acids 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. Often, in the present disclosure, a substituted moiety is substituted with 1 or 2 substituents.

[0055] The term "substituted" (each substituent independent of any other substituent) is intended to mean, within the context in which it is used, C-C alkyl, C-C alkoxy, halogen, amido, carboxamide, sulfone (including sulfonamide), keto, carboxy, C-C ester (oxyester or carbonylester), C-C keto, urethane-OC(O)-NR1R2 or -N(R1)-C(O)-O-R1, nitro, cyano, and amine (particularly including C-C alkylene-NR1R2, mono- or di-C-C alkyl-substituted amines, which may be optionally substituted with one or two hydroxyl groups). Each of these groups contains 1 to 6 carbon atoms, unless otherwise specified, within the context. In certain embodiments, preferred substituents include, for example, -NH-, -NHC(O)-, -O-, =O, -(CH2), depending on the context in which the substituent is used. m - (where m and n are 1, 2, 3, 4, 5 or 6, in the context), -S-, -S(O)-, SO2- or -NH-C(O)-NH-, -(CH2) n OH, -(CH2) n SH, -(CH2) n COOH, C1-C6 alkyl, -(CH2) n O-(C1-C6 alkyl), -(CH2) n C(O)-(C1-C6 alkyl), -(CH2) n OC(O)-(C1-C6 alkyl), -(CH2) n C(O)O-(C1-C6 alkyl), -(CH2) n NHC(O)-R1, -(CH2) n C(O)-NR1R2, -(OCH2) n OH, -(CHO) n COOH, C1-C6 alkyl, -(OCH2) n O-(C1-C6 alkyl), -(CHO) n C(O)-(C1-C6 alkyl), -(OCH2) n NHC(O)-R1, -(CHO) n C(O)-NR1R2, -S(O)2-R S , -S(O)-RS (R S is C1-C6 alkyl or -(CH2) m The alkylene groups include -NR1R2 groups), NO2, CN, or halogens (F, Cl, Br, I, preferably F or Cl). R1 ​​and R2 are each, within context, H or a C1-C6 alkyl group (optionally substituted with one or two hydroxyl groups or up to three halogen groups, preferably fluorine). The 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. Alkylene groups can also be substituted, as disclosed elsewhere herein, preferably with an optionally substituted C1-C6 alkyl group (methyl, ethyl, or hydroxymethyl or hydroxyethyl are preferred, thereby creating a chiral center), the side chain of an amino acid group as described elsewhere herein, an amide group as described above, or a urethane group, O-C(O)-NR1R2 group (wherein R1 and R2 are as described elsewhere herein), although many other groups can also 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. Note that for compounds where molecular substitution at a particular position is required (principally for valency reasons) but no substitution is indicated, that substituent is to be construed 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 ring, etc.), which 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 provided chemical structure. Other examples of aryl groups include, inter alia, "heteroaryl" groups having one or more nitrogen, oxygen, or sulfur atoms in a ring (single ring) that, in context, are heterocyclic aromatic ring systems, such as imidazole, furyl, pyrrole, furanyl, thiene, thiazole, pyridine, pyrimidine, pyrazine, triazole, oxazole, or fused ring systems, such as indole, quinoline, indolizine, azaindolizine, benzofurazan, and the like, which can be optionally substituted as described above.Heteroaryl groups which may be mentioned, inter alia, are 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) are substituted with one or more substituents. For example, an aryl group can be -(CH) n OH, -(CH2) n -O-(C1-C6) alkyl, -(CH2) n -O-(CH2) n -(C1-C6) alkyl, -(CH2) n -C(O)(C0-C6) alkyl, -(CH2) n-C(O)O(C0-C6) alkyl, -(CH2) n-OC(O)(C0-C6)alkyl, amine, mono- or di-(C1-C6 alkyl)amine (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, C1-C6 alkyl, preferably CH3, CF3, OMe, OCF3, NO2, or CN groups (each of which may be substituted in the ortho, meta, and / or para positions of the phenyl ring, preferably para), optionally substituted phenyl groups (wherein the phenyl group itself is preferably or connected via a linker group to a PTM group, including a ULM group), and / or at least one of F, Cl, OH, COOH, CH, CF, OMe, OCF, NO, or CN group (at the ortho, meta, and / or para positions of the phenyl ring, preferably para), an optionally substituted naphthyl group, an optionally substituted heteroaryl, preferably an optionally substituted isoxazole, including methyl-substituted isoxazole, optionally substituted oxazole, including methyl-substituted oxazole, a ... optionally substituted thiazoles including substituted thiazoles, optionally substituted isothiazoles including methyl substituted isothiazoles, optionally substituted pyrroles including methyl substituted pyrroles, optionally substituted imidazoles including methyl imidazoles, optionally substituted benzimidazoles or methoxybenzylimidazoles, optionally substituted oxoimidazoles or methyloxoimidazoles, optionally substituted diazole groups including methyl diazole groups, optionally substituted triazole groups including methyl substituted triazoles, optionally substituted pyridine groups including halo (preferably F) or methyl substituted pyridine groups or oxapyridine groups (the pyridine group is linked to the phenyl group by an oxygen), optionally substituted furans, optionally substituted benzofurans, optionally substituted dihydrobenzofurans, optionally substituted indoles, indolizines or azaindolizines (2, 3, or 4-azaindolizines), optionally substituted quinolines,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 appropriate groups defined herein.

[0059] The term "heteroaryl" or "hetaryl" refers to 5- to 16-membered heteroaryl (e.g., 10- to 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, benzoxofuranoside, 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 -(CH2) m -O-C1-C6 alkyl group or optionally substituted -(CH2) m It may mean, but is not limited to, 1,2,3-triazole substituted with a —C(O)—O—C1-C6 alkyl group), 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 is H, CN, NO, halo (preferably Cl or F), optionally substituted C-C alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g., CF), optionally substituted O(C-C 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 C1-C6 alkyl (preferably C1-C3 alkyl), R SS is H, CN, NO, halo (preferably F or Cl), optionally substituted C-C alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups), optionally substituted O—(C-C alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups), or optionally substituted —C(O)(C-C alkyl) (preferably substituted with one or two hydroxyl groups or up to three halo groups); R URE is H, C-C alkyl (preferably H or C-C alkyl) or —C(O)(C-C alkyl), each of which groups is optionally substituted with one or two hydroxyl groups or up to three halogen, 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 YCis H, OH, CN, NO, halo (preferably Cl or F), optionally substituted C-C alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g., CF), optionally substituted O(C-C 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 a C1-C6 alkyl group (preferably a C1-C3 alkyl).

[0060] The terms "aralkyl" and "heteroarylalkyl" refer to groups containing both aryl or heteroaryl, respectively, and alkyl and / or heteroalkyl and / or carbocyclic and / or heterocycloalkyl ring systems, 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. The arylalkyl group is attached to the 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, e.g., N, O, or S, and can be aromatic (heteroaryl) or non-aromatic. Thus, heteroaryl moieties are included in the definition of heterocycle, depending on the context in which they are used. Exemplary heteroaryl groups are described above.

[0063] Exemplary heterocyclics include 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, isooctane, among others. Examples include oxazolidinyl, 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, heterocycle, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, oxo (=O), and -SO-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 either heterocyclic ring is fused to a benzene or cyclohexane ring or to another heterocyclic ring (eg, indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, etc.).

[0065] The term "cycloalkyl" can 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" can 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, wherein these common substituents have the same meaning as in the definition of the corresponding group defined in this Description.

[0067] The term "hydrocarbyl" is intended to mean a compound containing carbon and hydrogen, which 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 the variable, as applied independently, 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, W in formulas (a1)-(e) [e.g., (a1), (a2), (a3), (a4), (b), (c), (d1), (d2), and (e)] is independently selected from the group consisting of CH, O, CHR, C=O, SO, NH, N, an optionally substituted cyclopropyl group, an optionally substituted cyclobutyl group, and N-alkyl; W3 in formulae (a1) to (e) is selected from C or N; X in formulas (a1) to (e) is independently selected from the group consisting of absence, O, S, and CH; Y in formulae (a1) to (e) is independently selected from the group consisting of CH, —C═CR′, NH, N-alkyl, N-aryl, N-heteroaryl, N-cycloalkyl, N-heterocyclyl, O, and S; Z in formulas (a1)-(e) is independently selected from the group consisting of absent, O, and S or CH2, with the proviso that both X and Z cannot be CH2 or absent; G and G' in formulae (a1) to (e) are independently selected from the group consisting of H, optionally substituted linear or branched alkyl, OH, R'OCOOR, R'OCONRR'', CH2-heterocyclyl optionally substituted with R', and benzyl optionally substituted with R'; Q1 to Q4 in formulae (a1) to (e) represent carbon atoms C or N substituted with groups 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; n in formulas (a1) to (e) 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 formulas (a1) to (e) includes, 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', -S02R', -S02NR'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., C1-C6 straight or branched alkyl optionally substituted with one or more halogen, cycloalkyl (e.g., C3-C6 cycloalkyl), or aryl (e.g., C5-C7 aryl)), optionally substituted alkoxyl group (e.g., methoxy, ethoxy, butoxy, propoxy, pentoxy, or hexoxy; where alkoxyl is selected from 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, -CF3, -CN, -NR'SONR'R'', -NR'CONR'R'', -CONR'COR'', -NR'C(=N-CN)NR'R'', -C(=N-CN)NR'R'', -N R'C(=N-CN)R'', -NR'C(=C-NO2)NR'R'', -SO2NR'COR'', -NO2, -COR', -C(C=N-OR')R'', -CR'=CR'R'', -CCR', -S(C=O)(C=N-R')R'', -SF5 and -OCF3, 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 group (L), a ULM, a CLM, or a combination thereof; Each of x, y, and z in formulas (a1) to (e) is independently 0, 1, 2, 3, 4, 5, or 6; R′ and R″ in formulae (a1) to (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; n' in formulas (a1) to (e) is an integer of 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, Equations (a1) to (e) [ka] represents a bond that can 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, W in formulas (a1)-(e) [e.g., (a1), (a2), (a3), (a4), (b), (c), (d1), (d2), and (e)] is independently selected from the group consisting of CH, O, CHR, C=O, SO, NH, N, an optionally substituted cyclopropyl group, an optionally substituted cyclobutyl group, and N-alkyl; W3 in formulae (a1) to (e) is selected from C or N; X in formulas (a1)-(e) is independently selected from the group consisting of absence, O, S, and CH; Y in formulas (a1) to (e) is independently selected from the group consisting of CH, —C═CR′, NH, N-alkyl, N-aryl, N-hetaryl, N-cycloalkyl, N-heterocyclyl, O, and S; Z in formulas (a1)-(e) is independently selected from the group O, and S or CH2, with the proviso that X and Z cannot both be CH2 or absent; G and G' in formulae (a1) to (e) are independently selected from the group consisting of H, optionally substituted linear or branched alkyl, OH, R'OCOOR, R'OCONRR'', CH2-heterocyclyl optionally substituted with R', and benzyl optionally substituted with R'; Q1 to Q4 in formulae (a1) to (e) represent carbon atoms C or N substituted with groups 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; n in formulas (a1) to (e) 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 formulas (a1) to (e) includes, 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', -S02R', -S02NR'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 comprising 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 chain alkyl (e.g., C1-C6 straight or branched chain alkyl optionally substituted with one or more halogen, cycloalkyl (e.g., C3-C6 cycloalkyl), or aryl (e.g., C5-C7 aryl)), optionally substituted alkoxyl group (e.g., methoxy, ethoxy, butoxy, propoxy, pentoxy, or hexoxy; where alkoxyl is 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, -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'', -SONR'COR'', -NO, -COR', -C(C=N-OR')R'', -CR'=CR'R'', -CCR', -S(C=O)(C=N-R')R'', -SF and -OCF, wherein at least one of W, X, Y, Z, G, G', R, R', R'', Q1-Q4, or A is covalently bonded (directly or indirectly, for example, 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 formulas (a1) to (e) is independently 0, 1, 2, 3, 4, 5, or 6; R′ and R″ in formulae (a1) to (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; n' in formulas (a1) to (e) is an integer of 1 to 10 (e.g., 1 to 4, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), Equations (a) to (f) [ka] represents a bond that can 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 independently selected from the group CH2, O, C=O, NH, and N-alkyl; A in formula (g) is selected from H, methyl, or optionally substituted straight or branched chain alkyl; n is an integer from 1 to 4, R of formula (g) is independently selected from H, O, OH, N, NH, NH, -Cl, -F, -Br, -I, methyl, optionally substituted linear or branched alkyl (e.g., optionally substituted linear or branched C-C alkyl), optionally substituted linear or branched alkoxy (e.g., optionally substituted linear or branched C-C alkoxy), -alkyl-aryl (e.g., -alkyl-aryl comprising at least one of C-C alkyl, C-C aryl, or a combination thereof), aryl (e.g., C-C aryl), amine, amide, or carboxy), wherein at least one R or W is modified to covalently bond to a PTM, a chemical linker group (L), a ULM, a CLM, or a combination thereof; In equation (g), [ka] represents a bond that can 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 CH2; 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 PTM); [ka] indicates the point of attachment of the CLM or ULM to the linker (L) or PTM).

[0077] In any aspect or embodiment described herein, R is selected from H, O, OH, N, NH, NH, C-C alkyl, C-C alkoxy, -alkyl-aryl (e.g., -alkyl-aryl comprising at least one of C-C alkyl, C-C aryl, or a combination thereof), aryl (e.g., C-C aryl), amine, amide, or carboxy).

[0078] In any aspect or embodiment described herein, at least one R (e.g., an R selected from H, O, OH, N, NH, NH, C-C alkyl, C-C alkoxy, -alkyl-aryl (e.g., -alkyl-aryl comprising at least one of C-C alkyl, C-C aryl, or combinations thereof), aryl (e.g., C-C 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 independently be covalently bonded to a linker and / or a linker attached to one or more PTM, ULM, 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, e.g., 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 group consisting of: [ka] [ka] [ka] [ka] (In the formula, W is independently selected from CH, O, CHR, C=O, SO, NH, N, an optionally substituted cyclopropyl group, an optionally substituted cyclobutyl group, and N-alkyl (e.g., CH, CHR, C=O, SO, NH, and N-alkyl); Q1, Q2, Q3, Q4, and Q5 each independently represent a carbon C or N substituted with a group independently selected from R', N, or N-oxide; R 1 is selected from absent, H, OH, CN, C1-C3 alkyl, and C=O; R 2 is selected from the group consisting of absent, H, OH, CN, C1-C3 alkyl, CHF2, CF3, CHO, C(=O)NH2; 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 CF3; X is C, CH, C═O, or N; X1 is C=O, N, CH, or CH2; 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)OR 2 , 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, R 1 , R 2 , R 3 , R 4 or R'), W, X, or Q group (such as Q1, Q2, Q3, Q4, or Q5) to a PTM or chemical linker group (L).

[0084] In any aspect or embodiment described herein, the CLM may be selected from the group consisting of W, X, R, R 1 , R 2 , R 3 , R 4 , R 5 , R', Q1, Q2, Q3, Q4, and Q5, are covalently attached to a PTM or chemical linker group (L).

[0085] In any aspect or embodiment described herein, W, X, R 1 , R 2 , R 3 , R 4 , R', Q1, Q2, Q3, Q4, and Q5 can independently be covalently bonded to a linker and / or a linker bonded to one or more PTM, ULM, or 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 independently selected from the group: CH, CHR, C=O, SO, 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); Q1 and Q2 are each independently H or C or N substituted with a group independently selected from C1-C3 alkyl; [ka] is a single or double bond).

[0087] In any aspect or embodiment described herein, W, R 1 , R 2 , Q1, Q2, Q3, Q4, R, and R' can independently be covalently bonded to a linker and / or a linker attached to one or more PTM groups.

[0088] In any aspect or embodiment described herein, R 1 , R 2, Q1, Q2, Q3, Q4, R, and R' can independently be covalently bonded to a linker and / or a linker attached to one or more PTM groups.

[0089] In any aspect or embodiment described herein, Q1, Q2, Q3, Q4, R, and R' can independently be covalently attached to a linker and / or a linker 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 of the CLM 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" may be an imide that binds to cereblon E3 ligase. These imides and linker attachment points may 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's [ka] indicates the point of attachment to the linker group or PTM, N* is a nitrogen atom shared with a chemical linker group or a PTM; W, Q4, and Q5 are each defined as described in any aspect or embodiment described herein.

[0095] Exemplary Linkers In certain embodiments, compounds described herein comprise 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, and (A L ) q is a group attached to ULM.

[0096] In any aspect or embodiment described herein, the linker (L) to 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, is separated by at least a carbon atom (e.g., —CH—), e.g., an acetal or aminal group. By way of further example, in any aspect or embodiment described herein, when the linker (L) and 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 may be a bond or a group of the formula -(A L ) q -, where A is a chemical moiety and q is an integer between 1 and 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 covalently binds to both the PTM and ULM, providing the link between the PTM and the protein target and the ULM and the E3 ubiquitin ligase to result in ubiquitination of the target protein.

[0098] In any aspect or embodiment described herein, the linker group L may be 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 the linkage of the PTM to the protein target and the linkage of the ULM to the 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), q of the linker is an integer of 1 or greater, Each A L is a bond, CR L1 R L2 , O, S, SO, SO2, NR L3 , SO2NR L3 ,SONR L3 ,CONR L3 , N.R. L3 CONR L4 , N.R. L3 SO2NR 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(=CNO2)NR L4 , 1 to 6 R L1 Groups and / or R L2 C optionally substituted with a group 3-11 Cycloalkyl, 1 to 9 R L1 Groups and / or R L2 C optionally substituted with a group 5-13Spirocycloalkyl, 1 to 6 R L1 Groups and / or R L2 C optionally substituted with a group 3-11 Heterocyclyl, 1 to 8 R L1 Groups and / or R L2 C optionally substituted with a group 5-13 Spiroheterocyclyl, 1 to 6 R L1 Groups and / or R L2 aryl optionally substituted with a group, and 1 to 6 R L1 Groups and / or R L2 heteroaryl optionally substituted with a group, wherein R L1 or R L2 each independently, optionally linked to other groups, 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 independently H, halo, and 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, NH2, SH, SO2C 1-8 Alkyl, P(O)(OC 1-8 Alkyl)(C 1-8 alkyl), P(O)(OC 1-8 Alkyl)2, CC-C 1-8 Alkyl, CCH, CH=CH(C 1-8 alkyl), C(C1-8 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, CO2H, halogen, CN, CF3, CHF2, CH2F, NO2, SF5, SO2NHC 1-8 Alkyl, SO2N(C 1-8 Alkyl)2, SONHC 1-8 Alkyl, SON(C 1-8 alkyl)2, CONHC 1-8 Alkyl, CON(C 1-8 alkyl)2, N(C 1-8 alkyl)CONH(C 1-8 alkyl), N(C 1-8 alkyl)CON(C 1-8 alkyl)2, NHCONH(C 1-8 alkyl), NHCON(C 1-8 alkyl)2, NHCONH2, N(C 1-8 alkyl)SO2NH(C 1-8 alkyl), N(C 1-8 alkyl) SO2N(C 1-8 alkyl)2, NH SO2NH(C 1-8 alkyl), NH SO2N(C 1-8 alkyl)2, or NH SO NH .

[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 is A L 1 and (A L ) q and the linker is a group that connects 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 is A L is a group connecting to 1 and ULM.

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

[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(CH2) n -(lower alkyl)-, -NR(CH2) n -(lower alkoxyl)-, -NR(CH2) n -(lower alkoxyl)-OCH2-, -NR(CH2) n -(lower alkoxyl)-(lower alkyl)-OCH2-, -NR(CH2) n -(cycloalkyl)-(lower alkyl)-OCH2-, -NR(CH2) n -(heterocycloalkyl)-, -NR(CH2CH2O) n -(lower alkyl)-O-CH2-, -NR(CH2CH2O) n -(heterocycloalkyl)-O-CH2-, -NR(CH2CH2O) n -Aryl-O-CH2-, -NR(CH2CH2O) n -(heteroaryl)-O-CH2-, -NR(CH2CH2O) n -(cycloalkyl)-O-(heteroaryl)-O-CH2-, -NR(CH2CH2O) n -(cycloalkyl)-O-aryl-O-CH2-, -NR(CH2CH2O) n -(lower alkyl)-NH-aryl-O-CH2-, -NR(CH2CH2O) n -(lower alkyl)-O-aryl-CH2, -NR(CH2CH2O)n -cycloalkyl-O-aryl-, -NR(CH2CH2O) n -Cycloalkyl-O-(heteroaryl)l-, -NR(CH2CH2) n -(cycloalkyl)-O-(heterocyclyl)-CH 2、 -NR(CH2CH2) n -(heterocyclyl)-(heterocyclyl)-CH2, and -N(R1R2)-(heterocyclyl)-CH2, where 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) may be an optionally substituted C-C 50 Alkyl (e.g., C1, C2, C3, C4, C5, C6, C7, C8, C9, 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 , C45 , C 46 , C 47 , C 48 , C 49 , or C 50 alkyl, 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, having the appropriate number of hydrogens, substitutions, or both to satisfy valences, (2) an optionally substituted cycloalkyl or bicyclic cycloalkyl, (3) an optionally substituted heterosilylalkyl or bicyclic heterosilylalkyl, (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 inter-heteroatom bonds (e.g., the heteroatoms are not covalently linked or adjacently positioned).

[0106] In any aspect or embodiment described herein, the linker (L) may be an optionally substituted C-C 50 Alkyl (e.g., C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , C 20 , C 21 , C 22 , C 23 , C 24 , C 25 , C 26 , C 27 , C 28 , C 29 , C 30 , C 31 , C 32 , C 33, C 34 , C 35 , C 36 , C 37 , C 38 , C 39 , C 40 , C 41 , C 42 , C 43 , C 44 , C 45 , C 46 , C 47 , C 48 , C 49 , or C 50 alkyl), wherein Each carbon may optionally independently be a CR L1 R L2 , O, S, SO, SO2, NR L3 , SO2NR L3 ,SONR L3 ,CONR L3 , N.R. L3 CONR L4 , N.R. L3 SO2NR 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(=CNO2)NR L4 , 1 to 6 R L1 Groups and / or R L2 C optionally substituted with a group 3-11 Cycloalkyl, 1 to 9 R L1 Groups and / or R L2 C optionally substituted with a group 5-13 Spirocycloalkyl, 1 to 6 R L1 Groups and / or R L2 C optionally substituted with a group 3-11 Heterocyclyl, 1 to 8 R L1 Groups and / or R L2 C optionally substituted with a group 5-13Spiroheterocyclyl, 1 to 6 R L1 Groups and / or R L2 aryl optionally substituted with a group, or 0 to 6 R L1 Groups and / or R L2 substituted or substituted with heteroaryl optionally substituted with a group, wherein R L1 or R L2 each independently, optionally linked to other groups, 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 independently H, halo, and 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, NH2, SH, SO2C 1-8 Alkyl, P(O)(OC 1-8 Alkyl)(C 1-8 alkyl), P(O)(OC 1-8 Alkyl)2, CC-C 1-8 Alkyl, CCH, CH=CH(C 1-8 alkyl), C(C 1-8 alkyl)=CH(C 1-8 alkyl), C(C 1-8 alkyl)=C(C 1-8 alkyl)2, Si(OH)3, Si(C 1-8 alkyl)3, Si(OH)(C 1-8 Alkyl)2, COC 1-8Alkyl, CO2H, halogen, CN, CF3, CHF2, CH2F, NO2, SF5, SO2NHC 1-8 Alkyl, SO2N(C 1-8 Alkyl)2, SONHC 1-8 Alkyl, SON(C 1-8 alkyl)2, CONHC 1-8 Alkyl, CON(C 1-8 alkyl)2, N(C 1-8 alkyl)CONH(C 1-8 alkyl), N(C 1-8 alkyl)CON(C 1-8 alkyl)2, NHCONH(C 1-8 alkyl), NHCON(C 1-8 alkyl)2, NHCONH2, N(C 1-8 alkyl)SO2NH(C 1-8 alkyl), N(C 1-8 alkyl) SO2N(C 1-8 alkyl)2, NH SO2NH(C 1-8 alkyl), NH SO2N(C 1-8 alkyl)2, or NH SO NH .

[0107] In any aspect or embodiment described herein, the linker group may be an optionally substituted C-C 50 Alkyl (e.g., C1, C2, C3, C4, C5, C6, C7, C8, C9, 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 , C33 ,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 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 optionally has an O, N, S, P, or Si atom with the appropriate number of hydrogen, substitutions (e.g., OH, halo, alkyl, methyl, ethyl, haloalkyl, hydroxyalkyl, alkoxy, methoxy, etc.), or both, to satisfy 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 heterocycloalkylbicyclic heteroalkyl having one or more heteroatoms selected from N, O, S, P, or Si atoms with the appropriate number of hydrogen, substitutions (e.g., OH, halo, alkyl, methyl, ethyl, haloalkyl, hydroxyalkyl, alkoxy, methoxy, etc.), or both to satisfy valence).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 from about 1 to about 50 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50) optionally substituted alkylene glycol units, where carbon or oxygen may be replaced with a heteroatom selected from N, S, P, or Si atoms, including the appropriate number of hydrogens to satisfy valence.

[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] (where 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] (where 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, m, n, o, p, q, and r of the linker are independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; When m, n, o, p, q, and r are zero, the N-O or N-O bond is absent; X in the linker is H or F. [ka] [ka] [ka] [ka] [ka] wherein each n and m in 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 a 4- to 8-membered ring containing no, 0-4 heteroatoms, and R Q and each R Q are independently H, halo, OH, CN, CF, optionally substituted straight or branched chain C-C alkyl, optionally substituted straight or branched chain C-C alkoxy, or two R Q groups are 4-8 membered ring systems containing 0-4 heteroatoms formed together with the atoms to which they are attached; YL1 are each independently a bond, an optionally substituted linear or branched C-C alkyl, and optionally one or more C atoms are O or NR YL1 optionally substituted C1-C6 alkene and optionally one or more C atoms replaced by O; optionally substituted C1-C6 alkyne and optionally one or more C atoms replaced by O; or optionally substituted straight or branched C1-C6 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 point of attachment to the 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 these are R Q and each R Q are independently H, -Cl-, -F-, OH, CN, CF3, optionally substituted straight or branched chain C1-C6 alkyl (e.g., methyl, ethyl), optionally substituted straight or branched chain C1-C6 alkoxy (e.g., methoxy, ethoxy), Y L1 are each independently a bond, an optionally substituted linear or branched C-C alkyl, and optionally one or more C atoms are O or NR YL1optionally substituted C1-C6 alkene and optionally one or more C atoms replaced by O; optionally substituted C1-C6 alkyne and optionally one or more C atoms replaced by O; or optionally substituted straight or branched C1-C6 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 point of attachment to the 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, ring, heterocycle, C 1-6 Alkyl and optionally one or more C atoms are O or NR YL1 Replaced by, C 1-6 Alkenes with optionally 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 R Q and each R Q is H, halo, OH, CN, CF3, hydroxyl, nitro, C≡CH, C 2-6 Alkenyl, C 2-6 Alkynyl, optionally substituted straight or branched chain C1-C6 alkyl, optionally substituted straight or branched chain C1-C6 alkoxy, optionally substituted OC1-3 Alkyl (e.g., optionally substituted with one or more -F), OH, NH, NR Y1 R Y2 , CN, or two R Q groups are 4-8 membered ring systems containing 0-4 heteroatoms formed together with the atoms to which they are attached; Y L1 are each independently a bond, NR YL1 ,O,S,NR YL2 , C.R. YL1 R YL2 , C=O, C=S, SO, SO2, optionally substituted linear or branched C1-C6 alkyl and optionally one or more C atoms replaced by O; optionally substituted linear or branched C1-C6 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 1-6 Alkyl (e.g., optionally substituted with one or more halo, C 1-6 alkoxyl), or two R Q groups, together with the atoms to which they are attached, form a 3-8 membered ring system containing 0-2 heteroatoms; R YL1 , R YL2 are each independently 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 point of attachment to the 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 with optionally one or more C atoms replaced by O, C 1-6 Alkenes with optionally 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 Q are independently H, -Cl, -F, OH, CN, CF, hydroxyl, optionally substituted straight or branched chain C-C alkyl (e.g., methyl, ethyl), or optionally substituted straight or branched chain C-C alkoxy; Y L1 are each independently a bond, NR YL1 , O, C.R. YL1 R YL2 , C=O, optionally substituted linear or branched C1-C6 alkyl and optionally one or more C atoms are O or NR YL1 Replaced by, C 1-6 Alkenes with optionally one or more C atoms replaced by O, C 1-6 alkyne and optionally one or more C atoms replaced by O, or optionally substituted linear or branched C1-C6 alkoxy, Q Lis a 3-6 membered heterocyclic, heterobicyclic, or heteroaryl ring, and 0-6 R 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 are each independently 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 point of attachment to the 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 mutant form thereof.

[0122] The compositions described below are exemplary 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 the target protein for ubiquitination and degradation. 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 use 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, R1 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 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); R2 is selected from hydrogen, halogen (e.g., F, Cl, or Br), C1-C3 alkyl, or C1-C3 fluoroalkyl; X1, X2, X3, X4, X5, X6, and X7 are each independently C, CH, or N, where X1, X2, and X3, when each is CH, are optionally substituted with R2; X8 is CH, S, or N; M is CH, 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 to 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 the chemical structures PTM-IIA, PTM-IIB, PTM-IIIA, and PTM-IIIB. [ka] (In the formula, R1 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); R2 is hydrogen, halogen (e.g., F, Cl, or Br), C1-C3 alkyl, or C1-C3 fluoroalkyl; X4 is CH or N; M is CH, 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 to 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 substitutions, each independently selected from halogen, OH, NH, N(C-C alkyl), straight or branched chain C-C alkyl (e.g., methyl or ethyl), straight or branched chain C-C hydroxyalkyl, straight or branched chain C-C alkoxy, and straight or branched chain C-C 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- to 7-membered (e.g., 4, 5, 6, or 7-membered) cycloalkyl or heterocycloalkyl containing 1 to 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, N(C-C alkyl), straight-chain or branched C-C alkyl, straight-chain or branched C-C hydroxyalkyl, straight-chain or branched C-C alkoxy, and straight-chain or branched C-C haloalkyl.

[0131] In any aspect or embodiment described herein, [ka] is a 4- to 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-chain or branched C-C alkyl (e.g., methyl), straight-chain or branched C-C alkoxy (e.g., methoxy), and straight-chain or branched C-C haloalkyl.

[0132] In any aspect or embodiment described herein, [ka] is: [ka] (In the formula, R3 and R4 are each independently selected from H, halogen, OH, NH2, 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; [ka] teeth, [ka] (i.e., the point of attachment of the PTM to the 6-membered heteroaryl); [ka] indicates the attachment point between the PTM and L or ULM, and if not present, [ka] can be attached to L or ULM through an atom (e.g., carbon or nitrogen) of the 6-membered heterocycloalkyl, R, or R).

[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] 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] is.

[0134] In any aspect or embodiment described herein, [ka] is: [ka] (In the formula, R3 is H or straight or branched C1-C3 alkyl (e.g., methyl or ethyl); R4 is H or 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 between the PTM and L or ULM, and if not present, [ka] can be attached to L or ULM via an atom of the 6-membered heterocycloalkyl (e.g., a carbon or nitrogen of the 6-membered heterocycloalkyl), R, or R).

[0135] In any aspect or embodiment described herein, [ka] is selected from: [ka] [ka] (wherein R3 and R4 are defined as described in any aspect or embodiment described herein).

[0136] In any aspect or embodiment described herein, [ka] is selected from: [ka] [ka] (In the formula, R3 and R4 are defined as described in any aspect or embodiment described herein; The heterocycloalkyl is bonded to L or PTM via an atom of the heterocycloalkyl or a substituent thereof (eg, R3, R4, or a methyl group).

[0137] In any aspect or embodiment described herein, the PTM has the following chemical structure: [ka] (In the formula, X, R, R, R, and R are defined as described in any aspect or embodiment described herein; PTM is bonded to L or ULM via an atom of the heterocycloalkyl A (e.g., a carbon or nitrogen of the heterocycloalkyl), R3, or R4).

[0138] In any aspect or embodiment described herein, the PTM has the following chemical structure: [ka] (In the formula, X, R, R, R, and R are defined as described 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-chain or branched C1-C4 alkyl.

[0140] In any aspect or embodiment described herein, R1 is [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 carbon 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, R1 is [ka] where R 1a , R 1b , and R 1C are each independently H or a straight or branched chain C1-C2 alkyl, or R 1a or R 1b together with the carbon 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, R4, and [ka] each of which is defined as set forth in any aspect or embodiment described herein; L or ULM is bonded via an atom of the heterocycloalkyl A (e.g., a carbon or nitrogen of the heterocycloalkyl), R, or R).

[0143] In any aspect or embodiment described herein, the PTM is selected from: [ka] (In the formula, X4, R 1a , R 1b , R 1c , R3, and R4 are each defined as described 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, R1 is [ka] wherein 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, R2 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 described herein, the PTM has the following chemical structure: [ka] [ka] wherein 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 pharmaceutically 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 pharmaceutically 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 targeted protein degradation. In certain embodiments, the therapeutic composition described herein can be used to provide protein degradation for the treatment or alleviation of an 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)), dementia with Lewy bodies, 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 pharmaceutically acceptable carrier, additive, or excipient, optionally co-administered with an additional bioactive agent, wherein the composition alleviates one or more symptoms of a disease or condition in the subject by degrading the disease or disorder or one or more symptoms thereof. The present disclosure relates to a method for treating or alleviating a condition, including an inflammatory disease, an autoimmune disease, or cancer, by 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)), dementia with Lewy bodies, Crohn's disease, leprosy (e.g., leprosy with type 1 inflammatory response), and neuroinflammation (such as that observed in Alzheimer's disease, PD, multiple sclerosis, traumatic brain injury, spinal cord injury, etc.).

[0152] The present disclosure further includes pharmaceutical compositions comprising pharmaceutically acceptable salts, particularly acid or base addition salts, of the compounds described herein. The acids used to prepare the pharmaceutically acceptable acid addition salts of the compounds 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, hydrogensulfate, 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 produce pharmaceutically acceptable salt forms of the compounds of the present disclosure. Chemical bases that can be used as reagents to prepare pharmaceutically 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 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 pharmaceutically acceptable lower alkanolammonium and other base salts of organic amines.

[0154] In accordance with the present disclosure, the compounds described herein may be administered orally, parenterally, or topically in single or divided doses. Administration of the active compound may range from continuous administration (intravenous infusion) to multiple oral doses per day (e.g., QID), and may include oral, topical, parenteral, intramuscular, intravenous, subcutaneous transdermal (which may contain 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, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. Enteric-coated oral tablets may also be used to improve the bioavailability of compounds from oral administration routes. The most effective dosage form will depend on the pharmacokinetics of the particular drug selected, as well as the type, location, and severity of the disease, condition, or symptom, and the patient's overall health. Administration of the compounds according to the present disclosure as sprays, mists, or aerosols for nasal, intratracheal, or pulmonary administration can 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 a pharmaceutically acceptable carrier, additive, or excipient.The compounds according to the present disclosure can be administered in immediate release, intermediate release, or sustained or controlled release form.The sustained or controlled release form is preferably administered orally, but can also be in suppository, transdermal, or other topical form.Intramuscular injection in liposome form or depot preparation can also be used to control or sustain the release of the compound 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 phosphate, 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 salt, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose esters, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, wax, polyethylene-polyoxypropylene-block polymer, 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 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 bland, 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 formulations, as are natural pharmaceutically 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 can 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 those 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 emulsifiers and suspending agents.In addition, if desired, some sweeteners, flavoring agents, or coloring agents 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 glycol.

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

[0160] Alternatively, the pharmaceutical compositions 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 compounds 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 pharmaceutically 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 techniques well known in the art of pharmaceutical formulation, 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 of the active ingredient, alone or in combination with another compound according to the present disclosure, more preferably about 1 milligram to about 600 milligrams, and even more preferably about 10 milligrams to about 500 milligrams.

[0165] It is also 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, the patient's 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 pharmaceutically acceptable salt or solvate, optionally in a pharmaceutically 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 pharmaceutically 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), 1 mg to 3000 mg, or 5 mg to 500 mg of active ingredient per unit dosage form. Often, 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 to 30 millimolar (mM), preferably about 0.1 to 30 micromolar (μM). This can be achieved, for example, by intravenous injection of a solution or formulation of the active ingredient, optionally in saline or an aqueous medium, or by administration as a bolus of the active ingredient. Oral administration can also be suitable to produce 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 dosage values ​​will vary depending on the severity of the condition to be alleviated. For any particular subject, specific dosage regimens 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 be further 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 contain an inert diluent or an edible carrier. Oral compositions may be enclosed in gelatin capsules or compressed into tablets. To administer an oral therapeutic agent, the active compound or its prodrug derivative may be incorporated with excipients and used in the form of tablets, troches, or capsules. Pharmaceutically compatible binders and / or adjuvant materials may be included as part of the composition.

[0172] Tablets, pills, capsules, lozenges, etc. may contain any of the following ingredients, or compounds of a similar nature: binders such as microcrystalline cellulose, tragacanth gum, 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 flavoring agents such as peppermint, methyl salicylate, or orange flavoring. If the unit dosage form is a capsule, in addition to the above-mentioned types of materials, it may contain a liquid carrier such as fatty oil. In addition, the unit dosage form may contain various other materials that modify the physical form of the dosage form, such as sugar coating, shellac, or enteric coating.

[0173] The active compound or its pharmaceutically 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] The 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, the anti-cancer 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, an anti-cancer agent or a wound healing agent, 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 glycol, 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 glass or plastic ampoules, disposable syringes or multiple dose vials.

[0176] If administered intravenously, preferred carriers are physiological 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 elimination from the body, such as a controlled-release formulation, 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.Methods for preparing such formulations will be apparent to those skilled in the art.

[0178] Liposomal suspensions can also be pharmaceutically acceptable carriers.Liposomal suspensions can be prepared according to methods known to those skilled in the art, for example, according to the method described in U.S. Patent No. 4,522,811 (the entirety of which is incorporated herein by reference).For example, liposomal preparations 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 surface of the container.Then, an aqueous solution of active compound is placed in the container.Then, the container is rotated by hand to allow lipid material to escape from the side of the container, and lipid aggregates are dispersed, thereby 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 pharmaceutically acceptable carrier. The method of treatment is useful for effecting protein degradation in a patient or subject, e.g., an animal, such as a human, in need thereof, 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 present compounds may be administered, including treatment of any disease state, condition, or symptom associated with the protein to which the present 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 therapeutic methods for effecting degradation of a target protein for the treatment or alleviation of diseases, such as Parkinson's disease (PD), primary tauopathies, dementia with Lewy bodies, Crohn's disease, leprosy, and / or neuroinflammation (such as those observed). In any aspect or embodiment, the disease is idiopathic PD, LRRK2 mutation-associated PD (e.g., PD associated with one or more activating LRRK2 mutations), PSP, CBD, leprosy with type 1 inflammatory response, Alzheimer's disease, PD, multiple sclerosis, traumatic brain injury, and / or spinal cord injury. Accordingly, in another aspect, the present disclosure provides methods for ubiquitinating / degrading a target protein in a cell. In certain embodiments, the method comprises administering a bifunctional compound of the present disclosure. The control or reduction of specific protein levels 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 pharmaceutically 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 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 pharmaceutically 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 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 description 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 mutant 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 linker group (L) to form a compound that binds to both cereblon E3 ubiquitin ligase and the LRRK2 protein and / or mutant form in the cell, thereby bringing the compound into proximity with the cereblon E3 ubiquitin ligase and ubiquitinating the LRRK2 protein bound to the compound, thereby degrading the ubiquitinated LRRK2.

[0186] In another aspect, the description 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 (ii) providing a protein targeting moiety that is a small molecule that binds to LRRK2 and / or its mutant LRRK2 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 cells expressing the LRRK2 protein in the presence of the molecule of step (i); and (iii) detecting whether the LRRK2 protein in the cells 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 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, accumulation, misfolding, or dysfunction of LRRK2 and / or mutant forms of LRRK2, wherein degradation of the LRRK2 protein confers a therapeutic effect on 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.

[0189] 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, accumulation, misfolding, or dysfunction of alpha-synuclein, wherein degradation of LRRK2 protein and / or mutant forms thereof confers a therapeutic effect on 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.

[0190] 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 alpha-synuclein, wherein degradation of LRRK2 protein and / or mutant forms thereof confers a therapeutic effect on 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.

[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 tau expression, overexpression, mutation, aggregation, misfolding, or dysfunction, wherein degradation of LRRK2 protein and / or mutant forms thereof confers a therapeutic effect on 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, bacterium, fungus, protozoan, or other microorganism, or may be a disease state caused by the expression, overexpression, mutation, misfolding, or malfunction 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 symptoms 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 symptoms of the disease or condition are 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 comprising 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 protein expression, overexpression, mutation, misfolding, or dysfunction (e.g., elevated levels of protein expressed in a patient) occurs, and degradation of the LRRK2 protein and / or mutant forms thereof in the patient reduces or stabilizes the levels of LRRK2 protein (mutated or not), thereby providing beneficial therapy or symptomatic relief 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 "bioactive 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 preventative / prophylactic effect for which the present compounds are used. Preferred bioactive agents for use herein include those that have pharmacological activity similar to that resulting from the use or administration of the present compounds, such as anti-cancer agents, anti-viral agents, particularly anti-HIV and anti-HCV agents, antibacterial agents, anti-fungal agents, etc.

[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 an ester, amide, other prodrug group, etc.) that, upon administration to a patient, directly or indirectly provides the compound or an active metabolite of the compound. [Example]

[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 a suitable ligand is not immediately available. It is not uncommon for the initial ligand to require repeated design and optimization cycles to improve suboptimal aspects identified by data obtained from suitable in vitro and pharmacological and / or ADMET assays. Part of the optimization / SAR experiments will involve exploring positions in the ligand that tolerate substitution and potentially suitable locations for attaching the chemical linking groups mentioned earlier in this specification. If crystallographic or NMR structural data is available, it can be used to focus such synthetic efforts.

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

[0203] Those skilled in the art can use known synthesis methods for combinations of PTMs and ULMs (e.g., CLMs) with or without chemical linking group(s). The chemical linking group(s) can be synthesized in a variety of compositions, lengths, and flexibility and can be functionalized to allow sequential attachment of PTM and ULM groups to the distal ends of the linker. In this manner, libraries of bifunctional molecules can be realized and profiled in in vitro and in vivo pharmacological and ADMET / PK studies. As with PTM and ULM groups, the final bifunctional molecules can undergo iterative 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 synthetic organic chemists, many of which can be found in texts such as "Greene's Protective Groups in Organic Synthesis" by Peter G.M.Wuts and Theodora W. Greene (Wiley) and "Organic Synthesis: The Disconnection Approach" by Stuart Warren and Paul Wyatt (Wiley).

[0205] Synthesis procedure

[0206] General synthetic 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 stirred at 25° C. for 1 hour. 4-Hydroxyphthalic acid (3.0 g, 16.5 mmol, 1.00 equiv.) was then added to the mixture, which was heated to 120° C. and stirred for an additional 11 hours. LCMS showed the desired MS, indicating the reaction was complete. The mixture was concentrated and then poured into water (20 mL) and 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-dimethoxyethane (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, with one new spot forming. The reaction mixture was quenched with 200 mL of water at 25 °C and then extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (50 mL × 3), dried over anhydrous 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 eq.) in methyl alcohol (20 mL) was added sodium hydroxide (4 M, 4.43 mL, 2 eq.). The mixture was stirred at 40 °C for 12 hours. 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 hours. 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) was added sulfuric acid (2 M, 10.6 mL, 40 equiv.), and the mixture was stirred at 70° C. for 1 hour. 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 equiv.) and 2-(2-hydroxyethoxy)ethyl 4-methylbenzenesulfonate (341 mg, 1.31 mmol, 1.2 equiv.) in N,N-dimethylformamide (4 mL) was added potassium carbonate (302 mg, 2.19 mmol, 2 equiv.). The mixture was stirred at 60° C. for 12 hours. LCMS showed the reaction was complete. The mixture was diluted with water (10 mL) and extracted with dichloromethane (10 mL×3). The combined organic layer was washed with brine (20 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (dichloromethane:methanol=1:0 to 50:1) to give 2-(2,6-dioxo-3-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 hours. LCMS showed the reaction was complete. The mixture was diluted with water (10 mL) and extracted with dichloromethane (10 mL × 3). The combined organic layer was washed with brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative reverse-phase thin-layer chromatography (dichloromethane:methanol=20:1) to give 2-[2-[2-(2,6-dioxo-3-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) was added NaH (4.16 g, 104.01 mmol, 60% in mineral oil, 1.5 equiv) in one portion at 0 °C under N. 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 phases were washed with brine (2 × 200 mL), dried over anhydrous NaSO, 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] To a mixture of 2-bromo-4-(1-methylcyclopropoxy)-1-nitro-benzene (14.3 g, 52.56 mmol, 1 equiv.), KCO (14.53 g, 105.11 mmol, 2 equiv.), and CsCO (17.12 g, 52.56 mmol, 1 equiv.) in 1,4-dioxane (100 mL) was added 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) (6.07 g, 5.26 mmol, 0.1 equiv.) at 20 °C, followed by heating to 100 °C and stirring for 16 h to give a yellow solution. TLC indicated the reaction was complete. The reaction was cooled to 20 °C and concentrated in vacuo. 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). 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 in one portion at 20 °C under N. 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] To a mixture of 2-methyl-4-(1-methylcyclopropoxy)aniline (9.8 g, 55.29 mmol, 1 equiv.) and EtN (13.99 g, 138.23 mmol, 19.24 mL, 2.5 equiv.) in DCM (100 mL) was added AcO (11.29 g, 110.58 mmol, 10.36 mL, 2 equiv.) in one portion under N at 0 °C. The mixture was stirred at 0 °C for 30 min, then heated to 20 °C and stirred for 16 h. TLC indicated the reaction was complete. The reaction was quenched with a saturated aqueous solution of NaHCO (30 mL) to adjust the pH to 7-8 and extracted with DCM (3 × 50 mL). The combined organic phase was washed with brine (3 × 50 mL), dried over anhydrous NaSO, 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 AcO (19.92 g, 195.09 mmol, 18.27 mL, 4.6 equiv.) 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 that the reaction was complete. The reaction was then filtered, the wet cake was washed with EtOAc (70 mL), and the filtrate was concentrated in vacuo. 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(g / )MeOH (7 M, 24.82 mL, 5 equiv.) 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), dried over anhydrous NaSO, 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) was added n-BuLi (2.5 M, 13.40 mL, 1.3 equiv) dropwise at −70° C. under N. The mixture was then stirred at −20° C. for 1 h, and a solution of ZnCl (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 mixture of 4,6-dichloropyrimidine (4.22 g, 28.34 mmol, 1.1 equiv.) and Pd(PPh3)4 (1.49 g, 1.29 mmol, 0.05 equiv.) in THF (4 mL) was stirred at 20 °C for 1 h and added to the solution. The cold bath was removed, and the mixture was stirred at 20 °C for 16 h to give a yellow solution. TLC showed the remaining starting material, with the formation of several new spots. The residue was poured into water (10 mL). The aqueous phase was extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with brine (2 × 20 mL), dried over anhydrous Na2SO4, 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), EtN (704.34 mg, 6.96 mmol, 968.82 μL, 6 equiv.) was added in one portion, and the mixture was stirred at 100° C. for 1 h. TLC indicated 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), dried over anhydrous NaSO, filtered, and concentrated in vacuo to afford 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 μL, 5 equiv.) in one portion at 25° C. The mixture was stirred at 25° C. for 16 h. HCl (4 M, 338.20 μL, 1 equiv.) in MeOH (5 mL) was added at 25° C., then heated to 60° C. and stirred for 0.5 h. LCMS indicated the reaction was complete. The mixture was cooled to 20° C. The residue was poured into NaHCO3 (5 mL) and adjusted to pH 7-8. The aqueous phase was extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed with brine (2 × 10 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (0–40% ethyl acetate / MeOH) to afford 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] A mixture of 5-(1-methylcyclopropoxy)-3-[6-[(3S)-3-methylpiperazin-1-yl]pyrimidin-4-yl]-1H-indazole (104.76 mg, 287.45 μmol, 1 equiv), 2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]oxyacetaldehyde (100 mg, 316.19 μmol, 1.1 equiv), NaOAc (70.74 mg, 862.34 μmol, 3 equiv), CHCOOH (17.26 mg, 287.45 μmol, 16.44 μL, 1 equiv) and NaBHCN (36.13 mg, 574.89 μmol, 2 equiv) in DMF (2 mL) 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 x 5 mL). The combined organic phases were washed with brine (2 x 5 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. 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 (12.08 mg, 18.17 umol, 6.32% yield, 100% purity) 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 μmol, 1 equiv.), KI (63.77 mg, 384.15 μmol, 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 μmol, 1 equiv.) in ACN (2 mL) was added DIPEA (124.12 mg, 960.37 μmol, 167.28 μL, 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 phases were washed with brine (2 × 2 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. 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%, 10 min) 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 (11.63 mg, 16.41 umol, 8.54% yield, 100% purity) 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 μmol, 1 equiv.), KI (65.81 mg, 396.42 μmol, 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 μmol, 0.9 equiv.) in ACN (2 mL) was added DIPEA (128.08 mg, 991.05 μmol, 172.62 μL, 5 equiv.) in one portion. 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 phases were washed with brine (2 × 2 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. 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%, 10 min) 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 (14.84 mg, 19.71 umol, 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 μmol, 1 equiv.), KI (61.01 mg, 367.54 μmol, 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 μmol, 0.9 equiv.) in MeCN (2 mL), DIPEA (118.75 mg, 918.84 μmol, 160.04 μL, 5 equiv.) was added in one portion. The mixture was stirred at 100° C. for 16 h. The residue was poured into water (2 mL). The aqueous phase was extracted with ethyl acetate (3 × 2 mL). The combined organic phases were washed with brine (2 × 2 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. 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%, 10 min) 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 (5.1 mg, 6.23 umol, yield 3.39%, purity 97.275%) as a white solid.

[0215] Exemplary Synthesis of Exemplary Compound 5 Step 1 [ka] 5-(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)-1H-indazole]-4-methylbenzenesulfonic acid ... A mixture of [3-dioxo-isoindolin-5-yl]oxyethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl (100 mg, 154.16 μmol, 1 equiv.), KI (51.18 mg, 308.32 μmol, 2 equiv.), and DIPEA (99.62 mg, 770.80 μmol, 134.26 μL, 5.00 equiv.) was stirred at 100°C for 15 hours. The 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 further purified by preparative HPLC (column: YMC-Actus Triart C18 150*30 mm*5 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 23%-63%, 11 min). 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 μmol, 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.), tert-butyl (2S,6R)-2,6-dimethylpiperazine-1-carboxylate (248.61 mg, 1.16 mmol, 1 equiv.) in DMSO (5 mL), EtN (352.17 mg, 3.48 mmol, 484.41 μL, 3 equiv.) was added in one portion, and the solution was stirred at 100° C. for 1 hour. LCMS (EB16-35-P1A1) showed complete consumption of the starting material. The mixture was cooled to 20° C. The residue was poured into water (5 mL). The mixture was extracted with ethyl acetate (3×5 mL). The combined organic phase was washed with brine (2 × 5 mL), dried over anhydrous NaSO, 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) in 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 poured into NaHCO (10 mL) and adjusted to pH 7-8. The mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic phase was washed with brine (2 × 10 mL), dried over anhydrous NaSO, 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 μmol, 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 μmol, 1.1 equiv) 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 μmol, 1 equiv) in MeCN (5 mL) was added DIPEA (108.66 mg, 840.73 μmol, 146.44 μL, 5 equiv) and KI (55.82 mg, 336.29 μmol, 2 equiv). 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 x 5 mL). The combined organic phase was washed with brine (2 x 5 mL), dried over anhydrous Na2SO4, 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*25 mm*10 um; mobile phase: water (0.04% NH3H2O ​​+ 10 mM Purification by HCl (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 µmol, 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 eq) 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 eq) in MeCN (5 mL) was added DIPEA (124.18 mg, 960.82 umol, 167.36 uL, 5 eq) and KI (63.80 mg, 384.33 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 x 5 mL). The combined organic phases were washed with brine (2 x 5 mL), dried over anhydrous Na2SO4, 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*25 mm*10 um; mobile phase: water (0.04% NH3 / H2O + 10 mM Purification by HCl (NH4HCO3)-ACN; B%: 45%-75%, gradient time (min): 8 min; flow rate (ml / min): 25) gave 5-[2-[2-[2-[2-[(2S,6R)-2,6-dimethyl-4-[6-[5-(1-methylcyclopropoxy)-1H-indazol-3-yl]pyrimidin-4-yl]piperazin-1-yl]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (5.9 mg, 6.98 µmol, 3.63% yield, 95.895% purity) 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 μmol, 1 equiv.) in MeCN (5 mL), 2-[2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]oxyethoxy]ethoxymethyl 4-methylbenzenesulfonate (347.37 mg, 635.58 μmol, 1.4 equiv.), DIEA (293.37 mg, 2.27 mmol, 395.38 μL, 5 equiv.), and KI (602.90 mg, 3.63 mmol, 8 equiv.) were added. 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), dried over anhydrous NaSO, 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 μmol, 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 μmol, 1 equiv.) 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]ethyl 4-methylbenzenesulfonate (384.29 mg, 635.58 μmol, 1.4 equiv.), DIEA (293.37 mg, 2.27 mmol, 395.38 μL, 5 equiv.), and KI (602.90 mg, 3.63 mmol, 8 equiv.). The mixture was stirred at 95° C. for 12 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), dried over anhydrous NaSO, 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 μmol, 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-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]oxyethoxy]ethoxy]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 in one portion at 25 °C under N. The mixture was stirred at 100°C and stirred for 16 hours. The reaction mixture was concentrated, cooled in an ice bath, and saturated NH4Cl was added to adjust the pH to 6. Saturated brine was added to it, 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 pale yellow solid.

[0221] Exemplary Synthesis of Exemplary Compound 11 Step 1 [ka] To a mixture of 1H-indazol-5-ol (5 g, 37.28 mmol, 1 equiv.) and CsCO (18.22 g, 55.91 mmol, 1.5 equiv.) in DMF (50 mL), 2-iodopropane (8.24 g, 48.46 mmol, 4.85 mL, 1.3 equiv.) was added in one portion at 25 °C. The mixture was stirred at 25 °C for 4 h. TLC (petroleum ether:ethyl acetate = 3:1, Rf = 0.58) indicated completion of the reaction. The mixture was poured into water (50 mL), and the aqueous phase was extracted with ethyl acetate (60 mL * 3). The combined organic phase was washed with brine (20 mL * 2), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give a residue. The residue 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), K2CO3 (3.14 g, 22.70 mmol, 1 equiv.) and I2 (5.76 g, 22.70 mmol, 4.57 mL, 1 equiv.) were added in one portion at 25 °C under N2. The mixture was stirred at 25 °C for 16 h. TLC (petroleum ether:ethyl acetate = 3:1) showed the reaction was complete. The mixture was diluted with brine (100 mL), and the aqueous phase was extracted with dichloromethane (100 mL * 3). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give a residue. The residue 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 pale 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), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give a residue. The residue 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), KPO (14.53 g, 68.46 mmol, 4 equiv.) and Pd(dppf)Cl (2.50 g, 3.42 mmol, 0.2 equiv.) were added in one portion under N at 25 °C. The mixture was heated to 90 °C with stirring under N 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), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give a residue. The residue 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 μmol, 1 equiv), tert-butyl (2S)-2-methylpiperazine-1-carboxylate (224.44 mg, 1.12 mmol, 1.5 equiv), and DIEA (965.56 mg, 7.47 mmol, 1.30 mL, 10 equiv) were placed in DMSO (10 mL) in a microwave tube. The sealed tube was heated at 180° C. in a microwave for 5 hours. The mixture was cooled to 25° C. The mixture was diluted with ethyl acetate (30 mL), washed with brine (10 mL*3), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (dichloromethane:methanol=3 / 1) to give 2-[[5-isopropoxy-3-[2-[(3S)-3-methylpiperazin-1-yl]-4-pyridyl]indazol-1-yl]methoxy]ethyl-trimethyl-silane (200 mg, 357.07 μmol, yield 47.79%, purity 86%) 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 μmol, 1 equivalent) 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 μmol, 84.98% yield, 62% purity) as a dark oil. Step 7 [ka] To a mixture of 5-isopropoxy-3-[2-[(3S)-3-methylpiperazin-1-yl]-4-pyridyl]-1H-indazole (100 mg, 284.54 μmol, 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 (206.45 mg, 341.45 μmol, 1.2 equiv) in CHCN (3 mL) was added DIEA (367.74 mg, 2.85 mmol, 495.61 μL, 10 equiv) and KI (236.17 mg, 1.42 mmol, 5 equiv) in one portion 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), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a residue. 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 give 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 (11.6 mg, 13.85 umol, yield 4.87%, purity 93.6%) as a pale 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) was added KOH (558.89 mg, 9.96 mmol, 3.75 equiv) and I2 (1.35 g, 5.31 mmol, 1.07 mL, 2 equiv). The mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with saturated Na2SO3 (10 mL) and extracted with EtOAc (20 mL*3). The combined organic layers were washed with brine (20 mL*2), dried over Na2SO4, 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 hours 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), dried over anhydrous Na2SO4, 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 μmol, 54.41% yield, 81% purity) as a yellow solid. Step 3 [ka] To a solution of tert-butyl (2S)-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), Pd(dppf)Cl (184.85 mg, 252.63 mmol, 0.15 equiv.) and KOAc (495.87 mg, 5.05 mmol, 3 equiv.) were added. The mixture was stirred at 90 °C under N for 1 h 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), dried over Na2SO4, 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] 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 µmol, 1 equiv.) in 1,4-dioxane (10 mL) and HO (2 mL) was added Pd(dppf)Cl (95.68 mg, 130.76 µmol, 0.15 equiv.) and NaCO (277.18 mg, 2.62 mmol, 3 equiv.). The mixture was stirred at 90 °C under N for 1.5 h. The mixture was cooled to 20 °C and concentrated under reduced pressure. The residue was poured into water (10 mL), and the aqueous phase was extracted with ethyl acetate (10 mL*3). The combined organic phases were washed with brine (10 mL*2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (column height: 20 g, 100-200 mesh silica gel, 0-20% ethyl acetate / 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 μmol, 1 equiv.) in MeOH (10 mL) was added HCl / dioxane (4 M, 528.51 μL, 5 equiv.) 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 poured into saturated aqueous NaHCO3 (pH = 7-8). The aqueous phase was extracted with ethyl acetate (20 mL * 3). The combined organic phase was washed with brine (20 mL * 2), dried over anhydrous Na2SO4, 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 μmol, 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 μmol, 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 (166.35 mg, 275.14 μmol, 1 equiv.) in MeCN (4 mL), KI (548.08 mg, 3.30 mmol, 12 equiv.) and DIPEA (426.71 mg, 3.30 mmol, 575.09 μL, 12 equiv.) were added. 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), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. 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%, 9 min) 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 (12.5 mg, 15.14 umol, 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 (162.07 mg, 271.65 μmol, 1.1 equiv) and 5-(1-methylcyclopropoxy)-3-[6-[(3S)-3-methylpiperazin-1-yl]pyrimidin-4-yl]-1H-indazole (90 mg, 246.95 μmol, 1.00 equiv) in MeCN (5 mL) was added KI (122.98 mg, 740.86 μmol, 3 equiv) and DIPEA (159.58 mg, 1.23 mmol, 215.07 μL, 5 equiv) in one portion at 20 °C under N. 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 (5 mL). The aqueous phase was extracted with ethyl acetate (3×5 mL). The combined organic phases were washed with brine (3×5 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. 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): 8 min; 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 (23.23 mg, 28.98 umol, yield 11.73%, purity 98.399%) as a red solid.

[0224] Exemplary Synthesis of Exemplary Compound 14 Step 1 [ka] To a mixture of 2-fluoro-5-methyl-phenol (7 g, 55.50 mmol, 1 equiv.) in AcOH (15.2 mL) and HSO (2 mL) was added NaNO (3.83 g, 55.50 mmol, 1 equiv.) in HO (35 mL) 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 added dropwise to a mixture of HNO (12 mL) and HO (35 mL) with stirring. 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 x 100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give 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] 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 CHCN (60 mL) was added KCO (8.56 g, 61.94 mmol, 2 equiv.) under N at 20 °C. 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 hours. 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 NaNO (1.57 g, 22.69 mmol, 1.1 equiv) in HO (5 mL) 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 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, dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue 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 (3.66 g, 14.42 mmol, 2.90 mL, 2 equiv.). The mixture was stirred at 25 °C for 3 h. The reaction mixture was diluted with saturated NaSO (30 mL) and extracted with EtOAc (50 mL). The combined organic layers were washed with brine (50 mL), dried over NaSO, 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), dried over Na2SO4, 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 K2CO3 (2.36 g, 17.05 mmol, 3 equiv.). The mixture was stirred at 100 °C for 4 hours. 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), dried over Na2SO4, 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 afford 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 tert-butyl (2S)-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), Pd(dppf)Cl (184.85 mg, 252.63 mmol, 0.15 equiv.) and KOAc (495.87 mg, 5.05 mmol, 3 equiv.) were added. The mixture was stirred at 90 °C under N for 1 h. 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, dried over Na2SO4, filtered, and concentrated under reduced pressure to give tert-butyl (S)-2-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1-carboxylate (540 mg, 571.64 umol, 33.94% yield) as a brown oil. Step 9 [ka] To a solution of tert-butyl (S)-2-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1-carboxylate (540 mg, 1.68 mmol, 1 equiv.) and 2-[(6-fluoro-3-iodo-5-isopropoxy-indazol-1-yl)methoxy]ethyl-trimethyl-silane (1.14 g, 2.52 mmol, 1.5 equiv.) in 1,4-dioxane (10 mL) and HO (2 mL) was added Pd(dppf)Cl (184.53 mg, 252.20 mmol, 0.15 equiv.) and NaCO (534.61 mg, 5.04 mmol, 3 equiv.). The mixture was stirred at 90 °C under N for 2 h. The reaction mixture was diluted with water (20 mL) and extracted with EA (30 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, 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 equiv.) in DCM (5 mL) was added TFA (1.54 g, 13.51 mmol, 1 mL, 8.10 equiv.). The mixture was stirred at 25 °C for 6 h. Then, NH3.HO (701.14 mg, 5.00 mmol, 770.48 µL, 25% purity, 3 equiv.) was added to the solution, and the mixture was stirred for 2 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (30 mL). The combined organic layers were washed with brine (20 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give 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] To a solution of 6-fluoro-5-isopropoxy-3-[2-[(3S)-3-methylpiperazin-1-yl]-4-pyridyl]-1H-indazole (100 mg, 270.68 μmol, 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 (163.66 mg, 270.68 μmol, 1 equiv.) in CHCN (2 mL) was added KI (539.21 mg, 3.25 mmol, 12 equiv.) and DIEA (419.81 mg, 3.25 mmol, 565.78 μL, 12 equiv.). The mixture was stirred at 90° C. for 12 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (30 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The 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 give 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 (24.3 mg, 29.74 umol, 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 stirred at 50 °C under N for 0.5 h. Then, a solution of 6-fluoro-5-isopropoxy-3-[6-[(3S)-3-methylpiperazin-1-yl]pyrimidin-4-yl]-1H-indazole (150 mg, 309.63 μmol, 1 equiv., TFA) and DIEA (600.27 mg, 4.64 mmol, 808.98 μL, 15 equiv.) in CHCN (3 mL) was added to the mixture. The mixture was then stirred at 90° C. under N for 16 hours. The reaction mixture was diluted with water (20 mL) and extracted with EA (30 mL). The combined organic layers were washed with brine (20 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue 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: 9 min; 100% B retention time: 1 min; flow rate: 25 ml / 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 (15 mg, 18.68 umol, 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 one portion at 20 °C under N. 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), dried over anhydrous NaSO, filtered, and concentrated in vacuo. 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 in one portion at 20 °C under N. 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), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (column height: 40 g, 30 mL / min, 100–200 mesh silica gel, 0% (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) was added n-BuLi (2.5 M, 2.50 mL, 1.3 equiv.) dropwise under N at −70° C. The mixture was then stirred at −20° C. for 5 min, and a solution of ZnCl (1 M, 7.21 mL, 1.5 equiv.) was added dropwise at −70° C. The mixture was stirred at −40° C. for 10 min. A mixture of 4,6-dichloropyrimidine (787.67 mg, 5.29 mmol, 1.1 equiv.) and Pd(PPh) (277.71 mg, 240.32 μmol, 0.05 equiv.) in THF (1 mL) was stirred at 20° C. for 30 min and added to the reaction. The cold bath was removed, and the mixture was stirred at 20 °C for 2 h to give a yellow solution. TLC (PE: EtOAc = 10:1, Rf = 0.83) showed one new spot. The residue was poured into water (10 mL). The aqueous phase was extracted with ethyl acetate (20 mL * 3). The combined organic phase was washed with brine (20 mL * 2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (40 g, 35 mL / min, 100-200 mesh silica gel, 0-5% ethyl acetate / petroleum ether (30 min)) 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) was added TFA (3 g, 26.31 mmol, 1.95 mL, 10.95 equiv.) in one portion at 20 °C under N. The mixture was stirred at 20 °C for 1 h. Then, NH.H.O (2.55 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), dried over anhydrous NaSO, 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 μmol, 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 μmol, 1 equiv) in THF (5 mL) and DCM (5 mL), tert-butyl 2,2,2-trichloroethanimidate (744.15 mg, 3.41 mmol, 609.96 μL, 6 equiv) and BF3.Et2O (241.68 mg, 851.40 μmol, 210.15 μL, 50% purity, 1.5 equiv) were added in one portion at 25 °C under N2. 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), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (DCM:MeOH=10:1, Rf=0.38, 12 g, 30 mL / min, 100-200 mesh silica gel, 0-20% (10 min) ethyl acetate / 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 μmol, 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 μmol, 1 equiv.), (2S)-benzyl 2-methylpiperazine-1-carboxylate (154.77 mg, 660.59 μmol, 1 equiv.) in DMSO (10 mL), EtN (200.54 mg, 1.98 mmol, 275.84 μL, 3 equiv.) was added in one portion and then stirred at 100° C. for 1 h. TLC (PE:EtOAc = 5:1, Rf = 0.50) indicated complete consumption of the starting material. The mixture was cooled to 20° C., and the residue was then poured into water (10 mL). The aqueous phase was extracted with ethyl acetate (3 × 10 mL). The combined organic phase was washed with brine (2 × 10 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. 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 afford benzyl (2S)-4-[6-(5-tert-butoxy-1H-indazol-3-yl)pyrimidin-4-yl]-2-methyl-piperazine-1-carboxylate (230 mg, 450.27 μmol, 68.16% yield, 98% purity) as a yellow gum. Step 7 [ka] To a mixture of benzyl (2S)-4-[6-(5-tert-butoxy-1H-indazol-3-yl)pyrimidin-4-yl]-2-methyl-piperazine-1-carboxylate (230 mg, 459.46 μmol, 1 equiv.) in EtOH (5 mL), Pd / C (100 mg, 459.46 μmol, 10% purity, 1 equiv.) was added in one portion under N at 20° C. The suspension was degassed under vacuum and purged several times with H. The mixture was stirred under H (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 x 50 mL) to give 5-tert-butoxy-3-[6-[(3S)-3-methylpiperazin-1-yl]pyrimidin-4-yl]-1H-indazole (140 mg, 382.03 µmol, 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 μmol, 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]ethyl 4-methylbenzenesulfonate (254.09 mg, 420.24 μmol, 1.1 equiv.) in MeCN (5 mL), DIPEA (246.87 mg, 1.91 mmol, 332.71 μL, 5 equiv.) was added 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 phases were washed with brine (2 × 5 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by reverse-phase HPLC (column: Phenomenex luna C18 100*40 mm*3 um; condition: water (0.225% FA)-ACN; starting B: 20-50; flow rate: 25 mL / min; gradient time: 8.5 min; 100% B retention time: 2 min). 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 μmol, 10.98% yield, 96% purity) as a white solid.

[0227] Exemplary Synthesis of Exemplary Compound 17 Step 1 [ka] A solution of 2-(benzylamino)ethanol (17 g, 112.43 mmol, 15.89 mL, 1 equiv) and EtN (11.38 g, 112.43 mmol, 15.65 mL, 1 equiv) in HO (200 mL) 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), dried over anhydrous NaSO, 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 (1.08 g, 28.48 mmol, 1.5 equiv.). After the addition, the reaction mixture was stirred at 20 °C for 1 h. TLC (PE: EtOAc = 5:1, Rf = 0.18) showed that the reaction was complete. The reaction mixture was quenched with water (5 mL), followed by the addition of 15% aqueous sodium hydroxide solution (5 mL) and water (15 mL). The solid was removed by filtration. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (column height: 40 g, 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) was added NaH (1.33 g, 33.29 mmol, 60% purity, 1 equiv) in one portion at 0 °C under N2. The mixture was stirred at 0 °C for 30 min, and 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 h. 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), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (column height: 40 g, 100–200 mesh silica gel, 0–2% (10 min) MeOH / 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] To a mixture of 2-[2-(2-benzyloxyethoxy)ethoxy]ethanol (3 g, 12.48 mmol, 9.01 mL, 1 equiv.), EtN (1.26 g, 12.48 mmol, 1.74 mL, 1 equiv.), and DMAP (1.53 g, 12.48 mmol, 1 equiv.) in DCM (20 mL), 4-methylbenzene-1-sulfonyl chloride (3.57 g, 18.73 mmol, 1.5 equiv.) was added in one portion at 0 °C under N. The reaction solution was then warmed to 20 °C and stirred for 2 h to give a white suspension. TLC (MeOH:DCM = 10:1, Rf = 0.83) and LCMS indicated the reaction was complete. The mixture was poured into HCl (2 M) and the pH was adjusted to 7–8. The aqueous phase was extracted with ethyl acetate (50 mL*3). The combined organic phase was washed with brine (50 mL*2), dried over anhydrous Na2SO4, 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) was added NaH (542.26 mg, 13.56 mmol, 60% purity, 3 equiv.) in one portion at 0° C. under N2. 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), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. 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] To a solution of 4-benzyl-2-[2-[2-[2-(2-benzyloxyethoxy)ethoxy]ethoxy]ethyl]morpholine (920 mg, 2.07 mmol, 1 equiv.) and BocO (905.31 mg, 4.15 mmol, 952.96 uL, 2 equiv.) in MeOH (10 mL) was added Pd / C (100 mg, 2.07 mmol, 10% purity, 1 equiv.) under N. The suspension was degassed under vacuum and purged with H several times. The mixture was stirred under H (45 psi) at 50 °C for 4 h. TLC showed the absence of 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] To a mixture of tert-butyl 2-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethyl]morpholine-4-carboxylate (400 mg, 1.10 mmol, 1 equiv.), EtN (334.10 mg, 3.30 mmol, 459.56 uL, 3 equiv.), and DMAP (134.46 mg, 1.10 mmol, 1 equiv.) in DCM (10 mL) was added 4-methylbenzenesulfonyl chloride (419.64 mg, 2.20 mmol, 2 equiv.) in one portion at 0 °C under N. 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 indicated 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), dried over anhydrous Na2SO4, 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, 0-10% MeOH / DCM) and SFC {column: REGIS(s,s)WHELK-O1 (250 mm*50 mm, 10 μm); condition: 0.1% NH3H2O PA; Start B: 20%; End B: 20%; Flow rate (ml / min): 70)} to obtain enantiomer 1 of tert-butyl (2*1)-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)-tert-butyl 2-[2-[2-[2-[2-(p-tolylsulfonyloxy)ethoxy]ethoxy]ethoxy]ethyl]morpholine-4-carboxylate (146 mg, 259.63 umol, 23.59% yield, 92.051% purity) (Rt=3.004 min, 146 mg) as a colorless oil. Step 8 [ka] of enantiomer 1 (2*) in DMF (5 mL) 1To a mixture of tert-butyl 2-[2-[2-[2-[2-(p-tolylsulfonyloxy)ethoxy]ethoxy]ethoxy]ethyl]morpholine-4-carboxylate (70 mg, 135.23 μmol, 1 equiv.) and 2-(2,6-dioxo-3-piperidyl)-5-hydroxy-isoindoline-1,3-dione (40.79 mg, 148.75 μmol, 1.1 equiv.), K2CO3 (37.38 mg, 270.46 μmol, 2 equiv.) was added in one portion under N2 at 20 °C. 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), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (column height: 12 g, 100-200 mesh silica gel, 0-100% (30 min) ethyl acetate / petroleum ether, 100% (10 min) ethyl acetate / petroleum ether) to afford 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 μmol, 53.40% yield, 89.5% purity) as a colorless gum. Step 9 [ka] in DCM (5 mL) 1To 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 μmol, 1 equiv.), TFA (27.60 mg, 242.07 μmol, 17.92 μL, 3 equiv.) was added in one portion under N at 25° C. The mixture was stirred at 25° C. for 30 minutes. TLC indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure and the solvent removed 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 μmol, 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 μmol, 1.1 equiv) 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 μmol, 1 equiv, TFA) in DMSO (2 mL) was added DIPEA (20.40 mg, 157.84 μmol, 27.49 μL, 2 equiv) in one portion at 20 °C under N. The mixture was stirred at 100 °C for 1 h. The aqueous phase was extracted with ethyl acetate (3 mL). The combined organic phase was washed with brine (3 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by reverse-phase HPLC (Phenomenex Luna C18 100*30 mm*5 μm column; conditions: 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 (7.6 mg, 9.21 μmol, 11.67% yield, 95% purity) as a yellow solid.

[0228] Exemplary Synthesis of Exemplary Compound 18 Step 1 [ka] in DMF (2 mL) 2To a mixture of tert-butyl 2-[2-[2-[2-[2-(p-tolylsulfonyloxy)ethoxy]ethoxy]ethoxy]ethyl]morpholine-4-carboxylate (146 mg, 282.05 μmol, 1 equiv.) and 2-(2,6-dioxo-3-piperidyl)-5-hydroxy-isoindoline-1,3-dione (85.08 mg, 310.26 μmol, 1.1 equiv.), K2CO3 (77.97 mg, 564.11 μmol, 2 equiv.) was added in one portion under N2 at 20 °C. The mixture was stirred at 70 °C for 2 h. The mixture was cooled to 25 °C and concentrated under reduced pressure at 25 °C. The residue was poured into water (5 mL). The aqueous phase was extracted with ethyl acetate (5 mL*3). The combined organic phase was washed with brine (5 mL*3), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. 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 afford 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 μmol, 67.51% yield) as a colorless gum. Step 2 [ka] in DCM (5 mL) 2To 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 μmol, 1 equiv.), TFA (21.71 mg, 190.43 μmol, 14.10 μL, 1 equiv.) was added in one portion under N at 25° C. The mixture was stirred at 25° C. for 30 minutes. TLC showed that the starting material had been consumed. The reaction mixture was concentrated under reduced pressure and the solvent removed 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 μmol, 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* 2To a mixture of )-morpholin-2-yl]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]isoindoline-1,3-dione (118 mg, 227.12 μmol, 1 equiv., TFA), DIPEA (58.71 mg, 454.25 μmol, 79.12 μL, 2 equiv.) was added in one portion at 20° C. under N. The mixture was stirred at 100° C. for 1 h, then HCl (4 M, 283.90 μL, 5 equiv.) was added and the solution was stirred at 65° C. for 30 min. The aqueous phase was extracted with ethyl acetate (3 mL*2). The combined organic phase was washed with brine (3 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. 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 (43.1 mg, 53.17 umol, 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 stirred at 120 °C under N for 16 h. The reaction mixture was poured into HO (10 mL * 2) and centrifuged to remove residual water, affording 5-hydroxy-2-(3-methyl-2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (114 mg, 355.93 μmol, 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 μmol, 1.2 equiv) and 5-hydroxy-2-(3-methyl-2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (114 mg, 395.48 μmol, 1 equiv) in DMF (5 mL) was added KCO (163.97 mg, 1.19 mmol, 3 equiv). 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 μmol, 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]ethoxy]-2-(3-methyl-2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (180 mg, 387.54 μmol, 1 equiv.) and 4-methylbenzenesulfonyl chloride (147.77 mg, 775.09 μmol, 2 equiv.) in DCM (3 mL) was added DMAP (4.73 mg, 38.75 μmol, 0.1 equiv.) and TEA (117.65 mg, 1.16 mmol, 161.82 μL, 3 equiv.). After the addition, the mixture was stirred at 20°C for 16 h. The filtrate was quenched with water (10 mL) and extracted with ethyl acetate (3 x 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 μmol, 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 μmol, 1 equiv.) and 5-(1-methylcyclopropoxy)-3-[6-[(3S)-3-methylpiperazin-1-yl]pyrimidin-4-yl]-1H-indazole (82.47 mg, 226.30 μmol, 1 equiv.) in ACN (4 mL) was added KI (187.83 mg, 1.13 mmol, 5 equiv.) and DIEA (146.24 mg, 1.13 mmol, 197.09 μL, 5 equiv.). The mixture was stirred at 100° C. for 6 h. The reaction was cooled, water (10 mL) was added and the mixture was extracted with ethyl acetate (3×10 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%, 9 min) 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 (11.1 mg, 13.58 umol, yield 6.00%, purity 99.21%) as a red solid.

[0230] Exemplary Synthesis of Exemplary Compound 20 Step 1 [ka] To a solution of 5-fluoroisobenzofuran-1,3-dione (1 g, 6.02 mmol, 1 equiv.) and 3-aminopiperidine-2,6-dione HCl salt (1.49 g, 9.03 mmol, 1.5 equiv.) in CH3COOH (10 mL) was added KOAc (1.18 g, 12.04 mmol, 2 equiv.). After the 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 equiv.) and tert-butyl piperazine-1-carboxylate (852.97 mg, 4.58 mmol, 1.1 equiv.) in NMP (10 mL) was added DIEA (1.61 g, 12.49 mmol, 2.18 mL, 3 equiv.). The sealed tube was heated 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 mmol of starting material) and EB12-32 (4.16 mmol of 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 equiv.) in MeOH (10 mL) was added HCl / dioxane (4 M, 2.00 mL, 2.95 equiv.). After the addition, the reaction solution was stirred at 65° C. for 1 hour. 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 of starting material) and EB12-35 (2.71 mmol of 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 the potassium hydroxide, 2-bromo-1,1-dimethoxyethane (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 cooled 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 μL, 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] To a solution of 5-(1-methylcyclopropoxy)-3-[6-[(3S)-3-methylpiperazin-1-yl]pyrimidin-4-yl]-1H-indazole (100 mg, 274.39 μmol, 1 equiv.) and 2-(2,2-dimethoxyethoxy)ethyl 4-methylbenzenesulfonate (83.51 mg, 274.39 μmol, 1 equiv.) in CHCN (3 mL) was added KI (227.75 mg, 1.37 mmol, 5 equiv.) and DIEA (70.93 mg, 548.78 μmol, 95.59 μL, 2 equiv.). After the 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 μmol, 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 μmol, 1 equiv.) in THF (3 mL) was added H2SO4 (2 M, 3.22 mL, 40 equiv.). After the addition, the reaction solution was stirred at 70 °C for 1 h. The reaction solution was quenched with saturated NaHCO3 (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 μmol, 73.58% yield, 89% purity) as a yellow solid. The crude product was used directly. Step 8 [ka] 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-(piperazine To a solution of (-1-yl)isoindoline-1,3-dione hydrochloride (50.45 mg, 133.18 μmol, 1 equiv.), NaOAc (32.77 mg, 399.53 μmol, 3 equiv.), HOAc (8.00 mg, 133.18 μmol, 7.62 μL, 1 equiv.), and NaBHCN (16.74 mg, 266.35 μmol, 2 equiv.) were 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*25mm*5um; mobile phase: [water (0.04% NH3H2O ​​+ 10mM NH4HCO3)-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] 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 μmol, 1 equiv.) and 2-(2,2-dimethoxyethoxy)ethyl 4-methylbenzenesulfonate (80.42 mg, 264.22 μmol, 1 equiv.) in CHCN (3 mL), KI (43.86 mg, 264.22 μmol, 1 equiv.) and DIPEA (34.15 mg, 264.22 μmol, 46.02 μL, 1 equiv.) were added in one portion under N at 20° C. The reaction mixture was then 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 μmol, 1 equiv.) in THF (5 mL) was added H2SO4 (2 M, 4.31 mL, 40 equiv.) in one portion under N2 at 20 °C. 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) indicated the reaction was complete. The solution was cooled to 20 °C. The solution was poured into water (5 mL) and NaHCO3, and 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), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give 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 μmol, 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 μmol, 1 equiv.) and 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindoline-1,3-dione hydrochloride (81.54 mg, 215.26 μmol, 2 equiv.) in DMF (2 mL) was added NaOAc (26.49 mg, 322.89 μmol, 3 equiv.) and acetic acid (3.23 mg, 53.81 μmol, 3.08 μL, 0.5 equiv.). The mixture was stirred at 25° C. for 0.5 h. Then, NaBH3CN (13.53 mg, 215.26 umol, 2 eq) was added to the mixture. The mixture was stirred at 20°C for 16 hours. 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*25 mm*5 um; mobile phase: water (0.04% NH3H2O ​​+ 10 mM Direct purification by elution with 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 µmol, 19.27% ​​yield, 100% purity) as a yellow solid.

[0232] Exemplary Synthesis of Exemplary Compound 22 Step 1 [ka] To a solution of 5-isopropoxy-3-[6-[(3S)-3-methylpiperazin-1-yl]pyrimidin-4-yl]-1H-indazole (320 mg, 822.85 μmol, 1 equiv., HCl salt) and 2-(2,2-diethoxyethoxy)ethyl 4-methylbenzenesulfonate (328.23 mg, 987.42 μmol, 1.2 equiv.) in CH3CN (6 mL) was added KI (1.37 g, 8.23 ​​mmol, 10 equiv.) and DIEA (1.06 g, 8.23 ​​mmol, 1.43 mL, 10 equiv.). The mixture was stirred at 90 °C for 18 h. LC-MS showed several new peaks, and approximately 41% of the desired compound was detected. The reaction mixture was diluted with water (20 mL) and extracted with EA (30 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, 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 μmol, 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 μmol, 1 equiv.) in THF (1 mL) was added H2SO4 (2 M, 1.25 mL, 10.25 equiv.). The mixture was stirred at 70 °C for 1 h. TLC showed that the reactants were consumed, and one major new spot with a more polar character was detected. The reaction mixture was diluted with saturated NaHCO3 (20 mL) and extracted with EA (30 mL). The combined organic layers were washed with brine (20 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give 2-[2-[(2S)-4-[6-(5-isopropoxy-1H-indazol-3-yl)pyrimidin-4-yl]-2-methyl-piperazin-1-yl]ethoxy]acetaldehyde (100 mg, 207.52 μmol, 85.11% yield, 91% purity) as a pale yellow solid. Step 3 [ka] 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-(piperidin-1-yl)- To a solution of (perazin-1-yl)isoindoline-1,3-dione (104.07 mg, 228.04 μmol, 1 equiv.) was added NaOAc (56.12 mg, 684.12 μmol, 3 equiv.), HOAC (13.69 mg, 228.04 μmol, 13.04 μL, 1 equiv.), and NaBHCN (42.99 mg, 684.12 μmol, 3 equiv.). The mixture was stirred at 25°C for 18 hours. LC-MS (EB134-92-P1C) showed that reactant 1 was consumed. LC-MS showed several new peaks, and approximately 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 conditions: column: Phenomenex Luna C18 100*30mm*5um; mobile phase: [water (0.225% FA)-ACN]; B%: 5%~35%, 18 min) to give 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 (27.70 mg, 34.88 umol, 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 KCO (7.25 g, 52.43 mmol, 3 equiv.). The mixture was then stirred at 60 °C under N for 16 h. 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 material 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 μL, 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 μL, 2.5 equiv) in DCM (10 mL) was added dropwise, and the mixture was then stirred at −60° C. for 15 minutes. Next, a solution of tert-butyl (3R)-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 minutes. TEA (1.11 g, 11.01 mmol, 1.53 mL, 3 equiv) was then added, and the mixture was warmed to −60° C. for 1 hour. 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. tert-Butyl (3S)-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 equiv., TFA) and tert-butyl (3S)-3-methyl-4-(4-oxobutyl)piperazine-1-carboxylate (446.11 mg, 1.65 mmol, 1.5 equiv.) in DCM (15 mL) and MeOH (15 mL) was added NaOAc (270.70 mg, 3.30 mmol, 3 equiv.), and the mixture was stirred for 20 minutes at 20° C. Then, HOAc (6.61 mg, 110.00 μmol, 6.29 μL, 0.1 equiv.) and NaBHCN (691.24 mg, 11.00 mmol, 10 equiv.) were added to the solution and stirred at 20° C. for 2 hours. TLC (dichloromethane:methanol = 10:1, Rf = 0.01) indicated the reaction was complete. The reaction mixture was poured into HO (20 mL). The mixture was extracted with ethyl acetate (30 mL * 3). The organic phase was washed with brine (20 mL), dried over anhydrous NaSO, and concentrated in vacuo to give a residue. The residue 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 μmol, 63.99% yield, 70% purity) as a yellow gum. Step 4 [ka] To a solution of 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 (200 mg, 335.17 μmol, 1 equiv) in DCM (4 mL) was added TFA (3.08 g, 27.01 mmol, 2 mL, 80.59 equiv) 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 μmol, 1 equiv., TFA) and 3-(6-chloropyrimidin-4-yl)-5-isopropoxy-1H-indazole (66.20 mg, 229.27 μmol, 0.7 equiv.) in DMSO (5 mL) was added DIEA (211.66 mg, 1.64 mmol, 285.25 μL, 5 equiv.). The mixture was then stirred at 100° C. under N for 2 hours. The reaction mixture was poured into HO (10 mL). The mixture was extracted with ethyl acetate (10 mL*3). The aqueous phase was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 100*40mm*3um; mobile phase: [water (0.225% FA)-ACN]; B%: 12%~42%, 10 min) to give 2-(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 CHCOOH (823.89 ug, 13.72 umol, 7.85 e -1To the resulting solution, NaOAc (45.02 mg, 548.78 umol, 2 eq) was added in one portion at 20°C under N2. The solution was stirred at 20°C for 5 h. NaBH3CN (34.49 mg, 548.78 umol, 2 eq) was then 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 x 10 mL). The combined organic phases were washed with brine (2 x 5 mL), dried over anhydrous Na2SO4, 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 afford tert-butyl 4-[[(2S)-2-methyl-4-[6-[5-(1-methylcyclopropoxy)-1H-indazol-3-yl]pyrimidin-4-yl]piperazin-1-yl]methyl]piperidine-1-carboxylate (110 mg, 172.72 μmol, 62.95% yield, 88.199% purity) as a yellow oil. 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 μmol, 1 equiv) in DCM (5 mL) was added TFA (66.99 mg, 587.48 μmol, 43.50 μL, 3 equiv) in one portion at 20°C under N2. The mixture was stirred at 20°C for 1 h. The residue was poured into NaHCO3 (5 mL) and adjusted to pH = 7-8. The aqueous phase was extracted with ethyl acetate (3 × 5 mL). The combined organic phase was washed with brine (3 × 5 mL), dried over anhydrous Na2SO4, 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 afford 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 μmol, 1 equiv.) and 4-piperidylmethanol (83.39 mg, 724.06 μmol, 2 equiv.) in DMSO (2 mL), DIEA (140.37 mg, 1.09 mmol, 189.18 μL, 3 equiv.) was added 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 poured into NaHCO3 (10 mL) and adjusted to pH 7-8. The aqueous phase was extracted with ethyl acetate (3 × 10 mL). The combined organic phase was washed with brine (2 × 10 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (100–200 mesh silica gel, 0–10% MeOH / DCM) to afford 2-(2,6-dioxo-3-piperidyl)-5-[4-(hydroxymethyl)-1-piperidyl]isoindoline-1,3-dione (120 mg, 283.18 μmol, 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 μmol, 1 equiv.) and TEA (98.09 mg, 969.34 μmol, 134.92 μL, 3 equiv.) in DCM (5 mL) was added TsCl (27.35 mg, 387.74 μmol, 1.2 equiv.) in one portion under N at 0°C. The mixture was stirred at 20°C for 20 hours to give a yellow solution. TLC (DCM:MeOH = 10:1, Rf = 0.45) indicated 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), dried over anhydrous NaSO, 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 afford [1-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]-4-piperidyl]methyl 4-methylbenzenesulfonate (160 mg, 228.91 μmol, 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 μmol, 1 equiv) and [1-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]-4-piperidyl]methyl 4-methylbenzenesulfonate (159.40 mg, 303.29 μmol, 1.4 equiv) in MeCN (5 mL) was added KI (179.81 mg, 1.08 mmol, 5 equiv) and DIPEA (84.00 mg, 649.91 μmol, 113.20 μL, 3 equiv) in one portion at 20 °C under N. The solution was stirred at 80° C. for 16 hours. The residue was poured into water (5 mL) and stirred for 5 minutes. The aqueous phase was extracted with ethyl acetate (3×10 mL). The combined organic phases were washed with brine (2×5 mL), dried over anhydrous Na2SO4, 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 at 0 °C under nitrogen. Once 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 quenched with aqueous NH4Cl (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 afford 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 (158.50 mg, 4.18 mmol, 1.5 equiv.) 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 the consumption of the starting material and the formation of one new spot. The reaction mixture was quenched by the addition of water (0.5 mL), followed by the addition of 15% aqueous NaOH solution (0.5 mL) and water (1.5 mL). The solid was removed by filtration. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-50% ethyl acetate / petroleum ether) to afford 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 μL, 2 equiv.) at 20° C. After the 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 afford 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] To a solution of tert-butyl 4-[2-(p-tolylsulfonyloxy)ethoxy]piperidine-1-carboxylate (131.54 mg, 329.27 μmol, 1 equiv.) and 5-(1-methylcyclopropoxy)-3-[6-[(3S)-3-methylpiperazin-1-yl]pyrimidin-4-yl]-1H-indazole (120 mg, 329.27 μmol, 1 equiv.) in CH3CN (3 mL) was added KI (273.30 mg, 1.65 mmol, 5 equiv.) and DIEA (127.67 mg, 987.81 μmol, 172.06 μL, 3 equiv.). After the addition, the reaction mixture was stirred at 90 °C for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 × 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 μmol, 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 μmol, 1 equiv) in DCM (2 mL) was added HCl / dioxane (4 M, 549.23 μL, 10 equiv) at 20° C. After the addition, the reaction mixture was stirred at 20° C. for 30 minutes. TLC (dichloromethane:methanol=10:1) showed consumption of the starting material. The reaction mixture was concentrated under reduced pressure to give 5-(1-methylcyclopropoxy)-3-[6-[(3S)-3-methyl-4-[2-(4-piperidyloxy)ethyl]piperazin-1-yl]pyrimidin-4-yl]-1H-indazole (108 mg, 206.50 μmol, 94.00%). Step 6 [ka] To a solution of 5-(1-methylcyclopropoxy)-3-[6-[(3S)-3-methyl-4-[2-(4-piperidyloxy)ethyl]piperazin-1-yl]pyrimidin-4-yl]-1H-indazole (105.23 mg, 214.05 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 CHCN (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%, 8 min) 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 (12.5 mg, 14.50 umol, yield 8.47%, purity 98%) as a yellow solid.

[0236] Exemplary Synthesis of Exemplary Compound 26 Step 1 [ka] To a solution of benzyl (3S)-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 CH3CN (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 benzyl (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 benzyl (3S)-4-[2-(4-tert-butoxycarbonylpiperazin-1-yl)ethyl]-3-methyl-piperazine-1-carboxylate (460 mg, 1.03 mmol, 1 equiv.) in MeOH (5 mL) under N was added Pd / C (200 mg, 2.06 mmol, 10% purity, 2 equiv.). The suspension was degassed under vacuum and purged several times with H. The mixture was stirred under H (15 psi) at 25 °C for 2 h. TLC showed no reactant remained, and one major new, more polar spot 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 μmol, 1 equiv.) and 2-[[3-(6-chloropyrimidin-4-yl)-5-isopropoxy-indazol-1-yl]methoxy]ethyl-trimethyl-silane (388.89 mg, 928.15 μmol, 1 equiv.) in DMSO (3 mL) was added DIEA (359.87 mg, 2.78 mmol, 485.00 μL, 3 equiv.). The mixture was stirred at 100 °C for 2 h. LC-MS (EB134-185-P1A) showed no remaining reactant 1. LC-MS showed several new peaks, and approximately 64% of the desired compound was detected. The reaction mixture was diluted with water (20 mL) and extracted with EA (30 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, 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 μmol, 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 μmol, 1 equiv.) in DCM (3 mL) was added TFA (7.19 g, 63.03 mmol, 4.67 mL, 125.15 equiv.). The mixture was stirred at 25 °C for 16 h. Then, NH3.HO (211.79 mg, 1.51 mmol, 232.74 μL, 25% purity, 3 equiv.) was added to the solution, and the mixture was stirred for 2 h. LC-MS (EB134-187-P1B) showed no reactant remained. LC-MS showed several new peaks, and approximately 97% of the desired compound was detected. The reaction mixture was diluted with water (20 mL) and extracted with EA (30 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give 5-isopropoxy-3-[6-[(3S)-3-methyl-4-(2-piperazin-1-ylethyl)piperazin-1-yl]pyrimidin-4-yl]-1H-indazole (150 mg, 313.17 μmol, 62.18% yield, 97% purity) as a yellow gum. Step 5 [ka] To a solution of 5-isopropoxy-3-[6-[(3S)-3-methyl-4-(2-piperazin-1-ylethyl)piperazin-1-yl]pyrimidin-4-yl]-1H-indazole (150 mg, 322.85 μmol, 1 equiv.) and [1-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]-4-piperidyl]methyl 4-methylbenzenesulfonate (169.68 mg, 322.85 μmol, 1 equiv.) in CHCN (5 mL) was added KI (428.76 mg, 2.58 mmol, 8 equiv.) and DIEA (333.81 mg, 2.58 mmol, 449.88 μL, 8 equiv.). The mixture was stirred at 80° C. for 16 h. LC-MS (EB134-190-P1D2) showed no remaining reactant 1. LC-MS showed several new peaks, and approximately 56% of the desired compound was detected. The reaction mixture was diluted with water (20 mL) and extracted with EA (30 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The 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 give 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 (47 mg, 55.39 umol, 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 (1.01 g, 12.06 mmol, 469.07 μL, 3 equiv.) under N at 25 °C. The reaction mixture was then heated to 80 °C and stirred for 5 h to give a white suspension. TLC (dichloromethane:methanol = 10:1) showed the reaction was complete. The mixture was concentrated in vacuo, and the residue was taken up in water (30 mL). The aqueous phase was extracted with ethyl acetate (30 mL * 3). The combined organic phase was washed with brine (30 mL), dried over anhydrous NaSO, 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), HCl (2 M, 5 mL, 4.64 equiv.) was added at 25° C., and the reaction mixture was then stirred at 50° C. for 2 hours to give an off-yellow solution. TLC (dichloromethane:methanol=10:1) showed that the reaction was complete. The residue was adjusted to pH=8 with NaHCO3(s), and the mixture was then 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), dried over anhydrous NaSO, 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. was then added 4-[2-(4-formyl-1-piperidyl)-2-(4-methyl-2 ... tert-Butyl [ethyl]piperazine-1-carboxylate (420 mg, 1.29 mmol, 1 equiv.) was added and stirred for 1 hour. Then, acetic acid (193.75 mg, 3.23 mmol, 184.52 uL, 2.5 equiv.) and sodium cyanoborohydride (162.20 mg, 2.58 mmol, 2 equiv.) were added and stirred at 25°C for 1 hour. The reaction mixture was then stirred at 25°C for 14 hours to give a yellow solution. TLC (dichloromethane:methanol = 10:1) showed the detection of a new spot. The residue was poured into ice water (w / w = 1 / 1) (35 mL). The aqueous phase was extracted with ethyl acetate (35 mL * 2). 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 in vacuo 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 μmol, 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 μmol, 1 equiv) in DCM (10 mL) was added TFA (3.08 g, 27.01 mmol, 2 mL, 55.02 equiv) at 25° C., and the reaction mixture was stirred at 25° C. for 0.5 h to give a yellow solution. TLC (dichloromethane:methanol=10:1) showed consumption of the starting material and the 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 μmol, 80.52% yield, 83% purity, 4% TFA) 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 μmol, 1 equiv., 4TFA) and 3-(6-chloropyrimidin-4-yl)-5-isopropoxy-1H-indazole (45.84 mg, 158.77 μmol, 1 equiv.) in DMSO (10 mL) was added DIEA (102.60 mg, 793.83 μmol, 138.27 μL, 5 equiv.) at 25° C. The reaction mixture was stirred at 25° C. for 30 minutes, and then 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), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 100*30 mm*5 um, 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 (6.8 mg, 8.42 umol, 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 μmol, 1 eq, 4 TFA) and 3-(6-chloropyrimidin-4-yl)-5-(1-methylcyclopropoxy)-1H-indazole (47.75 mg, 158.77 μmol, 1 eq) in DMSO (5 mL) was added DIEA (102.60 mg, 793.83 μmol, 138.27 μL, 5 eq) at 25° C. and stirred for 30 minutes. The reaction mixture was then 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), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column Phenomenex Luna C18 100*30mm*5um, mobile phase: water (0.225% FA)-ACN; B%: 5%~35%; 9 min) to give 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 (7.0 mg, 8.56 umol, yield 5.39%, purity 99.8%) as a yellow solid.

[0239] Exemplary Synthesis of Exemplary Compound 29 Step 1 [ka] To a solution of benzyl (3S)-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. NaBHCN (241.39 mg, 3.84 mmol, 3 equiv) was then 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) indicated completion of the reaction. The reaction mixture was poured into HO (10 mL). The mixture was extracted with ethyl acetate (20 mL * 3). The organic phase was washed with brine (20 mL), dried over anhydrous NaSO, 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)-benzyl 4-(2-chloroethyl)-3-methyl-piperazine-1-carboxylate (180 mg, 606.49 μmol, 47.37% yield) as a colorless oil. Step 2 [ka] (3S)-benzyl 4-(2-chloroethyl)-3-methyl-piperazine-1-carboxylate (180 mg, 606.49 μmol, 1 equiv.) and 4-(dimethoxymethyl)piperidine (144.85 mg, 909.73 μmol, 1.5 equiv.) were dissolved in EtOH (5 mL) and water (0.5 mL). NaHCO (101.90 mg, 1.21 mmol, 47.17 μL, 2 equiv.) was then added to the reaction mixture and stirred at 80° C. for 5 hours. TLC (dichloromethane:methanol = 10:1, Rf = 0.4) showed the reaction was complete. The reaction mixture was poured into H O (20 mL). The mixture was extracted with ethyl acetate (20 mL * 2). The organic phase was washed with brine (15 mL * 3), dried over anhydrous Na SO and concentrated in vacuo to give a residue. The residue was purified by preparative TLC (10% methanol / dichloromethane, Rf=0.4) to give (3S)-benzyl 4-[2-[4-(dimethoxymethyl)-1-piperidyl]ethyl]-3-methyl-piperazine-1-carboxylate (165 mg, 393.27 umol, 64.84% yield) as a colorless oil. Step 3 [ka] A solution of (3S)-4-[2-[4-(dimethoxymethyl)-1-piperidyl]ethyl]-3-methyl-piperazine-1-carboxylate (65 mg, 154.93 μmol, 1 equiv.) in THF (2 mL) and HSO (2 M, 2 mL, 25.82 equiv.) was stirred at 70 °C for 1 h. TLC (dichloromethane:methanol = 10:1, Rf = 0.2) indicated consumption of the starting material. The reaction mixture was poured into HO (20 mL) and basified with aqueous NaHCO to pH = 8. The mixture was extracted with ethyl acetate (20 mL * 5), dried over anhydrous NaSO, and concentrated in vacuo to give (3S)-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 (57 mg, 152.62 μmol, 1 equiv.) and 2-(2,6-dioxo-3-piperidyl)-5-piperazin-1-yl-isoindoline-1,3-dione (69.65 mg, 152.62 μmol, 1 equiv., TFA) in DCE (3 mL) and MeOH (0.5 mL) was added NaOAc (54.81 mg, 668.11 μmol, 4.38 equiv.) and the mixture was stirred for 20 minutes at 25° C. Then, HOAc (916.49 μg, 15.26 μmol, 8.73 e-1 μL, 0.1 equiv.) was added to the mixture and stirred for 20 minutes at 25° C. Then, NaBH3CN (54.81 mg, 872.15 umol, 5.71 equiv) was added to the solution and stirred at 25°C for 16 hours. TLC (dichloromethane:methanol = 10:1, Rf = 0.2) showed that the reaction was complete. The reaction mixture was poured into H2O (20 mL). The mixture was extracted with ethyl acetate (20 mL * 2). The organic phase was washed with brine (15 mL * 3), dried over anhydrous Na2SO4, and concentrated under vacuum to give a residue. The residue was purified by preparative TLC (10% methanol / dichloromethane, Rf=0.2) to give (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, 68.59 umol, 44.94% yield, 80% purity) as a white solid. Step 5 [ka] A mixture of benzyl (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 (60 mg, 85.73 μmol, 1 equiv) in TFA (4.62 g, 40.52 mmol, 3 mL, 472.60 equiv) was stirred at 70° C. for 8 hours. TLC (dichloromethane:methanol=10:1, Rf=0.01) showed 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 μmol, 1 equiv., TFA) and 3-(6-chloropyrimidin-4-yl)-5-(1-methylcyclopropoxy)-1H-indazole (21.24 mg, 70.62 μmol, 1 equiv.) were dissolved in DMSO (5 mL), and then DIEA (91.27 mg, 706.16 μmol, 123.00 μL, 10 equiv.) was added to the reaction mixture. The reaction mixture was stirred at 80° C. for 8 hours. The reaction mixture was poured into HO (20 mL). The mixture was extracted with ethyl acetate (20 mL*2). The organic phase was washed with brine (15 mL*3), dried over anhydrous Na2SO4 and concentrated under vacuum to give a residue. The 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 give 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 (8.4 mg, 9.78 umol, 13.85% yield, 96.64% purity) 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 μmol, 1 equiv.) and 3-(6-chloropyrimidin-4-yl)-5-isopropoxy-1H-indazole (51.04 mg, 176.77 μmol, 1 equiv.) in DMSO (3 mL) was added DIEA (228.46 mg, 1.77 mmol, 307.90 μL, 10 equiv.). The reaction mixture was stirred at 80° C. under N for 6 h. The filtrate was quenched with water (10 mL) and extracted with ethyl acetate (3×10 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 100*30mm*5um; mobile phase: [water (0.225% FA)-ACN]; B%: 12%~42%, 9 min) 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 (32.1 mg, 39.00 umol, 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 μmol, 1.5 equiv.) and NaOAc (59.30 mg, 722.91 μmol, 3 equiv.) in DCE (8 mL) and MeOH (2 mL), HOAc (14.47 mg, 240.97 μmol, 13.78 μL, 1 equiv.) and (3S)-benzyl 4-[2-(4-formyl-1-piperidyl)ethyl]-3-methyl-piperazine-1-carboxylate (90 mg, 240.97 μmol, 1 equiv.) were added. The reaction mixture was stirred at 25° C. for 1 hour. NaBHCN (30.29 mg, 481.94 μmol, 2 equiv.) was then added. After the addition, the reaction mixture was stirred at 25° C. for 16 hours. 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 afford benzyl (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, 85.32 μmol, 35.41% yield, 83.6% purity) as a colorless gum. Step 2 [ka] A mixture of benzyl (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 μmol, 1 equiv.) 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 μmol, 1.5 equiv, TFA) and 3-(6-chloropyrimidin-4-yl)-5-isopropoxy-1H-indazole (30 mg, 103.90 μmol, 1 equiv) in DMSO (3 mL) was added DIEA (94.00 mg, 727.32 μmol, 126.69 μL, 7 equiv). After the 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 give 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 (9.1 mg, 11.32 umol, 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.) in one portion at 0 °C under N. The 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), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (40 g, 0-10% (10 mL) ethyl acetate / petroleum ether) to afford 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, and 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 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), dried over anhydrous Na2SO4, 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) was added TsOH (3.43 g, 19.91 mmol, 1 equiv.) in one portion at 20 °C under N. The mixture was stirred at 20 °C for 1 h. TLC (petroleum ether:ethyl acetate = 2:3, Rf = 0.30) showed the reaction was complete. HO (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 (30 mL * 2, aq.), brine (30 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (40 g, 30 mL / min, 0 to 100% (30 min) ethyl acetate / petroleum ether) 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 equiv.), TEA (1.75 g, 17.26 mmol, 2.40 mL, 2.5 equiv.), and DMAP (253.04 mg, 2.07 mmol, 0.3 equiv.) in DCM (15 mL) was added TosCl (1.97 g, 10.36 mmol, 1.5 equiv.) at 0° C. The mixture was stirred at 20° C. for 2 hours 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), saturated NaHCO3 (10 mL, aq.), brine (10 mL), dried over anhydrous Na2SO4, 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 NaCO (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.). 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. The resulting mixture was extracted with EtOAc (30 mL*3). The combined extracts were washed with water (30 mL), brine (30 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue 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) was added TFA (866.94 mg, 7.60 mmol, 562.95 μL, 3 equiv.) in one portion at 20° C. under N. The mixture was stirred at 20° C. for 30 minutes. TLC indicated 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 NaBHCN (1.01 g, 16.07 mmol, 3 equiv.). The mixture was then stirred at 20 °C for 30 min. HOAc (321.67 mg, 5.36 mmol, 306.36 µL, 1 equiv.) 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 (10 mL). The aqueous phase was extracted with ethyl acetate (10 mL * 3). The combined organic phases were washed with brine (10 mL * 2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The 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 (229.75 mg, 1.15 mmol, 2 equiv.) and 5-[2-[1-(2-chloroethyl)azetidin-3-yl]oxyethoxy]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (250 mg, 573.58 µmol, 1 equiv.) in MeCN (5 mL), KI (476.07 mg, 2.87 mmol, 5 equiv.) and DIPEA (370.65 mg, 2.87 mmol, 499.53 µL, 5 equiv.) were added in one portion at 20 °C under N. The mixture was stirred at 80 °C for 16 h. The residue was poured into water (5 mL). The aqueous phase was extracted with ethyl acetate (5 mL*3). The combined organic phase was washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (0 to 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 μmol, 58.15% yield) as a yellow solid. Step 9 [ka] To a mixture of 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 μmol, 1 equiv) in DCM (5 mL) was added TFA (114.09 mg, 1.00 mmol, 74.08 μL, 3 equiv) in one portion under N at 20° C. 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 μmol, 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 μmol, 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 μmol, 1 equiv.) were dissolved in DMSO (5 mL), and then DIPEA (100.90 mg, 780.69 μmol, 135.98 μL, 3 equiv.) was added at 20° C. under N. 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 (10 mL). The aqueous phase was extracted with ethyl acetate (10 mL*3). The combined organic phase was washed with brine (10 mL*3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The 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, 13.44% yield, 100% purity) 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 at 0 °C under nitrogen. Once 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 quenched with aqueous NH4Cl (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 afford 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 (158.50 mg, 4.18 mmol, 1.5 equiv.) 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 the consumption of the starting material and the formation of one new spot. The reaction mixture was quenched by the addition of water (0.5 mL), followed by the addition of 15% aqueous NaOH solution (0.5 mL) and water (1.5 mL). The solid was removed by filtration. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-50% ethyl acetate / petroleum ether) to afford 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 μL, 2 equiv.) at 20° C. After the 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 afford 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] To a solution of tert-butyl 4-[2-(p-tolylsulfonyloxy)ethoxy]piperidine-1-carboxylate (131.54 mg, 329.27 μmol, 1 equiv.) and 5-(1-methylcyclopropoxy)-3-[6-[(3S)-3-methylpiperazin-1-yl]pyrimidin-4-yl]-1H-indazole (120 mg, 329.27 μmol, 1 equiv.) in CH3CN (3 mL) was added KI (273.30 mg, 1.65 mmol, 5 equiv.) and DIEA (127.67 mg, 987.81 μmol, 172.06 μL, 3 equiv.). After the addition, the reaction mixture was stirred at 90 °C for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 × 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 μmol, 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 μmol, 1 equiv) in DCM (2 mL) was added HCl / dioxane (4 M, 549.23 μL, 10 equiv) at 20° C. After the addition, the reaction mixture was stirred at 20° C. for 30 minutes. TLC (dichloromethane:methanol=10:1) showed consumption of the starting material. The reaction mixture was concentrated under reduced pressure to give 5-(1-methylcyclopropoxy)-3-[6-[(3S)-3-methyl-4-[2-(4-piperidyloxy)ethyl]piperazin-1-yl]pyrimidin-4-yl]-1H-indazole (108 mg, 206.50 μmol, 94.00% yield, 94% purity) as a yellow solid. The crude product was used directly. Step 6 [ka] To a solution of 5-(1-methylcyclopropoxy)-3-[6-[(3S)-3-methyl-4-[2-(4-piperidyloxy)ethyl]piperazin-1-yl]pyrimidin-4-yl]-1H-indazole (105.23 mg, 214.05 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 CHCN (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%, 8 min) 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 (12.5 mg, 14.50 umol, 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-diethoxyethane (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 portionwise at 0 °C. The mixture was then stirred at 0 °C for 3 h. TLC (petroleum ether:ethyl acetate = 5:1, Rf = 0.2) showed a new spot of reaction. The reaction was quenched with aqueous NH Cl (10 mL) and extracted with ethyl acetate (3 * 20 mL). The combined organic phase was washed with water, dried over Na SO , and concentrated in vacuo to give a residue. The residue 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, three-necked, 100 mL round-bottom flask equipped with an argon inlet adapter, septum, and stir bar, 4-(2,2-diethoxyethoxy)but-1-yne (600 mg, 3.22 mmol, 1 equiv) and THF (10 mL) were added 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 then DMF (470.95 mg, 6.44 mmol, 495.73 μL, 2 equiv) was added dropwise via syringe, turning the reaction colorless. The reaction was stirred at -78 °C for 30 minutes, 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 added to a cold solution of ethyl acetate (10 mL) and 10% KH2PO4 (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 μmol, 1 equiv., TFA) and 5-(2,2-diethoxyethoxy)pent-2-ynal (93.90 mg, 438.24 μmol, 2 equiv.) in DCE (5 mL) and MeOH (1 mL) was added NaOAc (53.92 mg, 657.36 μmol, 3 equiv.) and HOAc (2.63 mg, 43.82 μmol, 2.51 μL, 0.2 equiv.). The mixture was then stirred at 20° C. for 30 minutes. NaBHCN (41.31 mg, 657.36 μmol, 3 equiv.) was then added, and the solution was stirred at 20° C. for 2 hours. TLC (dichloromethane:methanol = 10:1, Rf = 0.37) showed consumption of the starting material. The reaction mixture was poured into HO (10 mL). The mixture was extracted with ethyl acetate (20 mL * 5). The organic phase was washed with brine (20 mL), dried over anhydrous NaSO, and concentrated in vacuo to give a residue. The residue 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 μmol, 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 μmol, 1 equiv.) in THF (2 mL) was added HSO (2 M, 2 mL, 86.50 equiv.). The mixture was then stirred at 65 °C for 1 h. TLC (dichloromethane:methanol = 10:1, Rf = 0.37) indicated consumption of the starting material. The reaction mixture was poured into HO (2 mL) and basified with aqueous NaHCO to pH = 8. The mixture was extracted with ethyl acetate (15 mL*5), dried over anhydrous NaSO and concentrated under vacuum to give 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 μmol, 1 equiv.) 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 μmol, 6.04 e-1 equiv.) in DCE (5 mL) and MeOH (2 mL) was added NaOAc (69.83 mg, 851.23 μmol, 3 equiv.) and HOAc (3.41 mg, 56.75 μmol, 3.25 μL, 0.2 equiv.). The mixture was then stirred at 25° C. for 60 min. Then NaBH3CN (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 poured into H2O (10 mL). The mixture was extracted with ethyl acetate (20 mL * 5). The organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated in vacuo to give a residue. 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 (19.4 mg, 23.60 umol, 8.32% yield, 97.68% purity) 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 equiv.) and 2-chloroacetaldehyde (593.89 mg, 3.03 mmol, 486.80 µL, 3 equiv.) in DCM (5 mL) and MeOH (5 mL) was added NaOAc (165.51 mg, 2.02 mmol, 2 equiv.) and HOAc (6.06 mg, 100.88 µmol, 5.77 µL, 0.1 equiv.). The mixture was then stirred at 20 °C for 20 min. NaBHCN (190.18 mg, 3.03 mmol, 3 equiv.) was then 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) indicated the reaction was complete. The reaction mixture was poured into HO (20 mL). The mixture was extracted with ethyl acetate (30 mL*3). The organic phase was washed with brine (20 mL), dried over anhydrous NaSO, and concentrated in vacuo to give a residue. The residue 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 μmol, 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 μmol, 1 equiv.) and 5-isopropoxy-3-[6-[(3S)-3-methylpiperazin-1-yl]pyrimidin-4-yl]-1H-indazole (110 mg, 312.12 μmol, 1 equiv.) were dissolved in anhydrous CH3CN (10 mL). KI (777.17 mg, 4.68 mmol, 15 equiv.) and DIEA (605.07 mg, 4.68 mmol, 815.46 μL, 15 equiv.) were then added to the reaction mixture. The reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was poured into HO (20 mL). The mixture was extracted with ethyl acetate (20 mL * 2). The organic phase was washed with brine (15 mL*3), dried over anhydrous Na2SO4, and concentrated in vacuo 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 μmol, 49.60% yield) as a white solid. Step 3 [ka] 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, 215.00 mmol, 1 equiv.) was dissolved in DCM (3 mL) and TFA (3.08 g, 27.01 mmol, 2 mL, 125.63 equiv.). The reaction was stirred at 25° C. for 1 hour. TLC (dichloromethane:methanol=10:1, Rf=0.01) indicated 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, which 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) was added NaOAc (52.50 mg, 639.99 umol, 3 equiv.) and the mixture was stirred at 25° C. for 20 min. To the mixture was then added HOAc (1.28 mg, 21.33 umol, 1.22 uL, 0.1 equiv) and stirred at 25°C for 20 minutes. NaBH3CN (53.62 mg, 853.31 umol, 4 equiv) was then added to the solution and the mixture was stirred at 25°C for 16 hours. The reaction mixture was poured into HO (20 mL). The mixture was extracted with ethyl acetate (20 mL*2). The organic phase was washed with brine (15 mL*3), dried over anhydrous Na2SO4 and concentrated under vacuum to give a residue. 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 (14.7 mg, 17.35 umol, 8.13% yield, 97.1% purity, FA) as a yellow solid.

[0246] Exemplary Synthesis of Exemplary Compound 36 Step 1 [ka] To a mixture of 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 EtN (267.34 mg, 2.64 mmol, 367.73 uL, 1 equiv.) in DCM (5 mL) was added 4-methylbenzene-1-sulfonyl chloride (503.69 mg, 2.64 mmol, 1 equiv.) in one portion at 0 °C under N. 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), dried over anhydrous NaSO, filtered, and concentrated in vacuo. 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), KI (1.62 g, 9.75 mmol, 5 equiv.) and DIPEA (1.26 g, 9.75 mmol, 1.70 mL, 5 equiv.) were added in one portion at 20 °C under N2. 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 (10 mL). The aqueous phase was extracted with ethyl acetate (10 mL*3). The combined organic phase was washed with brine (10 mL*3), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. 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) was added TFA (222.01 mg, 1.95 mmol, 144.16 uL, 1 equiv.) in one portion at 20 °C under N. The mixture was stirred at 20 °C for 30 min. The residue was poured into NaHCO (pH = 7-8). The aqueous phase was extracted with DCM (5 mL * 3). The combined organic phase was washed with brine (5 mL * 2), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The crude product was purified by reverse-phase HPLC (column: Phenomenex Luna C18 75*30mm*3um; condition: water (0.225% FA)-ACN; B%: 5%~35%; 9 min) to give 2-(2,6-dioxo-3-piperidyl)-5-[4-[3-(methylamino)propyl]piperazin-1-yl]isoindoline-1,3-dione (250 mg, 604.64 umol, 31.05% yield) as a yellow gum. Step 4 [ka] To a solution of 2-(2,6-dioxo-3-piperidyl)-5-[1-[3-(methylamino)propyl]-4-piperidyl]isoindoline-1,3-dione (100 mg, 242.44 μmol, 1.13 equiv) and 3-[6-[(3S)-4-(2-chloroethyl)-3-methyl-piperazin-1-yl]pyrimidin-4-yl]-5-isopropoxy-1H-indazole (89 mg, 214.49 μmol, 1 equiv) in MeCN (5 mL) was added DIPEA (83.17 mg, 643.48 μmol, 112.08 μL, 3 equiv). The mixture was stirred at 80° C. for 16 hours to give a yellow suspension. 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 (5 mL*3). The combined organic phase was washed with brine (5 mL*2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by preparative HPLC (column: Phenomenex Luna C18 75*30mm*3um; condition: water (0.225% FA)-ACN; B%: 17%~47%; 9 min) to give 2-(2,6-dioxo-3-piperidyl)-5-[4-[3-[2-[(2S)-4-[6-(5-isopropoxy-1H-indazol-3-yl)pyrimidin-4-yl]-2-methyl-piperazin-1-yl]ethyl-methyl-amino]propyl]piperazin-1-yl]isoindoline-1,3-dione (13.6 mg, 17.17 umol, yield 8.01%, purity 100%) as a yellow solid.

[0247] Exemplary Synthesis of Exemplary Compound 37 Step 1 [ka] To a mixture of tert-butyl N-(2-hydroxyethyl)-N-methyl-carbamate (200 mg, 1.14 mmol, 1 equiv.) in DCM (5 mL) was added DMP (968.22 mg, 2.28 mmol, 706.73 μL, 2 equiv.) in one portion at 20 °C under N2. The mixture was stirred at 20 °C for 16 h to give a white suspension. TLC (ethyl acetate:petroleum ether = 10:1) showed complete consumption of the starting material. The residue was poured into NaHCO3, adjusted to pH = 7-8, and Na2SO3 (10 mL) was added. The aqueous phase was extracted with DCM (5 mL * 3). The combined organic phase was washed with brine (5 mL * 2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (column height: 12 g, 100-200 mesh silica gel, 0-20% (10 ...

Claims

1. The following: 【Chemistry 1】 【Chemistry 2】 【Chemistry 3】 【Chemistry 4】 【Chemistry 5】 【Chemistry 6】 【Chemistry 7】 【Chemistry 8】 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 or a pharma- ceutically acceptable salt thereof.

2. 10. A pharmaceutical composition for treating a disease, disorder or condition causally associated with LRRK2 in a patient, comprising a compound of claim 1, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

3. The pharmaceutical composition of claim 2 , wherein the composition further comprises an additional bioactive agent.

4. 4. The pharmaceutical composition of claim 3, wherein the additional bioactive agent is an anti-inflammatory agent, a chemotherapeutic agent, or an immunomodulatory agent.

5. The pharmaceutical composition according to any one of claims 2 to 4, wherein the disease or disorder causally related to LRRK2 is idiopathic Parkinson's disease (PD), LRRK2 mutation-associated PD, primary tauopathy, dementia with Lewy bodies, Crohn's disease, leprosy, and / or neuroinflammation.

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