Selective Modulators of Mutant LRRK2 Proteolysis and Related Methods of Use

Abstract

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

Description

[0001] Cross - Reference to Related Applications

[0002] This disclosure claims the benefit and priority of U.S. Provisional Application No. 62 / 992,951, filed on March 21, 2020, titled SELECTIVE MODULATORS OF MUTANT LRRK2 PROTEOLYSIS AND ASSOCIATED METHODS OF USE, which is incorporated herein by reference in its entirety for all purposes.

[0003] Incorporation by Reference

[0004] All cited references are incorporated herein by reference in their entirety, including U.S. Patent Application Serial No. 14 / 686,640, filed on April 14, 2015, and published as U.S. Patent Application Publication No. 2015 / 0291562; and U.S. Patent Application Serial No. 14 / 792,414, filed on July 6, 2015, and published as U.S. Patent Application Publication No. 2016 / 0058872; and U.S. Patent Application Serial No. 15 / 953,108, filed on April 13, 2018, and published as U.S. Patent Application Publication No. 2018 / 0228907; and International Patent Application No. PCT / US2019 / 032163, filed on May 5, 2019, and published as International Patent Application Publication No. WO2019 / 222173A1. Technical Field

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

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

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

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

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

[0010] There are several major gain-of-function pathogenic and characteristic mutations in LRRK2, which are located in the Roco domain (N1437H, R1441G / C / H, Y1699C) to enable GTP hydrolysis, or in the kinase domain (G2019S and I2020T). G2019S is the most common LRRK2 mutation associated with Parkinson's disease (PD), a progressive neurodegenerative disorder characterized by resting tremor, rigidity, bradykinesia (slowness of movement), and postural instability. Histological hallmarks of PD include neurodegeneration of dopaminergic neurons in the substantia nigra pars compacta and intracellular inclusions called Lewy bodies and neurites composed of aggregated forms of α-synuclein. G2019S is associated with 1–2% of all PD patients and results in a two-fold increase in kinase activity in vitro (West AB et al: Parkinson’s disease–associated mutations in leucine-rich repeat kinase 2 augment kinase activity. Proc Natl Acad Sci U S A 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 controls catalytic activity. These mutations are thought to disrupt the inactive conformation and thereby increase catalytic activity (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).Several of the above Parkinson's disease-related mutations (R1441C / G, Y1699C, and I2020T) inhibit the phosphorylation of LRRK2 at Ser910 and Ser935, subsequently reducing the association of LRRK2 with 14-3-3 proteins, which is thought to represent the inactive form of LRRK2 (Nichols J et al: 14-3-3 binding to LRRK2 is disrupted by multiple Parkinson’s disease associated mutations and regulates cytoplasmic localisation. Biochem J 2010, 430:393–404).

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

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

[0013] Lewy bodies are the main histological hallmark of PD. Lewy bodies mainly consist of aggregates of α-synuclein, and mutations in α-synuclein that increase this aggregation also increase the risk of developing PD (Meade RM et al: Alpha-synuclein structure and Parkinson’s disease lessons and emerging principles. Mol Neurodegener 2019, 14:29-29). Depletion of LRRK2 with ASO (Zhao HT et al: LRRK2 antisense oligonucleotides ameliorate a-synuclein inclusion formation in a Parkinson’s disease mouse model. Molecular therapy. Nucleic acids 2017, 8:508–519) and genomic deletion of LRRK2 have been shown to reduce α-synuclein-mediated pathology in PD mouse models (Lin X et al: Leucine-rich repeat kinase 2 regulates the progression of neuropathology induced by Parkinson’s-disease-related mutant alpha-synuclein. Neuron 2009, 64:807–827). Mutations that increase LRRK2 activity, such as G2019S, increase α-synuclein aggregation in neuronal and mouse models of PD. This increase is reversed by LRRK2 kinase inhibitors (Volpicelli-Daley LA et al: G2019S-LRRK2 Expression Augments α-Synuclein Sequestration into Inclusions in Neurons. J Neurosci. July 13, 2016; 36(28):7415-27. doi:10.1523 / JNEUROSCI.3642-15.2016). There is some evidence that the G2019S mutant form of LRRK2 is resistant to inhibition by kinase inhibitors in the CNS, which may reduce its disease-modifying effects (Kelly K et al: The G2019S mutation in LRRK2 imparts resiliency to kinase inhibition. Exp Neurol. November 2018; 309:1-13).Although Lewy bodies are also present in the majority of PD cases upon postmortem examination, they are absent in a large number of PD cases associated with the LRRK2 G2019S mutation (Kalia LV et al: Clinical correlations with Lewy body pathology in LRRK2-related Parkinson disease. JAMA neurol 2015, 72:100–105). In addition to Lewy bodies being a common feature of PD, tau pathology is also a major feature upon postmortem examination of LRRK2 mutation carriers (Henderson MX et al: Alzheimer’s disease tau is a prominent pathology in LRRK2 Parkinson’s disease. Acta Neuropathol Commun 2019, 7.183-183). In one study, tau pathology was observed in 100% of LRRK2 mutation carriers, thus highlighting LRRK2 as an important target linking PD to tau pathology in the context of PD, although the genetic causality is not as strong as that between LRRK2 and primary tauopathies such as progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) (Ross OA et al (2006) Lrrk2 R1441 substitution and progressive supranuclear palsy. Neuropathol Appl Neurobiol 32(1):23–25; Sanchez-Contreras M et al (2017) Study of LRRK2 variation in tauopathy: progressive supranuclear palsy and corticobasal degeneration. Mov Disord 32(1):115–123). A common variation at the LRRK2 locus has recently been reported as a genetic determinant of survival in PSP (Jabbari E et al, Common variation at the LRRK2 locus is associated with survival in the primary tauopathy progressive supranuclear palsy. bioRxiv 2020.02.04.932335; doi:https: / / doi.org / 10.1101 / 2020.02.04.932335).It has been reported that increased expression of LRRK2 in PSP, through expression quantitative trait locus (eQTL) analysis, may lead to a reactive microglia-induced pro-inflammatory state that drives the persistent accumulation of misfolded τ protein and clinical disease progression. Functional variants of LRRK2 have also been associated with Crohn's Disease and leprosy type-1 inflammatory responses (Hui KY et al. Functional variants in the LRRK2 gene confer shared effects on risk for Crohn's disease and Parkinson's disease. Sci Transl Med. January 10, 2018; 10(423). pii: eaai7795. doi: 10.1126 / scitranslmed.aai7795; Fava et al. Pleiotropic effects for Parkin and LRRK2 in leprosy type-1 reactions and Parkinson's disease. Proc Natl Acad Sci U S A. July 30, 2019; 116(31):15616-15624. doi: 10.1073 / pnas.1901805116. Epub July 15, 2019).

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

[0015] Accordingly, a class of small molecules targeting LRRK2 has been reported to be useful for modulating LRRK2 protein, including LRRK2 protein with the G2019S mutation (International Patent Application Publication WO2019 / 222173A1, which is incorporated herein by reference).

[0016] There is a continuing need in the art for effective treatments for LRRK2-related diseases and disorders such as idiopathic PD, LRRK2 mutation-related PD (e.g., PD associated with one or more LRRK2 activating mutations), primary tauopathies (e.g., progressive supranuclear palsy (PSP) or corticobasal degeneration (CBD)), dementia with Lewy bodies, Crohn's disease, leprosy (e.g., leprosy with type 1 reaction), and / or neuroinflammation. SUMMARY OF THE INVENTION

[0017] The present disclosure describes heterobifunctional compounds that function to selectively or preferentially recruit mutant leucine-rich repeat kinase 2 (LRRK2) to an E3 ubiquitin ligase for targeted ubiquitination and subsequent proteasomal degradation compared to wild-type LRRK2, as well as methods for preparing and using the same heterobifunctional compounds. In particular, the compounds described herein preferentially bind to LRRK2 proteins containing the G2019S mutation. In addition, this specification provides methods of using an effective amount of a compound of the invention, as described herein, for treating or ameliorating a disease condition or one or more symptoms thereof, such as neurodegenerative diseases, e.g., Parkinson's disease, Parkinson's disease with dementia, Parkinson's disease risk syndromes, dementia with Lewy bodies, Lewy body variant Alzheimer's disease, combined Parkinson's disease and Alzheimer's disease, multiple system atrophy, striatonigral degeneration, olivopontocerebellar atrophy, and Shy-Drager syndrome, among others.

[0018] Accordingly, in one aspect, the present disclosure provides a heterobifunctional compound comprising an E3 ubiquitin ligase binding moiety (i.e., a ligand for an E3 ubiquitin ligase ("ULM" group)) and a protein targeting moiety that preferentially binds to a mutant form of LRRK2 having the G2019S mutation compared to less (or no) binding to wild-type LRRK2, such that the mutant LRRK2 protein is thereby preferentially positioned near the ubiquitin ligase for ubiquitination and subsequent preferential degradation (and / or inhibition) of the mutant LRRK2 protein. In a preferred embodiment, the ULM (E3 ubiquitin ligase binding moiety) is a cereblon E3 ubiquitin ligase binding moiety (CLM). For example, the structure of the bifunctional compound can be described as:

[0019]

[0020] The respective positions of the PTM and ULM moieties (e.g., CLM), as well as their numbers as shown herein, are provided only as examples and are not intended to limit the compounds in any way. As will be understood by those skilled in the art, bifunctional compounds as described herein can be synthesized such that the number and position of each functional moiety can be varied as needed.

[0021] In certain embodiments, the bifunctional compound further comprises a chemical linker (“L”). In this instance, the structure of the bifunctional compound can be described as:

[0022]

[0023] wherein PTM is a moiety that selectively or preferentially binds to LRRK2 protein having at least one mutation, which is the G2019S mutation, as compared to the binding of PTM to wild-type LRRK2, L is a linker, such as a bond or a chemical linking group that couples PTM to ULM, and ULM is a cereblon E3 ubiquitin ligase binding moiety (CLM).

[0024] For example, the structure of the bifunctional compound can be described as:

[0025]

[0026] wherein: PTM is a moiety that selectively or preferentially binds to LRRK2 protein having at least one mutation, which is the G2019S mutation, as compared to the binding of PTM to wild-type LRRK2; “L” is a linker that couples PTM and CLM (e.g., a bond or a chemical linking group); and CLM is a cereblon E3 ubiquitin ligase binding moiety that binds to cereblon.

[0027] In certain embodiments, the compounds described herein comprise multiple independently selected ULMs, multiple PTMs, multiple chemical linkers, or combinations thereof.

[0028] In any aspect or embodiment described herein, a PTM is a small molecule that selectively or preferentially binds to an LRRK2 protein having at least one mutation, which is the G2019S mutation, compared to the PTM of wild-type LRRK2. In any aspect or embodiment described herein, a PTM is a small molecule capable of selectively binding to an LRRK2 protein having at least one mutation (the G2019S mutation), wherein the selectivity of the PTM for the LRRK2 protein having at least one mutation (the G2019S mutation) is at least 1- to 60-fold (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-fold) compared to wild-type LRRK2. In any aspect or embodiment described herein, a PTM is a small molecule that binds to an LRRK2 protein having at least one mutation (the G2019S mutation), wherein the selectivity of the PTM for the LRRK2 protein having at least one mutation (the G2019S mutation) is at least 1- to 1000-fold (e.g., 50, 100, 200, 300, 400, 500, 600, 700, 800, 900-fold) compared to wild-type LRRK2.

[0029] In one embodiment, the CLM comprises a chemical group derived from an imide, thioimide, amide, or thioamide. In a specific embodiment, the chemical group is phthalimido, or an analogue or derivative thereof. In certain embodiments, the CLM is selected from thalidomide, lenalidomide, pomalidomide, analogues thereof, isomers thereof, and derivatives thereof. Other expected CLMs are described in U.S. Patent Application Publication No. 2015 / 0291562, the entire contents of which are incorporated herein by reference.

[0030] In certain embodiments, "L" is a bond. In additional embodiments, the linker "L" is a linker having a straight-chain non-hydrogen atom count in the range of 1 to 20. The linker "L" can contain, but is not limited to, one or more functional groups such as ethers, amides, alkanes, alkenes, alkynes, ketones, hydroxyls, carboxylic acids, thioethers, sulfoxides, and sulfones. The linker can contain aromatic, heteroaromatic, cyclic, bicyclic, or tricyclic moieties. Halogen (such as Cl, F, Br, and I) substitution can be included in the linker. In the case of fluorine substitution, single or multiple fluorines can be included.

[0031] 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 heteroarene, which is linked as a C-N bond or a C-C bond. Examples of CLM can be, but are not limited to, pomalidomide, lenalidomide, and thalidomide and their analogs.

[0032] In another aspect, the present specification provides a therapeutic composition comprising an effective amount of a compound as described herein or a salt form thereof, and a pharmaceutically acceptable carrier. The therapeutic composition can be used to trigger the targeted degradation and / or inhibition of LRRK2 protein having at least one mutation (the G2019S mutation) in a patient or subject in need thereof (e.g., an animal such as a human), and can be used to treat or ameliorate one or more disease states, conditions, or symptoms causally related to mutant LRRK2, said treatment being accomplished by preferentially degrading the mutant LRRK2 protein to control, stabilize, or reduce the protein level of mutant LRRK2 in the patient or subject. In certain embodiments, the therapeutic composition as described herein can be used to effect preferential degradation of mutant LRRK2 (e.g., G2019S) to treat or ameliorate a disease, disorder, or symptom, such as an infection, inflammation, or immune disorder, or cancer.

[0033] In yet another aspect, the present disclosure provides a method of ubiquitinating mutant LRRK2 in a cell. In certain embodiments, the method comprises administering a heterobifunctional compound as described herein, the compound comprising a PTM that selectively or preferentially binds to mutant LRRK2 as described herein and a CLM preferably linked together by a chemical linker moiety as described herein, to effect selective or preferential degradation of the mutant LRRK2 protein. Without wishing to be bound by theory, the inventors believe that, according to the present invention, when the mutant LRRK2 protein is placed near an E3 ubiquitin ligase, polyubiquitination of the mutant LRRK2 protein will occur by using the heterobifunctional compound, thereby triggering subsequent selective or preferential degradation of the mutant LRRK2 protein through the proteasome pathway, thereby controlling or reducing the level of mutant LRRK2 protein in the cells of the subject. The control or reduction of the mutant LRRK2 protein level provided by the present disclosure provides a treatment for a disease state, condition, or at least one causally related symptom, which is regulated by reducing or stabilizing the amount of mutant LRRK2 protein in the cells of the subject.

[0034] In yet another aspect, the present specification provides a method for treating or ameliorating a disease, condition, or its symptoms in a subject or patient (e.g., an animal such as a human), the method comprising administering to a subject in need thereof a composition comprising an effective amount (e.g., a therapeutically effective amount) of a heterobifunctional compound as described herein or a salt form thereof and a pharmaceutically acceptable carrier, wherein the composition is effective to treat or ameliorate the disease or disorder or its symptoms of the subject.

[0035] In another aspect, the present specification provides methods for assessing the effect of selectively or preferentially degrading mutant LRRK2 proteins according to the present disclosure in a biological system using compounds according to the present disclosure.

[0036] In another aspect, the present specification provides processes and intermediates for preparing the heterobifunctional compounds of the present invention, which are capable of targeting ubiquitination and selectively or preferentially degrading mutant LRRK2 proteins according to the present disclosure in cells.

[0037] The foregoing general fields of utility are given by way of example only and are not intended to limit the scope of the present disclosure and the appended claims. Based on the claims, description, and examples of the present disclosure, those of ordinary skill in the art will appreciate additional objects and advantages related to the compositions, methods, and processes of the present disclosure. For example, various aspects and embodiments of the present disclosure can be used in multiple combinations, all of which are expressly contemplated by this specification. These additional aspects and embodiments are expressly included within the scope of the present disclosure. Publications and other materials used herein to clarify the background of the present disclosure and to provide additional details regarding practice in specific instances are incorporated by reference. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] The drawings incorporated and forming a part of this specification illustrate several embodiments of the present disclosure and, together with the specification, are used to explain the principles of the present disclosure. The drawings are for illustrative purposes only of the embodiments of the present disclosure and should not be construed as limiting the present disclosure. Additional objects, features, and advantages of the present disclosure will become apparent from the following detailed description in conjunction with the drawings showing exemplary embodiments of the present disclosure.

[0039] Figure 1A and 1B . Illustration of the general principle by which the heterobifunctional protein degradation compounds as described herein operate. Figure 1A . Exemplary heterobifunctional protein degradation compounds comprise a protein targeting moiety (PTM; dark shaded rectangle), a ubiquitin ligase binding moiety (ULM; light shaded triangle), and optionally a linker moiety (L; black line) coupling or connecting the PTM to the ULM. Figure 1B Illustrates the functional use of a heterobifunctional protein degradation compound as described herein (a commercially available known brand compound). Briefly, the ULM (triangle) recognizes and binds to a specific E3 ubiquitin ligase, and the PTM (large rectangle) binds and recruits the target protein, bringing it close to the E3 ubiquitin ligase. Typically, the E3 ubiquitin ligase is complexed with an E2 ubiquitin-conjugating protein (E2) and catalyzes, either alone or through the E2 protein, the ligation of multiple ubiquitin molecules (black circles) to lysines on the target protein via isopeptide bonds. The polyubiquitinated protein (far right) is thus targeted for degradation by the proteasomal machinery of the cell. Detailed implementation manners

[0040] The following is a detailed description provided to assist those skilled in the art in implementing the present invention. Without departing from the spirit or scope of the present disclosure, those of ordinary skill in the art can make modifications and variations in the embodiments described herein. All publications, patent applications, patents, and other references mentioned herein are hereby incorporated by reference in their entirety expressly.

[0041] Currently described are compounds, compositions, and methods related to the surprising and unexpected finding that once an E3 ubiquitin ligase and the LRRK2 protein are placed in close proximity by a bifunctional compound that binds both the E3 ubiquitin ligase and the LRRK2 protein, the E3 ubiquitin ligase (e.g., the cereblon E3 ubiquitin ligase) ubiquitinates the human LRRK2 protein. Accordingly, the present disclosure provides compounds and compositions comprising an E3 ubiquitin ligase binding moiety ("ULM") conjugated to a protein targeting moiety ("PTM") targeting the LRRK2 protein via a bond or chemical linking group (L), which results in the ubiquitination of the LRRK2 protein and leads to the degradation of the LRRK2 protein by the proteasome (see Figure 1A and Figure 1B ).

[0042] In one aspect, the present specification provides compounds in which the PTM preferably binds to the LRRK2 protein. The present disclosure also provides a library of compositions and their use in generating targeted degradation of the LRRK2 protein in cells.

[0043] In certain aspects, the present disclosure provides heterobifunctional compounds comprising a ligand (e.g., a small molecule ligand (i.e., having a molecular weight below 2,000, 1,000, 500, or 200 daltons)) that is capable of binding an E3 ubiquitin ligase, such as cereblon. The compound also comprises a small molecule moiety capable of binding to LRRK2 such that the LRRK2 protein is in close proximity to the ubiquitin ligase to effect ubiquitination and degradation (and / or inhibition) of the LRRK2 protein. "Small molecule" means that in addition to the above, the molecule is non-peptidyl, i.e., it is not considered a peptide, e.g., it contains fewer than 4, 3, or 2 amino acids. According to the present specification, each of the PTM, ULM, and heterobifunctional molecule is a small molecule.

[0044] 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 pertains. The terms used in this specification are merely for the purpose of describing particular embodiments and are not intended to limit the present disclosure.

[0045] When providing a numerical range, it should be understood that each intermediate value between the upper and lower limits of the range (unless the context clearly indicates otherwise, such as in the case of a group containing multiple carbon atoms where each number of carbon atoms falling within the range is provided), the intermediate value reaches one-tenth of the lower limit unit) and any other stated or intermediate value within the stated range is encompassed within the present disclosure. The upper and lower limits of these smaller ranges may be independently included within the smaller ranges and are also encompassed within the present disclosure, subject to any specific excluded limit values within the range. In cases where the range includes one or both of the limit values, ranges excluding one or both of the included limit values are also included within the present disclosure.

[0046] The following terms are used to describe the present disclosure. In cases where a term is not specifically defined herein, the term is given the meaning generally recognized in the art by a person of ordinary skill, who applies the term in the context of its use to describe the present disclosure.

[0047] As used herein and in the appended claims, the article "a / an" is used herein to refer to one or more than one (i.e., at least one) grammatical object of the article, unless the context clearly indicates otherwise. For example, unless otherwise stated, "an element" refers to one element or more than one element.

[0048] In the claims and the above specification, all transitional phrases, such as "comprising / including", "carrying", "having", "containing", "involving", "holding", "composed of", etc., should be understood to be open-ended, i.e., meaning including but not limited to. As stated in Section 2111.03 of the United States Patent and Trademark Office's Manual of Patent Examining Procedure, only the transitional phrases "consisting of" and "consisting essentially of" should be closed or semi-closed transitional phrases, respectively.

[0049] It should also be understood that in certain methods or processes described herein that include more than one step or action, the order of the steps or actions of the method is not necessarily limited to the order of the steps or actions of the recited method, unless the context indicates otherwise.

[0050] The terms "co-administration" and "co-administering" or "combination therapy" refer to concurrent administration (administering two or more therapeutic agents simultaneously) and time-variable administration (administering one or more therapeutic agents at a different time from the administration of one or more additional therapeutic agents), provided that two or more therapeutic agents are present in the patient to some extent, preferably in effective amounts, at the same time. In certain preferred aspects, one or more of the heterobifunctional compounds described herein are co-administered with at least one additional bioactive agent (e.g., an anti-cancer agent). In particularly preferred aspects, co-administration of such compounds results in synergistic activity and / or therapy, such as anti-cancer activity.

[0051] Unless otherwise indicated, the term "compound" as used herein refers to any specific heterobifunctional compound disclosed herein, its pharmaceutically acceptable salts and solvates, and deuterated forms (if applicable) of any of the foregoing molecules. The deuterated compounds contemplated are those in which one or more of the hydrogen atoms contained in the pharmaceutical molecule have been replaced by 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.

[0052] The term "ubiquitin ligase" refers to a family of proteins that facilitate the transfer of one or more ubiquitins to a specific substrate protein. The addition of a series of multiple ubiquitins (polyubiquitination) is targeted at degrading the substrate protein. For example, cereblon is an E3 ubiquitin ligase that, alone or in combination with an E2 ubiquitin-conjugating enzyme, can ultimately result in a series of four ubiquitins being attached to a lysine residue on the target protein, thereby targeting the protein for degradation by the proteasome. Ubiquitin ligases are involved in polyubiquitination such that the first ubiquitin is attached to a lysine on the target protein; the second ubiquitin is attached to the first ubiquitin; the third ubiquitin is attached to the second ubiquitin, and the fourth ubiquitin is attached to the third ubiquitin. This polyubiquitination marks the protein for degradation by the proteasome.

[0053] The terms "patient" or "subject" are used throughout the specification to describe an animal, preferably a human or a domesticated animal, to which treatment with a composition according to the present disclosure is provided, including prophylactic treatment. For treating a disease, condition or symptom specific to a particular animal (such as a human patient), the term "patient" refers to the particular animal, including domesticated animals (such as dogs or cats) or farm animals (such as horses, cows, sheep, etc.). Generally, in the present disclosure, the terms "patient" and "subject" refer to a human patient, unless otherwise stated or implied in the context in which the term is used.

[0054] The terms "effective" and "therapeutically effective" are used to describe an amount of a compound or composition that, when used within its intended scope of use and after administration in a single dose or, more preferably, multiple doses within the scope of a treatment regimen, achieves an intended result, such as the amelioration of a disease or medical condition, or the improvement or reduction of one or more symptoms associated with the disease or medical condition. The terms "effective" and "therapeutically effective" include all other "effective amount" or "effective concentration" terms otherwise described or used in this application.

[0055] Compounds and Compositions

[0056] In one aspect, the present specification provides a heterobifunctional compound comprising an E3 ubiquitin ligase binding moiety ("ULM"), which moiety is a cereblon E3 ubiquitin ligase binding moiety ("CLM"). The CLM is covalently coupled to a protein targeting moiety (PTM) that binds to a protein, either directly by a bond or through a chemical linking group (L) according to the structure:

[0057] (A) PTM-L-CLM

[0058] wherein L is a bond or a chemical linking group, and PTM is a protein targeting moiety that binds to the protein LRRK2, wherein PTM is an LRRK2 targeting moiety. The term CLM includes all cereblon binding moieties.

[0059] In any aspect or embodiment, the CLM exhibits a half-maximal inhibitory concentration (IC 50 ) of less than about 200 μM for an E3 ubiquitin ligase (e.g., the cereblon E3 ubiquitin ligase). The IC 50 can be determined according to any suitable method known in the art (e.g., fluorescence polarization assay).

[0060] In certain embodiments, the heterobifunctional compounds described herein exhibit an IC 50 or a half-maximal degradation concentration (DC 50 ) of less than about 100, 50, 10, 1, 0.5, 0.1, 0.05, 0.01, 0.005, 0.001 mM, or less than about 100, 50, 10, 1, 0.5, 0.1, 0.05, 0.01, 0.005, 0.001 μM, or less than about 100, 50, 10, 1, 0.5, 0.1, 0.05, 0.01, 0.005, 0.001 nM, or less than about 100, 50, 10, 1, 0.5, 0.1, 0.05, 0.01, 0.005, 0.001 pM.

[0061] The term "alkyl" as used herein shall refer to a straight-chain, branched-chain, or cyclic fully saturated hydrocarbon group, preferably C1-C10 , preferably C1-C6, or more preferably C1-C3 alkyl, which may optionally be substituted by any suitable one or more functional groups. Examples of alkyl groups are methyl, ethyl, n-butyl, sec-butyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, isopropyl, 2-methylpropyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclopentylethyl, cyclohexylethyl, and cyclohexyl, etc. In certain embodiments, the alkyl group is capped with a halogen group (At, Br, Cl, F, or I).

[0062] The term "alkenyl" refers to a straight-chain, branched-chain, or cyclic C2-C 10 (preferably C2-C6) hydrocarbon group that contains at least one C═C bond.

[0063] The term "alkynyl" refers to a straight-chain, branched-chain, or cyclic C2-C 10 (preferably C2-C6) hydrocarbon group that contains at least one C≡C bond.

[0064] When used, the term "alkylene" refers to a -(CH2) n - group (n is usually an integer from 0 to 6), which may optionally be substituted. When substituted, the alkylene group is preferably substituted by a C1-C6 alkyl group (including cyclopropyl or tert-butyl) on one or more methylene groups, but may also be substituted by one or more halogen groups, preferably 1 to 3 halogen groups or one or two hydroxyl groups, O-(C1-C6 alkyl) groups, or amino acid side chains as further disclosed herein. In certain embodiments, the alkylene group may be substituted by a carbamate or an alkoxy group (or other suitable functional group), and the ethyl carbamate or alkoxy group (or other suitable functional group) may be further substituted by a polyethylene glycol chain (1 to 10, preferably 1 to 6, or more preferably 1 to 4 ethylene glycol units), and the polyethylene glycol chain is substituted by an alkyl chain substituted with a single halogen group, preferably a chlorine group (preferably but not exclusively at the distal end of the polyethylene glycol chain). In other embodiments, the alkylene (e.g., methylene) group may be substituted by an amino acid side chain group, such as the side chain group of a natural or non-natural 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.

[0065] The term "unsubstituted" shall mean substituted only by a hydrogen atom. The carbon atom range including C0 means that carbon is absent and is replaced by H. Thus, the carbon atom range of C0-C6 includes 1, 2, 3, 4, 5, and 6 carbon atoms, and for C0, H replaces carbon.

[0066] The term "substituted" or "optionally substituted" shall mean the presence of one or more substituents (independently up to five substituents, preferably up to three substituents, more preferably 1 or 2 substituents on a moiety in a compound according to the present disclosure, and may include substituents which may themselves be further substituted) at any carbon (or nitrogen) position on the molecule in the context, independently (i.e., when more than one substitution occurs, each substituent is selected independently of another substituent), and includes possible substituents: hydroxy, mercapto, carboxy, cyano (C≡N), nitro (NO2), halogen (preferably 1, 2 or 3 halogens, especially on an alkyl, especially methyl such as trifluoromethyl), alkyl (preferably C1-C 10， More preferably, C1-C6), aryl (especially phenyl and substituted phenyl, such as benzyl or benzoyl), alkoxy (preferably C1-C6 alkyl or aryl, including phenyl and substituted phenyl), thioether (preferably C1-C6 alkyl or aryl), acyl (preferably C1-C6 acyl), ester or thioester (preferably C1-C6 alkyl or aryl), including alkylene ester (such that it is attached to the alkylene, rather than to the ester functional group preferably substituted by C1-C6 alkyl or aryl), halogen (preferably F or Cl), amine (including five- or six-membered cyclic alkyleneamine, also including C1-C6 alkylamine or C1-C6 dialkylamine, where the alkyl may be substituted by one or two hydroxy groups) or an optionally substituted -N(C0-C6 alkyl)C(O)(O-C1-C6 alkyl) group (which may optionally be substituted by a polyethylene glycol chain, the polyethylene glycol chain being further attached to an alkyl containing a single halogen, preferably a chlorine substituent), hydrazine, acylamino, which are preferably independently substituted by one or two C1-C6 alkyls (including carbamoyl optionally substituted by one or two C1-C6 alkyls), alkanol (preferably C1-C6 alkyl or aryl), or alkanoic acid (preferably C1-C6 alkyl or aryl). Substituents according to the present disclosure may include, for example, -SiR1R2R3 groups, where each of R1 and R2 is as further described herein and R3 is H or C1-C6 alkyl, preferably R1, R2, R3 together are C1-C3 alkyl (including isopropyl or tert-butyl). Each of the above groups may be directly attached to the substituted moiety, or, the substituent may be attached to the substituted moiety (preferably in the case of an aryl or heteroaryl moiety) through an optionally substituted -(CH2) m- or an optionally substituted -(OCH2) m -, -(OCH2CH2) m - or -(CH2CH2O) m - group (which may be substituted by any one or more of the above substituents). As pointed out above, alkylene -(CH2) m - or -(CH2) n- groups or other chains such as ethylene glycol chains can be substituted at any position on the chain. Preferred substituents on the alkylene group include halogen or C1-C6 (preferably C1-C3) alkyl, which can optionally be substituted by 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 and optionally substituted amides (preferably carbamoyl substituted as described above) or carbamate groups (usually having one or two C0-C6 alkyl substituents, one or more of which groups can be further substituted). In certain embodiments, the alkylene group (usually a single methylene) is substituted by one or two optionally substituted C1-C6 alkyl groups (preferably C1-C4 alkyl groups, most commonly methyl or O-methyl or the side chains of amino acids as described herein). In the present disclosure, a portion of the molecule can optionally be substituted by up to five substituents, preferably up to three substituents. Most commonly, in the present disclosure, the substituted portion is substituted by one or two substituents.

[0067] The term "substituted" (each substituent being independent of any other substituent) as used in its context shall also refer to C1-C6 alkyl, C1-C6 alkoxy, halo, acylamino, formylamino, sulfone, including sulfonamide, keto, carboxyl, C1-C6 ester (oxidized ester or carbonyl ester), C1-C6 keto, carbamate -O-C(O)-NR1R2 or -N(R1)-C(O)-O-R1, nitro, cyano and amine (specifically including C1-C6 alkylene-NR1R2, mono- or di-C1-C6 alkyl substituted amines, which can optionally be substituted by one or two hydroxyl groups). In context, unless otherwise stated, each of these groups contains from 1 to 6 carbon atoms. In certain embodiments, preferred substituents will include, for example, -NH-, -NHC(O)-, -O-, =O, -(CH2) m - (where m and n are 1, 2, 3, 4, 5 or 6 in 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, -(CH2O) n COOH, C1-C6 alkyl, -(OCH2) n O-(C1-C6 alkyl), -(CH2O) n C(O)-(C1-C6 alkyl), -(OCH2) n NHC(O)-R1, -(CH2O) n C(O)-NR1R2, -S(O)2-R S , -S(O)-R S (R S is C1-C6 alkyl or -(CH2) m -NR1R2 group), NO2, CN or halo group (F, Cl, Br, I, preferably F or Cl), depending on the context in which the substituent is used. R1 and R2 are each H or C1-C6 alkyl (which may optionally be substituted by one or two hydroxyl groups or up to three halogen groups (preferably fluorine)) in the context. In the chemical context of the defined compounds and the substituents used, the term "substituted" shall also refer to optionally substituted aryl or heteroaryl or optionally substituted heterocyclic group as further described herein. The alkylene group may also be substituted as further disclosed herein, preferably by optionally substituted C1-C6 alkyl (methyl, ethyl or hydroxymethyl or hydroxyethyl are preferred, thus providing chiral centers), side chains of amino acid groups as further described herein, amido groups as described above, or carbamate group O-C(O)-NR1R2 group (wherein R1 and R2 are as further described herein), although many other groups may also be used as substituents. The various optionally substituted moieties may be substituted by 3 or more substituents, preferably not more than 3 substituents and preferably by 1 or 2 substituents. It should be noted that in a compound, substitution is required at a particular position in the molecule (mainly because of valency), but in the case where the substitution is not specified, the substituent is construed or understood as H, unless the context of the substitution indicates otherwise.

[0068] As used herein, the term "aryl" or "aromatic" refers to a substituted (as otherwise described herein) or unsubstituted monovalent aromatic group having a single ring (e.g., benzene, phenyl, benzyl, or a 5-, 6-, 7- or 8-membered ring) or fused rings (e.g., naphthyl, anthryl, phenanthryl, a 10- to 16-membered ring, etc.) (e.g., a 5- to 16-membered ring), and may be attached to a compound according to the present disclosure at a ring position or any available stable position as otherwise indicated in the presented chemical structure. In context, other examples of aryl may include heteroaromatic ring systems, "heteroaryl" groups having one or more nitrogen, oxygen or sulfur atoms in the ring (monocyclic) (such as imidazole, furanyl, pyrrole, furyl, thiophene, thiazole, pyridine, pyrimidine, pyrazine, triazole, oxazole) or fused ring systems (such as indole, quinoline, indolizine, aza-indolizine, benzofuran, etc.), which may be optionally substituted as described above. Heteroaryls that may be mentioned include nitrogen-containing heteroaryls such as pyrrole, pyridine, pyridone, pyridazine, pyrimidine, pyrazine, pyrazole, imidazole, triazole, triazine, tetrazole, indole, isoindole, indolizine, aza-indolizine, purine, indazole, quinoline, dihydroquinoline, tetrahydroquinoline, isoquinoline, dihydroisoquinoline, tetrahydroisoquinoline, quinazine, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, imidazopyridine, imidazotriazine, pyrazinopyridazine, acridine, phenanthridine, carbazole, carbazoline, pyrimidine, phenanthroline, phenanthrene, oxadiazole, benzimidazole, pyrrolopyridine, pyrrolopyrimidine and pyridopyrimidine; sulfur-containing aromatic heterocycles such as thiophene and benzothiophene; oxygen-containing aromatic heterocycles such as furan, pyran, cyclopentapyran, benzofuran and isobenzofuran; and aromatic heterocycles containing 2 or more heteroatoms selected from nitrogen, sulfur and oxygen such as thiazole, thiadiazole, isothiazole, benzoxazole, benzothiazole, benzothiadiazole, phenothiazine, isoxazole, furan, phenoxazine, pyrazolooxazole, imidazolothiazole, thiophenofuran, furanopyrrole, pyridazine, furanopyridine, furanopyrimidine, thiophenopyrimidine and oxazole, etc., all of which may be optionally substituted.

[0069] The term "substituted aryl" refers to an aromatic carbocyclic group composed of at least one aromatic ring or multiple fused rings, wherein at least one is an aromatic ring and one or more rings are substituted with one or more substituents. For example, an aryl may contain one or more substituents selected from the following: -(CH2) 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-C6alkyl)amine, wherein the alkyl on the amine is optionally substituted with: 1 or 2 hydroxyl groups or up to three halo groups (preferably F, Cl), OH, COOH, C1-C6alkyl (preferably CH3), CF3, OMe, OCF3, NO2, or CN group (each of which can be substituted at the ortho, meta, and / or para positions of the benzene ring, preferably para), optionally substituted phenyl (the phenyl itself is preferably connected to the PTM group through a linker group, including the ULM group), and / or F, Cl, OH, COOH, CH3, CF3, OMe, OCF3, NO2, or CN group (at the ortho, meta, and / or para positions of the benzene ring, preferably para), optionally substituted naphthyl, optionally substituted heteroaryl (preferably optionally substituted isoxazole, including methyl-substituted isoxazole), optionally substituted oxazole (including methyl-substituted oxazole), optionally substituted thiazole (including methyl-substituted thiazole), optionally substituted isothiazole (including methyl-substituted isothiazole), optionally substituted pyrrole (including methyl-substituted pyrrole), optionally substituted imidazole (including methylimidazole), optionally substituted benzimidazole or methoxybenzylimidazole, optionally substituted oxime oxazole or methyl oxime oxazole, optionally substituted diazole group (including methyl diazole group), optionally substituted triazole group (including methyl-substituted triazole group), optionally substituted pyridine group (including halo (preferably F) or methyl-substituted pyridine group or oxypyridine group (wherein the pyridine group is connected to the phenyl through oxygen), optionally substituted furan, optionally substituted benzofuran, optionally substituted dihydrobenzofuran, optionally substituted indole, indolizine or aza indolizine (2, 3 or 4-aza indene), optionally substituted quinoline, at least one of which and its combinations.

[0070] "Carboxyl" means the group -C(O)OR, where R is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, and the meanings of these general substituents are the same as the definitions of the corresponding groups defined herein.

[0071] The term "heteroaryl / hetaryl" can mean, but is not limited to, a 5- to 16-membered heteroaryl (e.g., a 5-, 6-, 7- or 8-membered monocyclic or a 10- to 16-membered heteroaryl having multiple fused rings), an optionally substituted quinoline (which can be attached to a pharmacophore or substituted on any carbon atom within the quinoline ring), an optionally substituted indole (including dihydroindole), an optionally substituted indolizine, an optionally substituted azaindolizine (2, 3 or 4-azaindolizine), an optionally substituted benzimidazole, benzodiazole, benzofuran, an optionally substituted imidazole, an optionally substituted isoxazole, an optionally substituted oxazole (preferably methyl-substituted), an optionally substituted diazole, an optionally substituted triazole, tetrazole, an optionally substituted benzofuran, an optionally substituted thiophene, an optionally substituted thiazole (preferably methyl- and / or mercapto-substituted), an optionally substituted isothiazole, an optionally substituted triazole (preferably substituted by methyl, triisopropylsilyl, optionally substituted -(CH2) m -O-C1-C6 alkyl or optionally substituted -(CH2) m -C(O)-O-C1-C6 alkyl-substituted 1,2,3-triazole), an optionally substituted pyridine (2-, 3- or 4-pyridine) or a group according to the chemical structure:

[0072]

[0073] wherein:

[0074] S c is CHR SS , NR URE or O;

[0075] R HET is H, CN, NO2, a halogen group (preferably Cl or F), an optionally substituted C1-C6 alkyl (preferably substituted by one or two hydroxyl groups or up to three halogen groups (e.g., CF3)), an optionally substituted O(C1-C6 alkyl (preferably substituted by one or two hydroxyl groups or up to three halogen groups) or an optionally substituted alkynyl-C≡C-R a where R a is H or C1-C6 alkyl (preferably C1-C3 alkyl);

[0076] R SS is H, CN, NO2, a halogen group (preferably F or Cl), an optionally substituted C1-C6 alkyl (preferably substituted by one or two hydroxyl groups or up to three halogen groups), an optionally substituted O-(C1-C6 alkyl) (preferably substituted by one or two hydroxyl groups or up to three halogen groups) or an optionally substituted -C(O)(C1-C6 alkyl) (preferably substituted by one or two hydroxyl groups or up to three halogen groups);

[0077] R UREis H, C1-C6 alkyl (preferably H or C1-C3 alkyl) or -C(O)(C1-C6 alkyl), wherein each group is optionally substituted with one or two hydroxyl groups or up to three halogens (preferably fluorine groups), or an optionally substituted heterocycle (such as piperidine, morpholine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, piperazine, each of which is optionally substituted), and

[0078] Y C is N or C-R YC wherein R YC is H, OH, CN, NO2, halo (preferably Cl or F), optionally substituted C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups (e.g., CF3)), optionally substituted O(C1-C6 alkyl (preferably substituted with one or two hydroxyl groups or up to three halo groups) or optionally substituted alkynyl -C≡C-R a wherein R a is H or C1-C6 alkyl (preferably C1-C3 alkyl);

[0079] The terms "aralkyl" and "heteroaralkyl" refer to groups that simultaneously contain an aryl or a heteroaryl respectively, as well as an alkyl and / or heteroalkyl and / or carbocyclic and / or heterocycloalkyl ring system as defined above.

[0080] As used herein, the term "arylalkyl" refers to an aryl as defined above attached to an alkyl as defined above. The arylalkyl is attached to the parent moiety through the alkyl, wherein the alkyl has 1 to 6 carbon atoms. The aryl in the arylalkyl can be substituted as defined above.

[0081] The term "heterocycle" refers to a cyclic group containing at least one heteroatom (such as N, O or S), and can be aromatic (heteroaryl) or non-aromatic. Thus, the heteroaryl moiety is included in the definition of heterocycle, depending on the context of its use. Exemplary heteroaryls are described above.

[0082] Exemplary heterocycles include: azetidinyl, benzimidazolyl, 1,4-benzodioxanyl, 1,3-benzodioxazolyl, benzoxazolyl, benzothiazolyl, benzothienyl, dihydroimidazolyl, dihydropyranyl, dihydrofuranyl, dioxolanyl, dioxolanyl, ethyleneurea, 1,3-dioxolane, 1,3-dioxane, 1,4-dioxane, furanyl, homopiperidinyl, imidazolyl, imidazolinyl, imidazolidinyl, indolinyl, indolyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolyl, morpholinyl, naphthyridinyl, oxazolidinyl, oxazolyl, pyridone, 2-pyrrolidone, pyridine, piperazinyl, N-methylpiperazinyl, piperidinyl, phthalimide, succinimide, pyrazinyl, pyrazolinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydroquinoline, thiazolidinyl, thiazolyl, thienyl, tetrahydrothiophene, oxane, oxetanyl, oxathiolanyl, thiane, etc.

[0083] The heterocyclic group may be optionally substituted by a member selected from the group consisting of: alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azide, cyano, halogen, hydroxy, keto, thione, carboxy, carboxyalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyloxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocycle, heterocyloxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl, oxo group (=O) and -SO2-heteroaryl. Such heterocyclic groups may have a single ring or multiple fused rings. Examples of nitrogen heterocycles and heteroaryls include but are not limited to pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinazoline, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, dihydroindole, morpholino, piperidinyl, tetrahydrofuranyl, etc. and heterocycles containing N-alkoxy-nitrogen. The term "heterocycle" also includes bicyclic groups in which any heterocycle is fused to a benzene ring or a cyclohexane ring or another heterocycle (e.g., indolyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, etc.).

[0084] The term "cycloalkyl" can mean, but is in no way limited to, a monovalent group derived from a monocyclic or polycyclic alkyl or cycloalkane as defined herein, such as a saturated monocyclic hydrocarbon group having three to twenty carbon atoms in the ring, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. The term "substituted cycloalkyl" can mean, but is in no way limited to, a monocyclic or polycyclic alkyl substituted by one or more substituents such as amino, halogen, alkyl, substituted alkyl, carbonyl oxy, carbonyl thio, aryl, nitro, mercapto or sulfo, and these general substituents have the same meaning as the corresponding groups defined in the legend.

[0085] "Heterocycloalkyl" refers to a monocyclic or polycyclic alkyl in which at least one ring carbon atom of its ring structure is replaced by a heteroatom selected from the group consisting of N, O, S or P. "Substituted heterocycloalkyl" refers to a monocyclic or polycyclic alkyl in which at least one ring carbon atom of its ring structure is replaced by a heteroatom selected from the group consisting of N, O, S or P, and the group contains one or more substituents selected from the group consisting of halogen, alkyl, substituted alkyl, carbonyl oxy, carbonyl thio, aryl, nitro, mercapto or sulfo, and these general substituents have the same meaning as the corresponding groups defined in the legend.

[0086] The term "hydrocarbyl" shall mean a compound containing carbon and hydrogen and can be fully saturated, partially unsaturated or aromatic and includes aryl, alkyl, alkenyl and alkynyl.

[0087] The term "independently" is used herein to indicate that independently applied variables vary independently between applications.

[0088] The term "lower alkyl" refers to methyl, ethyl or propyl.

[0089] The term "lower alkoxy" refers to methoxy, ethoxy or propoxy.

[0090] Exemplary CLM

[0091] Novel Imide Compounds

[0092] In any aspect or embodiment described herein, the description provides a CLM that can be used to bind and recruit cereblon. In certain embodiments, the CLM is selected from the group consisting of the following chemical structures:

[0093]

[0094]

[0095] Wherein:

[0096] W in formulas (a1) to (e) [e.g., (a1), (a2), (a3), (a4), (b), (c), (d1), (d2) and / or (e)] is independently selected from the group consisting of CH2, O, CHR, C═O, SO2, NH, N, optionally substituted cyclopropyl, optionally substituted cyclobutyl, and N-alkyl;

[0097] W3 in formulas (a1) to (e) is selected from C or N;

[0098] X in formulas (a1) to (e) is independently selected from the group consisting of absent, O, S, and CH2;

[0099] Y in formulas (a1) to (e) is independently selected from the group consisting of CH2, -C═CR', NH, N-alkyl, N-aryl, N-heteroaryl, N-cycloalkyl, N-heterocycloalkyl, O, and S;

[0100] Z in formulas (a1) to (e) is independently selected from the group consisting of absent, O, S, or CH2, provided that both X and Z cannot be CH2 or both absent;

[0101] G and G' in formulas (a1) to (e) are independently selected from the group consisting of H, optionally substituted straight-chain or branched-chain alkyl, OH, R'OCOOR, R'OCONRR”, CH2-heterocyclic group optionally substituted by R', and benzyl optionally substituted by R';

[0102] Q1 - Q4 in formulas (a1) to (e) represent C or N substituted by a group independently selected from H, R, N, or N-oxide;

[0103] A in formulas (a1) to (e) is independently selected from the group consisting of H, optionally substituted straight-chain or branched-chain alkyl, cycloalkyl, Cl, and F;

[0104] n in formulas (a1) to (e) represents an integer from 1 to 10 (e.g., 1 - 4, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10);

[0105] R in formulas (a1) to (e) includes but is not limited to: a bond, H, -C(═O)R' (e.g., carboxyl), -CONR'R” (e.g., amide group), -OR' (e.g., OH), -NR'R” (e.g., amine group), -SR', -SO2R', -SO2NR'R”, -CR'R”-, -CR'NR'R”-, (-CR'O) n'R”, an optionally substituted heterocyclic group, an optionally substituted aryl group (e.g., an optionally substituted C5-C7 aryl group), an optionally substituted alkyl-aryl group (e.g., an alkyl-aryl group comprising at least one of an optionally substituted C1-C6 alkyl group, an optionally substituted C5-C7 aryl group, or a combination thereof), an optionally substituted heteroaryl group, an optionally substituted alkyl group (e.g., a C1-C6 straight-chain or branched-chain alkyl group optionally substituted by one or more halogens, a cycloalkyl group (e.g., a C3-C6 cycloalkyl group), or an aryl group (e.g., a C5-C7 aryl group)), an optionally substituted alkoxy group (e.g., methoxy, ethoxy, butoxy, propoxy, pentyloxy, or hexyloxy; wherein the alkoxy group may be substituted by one or more halogens, alkyl groups, haloalkyl groups, fluoroalkyl groups, cycloalkyl groups (e.g., a C3-C6 cycloalkyl group), or aryl groups (e.g., a C5-C7 aryl group)), an optionally substituted cycloalkyl group, an optionally substituted heterocyclic group, -P(O)(OR')R”, -P(O)R'R”, -OP(O)(OR')R”, -OP(O)R'R”, -Cl, -F, -Br, -I, -CF3, -CN, -NR'SO2NR'R”, -NR'CONR'R”, -CONR'COR”, -NR’C(=N-CN)NR’R”, -C(=N-CN)NR’R”, -NR’C(=N-CN)R”, -NR’C(=C-NO2)NR'R”, -SO2NR'COR”, -NO2, -CO2R', -C(C=N-OR’)R”, -CR’=CR’R”, -CCR', -S(C=O)(C=N-R’)R”, -SF5, and -OCF3, wherein at least one of W, X, Y, Z, G, G', R, R', R”, Q1-Q4, or A is modified to be covalently linked to a PTM, a chemical linking group (L), a ULM, a CLM, or a combination thereof;

[0106] Each of x, y, and z in formulas (a1) to (e) is independently 0, 1, 2, 3, 4, 5, or 6;

[0107] R' and R” in formulas (a1) to (e) are independently selected from a bond, H, an optionally substituted straight-chain or branched-chain alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted heterocycle, -C(=O)R, and an optionally substituted heterocyclic group;

[0108] n' in formulas (a1) to (e) is an integer from 1 to 10 (e.g., 1-4, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10);

[0109] represents a single bond or a double bond; and

[0110] in formulas (a1) to (e) The bond can be stereospecific ((R) or (S)) or non-stereospecific.

[0111] In any aspect or embodiment described herein, the CLM comprises a chemical structure selected from the group consisting of:

[0112]

[0113]

[0114] Wherein:

[0115] W in formulas (a1) to (e) [e.g., (a1), (a2), (a3), (a4), (b), (c), (d1), (d2) and / or (e)] is independently selected from the group consisting of CH2, O, CHR, C=O, SO2, NH, N, optionally substituted cyclopropyl, optionally substituted cyclobutyl, and N-alkyl;

[0116] W3 in formulas (a1) to (e) is selected from C or N;

[0117] X in formulas (a1) to (e) is independently selected from the group consisting of O, S, and CH2;

[0118] Y in formulas (a1) to (e) is independently selected from the group consisting of CH2, -C=CR', NH, N-alkyl, N-aryl, N-heteroaryl, N-cycloalkyl, N-heterocyclic, O, and S;

[0119] Z in formulas (a1) to (e) is independently selected from the group consisting of O and S or CH2, provided that both X and Z cannot both be CH2 or both be absent;

[0120] G and G' in formulas (a1) to (e) are independently selected from the group consisting of H, optionally substituted straight-chain or branched-chain alkyl, OH, R'OCOOR, R'OCONRR", CH2-heterocyclic optionally substituted by R', and benzyl optionally substituted by R';

[0121] Q1-Q4 in formulas (a1) to (e) represent C or N substituted by a group independently selected from H, R, N, or N-oxide;

[0122] A in formulas (a1) to (e) is independently selected from the group consisting of H, optionally substituted straight-chain or branched-chain alkyl, cycloalkyl, Cl, and F;

[0123] n in formulas (a1) to (e) represents an integer from 1 to 10 (e.g., 1-4, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10);

[0124] The R in formulas (a1) to (e) includes, but is not limited to: a bond, H, -C(=O)R' (e.g., carboxyl), -CONR'R'' (e.g., amide), -OR' (e.g., OH), -NR'R'' (e.g., amine), -SR', -SO2R', -SO2NR'R'', -CR'R''-, -CR'NR'R''-, (-CR'O) n' R'', an optionally substituted heterocyclic group, an optionally substituted aryl group (e.g., an optionally substituted C5-C7 aryl group), an optionally substituted alkyl-aryl group (e.g., an alkyl-aryl group containing at least one of an optionally substituted C1-C6 alkyl group, an optionally substituted C5-C7 aryl group, or a combination thereof), an optionally substituted heteroaryl group, an optionally substituted straight-chain or branched alkyl group (e.g., a C1-C6 straight-chain or branched alkyl group optionally substituted by one or more halogens, cycloalkyl groups (e.g., C3-C6 cycloalkyl groups), or aryl groups (e.g., C5-C7 aryl groups)), an optionally substituted alkoxy group (e.g., methoxy, ethoxy, butoxy, propoxy, pentyloxy, or hexyloxy; wherein the alkoxy group can be substituted by one or more halogens, alkyl groups, haloalkyl groups, fluoroalkyl groups, cycloalkyl groups (e.g., C3-C6 cycloalkyl groups), or aryl groups (e.g., C5-C7 aryl groups)), an optionally substituted cycloalkyl group, an optionally substituted heterocyclic group, -P(O)(OR')R'', -P(O)R'R'', -OP(O)(OR')R'', -OP(O)R'R'', -Cl, -F, -Br, -I, -CF3, -CN, -NR'SO2NR'R'', -NR'CONR'R'', -CONR'COR'', -NR’C(=N-CN)NR’R'', -C(=N-CN)NR’R'', -NR’C(=N-CN)R'', -NR’C(=C-NO2)NR'R'', -SO2NR'COR'', -NO2, -CO2R', -C(C=N-OR’)R'', -CR’=CR’R'', -CCR', -S(C=O)(C=N-R’)R'', -SF5, and -OCF3, wherein at least one of W, X, Y, Z, G, G', R, R', R'', Q1-Q4, or A is covalently linked (directly or indirectly, e.g., through a functional group or atom such as O, S, N) to PTM, a chemical linking group (L), ULM, CLM, or a combination thereof;

[0125] Each of x, y, and z in formulas (a1) to (e) is independently 0, 1, 2, 3, 4, 5, or 6;

[0126] R' and R'' in formulas (a1) to (e) are independently selected from a bond, H, an optionally substituted straight-chain or branched alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted heterocycle, -C(=O)R, and an optionally substituted heterocyclic group;

[0127] In formulas (a1) to (e), n' is an integer from 1 to 10 (e.g., 1 - 4, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10);

[0128] In formulas (a1) to (e), represents a bond that can be stereospecific ((R) or (S)) or non - stereospecific.

[0129] In any aspect or embodiment described herein, CLM or ULM is selected from the structures of formula (g):

[0130]

[0131] Wherein:

[0132] W in formula (g) is independently selected from the group CH2, O, C = O, NH, and N - alkyl;

[0133] A in formula (g) is selected from H, methyl, or an optionally substituted straight - chain or branched alkyl;

[0134] n is an integer from 1 to 4;

[0135] R in formula (g) is independently selected from a bond, H, O, OH, N, NH, NH2, Cl, - F, - Br, - I, methyl, an optionally substituted straight - chain or branched alkyl (e.g., an optionally substituted straight - chain or branched C1 - C6 alkyl), an optionally substituted straight - chain or branched alkoxy (e.g., an optionally substituted straight - chain or branched C1 - C6 alkoxy), - alkyl - aryl (e.g., - alkyl - aryl containing at least one of C1 - C6 alkyl, C4 - C7 aryl, or a combination thereof), aryl (e.g., C5 - C7 aryl), amine, amide, or carboxyl, wherein at least one R or W is modified to covalently link to a PTM, a chemical linking group (L), a ULM, a CLM, or a combination thereof; and

[0136]

[0137] In any aspect or embodiment described herein, CLM or ULM is selected from the group consisting of:

[0138]

[0139] Wherein:

[0140] W is C = O or CH2;

[0141] N* is a nitrogen atom covalently linked to a PTM or linker, or a nitrogen atom shared with a PTM or linker (e.g., a heteroatom shared with an optionally substituted heterocyclic group of the linker (L) or PTM); and

[0142] Indicates the point where the CLM or ULM is connected to the linker (L) or PTM.

[0143] In any aspect or embodiment described herein, R is selected from: H, O, OH, N, NH, NH2, C1-C6 alkyl, C1-C6 alkoxy, -alkyl-aryl (e.g., -alkyl-aryl comprising at least one of C1-C6 alkyl, C4-C7 aryl, or a combination thereof), aryl (e.g., C5-C7 aryl), amine, amide, or carboxyl.

[0144] In any aspect or embodiment described herein, at least one R (e.g., an R group selected from H, O, OH, N, NH, NH2, C1-C6 alkyl, C1-C6 alkoxy, -alkyl-aryl (e.g., -alkyl-aryl comprising at least one of C1-C6 alkyl, C4-C7 aryl, or a combination thereof), aryl (e.g., C5-C7 aryl), amine, amide, or carboxyl) or W is modified to covalently link to a PTM, chemical linker group (L), ULM, CLM, or a combination thereof.

[0145] 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 coupled to a linker and / or a linker that connects one or more PTM, ULM, or CLM groups.

[0146] In any aspect or embodiment described herein, n is an integer from 1 to 4, and each R is an independently selected functional group or atom, such as O, OH, N, -Cl, -F, C1-C6 alkyl, C1-C6 alkoxy, -alkyl-aryl (e.g., -alkyl-aryl comprising at least one of C1-C6 alkyl, C4-C7 aryl, or a combination thereof), aryl (e.g., C5-C7 aryl), amine, amide, or carboxyl on the aryl or heteroaryl of the CLM, and optionally, one of them is modified to covalently link to a PTM, chemical linker group (L), ULM, CLM, or a combination thereof.

[0147] More specifically, non-limiting examples of CLMs include those shown below and those "hybrid" molecules generated by combinations of one or more different features shown in the following molecules, where at least one R or W is modified to covalently link to a PTM, chemical linker group (L), ULM, CLM, or a combination thereof.

[0148]

[0149]

[0150]

[0151]

[0152]

[0153]

[0154]

[0155]

[0156] In any aspect or embodiment described herein, the CLM comprises a chemical structure selected from the group consisting of:

[0157]

[0158]

[0159]

[0160]

[0161] Wherein:

[0162] W is independently selected from CH2, O, CHR, C═O, SO2, NH, N, optionally substituted cyclopropyl, optionally substituted cyclobutyl, and N-alkyl (e.g., CH2, CHR, C═O, SO2, NH, and N-alkyl);

[0163] Q1, Q2, Q3, Q4, Q5 each independently represent a carbon C or N substituted with a group independently selected from R', N, or N-oxide;

[0164] R 1 is selected from absent (i.e., a bond), H, OH, CN, C1-C3 alkyl, C═O;

[0165] R 2 is selected from the group consisting of absent (i.e., a bond), H, OH, CN, C1-C3 alkyl, CHF2, CF3, CHO, C(═O)NH2;

[0166] R 3 is selected from a bond, H, alkyl (e.g., C1-C6 or C1-C3 alkyl), substituted alkyl (e.g., substituted C1-C6 or C1-C3 alkyl), alkoxy (e.g., C1-C6 or C1-C3 alkoxy), substituted alkoxy (e.g., substituted C1-C6 or C1-C3 alkoxy);

[0167] R 4 is selected from a bond, H, alkyl, substituted alkyl;

[0168] R5 and R 6 are each independently a bond, H, halogen, C(=O)R', CN, OH, CF3;

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

[0170] X1 is C=O, N, CH or CH2;

[0171] R' is selected from a bond, H, halogen, amine, alkyl (e.g., C1-C3 alkyl), substituted alkyl (e.g., substituted C1-C3 alkyl), alkoxy (e.g., C1-C3 alkoxy), substituted alkoxy (e.g., substituted C1-C3 alkoxy), NR 2 R 3 、C(=O)OR 2 、optionally substituted phenyl;

[0172] n is 0 - 4;

[0173] is a single bond or a double bond; and

[0174] CLM is covalently linked to PTM, a chemical linker group (L), ULM, CLM, or a combination thereof.

[0175] In any aspect or embodiment described herein, CLM is covalently linked to PTM or a chemical linker group (L) via an R group (such as R, R 1 、R 2 、R 3 、R 4 or R'), a W, X or Q group (e.g., Q1, Q2, Q3, Q4 or Q5).

[0176] In any aspect or embodiment described herein, CLM is covalently linked to PTM or a chemical linker group (L) via W, X, R, R 1 、R 2 、R 3 、R 4 、R 5 、R', Q1, Q2, Q3, Q4 and Q5.

[0177] 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 each independently be covalently coupled to a linker and / or a linker attached to one or more PTM, ULM, CLM groups.

[0178] More specifically, non-limiting examples of CLMs include those shown below and "hybrid" molecules or compounds produced by combining one or more features of the following compounds:

[0179]

[0180]

[0181]

[0182] Wherein:

[0183] W is independently selected from the group consisting of CH2, CHR, C═O, SO2, NH, and N-alkyl; R 1 is selected from the group consisting of absent (i.e., a bond), H, CH, CN, C1-C3 alkyl; R 2 is selected from a bond, H, or C1-C3 alkyl;

[0184] R 3 is selected from a bond, H, alkyl, substituted alkyl, alkoxy, substituted alkoxy; R 4 is selected from a bond, methyl, or ethyl;

[0185] R 5 is selected from a bond, H, or a halogen group;

[0186] R 6 is selected from a bond, H, or a halogen group;

[0187] n is an integer from 0-4;

[0188] R and R' are independently a bond, H, a functional group, or an atom (e.g., H, a halogen (e.g., -Cl, -F), an amine, C1-C3 alkyl, C1-C3 alkyl, C1-C3 alkoxy, NR 2 R 3 , or C(═O)OR 2 ); or a point of attachment of a PTM or a chemical linker group (L);

[0189] Q1 and Q2 are each independently C or N substituted with a group independently selected from H or C1-C3 alkyl;

[0190] is a single bond or a double bond.

[0191] In any aspect or embodiment described herein, W, R 1 , R 2 , Q1, Q2, Q3, Q4, R, and R’ can be independently covalently coupled to a linker and / or a linker that attaches one or more PTM groups.

[0192] In any aspect or embodiment described herein, R 1, R 2 , Q1, Q2, Q3, Q4, R, and R' can be independently covalently coupled to a linker and / or a linker that attaches one or more PTM groups.

[0193] In any aspect or embodiment described herein, Q1, Q2, Q3, Q4, R, and R' can be independently covalently coupled to a linker and / or a linker that attaches one or more PTM groups.

[0194] In any aspect or embodiment described herein, R is modified to covalently link to a linker group (L) or a PTM or a combination thereof.

[0195] In any aspect or embodiment described herein, CLM is selected from:

[0196]

[0197]

[0198]

[0199] where R' is a halogen and R 1 as described herein.

[0200] In any aspect or embodiment described herein, "CLM" can be an imide that binds to the cereblon E3 ligase. These imides and linker attachment points can be, but are not limited to, one of the following structures:

[0201]

[0202]

[0203] In any aspect or embodiment described herein, ULM is selected from the group consisting of:

[0204]

[0205]

[0206] where:

[0207] of CLM represents the attachment point to the linker group or PTM; and

[0208] N* is a nitrogen atom shared with the chemical linker group or PTM.

[0209] In any aspect or embodiment described herein, ULM is selected from the group consisting of:

[0210]

[0211]

[0212] Wherein:

[0213] The representation of ULM is the point where it is connected to the linker group or PTM; and

[0214] N* is the nitrogen atom shared with the chemical linker group or PTM; and

[0215] W, Q4, and Q5 are each defined as described in any aspect or embodiment herein.

[0216] Exemplary Linkers

[0217] In any aspect or embodiment described herein, a compound as described herein comprises a PTM chemically linked to a ULM (e.g., CLM) via a chemical linker (L). In certain embodiments, the linker group L comprises one or more covalently linked structural units (e.g., -A L 1… (A L ) q - or -(A L ) q -), where A L 1 is a group that couples the PTM, and (A L ) q is a group that couples the ULM.

[0218] In any aspect or embodiment described herein, the connection of the linker (L) to the ULM (e.g., CLM) is a stable L-ULM connection. For example, in certain embodiments, when the linker (L) and the ULM are connected via a heteroatom (e.g., N, O, S), any additional heteroatoms (if present) are separated by at least one carbon atom (e.g., -CH2-), such as with an acetal or imine group. As a further example, in certain embodiments described herein, when the linker (L) and the ULM are connected via a heteroatom, the heteroatom is not part of an ester.

[0219] In any aspect or embodiment described herein, the linker group L is of the formula -(A L ) q-represents a key or chemical linker group, where A is a chemical moiety and q is an integer from 1 to 100 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79 or 80), and where L covalently binds to PTM and ULM and provides the binding of PTM to the protein target and ULM to the E3 ubiquitin ligase to effect ubiquitination of the target protein.

[0220] In any aspect or embodiment described herein, the linker group L is a bond or chemical linker group represented by the formula -(A L ) q -where A is a chemical moiety and q is an integer from 6 to 30 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25), and where L covalently binds to PTM and ULM and provides the binding of PTM to the protein target and ULM to the E3 ubiquitin ligase to effect ubiquitination of the target protein.

[0221] In any aspect or embodiment described herein, the linker group L is -(A L ) q -where:

[0222] (A L ) q is a group that links ULM (e.g., CLM) to PTM;

[0223] The q of the linker is an integer greater than or equal to 1;

[0224] Each A L is independently selected from a bond, CR L1 R L2 , O, S, SO, SO2, NR L3 , SO2NR L3 , SONR L3 , CONR L3 , NR L3 CONR L4 , NR L3 SO2NR L4 , CO, CRL1 =CR L2 、C≡C、SiR L1 R L2 、P(O)R L1 、P(O)OR L1 、NR L3 C(=NCN)NR L4 、NR L3 C(=NCN)、NR L3 C(=CNO2)NR L4 、 optionally substituted by 1 - 6 R L1 and / or R L2 groups of C 3-11 cycloalkyl, optionally substituted by 1 - 9 R L1 and / or R L2 groups of C 5-13 spirocycloalkyl, optionally substituted by 1 - 6 R L1 and / or R L2 groups of C 3-11 heterocyclic group, optionally substituted by 1 - 8 R L1 and / or R L2 groups of C 5-13 spiroheterocyclic group, optionally substituted by 1 - 6 R L1 and / or R L2 groups of aryl, optionally substituted by 1 - 6 R L1 and / or R L2 groups of heteroaryl, where R L1 or R L2 are each independently optionally linked to other groups to form a cycloalkyl and / or heterocyclic moiety, optionally substituted by 1 - 4 R L5 groups; and

[0225] R L1 、R L2 、R L3 、R L4 and R L5 are each independently H, halo, C 1-8 alkyl, OC 1-8 alkyl, SC 1-8 alkyl, NHC 1-8 alkyl, N(C 1-8 alkyl)2, C 3-11 cycloalkyl, aryl, heteroaryl, C 3-11 heterocyclic group, OC 3-8 cycloalkyl, SC 3-8 cycloalkyl, NHC 3-8 cycloalkyl, N(C 3-8 cycloalkyl)2, N(C 3-8 cycloalkyl)(C 1-8(alkyl), OH, 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 1-8 (alkyl), CO2H, halogen, CN, CF3, CHF2, CH2F, NO2, SF5, SO2NHC 1-8 (alkyl), SO2N(C 1-8 (alkyl), 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, NH SO2NH2。

[0226] In certain embodiments, q is an integer greater than or equal to 1.

[0227] In certain embodiments, for example, when q of the linker is greater than 2, (A L ) q is the group of A L 1 and (A L ) q where the linker couples PTM with ULM.

[0228] In certain embodiments, for example, when q of the linker is 2, A L 2 is a group that is linked to A L 1 and the ULM.

[0229] In certain embodiments, for example, when q of the linker is 1, the structure of the linker group L is -A L 1-, and A L 1 is a group that will link the ULM portion to the PTM portion.

[0230] In any aspect or embodiment described herein, the unit A of the linker (L) L comprises a group represented by a general structure selected from the group consisting of:

[0231] -NR(CH2) n -(lower alkyl)-, -NR(CH2) n -(lower alkoxy)-, -NR(CH2) n -(lower alkoxy)-OCH2-, -NR(CH2) n -(lower alkoxy)-(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)1-, -NR(CH2CH2) n -(cycloalkyl)-O-(heterocyclic group)-CH 2、 -NR(CH2CH2) n-(heterocyclic group)-(heterocyclic group)-CH2 and -N(R1R2)-(heterocyclic group)-CH2; wherein

[0232] n of the linker can be from 0 to 10;

[0233] R of the linker can be H or lower alkyl; and

[0234] R1 and R2 of the linker can form a ring with the connecting N.

[0235] In any aspect or embodiment described herein, the linker (L) comprises an optionally substituted C1-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 50an alkyl group, and includes all implicit sub-ranges, e.g., C1-C10, C1-C20; C2-C10, C2-20; C10-C20, C10-C50, etc.), wherein each carbon is optionally and independently substituted or replaced by: (1) a heteroatom selected from N, O, S, P, or Si atoms, having a suitable number of hydrogens, substituents, or both to satisfy the valence, (2) an optionally substituted cycloalkyl or bicycloalkyl, (3) an optionally substituted heterocycloalkyl or bicycloheteroalkyl, (4) an optionally substituted aryl or biaryl, or (5) an optionally substituted heteroaryl or biaryl. In any aspect or embodiment described herein, the linker (L) does not have heteroatom-heteroatom bonding (e.g., no heteroatoms are covalently linked or adjacent).

[0236] In any aspect or embodiment described herein, the linker (L) comprises an optionally substituted C1-C 50 alkyl group (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 group), wherein:

[0237] Each carbon is optionally substituted or replaced independently by: CR L1 R L2 、O、S、SO、SO2、NR L3 、SO2NR L3 ,SONR L3 、CONR L3 NR L3 CONR L4 NR L3 SO2NR L4 , CO, CR L1 =CR L2 、C≡C、SiR L1 R L2 、P(O)R L1 、P(O)OR L1 NR L3 C(=NCN)NR L4 NR L3 C(=NCN),NR L3 C(=CNO2)NR L4 , optionally 1-6 R L1 and / or R L2 C 3-11 Cycloalkyl, optionally substituted with 1-9 R L1 and / or R L2 C 5-13 Spirocycloalkyl, optionally substituted by 1-6 R L1 and / or R L2 C 3-11 Heterocyclic group, optionally substituted by 1-8 R L1 and / or R L2 C 5-13 Spiroheterocyclic group, optionally substituted by 1-6 R L1 and / or R L2 substituted aryl, optionally substituted with 1-6 R L1 and / or R L2 A heteroaryl group substituted with a group, wherein R L1 or R L2 Each independently optionally linked to other groups to form a cycloalkyl and / or heterocyclyl moiety, optionally substituted by 1-4 R L5 group substitution; and

[0238] R L1 , R L2 , R L3 , R L4 and R L5 are independently H, halo, C 1-8 Alkyl, OC 1-8 Alkyl, SC1-8 Alkyl, NHC 1-8 Alkyl, N(C 1-8 alkyl)2, C 3-11 Cycloalkyl, aryl, heteroaryl, C 3-11 heterocyclic group, OC 3-8 Cycloalkyl, SC 3-8 Cycloalkyl, NHC 3-8 Cycloalkyl, N(C 3-8 cycloalkyl)2, N(C 3-8 cycloalkyl)(C 1-8 alkyl), OH, 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 1-8 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, NH SO2NH2.

[0239] In any aspect or embodiment described herein, the linker group is an optionally substituted C1-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 50alkyl, including all implicit sub-ranges, such as C1-C10, C1-C20; C2-C10, C2-20; C10-C20, C10-C50, etc.) substituted, wherein each carbon atom is optionally substituted or replaced by: an O, N, S, P or Si atom with an appropriate number of hydrogens, a substituent (e.g., OH, halogen, alkyl, methyl, ethyl, haloalkyl, hydroxyalkyl, alkoxy, methoxy, etc.) or both to satisfy the valence; an optionally substituted aryl (e.g., an optionally substituted C5 or C6 aryl) or a bicyclic aryl (e.g., an optionally substituted C5-C20 bicyclic heteroaryl); an optionally substituted heteroaryl (e.g., an optionally substituted C5 or C6 heteroaryl) or a bicyclic heteroaryl (e.g., an optionally substituted heteroaryl or bicyclic heteroaryl having one or more heteroatoms selected from N, O, S, P and Si and having an appropriate number of hydrogens, substituents (e.g., OH, halogen, alkyl, methyl, ethyl, haloalkyl, hydroxyalkyl, alkoxy, methoxy, etc.) or both to satisfy the valence); an optionally substituted C1-C6 alkyl; an optionally substituted C1-C6 alkenyl; an optionally substituted C1-C6 alkynyl; an optionally substituted cycloalkyl (e.g., an optionally substituted C3-C7 cycloalkyl) or a bicyclic cycloalkyl (e.g., an optionally substituted C5-C20 bicyclic cycloalkyl); or an optionally substituted heterocycloalkyl (e.g., an optionally substituted 3-, 4-, 5-, 6- or 7-membered heterocyclic group) or a bicyclic heterocycloalkyl (e.g., an optionally substituted heterocycloalkyl bicyclic heterocycloalkyl having one or more heteroatoms selected from N, O, S, P or Si atoms and having an appropriate number of hydrogens, substituents (e.g., OH, halogen, alkyl, methyl, ethyl, haloalkyl, hydroxyalkyl, alkoxy, methoxy, etc.) or both to satisfy the valence). In any aspect or embodiment described herein, the optionally substituted alkyl linker is optionally substituted by one or more OH, halogen, straight-chain or branched C1-C6 alkyl (such as methyl or ethyl), straight-chain or branched C1-C6 haloalkyl, straight-chain or branched C1-C6 hydroxyalkyl, or straight-chain or branched C1-C6 alkoxy (e.g., methoxy).

[0240] In any aspect or embodiment described herein, the linker (L) does not have heteroatom-heteroatom bonding (e.g., no heteroatoms are covalently linked or adjacent).

[0241] In any aspect or embodiment described herein, 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, wherein a carbon or oxygen may be substituted with a heteroatom selected from N, S, P, or Si atoms and having a suitable number of hydrogens to satisfy valency.

[0242] In any aspect or embodiment described herein, L is selected from the group consisting of:

[0243]

[0244]

[0245] Wherein:

[0246] N* is a nitrogen atom covalently linked to or shared with CLM or PTM;

[0247] Each of m, n, o, and p is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; and

[0248] The chemical linker group is optionally substituted with 1, 2, 3, or 4 substituents independently selected from halogen (e.g., F or Cl) and C1-4 alkyl.

[0249] In any aspect or embodiment described herein, unit A of linker (L) L Comprises a structure selected from the group consisting of:

[0250]

[0251] Wherein N* is a nitrogen atom covalently linked to or shared with ULM or PTM;

[0252] In any aspect or embodiment described herein, unit A of linker (L) L Comprises a structure selected from the group consisting of:

[0253]

[0254] where N* is a nitrogen atom covalently linked to or shared with the ULM or PTM;

[0255] In any aspect or embodiment described herein, unit A of linker (L) L comprises a structure selected from the group consisting of:

[0256]

[0257]

[0258]

[0259]

[0260] wherein:

[0261] N* is a nitrogen atom covalently linked to or shared with the ULM or PTM; and

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

[0263] In any aspect or embodiment described herein, unit A of linker (L) L is selected from:

[0264]

[0265]

[0266]

[0267]

[0268]

[0269] where the dashed line or * represents the site of covalent attachment to or sharing with the ULM or PTM.

[0270] In any aspect or embodiment described herein, unit A of linker (L) L is selected from:

[0271]

[0272]

[0273]

[0274]

[0275]

[0276]

[0277] The dashed lines or * indicate sites covalently linked to CLMs or PTMs, or sites shared with CLMs or PTMs.

[0278] In any aspect or embodiment described herein, unit A of linker (L) L Contains a group represented by a general structure selected from the group consisting of:

[0279]

[0280]

[0281] in

[0282] 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;

[0283] When m, n, o, p, q and r are zero, there is no NO or OO bond,

[0284] The X of the linker is H or F.

[0285]

[0286]

[0287]

[0288]

[0289]

[0290] wherein each n and m of the linker can independently be 0, 1, 2, 3, 4, 5 or 6.

[0291] In any aspect or embodiment described herein, unit A of linker (L) L Selected from the group consisting of:

[0292]

[0293]

[0294] Each m and n is independently selected from 0, 1, 2, 3, 4, 5 or 6.

[0295] In any aspect or embodiment described herein, unit A of the linker (L) L is selected from the group consisting of:

[0296]

[0297]

[0298]

[0299]

[0300]

[0301]

[0302]

[0303]

[0304]

[0305]

[0306]

[0307]

[0308]

[0309]

[0310] 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.

[0311] In any aspect or embodiment described herein, unit A of the linker (L) L is selected from the group consisting of:

[0312]

[0313]

[0314]

[0315]

[0316]

[0317] In any aspect or embodiment described herein, the linker (L) comprises a structure selected from the structures shown below:

[0318]

[0319] Wherein:

[0320] W L1 and W L2 are each independently absent, or a 4- to 8-membered ring having 0 to 4 heteroatoms optionally substituted with R Q , each R Q being independently H, a halogen group, OH, CN, CF3, an optionally substituted straight-chain or branched C1-C6 alkyl group, an optionally substituted straight-chain or branched C1-C6 alkoxy group, or two R Q groups together with the atom to which they are attached form a 4- to 8-membered ring system having 0 to 4 heteroatoms;

[0321] Y L1 are each independently a bond; an optionally substituted straight-chain or branched C1-C6 alkyl group, and optionally one or more C atoms are replaced by O or NR YL1 ; an optionally substituted C1-C6 alkene, and optionally one or more C atoms are replaced by O; an optionally substituted C1-C6 alkyne, and optionally one or more C atoms are replaced by O; or an optionally substituted straight-chain or branched C1-C6 alkoxy group;

[0322] R YL1 is H, or an optionally substituted straight-chain or branched C 1-6 alkyl group;

[0323] n is 0-10; and

[0324] and represent connection points to the PTM or ULM moiety.

[0325] In any aspect or embodiment described herein, the linker (L) comprises a structure selected from the structures shown below:

[0326]

[0327] Wherein:

[0328] W L1 and W L2 are each independently absent, piperazine, piperidine, morpholine, optionally substituted with R Q , each R QIndependently, it is H, -Cl, -F, OH, CN, CF3, optionally substituted straight-chain or branched C1-C6 alkyl (e.g., methyl, ethyl), optionally substituted straight-chain or branched C1-C6 alkoxy (e.g., methoxy, ethoxy);

[0329] Y L1 Each independently is a bond; optionally substituted straight-chain or branched C1-C6 alkyl and optionally one or more C atoms are replaced by O or NR YL1 substituted; optionally substituted C1-C6 alkene and optionally one or more C atoms are replaced by O; optionally substituted C1-C6 alkyne and optionally one or more C atoms are replaced by O; or optionally substituted straight-chain or branched C1-C6 alkoxy;

[0330] R YL1 is H, or optionally substituted straight-chain or branched C 1-6 alkyl (e.g., methyl, ethyl);

[0331] n is 0-10; and

[0332] and represent the connection points to the PTM or ULM moieties.

[0333] In any aspect or embodiment described herein, the linker (L) comprises a structure selected from the structures shown below:

[0334]

[0335] Wherein:

[0336] W L1 and W L2 Each independently is absent; aryl; heteroaryl; ring; heterocycle; C 1-6 alkyl and optionally one or more C atoms are replaced by O or NR YL1 substituted; C 1-6 alkene and optionally one or more C atoms are replaced by O; C 1-6 alkyne and optionally one or more C atoms are replaced by O; bicyclic; biaryl; diheteroaryl or bisheterocycle, each optionally substituted by R Q substituted, each R Q independently is H, halo, OH, CN, CF3, hydroxy, nitro, C≡CH, C 2-6 alkenyl, C 2-6 alkynyl, optionally substituted straight-chain or branched C1-C6 alkyl, optionally substituted straight-chain or branched C1-C6 alkoxy, optionally substituted OC 1-3 alkyl (e.g., optionally substituted by 1 or more -F), OH, NH2, NR Y1 R Y2, CN, or 2 Rs Q The group, together with the atoms to which it is attached, forms a 4- to 8-membered ring system containing 0 to 4 heteroatoms;

[0337] Y L1 Each independently is a bond; NR YL1 ; O; S; NR YL2 ; CR YL1 R YL2 ; C═O; C═S; SO; SO2; an optionally substituted straight-chain or branched C1-C6 alkyl group and optionally one or more C atoms are replaced by O; an optionally substituted straight-chain or branched C1-C6 alkoxy group;

[0338] Q L is an optionally bridged 3- to 6-membered cycloaliphatic, bicyclic or aromatic ring having 0 to 4 heteroatoms, optionally substituted by 0 to 6 Rs Q substituted, each R Q independently is H, an optionally substituted straight-chain or branched C 1-6个 alkyl group (e.g., optionally substituted by one or more halogen atoms, C 1-6 alkoxy groups), or 2 Rs Q groups, together with the atoms to which they are attached, form a 3- to 8-membered ring system containing 0 to 2 heteroatoms;

[0339] R YL1 , R YL2 each independently is H, OH, an optionally substituted straight-chain or branched C 1-6 alkyl group (e.g., optionally substituted by one or more halogen atoms, C 1-6 alkoxy groups), or R 1 , R 2 groups, together with the atoms to which they are attached, form a 3- to 8-membered ring system containing 0 to 2 heteroatoms;

[0340] n is 0 to 10; and

[0341] and represent connection points to the PTM or ULM moiety.

[0342] In any aspect or embodiment described herein, the linker (L) comprises a structure selected from the structures shown below:

[0343]

[0344] Wherein:

[0345] W L1 and W L2 each independently is absent; cyclohexane; cyclopentane; piperazine; piperidine; morpholine; C 1-6alkyl and optionally one or more C atoms are replaced by O or NR YL1 ; C 1-6 alkene and optionally one or more C atoms are replaced by O; or C 1-6 alkyne and optionally one or more C atoms are replaced by O, each optionally substituted by R Q , each R Q independently is H, Cl-, -F-, OH, CN, CF3, hydroxy, optionally substituted straight-chain or branched C1-C6 alkyl (such as methyl, ethyl), optionally substituted straight-chain or branched C1-C6 alkoxy;

[0346] Y L1 each independently is a bond; NR YL1 ; O; CR YL1 R YL2 ; C=O; optionally substituted straight-chain or branched C1-C6 alkyl and optionally one or more C atoms are replaced by O or NR YL1 ; C 1-6 alkene and optionally one or more C atoms are replaced by O; C 1-6 alkyne and optionally one or more C atoms are replaced by O; or optionally substituted straight-chain or branched C1-C6 alkoxy;

[0347] Q L is a 3-6 membered heterocyclic, heterobicyclic or heteroaryl ring, optionally substituted by 0-6 R Q , each R Q independently is H, or optionally substituted straight-chain or branched C 1-6 alkyl (such as, methyl or ethyl, optionally substituted by 1 or more halogen groups, C 1-6 alkoxy substituted);

[0348] R YL1 , R YL2 each independently is H, optionally substituted straight-chain or branched C 1-6 alkyl (such as, optionally substituted by 1 or more halogen groups, C 1-6 alkoxy substituted);

[0349] n is 0-10; and

[0350] and represent connection points to the PTM or ULM portion.

[0351] Exemplary PTM

[0352] The term "protein target moiety" or PTM is used to describe small molecules that bind to LRRK2 and can be used to target PTMs for ubiquitination and degradation. The compositions described below illustrate members of the LRRK2-binding moieties that can be used in accordance with the present invention. These binding moieties are preferably linked to a ubiquitin ligase-binding moiety via a chemical linker group to present the LRRK2 protein in the vicinity of the ubiquitin ligase for ubiquitination and subsequent degradation.

[0353] In some instances, the term "target protein" is used to refer to the LRRK2 protein, which is a member of the ROCO protein family and serves as an upstream central integrator of multiple signaling pathways that are critical for normal neuronal function, and the protein is the target protein to be ubiquitinated and degraded.

[0354] The compositions described herein illustrate the use of some members of these types of small molecule target protein-binding moieties.

[0355] 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-I:

[0356]

[0357] Wherein:

[0358] X is CH or N;

[0359] W is O or S;

[0360] Q is selected from the group:

[0361] Wherein:

[0362] A 1 、A 2 and A 3 are each independently selected from N and CR 6 and for (a), no more than two of A 1 、A 2 and A 3 are simultaneously N, and ring B is an optionally substituted C3-C8 aryl, optionally substituted C3-C8 heteroaryl, optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 heterocycloalkyl, optionally substituted C3-C8 aryl, optionally substituted C3-C8 aryl,

[0363] The of Q represents the point of attachment to nitrogen, and

[0364] The of Q represents an optional covalent linkage to R PTM ;

[0365] R 2 is H or C 1-4 alkyl;

[0366] R 3A and R 3B are each independently selected from H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, CN, NO2, OR al , SR al , C(O)R bl , C(O)NR cl R dl , C(O)OR al , OC(O)R bl , OC(O)NR cl R dl , NR cl R dl , NR cl C(O)R bl , NR c1 C(O)OR a1 , NR c1 C(O)NR c1 R d1 , C(=NR e1 )R b1 , C(=NR e1 )NR c1 R d1 , NR c1 (=NR e1 )NR c1 R d1 , NR c1 S(O)R b1 , NR c1 S(O)2R b1 , NR c1 S(O)2NR c1 R d1 , S(O)R b1 , S(O)NR c1 Rd1 、 S(O)2R b1 and S(O)2NR cl R dl ; wherein R 1 's said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5 - 14 membered heteroaryl, 4 - 14 membered heterocycloalkyl, C 6-10 aryl - C 1-4 alkyl, C 3-7 cycloalkyl - C 1-4 alkyl, 5 - 10 membered heteroaryl - C 1-4 alkyl and 4 - 10 membered heterocycloalkyl - C 1-4 alkyl are each optionally substituted with 1, 2, 3, 4 or 5 substituents, said substituents being independently selected from Cy 2 、 Cy 2 -C 1-4 alkyl, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO2, OR al 、 SR al 、 C(O)R bl 、 C(O)NR cl R dl 、 C(O)OR al 、 OC(O)R b1 、 OC(O)NR c1 R d1 、 NR c1 R d1 、 NR c1 C(O)R b1 、 NR c1 C(O)OR a1 、 NR c1 C(O)NR c1 R d1 、 C(=NR e1 )R b1 、 C(=NR e1 )NR c1 R d1 、 NR c1 C(=NR e1 )NR c1 R d1 、 NR c1 S(O)R b1 、 NR c1S(O)2R b1 NR c1 S(O)2NR c1 R d1 、S(O)R b1 、S(O)NR c1 R d1 、S(O)2R b1 and S(O)2NR c1 R d1 ;

[0367] or R 3A and R 3B Together they form C 3-7 Cycloalkyl or 4-10 membered heterocycloalkyl ring, each of which is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from Cy 2 、Cy 2 -C 1-4 Alkyl, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR al , SR al 、C(O)R bl 、C(O)NR cl R dl 、C(O)OR al 、OC(O)R b1 、OC(O)NR c1 R d1 NR c1 R d1 NR c1 C(O)R b1 NR c1 C(O)OR a1 NR c1 C(O)NR c1 R d1 、C(=NR e1 )R b1 、C(=NR e1 )NR c1 R d1 NR c1 C(=NR e1 )NR c1 R d1 NR c1 S(O)R b1 NR c1 S(O)2R b1 NR c1 S(O)2NR c1 R d1, S(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1 and S(O)2NR c1 R d1 ;

[0368] R 4 is H, C 1-4 alkyl, halo, C 1-4 haloalkyl or CN;

[0369] R 5 is H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, CN, NO2, OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , NR c2 R d2 NR c2 C(O)R b2 , NR c2 C(O)OR a2 , NR c2 C(O)NR c2 R d2 , C(=NR e2 )R b2 , C(=NR e2 )NR c2 R d2 , NR c2 C(=NR e2 )NR c2 R d2 , NR c2 S(O)R b2 , NR c2 S(O)2R b2 , NRc2 S(O)2NR c2 R d2 、S(O)R b2 、S(O)NR c2 R d2 、S(O)2R b2 and S(O)2NR c2 R d2 ; wherein said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C6- 10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and R 1 4-10 membered heterocycloalkyl-C 1-4 Each alkyl group is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from Cy 3 、Cy 3 -C 1-4 Alkyl, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, CN, NO2, OR a2 , SR a2 、C(O)R b2 、C(O)NR c2 R d2 、C(O)OR a2 、OC(O)R b2 、OC(O)NR c2 R d2 NR c2 R d2 NR c2 C(O)R b2 NR c2 C(O)OR a2 NR c2 C(O)NR c2 R d2 、C(=NR e2 )R b2 、C(=NR e2 )NR c2 R d2 NR c2 C(=NRe2 )NR c2 R d2 、NR c2 S(O)R b2 、NR c2 S(O)2R b2 、NR c2 S(O)2NR c2 R d2 、S(O)R b2 、S(O)NR c2 R d2 、S(O)2R b2 or S(O)2NR c2 R d2 ;

[0370] Each R 6 is independently selected from H, a halogen group, C 1-6 alkyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, CN, NO2, OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)NR c3 R d3 , NR c3 , C(O)OR a3 , C(=NR e3 )NR c3 R d3 , NR c3 , C(=NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 , NR c3 S(O)2R b3 , NR c3 S(O)2NR c3 R d3and S(O)2NR c3 R d3 , wherein R 6 of said C 1-6 alkyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl is each optionally substituted with 1, 2, 3, 4 or 5 substituents, said substituents being independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO2, OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)NR c3 R d3 , NR c3 C(O)OR a3 , C(=NR e3 )NR c3 R d3 , NR c3 C(=NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 , NR c3 S(O)2R b3 , NR c3 S(O)2NR c3 R d3 and S(O)2NR c3 R d3 ;

[0371] Each Cy 1 is independently selected from C 6-10 aryl, C 3-10Cycloalkyl, 5- to 14-membered heteroaryl, and 4- to 14-membered heterocycloalkyl, each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 14-membered heteroaryl, 4- to 14-membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl, 4- to 10-membered heterocycloalkyl-C 1-4 alkyl, CN, NO2, OR a , SR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , OC(O)NR c R d , NR c R d , NR c C(O)R b , NR c C(O)OR a , NR c C(O)NR c R d , C(=NR e )R b , C(=NR e )NR c R d , NR c C(=NR e )NR c R d , NR c S(O)R b , NR c S(O)2R b , NR c S(O)2NR c R d , S(O)R b , S(O)NR c R d , S(O)2Rb and S(O)2NR c R d ;

[0372] Each Cy 2 is independently selected from C 6-10 aryl, C 3-10 cycloalkyl, 5- to 14-membered heteroaryl, and 4- to 14-membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 14-membered heteroaryl, 4- to 14-membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl, 4- to 10-membered heterocycloalkyl-C 1-4 alkyl, CN, NO2, OR al , SR al , C(O)R bl , C(O)NR cl R dl , C(O)OR al , OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 C(O)NR c1 R d1 , C(=NR e1 )R b1 , C(=NR e1 )NR c1 R d1 , NR c1 C(=NR e1 )NR c1 R d1 , NR c1 S(O)R b1 , NR c1 S(O)2R b1 , NR c1 S(O)2NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1, S(O)2R b1 and S(O)2NR c1 R d1 ;

[0373] Each Cy 3 is independently selected from C 6-10 aryl, C 3-10 cycloalkyl, 5- to 14-membered heteroaryl, and 4- to 14-membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C1-6 haloalkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 14-membered heteroaryl, 4- to 14-membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl, 4- to 10-membered heterocycloalkyl-C 1-4 alkyl, CN, NO2, OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)OR a2 , NR c2 C(O)NR c2 R d2 , C(=NR e2 )R b2 , C(=NR e2 )NR c2 R d2 , NR c2 C(=NR e2 )NR c2 R d2 , NR c2 S(O)R b2 , NR c2 S(O)2R b2 , NR c2 S(O)2NR c2 Rd2 、S(O)R b2 、S(O)NR c2 R d2 、S(O)2R b2 and S(O)2NR c2 R d2 ;

[0374] Each R a , R b , R c , R d , R al , R bl , R cl , R dl , R a2 , R b2 , R c2 , R d2 , R a3 , R b3 , R c3 and R d3 Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C 1-4 Alkyl, where R a , R b , R c , R d , R al , R bl , R cl , R dl , R a2 , R b2 , R c2 , R d2 , R a3 , R b3 , R c3 or R d3 The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl and 4-10 membered heterocycloalkyl-C 1-4 The alkyl is optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, OR a4 , SR a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , OC(O)R b4 , OC(O)NR c4 R d4 , NR c4 R d4 , NR c4 C(O)R b4 , NR c4 C(O)NR c4 R d4 , NR c4 C(O)OR a4 , C(=NR e4 )NR c4 R d4 , NR c4 C(=NR e4 )NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O)2R b4 , NR c4 S(O)2R b4 , NR c4 S(O)2NR c4 R d4 and S(O)2NR c4 R d4 ;

[0375] Each R a4 , R b4 , R c4 and R d4 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7Cycloalkyl, 5- or 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5- or 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 haloalkoxy;

[0376] Each R e 、R el 、R e2 、R e3 and R e4 is independently selected from H, C 1-4 alkyl, and CN;

[0377] R PTMis H; a halogen (e.g., Cl or F); -CN; -OH; -NO2; -NH2; an optionally substituted straight-chain or branched alkyl (e.g., an optionally substituted straight-chain or branched C1-C6 alkyl, an optionally substituted straight-chain or branched C1-C4 alkyl, or a C1-C8 alkyl optionally substituted by OH); an optionally substituted cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl); O - an optionally substituted straight-chain or branched C1-C4 alkyl; an optionally substituted C1-C4 alkynyl; an optionally substituted C1-C4 alkyne; an optionally substituted straight-chain or branched hydroxyalkyl (e.g., an optionally substituted straight-chain or branched C1-C7 hydroxyalkyl); an optionally substituted alkylcycloalkyl (e.g., including an optionally substituted C1-C6 alkyl, an optionally substituted C3-C10 cycloalkyl; or both); an optionally substituted alkyl-aryl (e.g., including an optionally substituted straight-chain or branched C1-C6 alkyl, an optionally substituted 5-10 membered heteroaryl or both); an optionally substituted alkyl-heteroaryl (e.g., including an optionally substituted straight-chain or branched C1-C6 alkyl, an optionally substituted 5-10 membered heteroaryl or both); an optionally substituted alkyl-heteroaryl (e.g., including a C1-C6 alkyl, an optionally substituted 5- or 6-membered heteroaryl optionally substituted by a C1-C4 alkyl; the heteroaryl is selected from oxazol-4-yl, 1,3,4-triazol-2-yl and imidazol-1-yl; or a combination thereof); an optionally substituted -NH-alkyl-heteroaryl (e.g., an optionally substituted straight-chain or branched C1-C5 alkyl, an optionally substituted 5-8 membered heteroaryl optionally substituted by a C1-C4 alkyl, N-CH2-pyrazol-4-yl or a combination thereof); an optionally substituted alkoxy (e.g., an optionally substituted straight-chain or branched C1-C6 alkyl or -OCH3); an optionally substituted O-heterocyclic group (e.g., including an optionally substituted 3-12 or 4-7 membered heterocyclic group; an optionally substituted heterocycloalkyl; an optionally substituted C 3-12 a monocyclic or bicyclic heterocyclic group; optionally substituted by at least one OH, C1-C5 alkyl (such as methyl), =O, NH2 or a combination thereof; or a combination thereof); an optionally substituted S-heterocyclic group (e.g., including an optionally substituted 4-7 membered heterocyclic group; an optionally substituted heterocycloalkyl; optionally substituted by at least one C1-C4 alkyl (such as methyl), =O or a combination thereof; or a combination thereof); an optionally substituted (e.g., optionally substituted by a straight-chain or branched C1-C4 alkyl; -(CH2) u CO(CH2) v CH3, -COCH3 or -CH2CH2COCH3, where each u and v is independently selected from 1, 2, 3, 4 or 5);

[0378] an optionally substituted (e.g., optionally substituted by a straight-chain or branched C1-C4 alkyl; -O(CH2) u CO(CH2)v CH3, -O(CH2) u CH((CH2) x CH3)(CH2) w CO(CH2) v CH3, -O-CH2COCH3, -O-CH2COCH2CH3, -O-CH(CH 3) COCH3, -OCH2COCH3 or -OCH2(CH3)COCH3, where each u, v, w, and x is independently selected from 1, 2, 3, 4, or 5); optionally substituted (e.g., optionally substituted by a straight-chain or branched C1-C4 alkyl; -(CH2) u CO(CH2) v NR PTM1a R PTM2a , -CONR PTM1a R PTM2a , -CH2CONR PTM1a R PTM2a , -CH2CH2CONR PTM1a R PTM2a , -CONHCH3 or -CH2CONHCH3, where each u and v is independently selected from 1, 2, 3, 4, or 5); optionally substituted (e.g., optionally substituted by a straight-chain or branched C1-C4 alkyl; -O(CH2) u CO(CH2) v NR PTM1a R PTM2a , -O(CH2) u CH((CH2) x CH3)(CH2) w CO(CH2) v NR PTM1a R PTM2a , -O-CH(CH3)CONR PTM1a R PTM2a , -O-CH2CONR PTM1a R PTM2a or -OCH2C(O)NHOCH3, where each u, v, w, and x is independently selected from 1, 2, 3, 4, or 5); optionally substituted (e.g., optionally substituted by a straight-chain or branched C1-C4 alkyl; -(CH2) u CHCH(CH2) w CO(CH2) v NR PTM1a R PTM2a or -CHCHCONR PTM1a R PTM2a, where each u, v, and w is independently selected from 1, 2, 3, 4, or 5); optionally substituted (e.g., optionally substituted with a straight-chain or branched C1-C4 alkyl group; -NH-(CH2) u CO(CH2) v NR PTM1a R PTM2a or -NH-CH2CONR PTM1a R PTM2a , where each u and v is independently selected from 1, 2, 3, 4, or 5); fluoroalkoxy (e.g., mono-, di-, and / or tri-fluoroalkoxy); optionally substituted monocyclic or bicyclic cycloalkyl (e.g., optionally substituted 3- to 12-membered cycloalkyl; optionally substituted with at least one of OH, ═O, straight-chain or branched C1-C6 alkyl (such as methyl, ethyl, or butyl), or NH2; or a combination thereof); optionally substituted hydroxycycloalkyl; optionally substituted aryl (e.g., optionally substituted C5-C10 aryl, optionally substituted 5- to 7-membered aryl; optionally substituted with at least one halogen or C1-C3 alkyl (e.g., methyl or ethyl); or a combination thereof); optionally substituted heteroaryl (e.g., optionally substituted 5- to 10-membered heteroaryl, optionally substituted 5- to 7-membered heteroaryl; optionally substituted 5-membered heteroaryl; optionally substituted with at least one halogen or C1-C3 alkyl (e.g., methyl or ethyl); or a combination thereof), optionally attached to Q through a C or N atom of the heteroaryl (e.g., optionally attached to Q, through an optionally substituted –(CH2) u O(CH2) v O(CH2) x -), or at least one of the optional linkages, or a combination thereof); optionally substituted monocyclic or bicyclic heterocyclic group (e.g., optionally substituted 3- to 12-membered heterocyclic group; C3-C12 monocyclic or bicyclic heterocycloalkyl, azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, or morpholin-4-yl, or homopiperazin-1-yl, each optionally substituted with OH, straight-chain or branched C1-C5 alkyl (methyl, ethyl, or butyl), or NH2), optionally attached to Q through a C or N atom of the heterocyclic group (e.g., optionally attached to Q, through an optionally substituted –(CH2) u O(CH2) v O(CH2) x -), or at least one of the optional linkages, or both);

[0379] t1 is selected from 1, 2, 3, 4, or 5;

[0380] each t2 is independently selected from 0, 1, 2, 3, 4, or 5;

[0381] R PTM1a and R PTM2aIndependently H, optionally substituted C1-C4 alkyl (such as CH3 or CH2CH 3) , optionally substituted C1-C4 alkoxy (such as -OCH2 or -CH2CH3), optionally substituted CH2OCH3 or R PTM1a , and R PTM2a are linked together to form an optionally substituted 3-10 membered ring;

[0382] n is an integer from 0 to 10; and

[0383] The representation of PTM is the point where it is connected to the chemical linker group or ULM.

[0384] In any aspect or embodiment described herein, the R of PTM-I PTM is modified to be covalently linked to the linker group (L) or ULM (such as CLM). In any aspect or embodiment described herein, the R of PTM-I PTM is modified to be covalently linked to the chemical linker group (L) or ULM.

[0385] In any aspect or embodiment described herein, W of PTM-I is O.

[0386] In any aspect or embodiment described herein, Q of PTM-I is group (a) and ring B is selected from:

[0387] wherein

[0388] R 1 , R 1A , R 1B , R 1C and R 1D are each independently selected from H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, CN, NO2 and OR a , SR a , C(O)R b , C(O)NRc R d 、C(O)OR a 、OC(O)R b 、OC(O)NR c R d NR c R d NR c C(O)R b NR c C(O)OR a NR c C(O)NR c R d 、C(=NR e )R b 、C(=NR e )NR c R d NR c C(=NR e )NR c R d NR c S(O)R b NR c S(O)2R b NR c S(O)2NR c R d 、S(O)R b 、S(O)NR c R d 、S(O)2Rb、S(O)2NR c R d and R PTM , where R 1 , R 1A , R 1B , R 1C and R 1D The C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from Cy 1 、Cy1 -C 1-4 alkyl, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO2, OR a , SR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , OC(O)NR c R d , NR c R d , NR c C(O)R b , NR c C(O)OR a , NR c C(O)NR c R d , C(=NR e )R b , C(=NR e )NR c R d , NR c C(=NR e )NR c R d , NR c S(O)R b , NR c S(O)2R b , NR c S(O)2NR c R d , S(O)R b , S(O)NR c R d , S(O)2R b and S(O)2NR c R d ;

[0389] or R 1A and R 1B together form a C 3-7 cycloalkyl or 4 - 10 membered heterocycloalkyl ring, each optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from Cy 1 , Cy 1 C 1-4 alkyl, halo, C 1-6 alkyl, C 2-6 alkenyl, C2-6 Alkynyl, C 1-6 Haloalkyl, CN, NO2, OR a , SR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , OC(O)NR c R d , NR c R d , NR c C(O)R b , NR c C(O)OR a , NR c C(O)NR c R d , C(=NR e )R b , C(=NR e )NR c R d , NR c C(=NR e )NR c R d , NR c S(O)R b , NR c S(O)2R b , NR c S(O)2NR c R d , S(O)R b , S(O)NR c R d , S(O)2Rb, S(O)2NR c R d and R PTM , wherein ring B or a substituent of ring B is covalently coupled to R PTM , a linking group (L), or at least one of CLM.

[0390] In any aspect or embodiment described herein, Q of PTM-I is group (a) and ring B is selected from:

[0391] wherein R PTM is as described herein, and represents a covalent linkage to a linking group (L) or CLM.

[0392] In any aspect or embodiment, Q of PTM-I is covalently coupled to a linker (L) or CLM.

[0393] In any aspect or embodiment described herein, Q of PTM-I is group (a):

[0394] wherein A 1 、A 2 and A 3 are CR 6 ; R 6 is independently selected from H, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, CN and NO2; ring B is a group as described herein, the of Q represents the point of attachment to nitrogen, and the of Q represents the site of attachment to at least one of R PTM , chemical linker (L) or CLM. In any aspect or embodiment, Q of PTM-I is covalently coupled to chemical linker (L) or CLM.

[0395] In any aspect or embodiment described herein, Q of PTM-I is:

[0396] wherein A 1 、A 2 and A 3 are defined in any aspect or embodiment described herein, the of Q represents the point of attachment to nitrogen, and represents the site of covalent attachment to at least one of R PTM , chemical linker (L) or CLM. In any aspect or embodiment, Q of PTM-I is covalently coupled to linker (L) or CLM.

[0397] In any aspect or embodiment described herein, Q of PTM-I is:

[0398]

[0399] wherein A 1 、A 2 and A 3 are defined in any aspect or embodiment described herein, the of Q represents the point of attachment to nitrogen, and represents the site of covalent attachment to at least one of R PTM , chemical linker (L) or CLM. In any aspect or embodiment, Q of PTM-I is covalently coupled to linker (L) or CLM.

[0400] In any aspect or embodiment described herein, Q of PTM-I is:

[0401]

[0402] Wherein:

[0403] A 1 and A 2 are each CR 6 ;

[0404] Each R 6 is independently selected from H, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, CN and NO2;

[0405] The represents the point of attachment to nitrogen; and

[0406] represents a covalent attachment to at least one of R PTM , chemical linking group (L) or CLM.

[0407] In any aspect or embodiment described herein, W of PTM-I is O.

[0408] In any aspect or embodiment described herein, R 2 of PTM-I is H.

[0409] In any aspect or embodiment described herein, R 5 of PTM-I is H or C 1-6 alkyl.

[0410] In any aspect or embodiment described herein, R 3A and R 3B of PTM-I are each independently selected from H, halo and C 1-6 alkyl.

[0411] In any aspect or embodiment described herein, R PTM is selected from a bond, methyl, ethyl, propyl, butyl, pentyl, hexyl, H, OH, ethyl,

[0412]

[0413]

[0414]

[0415] wherein represents the attachment site to the PTM, and or * represents the site covalently linked to the chemical linking group (L) or CLM.

[0416] In any aspect or embodiment, R PTM is covalently coupled to the linker (L) or CLM.

[0417] In any aspect or embodiment described herein, PTM-I is selected from the group consisting of:

[0418]

[0419] wherein R PTM is a bond, atom or chemical group as described herein, and R PTM of represents the point of attachment of the chemical linking group (L) or CLM.

[0420] In any aspect or embodiment described herein, R PTM is a 5- to 7-membered aryl or heteroaryl (e.g., 6-membered aryl or heteroaryl), wherein:

[0421] the heteroaryl has 1, 2 or 3 heteroatoms selected from O, N and S; and

[0422] R PTM is optionally substituted with: (a) Cy 1 or (b) a 3- to 10-membered cycloalkyl (e.g., 5- or 6-membered cycloalkyl), heterocycloalkyl (e.g., 5- or 6-membered heterocycloalkyl), spirocycloalkyl (e.g., 6- to 12-membered or 8- to 10-membered spirocycloalkyl), spiroheterocycloalkyl (e.g., 6- to 12-membered or 8- to 10-membered spiroheterocycloalkyl), bicyclic cycloalkyl (e.g., 6- to 10-membered bicyclic cycloalkyl) or bicyclic heterocycloalkyl (5- to 10-membered bicyclic heterocycloalkyl), wherein each of these is optionally substituted with 1, 2, 3 or 4 groups selected from the group consisting of H, C 1-3 alkyl, methyl, ethyl and halogen.

[0423] In any aspect or embodiment described herein, R PTM is a 5- to 7-membered aryl or heteroaryl (e.g., 6-membered aryl or heteroaryl), wherein:

[0424] the heteroaryl has 1, 2 or 3 heteroatoms selected from O, N and S; and

[0425] R PTMOptionally substituted with: 3- to 10-membered cycloalkyl (e.g., 5- or 6-membered cycloalkyl), heterocycloalkyl (e.g., 5- or 6-membered heterocycloalkyl), spirocycloalkyl (e.g., 6- to 12-membered spirocycloalkyl), spiroheterocycloalkyl (e.g., 6- to 12-membered spiroheterocycloalkyl), bicyclic cycloalkyl (e.g., 6- to 10-membered bicyclic cycloalkyl) or bicyclic heterocycloalkyl (5- to 10-membered bicyclic heterocycloalkyl), wherein each of these is optionally substituted with 1, 2, 3 or 4 groups selected from the group consisting of H, C 1-3 alkyl, methyl, ethyl and halogen.

[0426] In any aspect or embodiment described herein, R PTM1a or R PTM2a is selected from a bond, methyl, ethyl, propyl, butyl, pentyl, hexyl, H, OH, ethyl,

[0427]

[0428]

[0429]

[0430] wherein represents the attachment site to the PTM, and or * represents the site covalently linked to the chemical linking group (L) or CLM.

[0431] In any aspect or embodiment described herein, R PTM or the corresponding position of any PTM described herein (e.g., PTM-I and its derivatives) is a straight-chain or branched C1-C8 alkyl optionally substituted with OH.

[0432] In any aspect or embodiment described herein, R PTM or the corresponding position of any PTM described herein (e.g., its PTM-I derivatives) is H, OH, CN, an optionally substituted straight-chain or branched C1-C4 alkyl, an O-optionally substituted straight-chain or branched C1-C4 alkyl, an optionally substituted C1-C4 alkynyl, an optionally substituted C1-C4 alkyne, an optionally substituted monocyclic or bicyclic C3-C12 heterocyclic group (e.g., an optionally substituted C3-C12 monocyclic or bicyclic heterocycloalkyl such as a C3-C12 monocyclic or bicyclic heterocycloalkyl, azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl or morpholin-4-yl or homopiperazin-1-yl, each optionally substituted with one or more of OH, straight-chain or branched C1-C5 alkyl or NH2), or an optionally substituted -O-C 3-12A monocyclic or bicyclic heterocyclic group (e.g., optionally substituted -O-C 3-12 A monocyclic or bicyclic heterocycloalkyl group, such as -O-C optionally substituted by at least one OH, straight-chain or branched C1-C5 alkyl, or NH2 3-12 A monocyclic or bicyclic heterocycloalkyl group), or an optionally substituted C3-C12 membered ring (e.g., an optionally substituted C3-C12 non-aryl membered ring optionally substituted by one or more of OH, straight-chain or branched C1-C5 alkyl, or NH2), wherein when R PTM is a ring structure, it is optionally covalently linked to Q through a C or N of the R PTM ring 16 .

[0433] In any aspect or embodiment described herein, the PTM is represented by the chemical structure:

[0434]

[0435] wherein X, A 1 , A 2 , A 3 , R 2 , R 3A , R 3B , R 4 , R 5 and R PTM are as defined in any aspect or embodiment herein, and represents a covalent linkage to a chemical linking group (L) or CLM

[0436] In any aspect or embodiment described herein, the PTM is represented by the chemical structure:

[0437]

[0438] wherein R 2 , R 3A , R 3B , R 4 , R 5 and R PTM are as defined in any aspect or embodiment herein, and represents a covalent linkage to a chemical linking group (L) or CLM

[0439] In any aspect or embodiment described herein, the PTM (e.g., PTM-I, PTM-IIa, PTM-IIb, PTM-IIIa or PTM-IIIb, or PTMs of formulas IIIa-IIIh and IVa-IVh) is represented by a chemical structure selected from:

[0440]

[0441]

[0442] wherein represents a covalent linkage of the chemical linking group (L) or CLM.

[0443] In any aspect or embodiment described herein, the PTM (e.g., PTM-I, PTM-IIa, PTM-IIb, PTM-IIIa or PTM-IIIb, or PTMs of Formulas IIIa-IIIh and IVa-IVh) is represented by a chemical structure selected from:

[0444]

[0445]

[0446] wherein represents a covalent linkage of the chemical linking group (L) or CLM.

[0447] In any aspect or embodiment described herein, the PTM (e.g., PTM-I, PTM-IIa, PTM-IIb, PTM-IIIa or PTM-IIIb, or PTMs of Formulas IIIa-IIIh and IVa-IVh) is represented by a chemical structure selected from:

[0448]

[0449]

[0450] wherein represents a covalent linkage of the chemical linking group (L) or CLM.

[0451] In any aspect or embodiment described herein, the PTM (e.g., PTM-I, PTM-IIa, PTM-IIb, PTM-IIIa or PTM-IIIb, or PTMs of Formulas IIIa-IIIh and IVa-IVh) is represented by a chemical structure selected from:

[0452]

[0453]

[0454] wherein represents a covalent linkage of the chemical linking group (L) or CLM.

[0455] In any aspect or embodiment described herein, the PTM (e.g., PTM-I, PTM-IIa, PTM-IIb, PTM-IIIa or PTM-IIIb, or the PTMs of formulas IIIa-IIIh and IVa-IVh) is represented by a chemical structure selected from the following:

[0456]

[0457] wherein represents a covalent linkage of the chemical linking group (L) or CLM.

[0458] In any aspect or embodiment described herein, the PTM (e.g., PTM-I, PTM-IIa, PTM-IIb, PTM-IIIa or PTM-IIIb, or the PTMs of formulas IIIa-IIIh and IVa-IVh) is represented by a chemical structure selected from the following:

[0459]

[0460]

[0461]

[0462] wherein represents a covalent linkage of the chemical linking group (L) or CLM.

[0463] In any aspect or embodiment described herein, the PTM (e.g., PTM-I, PTM-IIa, PTM-IIb, PTM-IIIa or PTM-IIIb, or the PTMs of formulas IIIa-IIIh and IVa-IVh) is represented by a chemical structure selected from the following:

[0464]

[0465]

[0466]

[0467]

[0468] wherein represents a covalent linkage of the chemical linking group (L) or CLM.

[0469] In any aspect or embodiment described herein, the PTM (e.g., PTM-I, PTM-IIa, PTM-IIb, PTM-IIIa or PTM-IIIb, or PTMs of formulas IIIa-IIIh and IVa-IVh) is represented by a chemical structure selected from the following:

[0470]

[0471]

[0472]

[0473] wherein represents a covalent linkage of the chemical linking group (L) or CLM.

[0474] In any aspect or embodiment described herein, the PTM (e.g., PTM-I, PTM-IIa, PTM-IIb, PTM-IIIa or PTM-IIIb, or PTMs of formulas IIIa-IIIh and IVa-IVh) is represented by a chemical structure selected from the following:

[0475]

[0476]

[0477]

[0478] wherein represents a covalent linkage of the chemical linking group (L) or CLM.

[0479] In any aspect or embodiment described herein, the PTM (e.g., PTM-I, PTM-IIa, PTM-IIb, PTM-IIIa or PTM-IIIb, or PTMs of formulas IIIa-IIIh and IVa-IVh) is represented by a chemical structure selected from the following:

[0480]

[0481]

[0482]

[0483]

[0484]

[0485] wherein Represents a covalent attachment of a chemical linking group (L) or CLM.

[0486] In any aspect or embodiment described herein, the PTM (e.g., PTM-I, PTM-IIa, PTM-IIb, PTM-IIIa or PTM-IIIb, or PTMs of formulas IIIa-IIIh and IVa-IVh) is represented by a chemical structure selected from:

[0487]

[0488]

[0489]

[0490]

[0491]

[0492] wherein Represents a covalent attachment of a chemical linking group (L) or CLM.

[0493] In any aspect or embodiment described herein, the PTM (e.g., PTM-I, PTM-IIa, PTM-IIb, PTM-IIIa or PTM-IIIb, or PTMs of formulas IIIa-IIIh and IVa-IVh) is selected from:

[0494]

[0495] wherein the Represents the site of attachment of a chemical linking group (L) or CLM.

[0496] In any aspect or embodiment described herein, the PTM (e.g., PTM-I, PTM-IIa, PTM-IIb, PTM-IIIa or PTM-IIIb, or PTMs of formulas IIIa-IIIh and IVa-IVh) has a chemical structure:

[0497]

[0498]

[0499]

[0500] and wherein the Represents a covalent attachment to a chemical linking group or CLM.

[0501] In any aspect or embodiment described herein, a PTM (such as PTM-I, PTM-IIa, PTM-IIb, PTM-IIIa or PTM-IIIb, or PTMs of formulas IIIa-IIIh and IVa-IVh) has a chemical structure:

[0502] [[ID=--5]]

[0503]

[0504]

[0505]

[0506]

[0507]

[0508]

[0509]

[0510]

[0511]

[0512]

[0513]

[0514]

[0515]

[0516]

[0517]

[0518]

[0519]

[0520]

[0521]

[0522]

[0523]

[0524] Note: There seems to be a duplicate ID "5" in the original text. I've translated it as is, but it might need to be corrected in the original source for proper reference.

[0525]

[0526] wherein represents the attachment site of the linker or ULM, and wherein each PTM is coupled to at least one linker or ULM.

[0527] In any aspect or embodiment described herein, the heterobifunctional compound is represented by the chemical structure:

[0528]

[0529] wherein:

[0530] R 3A 、R 3B 、R 4 and R 5 are as defined herein;

[0531] X is CH or N;

[0532] R 7 is H, C1-C6 alkyl, C1-C6 alkoxy, or halogen;

[0533] A is a 4-7 membered aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;

[0534] L is a chemical linker group optionally coupled to the phthalimido group through an oxygen, amine group, or methyl group;

[0535] X is CH or N; and

[0536] Y is O or H2 (i.e., absent).

[0537] In any aspect or embodiment described herein, the heterobifunctional compound is represented by the following chemical structure:

[0538]

[0539]

[0540]

[0541] wherein:

[0542] Z1 is the R group of the CLM as described in any aspect or embodiment herein, which is modified to covalently link to L, such groups being selected from -C(=O)-, -CONR'-, -O-, -NR'-, a carbon shared with the cyclic group of L, or a nitrogen shared with the cyclic group of L;

[0543] n is an integer from 0 to 3 (e.g., 0, 1, 2, or 3);

[0544] R is selected from H, O, OH, N, NH, NH2, Cl, -F, -Br, -I, methyl, an optionally substituted straight or branched alkyl (e.g., an optionally substituted straight or branched C1-C6 alkyl), an optionally substituted straight or branched alkoxy (e.g., an optionally substituted straight or branched C1-C6 alkoxy), -alkyl-aryl (e.g., -alkyl-aryl comprising at least one or a combination of C1-C6 alkyl, C4-C7 aryl), aryl (e.g., C5-C7 aryl), amine, amide or carboxyl;

[0545] L, R 3A , R 3B , R 4 and R 5 are defined as in any aspect or embodiment described herein;

[0546] Each X is independently CH or N;

[0547] R 7 is H, C1-C6 alkyl, C1-C6 alkoxy or halogen;

[0548] A is a 4- to 7-membered aryl, heteroaryl, cycloalkyl or heterocycloalkyl or a 6- to 12-membered (e.g., 8- to 10-membered) spiroalkyl or spiroheterocycloalkyl, each optionally substituted with 1, 2, 3 or 4 groups selected from the group consisting of H, C 1-3 alkyl, methyl, ethyl and halogen;

[0549] X is CH or N;

[0550] A 1 , A 2 and A 3 are defined as in any aspect or embodiment described herein (e.g., A 1 and A 3 are each N or CH, and A 2 is CR 7 or N); and

[0551] Y is O or H2 (i.e., absent).

[0552] In any aspect or embodiment described herein, the heterobifunctional compound is represented by the chemical structure:

[0553]

[0554] wherein:

[0555] R 3A , R 3B , R 4 and R 5 are defined as described herein;

[0556] R 7 is H or a halogen;

[0557] A is a 4- to 7-membered heterocycloalkyl;

[0558] L is a chemical linker group optionally coupled to the phthalimido group through an oxygen, amine group, or methyl group;

[0559] X is CH or N; and

[0560] Y is O or H2 (i.e., absent).

[0561] In any aspect or embodiment described herein, the heterobifunctional compound is represented by the chemical structure:

[0562]

[0563]

[0564] wherein:

[0565] Z1 is an R group of the CLM as described in any aspect or embodiment herein, which is modified to covalently link to L, such groups being selected from -C(=O)-, -CONR'-, -O-, -NR'-, a carbon shared with the cyclic group of L, or a nitrogen shared with the cyclic group of L;

[0566] n is an integer from 0 to 3 (e.g., 0, 1, 2, or 3);

[0567] R is selected from H, O, OH, N, NH, NH2, Cl, -F, -Br, -I, methyl, an optionally substituted straight or branched alkyl (e.g., an optionally substituted straight or branched C1-C6 alkyl), an optionally substituted straight or branched alkoxy (e.g., an optionally substituted straight or branched C1-C6 alkoxy), -alkyl-aryl (e.g., -alkyl-aryl comprising at least one of C1-C6 alkyl, C4-C7 aryl, or a combination thereof), aryl (e.g., C5-C7 aryl), amine, amide, or carboxyl;

[0568] L, R 3A 、R 3B 、R 4 and R 5 are defined as in any aspect or embodiment described herein;

[0569] R 7 is H or a halogen;

[0570] A is a 4- to 7-membered heterocycloalkyl or a 6- to 12-membered (e.g., 8- to 10-membered) spiroheterocycloalkyl, each optionally substituted with 1, 2, 3, or 4 groups selected from H, C1-3 substituted with a group from the group consisting of an alkyl group, a methyl group, an ethyl group, and a halogen;

[0571] Each X is independently CH or N;

[0572] A 1 、A 2 and A 3 as defined in any aspect or embodiment described herein (e.g., A 1 and A 3 are each independently N or CH, and A 2 is CR 7 or N); and

[0573] Y is O or H2 (i.e., absent).

[0574] In any aspect or embodiment described herein, the heterobifunctional compound has the chemical structure:

[0575] PTM-L-CLM,

[0576] or a pharmaceutically acceptable salt or solvate thereof;

[0577] wherein:

[0578] (a) CLM is a small molecule E3 ubiquitin ligase binding moiety that binds to the cereblon E3 ubiquitin ligase and is represented by the following chemical structure:

[0579]

[0580]

[0581]

[0582]

[0583] wherein:

[0584] W is selected from the group consisting of CH2, O, CHR, C=O, SO2, NH, N, an optionally substituted cyclopropyl group, an optionally substituted cyclobutyl group, and an N-alkyl group;

[0585] Q1, Q2, Q3, Q4, Q5 each independently represent a carbon C or N substituted with a group independently selected from R', N, or an N-oxide;

[0586] R 1 is selected from absent (i.e., a bond), H, OH, CN, C1-C3 alkyl, C=O;

[0587] R 2Selected from the group consisting of absent (i.e., a bond), H, OH, CN, C1-C3 alkyl, CHF2, CF3, CHO, C(=O)NH2;

[0588] R 3 Selected from a bond, H, alkyl (e.g., C1-C6 or C1-C3 alkyl), substituted alkyl (e.g., substituted C1-C6 or C1-C3 alkyl), alkoxy (e.g., C1-C6 or C1-C3 alkoxy), substituted alkoxy (e.g., substituted C1-C6 or C1-C3 alkoxy);

[0589] R 4 Selected from a bond, H, alkyl, substituted alkyl;

[0590] R 5 and R 6 are each independently a bond, H, halogen, C(=O)R', CN, OH, CF3;

[0591] X is C, CH, C=O, or N;

[0592] X1 is C=O, N, CH or CH2;

[0593] R' is selected from a bond, H, halogen, amine, alkyl (e.g., C1-C3 alkyl), substituted alkyl (e.g., substituted C1-C3 alkyl), alkoxy (e.g., C1-C3 alkoxy), substituted alkoxy (e.g., substituted C1-C3 alkoxy), NR 2 R 3 , C(=O)OR 2 , optionally substituted phenyl;

[0594] n is 0-4;

[0595] is a single bond or a double bond; and

[0596] CLM is covalently linked to PTM, a chemical linker group (L), ULM or CLM;

[0597] (b) PTM is a small molecule leucine-rich repeat kinase 2 (LRRK2) targeting moiety that binds to human LRRK2 or a mutant thereof represented by the following chemical structure:

[0598]

[0599] Wherein:

[0600] X is CH or N;

[0601] W is O or S;

[0602] Q is selected from one of the following:

[0603] (a) or (b) Wherein:

[0604] A 1 、A 2 and A 3 are each independently selected from N and CR 6 , wherein for (a), A 1 、A 2 and A 3 no more than two of them are N at the same time,

[0605] Ring B is an optionally substituted C3-C8 aryl, an optionally substituted C3-C8 heteroaryl, an optionally substituted C3-C8 cycloalkyl, an optionally substituted C3-C8 heterocycloalkyl, an optionally substituted C3-C8 aryl, an optionally substituted C3-C8 aryl,

[0606] The of Q represents the connection point with nitrogen, and

[0607] The of Q represents an optional covalent connection with R PTM ;

[0608] R 2 is H or C 1-4 alkyl;

[0609] R 3A and R 3B are each independently selected from H, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, CN, NO2, OR al , SR al , C(O)R bl , C(O)NR cl R dl , C(O)OR al , OC(O)R bl , OC(O)NR cl R dl , NR cl R dl , NRcl C(O)R bl , NR c1 C(O)OR a1 , NR c1 C(O)NR c1 R d1 , C(=NR e1 )R b1 , C(=NR e1 )NR c1 R d1 , NR c1 (=NR e1 )NR c1 R d1 , NR c1 S(O)R b1 , NR c1 S(O)2R b1 , NR c1 S(O)2NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1 and S(O)2NR cl R dl ; wherein R 1 of said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl and 4-10 membered heterocycloalkyl-C 1-4 alkyl is each optionally substituted with from 1, 2, 3, 4 or 5 substituents independently selected from Cy 2 , Cy 2 -C 1-4 alkyl, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO2, OR al , SR al , C(O)R bl , C(O)NR cl R dl, C(O)OR al , OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 C(O)NR c1 R d1 , C(=NR e1 )R b1 , C(=NR e1 )NR c1 R d1 , NR c1 C(=NR e1 )NR c1 R d1 , NR c1 S(O)R b1 , NR c1 S(O)2R b1 , NR c1 S(O)2NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1 and S(O)2NR c1 R d1 ;

[0610] or R 3A and R 3B together form a C 3-7 cycloalkyl or 4- to 10-membered heteroalkyl ring, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cy 2 , Cy 2 -C 1-4 alkyl, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO2, OR al , SR al , C(O)R bl , C(O)NR cl R dl , C(O)OR al , OC(O)R b1 , OC(O)NR c1 Rd1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 C(O)NR c1 R d1 , C(=NR e1 )R b1 , C(=NR e1 )NR c1 R d1 , NR c1 C(=NR e1 )NR c1 R d1 , NR c1 S(O)R b1 , NR c1 S(O)2R b1 , NR c1 S(O)2NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1 and S(O)2NR c1 R d1 ;

[0611] R 4 is H, C 1-4 alkyl, halo, C 1-4 haloalkyl or CN;

[0612] R 5 is H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5 - 14 membered heteroaryl, 4 - 14 membered heterocycloalkyl, C 6-10 aryl - C 1-4 alkyl, C 3-7 cycloalkyl - C 1-4 alkyl, 5 - 10 membered heteroaryl - C 1-4 alkyl, 4 - 10 membered heterocycloalkyl - C 1-4 alkyl, CN, NO2, OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2, OC(O)R b2 , OC(O)NR c2 R d2 , NR c2 R d2 NR c2 C(O)R b2 , NR c2 C(O)OR a2 , NR c2 C(O)NR c2 R d2 , C(=NR e2 )R b2 , C(=NR e2 )NR c2 R d2 , NR c2 C(=NR e2 )NR c2 R d2 , NR c2 S(O)R b2 , NR c2 S(O)2R b2 , NR c2 S(O)2NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O)2R b2 and S(O)2NR c2 R d2 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C6- 10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl and R 1 's 4-10 membered heterocycloalkyl-C 1-4 alkyl is each optionally substituted with 1, 2, 3, 4 or 5 substituents, said substituents independently selected from Cy 3 , Cy 3 -C 1-4 alkyl, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6Halogenated alkyl, CN, NO2, OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)OR a2 , NR c2 C(O)NR c2 R d2 , C(=NR e2 )R b2 , C(=NR e2 )NR c2 R d2 , NR c2 C(=NR e2 )NR c2 R d2 , NR c2 S(O)R b2 , NR c2 S(O)2R b2 , NR c2 S(O)2NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O)2R b2 or S(O)2NR c2 R d2 ;

[0613] Each R 6 is independently selected from H, halogenated group, C 1-6 alkyl, C 1-6 halogenated alkyl, C 6-10 aryl, C 3-7 cycloalkyl, 5 - 6 membered heteroaryl, 4 - 7 membered heterocycloalkyl, CN, NO2, OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3, NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)NR c3 R d3 , NR c3 C(O)OR a3 , C(=NR e3 )NR c3 R d3 , NR c3 , C(=NR e3 )NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 , NR c3 S(O)2R b3 , NR c3 S(O)2NR c3 R d3 and S(O)2NR c3 R d3 , wherein R 6 of said C 1-6 alkyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, 4 or 5 substituents, said substituents being independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, CN, NO2, OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)NR c3 R d3 , NR c3 C(O)OR a3 , C(=NR e3)NR c3 R d3 NR c3 C(=NR e3 )NR c3 R d3 、S(O)R b3 、S(O)NR c3 R d3 、S(O)2R b3 NR c3 S(O)2R b3 NR c3 S(O)2NR c3 R d3 and S(O)2NR c3 R d3 ;

[0614] Each Cy 1 Independently selected from C 6-10 Aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl and 4-14 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Halogenated alkyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4 Alkyl, 4-10 membered heterocycloalkyl-C 1-4 Alkyl, CN, NO2, OR a , SR a 、C(O)R b 、C(O)NR c R d 、C(O)OR a 、OC(O)R b 、OC(O)NR c R d NR c R d NR c C(O)R b NR c C(O)OR a NR c C(O)NR c R d 、C(=NRe )R b 、C(=NR e )NR c R d 、NR c C(=NR e )NR c R d 、NR c S(O)R b 、NR c S(O)2R b 、NR c S(O)2NR c R d 、S(O)R b 、S(O)NR c R d 、S(O)2Rb and S(O)2NR c R d ;

[0615] Each Cy 2 is independently selected from C 6-10 aryl, C 3-10 cycloalkyl, 5- to 14-membered heteroaryl, and 4- to 14-membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 14-membered heteroaryl, 4- to 14-membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl, 4- to 10-membered heterocycloalkyl-C 1-4 alkyl, CN, NO2, OR al 、SR al 、C(O)R bl 、C(O)NR cl R dl 、C(O)OR al 、OC(O)R b1 、OC(O)NR c1 R d1 、NR c1 R d1 、NR c1 C(O)R b1 、NR c1 C(O)ORa1 , NR c1 C(O)NR c1 R d1 , C(=NR e1 )R b1 , C(=NR e1 )NR c1 R d1 , NR c1 C(=NR e1 )NR c1 R d1 , NR c1 S(O)R b1 , NR c1 S(O)2R b1 , NR c1 S(O)2NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1 and S(O)2NR c1 R d1 ;

[0616] Each Cy 3 is independently selected from C 6-10 aryl, C 3-10 cycloalkyl, 5- to 14-membered heteroaryl, and 4- to 14-membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C1-6 haloalkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 14-membered heteroaryl, 4- to 14-membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5- to 10-membered heteroaryl-C 1-4 alkyl, 4- to 10-membered heterocycloalkyl-C 1-4 alkyl, CN, NO2, OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , NR c2 Rd2 NR c2 C(O)R b2 NR c2 C(O)OR a2 NR c2 C(O)NR c2 R d2 、C(=NR e2 )R b2 、C(=NR e2 )NR c2 R d2 NR c2 C(=NR e2 )NR c2 R d2 NR c2 S(O)R b2 NR c2 S(O)2R b2 NR c2 S(O)2NR c2 R d2 、S(O)R b2 、S(O)NR c2 R d2 、S(O)2R b2 and S(O)2NR c2 R d2 ;

[0617] Each R a , R b , R c , R d , R al , R bl , R cl , R dl , R a2 , R b2 , R c2 , R d2 , R a3 , R b3 , R c3 and R d3 Independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-7 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 Aryl-C 1-4 Alkyl, C 3-7 Cycloalkyl-C 1-4 Alkyl, 5-10 membered heteroaryl-C 1-4Alkyl and 4-10 membered heterocycloalkyl-C 1-4 alkyl, wherein R a , R b , R c , R d , R al , R bl , R cl , R dl , R a2 , R b2 , R c2 , R d2 , R a3 , R b3 , R c3 or R d3 of said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl, C 3-7 cycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl and 4-10 membered heterocycloalkyl-C 1-4 alkyl is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, OR a4 , SR a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , OC(O)R b4 , OC(O)NR c4 R d4 , NR c4 R d4 , NR c4 C(O)R b4 , NR c4 , NR c4 R d4 , NR c4 , C(O)OR a4 , C(=NR e4 )NR c4 R d4 , NR c4 , C(=NR e4 )NR c4 R d4, S(O)R b4 , S(O)NR c4 R d4 , S(O)₂R b4 , NR c4 S(O)₂R b4 , NR c4 S(O)₂NR c4 R d4 and S(O)₂NR c4 R d4 ;

[0618] Each R a4 , R b4 , R c4 and R d4 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5- to 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl are each optionally substituted with 1, 2 or 3 substituents, said substituents being independently selected from OH, CN, amino, halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl and C 1-6 haloalkoxy;

[0619] Each R e , R el , R e2 , R e3 and R e4 is independently selected from H, C 1-4 alkyl and CN;

[0620] R PTMis H; a halogen (e.g., Cl or F); -CN; -OH; -NO2; -NH2; an optionally substituted straight-chain or branched alkyl (e.g., an optionally substituted straight-chain or branched C1-C6 alkyl, or an optionally substituted straight-chain or branched C1-C4 alkyl, or a C1-C8 alkyl optionally substituted by OH); an optionally substituted cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl); O - an optionally substituted straight-chain or branched C1-C4 alkyl; an optionally substituted C1-C4 alkynyl; an optionally substituted C1-C4 alkyne; an optionally substituted straight-chain or branched hydroxyalkyl (e.g., an optionally substituted straight-chain or branched C1-C7 hydroxyalkyl); an optionally substituted alkylcycloalkyl (e.g., including an optionally substituted C1-C6 alkyl, an optionally substituted C3-C10 cycloalkyl; or both); an optionally substituted alkyl-aryl (e.g., including an optionally substituted straight-chain or branched C1-C6 alkyl, an optionally substituted 5-10 membered heteroaryl, or both); an optionally substituted alkyl-heteroaryl (e.g., including an optionally substituted straight-chain or branched C1-C6 alkyl, an optionally substituted 5-10 membered heteroaryl, or both); an optionally substituted alkyl-heteroaryl (e.g., including a C1-C6 alkyl, an optionally substituted 5- or 6-membered heteroaryl, optionally substituted by a C1-C4 alkyl; the heteroaryl is selected from oxazol-4-yl, 1,3,4-triazol-2-yl and imidazol-1-yl; or a combination thereof); an optionally substituted -NH-alkyl-heteroaryl (e.g., an optionally substituted straight-chain or branched C1–C5 alkyl, an optionally substituted 5-8 membered heteroaryl, optionally substituted by a C1–C4 alkyl, N-CH2-pyrazol-4-yl or a combination thereof); an optionally substituted alkoxy (e.g., an optionally substituted straight-chain or branched C1–C6 alkyl or -OCH3); an optionally substituted O-heterocyclic group (e.g., including an optionally substituted 3-12 or 4-7 membered heterocyclic group; an optionally substituted heterocycloalkyl; an optionally substituted C 3-12 a monocyclic or bicyclic heterocycloalkyl; optionally substituted by at least one OH, a C1-C5 alkyl (such as methyl), =O, NH2 or a combination thereof; or a combination thereof); an optionally substituted S-heterocyclic group (e.g., including an optionally substituted 4-7 membered heterocyclic group; an optionally substituted heterocycloalkyl; optionally substituted by at least one C1-C4 alkyl (such as methyl), =O or a combination thereof; or a combination thereof); an optionally substituted (e.g., optionally substituted by a straight-chain or branched C1-C4 alkyl; -(CH2) u CO(CH2) v CH3, -COCH3 or -CH2CH2COCH3, where each u and v independently is selected from 1, 2, 3, 4 or 5); an optionally substituted (e.g., optionally substituted by a straight-chain or branched C1-C4 alkyl; -O(CH2) u CO(CH2) v CH3, -O(CH2)u CH((CH2) x CH3)(CH2) w CO(CH2) v CH3, -O-CH2COCH3, -O-CH2COCH2CH3, -O-CH(CH 3) COCH3, -OCH2COCH3 or -OCH2(CH3)COCH3 substituted, where each u, v, w, and x is independently selected from 1, 2, 3, 4, or 5); optionally substituted (e.g., optionally substituted by straight-chain or branched C1-C4 alkyl; -(CH2) u CO(CH2) v NR PTM1a R PTM2a , -CONR PTM1a R PTM2a , -CH2CONR PTM1a R PTM2a , -CH2CH2CONR PTM1a R PTM2a , -CONHCH3 or -CH2CONHCH3 substituted, where each u and v is independently selected from 1, 2, 3, 4, or 5); optionally substituted (e.g., optionally substituted by straight-chain or branched C1-C4 alkyl; -O(CH2) u CO(CH2) v NR PTM1a R PTM2a , -O(CH2) u CH((CH2) x CH3)(CH2) w CO(CH2) v NR PTM1a R PTM2a , -O-CH(CH3)CONR PTM1a R PTM2a , -O-CH2CONR PTM1a R PTM2a or -OCH2C(O)NHOCH3 substituted, where each u, v, w, and x is independently selected from 1, 2, 3, 4, or 5); optionally substituted (e.g., optionally substituted by straight-chain or branched C1-C4 alkyl substituted; -(CH2) u CHCH(CH2) w CO(CH2) v NR PTM1a R PTM2a or -CHCHCONR PTM1a R PTM2a , where each u, v, and w is independently selected from 1, 2, 3, 4, or 5); optionally substituted (e.g., optionally substituted by a linear or branched C1-C4 alkyl group; -NH-(CH2) u CO(CH2) v NR PTM1a R PTM2a or -NH-CH2CONR PTM1a R PTM2a (wherein each u and v is independently selected from 1, 2, 3, 4, or 5); fluoroalkoxy (e.g., mono-, di-, and / or tri-fluoroalkoxy); optionally substituted monocyclic or bicyclic cycloalkyl (e.g., optionally substituted 3- to 12-membered cycloalkyl; optionally substituted by at least one of OH, =O, linear or branched C1-C6 alkyl (such as methyl, ethyl, or butyl), or NH2; or a combination thereof); optionally substituted hydroxycycloalkyl; optionally substituted aryl (e.g., optionally substituted C5-C10 aryl, optionally substituted 5- to 7-membered aryl; optionally substituted by at least one halogen or C1-C3 alkyl (e.g., methyl or ethyl); or a combination thereof); optionally substituted heteroaryl (e.g., optionally substituted 5- to 10-membered heteroaryl, optionally substituted 5- to 7-membered heteroaryl; optionally substituted 5-membered heteroaryl; optionally substituted by at least one halogen or C1-C3 alkyl (e.g., methyl or ethyl); or a combination thereof), optionally attached to Q through a C or N atom of the heteroaryl (e.g., optionally attached to Q, optionally through an optionally substituted –(CH2) u O(CH2) v O(CH2) x -), or at least one of a combination thereof); optionally substituted monocyclic or bicyclic heterocyclic group (e.g., optionally substituted 3- to 12-membered heterocyclic group; C3-C12 monocyclic or bicyclic heterocycloalkyl, azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, or morpholin-4-yl, or homopiperazin-1-yl, each optionally substituted by OH, linear or branched C1-C5 alkyl (methyl, ethyl, or butyl group), or NH2), optionally attached to Q through a C or N atom of the heterocyclic group (e.g., optionally attached to Q, optionally through an optionally substituted –(CH2) u O(CH2) v O(CH2) x -), or at least one of both);

[0621] t1 is selected from 1, 2, 3, 4, or 5;

[0622] each t2 is independently selected from 0, 1, 2, 3, 4, or 5;

[0623] R PTM1a and R PTM2a are independently H, optionally substituted C1-C4 alkyl (e.g., CH3 or CH2CH 3), optionally substituted C1-C4 alkoxy (e.g., -OCH2 or -CH2CH3), optionally substituted CH2OCH3 or R PTM1a , and R PTM2a are linked together to form an optionally substituted 3- to 10-membered ring;

[0624] n is an integer from 0 to 10; and

[0625] The represents the site of attachment to a chemical linking group or CLM; and

[0626] (c) L is a bond or chemical linking group that covalently couples CLM to PTM.

[0627] Therapeutic Compositions

[0628] The present invention also provides a pharmaceutical composition comprising a combination of a therapeutically effective amount of at least one bifunctional compound as described herein with a pharmaceutically acceptable carrier, additive, or excipient.

[0629] In another aspect, the present specification provides a therapeutic composition comprising an effective amount of a compound as described herein or a salt form thereof, and a pharmaceutically acceptable carrier, additive, or excipient, and optionally an additional bioactive agent. The therapeutic composition effects targeted protein degradation in a patient or subject (e.g., an animal such as a human), and can be used to treat or ameliorate a disease state or condition that is modulated by degradation of a target protein. In certain embodiments, a therapeutic composition as described herein can be used to effect protein degradation to treat or ameliorate an LRRK2-mediated neurodegenerative disease, inflammatory disease, autoimmune disease, or cancer. In certain additional embodiments, the disease is Parkinson's disease, Parkinson's disease with dementia, Parkinson's disease risk syndrome, dementia with Lewy bodies, Alzheimer's disease Lewy body variant, combined Parkinson's disease and Alzheimer's disease, multiple system atrophy, striatonigral degeneration, olivopontocerebellar atrophy, and Shy-Drager syndrome.

[0630] In another aspect, the present disclosure relates to a method of treating a disease state or ameliorating one or more symptoms of a disease or disorder in a subject in need thereof by degrading the LRRK2 protein, the method comprising administering to the patient or subject an effective amount (e.g., a therapeutically effective amount) of at least one compound as described herein, optionally in combination with a pharmaceutically acceptable carrier, additive, or excipient, and optionally co-administered with an additional bioactive agent, wherein the composition is effective to treat or ameliorate the disease or condition or one or more symptoms thereof in the subject. The method according to the present disclosure can be used to treat certain disease states or conditions, including neurodegenerative diseases, by administering an effective amount of at least one compound described herein.

[0631] The present disclosure also includes pharmaceutical compositions that comprise pharmaceutically acceptable salts, particularly acid or base addition salts of the compounds as described herein. Acids useful in accordance with this aspect for preparing pharmaceutically acceptable acid addition salts of the foregoing compounds are those that form non-toxic acid addition salts, i.e., salts that contain pharmacologically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, glucuronate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)), among others.

[0632] Pharmaceutically acceptable base addition salts can also be used to produce pharmaceutically acceptable salt forms of the compounds according to the present disclosure. Chemical bases that can be used as reagents for preparing pharmaceutically acceptable base salts of the compounds of the present invention are those that form non-toxic base salts with these compounds. Such non-toxic base salts include, but are not limited to, those derived from such pharmacologically acceptable cations 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 lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines, among others.

[0633] According to the present disclosure, the compounds as described herein can be administered orally, parenterally, or topically in single or divided doses. The range of administration of the active compound can range from continuous (intravenous infusion) to several times a day orally (e.g., Q.I.D.), and can include oral, topical, parenteral, intramuscular, intravenous, subcutaneous, transdermal (which can include permeation enhancers), buccal, sublingual, intranasal, intraocular, intrathecal, and suppository administration, as well as other routes of administration. Enteric-coated oral tablets can also be used to improve the bioavailability of the compound from the oral route of administration. The most effective dosage form will depend on the pharmacokinetics of the particular agent selected and the severity of the patient's disease. The compounds according to the present disclosure can also be administered as sprays, mists, or aerosols for intranasal, intratracheal, or pulmonary administration. Accordingly, the present disclosure also relates to pharmaceutical compositions that comprise an effective amount of the compounds as described herein, optionally in combination with a pharmaceutically acceptable carrier, additive, or excipient. The compounds according to the present disclosure can be administered in immediate release, intermediate release, or sustained or controlled release forms. Sustained release or controlled release forms are preferably administered orally, but also in suppository and transdermal or other topical forms. Intramuscular injection in liposomal form or long-acting formulations can also be used to control or maintain the release of the compound at the injection site.

[0634] The compositions described herein can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers and can also be administered in the form of controlled release formulations. Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions include, but are not limited to, ion exchange agents, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffering substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polypropylene block polymers, polyethylene glycol, and lanolin.

[0635] The pharmaceutical compositions described herein can be administered orally, parenterally, by inhalation nebulization, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intraliver, intralesional, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally, or intravenously.

[0636] The sterile injectable form of the compositions described herein can be an aqueous or an oily suspension. These suspensions can be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be used, including synthetic mono- or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are suitable for the preparation of injectables, as are natural pharmaceutically acceptable oils such as olive oil or castor oil, especially in their polyoxyethylated forms. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as Ph.Helv or a similar alcohol.

[0637] The pharmaceutical compositions described herein can be administered orally in any orally acceptable dosage form, including, but not limited to, capsules, tablets, aqueous suspensions, or solutions. For tablets for oral use, common carriers include lactose and corn starch. Lubricants such as magnesium stearate are also commonly added. For oral administration in capsule form, diluents that can be used include lactose and dry corn starch. When an aqueous suspension is required for oral use, the active ingredient can be combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring, or coloring agents can be added.

[0638] Optionally, the pharmaceutical compositions described herein can be used for rectal administration in the form of suppositories. These can be prepared by mixing the drug with suitable non-irritating excipients that are solid at room temperature but liquid at rectal temperature and will thus melt in the rectum to release the drug. Such materials include cocoa butter, beeswax, and polyethylene glycol.

[0639] The pharmaceutical compositions described herein can also be administered topically. Suitable topical formulations are readily prepared for each of these areas or organs. For topical application, the pharmaceutical composition can be formulated as a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of the present disclosure include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, and water. In certain preferred aspects of the present disclosure, the compound can be coated onto a stent to be surgically implanted into a patient to inhibit or reduce the likelihood of occlusion occurring in the patient's stent.

[0640] Optionally, the pharmaceutical composition can be formulated as a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0641] For ophthalmic applications, the pharmaceutical composition can be formulated as a micronized suspension in isotonic, pH-adjusted sterile saline, or preferably, as a solution in isotonic, pH-adjusted sterile saline with or without a preservative such as benzalkonium chloride. Optionally, for ophthalmic applications, the pharmaceutical composition can be formulated as an ointment such as petrolatum.

[0642] The pharmaceutical compositions described herein can also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation, and can be prepared as solutions in physiological saline using benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0643] The amount of active pharmaceutical ingredient that can be combined with the carrier substances in the pharmaceutical compositions described herein to produce a single dosage form will vary depending on the host being treated, the condition of the disease, and the particular mode of administration. Preferably, the composition should be formulated to contain from about 0.05 mg to about 750 mg or more, more preferably from about 1 mg to about 600 mg, even more preferably from about 10 mg to about 500 mg of the active ingredient, either alone or in combination with another compound according to the present disclosure.

[0644] It should also be understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity and bioavailability of the specific compound used, age, weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the judgment of the treating physician, and the severity of the particular disease or condition being treated.

[0645] A patient or subject in need of treatment with a compound according to the methods described herein can be treated by administering to the patient (subject) an effective amount of a compound according to the present disclosure, which depends on its pharmaceutically acceptable salts, solvates or polymorphs, optionally in a pharmaceutically acceptable carrier or diluent, alone or in combination with another known therapeutic agent.

[0646] The active compound is combined with a pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver a therapeutically effective amount for the desired indication to the patient without causing a substantial toxic effect on the patient being treated. For all the conditions mentioned herein, the preferred dosage of the active compound is in the range of about 10 nanograms per kilogram (ng / kg) to 300 milligrams per kilogram (mg / kg), preferably 0.1 to 100 mg / kg per day, and more generally, 0.5 to about 25 mg per kilogram of body weight of the recipient / patient per day. A typical topical dosage range is 0.01 - 5% weight / weight in a suitable carrier.

[0647] The compound is conveniently administered in any suitable unit dosage form, including but not limited to dosage forms containing less than 1 milligram (mg), 1 mg to 3000 mg or 5 mg to 500 mg of the active ingredient per unit dosage form. An oral dosage of about 25 mg - 250 mg is usually convenient.

[0648] The active ingredient is preferably administered to achieve a peak plasma concentration of the active compound of about 0.00001 - 30 millimoles (mM), preferably about 0.1 - 30 micromoles (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 injection of a bolus of the active ingredient. Oral administration can also be suitable for producing an effective plasma concentration of the active agent.

[0649] The concentration of the active compound in the pharmaceutical composition will depend on the rate of absorption, distribution, inactivation, and excretion of the drug, as well as other factors known to those skilled in the art. It should be noted that the dosage values will also vary with the severity of the condition to be alleviated. It should also be understood that for any particular subject, the specific dosage regimen should be adjusted over time according to individual needs and the professional judgment of the person administering or supervising the administration of the composition, and the concentration ranges described herein are only exemplary and are not intended to limit the scope or practice of the claimed composition. The active ingredient can be administered in one dose, or it can be divided into multiple smaller doses and administered at different time intervals.

[0650] Oral compositions generally include an inert diluent or an edible carrier. They can be encapsulated in gelatin capsules or compressed into tablets. For the purposes of oral therapeutic administration, the active compound or its prodrug derivatives can be combined with excipients and used in the form of tablets, lozenges, or capsules. Pharmaceutically compatible binders, and / or auxiliary materials can be included as part of the composition.

[0651] Tablets, pills, capsules, lozenges, etc. can contain any of the following ingredients or compounds of similar nature: binders such as microcrystalline cellulose, tragacanth, or gelatin; excipients such as starch or lactose; disintegrants such as alginic acid, Primogel, or corn starch; lubricants such as magnesium stearate or Sterotes; glidants such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin; or flavoring agents such as peppermint, methyl salicylate, or orange flavoring. When the unit dosage form is a capsule, in addition to the above types of substances, it can contain a liquid carrier such as a vegetable oil. In addition, the dosage unit form can contain various other materials that modify the physical form of the dosage unit, such as coatings of sugar, shellac, or enteric solvents.

[0652] The active compound or its pharmaceutically acceptable salt can be administered as a component of elixirs, suspensions, syrups, wafers, chewable tablets, etc. In addition to the active compound, the syrup can contain sucrose as a sweetening agent and certain preservatives, dyes, coloring agents, and flavoring agents.

[0653] The active compound or its pharmaceutically acceptable salt can also be mixed with other active materials that do not impair the desired action, or with materials that supplement the desired action (such as anticancer agents), as described herein. In certain preferred aspects of the present disclosure, one or more compounds according to the present disclosure are co-administered with another bioactive agent, such as an anticancer agent or a wound healing agent, including antibiotics, as further described herein.

[0654] Solutions or suspensions for parenteral, intradermal, subcutaneous, or topical application can include the following components: sterile diluents such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol, or other synthetic solvents; antibacterial agents such as benzyl alcohol or methylparaben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetate, citrate, or phosphate, and agents for adjusting tonicity such as sodium chloride or dextrose. Parenteral formulations can be enclosed in ampoules, disposable syringes, or multi-dose vials made of glass or plastic.

[0655] If administered intravenously, a preferred carrier is saline or phosphate buffered saline (PBS).

[0656] In any of the aspects and embodiments described herein, the active compound is formulated with a carrier that will prevent the rapid elimination of the compound from the body, such as controlled release formulations that include implants and microencapsulation 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.

[0657] Liposome suspensions can also be a pharmaceutically acceptable carrier. These can be prepared by methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811 (the entire content of which is incorporated herein by reference). For example, liposomal formulations can be prepared by dissolving appropriate lipids (such as stearoyl phosphatidylethanolamine, stearoyl phosphatidylcholine, arachidoyl phosphatidylcholine, and cholesterol) in an inorganic solvent and then evaporating the solvent, leaving a dry lipid film on the surface of the container. Then an aqueous solution of the active compound is introduced into the container. Then the container is manually vortexed to release the lipid material from the sides of the container and disperse the lipid aggregates, thereby forming a liposome suspension.

[0658] Therapeutic Methods

[0659] In another aspect, the present specification provides a method of treatment that includes administering an effective amount of a compound or a salt form thereof as described herein, and a pharmaceutically acceptable carrier. The method of treatment can be used to effect protein degradation in a patient or subject in need thereof (such as an animal such as a human) for treating or ameliorating a disease state, condition, or related symptoms that can be treated by targeted protein degradation.

[0660] As used herein, the term "treat / treating / treatment, etc." refers to any action that provides a benefit to a patient to whom a compound of the invention can be administered, including treatment of any disease state, medical condition or symptom associated with a protein to which a compound of the invention binds. Disease states or medical conditions (including cancer) that can be treated using the compounds according to the disclosure are as described above.

[0661] This specification provides methods of treatment for achieving targeted protein degradation to treat or ameliorate a disease (e.g., cancer). In any aspect or embodiment described herein, the disease is multiple myeloma. Thus, in another aspect, this specification provides methods of ubiquitinating / degrading a target protein in a cell. In certain embodiments, the method comprises administering a bifunctional compound of the invention. Control or reduction of the level of a specific protein in a cell of a subject given the disclosure provides treatment of a disease state, medical condition or symptom. In any aspect or embodiment described herein, the method comprises administering an effective amount of a compound as described herein, optionally comprising a pharmaceutically acceptable excipient, carrier, adjuvant, another bioactive agent or a combination thereof.

[0662] In another embodiment, this specification provides a method for treating or ameliorating a disease, disorder or a symptom thereof in a subject or patient (e.g., an animal such as a human), the method comprising administering to a subject in need thereof a composition comprising an effective amount (e.g., a therapeutically effective amount) of a compound as described herein or a salt form thereof and a pharmaceutically acceptable excipient, carrier, adjuvant, another bioactive agent or a combination thereof, wherein the composition is effective to treat or ameliorate the disease or disorder or a symptom thereof in the subject.

[0663] In another aspect, this specification provides a method for using a compound according to the disclosure to identify the effect of targeted protein degradation in a biological system.

[0664] In another aspect, this specification provides a process for preparing a molecule that can cause the degradation of LRRK2 in a cell, which comprises the following steps: i. providing a small molecule that binds to LRRK2; ii. providing an E3 ubiquitin ligase binding moiety (ULM), preferably CLM, such as thalidomide, pomalidomide, lenalidomide or an analogue thereof; and iii. covalently coupling the small molecule of step (i) to the ULM of step (ii) through a chemical linker (L) to form a compound that binds to the cereblon E3 ubiquitin ligase and the LRRK2 protein in the cell, such that the cereblon E3 ubiquitin ligase is brought close to and ubiquitinates the LRRK2 protein bound thereto, such that the ubiquitinated LRRK2 is subsequently degraded.

[0665] In another aspect, the present specification provides a method for detecting whether a molecule can trigger the degradation of LRRK2 protein in cells, the method comprising the steps of: (i) providing a molecule whose ability to trigger the degradation of LRRK2 protein in cells is to be detected, 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 cells, the CLM being thalidomide, pomalidomide, lenalidomide or an analogue thereof; PTM is a protein targeting moiety, which is a small molecule that binds to LRRK2, and the LRRK2 has at least one lysine residue that can be ubiquitinated by the cereblon E3 ubiquitin ligase that binds to this molecule; L is a chemical linking group that covalently links CLM and PTM to form the molecule; (ii) incubating LRRK2 protein-expressing cells in the presence of the molecule of step (i); and (iii) detecting whether the LRRK2 protein in the cells is degraded.

[0666] In any aspect or embodiment described herein, the small molecule capable of binding to LRRK2 is the small molecule as described herein.

[0667] In another aspect of the treatment, the present disclosure provides a method for treating a human patient in need of treatment for a disease state, condition or symptom, the disease state, condition or symptom being causally related to LRRK2 expression, overexpression, mutation, misfolding or dysregulation, wherein the degradation of the LRRK2 protein will produce a therapeutic effect in the patient, the method comprising administering to the patient an effective amount of a compound according to the present disclosure, optionally in combination with another bioactive agent. The disease state, condition or symptom may be caused by a microbial agent or other exogenous 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 dysregulation of a protein that results in the disease state, condition or symptom.

[0668] In another aspect, the present disclosure provides a method for treating or ameliorating at least one symptom of a disease or condition of a subject, the method comprising the steps of: providing a subject identified as having a disease or condition causally related to the expression, overexpression, mutation, misfolding or dysregulation of the LRRK2 protein in the subject, and treating or ameliorating the symptoms of the disease or condition by degrading the LRRK2 protein in the cells of the subject; and administering to the subject a therapeutically effective amount of a compound comprising the small molecule of the present invention such that the LRRK2 protein is degraded, thereby treating or ameliorating at least one symptom of the disease or condition of the subject.

[0669] The term "disease state or condition" is used to describe any disease state or condition in which there is overexpression, mutation, misfolding, or dysregulation of protein expression (e.g., an elevated amount of a protein expressed in a patient), and in which degradation of the LRRK2 protein (whether mutated or not) that reduces or stabilizes the level of the LRRK2 protein in a patient provides a beneficial treatment or symptom relief to a patient in need. In some cases, the disease state, condition, or symptom can be cured.

[0670] Disease states, conditions, or symptoms that can be treated using the compounds according to the present disclosure include, for example, inflammatory and immune disorders, asthma, autoimmune diseases such as multiple sclerosis, neurodegenerative diseases such as Parkinson's disease, various cancers, ciliopathies, diabetes, heart disease, hypertension, inflammatory bowel disease, mental retardation, mood disorders, obesity, refractive errors, infertility, Angelman syndrome, Canavan disease, celiac disease, Charcot–Marie–Tooth disease, cystic fibrosis, Duchenne muscular dystrophy, hemochromatosis, hemophilia, Klinefelter's syndrome, neurofibromatosis, phenylketonuria, polycystic kidney disease, (PKD1) or 4 (PKD2) Prader–Willi syndrome, sickle cell disease, Tay–Sachs disease, and Turner syndrome.

[0671] The term "neurodegenerative disease" (or degenerative neurological disease) is used throughout the specification to refer to a pathological process that affects many bodily activities such as balance, movement, speech, breathing, and heart function. Many of these diseases are genetic and sometimes caused by medical conditions such as alcoholism, tumors, or strokes. Other causes can include toxins, chemicals, and viruses, and sometimes the cause is unknown. Exemplary neurodegenerative diseases can be treated with the compounds of the invention alone or in combination with at least one additional anti-neurodegenerative disease therapeutic agent, the therapeutic agents including those for treating Parkinson's disease, Parkinson's disease with dementia, Parkinson's disease risk syndrome, dementia with Lewy bodies, Alzheimer's disease Lewy body variant, combined Parkinson's disease and Alzheimer's disease, multiple system atrophy, striatonigral degeneration, olivopontocerebellar atrophy, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, and Shy–Drager syndrome. For example, Carmustine, Bexarotene, Tamibarotene, Imatinib, Paclitaxel, Azithromycin, Erythromycin, Doxycycline, Rifampicin, Acyclovir, Penciclovir, and Foscarnet.

[0672] The term "bioactive agent" is used to describe an agent other than the compounds according to the present disclosure, which is used in combination with the compounds of the present invention as a bioactive agent to help achieve the intended treatment, inhibition, and / or prevention of diseases using the compounds of the present invention. Preferred bioactive agents used herein include those agents having a pharmacological activity similar to that of using or administering the compounds of the present invention, and include, for example, anti-cancer agents, antiviral agents, especially including anti-HIV agents and anti-HCV agents, antibacterial agents, antifungal agents, and the like.

[0673] The term "additional anti-neurodegenerative disease agent" is used to describe an anti-neurodegenerative disease therapeutic agent, which can be combined with the compounds according to the present disclosure to treat neurodegenerative diseases. These agents include, for example, carmustine, bexarotene, tamibarotene, imatinib, paclitaxel, azithromycin, erythromycin, doxycycline, rifampicin, acyclovir, penciclovir, and foscarnet.

[0674] The term "pharmaceutically acceptable derivative" is used throughout the specification to describe any pharmaceutically acceptable prodrug form (such as esters, amides, and other prodrug groups), which directly or indirectly provides the compounds of the present invention or the active metabolites of the compounds of the present invention when administered to a patient.

[0675] Examples

[0676] Abbreviations

[0677] ACN Acetonitrile

[0678] AcOH Acetic acid

[0679] DCM Dichloromethane

[0680] DMF N,N-Dimethylformamide

[0681] DMSO Dimethyl sulfoxide

[0682] DIPEA N,N-Diisopropylethylamine

[0683] EtOAc / EA Ethyl acetate

[0684] EtOH Ethanol

[0685] HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

[0686] HPLC High performance liquid chromatography

[0687] Hz Hertz

[0688] KOAc Potassium acetate

[0689] LCMS Liquid chromatography / mass spectrometry

[0690] MHz Megahertz

[0691] NMR Nuclear Magnetic Resonance

[0692] MeOH Methanol

[0693] MS Mass Spectrometry

[0694] PE Petroleum Ether

[0695] Psi Pound per Square Inch

[0696] RT or r.t. Room Temperature

[0697] TEA Triethylamine

[0698] THF Tetrahydrofuran

[0699] TFA Trifluoroacetic Acid

[0700] TLC Thin Layer Chromatography

[0701] TMS Trimethylsilyl

[0702] General Synthetic Methods

[0703] The synthesis implementation and optimization of the bifunctional molecules as described herein can be carried out in a stepwise or modular manner. For example, if no suitable ligand is immediately available, the identification of a compound that binds to a target protein (i.e., LRRK2) may involve high-throughput or medium-throughput screening activities. It is not uncommon for the initial ligand to require iterative design and optimization cycles to improve suboptimal aspects identified through data from appropriate in vitro and pharmacological and / or ADMET assays. Part of the optimization / SAR activity will be to probe the positions where the ligand tolerates substitution and potentially the appropriate positions for attaching the chemical linker groups mentioned previously herein. In cases where crystallographic or NMR structural data are available, these can be used to focus such synthetic efforts.

[0704] In a very similar manner, ligands for E3 ligases can be identified and optimized.

[0705] With PTMs and UMLs (e.g., CLMs), those skilled in the art can use known synthetic methods to combine them with or without one or more chemical linker groups. One or more chemical linker groups of a range of compositions, lengths, and flexibilities can be synthesized and functionalized such that the PTM and UML groups can be sequentially attached to the distal end of the linker. Thus, a bifunctional molecule library can be realized and profiled in in vitro and in vivo pharmacological and ADMET / PK studies and in vivo. Similar to the PTM and UML groups, the final bifunctional molecules can undergo iterative design and optimization cycles to identify molecules with the desired properties.

[0706] In some cases, protecting group strategies and / or functional group interconversions (FGI) may be required to facilitate the preparation of the desired materials. Such chemical manipulations are well known to synthetic organic chemists, and many of these 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).

[0707] Synthetic Procedures

[0708] Synthetic Intermediate 1: 4,5-Dimethyl-7H-tetrazolo[1,5-a]pyrimidine-6-carboxylic acid

[0709]

[0710] Step 1: Ethyl 5-methyl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxylate

[0711] To a solution of 1H-tetrazol-5-amine (5 grams (g), 48.50 millimoles (mmol), 1 equivalent (eq), in H2O) in water (100 milliliters (mL)) was added formaldehyde (5.46 g, 72.75 mmol, 5.01 mL, 1.5 eq) and ethyl acetoacetate (6.31 g, 48.50 mmol, 6.13 mL, 1 eq). The mixture was stirred at 100 °C for 9 hours (hr) to obtain a white solution. The solution then became a suspension. LCMS (EB16-543-P1A1) indicated completion of the reaction. The mixture was cooled to 20 °C and concentrated under reduced pressure at 20 °C. The suspension was filtered, and the filter cake was concentrated in vacuo to give ethyl 5-methyl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxylate (7.2 g, 34.42 mmol, yield 70.96%), as a white solid.

[0712] Step 2: Ethyl 4,5-dimethyl-7H-tetrazolo[1,5-a]pyrimidine-6-carboxylate

[0713]

[0714] At 20 °C under N2, methyl iodide (6.06 g, 42.68 mmol, 2.66 mL, 1.24 eq) was added in one portion to a mixture of ethyl 5-methyl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxylate (7.2 g, 34.42 mmol, 1 eq) and Cs2CO3 (12.33 g, 37.86 mmol, 1.1 eq) in MeCN (70 mL). The mixture was stirred at 50 °C for 1 h. LCMS (EB16-545-P1A1) showed the reaction was complete. The aqueous phase was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with brine (50 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give ethyl 4,5-dimethyl-7H-tetrazolo[1,5-a]pyrimidine-6-carboxylate (7.5 g, 33.60 mmol, yield 97.61%) as a yellow solid.

[0715] Step 3: 4,5-Dimethyl-7H-tetrazolo[1,5-a]pyrimidine-6-carboxylic acid

[0716]

[0717] At 20 °C under N2, lithium hydroxide (1.29 g, 53.76 mmol, 3 eq) and H2O (5 mL) were added in one portion to a mixture of ethyl 4,5-dimethyl-7H-tetrazolo[1,5-a]pyrimidine-6-carboxylate (4 g, 17.92 mmol, 1 eq) in THF (30 mL). The mixture was stirred at 60 °C for 16 h. LCMS (EB16-548-P1A1) showed the reaction was complete. The mixture was cooled to 20 °C and concentrated under reduced pressure at 20 °C. The residue was acidified to pH = 1 with HCl. A solid formed and was collected by filtration. The filter cake was filtered under vacuum to give 4,5-dimethyl-7H-tetrazolo[1,5-a]pyrimidine-6-carboxylic acid (2.9 g, 14.86 mmol, yield 82.92%) as a white solid.

[0718] Synthesis of Intermediate 2: 4,5,7-Trimethyl-7H-tetrazolo[1,5-a]pyrimidine-6-carboxylic acid. The synthesis of Intermediate 2 was carried out in a manner similar to that of Synthesis Intermediate 1, using acetaldehyde instead of formaldehyde in Step 1.

[0719] Synthesis of Intermediate 3: 4,5,7,7-Tetramethyltetrazolo[1,5-a]pyrimidine-6-carboxylic acid. The synthesis of Intermediate 3 was carried out in a manner similar to that of Synthesis Intermediate 1, using ethyl 2-acetyl-3-methyl-but-2-enoate (prepared by condensing acetone and ethyl acetoacetate in Step 1).

[0720] Exemplary Synthesis Exemplary Compound 1: N-[3-[2-[(3R,5S)-4-[[1-[[1-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-5-yl]-4-piperidinyl]methyl]-4-piperidinyl]methyl]-3,5-dimethyl-piperazin-1-yl]-4-pyridinyl]-1H-indazol-5-yl]-4,5-dimethyl-7H-tetrazolo[1,5-a]pyrimidine-6-carboxamide

[0721] Step 1: tert-Butyl (3R,5S)-4-[(1-benzyloxycarbonyl-4-piperidinyl)methyl]-3,5-dimethyl-piperazine-1-carboxylate

[0722]

[0723] At 20 °C under N2, KI (2.32 g, 14.00 mmol, 3 eq) and DIPEA (1.81 g, 14.00 mmol, 2.44 mL, 3 eq) were added in one portion to a mixture of tert-butyl (3R,5S)-3,5-dimethylpiperazine-1-carboxylate (1 g, 4.67 mmol, 1 eq) and benzyl 4-(tosyloxymethyl)piperidine-1-carboxylate (1.88 g, 4.67 mmol, 1 eq) in MeCN (5 mL). The mixture was stirred at 100 °C for 16 h. LCMS (EB16-606-P1A6) showed the desired MS. 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 phases were washed with brine (5 mL * 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (DCM:MeOH = 10:1, Rf = 0.59, 20 g, 0 - 14% (10 min) ethyl acetate in petroleum ether, 14% (20 min) ethyl acetate in petroleum ether) to give tert-butyl (3R,5S)-4-[(1-benzyloxycarbonyl-4-piperidinyl)methyl]-3,5-dimethyl-piperazine-1-carboxylate (1.22 g, 2.74 mmol, yield 58.67%) as a yellow gum.

[0724] Step 2: Benzyl 4-[[(2R,6S)-2,6-dimethylpiperazin-1-yl]methyl]piperidine-1-carboxylate

[0725]

[0726] At 20 °C under N2, trifluoroacetic acid (TFA, 312.18 mg, 2.74 mmol, 202.71 μL, 1 eq) was added in one portion to a solution of tert-butyl (3R,5S)-4-[(1-benzyloxycarbonyl-4-piperidinyl)methyl]-3,5-dimethylpiperazine-1-carboxylate (1.22 g, 2.74 mmol, 1 eq) in DCM (5 mL). The mixture was stirred at 20 °C for 30 minutes. LCMS (EB16-610-P1A1) showed completion of the reaction. The residue was basified to pH = 7 - 8 with saturated NaHCO3. The aqueous phase was extracted with DCM (5 mL × 3). The combined organic phases were washed with brine (5 mL × 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give benzyl 4-[[(2R,6S)-2,6-dimethylpiperazin-1-yl]methyl]piperidine-1-carboxylate (930 mg, 2.69 mmol, yield 98.32%), as a yellow gum.

[0727] Step 3: Benzyl 4-[[(2R,6S)-4-(4-bromo-2-pyridinyl)-2,6-dimethylpiperazin-1-yl]methyl]piperidine-1-carboxylate

[0728]

[0729] At 25 °C, cesium carbonate (Cs2CO3, 1.75 g, 5.38 mmol, 2 eq) was added in one portion to a mixture of benzyl 4-[[(2R,6S)-2,6-dimethylpiperazin-1-yl]methyl]piperidine-1-carboxylate (930 mg, 2.69 mmol, 1 eq) and 4-bromo-2-fluoropyridine (473.74 mg, 2.69 mmol, 1 eq) in DMF (5 mL). The mixture was stirred at 100 °C for 12 hours. LCMS (EB16-612-P1A1) showed completion of the reaction. 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 phases were washed with brine (5 mL × 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (12 g, 0 - 50% (10 min) ethyl acetate in petroleum ether, 50% (10 min) ethyl acetate in petroleum ether) to give benzyl 4-[[(2R,6S)-4-(4-bromo-2-pyridinyl)-2,6-dimethylpiperazin-1-yl]methyl]piperidine-1-carboxylate (580 mg, 1.16 mmol, yield 42.97%), as a yellow gum.

[0730] Step 4: [2-[(3R,5S)-4-[(1-benzyloxycarbonyl-4-piperidinyl)methyl]-3,5-dimethylpiperazin-1-yl]-4-pyridinyl]boronic acid

[0731]

[0732] At 25 °C under N2, Pd(dppf)Cl2 (42.32 mg, 57.83 μmol, 0.05 eq) was added in one portion to a mixture of benzyl 4-[[(2R,6S)-4-(4-bromo-2-pyridinyl)-2,6-dimethyl-piperazin-1-yl]methyl]piperidine-1-carboxylate (580 mg, 1.16 mmol, 1 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (440.57 mg, 1.73 mmol, 1.5 eq) and KOAc (340.53 mg, 3.47 mmol, 3 eq) in dioxane (2 mL). The mixture was stirred at 100 °C for 2 h. LCMS (EB16-615-P1A1) showed completion of the reaction. The mixture was cooled to 25 °C, filtered and concentrated in vacuo to give [2-[(3R,5S)-4-[(1-benzyloxycarbonyl-4-piperidinyl)methyl]-3,5-dimethyl-piperazin-1-yl]-4-pyridinyl]boronic acid (669 mg, crude), as a dark brown solid. The crude product was used in the next step without further purification.

[0733] Step 5: Benzyl 4-[[(2R,6S)-2,6-dimethyl-4-[4-(5-nitro-1H-indazol-3-yl)-2-pyridinyl]piperazin-1-yl]methyl]piperidine-1-carboxylate

[0734]

[0735] At 25 °C under N2, 4-(di-tert-butylphosphino)-N,N-dimethylaniline; palladium(II) dichloride (101.57 mg, 143.45 μmol, 101.57 μL, 0.1 eq) was added in one portion to a mixture of [2-[(3R,5S)-4-[(1-benzyloxycarbonyl-4-piperidinyl)methyl]-3,5-dimethyl-piperazin-1-yl]-4-pyridinyl]boronic acid (669 mg, 1.43 mmol, 1 eq), 3-bromo-5-nitro-1H-indazole (381.90 mg, 1.58 mmol, 1.1 eq) and KOAc (422.34 mg, 4.30 mmol, 3 eq) in EtOH (10 mL) and H2O (2 mL). The mixture was stirred at 100 °C for 12 h. LCMS (EB16-616-P1A2) showed completion of the reaction. The mixture was cooled to 20 °C and concentrated under reduced pressure. 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 (12 g, silica gel 100 - 200 mesh, 0 - 100% (15 min) ethyl acetate in petroleum ether, 100% (15 min) ethyl acetate in petroleum ether) to give benzyl 4-[[(2R,6S)-2,6-dimethyl-4-[4-(5-nitro-1H-indazol-3-yl)-2-pyridinyl]piperazin-1-yl]methyl]piperidine-1-carboxylate (609 mg, 980.78 μmol, yield 68.37%, purity 94%) as a yellow gum.

[0736] Step 6: Benzyl 4-[[(2R,6S)-4-[4-(5-amino-1H-indazol-3-yl)-2-pyridinyl]-2,6-dimethyl-piperazin-1-yl]methyl]piperidine-1-carboxylate

[0737]

[0738] At 20 °C under N2, NH4Cl (279.06 mg, 5.22 mmol, 5 eq) was added in one portion to a mixture of benzyl 4-[[(2R,6S)-2,6-dimethyl-4-[4-(5-nitro-1H-indazol-3-yl)-2-pyridinyl]piperazin-1-yl]methyl]piperidine-1-carboxylate (609 mg, 1.04 mmol, 1 eq) and Fe (291.34 mg, 5.22 mmol, 5 eq) in H2O (1 mL) and EtOH (5 mL). The mixture was stirred at 80 °C for 1.5 h. LCMS (EB16-620-P1A1) showed the reaction was complete. The residue was filtered and the solution was concentrated in vacuo to afford benzyl 4-[[(2R,6S)-4-[4-(5-amino-1H-indazol-3-yl)-2-pyridinyl]-2,6-dimethylpiperazin-1-yl]methyl]piperidine-1-carboxylate (550 mg, 814.53 μmol, yield 78.07%, purity 82%) as a brown solid.

[0739] Step 7: Benzyl 4-[[(2R,6S)-4-[4-[5-(tert-butoxycarbonylamino)-1H-indazol-3-yl]-2-pyridinyl]-2,6-dimethylpiperazin-1-yl]methyl]piperidine-1-carboxylate

[0740]

[0741] At 20 °C under N2, DIPEA (140.05 mg, 1.08 mmol, 188.75 μL, 1.5 eq) was added in one portion to a mixture of benzyl 4-[[(2R,6S)-4-[4-(5-amino-1H-indazol-3-yl)-2-pyridinyl]-2,6-dimethylpiperazin-1-yl]methyl]piperidine-1-carboxylate (400 mg, 722.42 μmol, 1 eq) and Boc2O (173.43 mg, 794.66 μmol, 182.56 μL, 1.1 eq) in THF (5 mL). The mixture was stirred at 20 °C for 16 h. TLC showed the reaction was complete. The residue was poured into water (5 mL). The aqueous phase was extracted with ethyl acetate (5 mL × 3). The combined organic phases were washed with brine (5 mL × 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (12 g, 0 - 50% (10 min) ethyl acetate in petroleum ether, 50% (10 min) ethyl acetate in petroleum ether) to afford benzyl 4-[[(2R,6S)-4-[4-(5-(tert-butoxycarbonylamino)-1H-indazol-3-yl]-2-pyridinyl]-2,6-dimethylpiperazin-1-yl]methyl]piperidine-1-carboxylate (274 mg, 410.70 μmol, yield 56.85%, purity 98%) as an off-white solid.

[0742] Step 8: tert-Butyl N-[3-[2-[(3R,5S)-3,5-dimethyl-4-(piperidin-4-ylmethyl)piperazin-1-yl]-4-pyridinyl]-1H-indazol-5-yl]carbamate

[0743]

[0744] Under N2, Pd / C (50 mg, 419.08 μmol, 10% purity, 1 eq) was added to a mixture of benzyl (2R,6S)-4-[[4-[5-(tert-butoxycarbonylamino)-1H-indazol-3-yl]-2-pyridinyl]-2,6-dimethylpiperazin-1-yl]methylpiperidine-1-carboxylate (274 mg, 419.08 μmol, 1 eq) in THF (5 mL). The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred at 25 °C under H2 (15 psi) for 16 h. TLC showed completion of the reaction. The reaction mixture was filtered with MeOH (20 mL * 3) and the filtrate was concentrated to give tert-Butyl N-[3-[2-[(3R,5S)-3,5-dimethyl-4-(piperidin-4-ylmethyl)piperazin-1-yl]-4-pyridinyl]-1H-indazol-5-yl]carbamate (160 mg, 252.16 μmol, yield 60.17%, purity 81.9%) as a white solid.

[0745] Step 9: tert-Butyl N-[3-[2-[(3R,5S)-4-[[1-[[1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl]piperidin-4-yl]methyl]piperidin-4-yl]methyl]-3,5-dimethylpiperazin-1-yl]-4-pyridinyl]-1H-indazol-5-yl]carbamate

[0746]

[0747] At 20 °C under N2, AcOH (18.49 mg, 307.88 μmol, 17.61 μL, 1 eq) and borane; 2-methylpyridine (65.86 mg, 615.76 μmol, 2 eq) were added in one portion to a mixture of tert-butyl N-[3-[2-[(3R,5S)-3,5-dimethyl-4-(piperidin-4-ylmethyl)piperazin-1-yl]-4-pyridinyl]-1H-indazol-5-yl]carbamate (160 mg, 307.88 μmol, 1 eq) and 1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl]piperidine-4-carbaldehyde (170.58 mg, 461.82 μmol, 1.5 eq) in MeOH (5 mL). The mixture was stirred at 20 °C for 4 h. LCMS (EB16-636-P1A2) showed the required MS. 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 (dichloromethane:methanol = 10:1, Rf = 0.09, 0 - 20% (15 min) methanol in dichloromethane, 20% (5 min) methanol in dichloromethane) to give tert-butyl N-[3-[2-[(3R,5S)-4-[[1-[[1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl]-4-piperidinyl]methyl]-4-piperidinyl]methyl]-3,5-dimethylpiperazin-1-yl]-4-pyridinyl]-1H-indazol-5-yl]carbamate (220 mg, 231.83 μmol, yield 75.30%, purity 92%) as a yellow gum.

[0748] Step 10: 5-[4-[[4-[[(2R,6S)-4-[4-(5-amino-1H-indazol-3-yl)-2-pyridinyl]-2,6-dimethylpiperazin-1-yl]methyl]-1-piperidinyl]methyl]-1-piperidinyl]-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0749]

[0750] To a mixture of tert-butyl N-[3-[2-[(3R,5S)-4-[[1-[[1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl]-4-piperidinyl]methyl]-4-piperidinyl]methyl]-3,5-dimethylpiperazin-1-yl]-4-pyridinyl]-1H-indazol-5-yl]carbamate (220 mg, 251.99 μmol, 1 eq) in DCM (3 mL) was added TFA (86.20 mg, 755.97 μmol, 55.97 μL, 3 eq) in one portion at 20 °C. The mixture was stirred at 20 °C for 30 min. TLC (DCM:MeOH = 3:1, Rf = 0.14) showed completion of the reaction. The mixture was concentrated under reduced pressure to afford 5-[4-[[4-[[(2R,6S)-4-[4-(5-amino-1H-indazol-3-yl)-2-pyridinyl]-2,6-dimethylpiperazin-1-yl]methyl]-1-piperidinyl]methyl]-1-piperidinyl]-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (300 mg, crude, TFA), as a yellow gum.

[0751] Step 11: N-[3-[2-[(3R,5S)-4-[[1-[[1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl]-4-piperidinyl]methyl]-4-piperidinyl]methyl]-3,5-dimethylpiperazin-1-yl]-4-pyridinyl]-1H-indazol-5-yl]-4,5-dimethyl-7H-tetrazolo[1,5-a]pyrimidine-6-carboxamide (Compound 1)

[0752]

[0753] To a solution of 4,5-dimethyl-7H-tetrazolo[1,5-a]pyrimidine-6-carboxylic acid (Intermediate 1, 30.30 mg, 155.25 μmol, 1.2 eq) and 5-[4-[[4-[[(2R,6S)-4-[4-(5-amino-1H-indazol-3-yl)-2-pyridinyl]-2,6-dimethyl-piperazin-1-yl]methyl]-1-piperidinyl]methyl]-1-piperidinyl]-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione (100 mg, 129.38 μmol, 1 eq) in DMF (2 mL) was stirred at 0 °C for 10 min, then DIPEA (83.61 mg, 646.88 μmol, 112.68 μL, 5 eq) and HATU (49.19 mg, 129.38 μmol, 1 eq) were added. Then the mixture was stirred at 25 °C under N2 for 16 h. LCMS (EB16-642-P1A8) 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 phases were 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 * 25 mm * 10 μm; conditions: water (0.2% FA)-ACN; initial B: 0; end B: 40; flow rate: 35 mL / min; gradient time: 35 min; 100% B hold time: 4 min) to give N-[3-[2-[(3R,5S)-4-[[1-[[1-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-5-yl]-4-piperidinyl]methyl]-4-piperidinyl]methyl]-3,5-dimethyl-piperazin-1-yl]-4-pyridinyl]-1H-indazol-5-yl]-4,5-dimethyl-7H-tetrazolo[1,5-a]pyrimidine-6-carboxamide (29.3 mg, 30.53 μmol, yield 23.60%, purity 99%), as a yellow solid.

[0754] 11H NMR: (400 MHz, DMSO-d6) δ: 13.42 (s, 1H), 11.08 (s, 1H), 10.07 (s, 1H), 8.67 (s, 1H), 8.22 (d, J = 5.1 Hz, 1H), 7.67 - 7.51 (m, 3H), 7.28 (d, J = 13.8 Hz, 2H), 7.23 (d, J = 8.8 Hz, 1H), 7.16 (d, J = 5.3 Hz, 1H), 5.30 (s, 2H), 5.11 - 5.02 (m, 1H), 4.12 (d, J = 11.1 Hz, 2H), 4.03 (d, J = 12.9 Hz, 2H), 3.44 (s, 3H), 3.00 - 2.80 (m, 5H), 2.72 - 2.53 (m, 6H), 2.39 - 2.30 (m, 2H), 2.27 (s, 3H), 2.16 (d, J = 5.8 Hz, 2H), 2.05 - 1.97 (m, 1H), 1.95 - 1.71 (m, 7H), 1.37 (s, 1H), 1.12 (d, J = 5.8 Hz, 10H).

[0755] Exemplary synthesis of Exemplary Compound 2: N-[3-[2-[(3R,5S)-4-[[1-[[1-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-5-yl]-4-piperidinyl]methyl]-4-piperidinyl]methyl]-3,5-dimethyl-piperazin-1-yl]-4-pyridinyl]-1H-indazol-5-yl]-4,5,7-trimethyl-7H-tetrazolo[1,5-a]pyrimidine-6-carboxamide

[0756]

[0757] To a solution of 4,5,7-trimethyl-7H-tetrazolo[1,5-a]pyrimidine-6-carboxylic acid (32.48 mg, 155.25 μmol, 1.2 eq) and 5-[4-[[4-[[(2R,6S)-4-[4-(5-amino-1H-indazol-3-yl)-2-pyridinyl]-2,6-dimethyl-piperazin-1-yl]methyl]-1-piperidinyl]methyl]-1-piperidinyl]-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione (100 mg, 129.38 μmol, 1 eq) in DMF (2 mL) was stirred at 0 °C for 10 min, then DIPEA (83.60 mg, 646.88 μmol, 112.67 μL, 5 eq) and HATU (49.19 mg, 129.38 μmol, 1 eq) were added. The mixture was then stirred at 25 °C under N2 for 16 h. LCMS (EB16-643-P1A1) showed completion of the reaction. The residue was poured into water (10 mL). The aqueous phase was extracted with ethyl acetate (10 mL * 3). The combined organic phases were washed with brine (10 mL * 3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by reverse phase HPLC (column: Phenomenex luna C18 150 * 25 mm * 10 μm; conditions: water (0.2% FA)-ACN; initial B: 0; end B: 40; flow rate: 35 mL / min; gradient time: 35 min; 100% B hold time: 4 min) to give N-[3-[2-[(3R,5S)-4-[[1-[[1-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-5-yl]-4-piperidinyl]methyl]-4-piperidinyl]methyl]-3,5-dimethyl-piperazin-1-yl]-4-pyridinyl]-1H-indazol-5-yl]-4,5,7-trimethyl-7H-tetrazolo[1,5-a]pyrimidine-6-carboxamide (34.9 mg, 35.84 μmol, yield 27.70%, purity 99%), as a yellow solid.

[0758] 11H NMR: (400 MHz, DMSO) δ: 13.42 (s, 1H), 11.08 (s, 1H), 10.28 (s, 1H), 8.67 (s, 1H), 8.23 (d, J = 5.3 Hz, 1H), 8.15 (s, 1H), 7.67 - 7.58 (m, 2H), 7.56 - 7.50 (m, 1H), 7.28 (d, J = 13.6 Hz, 2H), 7.23 (d, J = 8.8 Hz, 1H), 7.16 (d, J = 5.4 Hz, 1H), 5.83 - 5.71 (m, 1H), 5.06 (dd, J = 5.4, 12.9 Hz, 1H), 4.12 (d, J = 12.0 Hz, 2H), 4.03 (d, J = 12.9 Hz, 2H), 3.44 (s, 3H), 3.01 - 2.82 (m, 5H), 2.72 - 2.55 (m, 5H), 2.40 - 2.33 (m, 2H), 2.20 (s, 3H), 2.17 (s, 2H), 2.06 - 1.97 (m, 1H), 1.94 - 1.71 (m, 7H), 1.56 (d, J = 6.4 Hz, 3H), 1.38 (s, 1H), 1.11 (d, J = 5.8 Hz, 10H).

[0759] Exemplary Synthesis of Exemplary Compound 3: N-[3-[2-[(3S,5R)-4-[2-[2-[4-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-5-yl]piperazin-1-yl]ethoxy]ethyl]-3,5-dimethylpiperazin-1-yl]-4-pyridinyl]-1H-indazol-5-yl]-4,5-dimethyl-7H-tetrazolo[1,5-a]pyrimidine-6-carboxamide

[0760] Step 1: (2R,6S)-4-(4-bromo-2-pyridinyl)-1-[2-(2,2-dimethoxyethoxy)ethyl]-2,6-dimethylpiperazine

[0761]

[0762] To a solution of (3R,5S)-1-(4-bromo-2-pyridyl)-3,5-dimethyl-piperazine (2g, 7.40 mmol, 1 eq) and 2-(2,2-dimethoxyethoxy)ethyl 4-methylbenzenesulfonate (2.3g, 7.56 mmol, 1.02 eq) in CH3CN (20 mL) was added DIEA (1.91g, 14.81 mmol, 2.58 mL, 2 eq) and KI (2.46g, 14.81 mmol, 2 eq). After addition, the reaction mixture was stirred at 120 °C for 16 h. LCMS (EB12-469-P1B) showed the desired MS. TLC (dichloromethane:methanol = 10:1) showed several new spots. After cooling, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0 to 100% ethyl acetate in petroleum ether) to afford (2R,6S)-4-(4-bromo-2-pyridyl)-1-[2-(2,2-dimethoxyethoxy)ethyl]-2,6-dimethyl-piperazine (2.1g, 4.79 mmol, yield 64.73%, purity 91.8%) as a yellow oil.

[0763] Step 2: (2R,6S)-1-[2-(2,2-Dimethoxyethoxy)ethyl]-2,6-dimethyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]piperazine

[0764]

[0765] To a solution of (2R,6S)-4-(4-bromo-2-pyridyl)-1-[2-(2,2-dimethoxyethoxy)ethyl]-2,6-dimethyl-piperazine (2.1g, 5.22 mmol, 1 eq) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.72g, 6.79 mmol, 1.3 eq) in dioxane (40 mL) was added KOAc (1.54g, 15.66 mmol, 3 eq) and Pd(dppf)Cl2 (381.93mg, 521.97 umol, 0.1 eq). After addition, the reaction mixture was stirred at 100 °C for 1 h under N2. LCMS (EB12-470-P1B1) showed the desired MS. The reaction mixture was filtered and concentrated under reduced pressure to afford (2R,6S)-1-[2-(2,2-dimethoxyethoxy)ethyl]-2,6-dimethyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]piperazine (3.8g, 4.98 mmol, yield 95.40%) as a brown oil.

[0766] Step 3: 3-[2-[(3R,5S)-4-[2-(2,2-dimethoxyethoxy)ethyl]-3,5-dimethyl-piperazin-1-yl]-4-pyridinyl]-5-nitro-1H-indazole

[0767]

[0768] (2R,6S)-1-[2-(2,2-dimethoxyethoxy)ethyl]-2,6-dimethyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinyl]piperazine (3.8 g, 4.98 mmol, 1 eq), 3-bromo-5-nitro-1H-indazole (1.81 g, 7.47 mmol, 1.5 eq), 4-di-tert-butylphosphino-N,N-dimethyl-aniline; dichloropalladium (352.66 mg, 498.05 μmol, 352.66 μL, 0.1 eq) and KOAc (1.47 g, 14.94 mmol, 3 eq) in a mixture of EtOH (30 mL) and H2O (6 mL) were stirred at 100 °C under N2 for 12 h. LCMS (EB12-473-P1B) showed the required MS. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0 - 15% methanol in dichloromethane solution) to afford 3-[2-[(3R,5S)-4-[2-(2,2-dimethoxyethoxy)ethyl]-3,5-dimethyl-piperazin-1-yl]-4-pyridinyl]-5-nitro-1H-indazole (2 g, 3.80 mmol, yield 76.24%, purity 92%) as a brown gum.

[0769] Step 4: 2-[2-[(2R,6S)-2,6-dimethyl-4-[4-(5-nitro-1H-indazol-3-yl)-2-pyridinyl]piperazin-1-yl]ethoxy]acetaldehyde

[0770]

[0771] To a solution of 3-[2-[(3R,5S)-4-[2-(2,2-dimethoxyethoxy)ethyl]-3,5-dimethylpiperazin-1-yl]-4-pyridinyl]-5-nitro-1H-indazole (700 mg, 1.44 mmol, 1 eq) in THF (5 mL) was added H2SO4 (2 M, 4 mL). After addition, the reaction solution was stirred at 70 °C for 1 h. TLC (dichloromethane:methanol = 10:1) showed consumption of the starting material and formation of a new spot. After cooling, the reaction was diluted with water (10 mL) and washed with ethyl acetate (2 x 10 mL). The aqueous phase was adjusted to pH = 14 with NaOH. The solid was collected by filtration. The solid was dried under reduced pressure to afford 2-[2-[(2R,6S)-2,6-dimethyl-4-[4-(5-nitro-1H-indazol-3-yl)-2-pyridinyl]piperazin-1-yl]ethoxy]acetaldehyde (500 mg, 1.04 mmol, yield 71.83%, purity 91%) as a yellow solid. The crude product was used directly in the next step.

[0772] Step 5: 5-[4-[2-[2-[(2R,6S)-2,6-dimethyl-4-[4-(5-nitro-1H-indazol-3-yl)-2-pyridinyl]piperazin-1-yl]ethoxy]ethyl]piperazin-1-yl]-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione

[0773]

[0774] To a solution of 2-[2-[(2R,6S)-2,6-dimethyl-4-[4-(5-nitro-1H-indazol-3-yl)-2-pyridinyl]piperazin-1-yl]ethoxy]acetaldehyde (250 mg, 570.15 μmol, 1 eq) and AcOH (525.00 mg, 8.74 mmol, 0.5 mL, 15.33 eq) in DCE (10 mL), MeOH (10 mL) and DMSO (2 mL) was added 2-(2,6-dioxo-3-piperidinyl)-5-piperazin-1-yl-isoindoline-1,3-dione (390.30 mg, 1.14 mmol, 2.00 eq) and NaOAc (140.32 mg, 1.71 mmol, 3 eq). The reaction solution was stirred at 25 °C for 30 min. Then NaBH3CN (107.49 mg, 1.71 mmol, 3 eq) was added and the reaction was stirred at 25 °C for 12 h. LCMS (EB12-480-P1D2) showed the desired MS. TLC (dichloromethane:methanol = 10:1) showed several new spots. The reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0 to 15% methanol in chloroform) to afford 5-[4-[2-[2-[(2R,6S)-2,6-dimethyl-4-[4-(5-nitro-1H-indazol-3-yl)-2-pyridinyl]piperazin-1-yl]ethoxy]ethyl]piperazin-1-yl]-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione (250 mg, 294.18 μmol, yield 51.60%, purity 90%) as a yellow solid.

[0775] Step 6: 5-[4-[2-[2-[(2R,6S)-4-[4-(5-amino-1H-indazol-3-yl)-2-pyridinyl]-2,6-dimethyl-piperazin-1-yl]ethoxy]ethyl]piperazin-1-yl]-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione

[0776]

[0777] To a mixture of 5-[4-[2-[2-[(2R,6S)-2,6-dimethyl-4-[4-(5-nitro-1H-indazol-3-yl)-2-pyridinyl]piperazin-1-yl]ethoxy]ethyl]piperazin-1-yl]-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione (250 mg, 326.87 μmol, 1 eq) in EtOH (3 mL) and H2O (0.5 mL) was added Fe (91.27 mg, 1.63 mmol, 5 eq) and NH4Cl (87.42 mg, 1.63 mmol, 5 eq). After addition, the reaction mixture was stirred at 80 °C for 1 h. LCMS (EB12-481-P1C1) showed the desired MS. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in 10% methanol in dichloromethane (10 mL). The mixture was filtered and the filtrate was concentrated under reduced pressure to afford 5-[4-[2-[2-[(2R,6S)-4-[4-(5-amino-1H-indazol-3-yl)-2-pyridinyl]-2,6-dimethyl-piperazin-1-yl]ethoxy]ethyl]piperazin-1-yl]-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione (140 mg, 188.23 μmol, yield 57.59%, purity 98.8%) as a yellow solid.

[0778] Step 7: N-[3-[2-[(3S,5R)-4-[2-[2-[4-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindolin-5-yl]piperazin-1-yl]ethoxy]ethyl]-3,5-dimethyl-piperazin-1-yl]-4-pyridinyl]-1H-indazol-5-yl]-4,5-dimethyl-7H-tetrazolo[1,5-a]pyrimidine-6-carboxamide (Compound 3)

[0779]

[0780] To a solution of 5-[4-[2-[2-[(2S,6R)-4-[4-(5-amino-1H-indazol-3-yl)-2-piperidinyl]-2,6-dimethyl-piperazin-1-yl]ethoxy]ethyl]piperazin-1-yl]-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione (140 mg, 190.52 μmol, 1 eq) and 4,5-dimethyl-7H-tetrazolo[1,5-a]pyrimidine-6-carboxylic acid (74.37 mg, 381.03 μmol, 2 eq) in DMF (2 mL) was added DIEA (123.11 mg, 952.58 μmol, 165.92 μL, 5 eq) and HATU (72.44 mg, 190.52 μmol, 1 eq). After addition, the reaction solution was stirred at 25 °C for 12 h. LCMS (EB12-482-P1D) showed the desired MS. The reaction solution was diluted 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 HPLC (column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 0%-40%; 35 min) to afford N-[3-[2-[(3S,5R)-4-[2-[2-[4-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-5-yl]piperazin-1-yl]ethoxy]ethyl]-3,5-dimethyl-piperazin-1-yl]-4-pyridinyl]-1H-indazol-5-yl]-4,5-dimethyl-7H-tetrazolo[1,5-a]pyrimidine-6-carboxamide (5.6 mg, 5.83 μmol, yield 3.06%, purity 95%) as a yellow solid.

[0781] 11H NMR: (400 MHz, CD3OD) δ: 8.65 (s, 1H), 8.40 (s, 1H), 8.17 (d, J = 5.3 Hz, 1H), 7.52 (d, J = 8.9 Hz, 1H), 7.38 - 7.32 (m, 2H), 7.24 (d, J = 5.3 Hz, 1H), 7.19 (d, J = 8.5 Hz, 1H), 6.93 (d, J = 2.1 Hz, 1H), 6.75 (dd, J = 2.1, 8.5 Hz, 1H), 5.30 (s, 2H), 5.02 (br dd, J = 5.5, 12.8 Hz, 1H), 4.53 (br t, J = 11.4 Hz, 2H), 3.92 - 3.81 (m, 4H), 3.67 (br t, J = 4.8 Hz, 2H), 3.55 (br s, 2H), 3.51 (s, 3H), 3.26 - 3.20 (m, 4H), 3.04 - 2.94 (m, 2H), 2.92 - 2.81 (m, 1H), 2.76 (br d, J = 2.8 Hz, 1H), 2.68 - 2.56 (m, 7H), 2.36 (s, 3H), 2.14 - 2.05 (m, 1H), 1.48 (br d, J = 5.4 Hz, 6H)

[0782] Exemplary Synthesis of Exemplary Compound 4: N-[3-[2-[(3S,5R)-4-[2-[2-[2-[4-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-5-yl]piperazin-1-yl]ethoxy]ethoxy]ethyl]-3,5-dimethylpiperazin-1-yl]-4-pyridinyl]-1H-indazol-5-yl]-4,5-dimethyl-7H-tetrazolo[1,5-a]pyrimidine-6-carboxamide. Compound 4 was prepared in a manner similar to Example 3.

[0783] 11H NMR: (400 MHz, MeOD) δ: 8.71 (s, 1H), 8.27 (d, J = 5.4 Hz, 1H), 7.55 - 7.48 (m, 2H), 7.41 (d, J = 8.5 Hz, 1H), 7.38 - 7.31 (m, 2H), 6.99 (d, J = 1.8 Hz, 1H), 6.87 (d, J = 8.5 Hz, 1H), 5.29 (s, 2H), 5.05 (dd, J = 5.4, 12.7 Hz, 1H), 4.55 (d, J = 13.9 Hz, 2H), 3.85 (d, J = 4.5 Hz, 2H), 3.79 - 3.53 (m, 10H), 3.51 (s, 3H), 3.22 (s, 4H), 3.05 - 2.93 (m, 2H), 2.91 - 2.51 (m, 9H), 2.34 (s, 3H), 2.16 - 2.07 (m, 1H), 1.49 (d, J = 6.3 Hz, 6H).

[0784] Exemplary synthesis of exemplary compound 5: N-[3-[2-[(3S,5R)-4-[2-[4-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-5-yl]piperazin-1-yl]ethyl]-3,5-dimethyl-piperazin-1-yl]-4-pyridinyl]-1H-indazol-5-yl]-4,5-dimethyl-7H-tetrazolo[1,5-a]pyrimidine-6-carboxamide

[0785] Step 1: tert-Butyl 4-[2-[(2R,6S)-4-(4-bromo-2-pyridinyl)-2,6-dimethyl-piperazin-1-yl]ethyl]piperazine-1-carboxylate

[0786]

[0787] Then, Cs2CO3 (5.43 g, 16.66 mmol, 3 eq) and KI (4.61 g, 27.76 mmol, 5.0 eq) were added to a solution of (3R,5S)-1-(4-bromo-2-pyridinyl)-3,5-dimethyl-piperazine (1.5 g, 5.55 mmol, 1 eq) and tert-butyl 4-(2-chloroethyl)piperazine-1-carboxylate (2.07 g, 8.33 mmol, 3.58 mL, 1.5 eq) in NMP (20 mL). The mixture was then stirred at 140 °C for 16 h. TLC (dichloromethane:methanol = 10:1, Rf = 0.5) showed a new spot. The residue was diluted with H2O (50 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (0 to 10% methanol in dichloromethane) to afford tert-butyl 4-[2-[(2R,6S)-4-(4-bromo-2-pyridinyl)-2,6-dimethyl-piperazin-1-yl]ethyl]piperazine-1-carboxylate (1.2 g, 2.26 mmol, yield 40.77%, purity 91%) as a yellow gum.

[0788] Step 2: Provide tert-butyl 4-[2-[(2R,6S)-2,6-dimethyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinyl]piperazin-1-yl]ethyl]piperazine-1-carboxylate

[0789]

[0790] To a solution of tert-butyl 4-[2-[(2R,6S)-4-(4-bromo-2-pyridinyl)-2,6-dimethylpiperazin-1-yl]ethyl]piperazine-1-carboxylate (1.2 g, 2.49 mmol, 1 eq) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.26 g, 4.97 mmol, 2 eq) in dioxane (10 mL) was added KOAc (732.30 mg, 7.46 mmol, 3 eq), Pd(dppf)Cl2 (182.00 mg, 248.73 μmol, 0.1 eq). The mixture was then stirred under N2 at 100 °C for 1 h. TLC (dichloromethane:methanol = 10:1, Rf = 0.3) showed a new spot for the reactants. The reaction mixture was filtered and concentrated under reduced pressure to afford tert-butyl 4-[2-[(2R,6S)-2,6-dimethyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinyl]piperazin-1-yl]ethyl]piperazine-1-carboxylate (1.3 g, crude), as a brown gum.

[0791] Step 3: tert-Butyl 4-(2-((2R,6S)-2,6-dimethyl-4-(4-(5-nitro-1H-indazol-3-yl)pyridin-2-yl)piperazin-1-yl)ethyl)piperazine-1-carboxylate

[0792]

[0793] To a solution of tert-butyl 4-(2-((2R,6S)-2,6-dimethyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazin-1-yl)ethyl)piperazine-1-carboxylate (1.3 g, 2.46 mmol, 1 eq) and 3-bromo-5-nitro-1H-indazole (713.03 mg, 2.95 mmol, 1.2 eq) in EtOH (10 mL) and H2O (2 mL) was added KOAc (722.83 mg, 7.37 mmol, 3 eq), 4-di-tert-butylphosphino-N,N-dimethyl-aniline; dichloropalladium (173.84 mg, 245.50 μmol, 173.84 μL, 0.1 eq). The mixture was then stirred at 100 °C under N2 for 2 h. TLC (dichloromethane:methanol = 10:1, Rf = 0.4) showed new spots for the reactants. The reaction mixture was poured into H2O (10 mL). The mixture was extracted with ethyl acetate (15 mL * 3). The organic phase was washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated in vacuo to give a residue. The residue was purified by silica gel column chromatography (0 to 15% methanol in dichloromethane) to give tert-butyl 4-(2-((2R,6S)-2,6-dimethyl-4-(4-(5-nitro-1H-indazol-3-yl)pyridin-2-yl)piperazin-1-yl)ethyl)piperazine-1-carboxylate (750 mg, 1.01 mmol, yield 41.12%, purity 76%) as a yellow solid.

[0794] Step 4: 3-[2-[(3S,5R)-3,5-dimethyl-4-(2-piperazin-1-ylethyl)piperazin-1-yl]-4-pyridinyl]-5-nitro-1H-indazole

[0795]

[0796] To a solution of tert-butyl 4-[2-[(2S,6R)-2,6-dimethyl-4-[4-(5-nitro-1H-indazol-3-yl)-2-pyridinyl]piperazin-1-yl]ethyl]piperazine-1-carboxylate (750 mg, 1.33 mmol, 1 eq) in DCM (10 mL) was added TFA (12.32 g, 108.05 mmol, 8 mL, 81.35 eq). After addition, the reaction solution was stirred at 20 °C for 1 h. LCMS (EB12-483-P1B) showed the desired MS. The reaction solution was diluted with water (50 mL) and washed with dichloromethane (2 x 30 mL). The aqueous phase was basified to pH ~14 with NaOH and extracted with ethyl acetate (3 x 50 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to afford 3-[2-[(3S,5R)-3,5-dimethyl-4-(2-piperazin-1-ylethyl)piperazin-1-yl]-4-pyridinyl]-5-nitro-1H-indazole (450 mg, 852.42 μmol, yield 64.18%, purity 88%) as a yellow solid.

[0797] Step 5: 5-[4-[2-[(2S,6R)-2,6-dimethyl-4-[4-(5-nitro-1H-indazol-3-yl)-2-pyridinyl]piperazin-1-yl]ethyl]piperazin-1-yl]-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione

[0798]

[0799] To a solution of 3-[2-[(3S,5R)-3,5-dimethyl-4-(2-piperazin-1-ylethyl)piperazin-1-yl]-4-pyridinyl]-5-nitro-1H-indazole (250 mg, 538.14 μmol, 1 eq) and 2-(2,6-dioxo-3-piperidinyl)-5-fluoro-isoindoline-1,3-dione (222.97 mg, 807.21 μmol, 1.5 eq) in DMSO (3 mL) was added DIEA (208.65 mg, 1.61 mmol, 281.20 μL, 3 eq). After addition, the reaction mixture was stirred at 100 °C for 12 h. LCMS (EB12-486-P1B1) showed the desired MS. TLC (dichloromethane:methanol = 10:1) showed several new spots. After cooling, the reaction solution was diluted with water (10 mL) and extracted with dichloromethane (3 x 10 mL). The organic layer was washed with brine (2 x 15 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0 to 10% methanol in dichloromethane) to afford 5-[4-[2-[(2S,6R)-2,6-dimethyl-4-[4-(5-nitro-1H-indazol-3-yl)-2-pyridinyl]piperazin-1-yl]ethyl]piperazin-1-yl]-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione (150 mg, 168.57 μmol, yield 31.32%, purity 81%) as a yellow solid.

[0800] Step 6: 5-[4-[2-[(2S,6R)-4-[4-(5-amino-1H-indazol-3-yl)-2-pyridinyl]-2,6-dimethyl-piperazin-1-yl]ethyl]piperazin-1-yl]-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione

[0801]

[0802] To a mixture of 5-[4-[2-[(2S,6R)-2,6-dimethyl-4-[4-(5-nitro-1H-indazol-3-yl)-2-pyridinyl]piperazin-1-yl]ethyl]piperazin-1-yl]-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione (150 mg, 208.11 μmol, 1 eq) in EtOH (3 mL) and H2O (0.5 mL) was added Fe (58.11 mg, 1.04 mmol, 5 eq) and NH4Cl (55.66 mg, 1.04 mmol, 5 eq). After addition, the reaction mixture was stirred at 80 °C for 1 h. LCMS (EB12-487-P1B1) showed the reaction was complete. After cooling, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. At 20 ℃The residue was triturated with 10% methanol in chloromethane for 15 min. The solid was removed by filtration and the filtrate was concentrated under reduced pressure to afford 5-[4-[2-[(2S,6R)-4-[4-(5-amino-1H-indazol-3-yl)-2-pyridinyl]-2,6-dimethyl-piperazin-1-yl]ethyl]piperazin-1-yl]-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione (70 mg, 89.17 μmol, yield 42.85%, purity 88%) as a yellow solid.

[0803] Step 7: N-[3-[2-[(3S,5R)-4-[2-[4-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-5-yl]piperazin-1-yl]ethyl]-3,5-dimethyl-piperazin-1-yl]-4-pyridinyl]-1H-indazol-5-yl]-4,5-dimethyl-7H-tetrazolo[1,5-a]pyrimidine-6-carboxamide (Compound 5)

[0804]

[0805] To a solution of 5-[4-[2-[(2S,6R)-4-[4-(5-amino-1H-indazol-3-yl)-2-piperidinyl]-2,6-dimethyl-piperazin-1-yl]ethyl]piperazin-1-yl]-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione (130 mg, 188.19 μmol, 1 eq) and 4,5-dimethyl-7H-tetrazolo[1,5-a]pyrimidine-6-carboxylic acid (37.14 mg, 190.30 μmol, 1.01 eq) in DMF (2 mL) was added DIEA (72.97 mg, 564.57 μmol, 98.34 μL, 3 eq) and HATU (71.56 mg, 188.19 μmol, 1 eq). After addition, the reaction solution was stirred at 25 °C for 18 h. LCMS (EB12-489-P1B72) showed the desired MS. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (3 x 5 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 150*25 mm*10 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 0 - 30%; 35 min) to afford N-[3-[2-[(3S,5R)-4-[2-[4-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindolin-5-yl]piperazin-1-yl]ethyl]-3,5-dimethyl-piperazin-1-yl]-4-pyridinyl]-1H-indazol-5-yl]-4,5-dimethyl-7H-tetrazolo[1,5-a]pyrimidine-6-carboxamide (10.7 mg, 12.26 μmol, yield 6.51%, purity 99.42%), as a yellow solid.

[0806] 11H NMR: (400 MHz, methanol-d4) δ: 8.69 (s, 1H), 8.41 (br s, 1H), 8.28 (d, J = 5.3 Hz, 1H), 7.54 - 7.47 (m, 2H), 7.45 (s, 1H), 7.36 (d, J = 6.6 Hz, 2H), 7.15 (s, 1H), 7.01 (br d, J = 6.9 Hz, 1H), 5.29 (s, 2H), 5.08 (dd, J = 5.5, 12.4 Hz, 1H), 4.59 (s, 3H), 4.43 (br s, 2H), 3.51 (s, 4H), 3.27 (br s, 4H), 3.02 (br t, J = 12.6 Hz, 2H), 2.93 - 2.82 (m, 1H), 2.80 - 2.75 (m, 1H), 2.75 - 2.69 (m, 3H), 2.66 (br t, J = 4.7 Hz, 4H), 2.35 (s, 3H), 2.19 - 2.05 (m, 1H), 1.44 (br d, J = 4.9 Hz, 6H)

[0807] Exemplary synthesis of Exemplary Compound 6: N-(3-{2-[(3R,5S)-4-{[1-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-4-yl}methyl)piperidin-4-yl]methyl}-3,5-dimethylpiperazin-1-yl]pyridin-4-yl}-1H-indazol-5-yl)-4,5,7,7-tetramethyl-4H,7H-[1,2,3,4]tetrazolo[1,5-a]pyrimidine-6-carboxamide

[0808] Exemplary Compound 6 was prepared using Intermediate 3 in a manner similar to the preparation of Exemplary Compound 1.

[0809]

[0810] Step 1:

[0811] To a mixture of methyl 3-oxobutanoate (29 g, 249.75 mmol, 26.85 mL, 1 eq), ZnCl2 (5.11 g, 37.46 mmol, 1.75 mL, 0.15 eq), and acetone (21.76 g, 374.63 mmol, 27.54 mL, 1.5 eq) was added dropwise AC2O (33.15 g, 324.68 mmol, 30.41 mL, 1.3 eq) in one portion. The mixture was stirred at 50 °C for 48 h to give a yellow solution. TLC (petroleum ether:ethyl acetate = 10:1, Rf = 0.4) showed no starting material and showed new spots. The residue was diluted with H2O (200 mL) and extracted with ethyl acetate (200 mL × 3). The combined organic layers were washed with brine (75 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (0 to 10% ethyl acetate in petroleum ether) to give methyl 2-acetyl-3-methyl-but-2-enoate (18 g, 73.76 mmol, yield 29.53%, purity 64%) as a colorless oil.

[0812]

[0813] Step 2:

[0814] To a mixture of methyl 2-acetyl-3-methyl-but-2-enoate (18 g, 115.25 mmol, 1 eq) and 1H-tetrazol-5-amine (9.80 g, 115.25 mmol, 1 eq) in EtOH (50 mL) was added molecular sieve (10 g, 115.25 mmol, 1 eq) at 20 °C under N2. The mixture was stirred at 50 °C for 16 h to give a yellow solution. TLC (petroleum ether:ethyl acetate = 10:1, Rf = 0.1) showed no starting material and showed new spots. The reaction mixture was filtered and concentrated under reduced pressure. The crude product was poured into H2O (100 mL). The mixture was extracted with ethyl acetate (150 mL * 3). The organic phase was washed with brine (80 mL), dried over anhydrous Na2SO4, and concentrated in vacuo to give a residue. The residue was purified by silica gel column chromatography (0 to 30% ethyl acetate in petroleum ether) to give methyl 5,7,7-trimethyl-4H-tetrazolo[1,5-a]pyrimidine-6-carboxylate (11 g, 48.29 mmol, yield 41.90%, purity 98%) as a white solid.

[0815]

[0816] Step 3:

[0817] At 20 °C under N2, methyl 5,7,7-trimethyl-4H-tetrazolo[1,5-a]pyrimidine-6-carboxylate (11 g, 49.28 mmol, 1 eq) in MeCN (100 mL) was added MeI (11.71 g, 82.50 mmol, 5.14 mL, 1.67 eq) and Cs2CO3 (19.27 g, 59.13 mmol, 1.2 eq) in one portion. The mixture was stirred at 50 °C for 1 h to obtain a yellow solution. The residue was diluted with H2O (200 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (85 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain methyl 4,5,7,7-tetramethyltetrazolo[1,5-a]pyrimidine-6-carboxylate (11 g, crude), as a yellow solid.

[0818]

[0819] Step 4:

[0820] To a mixture of methyl 4,5,7,7-tetramethyltetrazolo[1,5-a]pyrimidine-6-carboxylate (640 mg, 2.70 mmol, 1 eq) in THF (5 mL) at 20 °C was added LiOH (129.33 mg, 5.40 mmol, 2 eq) in H2O (5 mL). The mixture was stirred at 50 °C for 16 h to obtain a yellow solution. TLC (petroleum ether: ethyl acetate = 0:1, Rf = 0.04) showed no starting material. The THF was evaporated and the H2O solution was acidified to pH = 3 with 1 M HCl, extracted with EtOAc, dried over Na2SO4, filtered and concentrated under reduced pressure to obtain 4,5,7,7-tetramethyltetrazolo[1,5-a]pyrimidine-6-carboxylic acid (424 mg, crude), as a white solid.

[0821]

[0822] Step 5:

[0823] At 25 °C under N2, DIEA (48.66 mg, 376.49 μmol, 65.58 μL, 3 eq) and HATU (47.72 mg, 125.50 μmol, 1 eq) were added in one portion to a mixture of 5-[4-[[4-[[(2R,6S)-4-[4-(5-amino-1H-indazol-3-yl)-2-pyridinyl]-2,6-dimethyl-piperazin-1-yl]methyl]-1-piperidinyl]methyl]-1-piperidinyl]-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione (97 mg, 125.50 μmol, 1 eq) and 4,5,7,7-tetramethyltetrazolo[1,5-a]pyrimidine-6-carboxylic acid (45.68 mg, 188.24 μmol, purity 92%, 1.5 eq) in DMF (5 mL). The mixture was stirred at 25 °C for 16 h to give a yellow solution. LCMS showed the desired product. The residue was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: 3_Phenomenex Luna C18 75*30mm*3um; mobile phase: [water (0.1M FA NH4)-ACN]; B%: 0%-30%, 40 min) to afford N-[3-[2-[(3R,5S)-4-[[1-[[1-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindoline-5-yl]-4-piperidinyl]methyl]-4-piperidinyl]methyl]-3,5-dimethyl-piperazin-1-yl]-4-pyridinyl]-1H-indazol-5-yl]-4,5,7,7-tetramethyl-tetrazolo[1,5-a]pyrimidine-6-carboxamide (36.1 mg, 36.18 μmol, yield 28.83%, purity 98.04%) as a yellow solid.

[0824] Exemplary synthesis of Exemplary Compound 8: (7R)-N-(3-{2-[(3S)-4-{[1-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-4-yl}methyl)piperidin-4-yl]methyl}-3-methylpiperazin-1-yl]pyridin-4-yl}-1H-indazol-5-yl)-4,5,7-trimethyl-4H,7H-[1,2,3,4]tetrazolo[1,5-a]pyrimidine-6-carboxamide

[0825] Exemplary Compound 8 was prepared in a manner similar to Exemplary Compound 1 using the enantiomer 2 of 4,5,7-trimethyl-7H-tetrazolo[1,5-a]pyrimidine-6-carboxylic acid.

[0826]

[0827] Step 1:

[0828] The product 4,5,7-trimethyl-7H-tetrazolo[1,5-a]pyrimidine-6-carboxylic acid (9.5 g, 45.41 mmol, 1 eq) was separated by SFC (column: DAICEL CHIRALPAK IC (250 mm * 30 mm, 10 μm); conditions: 0.1% NH₃H₂O in ethanol; initial B: 20; final B: 20; flow rate: 100 mL / min) to obtain the enantiomer 1 designated as (7S)-4,5,7-trimethyl-7H-tetrazolo[1,5-a]pyrimidine-6-carboxylic acid (4.68 g, 22.15 mmol, yield 48.77%, purity 99%) (Rt = 3.080 min, 4.68 g), and the enantiomer 2 designated as (7R)-4,5,7-trimethyl-7H-tetrazolo[1,5-a]pyrimidine-6-carboxylic acid (4.1 g, 19.40 mmol, yield 42.73%, purity 99%) (Rt = 3.258 min, 4.1 g). Both enantiomers are off-white solids.

[0829] Enantiomer 1: Randomly designated as (7S)-4,5,7-trimethyl-7H-tetrazolo[1,5-a]pyrimidine-6-carboxylic acid (4.68 g, 22.15 mmol, yield 48.77%, purity 99%), obtained as an off-white solid (analytical chiral HPLC: ee% = 100%, 4.11 min, α = -211).

[0830] Enantiomer 2: Randomly designated as (7R)-4,5,7-trimethyl-7H-tetrazolo[1,5-a]pyrimidine-6-carboxylic acid (4.1 g, 19.40 mmol, yield 42.73%, purity 99%), obtained as an off-white solid (analytical chiral HPLC: ee% = 100%, 4.68 min, α = 266).

[0831] Exemplary synthesis of exemplary compound 9: (7S)-N-(3-{2-[(3S)-4-{[1-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-4-yl}methyl)piperidin-4-yl]methyl}-3-methylpiperazin-1-yl]pyridin-4-yl}-1H-indazol-5-yl)-4,5,7-trimethyl-4H,7H-[1,2,3,4]tetrazolo[1,5-a]pyrimidine-6-carboxamide

[0832] Exemplary compound 9 was prepared in a manner similar to exemplary compound 8 using enantiomer 1 of 4,5,7-trimethyl-7H-tetrazolo[1,5-a]pyrimidine-6-carboxylic acid.

[0833] Exemplary Synthesis of Exemplary Compound 10: N-(3-{2-[(3S)-4-{[1-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-4-yl}methyl)piperidin-4-yl]methyl}-3-methylpiperazin-1-yl]pyridin-4-yl}-1H-indazol-5-yl)-4,5-dimethyl-4H,7H-[1,2,3,4]tetrazolo[1,5-a]pyrimidine-6-carboxamide

[0834] Exemplary Compound 10 was prepared in a manner similar to Exemplary Compound 1 using Intermediate 1.

[0835] Exemplary Synthesis of Exemplary Compound 11: (7R)-N-{3-[2-(4-{[1-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-4-yl}methyl)piperidin-4-yl]methyl}piperazin-1-yl)pyridin-4-yl]-1H-indazol-5-yl}-4,5,7-trimethyl-4H,7H-[1,2,3,4]tetrazolo[1,5-a]pyrimidine-6-carboxamide

[0836] Exemplary Compound 11 was prepared in a manner similar to Exemplary Compound 1 using the enantiomer 2 of 4,5,7-trimethyl-7H-tetrazolo[1,5-a]pyrimidine-6-carboxylic acid.

[0837] Exemplary Synthesis of Exemplary Compound 12: (7S)-N-{3-[2-(4-{[1-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-4-yl}methyl)piperidin-4-yl]methyl}piperazin-1-yl)pyridin-4-yl]-1H-indazol-5-yl}-4,5,7-trimethyl-4H,7H-[1,2,3,4]tetrazolo[1,5-a]pyrimidine-6-carboxamide

[0838] Exemplary Compound 12 was prepared in a manner similar to Exemplary Compound 1 using the enantiomer 1 of 4,5,7-trimethyl-7H-tetrazolo[1,5-a]pyrimidine-6-carboxylic acid.

[0839] Exemplary Synthesis of Exemplary Compound 13: N-{3-[2-(4-{[1-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-4-yl}methyl)piperidin-4-yl]methyl}piperazin-1-yl)pyridin-4-yl]-1H-indazol-5-yl}-4,5-dimethyl-4H,7H-[1,2,3,4]tetrazolo[1,5-a]pyrimidine-6-carboxamide

[0840] In a manner similar to that of Exemplary Compound 1, Exemplary Compound 13 was prepared using Intermediate 1.

[0841] Exemplary synthesis of Exemplary Compound 14: (7R)-N-{3-[2-(4-{2-[1-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-4-yl}methyl)piperidin-4-yl]ethyl}piperazin-1-yl)pyridin-4-yl]-1H-indazol-5-yl}-4,5,7-trimethyl-4H,7H-[1,2,3,4]tetrazolo[1,5-a]pyrimidine-6-carboxamide

[0842]

[0843] Step 1:

[0844] To a solution of 4-(2,2-dimethoxyethyl)piperidine (118.67 mg, 684.97 μmol, 1.2 eq) and methyl 4-methylbenzenesulfonate [1-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-5-yl]-4-piperidinyl] (300 mg, 570.81 μmol, 1 eq) was added DIEA (737.71 mg, 5.71 mmol, 994.22 μL, 10 eq), KI (947.54 mg, 5.71 mmol, 10 eq) in MeCN (10 mL). The mixture was then stirred at 100 °C under N2 for 2 h. The residue was diluted with 20 mL of H2O and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with 15 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (0 to 10% methanol in dichloromethane) to obtain 5-[4-[[4-(2,2-dimethoxyethyl)-1-piperidinyl]methyl]-1-piperidinyl]-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione (280 mg, 515.74 μmol, yield 90.35%, purity 97%) as a yellow solid.

[0845]

[0846] Step 2:

[0847] To a solution of 5-[4-[[4-(2,2-dimethoxyethyl)-1-piperidinyl]methyl]-1-piperidinyl]-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione (280 mg, 531.69 μmol, 1 eq) in THF (2 mL) was added HCl (2 M, 1.51 mL, 5.69 eq), and the mixture was stirred at 25 °C for 1 h. The reaction mixture was poured into H2O (20 mL) and basified with aqueous NaHCO3 until pH = 8. The mixture was extracted with ethyl acetate (20 mL × 5) and dried over anhydrous Na2SO4, and concentrated in vacuo to give 2-[1-[[1-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-5-yl]-4-piperidinyl]methyl]-4-piperidinyl]acetaldehyde (250 mg, crude), as a yellow solid.

[0848]

[0849] Step 3:

[0850] To a solution of 2-[1-[[1-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-5-yl]-4-piperidinyl]methyl]-4-piperidinyl]acetaldehyde (250 mg, 520.23 μmol, 1 eq) and 5-nitro-3-(2-piperazin-1-yl-4-pyridinyl)-1H-indazole (178.57 mg, 550.57 μmol, 1.06 eq) in DCM (20 mL) and MeOH (30 mL) was added AcOH (3.12 mg, 52.02 μmol, 2.98 μL, 0.1 eq), and the mixture was stirred at 20 °C for 20 min. Then NaBH3CN (98.07 mg, 1.56 mmol, 3 eq) was added to the solution and the mixture was stirred at 20 °C for 16 h. TLC (dichloromethane:methanol = 5:1, Rf = 0.2) showed no starting material and showed new spots. The residue was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (0 to 50% methanol in dichloromethane) to give 2-(2,6-dioxo-3-piperidinyl)-5-[4-[[4-[2-[4-[4-(5-nitro-1H-indazol-3-yl)-2-pyridinyl]piperazin-1-yl]ethyl]-1-piperidinyl]methyl]-1-piperidinyl]isoindoline-1,3-dione (400 mg, 344.79 μmol, yield 66.28%, purity 68%), as a yellow solid.

[0851]

[0852] Step 4:

[0853] To a solution of 2-(2,6-dioxo-3-piperidinyl)-5-[4-[[4-[2-[4-[4-(5-nitro-1H-indazol-3-yl)-2-pyridinyl]piperazin-1-yl]ethyl]-1-piperidinyl]methyl]-1-piperidinyl]isoindoline-1,3-dione (400 mg, 507.04 μmol, 1 eq) in EtOH (10 mL) and H2O (5 mL) was added NH4Cl (135.61 mg, 2.54 mmol, 5 eq), Fe (141.58 mg, 2.54 mmol, 5 eq). The mixture was then stirred at 90 °C under N2 for 1 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (Phenomenex luna C18 100*40 mm*3 μm: water (0.05% NH3H2O + 10 mM NH4HCO3)-ACN; B%: 18%-48%, 10 min) to afford 5-[4-[[4-[2-[4-[4-(5-amino-1H-indazol-3-yl)-2-pyridinyl]piperazin-1-yl]ethyl]-1-piperidinyl]methyl]-1-piperidinyl]-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione (76 mg, 96.74 μmol, yield 19.08%, purity 96.6%) as a yellow solid.

[0854]

[0855] Step 5:

[0856] A solution of 5-[4-[[4-[2-[4-[4-(5-amino-1H-indazol-3-yl)-2-pyridinyl]piperazin-1-yl]ethyl]-1-piperidinyl]methyl]-1-piperidinyl]-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione (45 mg, 59.30 μmol, 1 eq) and (7R)-4,5,7-trimethyl-7H-tetrazolo[1,5-a]pyrimidine-6-carboxylic acid (12.40 mg, 59.30 μmol, 1 eq) in DMF (2 mL) was stirred at 20 °C for 10 minutes, then DIEA (38.32 mg, 296.48 μmol, 51.64 μL, 5 eq) and HATU (27.06 mg, 71.15 μmol, 1.2 eq) were added. The mixture was then stirred at 70 °C under N2 for 3 hours. LCMS showed the MS of the desired product. The residue was purified by preparative HPLC (column: 3_Phenomenex Luna C18 75*30 mm*3 μm; mobile phase: water (0.225% FA)-ACN; B%: 0%-30%, 35 min) to give (7R)-N-[3-[2-[4-[2-[1-[[1-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindolin-5-yl]-4-piperidinyl]methyl]-4-piperidinyl]ethyl]piperazin-1-yl]-4-pyridinyl]-1H-indazol-5-yl]-4,5,7-trimethyl-7H-tetrazolo[1,5-a]pyrimidine-6-carboxamide (14.9 mg, 15.52 μmol, yield 26.18%, purity 98.98%), as a yellow solid.

[0857] Exemplary synthesis Exemplary compound 15: (7R)-N-(3-{2-[4-(3-{4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}propyl)piperazin-1-yl]pyridin-4-yl}-1H-indazol-5-yl}-4,5,7-trimethyl-4H,7H-[1,2,3,4]tetrazolo[1,5-a]pyrimidine-6-carboxamide

[0858]

[0859] Step 1:

[0860] To a solution of 2-(2,6-dioxo-3-piperidinyl)-5-piperazin-1-ylisoindoline-1,3-dione (500 mg, 1.10 mmol, 1 eq, TFA) and 1-chloro-3-iodopropane (1.12 g, 5.48 mmol, 589.42 μL, 5 eq) in CH3CN (5 mL) was added K2CO3 ((151.42 mg, 1.10 mmol, 1 eq). After addition, the reaction mixture was stirred at 20 °C for 1 h. TLC showed a new spot. The residue was poured into water (5 mL) and stirred for 5 min. The aqueous phase was extracted with ethyl acetate (5 mL × 3). The combined organic phases were washed with brine (5 mL × 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (4 g, Rf = 0.43, silica gel 100 - 200 mesh, 0 - 70% (10 min) ethyl acetate in petroleum ether, 70% (10 min) ethyl acetate in petroleum ether) to afford 5-[4-(3-chloropropyl)piperazin-1-yl]-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione (260 mg, 564.85 μmol, yield 51.56%, purity 91%) as a yellow gum.

[0861]

[0862] Step 2:

[0863] At 20 °C under N2, KI (37.61 mg, 226.55 μmol, 2 eq) and DIPEA (29.28 mg, 226.55 μmol, 39.46 μL, 2 eq) were added in one portion to a mixture of (7R)-4,5,7-trimethyl-N-[3-(2-piperazin-1-ylpyridin-4-yl)-1H-indazol-5-yl]-7H-tetrazolo[1,5-a]pyrimidine-6-carboxamide (55 mg, 113.28 μmol, 1 eq) and 5-[4-(3-chloropropyl)piperazin-1-yl]-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (47.45 mg, 113.28 μmol, 1 eq) in MeCN (5 mL). The mixture was stirred at 80 °C for 10 h. LCMS showed approximately 78% of the desired MS. 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 phases were washed with brine (5 mL × 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by reverse-phase HPLC (column: 3_Phenomenex Luna C18 75 × 30 mm × 3 μm; conditions: water (0.2% FA)-ACN; initial B: 0; end B: 30; flow rate: 25 mL / min; gradient time: 35 min; 100% B hold time: 3 min) to give (7R)-N-[3-[2-[4-[3-[4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl]piperazin-1-yl]propyl]piperazin-1-yl]pyridin-4-yl]-1H-indazol-5-yl]-4,5,7-trimethyl-7H-tetrazolo[1,5-a]pyrimidine-6-carboxamide (19.5 mg, 21.34 μmol, yield 18.84%, purity 95%) as a yellow solid.

[0864] Exemplary Synthesis Exemplary Compound 17: (7R)-N-[3-(2-{4-[(1-{1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-4-yl}azetidin-3-yl)methyl]piperazin-1-yl}pyridin-4-yl)-1H-indazol-5-yl]-4,5,7-trimethyl-4H,7H-[1,2,3,4]tetrazolo[1,5-a]pyrimidine-6-carboxamide

[0865]

[0866] Step 1:

[0867] To a solution of tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate (7.6 g, 40.59 mmol, 1 eq) in DCM (80 mL) was added HCl / MeOH (4 M, 38.00 mL, 3.74 eq), and the mixture was stirred at 25 °C for 2 h. TLC (petroleum ether:ethyl acetate = 1:2, KMnO4, Plate 1) showed the formation of a new spot and complete consumption of the starting material. The reaction mixture was concentrated under reduced pressure to remove DCM and HCl / MeOH to give a residue. The crude product was used in the next step without further purification. Compound azetidin-3-ylmethanol (5.7 g, crude, HCl) was obtained as a pale yellow liquid.

[0868]

[0869] Step 2:

[0870] To a solution of azetidin-3-ylmethanol (2 g, 16.18 mmol, 1 eq, HCl) and tert-butyl 4-oxopiperidine-1-carboxylate (4.84 g, 24.28 mmol, 1.5 eq) in DCM (10 mL) and MeOH (2 mL) was added AcONa (6.64 g, 80.92 mmol, 5 eq) and HOAc (1.94 g, 32.37 mmol, 1.85 mL, 2 eq) over 30 min, and after mixing, NaBH3CN (3.05 g, 48.55 mmol, 3 eq) was added. The mixture was then stirred at 25 °C for 16 h. TLC (methanol:dichloromethane = 1:10, I2, Plate 1) showed the formation of a new spot and retention of the starting material. The reaction mixture was concentrated under reduced pressure to remove DCM. The residue was diluted with 40 mL of water and extracted with EA (30 mL * 4). The combined organic layers were washed with brine (60 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica chromatography ( 40 g Silica Flash Column, eluent 0–10% methanol / dichloromethane ether gradient @ 60 mL / min) to give tert-butyl 4-[3-(hydroxymethyl)azetidin-1-yl]piperidine-1-carboxylate (2.2 g, 8.14 mmol, yield 50.28%) as a colorless gum.

[0871]

[0872] Step 3:

[0873] To a solution of tert-butyl 4-[3-(hydroxymethyl)azetidin-1-yl]piperidine-1-carboxylate (2.2 g, 8.14 mmol, 1 eq) in MeOH (10 mL) was added HCl / dioxane (4 M, 10 mL). After addition, the reaction mixture was stirred at 20 °C for 2 h. LCMS showed the desired mass (Rt = 0.220 min). The reaction mixture was concentrated under reduced pressure to give [1-(4-piperidyl)azetidin-3-yl]methanol (1.8 g, crude, HCl) as a white solid. The crude product was used directly in the next step.

[0874]

[0875] Step 4:

[0876] To a solution of [1-(4-piperidyl)azetidin-3-yl]methanol (1.7 g, 8.22 mmol, 1 eq, HCl) in DMSO (20 mL) was added 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (2.27 g, 8.22 mmol, 1 eq) and DIEA (3.19 g, 24.67 mmol, 4.30 mL, 3 eq). After addition, the reaction solution was stirred at 100 °C for 2 h. LCMS showed the desired mass. After cooling, the reaction mixture was diluted with water (100 mL) and extracted with 10% methanol in dichloromethane (5 x 150 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0 to 20% methanol in dichloromethane) to give 2-(2,6-dioxopiperidin-3-yl)-5-[4-[3-(hydroxymethyl)azetidin-1-yl]-1-piperidyl]isoindoline-1,3-dione (1.4 g, 3.05 mmol, yield 37.12%, purity 93%) as a yellow solid.

[0877]

[0878] Step 5:

[0879] To a solution of 2-(2,6-dioxo-3-piperidinyl)-5-[4-[3-(hydroxymethyl)azetidin-1-yl]-1-piperidinyl]isoindoline-1,3-dione (1.2 g, 2.81 mmol, 1 eq) in DCM (15 mL) was added TosCl (1.07 g, 5.63 mmol, 2 eq), DMAP (34.38 mg, 281.38 μmol, 0.1 eq) and TEA (854.19 mg, 8.44 mmol, 1.17 mL, 3 eq). After addition, the reaction mixture was stirred at 20 °C for 16 h. LCMS showed the desired MS. The reaction mixture was diluted with water (30 mL) and extracted with dichloromethane (3 x 20 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0 to 6% methanol in dichloromethane) to afford methyl 4-methylbenzenesulfonate [1-[1-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-5-yl]-4-piperidinyl]azetidin-3-yl] ester (460 mg, 741.51 μmol, yield 26.35%, purity 93.6%) as a yellow solid.

[0880]

[0881] Step 6:

[0882] To a solution of methyl 4-methylbenzenesulfonate [1-[1-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-5-yl]-4-piperidinyl]azetidin-3-yl] ester (77 mg, 132.61 μmol, 1.07 eq) and (7R)-4,5,7-trimethyl-N-[3-(2-piperazin-1-ylpyridin-4-yl)-1H-indazol-5-yl]-7H-tetrazolo[1,5-a]pyrimidine-6-carboxamide (60 mg, 123.57 μmol, 1 eq) in CH3CN (2 mL) was added KI (41.03 mg, 247.15 μmol, 2 eq) and DIEA (31.94 mg, 247.15 μmol, 43.05 μL, 2 eq). After addition, the reaction mixture was stirred at 80 °C for 16 h. LCMS showed the desired mass. After cooling, the reaction mixture was filtered and the filter cake was washed with DMSO (2 mL). The filtrate was purified by preparative HPLC (column: 3_Phenomenex Luna C18 75*30mm*3um; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 30%-60%; 35 min) to give (7R)-N-[3-[2-[4-[[1-[1-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-5-yl]-4-piperidinyl]azetidin-3-yl]methyl]piperazin-1-yl]-4-pyridinyl]-1H-indazol-5-yl]-4,5,7-trimethyl-7H-tetrazolo[1,5-a]pyrimidine-6-carboxamide (9.5 mg, 10.50 μmol, yield 8.50%, purity 98.81%) as a yellow solid.

[0883] Exemplary synthesis of Exemplary Compound 18: (7R)-N-(3-{2-[4-({1'-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]-[1,4'-bipiperidin]-4-yl}methyl)piperazin-1-yl]pyridin-4-yl}-1H-indazol-5-yl}-4,5,7-trimethyl-4H,7H-[1,2,3,4]tetrazolo[1,5-a]pyrimidine-6-carboxamide

[0884]

[0885] Step 1:

[0886] To a solution of 5-nitro-3-(2-piperazin-1-ylpyridin-4-yl)-1H-indazole (1 g, 3.08 mmol, 1 eq) and tert-butyl 4-formylpiperidine-1-carboxylate (723.32 mg, 3.39 mmol, 1.1 eq) in MeOH (10 mL) and HOAc (1 mL) was added borane; 2-methylpyridine (659.57 mg, 6.17 mmol, 2 eq). After addition, the reaction mixture was stirred at 30 °C for 2 h. LCMS showed the required mass. The reaction mixture was diluted with water (30 mL) and basified to pH 12 with solid NaOH. The mixture was then filtered to obtain a filter cake. The residue was purified by silica gel column chromatography (0 to 10% methanol in dichloromethane) to give tert-butyl 4-[[4-[4-(5-nitro-1H-indazol-3-yl)-2-pyridinyl]piperazin-1-yl]methyl]piperidine-1-carboxylate (1.6 g, 2.99 mmol, yield 97.04%, purity 97.54%) as a yellow solid.

[0887]

[0888] Step 2:

[0889] To a solution of tert-butyl 4-[[4-[4-(5-nitro-1H-indazol-3-yl)-2-pyridinyl]piperazin-1-yl]methyl]piperidine-1-carboxylate (1.6 g, 3.07 mmol, 1 eq) in MeOH (10 mL) was added HCl / dioxane (4 M, 10 mL, 13.04 eq). After addition, the reaction solution was stirred at 20 °C for 16 h. LCMS showed the required mass. The reaction was concentrated under reduced pressure. The resulting material was dissolved in water (50 mL) and neutralized to pH 7 with solid NaOH. The solid was collected by filtration to afford 5-nitro-3-[2-[4-(piperidin-4-ylmethyl)piperazin-1-yl]-4-pyridinyl]-1H-indazole (860 mg, crude) as a yellow solid. The crude product was used directly in the next step.

[0890]

[0891] Step 3:

[0892] To a solution of 5-nitro-3-[2-[4-(4-piperidinylmethyl)piperazin-1-yl]-4-pyridinyl]-1H-indazole (860 mg, 2.04 mmol, 1 eq) and tert-butyl 4-oxopiperidine-1-carboxylate (2.03 g, 10.20 mmol, 5 eq) in MeOH (50 mL) and HOAc (5 mL) was added borane; 2-methylpyridine (654.72 mg, 6.12 mmol, 3 eq). After addition, the reaction solution was stirred at 35 °C for 12 h. LCMS showed the desired MS. The reaction was diluted with water (100 mL) and washed with ethyl acetate (100 mL). The aqueous phase was basified to pH 14 with solid KOH and extracted with ethyl acetate (3 x 50 mL). The aqueous phase was filtered to collect the solid. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0 to 50% methanol in dichloromethane) to afford tert-butyl 4-[4-[[4-[4-(5-nitro-1H-indazol-3-yl)-2-pyridinyl]piperazin-1-yl]methyl]-1-piperidinyl]piperidine-1-carboxylate (750 mg, 1.14 mmol, yield 55.88%, purity 91.94%) as a yellow solid.

[0893]

[0894] Step 4:

[0895] To a solution of tert-butyl 4-[4-[[4-[4-(5-nitro-1H-indazol-3-yl)-2-pyridinyl]piperazin-1-yl]methyl]-1-piperidinyl]piperidine-1-carboxylate (750 mg, 1.24 mmol, 1 eq) in DCM (5 mL) was added TFA (3.08 g, 27.01 mmol, 2 mL, 21.78 eq). After addition, the reaction was stirred at 20 °C for 1 h. LCMS showed the desired MS. The reaction mixture was concentrated under reduced pressure to afford 5-nitro-3-[2-[4-[[1-(4-piperidinyl)-4-piperidinyl]methyl]piperazin-1-yl]-4-pyridinyl]-1H-indazole (900 mg, crude, TFA) as a yellow gum. The crude product was used directly in the next step.

[0896]

[0897] Step 5:

[0898] To a solution of 5-nitro-3-[2-[4-[[1-(4-piperidinyl)-4-piperidinyl]methyl]piperazin-1-yl]-4-pyridinyl]-1H-indazole (900 mg, 1.45 mmol, 1 eq, TFA) and 2-(2,6-dioxo-3-piperidinyl)-5-fluoro-isoindoline-1,3-dione (602.76 mg, 2.18 mmol, 1.5 eq) in DMSO (10 mL) was added DIEA (940.08 mg, 7.27 mmol, 1.27 mL, 5 eq). After addition, the reaction mixture was stirred at 100 °C for 12 h. LCMS showed the desired MS. After cooling, the reaction solution was diluted with water (100 mL). The solid was collected by filtration and dried under reduced pressure to give 2-(2,6-dioxo-3-piperidinyl)-5-[4-[4-[[4-[4-(5-nitro-1H-indazol-3-yl)-2-pyridinyl]piperazin-1-yl]methyl]-1-piperidinyl]-1-piperidinyl]isoindoline-1,3-dione (800 mg, 862.21 μmol, yield 59.27%, purity 82%) as a yellow solid. The crude product was used directly in the next step.

[0899]

[0900] Step 6:

[0901] To a mixture of 2-(2,6-dioxo-3-piperidinyl)-5-[4-[4-[[4-[4-(5-nitro-1H-indazol-3-yl)-2-pyridinyl]piperazin-1-yl]methyl]-1-piperidinyl]-1-piperidinyl]isoindoline-1,3-dione (400 mg, 525.74 μmol, 1 eq) in EtOH (3 mL) and H2O (0.5 mL) were added Fe (146.80 mg, 2.63 mmol, 5 eq) and NH4Cl (140.61 mg, 2.63 mmol, 5 eq). After addition, the reaction mixture was stirred at 80 °C for 2 h. LCMS showed the desired MS. After cooling, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The resulting residue was dissolved in DMSO (10 mL), and then water (80 mL) was added. The solid was collected by filtration. The solid was dried under reduced pressure to afford 5-[4-[4-[[4-[4-(5-amino-1H-indazol-3-yl)-2-pyridinyl]piperazin-1-yl]methyl]-1-piperidinyl]-1-piperidinyl]-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione (130 mg, 125.40 μmol, yield 23.85%, purity 70.5%) as a yellow solid.

[0902]

[0903] Step 7:

[0904] To a solution of (7R)-4,5,7-trimethyl-7H-tetrazolo[1,5-a]pyrimidine-6-carboxylic acid (37.21 mg, 177.87 μmol, 1 eq) and 5-[4-[4-[[4-[4-(5-amino-1H-indazol-3-yl)-2-pyridinyl]piperazin-1-yl]methyl]-1-piperidinyl]methyl]-1-piperidinyl]-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione (130 mg, 177.87 μmol, 1 eq) in DMF (2 mL) was added DIEA (68.97 mg, 533.62 μmol, 92.94 μL, 3 eq) and HATU (67.63 mg, 177.87 μmol, 1 eq). After addition, the reaction solution was stirred at 25 °C for 16 h. LCMS showed the desired MS. The reactants were filtered and the filter cake was washed with DMSO (1 mL). The filtrate was purified by preparative HPLC (column: 3_Phenomenex Luna C18 75*30 mm*3 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 0-30%; 35 min) to give (7R)-N-[3-[2-[4-[[1-[1-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindolin-5-yl]-4-piperidinyl]-4-piperidinyl]methyl]piperazin-1-yl]-4-pyridinyl]-1H-indazol-5-yl]-4,5,7-trimethyl-7H-tetrazolo[1,5-a]pyrimidine-6-carboxamide (10.7 mg, 11.45 μmol, yield 6.44%, purity 98.66%) as a yellow solid.

[0905] Exemplary synthesis of Exemplary Compound 20: (7R)-N-[3-(2-{4-[2-(2-{6-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]-2,6-diazaspiro[3.3]heptan-2-yl}ethoxy)ethyl]piperazin-1-yl}pyridin-4-yl)-1H-indazol-5-yl]-4,5,7-trimethyl-4H,7H-[1,2,3,4]tetrazolo[1,5-a]pyrimidine-6-carboxamide

[0906] Exemplary Compound 20 was prepared in a manner similar to Exemplary Compound 3.

[0907] Exemplary Synthesis of Exemplary Compound 21: (7S)-N-{3-[2-(4-{2-[4-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-4-yl}methyl)piperazin-1-yl]ethyl}piperazin-1-yl)pyridin-4-yl]-1H-indazol-5-yl}-4,5,7-trimethyl-4H,7H-[1,2,3,4]tetrazolo[1,5-a]pyrimidine-6-carboxamide

[0908]

[0909] Step 1:

[0910] To a solution of 5-nitro-3-(2-piperazin-1-ylpyridin-4-yl)-1H-indazole (500 mg, 1.54 mmol, 1 eq) and tert-butyl 4-(2-chloroethyl)piperazine-1-carboxylate (500 mg, 2.01 mmol, 1.3 eq) in CH3CN (10 mL) were added KI (511.82 mg, 3.08 mmol, 2 eq) and DIEA (398.48 mg, 3.08 mmol, 537.04 uL, 2 eq). After addition, the reaction mixture was stirred at 80 °C for 3 h. LCMS showed the desired MS. After cooling, the reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (3 x 10 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0 to 10% methanol in dichloromethane) to afford tert-butyl 4-[2-[4-[4-(5-nitro-1H-indazol-3-yl)pyridin-2-yl]piperazin-1-yl]ethyl]piperazine-1-carboxylate (303 mg, 558.99 umol, yield 36.26%, purity 99%) as a yellow solid.

[0911]

[0912] Step 2:

[0913] To a solution of tert-butyl 4-[2-[4-[4-(5-nitro-1H-indazol-3-yl)-2-pyridinyl]piperazin-1-yl]ethyl]piperazine-1-carboxylate (303 mg, 564.64 μmol, 1 eq) in DCM (3 mL) was added TFA (770.00 mg, 6.75 mmol, 0.5 mL, 11.96 eq). After addition, the reaction mixture was stirred at 20 °C for 1 h. LCMS showed that the reactant had been consumed and the desired MS was detected. The reaction mixture was concentrated in vacuo. The residue was dissolved in DCM (2 mL) and treated with DIEA (1 mL). The mixture was concentrated under reduced pressure to afford 5-nitro-3-[2-[4-(2-piperazin-1-ylethyl)piperazin-1-yl]-4-pyridinyl]-1H-indazole (240 mg, crude), as a yellow solid. The crude product was used directly in the next step.

[0914]

[0915] Step 3:

[0916] To a solution of 5-nitro-3-[2-[4-(2-piperazin-1-ylethyl)piperazin-1-yl]-4-pyridinyl]-1H-indazole (240 mg, 549.82 μmol, 1 eq) and 1-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-5-yl]piperidine-4-carbaldehyde (203.09 mg, 549.82 μmol, 1 eq) in MeOH (10 mL) and HOAc (1 mL) was added borane; 2-methylpyridine (117.62 mg, 1.10 mmol, 2 eq). After addition, the reaction solution was stirred at 20 °C for 2 h. LCMS showed that the starting materials had been consumed and the desired MS was detected. The reaction mixture was diluted with water (20 mL) and extracted with dichloromethane (3 x 15 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0 to 40% methanol in dichloromethane) to afford 2-(2,6-dioxo-3-piperidinyl)-5-[4-[[4-[2-[4-[4-(5-nitro-1H-indazol-3-yl)-2-pyridinyl]piperazin-1-yl]ethyl]piperazin-1-yl]methyl]-1-piperidinyl]isoindoline-1,3-dione (445 mg, 523.38 μmol, yield 95.19%, purity 92.9%), as a yellow solid.

[0917]

[0918] Step 4:

[0919] To a solution of 2-(2,6-dioxo-3-piperidinyl)-5-[4-[[4-[2-[4-[4-(5-nitro-1H-indazol-3-yl)-2-pyridinyl]piperazin-1-yl]ethyl]piperazin-1-yl]methyl]-1-piperidinyl]isoindoline-1,3-dione (445 mg, 563.38 μmol, 1 eq) in EtOH (5 mL) and H2O (1 mL) was added Fe (157.31 mg, 2.82 mmol, 5 eq) and NH4Cl (150.68 mg, 2.82 mmol, 5 eq). After addition, the reaction mixture was stirred at 80 °C for 1 h. LCMS showed the desired MS. After cooling, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was triturated with 10% methanol in dichloromethane at 20 °C for 10 min. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure to afford 5-[4-[[4-[2-[4-[4-(5-amino-1H-indazol-3-yl)-2-pyridinyl]piperazin-1-yl]ethyl]piperazin-1-yl]methyl]-1-piperidinyl]-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione (120 mg, 138.97 μmol, yield 24.67%, purity 88%) as a yellow solid.

[0920]

[0921] Step 5:

[0922] To a solution of 5-[4-[[4-[2-[4-[4-(5-amino-1H-indazol-3-yl)-2-pyridinyl]piperazin-1-yl]ethyl]piperazin-1-yl]methyl]-1-piperidinyl]-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione (55 mg, 72.38 μmol, 1 eq) and (7S)-4,5,7-trimethyl-7H-tetrazolo[1,5-a]pyrimidine-6-carboxylic acid (17 mg, 81.26 μmol, 1.12 eq) in DMF (2 mL) was added DIEA (46.77 mg, 361.89 μmol, 63.03 μL, 5 eq) and HATU (27.52 mg, 72.38 μmol, 1 eq). After addition, the reaction mixture was stirred at 25 °C for 12 h. LCMS showed the desired MS. The reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (3 x 15 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: 3_Phenomenex Luna C18 75*30mm*3um; mobile phase: [water (0.225% FA)-ACN]; B%: 0 - 35%; 35 min) to afford (7S)-N-[3-[2-[4-[2-[4-[[1-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindolin-5-yl]-4-piperidinyl]methyl]piperazin-1-yl]ethyl]piperazin-1-yl]-4-pyridinyl]-1H-indazol-5-yl]-4,5,7-trimethyl-7H-tetrazolo[1,5-a]pyrimidine-6-carboxamide (12.8 mg, 13.11 μmol, yield 18.11%, purity 97.40%) as a yellow solid.

[0923] Exemplary synthesis of Exemplary Compound 22: (7R)-N-{3-[2-(4-{2-[1-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-4-yl}methyl)piperidin-4-yl]-2,2-difluoroethyl}piperazin-1-yl)pyridin-4-yl]-1H-indazol-5-yl}-4,5,7-trimethyl-4H,7H-[1,2,3,4]tetrazolo[1,5-a]pyrimidine-6-carboxamide

[0924] Exemplary Compound 22 was prepared in a manner similar to Exemplary Compound 1, using tert-butyl 4-[2-[4-(4-bromo-2-pyridinyl)piperazin-1-yl]-1,1-difluoroethyl]piperidine-1-carboxylate.

[0925]

[0926] Step 1:

[0927] Stir a solution of tert-butyl 4-(2-bromoacetyl)piperidine-1-carboxylate (2.78 g, 9.08 mmol, 1 eq) in MeCN (10 mL) at 20 °C. Then add benzyl piperazine-1-carboxylate (2 g, 9.08 mmol, 1.75 mL, 1 eq) to the mixture and stir at 20 °C under N2 for 16 h. TLC (dichloromethane:methanol = 10:1, Rf = 0.6) showed no starting material and showed a new spot. Dilute the residue with H2O (200 mL) and extract with ethyl acetate (70 mL × 3). Wash the combined organic layers with brine (80 mL), dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure to obtain a residue. Purify the residue by silica gel column chromatography (0 to 10% dichloromethane in methanol) to obtain benzyl 4-[2-(1-tert-butoxycarbonyl-4-piperidyl)-2-oxo-ethyl]piperazine-1-carboxylate (1.9 g, 3.84 mmol, yield 42.27%, purity 90%) as a yellow gum.

[0928]

[0929] Step 2:

[0930] Stir a solution of benzyl 4-[2-(1-tert-butoxycarbonyl-4-piperidyl)-2-oxo-ethyl]piperazine-1-carboxylate (1.9 g, 4.26 mmol, 1 eq) in DCM (30 mL) at 0 °C for 20 min. Then add DAST (24.06 g, 149.25 mmol, 19.72 mL, 35 eq) to the mixture and stir at 20 °C under N2 for 16 h. TLC (petroleum ether:ethyl acetate = 1:1, Rf = 0.5) showed no starting material and showed a new spot. Cool the reaction mixture to 0 °C and quench with an aqueous solution of NaHCO3 (200 mL), and extract with ethyl acetate (100 mL × 2). Wash the combined organic layers with brine (45 mL), dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure to obtain a residue. Purify the residue by silica gel column chromatography (0 to 50% ethyl acetate in petroleum ether) to obtain benzyl 4-[2-(1-tert-butoxycarbonyl-4-piperidyl)-2,2-difluoro-ethyl]piperazine-1-carboxylate (1.4 g, 2.55 mmol, yield 59.68%, purity 85%) as a colorless gum.

[0931]

[0932] Step 3:

[0933] To a solution of benzyl 4-[2-(1-tert-butoxycarbonylpiperidin-4-yl)-2,2-difluoroethyl]piperazine-1-carboxylate (1.4 g, 2.99 mmol, 1 eq) in EtOH (10 mL) and EtOAc (10 mL), then Pd / C (0.2 g, 299.43 μmol, purity 10%, 0.1 eq) was added to the mixture and stirred at 25 °C under H2 (15 PSI) for 16 h. TLC (petroleum ether:ethyl acetate = 1:1, Rf = 0.01) showed no starting material and showed new spots. The reaction mixture was filtered and concentrated under reduced pressure to give tert-butyl 4-(1,1-difluoro-2-piperazin-1-ylethyl)piperidine-1-carboxylate (900 mg, crude), as a colorless gum.

[0934]

[0935] Step 4:

[0936] To a solution of tert-butyl 4-(1,1-difluoro-2-piperazin-1-ylethyl)piperidine-1-carboxylate (900 mg, 2.70 mmol, 1 eq), 4-bromo-2-fluoropyridine (500 mg, 2.84 mmol, 1.05 eq) and K2CO3 (746.15 mg, 5.40 mmol, 2 eq) in DMSO (15 mL). Then the mixture was stirred at 100 °C under N2 for 4 h. TLC (petroleum ether:ethyl acetate = 3:1, Rf = 0.5) showed no starting material and showed new spots. The residue was diluted with H2O (50 mL) and extracted with ethyl acetate (60 mL × 3). The combined organic layers were washed with 40 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (0 to 30% ethyl acetate in petroleum ether) to give tert-butyl 4-[2-[4-(4-bromo-2-pyridyl)piperazin-1-yl]-1,1-difluoroethyl]piperidine-1-carboxylate (1 g, 1.94 mmol, yield 71.91%, purity 95%), as a white solid.

[0937] Exemplary synthesis of exemplary compound 23: (7R)-N-{3-[2-(4-{2-[4-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-4-yl}methyl)piperidin-1-yl]ethyl}piperazin-1-yl)pyridin-4-yl]-1H-indazol-5-yl}-4,5,7-trimethyl-4H,7H-[1,2,3,4]tetrazolo[1,5-a]pyrimidine-6-carboxamide

[0938] The enantiomer 2 of 4,5,7-trimethyl-7H-tetrazolo[1,5-a]pyrimidine-6-carboxylic acid was used to prepare the exemplary compound 23 in a manner similar to that of the exemplary compound 21.

[0939]

[0940] Step 1:

[0941] To a solution of tert-butyl 4-methylenepiperidine-1-carboxylate (6.24 g, 31.65 mmol, 1 eq) at 25 °C was added 9-BBN (0.5 M, 63.29 mL, 1 eq). The reaction mixture was stirred at 80 °C under N2 for 1 h. After cooling, 4-bromopyridine (5 g, 31.65 mmol, 1 eq), Pd(dppf)Cl2 (1.39 g, 1.90 mmol, 0.06 eq), K2CO3 (6.56 g, 47.47 mmol, 1.5 eq), DMF (50 mL) and H2O (5 mL) were added to the reactants. The resulting mixture was heated to 60 °C for 12 h. LCMS showed the desired MS. After cooling, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The organic layer was washed with brine (2 x 100 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0 to 40% ethyl acetate in petroleum ether) to afford tert-butyl 4-(pyridin-4-ylmethyl)piperidine-1-carboxylate (3.49 g, 11.66 mmol, yield 36.83%, purity 92.3%) as a pale yellow oil.

[0942]

[0943] Step 2:

[0944] To a solution of tert-butyl 4-(pyridin-4-ylmethyl)piperidine-1-carboxylate (3.49 g, 12.63 mmol, 1 eq) in EtOH (50 mL) and HOAc (758.33 mg, 12.63 mmol, 722.21 uL, 1 eq) at 25 °C was added PtO2 (430.12 mg, 1.89 mmol, 0.15 eq). Then the mixture was stirred at 70 °C under H2 (50 psi) for 24 h. TLC (PE:EA = 1:1) showed consumption of the starting material and formation of a new spot. After cooling, the reactant was filtered and the filtrate was concentrated under reduced pressure to afford tert-butyl 4-(piperidin-4-ylmethyl)piperidine-1-carboxylate (3.9 g, crude) as a brown oil.

[0945]

[0946] Step 3:

[0947] To a solution of tert-butyl 4-(4-piperidinylmethyl)piperidine-1-carboxylate (3.7 g, 13.10 mmol, 1.21 eq) and 2-(2,6-dioxo-3-piperidinyl)-5-fluoro-isoindoline-1,3-dione (3 g, 10.86 mmol, 1 eq) in DMSO (40 mL) was added DIEA (5.61 g, 43.44 mmol, 7.57 mL, 4 eq). After addition, the reaction mixture was stirred at 100 °C for 2 h. TLC (petroleum ether:ethyl acetate = 1:1) showed a new spot. After cooling, the reaction was diluted with ethyl acetate (200 mL) and washed with brine (3 x 100 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0 to 50% ethyl acetate in petroleum ether) to afford tert-butyl 4-[[1-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindolin-5-yl]-4-piperidinyl]methyl]piperidine-1-carboxylate (2.86 g, 4.41 mmol, yield 40.58%, purity 83%) as a yellow solid.

[0948] Exemplary synthesis of Exemplary Compound 24: (7R)-N-[3-(2-{4-[1-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-4-yl}methyl)azetidin-3-yl]piperazin-1-yl}pyridin-4-yl)-1H-indazol-5-yl]-4,5,7-trimethyl-4H,7H-[1,2,3,4]tetrazolo[1,5-a]pyrimidine-6-carboxamide

[0949]

[0950] Step 1:

[0951] A solution of tert-butyl 3-oxoazetidine-1-carboxylate (170 mg, 993.03 μmol, 1 eq) and 5-nitro-3-(2-piperazin-1-ylpyridin-4-yl)-1H-indazole (305.97 mg, 943.38 μmol, 0.95 eq) in HOAc (1 mL) and MeOH (10 mL) was stirred at 20 °C for 20 minutes, and then borane; 2-methylpyridine (212.43 mg, 1.99 mmol, 2 eq) was added. The mixture was then stirred at 30 °C under N2 for 16 hours. TLC (dichloromethane:methanol = 10:1, Rf = 0.3) showed no starting material and showed a new spot. The residue was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (0 to 20% dichloromethane in methanol) to give tert-butyl 3-[4-[4-(5-nitro-1H-indazol-3-yl)pyridin-2-yl]piperazin-1-yl]azetidine-1-carboxylate (460 mg, 774.13 μmol, yield 77.96%, purity 80.7%) as a yellow solid.

[0952]

[0953] Step 2:

[0954] TFA (4.25 g, 37.28 mmol, 2.76 mL, 38.86 eq) was added to a solution of tert-butyl 3-[4-[4-(5-nitro-1H-indazol-3-yl)pyridin-2-yl]piperazin-1-yl]azetidine-1-carboxylate (460 mg, 959.27 μmol, 1 eq) in DCM (3 mL), and the mixture was then stirred at 20 °C for 1 hour. TLC (dichloromethane:methanol = 5:1, Rf = 0.01) showed no starting material and showed a new spot. The residue was concentrated under reduced pressure to give 3-[2-[4-(azetidin-3-yl)piperazin-1-yl]pyridin-4-yl]-5-nitro-1H-indazole (360 mg, crude, TFA) as a yellow solid.

[0955]

[0956] Step 3:

[0957] A solution of 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4-carbaldehyde (292.06 mg, 790.69 μmol, 1 eq) and 3-(2-(4-(azetidin-3-yl)piperazin-1-yl)pyridin-4-yl)-5-nitro-1H-indazole (300.00 mg, 790.69 μmol, 1 eq) in HOAc (1 mL) and MeOH (20 mL) was stirred at 20 °C for 20 minutes, and then borane; 2-methylpyridine (169.15 mg, 1.58 mmol, 2 eq) was added. The mixture was then stirred under N2 at 30 °C for 16 hours. TLC (dichloromethane:methanol = 5:1, Rf = 0.1) showed no starting material and showed a new spot. The residue was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (0 to 50% dichloromethane in methanol) to give 2-(2,6-dioxopiperidin-3-yl)-5-(4-((3-(4-(4-(5-nitro-1H-indazol-3-yl)pyridin-2-yl)piperazin-1-yl)azetidin-1-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione (360 mg, 412.67 μmol, yield 52.19%, purity 84%) as a yellow solid.

[0958]

[0959] Step 4:

[0960] To a solution of 2-(2,6-dioxo-3-piperidinyl)-5-[4-[[3-[4-[4-(5-nitro-1H-indazol-3-yl)-2-pyridinyl]piperazin-1-yl]azetidin-1-yl]methyl]-1-piperidinyl]isoindoline-1,3-dione (360 mg, 491.28 μmol, 1 eq) in EtOH (10 mL) and H2O (5 mL) was added Fe (137.18 mg, 2.46 mmol, 5 eq), NH4Cl (131.39 mg, 2.46 mmol, 5 eq). The mixture was then stirred at 90 °C under N2 for 1 h. LCMS showed the desired product. The residue was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (Phenomenex Gemini-NX 150*30 mm*5 μm; water (0.05% HCl)-ACN; B%: 10%-40%, 10 min) to afford 5-[4-[[3-[4-[4-(5-amino-1H-indazol-3-yl)-2-pyridinyl]piperazin-1-yl]azetidin-1-yl]methyl]-1-piperidinyl]-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione (177 mg, 231.70 μmol, yield 47.16%, purity 92%) as a yellow solid.

[0961]

[0962] Step 5:

[0963] A solution of 5-[4-[[3-[4-[4-(5-amino-1H-indazol-3-yl)-2-pyridinyl]piperazin-1-yl]azetidin-1-yl]methyl]-1-piperidinyl]-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione (78 mg, 110.98 μmol, 1 eq) and (7R)-4,5,7-trimethyl-7H-tetrazolo[1,5-a]pyrimidine-6-carboxylic acid (23.22 mg, 110.98 μmol, 1 eq) in DMF (4 mL) was stirred at 20 °C for 10 minutes, then DIEA (71.72 mg, 554.92 μmol, 96.65 μL, 5 eq) and HATU (42.20 mg, 110.98 μmol, 1 eq) were added. The mixture was then stirred under N2 at 30 °C for 16 h. LCMS showed the desired product. The residue was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: 3_Phenomenex Luna C18 75*30 mm*3 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 0%-30%, 35 min) to give (7R)-N-[3-[2-[4-[1-[[1-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-5-yl]-4-piperidinyl]methyl]azetidin-3-yl]piperazin-1-yl]-4-pyridinyl]-1H-indazol-5-yl]-4,5,7-trimethyl-7H-tetrazolo[1,5-a]pyrimidine-6-carboxamide (19.1 mg, 21.21 μmol, yield 19.11%, purity 99.27%), as a yellow solid.

[0964] Exemplary synthesis of exemplary compound 25: (7R)-N-{3-[2-(4-{2-[4-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-4-yl}methyl)piperazin-1-yl]ethyl}piperazin-1-yl)pyridin-4-yl]-1H-indazol-5-yl}-4,5,7-trimethyl-4H,7H-[1,2,3,4]tetrazolo[1,5-a]pyrimidine-6-carboxamide

[0965]

[0966] Step 1:

[0967] To a solution of tert-butyl 4-(2-chloroethyl)piperazine-1-carboxylate (200 mg, 804.02 μmol, 1 eq) in DCM (2 mL) was added TFA (3.08 g, 27.01 mmol, 2 mL, 33.60 eq), and the mixture was then stirred at 20 °C for 1 h. TLC (dichloromethane:methanol = 10:1, Rf = 0.02) showed no starting material and showed a new spot. The residue was concentrated under reduced pressure to give 1-(2-chloroethyl)piperazine (119 mg, crude, TFA), as a colorless oil.

[0968]

[0969] Step 2:

[0970] A solution of 1-(2-chloroethyl)piperazine (119 mg, 800.63 μmol, 1 eq) and 1-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-5-yl]piperidine-4-carbaldehyde (295.73 mg, 800.63 μmol, 1 eq) in HOAC (1 mL) and MeOH (10 mL) was stirred at 20 °C for 20 min, and then borane; 2-methylpyridine (171.27 mg, 1.60 mmol, 2 eq) was added. The mixture was then stirred under N2 at 30 °C for 16 h. TLC (dichloromethane:methanol = 10:1, Rf = 0.3) showed no starting material and showed a new spot. The residue was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (0 to 25% dichloromethane in methanol) to give 5-[4-[[4-(2-chloroethyl)piperazin-1-yl]methyl]-1-piperidinyl]-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione (390 mg, 769.12 μmol, yield 96.06%, purity 99%), as a yellow solid.

[0971]

[0972] Step 3:

[0973] A solution of (7R)-4,5,7-trimethyl-N-[3-(2-piperazin-1-ylpyridin-4-yl)-1H-indazol-5-yl]-7H-tetrazolo[1,5-a]pyrimidine-6-carboxamide (40 mg, 82.38 μmol, 1 eq), 5-[4-[[4-(2-chloroethyl)piperazin-1-yl]methyl]piperidin-1-yl]-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (45 mg, 89.64 μmol, 1.09 eq), DIEA (106.47 mg, 823.82 μmol, 143.49 μL, 10 eq) and KI (136.75 mg, 823.82 μmol, 10 eq) in MeCN (10 mL). The mixture was then stirred at 80 °C under N2 for 4 h. LCMS showed the desired product. The residue was diluted with H2O (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: 3_Phenomenex Luna C18 75*30mm*3um; mobile phase: [water (0.225% FA)-ACN]; B%: 0%-30%, 35 min) to give (7R)-N-[3-[2-[4-[2-[4-[[1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl]piperidin-4-yl]methyl]piperazin-1-yl]ethyl]piperazin-1-yl]pyridin-4-yl]-1H-indazol-5-yl]-4,5,7-trimethyl-7H-tetrazolo[1,5-a]pyrimidine-6-carboxamide (8.8 mg, 9.04 μmol, yield 10.97%, purity 97.66%), as a yellow solid.

[0974] Exemplary synthesis of exemplary compound 26: (7R)-N-(3-{2-[6-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-4-yl}methyl)-2,6-diazaspiro[3.3]heptan-2-yl]pyridin-4-yl}-1H-indazol-5-yl)-4,5,7-trimethyl-4H,7H-[1,2,3,4]tetrazolo[1,5-a]pyrimidine-6-carboxamide

[0975]

[0976] Step 1:

[0977] At 100 °C under N2, K2CO3 (2.36 g, 17.04 mmol, 70.14 mL, 3 eq) was added in one portion to a mixture of 4-bromo-2-fluoropyridine (1 g, 5.68 mmol, 1 eq) and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate; oxalic acid (1.38 g, 2.84 mmol, 0.5 eq) in DMSO (10 mL). The mixture was stirred at 100 °C for 2 h to obtain a yellow solution. TLC and LCMS showed that the reaction was complete. 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 * 4). 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 (petroleum ether:ethyl acetate = 10:1, Rf = 0.56, 12 g, 0 - 50% (10 min) ethyl acetate in petroleum ether, 50% (5 min) ethyl acetate in petroleum ether) to give tert-butyl 6-(4-bromopyridin-2-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (1.3 g, 3.67 mmol, yield 64.61%), as a white solid.

[0978]

[0979] Step 2:

[0980] At 25 °C under N2, KOAc (1.58 g, 16.12 mmol, 3 eq) was added in one portion to a mixture of 2-[(3-bromo-5-nitroindazol-1-yl)methoxy]ethyl-trimethyl-silane (2 g, 5.37 mmol, 1 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (2.05 g, 8.06 mmol, 1.5 eq) and Pd(dppf)Cl2 (196.54 mg, 268.61 μmol, 0.05 eq) in dioxane (20 mL). The mixture was stirred at 100 °C for 1 h. TLC showed that the reaction was complete. The mixture was cooled to 25 °C, filtered and concentrated in vacuo to give [5-nitro-1-(2-trimethylsilylethoxymethyl)indazol-3-yl]boronic acid (1.8 g, crude), as a dark brown solid. The crude product was used in the next step without purification.

[0981]

[0982] Step 3:

[0983] At 25 °C under N2, potassium acetate (KOAc, 1.08 g, 11.01 mmol, 3 eq) was added in one portion to a solution of tert-butyl 6-(4-bromo-2-pyridyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (1.3 g, 3.67 mmol, 1 eq), [5-nitro-1-(2-trimethylsilylethoxymethyl)indazol-3-yl]boronic acid (1.73 g, 5.14 mmol, 1.4 eq), and 4-di-tert-butylphosphino-N,N-dimethylaniline; palladium(II) dichloride (259.85 mg, 366.98 μmol, 259.85 μL, 0.1 eq) in EtOH (10 mL) and H2O (4 mL). The mixture was stirred at 100 °C for 2 h. LCMS showed completion of the reaction. The mixture was cooled to 20 °C and concentrated under reduced pressure. 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, 0 - 40% (10 min) ethyl acetate in petroleum ether, 40% (10 min) ethyl acetate in petroleum ether) to afford tert-butyl 6-[4-[5-nitro-1-(2-trimethylsilylethoxymethyl)indazol-3-yl]-2-pyridyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (1.2 g, 2.12 mmol, 57.70% yield) as a yellow solid.

[0984]

[0985] Step 4:

[0986] To a mixture of tert-butyl 6-[4-[5-nitro-1-(2-trimethylsilylethoxymethyl)-1H-indazol-3-yl]-2-pyridinyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (600 mg, 1.06 mmol, 1 eq) in DCM (5 mL) was added TFA (362.16 mg, 3.18 mmol, 235.17 μL, 3 eq) in one portion at 20 °C. The mixture was stirred at 20 °C for 2 h. To the mixture was added dioxane (10 mL) and NH₃·H₂O (556.55 mg, 6.35 mmol, 611.60 μL, purity 40%, 6 eq) in one portion at 20 °C. The mixture was stirred at 20 °C for 2 h. LCMS showed the reaction was complete. The residue was poured into water (5 mL), and the aqueous phase was extracted with DCM (5 mL × 3). The combined organic phases were washed with brine (5 mL × 2), dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo to give 3-[2-(2,6-diazaspiro[3.3]heptan-2-yl)-4-pyridinyl]-5-nitro-1H-indazole (300 mg, 561.92 μmol, yield 53.08%, purity 63%) as a yellow solid.

[0987]

[0988] Step 5:

[0989] At 20 °C under N2, CH3COOH (53.56 mg, 891.94 μmol, 51.01 μL, 1 eq) and borane; 2-methylpyridine (190.80 mg, 1.78 mmol, 2 eq) were added in one portion to a mixture of 3-[2-(2,6-diazaspiro[3.3]heptan-2-yl)-4-pyridinyl]-5-nitro-1H-indazole (300 mg, 891.94 μmol, 1 eq) and 1-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-5-yl]piperidine-4-carbaldehyde (329.45 mg, 891.94 μmol, 1 eq) in MeOH (10 mL). The mixture was stirred at 30 °C for 16 h. LCMS showed the required MS. 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 (dichloromethane:methanol = 10:1, Rf = 0.32, 0 - 10% (10 min) methanol in dichloromethane, 10% (5 min) methanol in dichloromethane) to give 2-(2,6-dioxo-3-piperidinyl)-5-[4-[[2-[4-(5-nitro-1H-indazol-3-yl)-2-pyridinyl]-2,6-diazaspiro[3.3]heptan-6-yl]methyl]-1-piperidinyl]isoindoline-1,3-dione (600 mg, 565.45 μmol, yield 63.40%, purity 65%) as a yellow gum.

[0990]

[0991] Step 6:

[0992] At 20 °C under N2, NH4Cl (232.67 mg, 4.35 mmol, 5 eq) was added in one portion to a mixture of 2-(2,6-dioxo-3-piperidinyl)-5-[4-[[2-[4-(5-nitro-1H-indazol-3-yl)-2-pyridinyl]-2,6-diazaspiro[3.3]heptan-6-yl]methyl]-1-piperidinyl]isoindoline-1,3-dione (600 mg, 869.92 μmol, 1 eq) and Fe (242.90 mg, 4.35 mmol, 5 eq) in EtOH (10 mL), H2O (5 mL) and DCM (5 mL). The mixture was stirred at 80 °C for 30 minutes. LCMS showed the reaction was complete. The residue was filtered with ethyl acetate (10 mL * 5) and the solution was concentrated in vacuo. The crude product was purified by reverse phase HPLC (column: YMC-Triart Prep C18 150 * 40 mm * 7 μm; conditions: water (0.05% HCl)-ACN; initial B: 5; end B: 35; flow rate: 60 mL / min; gradient time: 25 min; 100% B hold time: 2 min) to obtain 5-(4-((6-(4-(5-amino-1H-indazol-3-yl)pyridin-2-yl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (110 mg, 166.07 μmol, yield 19.09%, purity 99.6%), as a yellow solid.

[0993]

[0994] Step 7:

[0995] A solution of (7R)-4,5,7-trimethyl-7H-tetrazolo[1,5-a]pyrimidine-6-carboxylic acid (34.88 mg, 166.73 μmol, 1 eq) and 5-[4-[[2-[4-(5-amino-1H-indazol-3-yl)-2-pyridinyl]-2,6-diazaspiro[3.3]heptan-6-yl]methyl]-1-piperidinyl]-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione (110 mg, 166.73 μmol, 1 eq) in DMF (2 mL) was stirred at 0 °C for 10 minutes, then DIPEA (107.74 mg, 833.67 μmol, 145.21 μL, 5 eq) and HATU (63.40 mg, 166.73 μmol, 1 eq) were added. The mixture was then stirred at 25 °C under N2 for 16 hours. LCMS showed the desired MS. The residue was poured into water (2 mL). The aqueous phase was extracted with ethyl acetate (2 mL * 3). The combined organic phases were washed with brine (2 mL * 2), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by reverse-phase HPLC (column: 3_Phenomenex Luna C18 75 * 30 mm * 3 μm; conditions: water (0.225% FA)-ACN; initial B: 0; end B: 30; flow rate: 25 mL / min; gradient time: 35 minutes; 100% B hold time: 3 minutes) to give (7R)-N-[3-[2-[6-[[1-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxo-isoindolin-5-yl]-4-piperidinyl]methyl]-2,6-diazaspiro[3.3]heptan-2-yl]-4-pyridinyl]-1H-indazol-5-yl]-4,5,7-trimethyl-7H-tetrazolo[1,5-a]pyrimidine-6-carboxamide (29 mg, 34.01 μmol, yield 20.40%, purity 99.78%) as a yellow solid.

[0996] Exemplary synthesis of exemplary compound 27: (7S)-N-{3-[2-(4-{2-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}methyl)piperidin-1-yl]ethyl}piperazin-1-yl)pyridin-4-yl]-1H-indazol-5-yl}-4,5,7-trimethyl-4H,7H-[1,2,3,4]tetrazolo[1,5-a]pyrimidine-6-carboxamide

[0997]

[0998] Step 1:

[0999] At 20 °C under N2, NaOAc (1.08 g, 13.15 mmol, 3 eq), HOAc (131.59 mg, 2.19 mmol, 125.32 μL, 0.5 eq), and NaBH3CN (826.20 mg, 13.15 mmol, 3 eq) were added in one portion to a solution of 2-(2,6-dioxo-3-piperidinyl)-5-piperazin-1-yl-isoindoline-1,3-dione (2 g, 4.38 mmol, 1 eq, TFA) and tert-butyl 4-formylpiperidine-1-carboxylate (1.40 g, 6.57 mmol, 1.5 eq) in MeOH (20 mL). The solution was stirred at 20 °C for 1 h. TLC (DCM:MeOH = 10:1, Rf = 0.43) showed completion of the reaction and a major spot (Rf = 0.43) on the TLC. The residue was poured into water (20 mL). The aqueous phase was extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with brine (2 x 20 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (column: 40 g, 100 - 200 mesh silica gel, 0 - 50% (5 min) ethyl acetate in petroleum ether, 50 - 100% (10 min) ethyl acetate in petroleum ether) to give tert-butyl 4-[[4-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-5-yl]piperazin-1-yl]methyl]piperidine-1-carboxylate (2.2 g, 3.99 mmol, yield 90.98%, purity 97.8%) as a yellow gum.

[1000]

[1001] Step 2:

[1002] At 20 °C under N2, TFA (1.39 g, 12.23 mmol, 905.58 μL, 3 eq) was added in one portion to a solution of tert-butyl 4-[[4-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-5-yl]piperazin-1-yl]methyl]piperidine-1-carboxylate (2.2 g, 4.08 mmol, 1 eq) in DCM (2 mL). The mixture was stirred at 20 °C for 30 min to give a yellow solution. TLC (DCM:MeOH = 10:1, Rf = 0.43) showed completion of the starting material. The solution was concentrated in vacuo to give 2-(2,6-dioxo-3-piperidinyl)-5-[4-(4-piperidinylmethyl)piperazin-1-yl]isoindoline-1,3-dione (3 g, 3.73 mmol, yield 91.61%, purity 97.3%, 3TFA) as a yellow gum.

[1003]

[1004] Step 3:

[1005] At 20 °C under N2, CH3COOH (0.1 mL) and NaBH3CN (290.63 mg, 4.62 mmol, 3 eq) were added in one portion to a mixture of 5-nitro-3-(2-piperazin-1-yl-4-pyridinyl)-1H-indazole (500 mg, 1.54 mmol, 1 eq) and 2-chloroacetaldehyde (520 mg, 2.65 mmol, 426.23 μL, purity 40%, 1.72 eq) in DCE (20 mL) and MeOH (20 mL). The mixture was stirred at 20 °C for 2 h. LCMS showed the desired MS. 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 (dichloromethane:methanol = 10:1, Rf = 0.27, 0 - 50% (15 min) ethyl acetate in petroleum ether, 10% (5 min) ethyl acetate in petroleum ether) to give 3-[2-[4-(2-chloroethyl)piperazin-1-yl]-4-pyridinyl]-5-nitro-1H-indazole (350 mg, 904.78 μmol, yield 58.69%) as a yellow solid.

[1006]

[1007] Step 4:

[1008] At 20 °C under N2, KI (300.39 mg, 1.81 mmol, 2 eq) and DIPEA (233.87 mg, 1.81 mmol, 315.19 μL, 2 eq) were added in one portion to a mixture of 3-[2-[4-(2-chloroethyl)piperazin-1-yl]-4-pyridinyl]-5-nitro-1H-indazole (350 mg, 904.78 μmol, 1 eq) and 2-(2,6-dioxo-3-piperidinyl)-5-[4-(4-piperidinylmethyl)piperazin-1-yl]isoindoline-1,3-dione (397.66 mg, 508.79 μmol, 5.62e-1 eq, 3TFA) in MeCN (10 mL). The mixture was stirred at 80 °C for 16 h. LCMS showed no starting material. H2O (10 mL) was added to the residue, and the formed solid was filtered under vacuum to give 2-(2,6-dioxo-3-piperidinyl)-5-[4-[[1-[2-[4-[4-(5-nitro-1H-indazol-3-yl)-2-pyridinyl]piperazin-1-yl]ethyl]-4-piperidinyl]methyl]piperazin-1-yl]isoindoline-1,3-dione (600 mg, crude) as a yellow solid.

[1009]

[1010] Step 5:

[1011] At 20 °C under N2, Fe (212.10 mg, 3.80 mmol, 5 eq) was added in one portion to a mixture of 2-(2,6-dioxo-3-piperidinyl)-5-[4-[[1-[2-[4-[4-(5-nitro-1H-indazol-3-yl)-2-pyridinyl]piperazin-1-yl]ethyl]-4-piperidinyl]methyl]piperazin-1-yl]isoindoline-1,3-dione (600 mg, 759.61 μmol, 1 eq) and NH4Cl (203.16 mg, 3.80 mmol, 5 eq) in EtOH (10 mL), H2O (2 mL) and DCM (2 mL). The mixture was stirred at 80 °C for 1 h. LCMS showed completion of the reaction. The residue was filtered with ethyl acetate (10 mL * 5) and the solution was concentrated in vacuo. The crude product was purified by reverse phase HPLC (column: 3_Phenomenex Luna C18 75 * 30 mm * 3 μm; conditions: water (0.05% HCl)-ACN; initial B: 10, end B: 80; flow rate: 25 mL / min; gradient time: 35 min; 100% B hold time: 1 min) to afford 5-[4-[[1-[2-[4-[4-(5-amino-1H-indazol-3-yl)-2-pyridinyl]piperazin-1-yl]ethyl]-4-piperidinyl]methyl]piperazin-1-yl]-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione (180 mg, 232.14 μmol, yield 30.56%, purity 98%), as a yellow solid.

[1012]

[1013] Step 6:

[1014] At 25 °C under N2, DIEA (45.92 mg, 355.31 μmol, 61.89 μL, 3 eq) and HATU (45.03 mg, 118.44 μmol, 1 eq) were added in one portion to a mixture of 5-[4-[[1-[2-[4-[4-(5-amino-1H-indazol-3-yl)-2-pyridinyl]piperazin-1-yl]ethyl]-4-piperidinyl]methyl]piperazin-1-yl]-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione (90 mg, 118.44 μmol, 1 eq) and 4,5,7,7-tetramethyltetrazolo[1,5-a]pyrimidine-6-carboxylic acid (43.11 mg, 177.66 μmol, purity 92%, 1.5 eq) in DMF (5 mL). The mixture was stirred at 25 °C for 16 h to give a yellow solution. LCMS showed the desired product. The residue was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: 3_Phenomenex Luna C18 75*30 mm*3 μm; mobile phase: [water (0.1 M FANH4)-ACN]; B%: 0%-30%, 40 min) to give N-[3-[2-[4-[2-[4-[[4-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-5-yl]piperazin-1-yl]methyl]-1-piperidinyl]ethyl]piperazin-1-yl]-4-pyridinyl]-1H-indazol-5-yl]-4,5,7,7-tetramethyltetrazolo[1,5-a]pyrimidine-6-carboxamide (18.9 mg, 19.17 μmol, yield 16.18%, purity 97.88%), as a yellow solid.

[1015] Exemplary synthesis of Exemplary Compound 28: (7S)-N-(3-{2-[(3S)-4-{2-[4-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-4-yl}methyl)piperazin-1-yl]ethyl}-3-methylpiperazin-1-yl]pyridin-4-yl}-1H-indazol-5-yl)-4,5,7-trimethyl-4H,7H-[1,2,3,4]tetrazolo[1,5-a]pyrimidine-6-carboxamide

[1016] Exemplary Compound 28 was prepared in a manner similar to Exemplary Compound 27.

[1017] Exemplary Synthesis of Exemplary Compound 29: N-{3-[2-(4-{[1-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-4-yl}methyl)piperidin-4-yl]methyl}piperazin-1-yl)pyridin-4-yl]-1H-indazol-5-yl}-4,5,7,7-tetramethyl-4H,7H-[1,2,3,4]tetrazolo[1,5-a]pyrimidine-6-carboxamide

[1018]

[1019] Step 1:

[1020] Borane; 2-methylpyridine (329.78 mg, 3.08 mmol, 2 eq) was added to a solution of 5-nitro-3-(2-piperazin-1-yl-4-pyridyl)-1H-indazole (500 mg, 1.54 mmol, 1 eq) and tert-butyl 4-formylpiperidine-1-carboxylate (450 mg, 2.11 mmol, 1.37 eq) in HOAc (1 mL) and MeOH (10 mL). After addition, the reaction solution was stirred at 20 °C for 2 h. LCMS showed the desired MS. The reaction was diluted with brine (100 mL). The solid was collected by filtration and dried under reduced pressure to afford tert-butyl 4-[[4-[4-(5-nitro-1H-indazol-3-yl)-2-pyridyl]piperazin-1-yl]methyl]piperidine-1-carboxylate (730 mg, 1.20 mmol, yield 78.07%, purity 86%) as a yellow solid.

[1021]

[1022] Step 2:

[1023] TFA (7.70 g, 67.53 mmol, 5 mL, 48.25 eq) was added to a solution of tert-butyl 4-[[4-[4-(5-nitro-1H-indazol-3-yl)-2-pyridyl]piperazin-1-yl]methyl]piperidine-1-carboxylate (730 mg, 1.40 mmol, 1 eq) in DCM (10 mL). After addition, the reaction solution was stirred at 20 °C for 3 h. LCMS showed that the starting material had been consumed and the desired MS was detected. The reaction was concentrated under reduced pressure to give 5-nitro-3-[2-[4-(4-piperidinylmethyl)piperazin-1-yl]-4-pyridyl]-1H-indazole (589 mg, crude) as a yellow gum. The crude product was used directly in the next step.

[1024]

[1025] Step 3:

[1026] To a solution of 5-nitro-3-[2-[4-(piperidin-4-ylmethyl)piperazin-1-yl]-4-pyridinyl]-1H-indazole (589 mg, 1.40 mmol, 1 eq) and 1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl]piperidine-4-carbaldehyde (619.39 mg, 1.68 mmol, 1.2 eq) in HOAc (5 mL) and MeOH (50 mL) was added borane; 2-methylpyridine (298.94 mg, 2.79 mmol, 2 eq). After addition, the reaction mixture was stirred at 20 °C for 12 h. LCMS showed that the starting materials had been consumed and the desired MS was detected. The reaction mixture was diluted with water (50 mL) and extracted with 10% methanol in dichloromethane (3 x 50 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0 to 40% methanol in dichloromethane) to afford 2-(2,6-dioxopiperidin-3-yl)-5-[4-[[4-[[4-[4-(5-nitro-1H-indazol-3-yl)-2-pyridinyl]piperazin-1-yl]methyl]-1-piperidinyl]methyl]-1-piperidinyl]isoindoline-1,3-dione (1 g, 1.25 mmol, yield 89.35%, purity 96.75%) as a yellow solid.

[1027]

[1028] Step 4:

[1029] To a solution of 2-(2,6-dioxopiperidin-3-yl)-5-[4-[[4-[[4-[4-(5-nitro-1H-indazol-3-yl)-2-pyridinyl]piperazin-1-yl]methyl]-1-piperidinyl]methyl]-1-piperidinyl]isoindoline-1,3-dione (500 mg, 645.27 μmol, 1 eq) in EtOH (5 mL) and H2O (2 mL) was added Fe (180.18 mg, 3.23 mmol, 5 eq) and NH4Cl (172.58 mg, 3.23 mmol, 5 eq). After addition, the reaction mixture was stirred at 80 °C for 1 h. LCMS showed the desired MS. After cooling, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was triturated with 10% methanol in dichloromethane (20 mL) and filtered. The filtrate was concentrated under reduced pressure to give 5-[4-[[4-[[4-[4-(5-amino-1H-indazol-3-yl)-2-pyridinyl]piperazin-1-yl]methyl]-1-piperidinyl]methyl]-1-piperidinyl]-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (110 mg, 143.24 μmol, yield 22.20%, purity 97%) as a yellow solid.

[1030]

[1031] Step 5:

[1032] At 25 °C under N2, DIEA (52.05 mg, 402.75 μmol, 70.15 μL, 3 eq) and HATU (51.05 mg, 134.25 μmol, 1 eq) were added in one portion to a mixture of 5-[4-[[4-[[4-[4-(5-amino-1H-indazol-3-yl)-2-pyridinyl]piperazin-1-yl]methyl]-1-piperidinyl]methyl]-1-piperidinyl]-2-(2,6-dioxo-3-piperidinyl)isoindoline-1,3-dione (100 mg, 134.25 μmol, 1 eq) and 4,5,7,7-tetramethyltetrazolo[1,5-a]pyrimidine-6-carboxylic acid (56.19 mg, 201.37 μmol, purity 80%, 1.5 eq) in DMF (5 mL). The mixture was stirred at 25 °C for 16 h to obtain a yellow solution. LCMS showed the desired product. The residue was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: 3_Phenomenex Luna C18 75*30 mm*3 μm; mobile phase: [water (0.1 M FANH4)-ACN]; B%: 0%-30%; 40 min) to give N-[3-[2-[4-[[1-[[1-[2-(2,6-dioxo-3-piperidinyl)-1,3-dioxoisoindolin-5-yl]-4-piperidinyl]methyl]-4-piperidinyl]methyl]piperazin-1-yl]-4-pyridinyl]-1H-indazol-5-yl]-4,5,7,7-tetramethyltetrazolo[1,5-a]pyrimidine-6-carboxamide (12 mg, 12.25 μmol, yield 9.13%, purity 97%), as a yellow solid.

[1033] Exemplary synthesis of Exemplary Compound 30: N-(3-{2-[(3S)-4-{2-[4-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-4-yl}methyl)piperazin-1-yl]ethyl}-3-methylpiperazin-1-yl]pyridin-4-yl}-1H-indazol-5-yl)-4,5,7,7-tetramethyl-4H,7H-[1,2,3,4]tetrazolo[1,5-a]pyrimidine-6-carboxamide

[1034] Exemplary Compound 30 was prepared in a manner similar to Exemplary Compound 29.

[1035] Exemplary synthesis of exemplary compound 31: (7S)-N-(3-{2-[(3S)-4-{2-[4-({4-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperazin-1-yl}methyl)piperidin-1-yl]ethyl}-3-methylpiperazin-1-yl]pyridin-4-yl}-1H-indazol-5-yl)-4,5,7-trimethyl-4H,7H-[1,2,3,4]tetrazolo[1,5-a]pyrimidine-6-carboxamide

[1036] Exemplary compound 30 was prepared in a manner similar to exemplary compound 29.

[1037] Exemplary synthesis of exemplary compound 32: N-(3-{2-[(2S)-2-{[4-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl]piperidin-4-yl}methyl)piperazin-1-yl]methyl}morpholin-4-yl]pyridin-4-yl}-1H-indazol-5-yl)-4,5,7,7-tetramethyl-4H,7H-[1,2,3,4]tetrazolo[1,5-a]pyrimidine-6-carboxamide

[1038] Exemplary compound 30 was prepared in a manner similar to exemplary compound 29.

[1039]

[1040] Step 1:

[1041] To a mixture of tert-butyl (2R)-2-(hydroxymethyl)morpholine-4-carboxylate (2 g, 9.21 mmol, 1 eq) in DCM (20 mL) at N2 and 20 °C was added TFA (4.62 g, 40.52 mmol, 3 mL, 4.40 eq) in one portion. The mixture was stirred at 20 °C for 30 minutes. TLC showed the reaction was complete. The solution was concentrated in vacuo to give [(2R)-morpholin-2-yl]methanol (2 g, 8.65 mmol, yield 93.98%, TFA) as a colorless oil.

[1042]

[1043] Step 2:

[1044] At 100 °C under N2, K2CO3 (11.96 g, 86.52 mmol, 70.14 mL, 10 eq) was added in one portion to a mixture of 4-bromo-2-fluoropyridine (1.52 g, 8.65 mmol, 1 eq) and [(2R)-morpholin-2-yl]methanol (2 g, 8.65 mmol, 1 eq, TFA) in DMSO (10 mL). The mixture was stirred at 100 °C for 2 h to obtain a yellow solution. TLC (petroleum ether:ethyl acetate =...

Claims

1. A compound having the following chemical structure: PTM-L-CLM, or a pharmaceutically acceptable salt thereof; wherein: (a) said CLM is: wherein: W is CH2 or C=O; each X is O; Z is O; G is H; Q1, Q2, Q3 and Q4 are C; A is H; R is a bond or H, wherein one of the Rs is covalently linked to said L; n is 1, 2, 3 or 4; and represents a bond which may be stereospecific or non-stereospecific; (b) said PTM is: wherein the represents a connection site with the (c) said L is: wherein: Wherein Or * represents a site covalently linked to the CLM or the PTM; m and n are 0; o and p are each independently 0, 1, 2 or 3; and L is optionally substituted with 1, 2, 3 or 4 substituents independently selected from halogen and C 1-4 alkyl.

2. The compound according to claim 1, wherein said PTM is: Among them represents the linking site of the said L.

3. The compound according to claim 1, wherein said PTM is: wherein represents the connection site of said L.

4. The compound according to claim 1, wherein: (a) said CLM is represented by: Wherein: The represents a connection point with the N* is the nitrogen atom shared with said L; (b) said PTM is: wherein the represents a connection point to the (c) said L is: Wherein Or * represents a site covalently linked to the CLM or the PTM, or a site shared with the CLM or the PTM.

5. A compound, wherein said compound is: or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 5, wherein said compound is: or a pharmaceutically acceptable salt thereof.

7. A pharmaceutical composition comprising the compound according to any one of claims 1 to 6 and a pharmaceutically acceptable carrier.

8. The pharmaceutical composition according to claim 7, wherein said composition further comprises an additional bioactive agent.

9. The pharmaceutical composition according to claim 8, wherein said additional bioactive agent is an anti-neurodegenerative agent, an anti-inflammatory agent, a chemotherapeutic agent or an immunomodulator.

10. Use of an effective amount of the compound according to any one of claims 1 to 6 or a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of the compound according to any one of claims 1 to 6 in the manufacture of a medicament for the treatment of a disease or disorder causally related to LRRK2 in a subject, wherein said disease or disorder is a neurodegenerative disorder, an immune disorder, an inflammatory disorder or cancer.

11. The use according to claim 10, wherein said neurodegenerative disease is selected from Parkinson's disease, Parkinson's disease with dementia, Parkinson's disease risk syndrome, dementia with Lewy bodies, Lewy body variant Alzheimer's disease, combined Parkinson's disease and Alzheimer's disease, multiple system atrophy, striatonigral degeneration, olivopontocerebellar atrophy, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis and Shy-Drager syndrome.

12. The use according to claim 10, wherein said neurodegenerative disease is Parkinson's disease.

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