PROTAC compounds based on benzimidazole and benzimidazole for the targeted degradation of leucine-rich repeat kinase 2 (LRRK2).

Abstract

This article provides compounds (e.g., compounds of formula (la)) that recruit LRRK2 protein or its mutant form to E3 ubiquitin ligases for targeting ubiquitination and subsequent proteasome degradation.

Description

Cross-reference to related applications

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 586,344, filed September 28, 2023, the entire contents of which are incorporated herein by reference. Background Technology

[0002] The Lewy body is a major histological marker of Parkinson's disease (PD). The Lewy body is primarily composed of α-synuclein aggregates, and mutations in α-synuclein that increase these aggregates also increase the risk of PD (Meade RM et al., *Molecular Neurodegeneration*, 2019, 14. 29-29). It has been shown that depletion of leucine-rich repeat kinase 2 (LRRK2) with ASO and genomic deletion of LRRK2 can alleviate α-synuclein-mediated pathology in PD mouse models (Lin X et al., *Neuron*, 2009, 64:807–27). Mutations that increase LRRK2 activity, such as G2019S, increase α-synuclein aggregation in neurons and PD mouse models. This increase was reversed with LRRK2 kinase inhibitors (Volpicelli-Daley LA et al., *Journal of Neuroscience*, July 13, 2016; 36(28):7415-27). There is some evidence that the G2019S mutant form of LRRK2 is resistant to inhibition by kinase inhibitors in the central nervous system (CNS), potentially reducing its disease-modifying role (Kelly K et al., *Exp Neurol.*, November 2018; 309:1–13). Although most PD cases also have Lewy bodies upon postmortem examination, Lewy bodies are not present in a large number of LRRK2 G2019S mutation-associated PD cases (Kalia LV et al., *JAMA Neurol.*, 2015, 72:100–05). In addition to Lewy bodies being a common feature of PD, Tau pathology is also a major feature of postmortem LRRK2 mutation carriers (Henderson MX et al., Acta Neuropathol Commun 2019, 7. 183).

[0003] LRRK2 is highly expressed in neutrophils, monocytes, and macrophages in the immune system, as well as in brain microglia, and is a regulator of the intrinsic regulation of microglia activation and lysosomal degradation (Ma et al., Human Molecular Genetics, 2014, 1 Feb; 23(3):831–41). Prolonged activation of these immune cells through PD processes or mutations in LRRK2 may increase neuroinflammation and lead to a greater risk of PD and / or Tau pathology. In addition to PD, LRRK2 is also associated with other diseases such as cancer, leprosy, and Crohn's disease (Lewis PA, (2012). Sci Signal, 5(207), pe2).

[0004] There remains a persistent need in the field for effective treatments for LRRK2-related diseases and conditions, such as idiopathic PD, LRRK2 mutation-related PD (e.g., PD associated with one or more LRRK2 activating mutations), primary tau protein diseases (e.g., progressive supranuclear palsy (PSP) or corticobasal degeneration (CBD)), lewy body dementia, Crohn's disease, leprosy (e.g., leprosy with type 1 inflammatory response), and / or neuroinflammation. Summary of the Invention

[0005] This article provides compounds, their pharmaceutically acceptable salts, and pharmaceutical compositions comprising these compounds and salts, which recruit the LRRK2 protein, or a mutant form thereof, to the E3 ubiquitin ligase for targeting ubiquitination and subsequent proteasome degradation. Therefore, these compounds can be used to treat a variety of indications, including Parkinson's disease (PD).

[0006] Specifically, this paper provides compounds of formula (Ia): , Or its pharmaceutically acceptable salt, wherein the variables are as defined herein.

[0007] This article also provides pharmaceutical compositions comprising the compounds described herein or pharmaceutically acceptable salts thereof and pharmaceutically acceptable carriers.

[0008] In addition, this article provides methods for treating diseases, conditions, or symptoms causally related to LRRK2, the methods comprising administering to a subject an effective amount of any compound described herein, or a pharmaceutical composition comprising an effective amount of one or more compounds described herein or a pharmaceutically acceptable salt thereof.

[0009] In addition, this document provides for the use of effective amounts of any of the compounds described herein or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising effective amounts of one or more of the compounds described herein or pharmaceutically acceptable salts thereof, for the treatment of diseases, conditions, or symptoms causally related to LRRK2.

[0010] Furthermore, this document provides the use of effective amounts of any of the compounds described herein or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising effective amounts of one or more of the compounds described herein or pharmaceutically acceptable salts thereof, for the preparation of a medicament for the treatment of diseases, conditions, or symptoms causally related to LRRK2. Detailed Implementation

[0011] Leucine-rich repeat kinase 2 (LRRK2) is a member of the leucine-rich repeat kinase family. The catalytic activity of LRRK2 is associated with both the kinase and GTPase domains, and LRRK2 is a heterodimer of its active form (Greggio E et al., *Journal of Biochemistry*, 2008, 283:16906–16914). GTP binding is essential for kinase activity, and mutations that inhibit GTP binding have been shown to eliminate LRRK2 kinase activity (Ito G et al., *Biochemistry*, 2007, 46:1380–88). LRRK2 expression levels are highest in immune cells such as neutrophils, monocytes, and B cells, in the lungs and kidneys, with lower levels in the brain, where LRRK2 is expressed in dopaminergic neurons of the substantia nigra (WestAB et al., *Journal of Comparative Neurology*, 2014, 522:2465–2480).

[0012] Several dominant gain-of-function pathogenic and characteristic mutations exist in LRRK2 located in the Roco domain (N1437H, R1441G / C / H, Y1699C) or kinase domain (G2019S and I2020T) that influence GTP hydrolysis. 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 markers of PD include neurodegeneration of dopaminergic neurons in the substantia nigra pars compacta and intracellular inclusions called Lewy bodies and neurites composed of aggregates of α-synuclein. G2019S is associated with 1–2% of all PD patients and induces a 2-fold increase in kinase activity in vitro (West AB et al., Proceedings of the National Academy of Sciences of the United States of America, 2005, 102: 16842–47) and a 4-fold increase in autophosphorylation at Ser1292 (Sheng Z et al., Sci Transl Med, 2012, 4:164ra161). Several of the aforementioned Parkinson's disease-related mutations (R1441C / G, Y1699C, and I2020T) inhibit phosphorylation of LRRK2 at Ser910 and Ser935, thereby reducing the association of LRRK2 with the 14-3-3 protein, which is considered to represent an inactive form of LRRK2 (Nichols J et al., Biochem J, 2010, 430:393–404).

[0013] Furthermore, LRRK2 is associated with autosomal dominant PD through mutations in a chromosome 12 region called PARK8, which is associated with the LRRK2 gene (Funayama M et al., Annals of Neurology 2002, 51:296–301; Zimprich A et al., Neuron 2004, 44:601–607; Paisan-Ruiz C et al., Neuron 2004, 44:595–600).

[0014] LRRK2 is highly expressed in neutrophils, monocytes, and macrophages in the immune system, as well as in brain microglia, and is a regulator of the intrinsic regulation of microglia activation and lysosomal degradation processes (Ma et al., Human Molecular Genetics, 2014, Feb. 1; 23(3):831–41). Prolonged activation of these immune cells through PD processes or mutations in LRRK2 may increase neuroinflammation and lead to a greater risk of PD and / or Tau pathology. In addition to PD, LRRK2 is also associated with other diseases such as cancer, leprosy, and Crohn's disease (Lewis PA, (2012). Science Signal Transduction 5(207), pe2).

[0015] This article provides compounds (e.g., compounds of formula (Ia)), pharmaceutically acceptable salts of these compounds, and pharmaceutical compositions comprising these compounds and salts that recruit LRRK2 protein or its mutant form to E3 ubiquitin ligases for targeting ubiquitination and subsequent proteasome degradation.

[0016] Therefore, these compounds, as well as pharmaceutically acceptable salts of these compounds and pharmaceutical compositions containing these compounds or pharmaceutically acceptable salts thereof, can be used to treat a variety of indications, including Parkinson's disease.

[0017] definition The following lists definitions of various terms used to describe the compounds and compositions described herein. These definitions apply to the terminology used throughout this specification and claims, unless otherwise limited, either individually or as part of a larger group, in specific instances.

[0018] Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art. Typically, the nomenclature used herein, as well as laboratory procedures for cell culture, molecular genetics, organic chemistry, and peptide chemistry, are those well-known and commonly used in the art.

[0019] As used herein, the articles “a” and “an” refer to one or more (i.e., at least one) of the grammatical objects of an item. For example, “an element” means one or more elements. Furthermore, the use of the term “including” and other forms such as “include,” “includes,” and “included” is not restrictive.

[0020] As used herein, the term “about” will be understood by one of ordinary skill in the art and will vary to some extent in the context of its use. As used herein, the terms “administering,” “administer,” and “administration” refer to the provision of a therapeutic agent to a subject. Various techniques for administering therapeutic agents available in the art include, but are not limited to, intravenous, oral, aerosol, parenteral, ocular, pulmonary, and topical administration.

[0021] The terms “treat,” “treated,” “treating,” or “treatment” include reducing or alleviating at least one symptom related to or caused by the treated state, condition, or disease. In embodiments, treatment includes reducing symptoms of inflammation and age-related conditions.

[0022] As used herein, the terms “preventing,” “prevent,” and “prevention” mean the absence of a condition or disease, or the prevention of further development of a condition or disease if one has already developed. The ability to prevent some or all of the symptoms associated with a condition or disease is also considered.

[0023] "Bioactive agent" means any pharmaceutical agent other than the compounds according to this disclosure, which, in combination with the compounds of the present invention, is used as a biologically active pharmaceutical agent to help achieve the intended therapeutic, inhibitory, and / or preventative / protective effect of using the compounds of the present invention. Preferred bioactive agents as used herein include those with pharmacological activity similar to that of the compounds of the present invention used or applied, and include, for example, anticancer agents, antiviral agents, particularly anti-HIV and anti-HCV agents, antimicrobial agents, antifungal agents, etc.

[0024] As used herein, the term "contact" means bringing together the indicated portions of an in vitro or in vivo system. For example, "contacting" cells with a compound includes administering the compound of the invention to an individual, subject, or patient (such as a human), and, for example, introducing the compound into a sample containing a purified formulation (containing cells).

[0025] As used herein, the term "cell" is intended to refer to cells in vitro, ex vivo, or in vivo. In some embodiments, ex vivo cells may be a portion of a tissue sample excised from an organism such as a mammal. In some embodiments, ex vivo cells may be cells in a cell culture. In embodiments, in vivo cells may be cells living in an organism such as a mammal.

[0026] As used herein, the terms “patient,” “individual,” or “subject” refer to a human or non-human mammal. Non-human mammals include, for example, livestock and pets such as sheep, cattle, pigs, dogs, cats, and rodents. Preferably, the patient, subject, or individual is a human.

[0027] As used herein, the term "effective amount" refers to a non-toxic but sufficient quantity of a drug agent to provide the desired biological outcome. This outcome may be a reduction or relief of signs, symptoms, or causes of disease, or any other desired alteration of a biological system. In any individual case, the appropriate therapeutic amount can be determined by a person skilled in the art using routine laboratory methods.

[0028] As used herein, the term “pharmaceutically acceptable” means a material, such as a carrier or diluent, that does not eliminate the biological activity or properties of a compound and is relatively non-toxic; that is, the material can be administered to an individual without causing undesirable biological effects or interacting with any component of a composition containing the material in a harmful manner.

[0029] As used herein, the term "pharmaceutically acceptable salt" refers to a derivative of the described compound in which the parent compound is modified by converting an existing acid or base moiety into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to: mineral salts or organic acid salts of basic residues such as amines; basic salts or organic salts of acidic residues such as carboxylic acids; and so on. Pharmaceutically acceptable salts of this disclosure include, for example, conventional non-toxic salts of parent compounds formed from non-toxic inorganic or organic acids. Pharmaceutically acceptable salts of this disclosure can be synthesized by conventional chemical methods from parent compounds containing basic or acidic moieties. Typically, these salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of a suitable base or acid in water, in an organic solvent, or in a mixture of both; typically, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. The phrase "pharmaceutically acceptable salt" is not limited to a single salt or a 1:1 salt. For example, "pharmaceutically acceptable salt" also includes disalts, such as dihydrochlorides. A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.

[0030] As used herein, the term "composition" or "pharmaceutical composition" refers to a mixture of at least one compound that can be used in this disclosure with a pharmaceutically acceptable carrier. Pharmaceutical compositions facilitate the administration of compounds to patients or subjects. Various techniques for administering compounds available in the art include, but are not limited to, intravenous, oral, aerosol, parenteral, ocular, pulmonary, and topical administration.

[0031] As used herein, the term "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or carrier, such as a liquid or solid filler, stabilizer, dispersant, suspending agent, diluent, excipient, thickener, solvent, or encapsulating material, relating to the delivery or transport of a compound useful in this disclosure to or to a patient, such that the compound can perform its intended function. Typically, such constructs carry or transport from one organ or part of the body to another organ or part of the body. Each carrier must be "acceptable" in the sense of compatibility with other components of formulations containing compounds useful in this disclosure and harmless to the patient. Examples of materials that can serve as pharmaceutically acceptable carriers include: sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth gum; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerol, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; surfactants; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; phosphate buffer solutions; and other non-toxic compatible substances used in pharmaceutical formulations.

[0032] The term "pharmaceutically acceptable carrier" also includes any and all coating agents, antibacterial and antifungal agents, and absorption delay agents that are compatible with the activity of compounds useful in this disclosure and are physiologically acceptable to a patient. Additional active compounds may also be incorporated into the composition. "Pharmaceutically acceptable carrier" may further include pharmaceutically acceptable salts of the compounds described herein. Additional ingredients that may be included in the pharmaceutical composition are known in the art and described in references such as Remington's Pharmaceutical Sciences (edited by Genaro, Mark Publishing Co., Easton, PA, 1985), which are incorporated herein by reference.

[0033] The "pharmaceutically effective amount" or "pharmaceutically acceptable amount" of a compound is the amount necessary or sufficient for treating or preventing a condition, such as preventing various morphological and physical symptoms of the condition, disease, or symptom described herein. The effective amount can vary depending on factors such as the size and weight of the subject, the type of disease, or the specific compound of the invention. For example, the choice of compounds provided herein can affect what constitutes an "effective amount." Those skilled in the art can investigate the factors included herein and determine the effective amount of the compounds of the invention without excessive experimentation.

[0034] Unless otherwise stated, as used herein, the term "alkyl" on its own or as part of another substituent means a straight-chain or branched hydrocarbon having a specified number of carbon atoms (i.e., C64 ... 1-6 Alkyl groups (meaning alkyl groups having one to six carbon atoms) and include both straight-chain and branched groups. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, and hexyl. 1-6 Other examples of alkyl groups include ethyl, methyl, isopropyl, isobutyl, n-pentyl, and n-hexyl.

[0035] Unless otherwise stated, the terms “halogenated” or “halogen” as used herein, alone or as part of another substituent, refer to a fluorine, chlorine, bromine or iodine atom, preferably fluorine, chlorine or bromine, more preferably fluorine or chlorine.

[0036] "Alkoxy" refers to an alkyl group represented by -O-alkyl linked by an oxygen atom. For example, "C1-4 alkoxy" includes methoxy, ethoxy, propoxy, and butoxy.

[0037] The term "haloalkyl" includes monohaloalkyl, polyhaloalkyl, and perhaloalkyl, wherein the halogen is independently selected from fluorine, chlorine, bromine, and iodine.

[0038] The term "acyl" refers to the group -COCH3.

[0039] As used herein, the term "alkynyl" refers to an unsaturated straight-chain or branched hydrocarbon having at least one carbon-carbon triple bond. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentyynyl, hexynyl, methylpropynyl, etc.

[0040] As used herein, the term "cycloalkyl" means a fully saturated non-aromatic carbocyclic system having one, two, or three rings, wherein such rings may be fused. The term "fused" means that the second ring exists (i.e., is connected or formed) by sharing (i.e., co-occurring) two adjacent atoms with the first ring. Cycloalkyl also includes bicyclic structures that may be inherently bridged or spirocyclic, wherein each individual ring in the bicyclic has 3-8 distinct atoms. The term "cycloalkyl" includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[3.1.0]hexyl, spiro[3.3]heptyl, and bicyclo[1.1.1]pentyl. In the examples, cycloalkyl refers to C 3-11 Cycloalkyl. In the examples, cycloalkyl refers to C1463. 3-6 Cycloalkyl. In the examples, cycloalkyl refers to C1463. 3-5 Cycloalkyl. In the examples, cycloalkyl refers to C3 cycloalkyl.

[0041] As used herein, the term "heterocyclic group" refers to a non-aromatic carbocyclic system containing one, two, three, or four heteroatoms independently selected from N, O, and S and having one, two, or three rings, wherein such rings may be fused, where fusion is as defined above. The term "heterocyclic group" includes unsaturated compounds such as dihydropyridyl, dihydropyridazinyl, dihydropyrimidinyl, and dihydropyrazinyl. Heterocyclic groups also include bicyclic structures that may be inherently bridged or spirocyclic, wherein each individual ring in the bicyclic has 3-8 distinct atoms and contains 0, 1, or 2 N, O, or S atoms. The term "heterocyclic group" includes cyclic esters (i.e., lactones) and cyclic amides (i.e., lactams), and specifically includes, but is not limited to, epoxy groups, oxacyclobutyl groups, tetrahydrofuranyl groups, tetrahydropyranyl groups (i.e., oxacyclohexyl groups), pyranyl groups, dioxalyl groups, aziridinyl groups, aziridine groups, pyrrolidinyl groups, 2,5-dihydro-1H-pyrrolidinyl groups, oxazolyl groups, thiazolyl groups, piperidinyl groups, morpholinyl groups, piperazinyl groups, thiomorpholinyl groups, 1,3-oxazinyl groups, 1,3-thiazolyl groups, 2-azabicyclo[2.1.1]hexyl groups, 5-azabicyclo[2.1.1]hexyl groups, 6-azabicyclo[3.1.1]heptyl groups, 2-azabicyclo[2.2.1]heptyl groups, 3-azabicyclo[3.1.1]heptyl groups, and 2-azabicyclo[2.1.1]heptyl groups. [3.1.1]Heptyl, 3-azabicyclo[3.1.0]hexyl, 2-azabicyclo[3.1.0]hexyl, 3-azabicyclo[3.2.1]octyl, 8-azabicyclo[3.2.1]octyl, 3-oxa-7-azabicyclo[3.3.1]nonyl, 3-oxa-9-azabicyclo[3.3.1]nonyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 6-oxa-3-azabicyclo[3.1.1]heptyl, 2-azaspiro[3.3]heptyl, 2-oxa-6-azaspiro[3.3]heptyl, 2-oxaspiro[3.3]heptyl, 2-oxaspiro[3.5]nonyl, 3-oxaspiro[5.3]nonyl and 8-oxabicyclo[3.2.1]octyl. In the embodiments, the heterocyclic group refers to a 4-12 member heterocyclic group. In the embodiments, the heterocyclic group refers to a 5-10 member heterocyclic group. In the embodiments, the heterocyclic group refers to a 6-10 member heterocyclic group. In the embodiments, the heterocyclic group refers to a 5-8 member heterocyclic group. In the embodiments, the heterocyclic group refers to a 6-8 member heterocyclic group. In the embodiments, the heterocyclic group refers to a 4-7 member heterocyclic group. In the embodiments, the heterocyclic group refers to a 6 member heterocyclic group.

[0042] A 6-membered heterocyclic group is a heterocyclic group having six ring atoms, wherein one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S. Exemplary 6-membered heterocyclic groups include piperidinyl, piperazine, dioxane, thiaalkyl, dithiaalkyl, morpholinyl, thiomorpholinyl, and dihydropyridinyl.

[0043] The term "heterocyclic alkyl" refers to a fully saturated heterocyclic group.

[0044] It should be understood that if a cycloalkyl or heterocyclic moiety can be bonded to a specified moiety by different ring atoms or otherwise connected (i.e., shown or described without specifying a particular connection point), then all possible points are intended to be connected, whether by a carbon atom or, for example, a trivalent nitrogen atom.

[0045] The compounds described herein can exist as tautomers and optical isomers (e.g., enantiomers, diastereomers, diastereomer mixtures, racemic mixtures, etc.).

[0046] When the stereochemical configuration at the chiral center of a compound having one or more chiral centers is described by its chemical name (e.g., where the configuration is indicated by "R" or "S" in the chemical name) or structure (e.g., the configuration is indicated by a "wedge" bond), the indicated configuration has an enrichment of greater than 50%, 60%, 70%, 80%, 90%, 99%, or 99.9% relative to the opposite configuration. "Enrichment of the indicated configuration relative to the opposite configuration" is a molar percentage and is determined by dividing the number of compounds having the indicated stereochemical configuration at the chiral center by the total number of all compounds in the mixture having the same or opposite stereochemical configurations.

[0047] When a geometric isomer is described by name or structure, the enrichment of the indicated isomer relative to the opposite isomer is greater than 50%, 60%, 70%, 80%, 90%, 99%, or 99.9%. "Enrichment of the indicated isomer relative to the opposite isomer" is a molar percentage and is determined by dividing the number of compounds having the indicated geometry by the total number of all compounds in the mixture having the same or opposite geometry.

[0048] When the stereochemistry of a compound containing a 1,4-substituted cyclohexyl or a 1,3-substituted cyclobutyl group in variable L is described using a "wedge" bond, the stereochemistry of the ring-on groups is defined relative to each other. That is, the ring-on groups have either a trans or cis orientation relative to each other, which can be described by either trans or cis confirmation. For example, the stereochemistry of the cyclohexyl ring-on group in variable L can be described using a 1,4-trans stereochemistry, both of which describe the same compound. Therefore, the compound of formula (Ia) can be described as: or .

[0049] Similarly, the stereochemistry of the groups on the cyclohexyl ring in variable L can be described using 1,4-cis stereochemistry, both of which describe the same compound. Therefore, the compound of formula (Ia) can be described as: or .

[0050] It should be understood that the choice of trans or cis isomers depicted is arbitrary and is intended only to show the relative configurations of the groups on the ring.

[0051] When a compound is named or described by structure without indicating stereochemistry, it is understood that the name or structure covers a possible stereoisomer or a geometric isomer that does not contain other stereoisomers, or a mixture of the stereoisomers or geometric isomers covered.

[0052] If there is a difference between the structure and name of a compound, the structure shall prevail.

[0053] The terms "independently chosen" or "each independently" are used in this document to indicate that, for variables appearing in more than one position in a genus, the identity of the variable is determined separately in each case. For example, if R x R appears as a substituent on two different atoms. x Two instances can be the same part or different parts. If a single atom is R x The same applies when more than one instance replaces it. In each case, R x Their identity is determined independently of other identities.

[0054] compound This article provides compounds of formula (Ia): Or its pharmaceutically acceptable salt. in: X 1 For CR 1 Or N; X 2 For H, C 1-3 Alkyl or O; R 1 R 2 R 3 R 4 and R 5 Each is independently selected from H, acetyl, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, OC 3-6 cycloalkyl and C 1-6 Alkoxy, wherein the C 3-10 cycloalkyl, OC 3-6 cycloalkyl and C 1-6 The alkoxy group is optionally surrounded by 1 or 2 carbon atoms. 1-6 Alkyl or cyano substitution; R6 Halogenated or C 1-3 alkyl; R 7 For H or C 1-3 alkyl; one It is a double bond, and one It is a single bond; the condition is that when R 4 N When C is a double bond, then R 4 It does not exist; and the condition is that when X 2 When it is O, C X 2 It is a double bond; Each L is independently selected from C 1-6 Alkyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, O, C 3-11 Cycloalkyl and 4-12 membered heterocyclic alkyl groups, wherein C 3-11 Cycloalkyl and 4-12 membered heterocyclic alkyl groups are optionally substituted with 1, 2 or 3 R groups. L Replace, where each R L Independently selected from halogenated, CN and C 1-6 alkyl; n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; m can be 0, 1, or 2.

[0055] In the embodiment of formula (Ia), R 7 It can be H or -CH3.

[0056] In the embodiment of formula (Ia), m is 0 or 1, and R 6 When present, it is halogenated.

[0057] In the embodiments, the compound of formula (Ia) is the compound of formula (I): Or its pharmaceutically acceptable salt. in: X 1 For CR 1 Or N; X 2 It is H or O; R 1 R 2 R 3 R 4 and R 5 Each is independently selected from H, acetyl, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6cycloalkyl, OC 3-6 cycloalkyl and C 1-6 Alkoxy, where C 3-6 cycloalkyl, OC 3-6 cycloalkyl and C 1-6 The alkoxy group is optionally surrounded by 1 or 2 carbon atoms. 1-6 Alkyl substitution; one It is a double bond, and one It is a single bond; the condition is that when R 4 N When C is a double bond, then R 4 It does not exist; and the condition is that when X 2 When it is O, C X 2 It is a double bond; Each L is independently selected from C 1-6 Alkyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, O, C 3-11 Cycloalkyl and 4-12 membered heterocyclic alkyl groups, wherein C 3-11 Cycloalkyl and 4-12 membered heterocyclic alkyl groups are optionally substituted with 1, 2 or 3 R groups. L Replace, where each R L Independently selected from halogenated, CN and C 1-6 Alkyl; and n can be 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0058] In the embodiments of formulas (Ia) and (I), X 1 For CR 1 Or N; X 2 It is H or O; R 1 R 2 R 3 R 4 and R 5 Each is independently selected from H, halogenated, and C. 1-6 Alkyl, C 3-6 cycloalkyl, OC 3-6 cycloalkyl and C 1-6 Alkoxy, where C 3-6 cycloalkyl, OC 3-6 cycloalkyl and C 1-6 The alkoxy group is optionally surrounded by 1 or 2 carbon atoms. 1-6 Alkyl substitution; Each L is independently selected from C 1-6 Alkyl, C 2-6 alkynyl group, C 1-6Alkoxy, O, C 3-11 Cycloalkyl and 4-12-membered heterocyclic alkyl groups, wherein the 4-12-membered heterocyclic alkyl group is optionally substituented by one or two R groups. L Replace, where each R L Independently selected from halogenated, CN and C 1-6 Alkyl; and n can be 1, 2, 3, 4, 5, 6, 7 or 8.

[0059] In the embodiments of formulas (Ia) and (I), X 1 For CH or N; X 2 It is H or O; R 2 R 3 R 4 and R 5 Each is independently selected from H and C. 1-6 Alkyl, OC 3-6 cycloalkyl and C 1-6 Alkoxy, of which OC 3-6 cycloalkyl and C 1-6 The alkoxy group is optionally surrounded by 1 or 2 carbon atoms. 1-4 Alkyl substitution; Each L is independently selected from C 1-6 Alkyl, C 2-6 alkynyl group, C 1-6 Alkoxy, O, C 3-11 Cycloalkyl and 4-12-membered heterocyclic alkyl groups, wherein the 4-12-membered heterocyclic alkyl group is optionally substituented by one or two R groups. L Replace, where each R L Halogenated or C 1-6 Alkyl; and n can be 1, 2, 3, 4, 5, or 6.

[0060] In the embodiments of formulas (Ia) and (I), X 1 For CH or N; X 2 It is H or O; R 3 R 4 and R 5 Each independently is H or C 1-6 alkyl; R 2 To be optionally bounded by 1 or 2 C 1-4 Alkyl-substituted OC 3-6 cycloalkyl; Each L is independently selected from C 1-6 Alkyl, C 2-6 alkynyl group, C 1-6Alkoxy, O, C 3-11 Cycloalkyl and 4-12-membered heterocyclic alkyl groups, wherein the 3-12-membered heterocyclic alkyl groups are optionally substituents R. L Replace, where each R L Halogenated or C 1-6 Alkyl; and n can be 1, 2, 3, 4, 5, or 6.

[0061] In the embodiments of formulas (Ia) and (I), R 3 For H.

[0062] In the embodiments, the compound of formula (I) is the same as the compound of formula (II): , Or its pharmaceutically acceptable salt.

[0063] In the embodiments of formulas (Ia), (I), and (II), R 4 N C is a double bond; X 2 For H; and R 4 It does not exist.

[0064] In the embodiments of formulas (Ia), (I), and (II), X 2 C is a double bond; and X 2 It is O.

[0065] In the embodiments, the compounds of formula (Ia), (I), or (II) are compounds of formula (IIA): , Or its pharmaceutically acceptable salt.

[0066] In the embodiments, the compounds of formula (Ia), (I), or (II) are compounds of formula (IIB): , Or its pharmaceutically acceptable salt.

[0067] In the embodiments of formulas (Ia), (I), (II), (IIA) and (IIB), R 1 For H.

[0068] In the embodiments of formulas (Ia), (I), (II), (IIA) and (IIB), R 2 C 1-4 Alkoxy, C 3-8 cycloalkyl or OC 3-5cycloalkyl, wherein the C 3-8 cycloalkyl and OC 3-5 Each cycloalkyl group is optionally surrounded by one or two C atoms. 1-4 Alkyl or cyano substitution. In the embodiments of formulas (Ia), (I), (II), (IIA) and (IIB), R 2 To be optionally bounded by 1 or 2 C 1-4 Alkyl-substituted OC 3-5 Cycloalkyl. In other embodiments of formulas (I)-(IIB), R 2 For optional use by C 1-3 Alkyl-substituted OC 3-5 Cycloalkyl. In further embodiments of formulas (I)-(IIB), R 2 OC replaced by CH3 3-5 Cycloalkyl.

[0069] In the embodiments of formulas (Ia), (I), (II), (IIA) and (IIB), R 2 For -OCH3, -OCH2CH3, -OCH(CH3)2, -OC(CH3)3, , , , or .

[0070] In the embodiments of formulas (Ia), (I), (II), (IIA) and (IIB), R 2 Selected from , , , , and .

[0071] In the embodiments of formulas (Ia), (I), (II), (IIA) and (IIB), R 2 Selected from: , , and .

[0072] In the embodiments of formulas (Ia), (I), (II), (IIA) and (IIB), R 2 for: or .

[0073] In the embodiments of formulas (Ia), (I), (II), (IIA) and (IIB), R 2 for: .

[0074] In the embodiments of formulas (Ia), (I), (II) and (IIA), R 4 For H, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 3-10 cycloalkyl, wherein the C 3-10 The cycloalkyl group is optionally surrounded by 1 or 2 Cs 1-6 Alkyl or cyano substitution. In the embodiments of formulas (Ia), (I), (II), and (IIA), R 4 C 1-3 Alkyl group. In the embodiments of formulas (Ia), (I), (II) and (IIA), R 4 It is methyl. In the embodiments of formula (I)-(IIA), R 4 It is a C3 alkyl group. In the examples of formulas (I)-(IIA), R 4 It is isopropyl.

[0075] In the embodiments of formulas (Ia), (I), (II), (IIA) and (IIB), R 5 For H, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 3-10 cycloalkyl, wherein the C 3-10 The cycloalkyl group is optionally surrounded by 1 or 2 Cs 1-6 Alkyl or cyano substitution. In the embodiments of formulas (Ia), (I), (II), (IIA) and (IIB), R 5 For H.

[0076] In the embodiments of formulas (Ia), (I), (II), (IIA) and (IIB), each L is independently selected from C. 1-6 Alkyl, C 2-6 alkynyl group, C 1-6 Alkoxy, O, C 3-11 Cycloalkyl and 4-12-membered heterocyclic alkyl groups, wherein the 4-12-membered heterocyclic alkyl group is optionally substituented by one or two R groups. L Replace, where R L C 1-6 alkyl.

[0077] In the embodiments of formulas (Ia), (I), (II), (IIA) and (IIB), at least two L are optionally replaced by one or two substituents R. L Substituted 4-12 membered heterocyclic alkyl groups, wherein R L C 1-6Alkyl groups. In the embodiments of formulas (Ia), (I), (II), (IIA), and (IIB), at least three L are 4-12-membered heterocyclic alkyl groups, wherein the 4-12-membered heterocyclic alkyl groups are optionally substituents R by one or two substituents. L Replace, where R L C 1-6 Alkyl group. In the embodiments of formulas (Ia), (I), (II), (IIA) and (IIB), each L is independently selected from C. 1-6 Alkyl, C 2-4 alkynyl group, C 1-6 Alkoxy, O, C 3-7 Cycloalkyl and 6-8-membered heterocyclic alkyl groups, wherein the 6-8-membered heterocyclic alkyl group is optionally substituented by one or two R groups. L Replace, and where R L C 1-3 Alkyl group. In the embodiments of formulas (Ia), (I), (II), (IIA) and (IIB), each L is independently selected from C. 1-3 Alkyl, C 2-4 alkynyl group, C 1-3 Alkoxy, O, C 3-7 Cycloalkyl and 6-8-membered heterocyclic alkyl groups, wherein the 6-8-membered heterocyclic alkyl group is optionally substituented by one or two R groups. L Replace, and where R L It is a methyl group.

[0078] In the embodiments of formulas (Ia), (I), (II), (IIA), and (IIB), n is 1, 2, 3, 4, 5, 6, 7, 8, or 9. In the embodiments of formulas (Ia), (I), (II), (IIA), and (IIB), n is 1, 2, 3, 4, 5, 6, 7, or 8. In the embodiments of formulas (Ia), (I), (II), (IIA), and (IIB), n is 2, 3, 4, 5, 6, or 7. In the embodiments of formulas (Ia), (I), (II), (IIA), and (IIB), n is 3, 4, 5, 6, 7, or 8. In the embodiments of formulas (Ia), (I), (II), (IIA), and (IIB), n is 1, 2, 3, 4, 5, or 6. In the embodiments of formulas (Ia), (I), (II), (IIA), and (IIB), n is 2, 3, 4, 5, or 6. In the embodiments of formulas (Ia), (I), (II), (IIA), and (IIB), n is 3, 4, 5, or 6.

[0079] In the embodiments of formulas (Ia), (I), (II), (IIA), and (IIB), n is 1. In the embodiments of formulas (Ia), (I), (II), (IIA), and (IIB), n is 2. In the embodiments of formulas (Ia), (I), (II), (IIA), and (IIB), n is 3. In the embodiments of formulas (Ia), (I), (II), (IIA), and (IIB), n is 4. In the embodiments of formulas (Ia), (I), (II), (IIA), and (IIB), n is 5. In the embodiments of formulas (Ia), (I), (II), (IIA), and (IIB), n is 6. In the embodiments of formulas (Ia), (I), (II), (IIA), and (IIB), n is 7. In the embodiments of formulas (Ia), (I), (II), (IIA), and (IIB), n is 8. In the embodiments of formulas (Ia), (I), (II), (IIA), and (IIB), n is 9. In the embodiments of formulas (Ia), (I), (II), (IIA), and (IIB), n is 10.

[0080] In the embodiments of formulas (I)-(IIB), n is 2, 3, 4, 5, 6, 7, or 8, and at least two L are optionally substituents R by one or two substituents. L Substituted 4-12 membered heterocyclic alkyl groups, wherein R L C 1-6 Alkyl group. In other embodiments of formulas (I)-(IIB), n is 3, 4, 5, 6, 7 or 8, and at least three L are 4-12 membered heterocyclic alkyl groups, wherein the 4-12 membered heterocyclic alkyl groups are optionally substituents R by one or two substituents. L Replace, where R L C 1-6 alkyl.

[0081] In the embodiments of formulas (Ia), (I), (II), (IIA), and (IIB), n is 5, and each L together forms a connector selected from (4-12 membered heterocyclic alkyl)-(C 1-6 alkyl)-(4-12 membered heterocyclic alkyl)-(C 1-6 (alkyl)-(4-12-membered heterocyclic alkyl); (4-12-membered heterocyclic alkyl)-(C 1-6 alkyl)-(C 3-12 (4-12-membered heterocyclic alkyl)-(O)-(4-12-membered heterocyclic alkyl)-(C 1-6 alkyl)-(4-12 membered heterocyclic alkyl)-(C 1-6 alkoxy)-(C 3-6 (alkynyl); and (4-12 membered heterocyclic alkyl)-(C 1-6 alkyl)-(4-12 membered heterocyclic alkyl)-(O)-(C3-6 (alkynyl), wherein each 4-12 membered heterocyclic alkyl group is optionally substituent by 1 or 2 substituents R. L Replace, where R L C 1-6 alkyl.

[0082] In the embodiments of formulas (Ia), (I), (II), (IIA), and (IIB), n is 5, and each L together forms a connector selected from (5-6 membered heterocyclic alkyl)-(C 1-6 alkyl)-(5-6 membered heterocyclic alkyl)-(C 1-6 (alkyl)-(5-6 membered heterocyclic alkyl); (5-6 membered heterocyclic alkyl)-(C 1-6 alkyl)-(C 5-6 (5-6 membered heterocyclic alkyl)-(O)-(5-6 membered heterocyclic alkyl)-(C 1-6 alkyl)-(5–6-membered heterocyclic alkyl)-(C 1-6 alkoxy)-(C 3-6 (alkynyl); and (5-6 membered heterocyclic alkyl)-(C 1-6 alkyl)-(5-6 membered heterocyclic alkyl)-(O)-(C 3-6 (alkynyl), wherein each 5-6 membered heterocyclic alkyl group is optionally substituent by 1 or 2 substituents R. L Replace, where R L C 1-6 alkyl.

[0083] In the embodiments of formulas (Ia), (I), (II), and (IIA), the compound is the compound of formula (IIAa): , Or its pharmaceutically acceptable salt. in: Each ring A is independently selected from piperidinyl, hexahydropyridinyl, hexahydropyrimidinyl, and piperidinyl, wherein each ring A is optionally substituent R by one or two substituents. L Replace, where R L C 1-6 alkyl; Ring B is selected from cyclohexyl, piperidinyl, hexahydropyridinyl, hexahydropyrimidinyl, and piperazinyl, wherein each ring B is optionally substituent R by one or two substituents. L Replace, where R L C 1-6 Alkyl; and Each Y is independently O, C 1-6 Alkyl or C 1-6 Alkyl group.

[0084] In the embodiments of formulas (Ia), (I), (II) and (IIA), the compound is the compound of formula (IIAb): , Or its pharmaceutically acceptable salt. in: Each ring A is independently selected from piperidinyl, hexahydropyridinyl, hexahydropyrimidinyl, and piperidinyl, wherein each ring A is optionally substituent R by one or two substituents. L Replace, where R L C 1-6 alkyl; Ring B is selected from cyclohexyl, piperidinyl, hexahydropyridinyl, hexahydropyrimidinyl, and piperazinyl, wherein each ring B is optionally substituent R by one or two substituents. L Replace, where R L C 1-6 Alkyl; and Each Y is independently O, C 1-6 Alkyl or C 1-6 Alkyl group.

[0085] In the embodiments of formulas (I), (II), and (IIB), the compound is a compound of formula (IIBa): , Or its pharmaceutically acceptable salt. in: Each ring A is independently selected from piperidinyl, hexahydropyridazinyl, hexahydropyrimidinyl, and piperazinyl; Y 1 C 1-6 alkyl; Y 2 For O or C 1-6 alkoxy groups; and Z is a C3-6 acetylene group.

[0086] In the embodiments of formulas (Ia)-(IIBa), R L C 1-4 Alkyl group. In the embodiments of formulas (Ia), (I), (II), (IIA) and (IIB), R L C 1-3 Alkyl group. In the embodiments of formula (Ia)-(IIBa), R L It is a methyl group.

[0087] In the embodiments of formulas (Ia)-(IIBa), (L) n Selected from: In the embodiments of formulas (Ia)-(IIBa), (L) n Selected from: In the embodiment of formula (Ia), the compound is the compound of formula (III): (III); Or its pharmaceutically acceptable salt, wherein R 4 C 1-3 alkyl; L 1 and L 3 Each is independently a 5- to 6-membered heterocyclic group; and L 2 C 3-6 Cycloalkyl.

[0088] In the embodiments of formulas (Ia)-(III), the compound is the compound of formula (IIIa): (IIIa); Or its pharmaceutically acceptable salt.

[0089] In the embodiments of formulas (III) and (IIIa), L 1 It is a 6-membered heterocyclic group. In the embodiments of formulas (III) and (IIIa), L 1 It is piperidinyl or piperazine. In the embodiments of formula (III) and (IIIa), L 1 It is piperazine-based.

[0090] In the embodiments of formulas (III) and (IIIa), L 3 It is a 6-membered heterocyclic group. In the embodiments of formulas (III) and (IIIa), L 3 It is piperidinyl or piperazine. In the embodiments of formula (III) and (IIIa), L 3 It is piperidinyl.

[0091] In the embodiments of formulas (III) and (IIIa), L 2 It is cyclopropyl. In the embodiments of formula (III) and (IIIa), L 2 It is cyclobutyl. In the embodiments of formula (III) and (IIIa), L 2 It is cyclopentyl. In the embodiments of formula (III) and (IIIa), L 2 It is a cyclohexyl group.

[0092] In the embodiments, the compounds of formula (Ia) are selected from: In the embodiments, certain variables (L) are included in the described compound. n Compounds with an attached 3-(3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione group exhibit improved activity. See, for example, Table 3.

[0093] Pharmaceutical Composition This document also provides pharmaceutical compositions comprising any of the compounds described herein or their pharmaceutically acceptable salts and pharmaceutically acceptable carriers.

[0094] In some embodiments, the pharmaceutical composition further comprises additional bioactive agents. In some embodiments, the additional bioactive agents are anti-inflammatory agents, chemotherapeutic agents, or immunomodulators.

[0095] In one embodiment, the pharmaceutical composition achieves targeted protein degradation in a patient or subject, such as an animal (e.g., a human), and can be used to treat or improve a disease state or symptom regulated by the degradation of the target protein. In embodiments, the therapeutic compositions as described herein can be used to achieve protein degradation to treat or improve LRRK2-mediated inflammatory diseases, autoimmune diseases, or cancer. In another embodiment, the disease is idiopathic Parkinson's disease (PD), LRRK2 mutation-associated Parkinson's disease (PD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Lewy body dementia, Crohn's disease, leprosy with type 1 inflammatory response, neuroinflammation, Kennedy's disease, TDP-43 ALS, c9orf ALS, Huntington's disease, Alzheimer's disease, Pick's disease, multiple system atrophy, systemic lupus erythematosus (SLE), acute kidney injury, rhabdomyolysis, lipofuscinosis, Fabry's disease, Batten's disease, ulcerative colitis, irritable bowel syndrome, Kufor–Rakeb syndrome, and Gaucher disease. Diseases, frontotemporal dementia, spinocerebellar ataxia (SCA) 1, 2, 3, 6, 7 and 17 and / or dentate nucleus, globus pallidus pallidus Lewy body atrophy (DRPLA).

[0096] In one embodiment, the disease is idiopathic PD. In another embodiment, the disease is LRRK2 mutation-related PD. In yet another embodiment, the disease is progressive supranuclear palsy (PSP). In yet another embodiment, the disease is systemic lupus erythematosus (SLE).

[0097] Treatment Furthermore, this document discloses a method for treating diseases, conditions, or symptoms causally related to LRRK2, the method comprising administering to a subject an effective amount of any compound provided herein or a pharmaceutically acceptable salt thereof, or an effective amount of any compound provided herein or a pharmaceutically acceptable salt thereof as part of a pharmaceutical composition.

[0098] Furthermore, this document discloses the use of an effective amount of any compound provided herein or a pharmaceutically acceptable salt thereof, or as part of a pharmaceutical composition, for the treatment of diseases, conditions, or symptoms causally related to LRRK2.

[0099] Furthermore, this document discloses the use of effective amounts of any compound provided herein or a pharmaceutically acceptable salt thereof, or as part of a pharmaceutical composition, in the preparation of a medicament for the treatment of diseases, conditions, or symptoms causally related to LRRK2.

[0100] In this embodiment, the disease or condition is idiopathic Parkinson's disease (PD), LRRK2 mutation-associated Parkinson's disease (PD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Lewy body dementia, Crohn's disease, leprosy with type 1 inflammatory response, neuroinflammation, Kennedy's disease, TDP-43 ALS, c9orf ALS, Huntington's disease, Alzheimer's disease, Pick's disease, multiple system atrophy, systemic lupus erythematosus (SLE), acute kidney injury, rhabdomyolysis, lipofuscinosis, Fabry disease, Barten disease, ulcerative colitis, irritable bowel syndrome, Kouf-Lachby syndrome, Gaucher disease, frontotemporal dementia, spinocerebellar ataxia (SCA) 1, 2, 3, 6, 7 and 17 and / or dentate nucleus-globus pallidus Lewy body atrophy (DRPLA). In this embodiment, the disease is idiopathic PD. In one embodiment, the disease is LRRK2 mutation-related PD. In another embodiment, the disease is progressive supranuclear palsy (PSP). In yet another embodiment, the disease is systemic lupus erythematosus (SLE).

[0101] This article also provides a method for treating Parkinson's disease, the method comprising administering to a subject an effective amount of any compound disclosed herein or a pharmaceutically acceptable salt thereof, or an effective amount of any compound disclosed herein or a pharmaceutically acceptable salt thereof as part of a pharmaceutical composition.

[0102] Furthermore, this document discloses the use of an effective amount of any compound provided herein or a pharmaceutically acceptable salt thereof, or as part of a pharmaceutical composition, for the treatment of Parkinson's disease.

[0103] Furthermore, this document discloses the use of an effective amount of any compound provided herein or a pharmaceutically acceptable salt thereof, or as part of a pharmaceutical composition, in the preparation of a medicament for the treatment of Parkinson's disease.

[0104] In this embodiment, the Parkinson's disease is LRRK2 mutation-associated Parkinson's disease.

[0105] This article provides a method for treating progressive supranuclear palsy (PSP), the method comprising administering to a subject an effective amount of any compound disclosed herein or a pharmaceutically acceptable salt thereof, or an effective amount of any compound disclosed herein or a pharmaceutically acceptable salt thereof as part of a pharmaceutical composition.

[0106] Furthermore, this document discloses the use of an effective amount of any compound provided herein or a pharmaceutically acceptable salt thereof, or an effective amount of any compound provided herein or a pharmaceutically acceptable salt thereof, as part of a pharmaceutical composition, for the treatment of progressive supranuclear palsy (PSP).

[0107] Furthermore, this document discloses the use of an effective amount of any compound provided herein or a pharmaceutically acceptable salt thereof, or an effective amount of any compound provided herein or a pharmaceutically acceptable salt thereof, as part of a pharmaceutical composition, for the preparation of a medicament for the treatment of progressive supranuclear palsy (PSP).

[0108] This article also provides a method for treating systemic lupus erythematosus (SLE), the method comprising administering to a subject an effective amount of any compound disclosed herein or a pharmaceutically acceptable salt thereof, or an effective amount of any compound disclosed herein or a pharmaceutically acceptable salt thereof as part of a pharmaceutical composition.

[0109] Furthermore, this document discloses the use of an effective amount of any compound provided herein or a pharmaceutically acceptable salt thereof, or as part of a pharmaceutical composition, for the treatment of systemic lupus erythematosus (SLE).

[0110] Furthermore, this document discloses the use of an effective amount of any compound provided herein or a pharmaceutically acceptable salt thereof, or an effective amount of any compound provided herein or a pharmaceutically acceptable salt thereof, as part of a pharmaceutical composition, for the preparation of a medicament for the treatment of systemic lupus erythematosus (SLE).

[0111] This disclosure also relates to a method for treating a disease state or improving one or more symptoms of a disease or condition by degrading an LRRK2 protein (e.g., wild-type LRRK2 protein or LRRK2 mutant protein (e.g., including one or more mutations of LRRK2 selected from G2019S, I2020T, N1437H, R1441G / C / H and Y1699C)), said method comprising administering to a subject an effective amount of at least one compound as described herein or a pharmaceutically acceptable salt thereof, optionally in combination with another bioactive agent, or as part of a pharmaceutical composition, said compound or pharmaceutical composition being effective in treating or improving the subject's disease or condition or one or more symptoms thereof.

[0112] Furthermore, this document discloses the use of an effective amount of any compound provided herein or a pharmaceutically acceptable salt thereof, or an effective amount of any compound provided herein or a pharmaceutically acceptable salt thereof, as part of a pharmaceutical composition, for treating a disease state or improving one or more symptoms of a disease or condition by degrading LRRK2 protein (e.g., wild-type LRRK2 protein or LRRK2 mutant protein (e.g., including one or more mutant LRRK2 proteins selected from G2019S, I2020T, N1437H, R1441G / C / H and Y1699C)).

[0113] Furthermore, this document discloses the use of an effective amount of any compound provided herein or a pharmaceutically acceptable salt thereof, or an effective amount of any compound provided herein or a pharmaceutically acceptable salt thereof, as part of a pharmaceutical composition, for the preparation of a medicament for treating a disease state or improving one or more symptoms of a disease or condition by degrading LRRK2 protein (e.g., wild-type LRRK2 protein or LRRK2 mutant protein (e.g., including one or more mutant LRRK2 proteins selected from G2019S, I2020T, N1437H, R1441G / C / H and Y1699C)).

[0114] The methods and uses according to this disclosure can be used to treat certain disease states, symptoms, or signs, including inflammatory diseases, autoimmune diseases, or cancer, by administering an effective amount of at least one of the compounds described herein. For example, the methods according to this disclosure can be used to treat one or more of the following: Parkinson's disease (PD), idiopathic PD, LRRK2 mutation-associated PD (e.g., PD associated with one or more LRRK2 activating mutations), primary tau protein diseases (e.g., progressive supranuclear palsy (PSP) or corticobasal degeneration (CBD)), Lewy body dementia, Crohn's disease, leprosy (e.g., leprosy with type 1 inflammatory response), and neuroinflammatory diseases (such as those observed in Alzheimer's disease, PD, multiple sclerosis, traumatic brain injury, spinal cord injury, etc.).

[0115] This article also provides a method for preparing a small molecule that may lead to the degradation of LRRK2 in cells, the method comprising the steps of: (i) providing a small molecule that binds to LRRK2 or a mutant form thereof; (ii) providing an E3 ubiquitin ligase-binding moiety (ULM), preferably a CLM, such as thalidomide, pomalidomide, lenalidomide, or analogues thereof; and (iii) via a chemical linker (L). n The small molecule from step (i) is covalently coupled to the ULM from step (ii) to form a compound that binds to both the cerebellar protein E3 ubiquitin ligase and the LRRK2 protein and / or its mutant form in the cell, such that the cerebellar protein E3 ubiquitin ligase is brought close and ubiquitinated to the bound LRRK2 protein, such that the ubiquitinated LRRK2 protein is subsequently degraded.

[0116] Furthermore, this paper discloses a method for detecting whether a small molecule can trigger the degradation of LRRK2 protein in cells, the method comprising the following steps: (i) providing a small molecule, wherein the ability of said molecule to trigger the degradation of LRRK2 protein in cells is to be detected, said small molecule comprising the following structure: CLM–L–PTM, wherein CLM is a cerebellar E3 ubiquitin ligase binding moiety capable of binding to cerebellar E3 ubiquitin ligase in cells, said 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 / or its mutant LRRK form, said LRRK2 having at least one lysine residue that can be ubiquitinated by cerebellar E3 ubiquitin ligase bound to said molecule's CLM; and L is a chemical linker group that covalently links CLM to PTM to form the small molecule; (ii) incubating LRRK2 protein expressing cells in the presence of said small molecule in step (i); and (iii) detecting whether the LRRK2 protein in said cells has been degraded.

[0117] In the embodiments, the small molecules capable of binding LRRK2 are those that bind to LRRK2. In the embodiments, the small molecules that bind to the LRRK2 protein are as described herein.

[0118] This disclosure further provides a method for treating a human patient requiring treatment for a disease state, symptom, or condition causally associated with LRRK2 and / or LRRK2 mutations, expression, overexpression, mutation, aggregation, accumulation, misfolding, or dysregulation, wherein degradation of the LRRK2 protein would produce a therapeutic effect in the patient, the method comprising administering to the patient an effective amount of any compound according to this disclosure, optionally in combination with another bioactive agent, or an effective amount of any pharmaceutical composition according to this disclosure.

[0119] This disclosure also provides a method for treating a human patient in response to said treatment for a disease state, symptom, or condition causally associated with α-synuclein expression, overexpression, mutation, aggregation, accumulation, misfolding, or dysregulation, wherein degradation of the LRRK2 protein and / or its mutated form would produce a therapeutic effect in the patient, the method comprising administering to the patient an effective amount of any compound according to this disclosure, optionally in combination with another bioactive agent, or an effective amount of any pharmaceutical composition according to this disclosure.

[0120] Furthermore, this document discloses a method for treating human patients who require treatment for a disease state, symptom, or condition causally associated with Tau overexpression, mutation, aggregation, misfolding, or dysregulation, wherein degradation of the LRRK2 protein and / or its mutated form will produce a therapeutic effect in the patient, the method comprising administering to the patient an effective amount of any compound according to this disclosure, optionally in combination with another bioactive agent, or an effective amount of any pharmaceutical composition according to this disclosure.

[0121] In the embodiments, the disease state, symptom, or condition may be caused by microbial agents or other exogenous agents (such as viruses, bacteria, fungi, protozoa, or other microorganisms), or may be a disease state caused by the expression, overexpression, mutation, misfolding, or dysregulation of proteins, which leads to the disease state, symptom, or condition.

[0122] In the embodiments, disease states, symptoms, or symptoms that can be treated with compounds or pharmaceutical compositions according to this disclosure include, for example, Parkinson's disease (PD), idiopathic PD, LRRK2 mutation-associated PD (e.g., PD associated with one or more LRRK2 activating mutations), primary tau protein diseases (e.g., progressive supranuclear palsy (PSP) or corticobasal degeneration (CBD)), Lewy body dementia, Crohn's disease, leprosy (e.g., leprosy with type 1 inflammatory response), and / or neuroinflammatory diseases (as observed in Alzheimer's disease, PD, multiple sclerosis, traumatic brain injury, spinal cord injury, etc.).

[0123] This article also provides a method for treating or improving at least one symptom of a disease or condition in a subject, the method comprising the following steps: a) Providing a subject, the subject being identified as having symptoms of a disease or condition causally related to the expression, overexpression, mutation, misfolding, or dysregulation of LRRK2 protein and / or its mutant forms in the subject, and treating or improving the symptoms of the disease or condition by degrading LRRK2 protein and / or its mutant forms in the subject's cells; and b) Administering to a subject an effective amount of a compound comprising a small molecule of the present disclosure, such that the LRRK2 protein and / or its mutant form are degraded, thereby treating or improving at least one symptom of the subject’s disease or condition.

[0124] Application / Dosage / Formulation Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide, oils (specifically, cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, oral compositions may also include adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and aromatizers.

[0125] Injectable formulations (e.g., sterile injectable aqueous or oily suspensions) can be formulated using suitable dispersants or wetting agents and suspending agents according to known techniques. Sterile injectable formulations can also be sterile injectable solutions, suspensions, or emulsions in the form of non-toxic, parenteral-acceptable diluents or solvents, such as solutions in the form of 1,3-butanediol. Acceptable mediators and solvents that can be used include water, Ringer's solution, USP, and isotonic sodium chloride solution. Additionally, sterile, non-volatile oils are conventionally used as solvents or suspension media. For this purpose, any mild fixed oil can be used, including synthetic monoglycerides or diglycerides. Furthermore, fatty acids such as oleic acid are used to prepare injectables.

[0126] To prolong the action of a drug, it is generally desirable to slow the absorption of drugs administered subcutaneously or intramuscularly. This can be achieved using liquid suspensions of poorly water-soluble crystalline or amorphous materials. The absorption rate of the drug then depends on its dissolution rate, which in turn can depend on the crystal size and crystal form. Alternatively, delayed absorption of parenteral drug forms is achieved by dissolving or suspending the drug in an oily medium.

[0127] The composition for rectal or vaginal application is preferably a suppository, which can be prepared by mixing the compound of the present disclosure with a suitable non-irritating excipient or carrier (such as cocoa butter, polyethylene glycol or suppository wax), which is solid at room temperature but liquid at body temperature and thus can melt in the rectal or vaginal cavity and release the active compound.

[0128] Similar solid compositions can also be used as fillers in soft-filled and hard-filled gelatin capsules, which use excipients such as lactose (or milk sugar) and high molecular weight polyethylene glycol.

[0129] The active compound can also be in microencapsulated form with one or more excipients as described above. Solid dosage forms such as tablets, sugar-coated pills, capsules, pellets, and granules can be prepared using coatings and shells, such as enteric coatings, release-controlled coatings, and other coatings well known in the field of pharmaceutical formulation. In such solid dosage forms, the active compound can be mixed with at least one inert diluent, such as sucrose, lactose, or starch. Normally, in addition to an inert diluent, such dosage forms may contain other substances, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pellets, the dosage form may also contain a buffer.

[0130] Dosage forms for topical or transdermal application of the compounds of this disclosure include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalers, or patches. Under aseptic conditions, the active ingredient is mixed with a pharmaceutically acceptable carrier and any desired preservatives or buffers, if necessary. Ophthalmic formulations, ear drops, eye ointments, powders, and solutions are also considered to be within the scope of this disclosure.

[0131] In addition to the active compounds disclosed herein, the ointments, pastes, creams and gels may also contain excipients such as animal and vegetable fats, oils, waxes, paraffin wax, starch, astragalus gum, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid, talc and zinc oxide or mixtures thereof.

[0132] In addition to the compounds disclosed herein, powders and aerosols may also contain excipients such as lactose, talc, silica, aluminum hydroxide, calcium silicate, and polyamide powders or mixtures thereof. Aerosols may also contain conventional propellants such as chlorofluorocarbons (CFCs).

[0133] Transdermal patches offer the added advantage of providing controlled delivery of compounds into the body. Such dosage forms can be prepared by dissolving or dispersing the compound in a suitable medium. Absorption enhancers can also be used to increase the flow of the compound across the skin. The rate can be controlled by providing a rate-controlled membrane or by dispersing the compound in a polymer matrix or gel.

[0134] The disclosed compound can be administered intratympanicly, wherein a long, narrow, perforated needle is passed through the ear canal and through the eardrum to deliver the drug into the middle ear space, where the compound is absorbed by the inner ear.

[0135] According to the treatment methods of this disclosure, a subject's condition is treated or prevented by administering a therapeutically effective amount of the disclosed compound to the subject, wherein such an amount and duration of administration are necessary to achieve the desired outcome. As used herein, the term "therapeuticly effective amount" for a compound of this disclosure means an amount of compound sufficient to alleviate the subject's symptoms. As is well understood in the medical field, a therapeutically effective amount of the disclosed compound would be used in any medical treatment with a reasonable benefit / risk ratio.

[0136] In general, the compounds disclosed herein will be administered, alone or in combination with one or more therapeutic agents, in a therapeutically effective amount using any commonly used and acceptable method known in the art. Therapeuticly effective amounts can vary considerably depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used, and other factors. Generally, a daily dose of about 0.03 mg / kg body weight to 2.5 mg / kg body weight indicates that satisfactory results have been obtained systematically. In larger mammals (e.g., humans), the indicated daily dose is conveniently administered in the range of about 0.5 mg to about 100 mg, for example, in fractional doses up to four times daily or in a sustained-release form. Suitable unit dosage forms for oral administration contain about 1 mg to 50 mg of the active ingredient.

[0137] In embodiments, the therapeutic amount or dose of the compounds of this disclosure can range from about 0.1 mg / kg to about 500 mg / kg, and alternatively from about 1 mg / kg to about 50 mg / kg. Generally, a treatment regimen according to this disclosure comprises administering about 10 mg to about 1000 mg of the compounds of this disclosure daily in single or multiple doses to a patient requiring such treatment. The therapeutic amount or dose will also vary depending on the route of administration and the possibility of use with other pharmaceutical agents.

[0138] When the subject's symptoms improve, a maintenance dose of the disclosed compounds, compositions, or combinations may be administered if necessary. Subsequently, as symptoms change and have been reduced to the desired level, the dose or frequency, or both, may be reduced to a level that maintains the improved symptoms, and treatment should be discontinued. However, in the event of any recurrence of disease symptoms, the subject may require long-term intermittent treatment.

[0139] However, it should be understood that the total daily dosage of the compounds and compositions disclosed herein will be determined by the attending physician within the bounds of reasonable medical judgment. The specific inhibitor dosage for any particular patient will depend on a variety of factors, including the condition being treated and its severity; the activity of the specific compound used; the specific composition used; the patient's age, weight, general health condition, sex, and diet; the timing, route of administration, and excretion rate of the specific compound used; the duration of treatment; drugs used in combination with or concurrently with the specific compound used; and similar factors well known in the medical field.

[0140] This disclosure also provides pharmaceutical combinations, such as kits, comprising a) a first pharmaceutical agent, which is a compound of this disclosure in free form or in a pharmaceutically acceptable salt form as disclosed herein, and b) at least one adjuvant. The kit may include instructions for use.

[0141] Examples of materials that can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers; alumina; aluminum stearate; lecithin; serum proteins (such as human serum albumin); buffers (such as phosphates, glycine, sorbic acid, or potassium sorbate); mixtures of metaglycerides 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; polyacrylates; waxes; polyethylene-polyoxypropylene block polymers; lanolin; and sugars (such as lactose, glucose, and sucrose). Starch (such as corn starch and potato starch); cellulose and its derivatives (such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate); powdered tragacanth gum; malt; gelatin; talc; excipients (such as cocoa butter and suppository wax); oils (such as peanut oil, cottonseed oil, safflower oil, sesame oil; olive oil, corn oil, and soybean oil); glycols (such as propylene glycol or polyethylene glycol); esters (such as ethyl oleate and ethyl laurate); agar; buffers (such as magnesium hydroxide and aluminum hydroxide); alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; and phosphate buffer solutions. Furthermore, non-toxic and compatible lubricants, such as sodium dodecyl sulfate and magnesium stearate, as well as colorants, release agents, coating agents, sweeteners, flavorings and aromatizers, preservatives, and antioxidants may also be present in the composition, according to the formulator's judgment. Protein kinase inhibitors or their pharmaceutical salts may be formulated into pharmaceutical compositions for administration to animals or humans. These pharmaceutical compositions, which contain a certain amount of a protein inhibitor effective for treating or preventing protein kinase-mediated symptoms and a pharmaceutically acceptable carrier, are other embodiments of this disclosure.

[0142] Reagent test kit This document provides a kit containing a compound capable of inducing LRRK2 degradation in subjects, and instructions for use in treating LRRK2-related conditions, the compound comprising one or more of the compounds described herein.

[0143] This document also provides a kit containing the compounds described herein for the treatment of any of the indications described herein.

[0144] Those skilled in the art will recognize that many equivalents can be confirmed by routine experimentation alone regarding the specific procedures, embodiments, claims, and examples described herein. Such equivalents are considered to be within the scope of this disclosure and are covered by the appended claims. For example, it should be understood that modifications made using art-recognized alternatives and by routine experimentation alone, in terms of reaction conditions (including but not limited to reaction time, reaction size / volume) and experimental reagents (such as solvents, catalysts, pressure, atmospheric conditions, e.g., nitrogen atmosphere) and reducing / oxidizing agents, are within the scope of this application.

[0145] It should be understood that whenever values ​​and ranges are provided herein, all values ​​and ranges covered by these values ​​and ranges are intended to be covered within the scope of this disclosure. Furthermore, all values ​​falling within these ranges, as well as the upper or lower limits of the value ranges, are also contemplated in this application.

[0146] The following examples further illustrate aspects of this disclosure. However, they are by no means intended to limit the teachings of this disclosure.

[0147] Example The compounds and methods described herein are further illustrated by the following examples, but these examples should not be construed as further limitations. Unless otherwise stated, the practice of this disclosure will employ conventional techniques of organic synthesis, cell biology, cell culture, and molecular biology, all of which are within the scope of the art.

[0148] abbreviations Synthesis program Exemplary synthesis of compound 1: intermediate trans Synthesis of 4-[4-(dimethoxymethyl)cyclohexyloxy]piperidine-1-carboxylic acid benzyl ester Step 1 At 0℃ trans Ethyl 4-hydroxycyclohexanecarboxylate (20 g, 116.13 mmol, 1 equivalent) was added to a solution of TMSCl (13.88 g, 127.74 mmol, 16.21 mL, 1.1 equivalent) and TEA (14.10 g, 139.36 mmol, 19.40 mL, 1.2 equivalent) in THF (200 mL), and the reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. Et3SiH (20.25 g, 174.19 mmol, 27.82 mL, 1.5 equivalents) and TMSOTf (14.20 g, 63.87 mmol, 11.54 mL, 0.55 equivalents) were added dropwise to the residue and benzyl 4-oxoperidin-1-carboxylate (31.15 g, 133.55 mmol, 26.63 mL, 1.15 equivalents) in a stirred solution of DCM (300 mL) under N2 at -65 °C, and the reaction mixture was stirred under N2 at 0 °C for 3 hours. The reaction mixture was quenched by adding water (300 mL) and stirred with DCM (200 mL). 3) Extraction. The combined organic layers were washed with brine (300 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by rapid silica gel chromatography (ISCO®; 120 g SepaFlash® silica rapid column, elution with 0–20% ethyl acetate / petroleum ether gradient at 100 mL / min). A colorless oil was obtained. trans 4-(4-ethoxycarbonylcyclohexyl)piperidine-1-carboxylic acid benzyl ester (40.8 g, 104.75 mmol, 90.20% yield).

[0149] Step 2 Towards trans Benzyl 4-(4-ethoxycarbonylcyclohexyloxy)piperidine-1-carboxylate (40.8 g, 104.75 mmol, 1 equivalent) was added to a solution of Pd / C (8 g, 104.75 mmol, 10%, 1 equivalent) in EtOH (40 mL), and the mixture was stirred at 25 °C for 4 hours under H2 (15 psi). TLC (petroleum ether:ethyl acetate = 3:1, I2) showed the formation of new spots. The reaction mixture was filtered and concentrated under reduced pressure to give the residue. A colorless solid was obtained. trans 4-(4-piperidinyloxy)cyclohexanecarboxylate (26.7 g, 104.56 mmol, 99.82% yield).

[0150] Step 3 At 0℃ trans Ethyl 4-(4-piperidinyloxy)cyclohexanecarboxylate (10 g, 39.16 mmol, 1 equivalent) was added to a solution of 4-(4-piperidinyloxy)cyclohexanecarboxylate in THF (70 mL), and LiAlH4 (2.23 g, 58.74 mmol, 1.5 equivalent) was added. The solution was stirred at 0 °C under N2 for 2 h. TLC (dichloromethane:methanol = 5:1) showed that the starting material was completely consumed. The reaction mixture was quenched at 0 °C by adding water (2 mL) and 10% NaOH (4 mL), then dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. A pale yellow solid was obtained. trans -[4-(4-piperidinyloxy)cyclohexyl]methanol (7.9 g, 37.03 mmol, 94.57% yield).

[0151] Step 4 Under N2 at 0°C trans CbzCl (31.19 g, 182.83 mmol, 25.99 mL, 1.3 equivalent) and TEA (42.69 g, 421.91 mmol, 58.72 mL, 3 equivalent) were added to a mixture of 300 mL of [4-(4-piperidinoxy)cyclohexyl]methanol (30 g, 140.64 mmol, 1 equivalent) in DCM. After addition, the reaction mixture was stirred at 25 °C for 1 h to give a pale yellow suspension. The reaction was quenched with H2O (200 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic phases were washed with water, dried over Na2SO4, and concentrated under vacuum to give a residue. The residue was purified by silica gel column chromatography (0-100% ethyl acetate / petroleum ether) to give a colorless oil. trans 4-[4-(hydroxymethyl)cyclohexyloxy]piperidine-1-carboxylic acid benzyl ester (37 g, 106.49 mmol, 75.72% yield).

[0152] Step 5 Add DMP (55.50 g, 130.85 mmol, 40.51 mL, 1.23 equivalents) to trans Benzyl 4-[4-(hydroxymethyl)cyclohexyloxy]piperidine-1-carboxylate (37 g, 106.49 mmol, 1 equivalent) was added to a solution of DCM (200 mL) and the mixture was stirred at 25 °C for 2 hours to obtain a yellow solution. The reaction mixture was quenched at 0 °C by adding saturated NaHCO3 (pH ~8) and then stirred with DCM (100 mL) 3) Extraction. The combined organic layers were extracted with saturated Na2SO3 (100 mL). 2) and saline (60 mL) 2) Wash, dry with Na2SO4, filter, and concentrate under reduced pressure to obtain the residue. Purify the residue by silica gel chromatography (petroleum ether / ethyl acetate = 100 / 1, 1 / 1) to obtain a colorless oil. trans 4-(4-formylcyclohexyloxy)piperidine-1-carboxylic acid benzyl ester (30 g, 85.98 mmol, 80.74% yield, 99% purity).

[0153] Step 6 Under N2 at 25°C transBenzyl 4-(4-formylcyclohexyloxy)piperidine-1-carboxylate (30 g, 86.85 mmol, 1 equivalent) was added in a single reaction to a solution of 4-(4-formylcyclohexyloxy)piperidine-1-carboxylate in 200 mL of MeOH, along with TosOH (747.77 mg, 4.34 mmol, 0.05 equivalent) and trimethoxymethane (46.08 g, 434.24 mmol, 47.60 mL, 5 equivalent). The mixture was stirred at 25 °C for 2 hours. The reaction solution was quenched with 100 mL of H₂O and thiamethoxam (3... Extraction was performed using 200 mL of the extract. The combined organic phases were washed with water, dried over Na₂SO₄, and concentrated under vacuum to obtain a residue. The residue was purified by silica gel column chromatography (0-30% ethyl acetate / petroleum ether) to give a colorless oil. trans 4-[4-(dimethoxymethyl)cyclohexyloxy]piperidine-1-carboxylic acid benzyl ester (31 g, 75.22 mmol, 86.62% yield, 95% purity).

[0154] Step 7 At 25°C under H2 (15 PSI) conditions... trans Benzyl 4-[4-(dimethoxymethyl)cyclohexyloxy]piperidine-1-carboxylate (31 g, 79.18 mmol, 1 equivalent) was added to a mixture of EtOH (200 mL) with Pd / C (8 g, 79.18 mmol, 10% purity, 1 equivalent) for 16 hours. TLC (petroleum ether:ethyl acetate = 3:1) showed a new spot. The residue was filtered and concentrated under vacuum to give a white solid. trans -4-[4-(dimethoxymethyl)cyclohexyloxy]piperidine (18.6 g, 72.27 mmol, 91.27% yield).

[0155] Synthesis of intermediate 5-(1-methylcyclopropoxy)-3-(6-piperazin-1-ylpyrimidin-4-yl)-1H-pyrazolo[3,4-c]pyridine: Step 1 Under nitrogen atmosphere, (+ / -)-2,2-bis(diphenylphosphino)-1,1-dinaphthyl (2.16 g, 3.48 mmol, 0.06 equivalent), cesium carbonate (28.32 g, 86.92 mmol, 1.5 equivalent), and bis(dibenzylacetone)palladium(0) (666 mg, 1.16 mmol, 0.02 equivalent) were added to a solution of 2-chloro-4-methyl-5-nitropyridine (10 g, 57.95 mmol, 1 equivalent), 1-methylcyclopropanol (8.36 g, 115.90 mmol, 2 equivalent) in toluene (100 mL), cesium carbonate (28.32 g, 86.92 mmol, 1.5 equivalent), and bis(dibenzylacetone)palladium(0) (666 mg, 1.16 mmol, 0.02 equivalent). The reaction mixture was stirred at 100 °C for 3 h and then cooled. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate = 1:0 to 20:1). 4-Methyl-2-(1-methylcyclopropoxy)-5-nitropyridine (7.7 g, 36.98 mmol, 63.82% yield) was obtained as a colorless oil.

[0156] Step 2 Palladium / activated carbon (0.8 g, 10% purity) was added to a solution of 4-methyl-2-(1-methylcyclopropoxy)-5-nitro-pyridine (8.6 g, 41.30 mmol, 1 equivalent) in ethanol (100 mL) under nitrogen atmosphere. The reaction was stirred at 20 °C for 12 h under hydrogen atmosphere (15 Psi). TLC (petroleum ether:ethyl acetate = 3:1) showed the detection of new spots. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was used directly in the next step. 4-methyl-6-(1-methylcyclopropoxy)pyridine-3-amine (7.1 g, 39.84 mmol, 96% yield) was given as a pink solid.

[0157] Step 3 Triethylamine (8.06 g, 79.67 mmol, 11 mL, 2 equivalents) and acetic anhydride (6.10 g, 59.75 mmol, 5.6 mL, 1.5 equivalents) were added to a solution of 4-methyl-6-(1-methylcyclopropoxy)pyridin-3-amine (7.1 g, 39.84 mmol, 1 equivalent) in dichloromethane (100 mL) at 0 °C. The reaction mixture was stirred at 20 °C for 1 hour. TLC (petroleum ether:ethyl acetate = 1:1) showed the detection of new spots. Water (100 mL) was added and the mixture was stirred with dichloromethane (50 mL) 2) Extraction. The combined organic phases were washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate = 10:1 to 0:1). N-[4-methyl-6-(1-methylcyclopropoxy)-3-pyridyl]acetamide (8.3 g, 37.68 mmol, 94.59% yield, 100% purity) was given as a brown oil.

[0158] Step 4 A mixture of N-[4-methyl-6-(1-methylcyclopropoxy)-3-pyridyl]acetamide (7.3 g, 33.14 mmol, 1 equivalent), potassium acetate (4.88 g, 49.71 mmol, 1.5 equivalent), and acetic anhydride (15.56 g, 152.45 mmol, 14.28 mL, 4.6 equivalent) in toluene (150 mL) was heated to 80 °C. Amyl nitrite (15.53 g, 132.57 mmol, 17.8 mL, 4 equivalent) was added dropwise. The reaction mixture was stirred at 80 °C for 12 hours. LC-MS showed the desired MS. The mixture was filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate = 1:0 to 20:1). 1-[5-(1-methylcyclopropoxy)pyrazolo[3,4-c]pyridin-1-yl]acetone was given as a yellow solid (4.9 g, 21.19 mmol, 63.94% yield).

[0159] Step 5 Potassium carbonate (4.39 g, 31.78 mmol, 1.5 equivalent) was added to a solution of 1-[5-(1-methylcyclopropoxy)pyrazolo[3,4-c]pyridin-1-yl]acetone (4.9 g, 21.19 mmol, 1 equivalent) in methanol (50 mL). The reaction mixture was stirred at 20 °C for 1 hour. Ethyl acetate (100 mL) was added, and HCl solution (1 M) was added to adjust the pH to 7. Water (100 mL) was added to the mixture, and the aqueous phase was diluted with ethyl acetate (100 mL) 2) Extraction. The combined organic phases were washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was used directly in the next step. 5-(1-methylcyclopropoxy)-1H-pyrazolo[3,4-c]pyridine (3.9 g, 20.61 mmol, 97% yield) was given as a yellow solid.

[0160] Step 6 Potassium hydroxide (1.85 g, 33.03 mmol, 2.5 equivalents) and iodine (3.69 g, 14.53 mmol, 2.93 mL, 1.1 equivalents) were added to a solution of 5-(1-methylcyclopropoxy)-1H-pyrazolo[3,4-c]pyridine (2.5 g, 13.21 mmol, 1 equivalent) in N,N-dimethylformamide (25 mL). The reaction mixture was stirred at 20 °C for 12 h. The mixture was quenched by adding saturated sodium sulfite. Water (100 mL) was added to the mixture, and HCl solution (1 M) was added to the mixture to adjust the pH to 4. The solid was filtered and dried under vacuum. The mixture was used directly for the next step. 3-iodo-5-(1-methylcyclopropoxy)-1H-pyrazolo[3,4-c]pyridine (3.9 g, 12.38 mmol, 94% yield) was obtained as a pale yellow solid.

[0161] Step 7 Sodium hydride (594 mg, 14.85 mmol, 60% purity in mineral oil, 1.2 equivalents) was added to a solution of 3-iodo-5-(1-methylcyclopropoxy)-1H-pyrazolo[3,4-c]pyridine (3.9 g, 12.38 mmol, 1 equivalent) in tetrahydrofuran (40 mL) at 0 °C, and the mixture was stirred at 0 °C for 0.5 h. Then, triphenylmethyl chloride (3.80 g, 13.61 mmol, 1.1 equivalents) was added to the mixture at 0 °C, and the reaction mixture was stirred at 20 °C for 10 h. Saturated ammonium chloride (100 mL) was added to the mixture, and the aqueous phase was diluted with ethyl acetate (100 mL). 3) Extraction. The combined organic phases were washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate = 1:0 to 20:1). 3-Iodo-5-(1-methylcyclopropoxy)-1-triphenylmethyl-pyrazolo[3,4-c]pyridine (5.9 g, 10.58 mmol, 85% yield) was confirmed as a pale yellow solid.

[0162] Step 8 Pd(dppf)Cl2 (301.91 mg, 412.61 μmol, 0.1 equivalent) and KOAc (1.21 g, 12.38 mmol, 3 equivalent) were added to a solution of 3-iodo-5-(1-methylcyclopropoxy)-1-triphenylmethyl-pyrazolo[3,4-c]pyridine (2.3 g, 4.13 mmol, 1 equivalent) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1,3,2-dioxacyclopentaborane (2.10 g, 8.25 mmol, 2 equivalent) in dioxane (20 mL). The mixture was then stirred at 100 °C for 16 h under N2 and cooled. The reaction mixture was filtered and concentrated under reduced pressure to give 5-(1-methylcyclopropoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1-triphenylmethyl-pyrazolo[3,4-c]pyridine (2.3 g, crude product) as a gray gel.

[0163] Step 9 To a solution of 5-(1-methylcyclopropoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1-triphenylmethyl-pyrazolo[3,4-c]pyridine (2.3 g, 4.13 mmol, 1 equivalent) and 4,6-dichloropyrimidine (921.95 mg, 6.19 mmol, 1.5 equivalent) in dioxane (20 mL) and H2O (4 mL), Na2CO3 (1.31 g, 12.38 mmol, 3 equivalent) and Pd(dppf)Cl2 (301.88 mg, 412.56 μmol, 0.1 equivalent) was added. The mixture was then stirred at 100 °C for 1 h under N2. TLC (petroleum ether:ethyl acetate = 5:1, Rf = 0.7) showed no starting material and a major new spot was detected. The reaction mixture was filtered and concentrated under reduced pressure. H₂O (20 mL) was added to quench the reaction, and the mixture was then diluted with ethyl acetate (3... Extracted by 20 mL. The combined organic phases were washed with water, dried over Na2SO4, and concentrated under vacuum to obtain the residue. The residue was purified by silica gel column chromatography (0 to 30% ethyl acetate / petroleum ether) to give 3-(6-chloropyrimidin-4-yl)-5-(1-methylcyclopropoxy)-1-triphenylmethyl-pyrazolo[3,4-c]pyridine (1.73 g, 2.54 mmol, 61.66% yield, 80% purity) as a grayish-white solid.

[0164] Step 10 DIEA (641.40 mg, 4.96 mmol, 864.42 μL, 3 equivalents) was added to a solution of 3-(6-chloropyrimidin-4-yl)-5-(1-methylcyclopropoxy)-1-triphenylmethyl-pyrazolo[3,4-c]pyridine (0.9 g, 1.65 mmol, 1 equivalent) and piperazine-1-carboxylic acid tert-butyl ester (462.17 mg, 2.48 mmol, 1.5 equivalents) in DMSO (10 mL), and the reaction mixture was stirred at 80 °C under N2 for 16 hours and then cooled. The reaction was quenched with NH4Cl solution (80 mL), and the mixture was further quenched with ethyl acetate (3... Extracted by 60 mL. The combined organic phases were washed with water, dried over Na2SO4, and concentrated under vacuum to give the residue. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 100 / 1, 1 / 1) to give tert-butyl 4-[6-[5-(1-methylcyclopropoxy)-1-triphenylmethyl-pyrazolo[3,4-c]pyridin-3-yl]pyrimidin-4-yl]piperazine-1-carboxylate (1 g, 1.35 mmol, 81.90% yield, 94% purity) as a white solid.

[0165] Step 11 To a solution of tert-butyl 4-[6-[5-(1-methylcyclopropoxy)-1-triphenylmethyl-pyrazolo[3,4-c]pyridin-3-yl]pyrimidin-4-yl]piperazine-1-carboxylate (1 g, 1.44 mmol, 1 equivalent) in DCM (6 mL), HCl / dioxane (4 M, 6 mL, 16.65 equivalent) was added, and the reaction mixture was stirred at 40 °C under N2 for 4 hours. After cooling, the reaction mixture was filtered, and the filter cake was collected. The solid was dissolved in water (50 mL), and the solution was alkalized to pH ~13 with NaOH and then dissolved in ethyl acetate (50 mL). 3) Extraction. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give 5-(1-methylcyclopropoxy)-3-(6-piperazin-1-ylpyrimidin-4-yl)-1H-pyrazolo[3,4-c]pyridine as a red solid (490 mg, 1.39 mmol, 96.75% yield).

[0166] Exemplary final synthesis of compound 1: Step 1 BnOH (13.6 mL, 131.19 mmol, 3.0 equivalent) and Cs₂CO₃ (57.0 g, 174.91 mmol, 4.0 equivalent) were added to a stirred solution of 2,6-difluoro-3-nitropyridine (7.0 g, 43.73 mmol, 1.0 equivalent) in acetonitrile (140 mL). The resulting mixture was heated to 55 °C for 5 hours and then cooled. The reaction mixture was filtered and concentrated under vacuum. The residue was purified by passing it through a Biotage® combi flash (column: 120 g Biotage® silica fast column; eluent: gradient 0–3% ethyl acetate / petroleum ether; gradient time: 20 min; hold time: 100 min; flow rate: 100 mL / min). The pure fractions were combined and concentrated under reduced pressure to give 2,6-dibenzyloxy-3-nitropyridine as a yellow solid (16.5 g, 39.74 mmol, 90.87% yield, 81% purity).

[0167] Step 2 Fe (8.9 g, 158.95 mmol, 8.0 equivalent) and NH4Cl (15.9 g, 298.02 mmol, 15.0 equivalent) were added to a stirred solution of 2,6-dibenzyloxy-3-nitropyridine (8.25 g, 19.87 mmol, 81% purity, 1.0 equivalent) in i-PrOH (160 mL) and H2O (80 mL). The resulting mixture was heated to 90 °C for 12 hours (in duplicate). The reaction mixture was cooled to ambient temperature and ethyl acetate (200 mL) was added. The mixture was filtered to remove insoluble solids, and the filter cake was washed with ethyl acetate (75 mL × 2). The combined organic extracts were washed with brine (150 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by passing it through a Biotage® combi flash (column: 120 g Biotage® silica fast column; eluent: gradient 0–5% ethyl acetate / petroleum ether; gradient time: 30 min; hold time: 120 min; flow rate: 100 mL / min). The purified fractions were combined and concentrated under reduced pressure to give 2,6-dibenzyloxypyridine-3-amine (11.5 g, 29.95 mmol, 75.38% yield, 80% purity) as a yellow oil.

[0168] Step 3 DIEA (5.7 mL, 32.64 mmol, 2.5 equivalence) was added to a solution of 2,6-dibenzyloxypyridine-3-amine (4.0 g, 13.06 mmol, 1.0 equivalence) in DMSO (45 mL). The reaction mixture was stirred at 100 °C for 16 h and then cooled. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (50 mL × 2) and dried over Na2SO4. The mixture was filtered and concentrated under reduced pressure to obtain a residue, which was purified by passing it through a Biotage® combiflash (column: 80 g Biotage® silica fast column; eluent: gradient 0–5% tetrahydrofuran / petroleum ether; gradient time: 15 min; hold time: 30 min; flow rate: 70 mL / min). The purified fraction was concentrated under reduced pressure to provide 2,6-dibenzyloxy-N-(4-bromo-2-nitro-phenyl)pyridine-3-amine (3.47 g, 6.85 mmol, 52% yield) as a brown solid.

[0169] Step 4 NH₄Cl (5.50 g, 102.80 mmol, 15.0 equivalent) and Fe (1.91 g, 34.27 mmol, 5.0 equivalent) were added to a solution of 2,6-dibenzyloxy-N-(4-bromo-2-nitro-phenyl)pyridin-3-amine (3.47 g, 6.85 mmol, 1.0 equivalent) in methanol (50 mL) and water (5 mL). The mixture was stirred at 90 °C for 1 hour and then cooled. The mixture was filtered and the filtrate was concentrated under reduced pressure. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give 4-bromo-N₁-(2,6-dibenzyloxy-3-pyridinyl)phenyl-1,2-diamine (2.97 g, 6.23 mmol, 90% yield) as a colorless liquid.

[0170] Step 5 CDI (9.43 g, 58.15 mmol, 10.0 equivalent) was added to a solution of 4-bromo-N1-(2,6-dibenzyloxy-3-pyridyl)benzene-1,2-diamine (2.77 g, 1.84 mmol, 1.0 equivalent) in 1,4-dioxane (90 mL). The mixture was stirred at 120 °C for 12 h and then cooled. The mixture was concentrated to remove most of the solvent and diluted with water (50 mL). The aqueous phase was extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with water (15 mL × 6) and brine (15 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by passing it through a Biotage® combi flash (column: 80 g Biotage® silica fast column; eluent: gradient 0–30% ethyl acetate / petroleum ether; gradient time: 20 min; hold time: 10 min; flow rate: 70 mL / min). The pure fraction was collected and concentrated under reduced pressure to give 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1H-benzimidazole-2-one (2.7 g, 5.37 mmol, 92% yield) as a white solid.

[0171] Step 6 Cs₂CO₃ (1.62 g, 4.98 mmol, 2.5 equivalents) and iodomethane (0.37 mL, 5.97 mmol, 3.0 equivalents) were added to a solution of 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1H-benzimidazol-2-one (1.0 g, 1.99 mmol, 1.0 equivalent) in DMF (10 mL). The mixture was stirred at 25 °C for 16 hours. The reaction mixture was quenched with water (15 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with water (10 mL × 3) and brine (15 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by passing it through a Biotage® combi flash (column: 40 g Biotage® silica fast column; eluent: gradient 0–23% ethyl acetate / petroleum ether; gradient time: 30 min; hold time: 5 min; flow rate: 35 mL / min). The purified fraction was collected and concentrated under reduced pressure to give 5-bromo-1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-benzimidazol-2-one (1.03 g, 1.99 mmol, 91% yield) as a white foam.

[0172] Step 7 To 5-bromo-1-(2,6-dibenzyloxy-3-pyridyl)-3-methyl-benzimidazol-2-one (500 mg, 968.27 μmol, 1 equivalent) and trans -4-[4-(dimethoxymethyl)cyclohexyloxy]piperidine (299.04 mg, 1.16 mmol, 1.2 equivalents) was added to a solution of dioxane (10 mL) along with XPHOS-PD-G2 (76.18 mg, 96.83 μmol, 0.1 equivalents) and Cs₂CO₃ (946.44 mg, 2.90 mmol, 3 equivalents). The mixture was stirred at 90 °C under N₂ for 16 hours and then cooled. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL × 2). The combined organic layers were washed with brine (20 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by silica gel chromatography (column height: 20 g, 100-200 mesh silica gel, 0-30% (5 min) ethyl acetate / petroleum ether, 30-100% (15 min) ethyl acetate / petroleum ether, 50-100% (5 min) ethyl acetate / petroleum ether) to obtain a yellow solid. trans -1-(2,6-dibenzyloxy-3-pyridyl)-5-[4-[4-(dimethoxymethyl)cyclohexyloxy]-1-piperidinyl]-3-methyl-benzimidazole-2-one (520 mg, 750.53 μmol, 77.51% yield, N / A purity).

[0173] Step 8 Towards trans A solution of 1-(2,6-dibenzyloxy-3-pyridyl)-5-[4-[4-(dimethoxymethyl)cyclohexyloxy]-1-piperidinyl]-3-methyl-benzimidazol-2-one (520 mg, 750.53 μmol, 1 equivalent) in DMF (20 mL) was mixed with Pd / C (300 mg, 10% purity) and Pd(OH)2 (200 mg, 10% purity). The mixture was stirred at 40 °C for 16 hours under a H2 atmosphere (40 psi). The mixture was filtered and extracted with EtOAc (30 mL × 2). The combined organic layers were washed with 20 mL of brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by silica gel chromatography (column height: 4 g, 100-200 mesh silica gel, 0-30% (5 min) ethyl acetate / petroleum ether, 30-85% (15 min) ethyl acetate / petroleum ether, 50-100% (5 min) ethyl acetate / petroleum ether) to obtain a yellow solid. trans -3-[5-[4-[4-(dimethoxymethyl)cyclohexyloxy]-1-piperidinyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidin-2,6-dione (182 mg, 353.66 μmol, 47.12% yield, N / A purity).

[0174] Step 9 Towards trans A solution of 3-[5-[4-[4-(dimethoxymethyl)cyclohexyloxy]-1-piperidinyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidin-2,6-dione (182 mg, 353.66 μmol, 1 equivalent) in acetone (4 mL) and H₂O (0.4 mL) was mixed with TsOH (24.36 mg, 141.47 μmol, 0.4 equivalent). The mixture was then stirred at 80 °C for 16 hours and then cooled. Saturated NaHCO₃ (30 mL) was added to adjust the pH to 8, and the mixture was filtered to give a grayish-white solid. trans -4-[[1-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazol-5-yl]-4-piperidinyl]oxy]cyclohexaneformaldehyde (212 mg, crude product).

[0175] Step 10 Towards trans -4-[[1-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazol-5-yl]-4-piperidinyl]oxy]cyclohexanecarboxaldehyde (66.67 mg, 142.29 μmol, 1 equivalent) and 5-(1-methylcyclopropoxy)-3-(6-piperazin-1-ylpyrimidin-4-yl)-1H-pyrazolo[3,4-c]pyridine (50 mg, 142.29 μmol, 1 equivalent) were added to a solution of DCM (5 mL) and DMSO (3 mL), followed by stirring at 20 °C for 0.5 h. Then NaBH(OAc)3 (75.39 mg, 355.72 μmol, 2.5 equivalent) was added. After addition, the reaction mixture was stirred at 20°C for 3 hours. The reaction mixture was filtered and concentrated under vacuum. The impurities were then subjected to preparative HPLC (column: Ultimate C18 150). 40 mm 10 μm; mobile phase: [water (NH4HCO3)-ACN]; gradient: 28%-68% over 32 min. B) Purification to give compound 1 as a white solid (51.4 mg, 63.58 μmol, 44.69% yield, 99.45% purity).

[0176] Exemplary synthesis of compound 2: Synthesis of intermediate 3-[6-[4-[(2,2-dimethylpiperazin-1-yl)methyl]-1-piperidinyl]pyrimidin-4-yl]-5-(1-methylcyclopropoxy)-1H-indazole Step 1 3,3-Dimethylpiperidine-1-carboxylate tert-butyl ester (1.70 g, 7.93 mmol, 1 equivalent) was added to a solution of 4-formylpiperidine-1-carboxylate (1.78 g, 7.21 mmol, 1 equivalent) and HOAc (25.98 mg, 432.69 μmol, 24.75 μL, 0.06 equivalent) in DCM (10 mL), and the mixture was stirred at 25 °C for 20 h under N2. NaBH(OAc)3 (2.29 g, 10.80 mmol, 1.50 equivalent) was added, and the mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched by adding saturated NaHCO3 to pH = 8-9, and stirred with DCM (20 mL). 3) Extraction. The combined organic layers were rinsed with brine (50 mL). 2) The residue was washed, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by rapid silica gel chromatography (0–25% ethyl acetate / petroleum ether) to give tert-butyl 4-((1-((benzyloxy)carbonyl)piperidin-4-yl)methyl)-3,3-dimethylpiperazine-1-carboxylate (2.11 g, 4.73 mmol, 65.57% yield) as a colorless oil.

[0177] Step 2 Pd / C (500 mg, 10%) was added to a solution of 4-[(1-benzyloxycarbonyl-4-piperidinyl)methyl]-3,3-dimethyl-piperazine-1-carboxylate (2.1 g, 4.71 mmol, 1 equivalent) in MeOH (20 mL) under N2. The suspension was degassed under vacuum and purged several times with H2. The mixture was stirred at 25 °C for 1 h under H2 (15 psi). TLC (petroleum ether:ethyl acetate = 1:1) showed that the reaction was complete. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give 3,3-dimethyl-4-(4-piperidinylmethyl)piperazine-1-carboxylate (1.39 g, 4.46 mmol, 94.70% yield) as a white gel.

[0178] Step 3 TEA (176.08 mg, 1.74 mmol, 242.20 μL, 5 equivalents) and tert-butyl 3,3-dimethyl-4-(4-piperidinylmethyl)piperazine-1-carboxylate (216.79 mg, 696.05 μL, 2 equivalents) were added to a solution of 2-[[3-(6-chloropyrimidin-4-yl)-5-(1-methylcyclopropoxy)indazole-2-yl]methoxy]ethyl-trimethyl-silane (synthesis described below, 0.15 g, 348.03 μL, 1 equivalent) in DMSO (3 mL). The mixture was stirred at 100 °C for 1 hour and then cooled. The reaction mixture was quenched at 25 °C by adding EtOAc (50 mL) and water (50 mL). The organic layer was quenched with water (30 mL). 3) Wash, dry with Na2SO4, filter, and concentrate under reduced pressure to obtain the residue. Purify the residue by rapid silica gel chromatography (ISCO®; 4 g SepaFlash® silica rapid column, 50 mL / min with 0–20% ethyl acetate / petroleum ether gradient eluent) to obtain tert-butyl piperazine-1-carboxylate (0.19 g, 266.99 μmol, 76.72% yield, 99.210% purity) as a pale yellow solid.

[0179] Step 4 To a solution of tert-butyl piperazine-1-carboxylate (0.18 g, 254.96 μL, 1 equivalent) in MeOH (3 mL), HCl / EtOAc (4 M, 127.48 μL, 2 equivalents) was added. The mixture was stirred at 25 °C for 4 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent to give 3-[6-[4-[(2,2-dimethylpiperazin-1-yl)methyl]-1-piperidinyl]pyrimidin-4-yl]-5-(1-methylcyclopropoxy)-1H-indazole (0.13 g, crude product, HCl salt) as a white solid.

[0180] Synthesis of intermediate 2-[[3-(6-chloropyrimidin-4-yl)-5-(1-methylcyclopropoxy)indazole-2-yl]methoxy]ethyl-trimethyl-silane: Step 1 NaH (4.16 g, 104.01 mmol, 60% mineral oil, 1.5 equivalence) was added in a single addition to a solution of 2-bromo-4-fluoro-1-nitrobenzene (16.78 g, 76.28 mmol, 1.1 equivalence) and 1-methylcyclopropanol (5 g, 69.34 mmol, 1 equivalence) in DMF (160 mL) at 0 °C under N2. The mixture was then heated to 20 °C and stirred for 4 hours. The residue was poured into water (200 mL) and stirred for 10 minutes. The aqueous phase was extracted with ethyl acetate (3 × 300 mL). The combined organic phases were washed with brine (2 × 200 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (100-200 mesh silica gel, 0-2% ethyl acetate / petroleum ether) to give 2-bromo-4-(1-methylcyclopropoxy)-1-nitrobenzene (14.3 g, 52.56 mmol, 75.79% yield) as a yellow oil.

[0181] Step 2 At 20 °C, 2,4,6-trimethyl-1,3,5,2,4,6-trioxaborane (32.99 g, 131.39 mmol, 36.73 mL, 50% in EtOAc, 2.5 equivalents) and Pd(PPh3)4 (6.07 g, 5.26 mmol, 0.1 equivalents) were added to a mixture of 2-bromo-4-(1-methylcyclopropoxy)-1-nitrobenzene (14.3 g, 52.56 mmol, 1 equivalent), K2CO3 (14.53 g, 105.11 mmol, 2 equivalents), and Cs2CO3 (17.12 g, 52.56 mmol, 1 equivalent) in 1,4-dioxane (100 mL). The mixture was then heated to 100 °C and stirred for 16 hours to obtain a yellow solution. TLC showed that the reaction was complete. The reaction was cooled to 20°C and concentrated under vacuum. PE:EtOAc (10:1, 100 mL) was added to the residue, and the mixture was filtered through a silica pad. The filter pad was washed with petroleum ether:EtOAc (10:1, 1000 mL). The residue was purified by silica gel chromatography (100-200 mesh silica gel, 0-1% ethyl acetate / petroleum ether) to give 2-methyl-4-(1-methylcyclopropoxy)-1-nitrobenzene (11 g, crude product) as a yellow oil.

[0182] Step 3 10% Pd / C (4 g, 5.31 mmol, 0.1 equivalent) and ammonium formate (40.17 g, 636.99 mmol, 12 equivalent) were added in a single step to a mixture of 2-methyl-4-(1-methylcyclopropoxy)-1-nitro-benzene (11 g, 53.08 mmol, 1 equivalent) in EtOH (100 mL) at 20 °C under N2. The mixture was stirred at 20 °C for 2 hours to give a black mixture. TLC showed that the reaction was complete. The mixture was filtered through a silica gel pad, washed with EtOAc (3 × 200 mL), and concentrated under vacuum. The residue was purified by silica gel chromatography (0-10% ethyl acetate / petroleum ether) to give 2-methyl-4-(1-methylcyclopropoxy)aniline (9.8 g, crude product) as a red oil.

[0183] Step 4 Ac₂O (11.29 g, 110.58 mmol, 1 equivalent) was added in a single step to a mixture of 2-methyl-4-(1-methylcyclopropoxy)aniline (9.8 g, 55.29 mmol, 1 equivalent) and Et₃N (13.99 g, 138.23 mmol, 19.24 mL, 2.5 equivalent) in DCM (100 mL) at 0 °C under N₂. The mixture was stirred at 0 °C for 30 min, then heated to 20 °C and stirred for 16 h. TLC showed the reaction was complete. The reaction mixture was quenched with saturated NaHCO₃ aqueous solution (30 mL) to adjust the pH to 7–8 and extracted with DCM (3 × 50 mL). The combined organic phases were washed with brine (3 × 50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (20-40% ethyl acetate / petroleum ether) to give N-[2-methyl-4-(1-methylcyclopropoxy)phenyl]acetamide (9.3 g, 42.41 mmol, 76.71% yield) as a yellow oil.

[0184] Step 5 KOAc (6.24 g, 63.62 mmol, 1.5 equivalent) and Ac₂O (19.92 g, 195.09 mmol, 18.27 mL, 4.6 equivalent) were added to a solution of N-[2-methyl-4-(1-methylcyclopropoxy)phenyl]acetamide (9.3 g, 42.41 mmol, 1 equivalent) in toluene (100 mL) at 20 °C. The solution was heated to 80 °C, and then 3-methylbutyl nitrite (19.87 g, 169.65 mmol, 22.84 mL, 4 equivalent) was added dropwise. After the addition, the mixture was stirred at 80 °C for 2 hours. TLC showed that the reaction was complete. The reaction solution was then filtered, the wet filter cake was washed with EtOAc (70 mL), and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (100-200 mesh silica gel, 0-10% ethyl acetate / petroleum ether) to give 1-[5-(1-methylcyclopropoxy)indazole-1-yl]acetone (8 g, crude product) as a yellow solid.

[0185] Step 6 NH3 (g / L) MeOH (7 M, 24.82 mL, 5 equivalents) was added in a single batch to a mixture of 1-[5-(1-methylcyclopropoxy)indazole-1-yl]acetone (8 g, 34.74 mmol, 1 equivalent) in MeOH (80 mL) at 20 °C. The mixture was stirred at 20 °C for 2 hours to give a yellow solution. TLC showed that the reaction was complete. The solution was concentrated under vacuum to give 5-(1-methylcyclopropoxy)-1H-indazole (7.8 g, crude product) as a yellow solid.

[0186] Step 7 N-dicyclohexylmethylamine (10.52 g, 53.87 mmol, 1.3 equivalent) and SEM-Cl (8.29 g, 49.73 mmol, 8.80 mL, 1.2 equivalent) were added in a single step to a mixture of 5-(1-methylcyclopropoxy)-1H-indazole (7.8 g, 41.44 mmol, 1 equivalent) in THF (80 mL) at 20 °C. The mixture was stirred at 20 °C for 16 h to give an orange solution. TLC showed that the reaction was complete. The residue was poured into water (60 mL). The aqueous phase was extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with brine (2 × 50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (100-200 mesh silica gel, 0-10% ethyl acetate / petroleum ether) to give trimethyl-[2-[[5-(1-methylcyclopropoxy)indazole-2-yl]methoxy]ethyl]silane (5.4 g, 16.96 mmol, 40.92% yield), which was a yellow oil.

[0187] Step 8 n-BuLi (2.5 M, 13.40 mL, 1.3 equivalents) was added dropwise to a mixture of trimethyl-[2-[[5-(1-methylcyclopropoxy)indazol-2-yl]methoxy]ethyl]silane (4.36 g, 13.70 mmol, 5.32e-1 equivalents) in THF (6 mL) at -70 °C under N2. The mixture was then stirred at -78 °C for 1 hour, and a solution of ZnCl2 (0.7 M, 55.20 mL, 1.5 equivalents) was added dropwise at -20 °C. The mixture was stirred at -20 °C for 1 hour. A mixture of 4,6-dichloropyrimidine (4.22 g, 28.34 mmol, 1.1 equivalents) and Pd(PPh3)4 (1.49 g, 1.29 mmol, 0.05 equivalents) in THF (4 mL) was added dropwise at 20 °C. o The mixture was stirred at C for 1 hour and added to the solution. The cold bath was removed, and the mixture was stirred at 20°C for 16 hours to obtain a yellow solution. The residue was poured into water (10 mL). The aqueous phase was extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with brine (2 × 20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (100-200 mesh silica gel, 0-10% ethyl acetate / petroleum ether) to give 2-[[3-(6-chloropyrimidin-4-yl)-5-(1-methylcyclopropoxy)indazole-2-yl]methoxy]ethyl-trimethyl-silane (2.9 g, crude product) as a yellow oil.

[0188] Exemplary final synthesis of compound 2: Step 1 Cesium carbonate (8.37 g, 25.68 mmol, 3 equivalents) was added to a mixture of 6-bromo-3-(2,6-dibenzyloxy-3-pyridyl)-1H-benzimidazol-2-one (4.3 g, 8.56 mmol, 1 equivalent) and 2-iodopropane (2.18 g, 12.84 mmol, 1.28 mL, 1.5 equivalents) in N,N-dimethylformamide (40 mL). The mixture was stirred at 50 °C for 12 hours. Thin-layer chromatography (petroleum ether:ethyl acetate = 2:1) showed that the reaction was complete. The mixture was cooled to 20 °C and poured into water (w / w = 1 / 1) (100 mL) and mixed with ethyl acetate (100 mL). 2) Extraction. The combined organic phases were rinsed with 100 mL of brine. 3) The sample was washed, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by rapid silica gel chromatography (ISCO®; 80 g SepaFlash® silica column, eluent gradient of 0%–20% ethyl acetate / petroleum ether at 80 mL / min). 5-Bromo-1-(2,6-dibenzyloxy-3-pyridyl)-3-isopropyl-benzimidazol-2-one (4 g, 7.35 mmol, 86% yield) was obtained as a red solid.

[0189] Step 2 Add cesium carbonate (1.50 g, 4.59 mmol, 2.5 equivalents), [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium; dicyclohexyl-[2-(2,6-diisopropoxyphenyl)phenyl]phosphine (154 mg, 0.18 mmol, 0.1 equivalents), and 1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-2H-imidazol-1-cation-2-anion; 3-chloropyridine; dichloropalladium (179 mg, 0.18 mmol, 1.2 equivalents) to a mixture of 5-bromo-1-(2,6-dibenzyloxy-3-pyridinyl)-3-isopropyl-benzimidazole-2-one (1 g, 1.84 mmol, 1 equivalent) and 4-(dimethoxymethyl)piperidine (351 mg, 2.20 mmol, 1.2 equivalents) in dioxane (10 mL) to a mixture of 5-bromo-1-(2,6-dibenzyloxy-3-pyridinyl)-3-isopropyl-benzimidazole-2-one (1 g, 1.84 mmol, 1 equivalent), [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium; dicyclohexyl-[2-(2,6-diisopropoxyphenyl)phenyl]phosphine (154 mg, 0.18 mmol, 0.1 equivalents), 3-chloropyridine; dichloropalladium (179 mg, 0.18 mmol, 1.2 equivalents), 3-dichloropyridine, ... (mmol, 0.1 equivalent). The mixture was stirred at 100 °C for 12 hours and then cooled to 20 °C, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (ISCO®; 20 g SepaFlash® silica rapid column, eluent of 0–30% ethyl acetate / petroleum ether gradient at 70 mL / min). 1-(2,6-dibenzyloxy-3-pyridyl)-5-[4-(dimethoxymethyl)-1-piperidinyl]-3-isopropyl-benzimidazol-2-one (600 mg, 0.85 mmol, 46% yield, 88% purity) was obtained as a yellow oil.

[0190] Step 3 Palladium / carbon (100 mg, 10% purity) and palladium hydroxide (100 mg, 10%) were added to a solution of 1-(2,6-dibenzyloxy-3-pyridyl)-5-[4-(dimethoxymethyl)-1-piperidinyl]-3-isopropyl-benzimidazol-2-one (600 mg, 0.96 mmol, 1 equivalent) in ethyl acetate (10 mL) under nitrogen atmosphere. The mixture was stirred at 50 °C for 12 hours under hydrogen atmosphere (50 psi) and then cooled to 20 °C, filtered, and concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography (dichloromethane:methanol = 15:1). 3-[5-[4-(dimethoxymethyl)-1-piperidinyl]-3-isopropyl-2-oxo-benzimidazol-1-yl]piperidin-2,6-dione (320 mg, 0.71 mmol, 74% yield, 99% purity) was obtained as a white solid.

[0191] Step 4 Trifluoroacetic acid (665 mg, 5.83 mmol, 0.43 mL, 39.90 equivalents) was added to a mixture of 3-[5-[4-(dimethoxymethyl)-1-piperidinyl]-3-isopropyl-2-oxo-benzimidazol-1-yl]piperidin-2,6-dione (65 mg, 0.15 mmol, 1 equivalent) in dichloromethane (2 mL). The mixture was stirred at 20 °C for 1 hour and then concentrated under reduced pressure. 1-[1-(2,6-dioxo-3-piperidinyl)-3-isopropyl-2-oxo-benzimidazol-4-yl]piperidin-4-carboxaldehyde (58 mg, 0.15 mmol, 99.55% yield) was obtained as a yellow oil.

[0192] Step 5 HOAc (24.85 mg, 413.87 μmol, 23.69 μL, 3 equivalents) was added to a mixture of 1-[1-(2,6-dioxo-3-piperidinyl)-3-isopropyl-2-oxo-benzimidazol-5-yl]piperidin-4-carboxaldehyde (60 mg, 137.96 μmol, 1 equivalent) and 3-[6-[4-[(2,2-dimethylpiperazin-1-yl)methyl]-1-piperidinyl]pyrimidin-4-yl]-5-(1-methylcyclopropoxy)-1H-indazole (65.62 mg, 137.96 μmol, 1 equivalent) in DCM (5 mL) for 1 hour, followed by the addition of NaBH(OAc)3 (58.48 mg, 275.92 μmol, 2 equivalents) at 25 °C for 15 hours. The residue was filtered and concentrated under vacuum. The residue was passed through a preparative HPLC system (column: Ultimate C18 150). 40 mm 10 μm; mobile phase: [water (FA)-ACN]; gradient: 0%-36% over 36 min. B) Purification to give compound 2 as a white solid (58 mg, 67.27 μmol, 48.76% yield, 99.52% purity).

[0193] Exemplary synthesis of compound 3: Synthesis of intermediate 4-[[1-[1-(2,6-dioxo-3-piperidinyl)benzimidazol-4-yl]-4-piperidinyl]oxy]cyclohexaneformaldehyde Step 1 Add 4-[4-(dimethoxymethyl)cyclohexyloxy]piperidine (1.81 g, 7.05 mmol, 1 equivalent) and cesium carbonate (4.17 g, 12.81 mmol, 2 equivalent) to a stirred solution of 3-fluoro-2-nitro-aniline (1 g, 6.41 mmol, 1 equivalent) in N,N-dimethylformamide (20 mL). Stir the reaction mixture at 100 °C for 2 hours and then cool. Add water (200 mL) to the mixture, and dilute the aqueous phase with... Ethyl acetate Extraction was performed using 100 mL × 2. The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The residue was then subjected to silica gel chromatography (petroleum ether: Ethyl acetate Purification was performed using a ratio of 100:1 to 3:1 to obtain 3-[4-[4-(dimethoxymethyl)cyclohexyloxy]-1-piperidinyl]2-nitroaniline (1.5 g, 3.81 mmol, 59% yield), which was a yellow oil.

[0194] Step 2 To a stirred solution of 3-[4-[4-(dimethoxymethyl)cyclohexyloxy]-1-piperidinyl]-2-nitroaniline (1.5 g, 3.81 mmol, 1 equivalent) and 2,6-dibenzyloxy-3-bromopyridine (1.69 g, 4.57 mmol, 1.2 equivalent) in dioxane (20 mL), methanesulfonic acid (2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-diphenyl)(2-methylamino-1,1-diphenyl-2-yl)palladium(II) (328 mg, 0.38 mmol, 0.1 equivalent) and cesium carbonate (2.48 g, 7.62 mmol, 2 equivalent) was added. The reaction mixture was stirred at 100 °C for 12 hours and cooled. The mixture was filtered, and the filtrate was concentrated under vacuum. The residue was subjected to silica gel chromatography (petroleum ether: Ethyl acetate Purification was performed using a ratio of 100:1 to 3:1 to obtain 2,6-dibenzyloxy-N-[3-[4-[4-(dimethoxymethyl)cyclohexyloxy]-1-piperidinyl]-2-nitro-phenyl]pyridine-3-amine (2.2 g, 3.22 mmol, 84% yield) as a yellow solid.

[0195] Step 3 Ammonium chloride (1.72 g, 32.22 mmol, 1 equivalent) and iron (900 mg, 16.11 mmol, 5 equivalent) were added to a stirred solution of 2,6-dibenzyloxy-N-[3-[4-[4-(dimethoxymethyl)cyclohexyloxy]-1-piperidinyl]-2-nitro-phenyl]pyridine-3-amine (2.2 g, 3.22 mmol, 1 equivalent) in ethanol (20 mL) and water (5 mL). The reaction mixture was stirred at 80 °C for 12 hours and then cooled. The mixture was filtered, and the filtrate was concentrated under vacuum. The residue was subjected to silica gel chromatography (petroleum ether: Ethyl acetate Purification was performed using a ratio of 100:1 to 1:1 to obtain N1-(2,6-dibenzyloxy-3-pyridyl)-3-[4-[4-(dimethoxymethyl)cyclohexyloxy]-1-piperidinyl]phenyl-1,2-diamine (1.2 g, 1.84 mmol, 57% yield), which was a yellow oil.

[0196] Step 4 To a solution of N1-(2,6-dibenzyloxy-3-pyridyl)-3-[4-[4-(dimethoxymethyl)cyclohexyloxy]-1-piperidinyl]benzyl-1,2-diamine (1 g, 1.53 mmol, 1 equivalent) in methanol (10 mL), p-toluenesulfonic acid (26 mg, 0.15 mmol, 0.1 equivalent) and trimethoxymethane (488 mg, 4.60 mmol, 3 equivalent) were added. The mixture was stirred at 60 °C for 2 hours and then cooled. The mixture was concentrated under vacuum. Without further purification, 1-(2,6-dibenzyloxy-3-pyridyl)-4-[4-[4-(dimethoxymethyl)cyclohexyloxy]-1-piperidinyl]benzimidazole (18 mg, 0.03 mmol, 88% yield) was obtained as a yellow oil.

[0197] Step 5 Trifluoroacetic acid (770 mg, 6.75 mmol, 0.5 mL, 32.72 equivalents) was added to a solution of 3-[4-[4-[4-(dimethoxymethyl)cyclohexyloxy]-1-piperidinyl]benzimidazol-1-yl]piperidin-2,6-dione (100 mg, 0.21 mmol, 1 equivalent) in dichloromethane (2.5 mL). The mixture was stirred at 25 °C for 0.5 h and then concentrated under vacuum. 4-[[1-[1-(2,6-dioxo-3-piperidinyl)benzimidazol-4-yl]-4-piperidinyl]oxy]cyclohexanecarboxaldehyde (90 mg, 0.21 mmol, 99% yield) as a white solid, without the need for purification.

[0198] Synthesis of intermediate 5-(1-methylcyclopropoxy)-3-(6-piperazin-1-pyrimidin-4-yl)-1H-indazole Step 1 Et3N (704.34 mg, 6.96 mmol, 968.82 uL, 3 equivalents) was added to a solution of 2-[[3-(6-chloropyrimidin-4-yl)-5-(1-methylcyclopropoxy)indazole-2-yl]methoxy]ethyl-trimethyl-silane (1 g, 2.32 mmol, 1 equivalent) and piperazine-1-carboxylic acid tert-butyl ester (648.20 mg, 3.48 mmol, 1.5 equivalents) in DMSO (5 mL). After addition, the reaction mixture was stirred at 100 °C for 1 hour. After cooling, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 × 10 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0 to 50% ethyl acetate / petroleum ether) to give tert-butyl 4-[6-[5-(1-methylcyclopropoxy)-2-(2-trimethylsilylethoxymethyl)inzol-3-yl]pyrimidin-4-yl]piperazine-1-carboxylate (1.2 g, 1.96 mmol, 84.60% yield, 95% purity) as a pale yellow solid.

[0199] Step 2 To a solution of tert-butyl piperazine-1-carboxylate (1.2 g, 2.07 mmol, 1 equivalent) in MeOH (5 mL), HCl / dioxane (4 M, 5 mL, 9.68 equivalents) was added. Following the addition, the reaction solution was stirred at 65 °C for 1 hour. After cooling, the reaction mixture was concentrated under reduced pressure to give 5-(1-methylcyclopropoxy)-3-(6-piperazine-1-ylpyrimidin-4-yl)-1H-indazole (770 mg, 1.81 mmol, 87.37% yield, 90.7% purity, HCl) as a yellow solid. The crude product was used directly in the next step.

[0200] Exemplary final synthesis of compound 3: 4-[[1-[1-(2,6-dioxo-3-piperidinyl)benzimidazol-4-yl]-4-piperidinyl]oxy]cyclohexaneformaldehyde (90 mg, 0.21 mmol, 1 equivalent) was applied to... N , NSodium triacetoxyborohydride (87 mg, 0.41 mmol, 2 equivalents) and 5-(1-methylcyclopropoxy)-3-(6-piperazin-1-ylpyrimidin-4-yl)-1H-indazole (71 mg, 0.18 mmol, 0.9 equivalents, hydrochloric acid) were added to a solution of dimethylformamide (3 mL), followed by the addition of N-methylmorpholine (62 mg, 0.62 mmol, 0.09 mL, 3 equivalents). The mixture was stirred at 25 °C for 3 hours and then filtered. The mixture was subjected to preparative HPLC: (column: Phenomenex luna C18 150) 25 mm Purification was performed using a mobile phase of [water (FA)-ACN] (10 μm; B%: 12%-42%, 7 min). Compound 3 was obtained as a white solid (27 mg, 0.03 mmol, 17% yield, 96% purity).

[0201] Exemplary synthesis of compound 4: Synthesis of intermediates for 2,6-dibenzyloxy-N-[5-[4-[4-(dimethoxymethyl)cyclohexyloxy]-1-piperidinyl]-2-nitro-phenyl]pyridine-3-amine Step 1 Potassium carbonate (1.24 g, 8.94 mmol, 2 equivalents) and 4-[4-(dimethoxymethyl)cyclohexyloxy]piperidine (1.15 g, 4.47 mmol, 1 equivalent) were added to a solution of 5-bromo-2-nitroaniline (1.07 g, 4.92 mmol, 1.1 equivalents) in N,N-dimethylformamide (10 mL). The mixture was stirred at 120 °C for 12 h and then cooled. The reaction mixture was partitioned between ethyl acetate (100 mL) and water (80 mL). The organic phase was separated, washed with saturated sodium chloride (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (silica, petroleum ether / ethyl acetate = 10:1 to 1:1). The following were given as yellow solids: 5-[4-[4-(dimethoxymethyl)cyclohexyloxy]-1-piperidinyl]-2-nitro-aniline (0.694 g, 1.76 mmol, 39.44% yield) and 5-[4-[4-(dimethoxymethyl)cyclohexyloxy]-1-piperidinyl]-2-nitro-aniline (0.694 g, 1.76 mmol, 39.44% yield).

[0202] Step 2 A mixture of 5-[4-[4-(dimethoxymethyl)cyclohexyloxy]-1-piperidinyl]-2-nitroaniline (690 mg, 1.75 mmol, 1 equivalent), 2,6-dibenzyloxy-3-bromopyridine (779.10 mg, 2.10 mmol, 1.2 equivalent), dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphine; methanesulfonate; [2-[2-(methylamino)phenyl]phenyl]palladium(1+) (150.89 mg, 0.17 mmol, 0.1 equivalent) and cesium carbonate (1.14 g, 3.51 mmol, 2 equivalent) in dioxane (10 mL) was degassed and purged with nitrogen for 3 cycles. The mixture was then heated at 90 °C for 10 hours under N2 atmosphere and cooled. The reaction mixture was partitioned between ethyl acetate (50 mL) and water (30 mL). The organic phase was separated, washed with brine (15 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (silica, petroleum ether / ethyl acetate = 5 / 1). 2,6-Dibenzyloxy-N-[5-[4-[4-(dimethoxymethyl)cyclohexyloxy]-1-piperidinyl]-2-nitro-phenyl]pyridine-3-amine (1.12 g, 1.64 mmol, 93.5% yield) was given as a red solid.

[0203] Compound 4 was prepared in a manner similar to that of compound 3 by using the intermediate 2,6-dibenzyloxy-N-[5-[4-[4-(dimethoxymethyl)cyclohexyloxy]-1-piperidinyl]-2-nitro-phenyl]pyridine-3-amine instead of 2,6-dibenzyloxy-N-[3-[4-[4-(dimethoxymethyl)cyclohexyloxy]-1-piperidinyl]-2-nitro-phenyl]pyridine-3-amine.

[0204] Exemplary synthesis of compound 5: Synthesis of intermediate 3-(2,6-bis(benzyloxy)pyridin-3-yl)-5-(4-(((1r,4r)-4-(dimethoxymethyl)cyclohexyl)-oxy)piperidin-1-yl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one Step 1 Potassium carbonate (2.36 g, 17.10 mmol, 2.2 equivalents) was added to a stirred solution of 5-bromo-2-nitro-aniline (1.69 g, 7.77 mmol, 1 equivalent) and 4-[4-(dimethoxymethyl)cyclohexyloxy]piperidine (2 g, 7.77 mmol, 1 equivalent) in N,N-dimethylformamide (20 mL). The reaction mixture was stirred at 120 °C for 12 h and then cooled. Water (200 mL) was added to the mixture and the mixture was extracted with ethyl acetate (150 mL × 2). The combined organic layers were washed with brine (200 mL × 2), dried over anhydrous sodium sulfate, filtered, and the residue was concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 100:1-2:1) to obtain 5-[4-[4-(dimethoxymethyl)cyclohexyloxy]-1-piperidinyl]-2-nitroaniline (1.5 g, 3.81 mmol, 49% yield), which was a yellow oil.

[0205] Step 2 To a stirred solution of 5-(4-(((1r,4r)-4-(dimethoxymethyl)cyclohexyl)oxy)piperidin-1-yl)-2-nitroaniline (1.5 g, 3.81 mmol, 1 equivalent) and 2,6-dibenzyloxy-3-bromopyridine (1.69 g, 4.57 mmol, 1.2 equivalent) in dioxane (20 mL), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-diphenyl)(2'-methylamino-1,1'-diphenyl-2-yl)palladium(II) (328 mg, 0.38 mmol, 0.1 equivalent) and cesium carbonate (2.48 g, 7.62 mmol, 2 equivalent) were added. The reaction mixture was stirred at 100 °C for 12 hours and then cooled. The mixture was filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 100:1-3:1) to obtain 2,6-bis(benzyloxy)-N-(5-(4-(((1r,4r)-4-(dimethoxymethyl)cyclohexyl)oxy)piperidin-1-yl)-2-nitrophenyl)pyridine-3-amine (2.2 g, 3.22 mmol, 84% yield) as a yellow solid.

[0206] Step 3 Ammonium chloride (1.72 g, 32.22 mmol, 1 equivalent) and iron (899 mg, 16.11 mmol, 5 equivalents) were added to a stirred solution of 2,6-bis(benzyloxy)-N-(5-(4-(((1r,4r)-4-(dimethoxymethyl)cyclohexyl)oxy)piperidin-1-yl)-2-nitrophenyl)pyridine-3-amine (2.2 g, 3.22 mmol, 1 equivalent) in ethanol (20 mL) and water (5 mL). The reaction mixture was stirred at 80 °C for 12 hours and then cooled. The mixture was filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 100:1-1:1) to obtain N1-(2,6-bis(benzyloxy)pyridin-3-yl)-5-(4-(((1r,4r)-4-(dimethoxymethyl)cyclohexyl)oxy)piperidin-1-yl)phenyl-1,2-diamine (1.2 g, 1.84 mmol, 57% yield), which was a yellow oil.

[0207] Step 4 To a stirred solution of N1-(2,6-bis(benzyloxy)pyridin-3-yl)-5-(4-(((1r,4r)-4-(dimethoxymethyl)cyclohexyl)oxy)piperidin-1-yl)phenyl-1,2-diamine (1.2 g, 1.84 mmol, 1 equivalent) in tetrahydrofuran (12 mL), 4-dimethylaminopyridine (22 mg, 0.18 mmol, 0.1 equivalent) and 1,1-carbonyldiimidazole (596 mg, 3.68 mmol, 2 equivalent) were added. The reaction mixture was stirred at 20 °C for 12 hours. The mixture was then concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 100:1-2:1) to obtain 1-(2,6-bis(benzyloxy)pyridin-3-yl)-6-(4-(((1r,4r)-4-(dimethoxymethyl)cyclohexyl)oxy)piperidin-1-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (1 g, 1.47 mmol, 80% yield) as a yellow solid.

[0208] Step 5 Sodium hydride (88 mg, 2.21 mmol, 60% purity, 1.5 equivalence) was added to a stirred solution of 1-(2,6-bis(benzyloxy)pyridin-3-yl)-6-(4-(((1r,4r)-4-(dimethoxymethyl)cyclohexyl)oxy)piperidin-1-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (1 g, 1.47 mmol, 1 equivalent) in tetrahydrofuran (10 mL). The mixture was stirred at this temperature for 0.5 h, and methyl iodoform (313 mg, 2.21 mmol, 0.14 mL, 1.5 equivalence) was added to the mixture. The resulting mixture was stirred at 20 °C for 12 h. The mixture was cooled to 0 °C, quenched with saturated ammonium chloride (150 mL), and quenched with ethyl acetate (100 mL). 2) Extraction. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate = 100:1-1:1) to obtain 3-(2,6-bis(benzyloxy)pyridin-3-yl)-5-(4-(((1r,4r)-4-(dimethoxymethyl)cyclohexyl)oxy)piperidin-1-yl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (900 mg, 1.30 mmol, 88% yield) as a yellow solid.

[0209] Compound 5 was prepared in a manner similar to that of Compound 1 by using the intermediates 5-(1-methylcyclopropoxy)-3-(6-piperazin-1-ylpyrimidin-4-yl)-1H-indazole and 3-(2,6-bis(benzyloxy)pyridin-3-yl)-5-(4-(((1r,4r)-4-(dimethoxymethyl)cyclohexyl)-oxy)piperidin-1-yl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one instead of 5-(1-methylcyclopropoxy)-3-(6-piperazin-1-ylpyrimidin-4-yl)-1H-pyrazolo[3,4-c]pyridine and trans-1-(2,6-dibenzyloxy-3-pyridinyl)-5-[4-[4-(dimethoxymethyl)cyclohexyloxy]-1-piperidinyl]-3-methyl-benzimidazol-2-one.

[0210] An exemplary synthesis of compound 6 was performed using the intermediate 5-(1-methylcyclopropoxy)-3-(6-piperazin-1-ylpyrimidin-4-yl)-1H-indazole instead of 5-(1-methylcyclopropoxy)-3-(6-piperazin-1-ylpyrimidin-4-yl)-1H-pyrazolo[3,4-c]pyridine, to prepare the compound in a manner similar to that of compound 1. Step 1 At 0 °C, 4-methylmorpholine (71 mg, 0.70 mmol, 0.077 mL, 3 equivalents) and sodium triacetoxyborohydride (99 mmg, 0.47 mmol, 2 equivalents) were added to a mixture of 4-[[1-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazol-5-yl]-4-piperidinyl]oxy]cyclohexaneformaldehyde (109 mg, 0.23 mmol, 1 equivalent, 1 equivalent, 3 mL) and 5-(1-methylcyclopropoxy)-3-(6-piperazin-1-ylpyrimidin-4-yl)-1H-indazole (107 mg, 0.23 mmol, 1 equivalent, 3 mL) in N,N-dimethylformamide (3 mL). The mixture was stirred at 20 °C for 12 hours and then concentrated under reduced pressure. The residue was passed through a semi-preparative reversed-phase column (YMC Triart C18 150). 25 mm 5 μm; mobile phase: [water (TFA)-ACN]; B%: 20%-40%, 10 min) and (column: YMC Triart C18 150) 25 mm Purification was performed using a mobile phase of [water (TFA)-ACN] (5 μm; B%: 23%-43%, 10 min). Compound 6 was obtained as a grayish-white solid (60.7 mg, 0.072 mmol, 31% yield, 95.59% purity).

[0211] Exemplary synthesis of compound 7: Step 1 A portion of sodium hydride (2.44 g, 60.90 mmol, 60% purity, 1.5 equivalence) was added to a stirred, cooled (0 °C) solution of 5-bromo-1H-benzimidazole (8 g, 40.60 mmol, 1 equivalent) in tetrahydrofuran (80 mL). The mixture was stirred at 0 °C for 0.5 h and SEM-Cl (8.12 g, 48.72 mmol, 8.62 mL, 1.2 equivalence) was added. The reaction mixture was stirred at 20 °C for 2 h and then quenched by adding saturated ammonium chloride aqueous solution (250 mL), and the mixture was extracted with ethyl acetate (150 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 5:1-0:1) to give 2-[(5-bromobenzimidazol-1-yl)methoxy]ethyl-trimethyl-silane (10 g, 30.55 mmol, 75% yield) as a yellow oil.

[0212] Step 2 To a stirred solution of 2-[(5-bromobenzimidazol-1-yl)methoxy]ethyl-trimethylsilane (10 g, 30.55 mmol, 1 equivalent) and 4-(dimethoxymethyl)piperidine (5.35 g, 33.61 mmol, 1.1 equivalent) in dioxane (100 mL), RuPhos Pd G3 (1.28 g, 1.53 mmol, 0.05 equivalent) and cesium carbonate (21.90 g, 67.22 mmol, 2.2 equivalent) were added. The reaction mixture was stirred at 100 °C for 12 hours under nitrogen and then cooled. The mixture was filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 10:1-1:1) to give 2-[[5-[4-(dimethoxymethyl)-1-piperidinyl]benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (6.5 g, 16.03 mmol, 52% yield) as a yellow oil.

[0213] Step 3 A solution of tetrabutylammonium fluoride (1 M, 13.31 mL, 1.2 equivalents) was added to a stirred solution of 2-[[5-[4-(dimethoxymethyl)-1-piperidinyl]benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (4.50 g, 11.09 mmol, 1 equivalent) in tetrahydrofuran (50 mL). The reaction mixture was stirred at 60 °C for 12 h and then cooled. Water (300 mL) was added, and the mixture was extracted with ethyl acetate (150 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The residue was subjected to preparative HPLC (column: Kromasil Eternity XT 250). 80mm Purification was performed to obtain 5-[4-(dimethoxymethyl)-1-piperidinyl]-1H-benzimidazole (2.6 g, 9.44 mmol, 85% yield) as a yellow solid. (10 μm; mobile phase: [water (ammonia hydroxide v / v)-ACN]; B%: 18%-48%, 20 min)

[0214] Step 4 To a stirred solution of 5-[4-(dimethoxymethyl)-1-piperidinyl]-1H-benzimidazole (300 mg, 1.09 mmol, 1 equivalent) and 2,6-dibenzyloxy-3-bromopyridine (484.07 mg, 1.31 mmol, 1.2 equivalent) in dimethyl sulfoxide (5 mL), N,N'-bis(2-furanylmethyl)oxalamide (108.19 mg, 435.82 μol, 0.4 equivalent), potassium phosphate (231.28 mg, 1.09 mmol, 1 equivalent), and copper oxide (31.18 mg, 217.91 μol, 22.27 μL, 0.2 equivalent) were added. The reaction mixture was stirred at 120 °C for 12 hours and then cooled. The mixture was filtered, and the filtrate was diluted with water (300 mL). The mixture was extracted with ethyl acetate (150 mL × 2), and the combined organic layers were washed with brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The residue was subjected to preparative HPLC (column: Waters Xbridge C18 150). 50 mm 10 μm; mobile phase: [water (ammonium bicarbonate)-ACN]; B%: 51%-81%, 10 min) to purify to give a mixture (900 mg). The crude product was passed through an SFC column (DAICEL CHIRALPAK AD (250 mm)). (30 mm, 10 μm); mobile phase: [0.1% ammonium hydroxide IPA]; B%: 50%-50%, 3.6 min) Further purification was carried out to obtain 1-(2,6-dibenzyloxy-3-pyridyl)-5-[4-(dimethoxymethyl)-1-piperidinyl]benzimidazole (500 mg, 885.47 μmol, 55% yield) and 1-(2,6-dibenzyloxy-3-pyridyl)-6-[4-(dimethoxymethyl)-1-piperidinyl]benzimidazole (400 mg, 708.38 μmol, 44.44% yield) as yellow oils.

[0215] Step 5 Adding Pd / C to a stirred solution of 1-(2,6-dibenzyloxy-3-pyridyl)-6-[4-(dimethoxymethyl)-1-piperidinyl]benzimidazole (400 mg, 0.71 mmol, 1 equivalent) in tetrahydrofuran (10 mL) showed detection of the desired product. The mixture was filtered, and the filtrate was concentrated under vacuum. The residue was heated to 20 °C. oGrinding with N,N-dimethylformamide (6 mL) at C for 10 minutes yielded 3-[6-[4-(dimethoxymethyl)-1-piperidinyl]benzimidazol-1-yl]piperidin-2,6-dione (170 mg, 0.44 mmol, 62% yield) as a white solid.

[0216] Step 6 Trifluoroacetic acid (2.46 g, 21.61 mmol, 1.60 mL, 52.19 equivalents) was added to a stirred solution of 3-[6-[4-(dimethoxymethyl)-1-piperidinyl]benzimidazol-1-yl]piperidin-2,6-dione (160 mg, 0.41 mmol, 1 equivalent) in dichloromethane (3 mL). The reaction mixture was stirred at 20 °C for 1 h. LC-MS showed the desired MS. The mixture was concentrated under vacuum. The residue was used directly in the next step without further purification to obtain 1-[3-(2,6-dioxo-3-piperidinyl)benzimidazol-5-yl]piperidin-4-carboxaldehyde (140 mg, 0.41 mmol, 99% yield) as a yellow oil.

[0217] Step 7 Add 5-(1-methylcyclopropoxy)-3-[6-[4-(piperazin-1-ylmethyl)-1-piperidinyl]pyrimidin-4-yl]-1H-indazole (prepared in a manner similar to intermediate 3-[6-[4-[(2,2-dimethylpiperazin-1-yl)methyl]-1-piperidinyl]pyrimidin-4-yl]-5-(1-methylcyclopropoxy)-1H-indazole, 82 mg, 0.15 mmol, 0.72 equivalents, 3 hydrochloride) and N-methylmorpholine (41 mg, 0.41 mmol, 2 equivalents) to a stirred solution of 1-[3-(2,6-dioxo-3-piperidinyl)benzimidazol-5-yl]piperidinyl]pyrimidin-4-yl]-5-(1-methylcyclopropoxy)-1H-indazole. Sodium triacetoxyborohydride (87 mg, 411.31 μmol, 2 equivalents) was added, and the mixture was stirred at 20 °C for 12 hours. The mixture was concentrated under vacuum, and the residue was subjected to preparative HPLC (column: Phenomenex luna C18 150). 25 mm 10 μm; mobile phase: [water (FA)-ACN]; B%: 2%-32%, 9 min) Purification yielded compound 7 as a purple solid (51.82 mg, 67.13 μmol, 32% yield).

[0218] Exemplary synthesis of compound 8: Step 1 To a mixture of 7-bromoindoline-2,3-dione (12 g, 53.09 mmol, 1 equivalent), potassium carbonate (11.01 g, 79.64 mmol, 1.5 equivalent), and water (1.2 mL) in N,N-dimethylformamide (60 mL), 24 mL of N,N-dimethylformamide containing iodomethane (8.44 g, 59.43 mmol, 3.7 mL, 1.12 equivalent) was added dropwise. The mixture was stirred at 25 °C for 2 hours. Water (120 mL) was added, and the mixture was stirred at 0 °C for 1 hour. The resulting precipitate was collected by filtration, washed with water (50 mL × 2), and dried under vacuum to give a residue. The residue was used for the next step without further purification. 7-bromo-1-methylindoline-2,3-dione (8 g, 33.33 mmol, 62% yield) was given as a red solid.

[0219] Step 2 Hydrogen peroxide (38 g, 335.15 mmol, 32.20 mL, 30% in H₂O, 10.06 equivalents) was added dropwise to a mixture of 7-bromo-1-methyldihydroindole-2,3-dione (8 g, 33.33 mmol, 1 equivalent) and sodium hydroxide (2 M, 199.96 mL, 12) while maintaining the reaction temperature below 15 °C. The mixture was stirred at 25 °C for 5 hours. The pH of the reaction mixture was adjusted to 4.0 with hydrochloric acid (1 M), and the mixture was stirred at 10 °C for 1 hour. The mixture was then extracted with ethyl acetate (80 mL × 3). The combined organic phases were washed with water (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was used for the next step without further purification. 3-Bromo-2-(methylamino)benzoic acid (6.0 g, crude product) was obtained as a brown oil.

[0220] Step 3 Diphenylphosphoazide (10.76 g, 39.10 mmol, 8.47 mL, 1.50 equivalent) was added dropwise to a solution of 3-bromo-2-(methylamino)benzoic acid (6 g, 26.08 mmol, 1 equivalent, crude product) and N,N-diisopropylethylamine (5.04 g, 39.01 mmol, 6.80 mL, 1.50 equivalent) in N,N-dimethylformamide (40 mL) at 75 °C. The reaction mixture was stirred at 75 °C for 3 h and cooled. Water (30 mL) was added at 25 °C, and the mixture was stirred at 0 °C for 0.5 h. The resulting precipitate was collected by filtration, washed with water (30 mL) and diisopropyl ether (15 mL), and dried under vacuum at 50 °C to give the residue. The residue was used in the next step without further purification. 7-Bromo-1-methyl-1H-benzo[] was obtained as a grayish-white solid. d Imidazole-2(3H)-one (4 g, 17.62 mmol, 67% yield).

[0221] Step 4 Sodium nitrite (35.17 g, 509.76 mmol, 1.5 equivalent) was added to a solution of 2-aminopentanoic acid (50 g, 339.84 mmol, 1 equivalent) in water (300 mL) and hydrochloric acid (37%, 50 mL) at -5 °C. The mixture was stirred at 25 °C for 12 hours. The reaction solution was filtered, and the filtrate was concentrated under vacuum to give a crude product. The residue was used for the next step without further purification. 5-oxotetrahydrofuran-2-carboxylic acid (34 g, crude product) was obtained as a colorless oil.

[0222] Step 5 At 0°C, 5-oxotetrahydrofuran-2-carboxylic acid (67 g, 514.99 mmol, 1 equivalent) was reacted. crude product Thionyl chloride (135 g, 1.13 mol, 82.32 mL, 2.20 equivalents) was added to a solution of dichloromethane (400 mL). The mixture was stirred at 85 °C for 3 hours, and then at 25 °C for 6 hours. The reaction mixture was concentrated under vacuum to give the product. The residue was dissolved in dichloromethane (400 mL) and stirred at 0 °C. rightMethoxyaniline (56.52 g, 411.99 mmol, 53.32 mL, 0.8 equivalents) and triethylamine (104.22 g, 1.03 mol, 143.36 mL, 2 equivalents) were added to the solution. The mixture was stirred at 25 °C for 12 hours. Water (500 mL) was added, and the mixture was extracted with ethyl acetate (500 mL × 3). The combined organic phases were washed with brine (200 mL), dried, filtered, and concentrated under vacuum. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 3 / 1 to 1 / 1) to the desired product (Rf = 0.20). N-(4-methoxybenzyl)-5-oxotetrahydrofuran-2-carboxamide (59 g, 236.70 mmol, 45% yield) was given as a yellow solid.

[0223] Step 6 2-Methylprop-2-ol potassium (1 M, 40.12 mL, 1 equivalent) was added dropwise to a solution of N-(4-methoxybenzyl)-5-oxotetrahydrofuran-2-carboxamide (10 g, 40.12 mmol, 1 equivalent) in tetrahydrofuran (120 mL) at -78 °C under nitrogen. The resulting reaction mixture was stirred at -40 °C for 1 hour. The reaction mixture was quenched at -40 °C by adding ammonium chloride (50 mL), and then diluted with water (150 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (100 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 (petroleum ether / ethyl acetate = 5 / 1 to 2 / 1). 3-hydroxy-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dione (7.5 g, 30.09 mmol, 75% yield) was obtained as a pale yellow solid.

[0224] Step 7 1,3-bis((trifluoromethyl)sulfonyl)hydrogen peroxide (5.67 g, 18.05 mmol, 1.5 equivalent) was added to a solution of 3-hydroxy-1-(4-methoxybenzyl)piperidine-2,6-dione (3 g, 12.04 mmol, 1 equivalent) and pyridine (1.90 g, 24.02 mmol, 1.94 mL, 2.00 equivalent) in dichloromethane (100 mL) at -20 °C. The mixture was stirred at -20 °C for 2 hours. The reaction mixture was loaded directly onto a silica gel column and eluted with petroleum ether / ethyl acetate (10 / 1 to 2 / 1). 1-(4-methoxybenzyl)-2,6-dioxopiperidine-3-yl trifluoromethanesulfonic acid (4.2 g, 11.01 mmol, 92% yield) was given as a colorless oil.

[0225] Step 8 Add potassium 2-methylprop-2-ol (1 M, 10.67 mL, 1.21 equivalents) to a solution of 7-bromo-1-methyl-1H-benzo[d]imidazol-2(3H)-one (2.00 g, 8.81 mmol, 1 equivalent) in tetrahydrofuran (40 mL) and stir the mixture at 0 °C for 0.5 h. Add dropwise 20 mL of tetrahydrofuran containing 1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl trifluoromethanesulfonic acid (4.2 g, 11.01 mmol, 1.25 equivalents). Stir the mixture at 0–25 °C for 0.5 h. Quench the reaction mixture by adding 10 mL of 10% ammonium chloride solution at 0 °C and stirring at 0 °C for 1 h, then extract with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a solid. The solid was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 6 / 1 to 1 / 1). 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione (3.5 g, 7.64 mmol, 87% yield) was given as a white solid.

[0226] Step 9 To a stirred solution of 3-(4-bromo-3-methyl-2-oxo-benzimidazol-1-yl)-1-[(4-methoxyphenyl)methyl]piperidin-2,6-dione (2 g, 4.36 mmol, 1 equivalent) and 4-(dimethoxymethyl)piperidine (1.04 g, 6.55 mmol, 1.5 equivalent) in dioxane (20 mL), 1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-2H-imidazol-1-cation-2-anion; 3-chloropyridine; palladium dichloro (424.51 mg, 436.39 μmol, 0.1 equivalent) and cesium carbonate (2.84 g, 8.73 mmol, 2 equivalent) were added. The resulting mixture was stirred at 100 °C for 2 hours under N2 and then cooled. The mixture was slowly poured into 1 M HCl (150 mL) at 0 °C and the pH of the mixture was adjusted to 8 with an aqueous sodium bicarbonate solution. The mixture was extracted with dichloromethane (100 mL × 2), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (PE:EA = 10:1-1:2) to give 3-[4-[4-(dimethoxymethyl)-1-piperidinyl]-3-methyl-2-oxo-benzimidazol-1-yl]-1-[(4-methoxyphenyl)methyl]piperidin-2,6-dione (900 mg, 1.68 mmol, 38% yield) as a white solid.

[0227] Step 10 A solution of H₂SO₄ (2 M, 4.50 mL, 5.37 equivalents) was added to a stirred solution of 3-[4-[4-(dimethoxymethyl)-1-piperidinyl]-3-methyl-2-oxo-benzimidazol-1-yl]-1-[(4-methoxyphenyl)methyl]piperidin-2,6-dione (900 mg, 1.68 mmol, 1 equivalent) in tetrahydrofuran (5 mL). The reaction mixture was stirred at 45 °C for 12 hours and then cooled. The pH of the mixture was adjusted to 8 by adding sodium bicarbonate solution, and the aqueous layer was then extracted with ethyl acetate (100 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. This yields 1-[1-[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidinyl]-3-methyl-2-oxo-benzimidazol-4-yl]piperidin-4-carboxaldehyde (700 mg, 1.43 mmol, 85% yield) as a yellow solid, which can be used directly without further purification.

[0228] Compound 8 was prepared in a manner similar to that of compound 7 by using the intermediate 1-[1-[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidinyl]-3-methyl-2-oxo-benzimidazol-4-yl]piperidin-4-carboxaldehyde instead of 1-[1-(2,6-dioxo-3-piperidinyl)-3-isopropyl-2-oxo-benzimidazol-4-yl]piperidin-4-carboxaldehyde.

[0229] Exemplary synthesis of compound 9: intermediate trans Synthesis of 1-(2,6-dibenzyloxy-3-pyridyl)-4-[4-[4-(dimethoxymethyl)cyclohexyloxy]-1-piperidinyl]-3-methylbenzimidazol-2-one Step 1 To a stirred solution of N1-(2,6-dibenzyloxy-3-pyridyl)-3-[4-[4-(dimethoxymethyl)cyclohexyloxy]-1-piperidinyl]benzene-1,2-diamine (1.2 g, 1.84 mmol, 1 equivalent) in tetrahydrofuran (12 mL), 4-dimethylaminopyridine (22 mg, 0.18 mmol, 0.1 equivalent) and 1,1-carbonyldiimidazole (596 mg, 3.68 mmol, 2 equivalent) were added. The reaction mixture was stirred at 20 °C for 12 hours and then concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate = 100:1–2:1) to obtain a yellow solid. trans -3-(2,6-dibenzyloxy-3-pyridyl)-7-[4-[4-(dimethoxymethyl)cyclohexyloxy]-1-piperidinyl]-1H-benzimidazole-2-one (1 g, 1.47 mmol, 80% yield).

[0230] Step 2 At 0℃ transSodium hydride (88 mg, 2.21 mmol, 60% purity, 1.5 equivalents) was added to a stirred solution of 3-(2,6-dibenzyloxy-3-pyridyl)-7-[4-[4-(dimethoxymethyl)cyclohexyloxy]-1-piperidinyl]-1H-benzimidazol-2-one (1 g, 1.47 mmol, 1 equivalent) in tetrahydrofuran (10 mL). The mixture was stirred at this temperature for 0.5 h, and then methyl iodoform (313 mg, 2.21 mmol, 137.56 uL, 1.5 equivalents) was added. The resulting mixture was stirred at 20 °C for 12 h. The mixture was cooled to 0 °C, quenched with saturated ammonium chloride (150 mL), and quenched with ethyl acetate (100 mL). 2) Extraction. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate = 100:1-1:1) to obtain 1-(2,6-dibenzyloxy-3-pyridyl)-4-[4-[4-(dimethoxymethyl)cyclohexyloxy]-1-piperidinyl]-3-methyl-benzimidazol-2-one (900 mg, 1.30 mmol, 88% yield) as a yellow solid.

[0231] Use intermediates trans -1-(2,6-dibenzyloxy-3-pyridyl)-4-[4-[4-[4-(dimethoxymethyl)cyclohexyloxy]-1-piperidinyl]-3-methylbenzimidazol-2-one substituted trans Compound 9 was prepared in a manner similar to that of compound 1, using 1-(2,6-dibenzyloxy-3-pyridyl)-5-[4-[4-(dimethoxymethyl)cyclohexyloxy]-1-piperidinyl]-3-methyl-benzimidazole-2-one.

[0232] An exemplary synthesis of compound 12, which is prepared in a manner similar to that of compound 2.

[0233] Step 1 Add 4-methylmorpholine (74 mg, 0.73 mmol, 0.080 mL, 3 equivalents) to a solution of 5-(1-methylcyclopropoxy)-3-[6-[4-(piperazin-1-ylmethyl)-1-piperidinyl]pyrimidin-4-yl]-1H-indazole (135 mg, 0.24 mmol, 1 equivalent, 3 mL) in N,N-dimethylformamide (2 mL). Stir the solution at 20 °C for 30 min, and then add 1-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazol-5-yl]piperidin-4-carboxaldehyde (90 mg, 0.24 mmol, 1 equivalent). Stir the mixture at 20 °C for 30 min, and then add sodium triacetoxyborohydride (103 mg, 0.49 mmol, 2 equivalents), and stir the mixture at 20 °C for another 12 h. The mixture was concentrated under reduced pressure, and the resulting residue was passed through a semi-preparative reversed-phase column (Phenomenex luna C18 150). 25 mm Purification was performed using a mobile phase of [water (FA)-ACN] (10 μm; B%: 2%-32%, 10 min). Compound 12 was obtained as an orange solid (63.7 mg, 0.079 mmol, 32% yield, 99.15% purity).

[0234] Exemplary synthesis of compound 16: Synthesis of intermediate 3-(2,6-dibenzyloxy-3-pyridyl)-5-[4-(dimethoxymethyl)-1-piperidinyl]-1-methyl-benzimidazol-2-one Step 1 Potassium carbonate (15.94 g, 115.30 mmol, 3 equivalents) was added to a mixture of 5-fluoro-2-nitro-aniline (6 g, 38.43 mmol, 1 equivalent) and 4-(dimethoxymethyl)piperidine (12.24 g, 76.87 mmol, 2 equivalents) in N,N-dimethylformamide (80 mL). The mixture was stirred at 120 °C for 12 hours and then cooled to 0 °C. Water (100 mL) was added, which caused the formation of a solid. The mixture was filtered, and the filter cake was treated with water (5 mL). 3) Wash and dry to give 5-[4-(dimethoxymethyl)-1-piperidinyl]-2-nitro-aniline as a yellow solid (10.5 g, 35.55 mmol, 92.51% yield).

[0235] Step 2 Dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphine; methanesulfonate; [2-[2-(2-(methylamino)phenyl]phenyl]palladium(1+) (697 mg, 0.81 mmol, 0.1 equivalent)) and cesium carbonate (7.92 g, 24.31 mmol, 3 equivalent) were added to a mixture of 5-[4-(dimethoxymethyl)-1-piperidinyl]-2-nitro-aniline (2.63 g, 8.91 mmol, 1.1 equivalent) and 2,6-dibenzyloxy-3-bromo-pyridine (3 g, 8.10 mmol, 1 equivalent) in dioxane (50 mL) under nitrogen atmosphere. The mixture was stirred at 90 °C for 12 hours and then cooled to 20 °C. Ethyl acetate (50 mL) was added, and the mixture was stirred at 20 °C for 30 minutes, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, dichloromethane / ethyl acetate = 100 / 1, 1 / 1). 2,6-Dibenzyloxy-N-[5-[4-(dimethoxymethyl)-1-piperidinyl]-2-nitro-phenyl]pyridine-3-amine (4.9 g, 7.21 mmol, 89% yield, 86% purity) was obtained as a yellow solid.

[0236] Step 3 Reduced iron powder (2.01 g, 35.92 mmol, 5 equivalents) and ammonium chloride (3.84 g, 71.84 mmol, 1 equivalent) were added to a mixture of 2,6-dibenzyloxy-N-[5-[4-(dimethoxymethyl)-1-piperidinyl]-2-nitro-phenyl]pyridine-3-amine (4.2 g, 7.18 mmol, 1 equivalent) in ethanol (90 mL) and water (30 mL). The mixture was stirred at 80 °C for 12 hours and then cooled to 20 °C. Ethyl acetate (100 mL) was added, and the mixture was stirred at 20 °C for 30 minutes, filtered, and the filtrate was concentrated under reduced pressure. The residue was poured into ice water (w / w = 1 / 1) (100 mL) and concentrated with ethyl acetate (100 mL). 2) Extraction. The combined organic phases were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, dichloromethane / ethyl acetate = 100 / 1, 1 / 1). N2-(2,6-dibenzyloxy-3-pyridyl)-4-[4-(dimethoxymethyl)-1-piperidinyl]phenyl-1,2-diamine (3.8 g, 6.85 mmol, 95% yield) was obtained as a brown oil.

[0237] Step 4 At 0 °C, 4-dimethylaminopyridine (84 mg, 0.69 mmol, 0.1 equivalent) and di(1H-imidazol-1-yl) ketone (2.22 g, 13.70 mmol, 2 equivalent) were added to a solution of N2-(2,6-dibenzyloxy-3-pyridyl)-4-[4-(dimethoxymethyl)-1-piperidinyl]phenyl-1,2-diamine (3.8 g, 6.85 mmol, 1 equivalent) in tetrahydrofuran (50 mL). The mixture was stirred at 20 °C for 12 hours and poured into ice water (w / w = 1 / 1) (50 mL), and diluted with ethyl acetate (50 mL). 2) Extraction. The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, petroleum ether / ethyl acetate = 100 / 1, 1 / 2). 3-(2,6-dibenzyloxy-3-pyridyl)-5-[4-(dimethoxymethyl)-1-piperidinyl]-1H-benzimidazol-2-one (3.2 g, 5.51 mmol, 80% yield) was obtained as a brown solid.

[0238] Step 5 Sodium hydride (299 mg, 7.49 mmol, 60% purity, 1.5 equivalent) was added to a mixture of 3-(2,6-dibenzyloxy-3-pyridyl)-5-[4-(dimethoxymethyl)-1-piperidinyl]-1H-benzimidazol-2-one (2.9 g, 4.99 mmol, 1 equivalent) in tetrahydrofuran (60 mL) at 0 °C. The mixture was stirred at 0 °C for 30 min, and then a solution of iodomethane (780 mg, 5.49 mmol, 0.34 mL, 1.1 equivalent) in tetrahydrofuran (20 mL) was added. The mixture was stirred at 20 °C for 2 h. The mixture was quenched by adding saturated ammonium chloride (50 mL) and thiamethoxam (100 mL) with ethyl acetate (100 mL). 2) Extraction was performed, and the organic phase was concentrated under reduced pressure. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, petroleum ether / ethyl acetate = 100 / 1, 1 / 1). 3-(2,6-dibenzyloxy-3-pyridyl)-5-[4-(dimethoxymethyl)-1-piperidinyl]-1-methyl-benzimidazol-2-one (2.7 g, 4.36 mmol, 87% yield, 96% purity) was obtained as a yellow solid.

[0239] Compound 16 was prepared in a manner similar to that of compound 7 by using 3-(2,6-dibenzyloxy-3-pyridyl)-5-[4-(dimethoxymethyl)-1-piperidinyl]-1-methyl-benzimidazole-2-one instead of 1-(2,6-dibenzyloxy-3-pyridyl)-5-[4-(dimethoxymethyl)-1-piperidinyl]benzimidazole.

[0240] Exemplary synthesis of compound 18 Step 1 A solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (2 g, 9.94 mmol, 1 equivalent) in THF (20 mL) was cooled to 0 °C, and NaH (794.91 mg, 19.87 mmol, 60% purity, 2 equivalents) was added. The reaction mixture was stirred at 0 °C for 0.5 h, and then 3-bromoprop-1-yne (1.77 g, 14.91 mmol, 1.28 mL, 1.5 equivalents) was added, and the reaction mixture was stirred at 25 °C under N2 for 16 h. The reaction mixture was quenched at 0 °C by adding H2O (10 mL × 2) and quenched with EtOAc (10 mL). 3) Extraction. The combined organic layers were rinsed with brine (10 mL) 3) Wash, dry with Na2SO4, filter, and concentrate under reduced pressure to obtain the residue. Purify the residue by rapid silica gel chromatography (ISCO®; 12 g SepaFlash® silica rapid column, eluent gradient of 0–10% ethyl acetate / petroleum ether at 60 mL / min) to obtain tert-butyl 4-propane-2-alkynyloxypiperidine-1-carboxylate (720 mg, 3.01 mmol, 30.28% yield) as a yellow liquid.

[0241] Step 2 Cs₂CO₃ (1.16 g, 3.56 mmol, 3.56 equivalents), CuI (33.8 mg, 177.47 μmol, 1.78 e⁻¹ equivalents), and Pd(PPh₃)₂Cl₂ (124 mg, 176.66 μmol, 1.77 e⁻¹ equivalents) were added to a mixture of tert-butyl 4-prop-2-alkynyloxypiperidine-1-carboxylate (318 mg, 1.33 mmol, 1.33 equivalents) and 3-(4-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (300 mg, 887.16 μmol, 8.88 e⁻¹ equivalents) in DMF (5 mL). The mixture was stirred at 80 °C for 16 hours and then cooled. The mixture was filtered and concentrated under vacuum. The residue was purified by passing it through a Biotage® combiflash (20 g SepaFlash® silica fast column; elution: gradient 0–100% ethyl acetate / petroleum ether; gradient time: 25 min; hold time: 20 min; flow rate: 35 mL / min). The purified fractions were combined and concentrated under reduced pressure to give tert-butyl 4-[3-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazol-4-yl]prop-2-alkynyloxy]piperidine-1-carboxylate (265 mg, 405.60 μmol, 40.60% yield, 76% purity).

[0242] Step 3 TFA (15 M, 1.35 mL, 37.96 equivalents) was added to a mixture of 4-[3-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazol-4-yl]prop-2-alkynyl]piperidin-1-carboxylic acid tert-butyl ester (265 mg, 533.68 μmol, 1 equivalent) in DCM (5 mL), and the mixture was stirred at 25 °C for 2 h. TLC (petroleum ether:ethyl acetate = 3:1) showed a new spot. The residue was filtered and concentrated under vacuum to give 3-[3-methyl-2-oxo-4-[3-(4-piperidinyloxy)prop-1-alkynyl]benzimidazol-1-yl]piperidin-2,6-dione (200 mg, crude product, TFA) as a brown oil.

[0243] Step 4 Add HOAc (407.73 mg, 6.79 mmol, 388.31 uL, 17.33 equivalents) to a mixture of 3-[3-methyl-2-oxo-4-[3-(4-piperidinoxy)prop-1-ynyl]benzimidazol-1-yl]piperidin-2,6-dione (200 mg, 391.80 μmol, 1 equivalent, TFA) and 1-[6-[5-(1-methylcyclopropoxy)-2H-indazol-3-yl]pyrimidin-4-yl]piperidin-4-carboxaldehyde (50.48 mg, 133.75 μmol, 3.41 e-1 equivalent) in DCM (10 mL) and DMSO (0.5 mL). The mixture was stirred at 0°C for 1 hour, then NaBH(OAc)3 (83.04 mg, 391.80 μmol, 1 equivalent) was added, and the mixture was stirred at 0°C for 12 hours. The mixture was then filtered and concentrated under vacuum. The resulting residue was subjected to preparative HPLC (column: Phenomenex C18 75). 30 mm Purification was performed using a mobile phase of [water (FA)-ACN], B%: 8%-38%, for 25 minutes. Compound 18 was obtained as a white solid (16.1 mg, 20.90 μmol, 5.34% yield, 98.4% purity).

[0244] Exemplary synthesis of compound 19: Step 1 Under a nitrogen atmosphere, 2-tert-butyl-1,3-diisopropylisourea (25.99 g, 130 mmol) was added dropwise to a stirred solution of 4-methyl-5-nitropyridin-2-ol (10 g, 65 mmol) in THF (300 mL) at 0 °C. The reaction mixture was then stirred at 20 °C for 16 h under a nitrogen atmosphere. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (150 mL × 3). The combined organic phases were washed with brine (80 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-50% ethyl acetate / petroleum ether) to give 2-tert-butoxy-4-methyl-5-nitropyridinium (7.7 g, 56%) as a colorless oil.

[0245] Step 2 10% palladium / carbon (1 g, 4 mmol) was added to a stirred solution of 2-tert-butoxy-4-methyl-5-nitro-pyridine (7.7 g, 37 mmol) in THF (100 mL) and EtOH (100 mL). The suspension was degassed and purged several times with hydrogen. The mixture was stirred at 50 °C for 16 hours under hydrogen (50 psi). The reaction mixture was filtered through diatomaceous earth and washed with THF (100 mL × 3) and ethyl acetate (100 mL × 3) to give 6-tert-butoxy-4-methyl-pyridine-3-amine (5.6 g, 85%) as a yellow solid.

[0246] Step 3 Triethylamine (5.23 mL, 38 mmol) was added to a solution of 6-tert-butoxy-4-methylpyridin-3-amine (2.5 g, 14 mmol) in dichloromethane (30 mL) under a nitrogen atmosphere at 0 °C, followed by dropwise addition of acetic anhydride (2.83 mL, 30 mmol). The mixture was stirred at 0 °C for 30 min, then at 25 °C for 1 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 × 40 mL). The combined organic phases were washed with water (40 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-50% ethyl acetate / petroleum ether) to give N-(6-tert-butoxy-4-methyl-3-pyridinyl)acetamide (3.5 g, 89%, 85% purity) as a yellow solid.

[0247] Step 4 Acetic anhydride (0.98 mL, 10 mmol) and potassium acetate (331 mg, 3 mmol) were added to a solution of N-(6-tert-butoxy-4-methyl-3-pyridyl)acetamide (0.50 g, 2 mmol) in toluene (10 mL). The solution was heated to 80 °C, and isoamyl nitrite (0.91 mL, 6.8 mmol) was added dropwise. The mixture was stirred at 80 °C for 16 hours. The reaction mixture was filtered through diatomaceous earth, and the filtrate was diluted with water (50 mL) and extracted with ethyl acetate (3 × 40 mL). The combined organic phases were washed with water (40 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-30% ethyl acetate / petroleum ether) to give 1-(5-tert-butoxypyrazolo[3,4-c]pyridin-1-yl)acetone (0.3 g, 57%) as a yellow solid.

[0248] Step 5 A single addition of NH3 / MeOH (7 M, 2.5 mL) was made into a mixture of 1-(5-tert-butoxypyrazolo[3,4-c]pyridin-1-yl)acetone (2.7 g, 12 mmol) and MeOH (10 mL). The reaction mixture was stirred at 25 °C for 1 hour and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-50% ethyl acetate / petroleum ether) to give 5-tert-butoxy-1H-pyrazolo[3,4-c]pyridine (1.57 g, 71%) as a yellow solid.

[0249] Step 6 Potassium hydroxide (1.84 g, 33 mmol) and iodine (3.31 mL, 16 mmol) were added to a solution of 5-tert-butoxy-1H-pyrazolo[3,4-c]pyridine (1.57 g, 8 mmol) in DMF (20 mL), and the solution was stirred at 25 °C for 1 hour. The reaction mixture was diluted with saturated sodium thiosulfate solution (50 mL) and extracted with ethyl acetate (2 × 30 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-30% ethyl acetate / petroleum ether) to give 5-tert-butoxy-3-iodo-1H-pyrazolo[3,4-c]pyridine (2.3 g, 88%) as a yellow solid.

[0250] Step 7 NaH (435 mg, 11 mmol, 60%) was added to a solution of 5-tert-butoxy-3-iodo-1H-pyrazolo[3,4-c]pyridine (2.3 g, 7 mmol) in DMF (10 mL) at 0 °C under a nitrogen atmosphere. The solution was stirred at 0 °C for 0.5 h, followed by the addition of triphenylmethyl chloride (2.43 g, 9 mmol). The reaction mixture was stirred at 25 °C for 2 h under a nitrogen atmosphere. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with brine (30 mL × 3), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-6% ethyl acetate / petroleum ether) to give 5-tert-butoxy-3-iodo-1-triphenylmethyl-pyrazolo[3,4-c]pyridine (3.6 g, 89%) as a yellow solid.

[0251] Step 8 Pd(dppf)Cl2 (131 mg, 0.2 mmol) and potassium acetate (526 mg, 5 mmol) were added to a solution of 5-tert-butoxy-3-iodo-1-triphenylmethyl-pyrazolo[3,4-c]pyridine (1 g, 2 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1,3,2-dioxacyclopentaborane (908 mg, 3 mmol) in dioxane (20 mL). The mixture was stirred at 100 °C for 16 hours under a nitrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give 5-tert-butoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1-triphenylmethyl-pyrazolo[3,4-c]pyridine (1.5 g, crude product), which was used directly in the next step. MS (ESI) m / z : 478.1 [M-81] + .

[0252] Step 9 Sodium carbonate (568 mg, 5 mmol) and Pd(dppf)Cl2 (131 mg, 0.2 mmol) were added to a solution of 5-tert-butoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1-triphenylmethyl-pyrazolo[3,4-c]pyridine (1 g, 2 mmol) and 4,6-dichloropyrimidine (399 mg, 3 mmol) in dioxane (10 mL) and water (2 mL). The mixture was stirred at 100 °C for 1 hour under a nitrogen atmosphere. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with brine (30 mL × 3), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0 to 30% ethyl acetate / petroleum ether) to give 5-tert-butoxy-3-(6-chloropyrimidin-4-yl)-1-triphenylmethyl-pyrazolo[3,4-c]pyridine (0.9 g, 52%, 56% purity) as a yellow solid. MS (ESI) m / z 546.2 [M+H] + .

[0253] Step 10 DIEA (0.86 mL, 5 mmol) was added to a solution of piperazine-1-carboxylate (472 mg, 2 mmol) and 5-tert-butoxy-3-(6-chloropyrimidin-4-yl)-1-triphenylmethyl-pyrazolo[3,4-c]pyridine (0.9 g, 2 mmol) in DMSO (10 mL). The mixture was stirred at 100 °C for 1 hour under a nitrogen atmosphere. The reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate (3 × 40 mL). The combined organic phases were washed with brine (40 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0 to 30% ethyl acetate / petroleum ether) to give 4-[6-(5-tert-butoxy-1-triphenylmethyl-pyrazolo[3,4-c]pyridin-3-yl)pyrimidin-4-yl]piperazine-1-carboxylic acid benzyl ester (0.9 g, 75%) as a yellow solid.

[0254] Step 11 TFA (4 mL) was added to a solution of 4-[6-(5-tert-butoxy-1-triphenylmethyl-pyrazolo[3,4-c]pyridin-3-yl)pyrimidin-4-yl]piperazine-1-carboxylic acid benzyl ester (1 g, 1 mmol) in dichloromethane (20 mL). The mixture was stirred at 0 °C for 3 h. The reaction mixture was diluted with water (10 mL), and sodium bicarbonate was added to adjust the pH to 8. The resulting mixture was extracted with dichloromethane (40 mL × 3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0 to 100% ethyl acetate / petroleum ether) to give 800 mg of crude product as a yellow oil. The material was purified by preparative HPLC (38%–78% acetonitrile / water (ammonium bicarbonate), over 20 minutes) to give a yellow solid, 4-[6-(5-tert-butoxy-1H-pyrazolo[3,4-c]pyridin-3-yl)pyrimidin-4-yl]piperazine-1-carboxylic acid benzyl ester (230 mg, 34%). MS (ESI) m / z 488.3 [M+H] + .

[0255] Step 12 10% palladium / carbon (70 mg) was added to a stirred solution of 4-[6-(5-tert-butoxy-1H-pyrazolo[3,4-c]pyridin-3-yl)pyrimidin-4-yl]piperazine-1-carboxylic acid benzyl ester (230 mg, 0.5 mmol) in EtOH (10 mL) and ethyl acetate (10 mL). The suspension was degassed and purged several times with hydrogen. The reaction mixture was stirred at 40 °C for 16 hours under hydrogen (15 psi.) and then filtered through diatomaceous earth. The diatomaceous earth was washed with THF (30 mL × 3) and ethyl acetate (20 mL × 3), and the combined filtrates were concentrated under reduced pressure to give 5-tert-butoxy-3-(6-piperazine-1-ylpyrimidin-4-yl)-1H-pyrazolo[3,4-c]pyridine (160 mg, 96%) as a yellow solid.

[0256] Step 13 A solution of 5-tert-butoxy-3-(6-piperazin-1-ylpyrimidin-4-yl)-1H-pyrazolo[3,4-c]pyridine (25 mg, 71 μmol) in dichloromethane (10 mL) and DMSO (2 mL) was mixed with 4-[[1-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazol-5-yl]-4-piperidinyl]oxy]cyclohexylcarbaldehyde (33.1 mg, 71 μmol) at 0 °C. The mixture was stirred in acetic acid at 0 °C for 0.5 h, followed by the addition of acetic acid (2.02 μL, 35 μmol). The mixture was stirred at 0 °C for 2 h, followed by the addition of sodium triacetoxyborohydride (29.98 mg, 141 μmol). The reaction mixture was stirred at 0 °C for 2 h, then diluted with water (40 mL) and extracted with dichloromethane (30 mL × 3). The organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC (36%–76% acetonitrile / water (ammonium bicarbonate), over 20 minutes) to give compound 19 (22.4 mg, 39%) as a grayish-white solid. MS (ESI) m / z 806.5 [M+H] + .

[0257] Exemplary synthesis of compound 20: Step 1 Silver carbonate (3.42 mL, 75 mmol) was added to a mixture of 4-methyl-5-nitro-pyridin-2-ol (10 g, 65 mmol) and 2-iodopropane (19.4 mL, 195 mmol) in toluene (240 mL). The mixture was stirred at 60 °C for 16 hours under a nitrogen atmosphere. The reaction mixture was filtered through diatomaceous earth, and the filtrate was diluted with water (50 mL) and extracted with ethyl acetate (3 × 200 mL). The combined organic phases were washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0–15% ethyl acetate / petroleum ether) to give 2-isopropoxy-4-methyl-5-nitro-pyridinium (12 g, 94%) as a yellow solid.

[0258] Step 2 10% palladium / carbon (1.4 g) was added to a mixture of 2-isopropoxy-4-methyl-5-nitro-pyridine (12 g, 61 mmol) and THF (200 mL). The suspension was degassed and purged several times with hydrogen, then stirred at 25 °C for 16 hours under hydrogen (40 psi). The reaction mixture was filtered through diatomaceous earth, washed with MeOH (500 mL), and concentrated under reduced pressure to give 6-isopropoxy-4-methyl-pyridine-3-amine (10.1 g, 99%) as a yellow gel.

[0259] Step 3 Triethylamine (21 mL, 0.15 mol) was added to a solution of 6-isopropoxy-4-methyl-pyridin-3-amine (10 g, 60 mmol) in dichloromethane (100 mL) under a nitrogen atmosphere at 0 °C, followed by dropwise addition of acetic anhydride (11.3 mL, 0.12 mol). The mixture was stirred at 0 °C for 30 min, then at 25 °C for 1 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-50% ethyl acetate / petroleum ether) to give N-(6-isopropoxy-4-methyl-3-pyridinyl)acetamide (12 g, 96%) as a yellow solid.

[0260] Step 4 Acetic anhydride (25 mL, 0.27 mol) and potassium acetate (8.48 g, 86 mmol) were added to a solution of N-(6-isopropoxy-4-methyl-3-pyridyl)acetamide (12 g, 58 mmol) in toluene (80 mL). The solution was heated to 80 °C, and isoamyl nitrite (31 mL, 0.23 mol) was added dropwise. The reaction mixture was stirred at 80 °C for 16 hours and then filtered through diatomaceous earth. The filtrate was diluted with water (50 mL) and extracted with ethyl acetate (3 × 200 mL). The combined organic phases were washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-30% ethyl acetate / petroleum ether) to give 1-(5-isopropoxypyrazolo[3,4-c]pyridin-1-yl)acetone (7.5 g, 59%) as a yellow solid.

[0261] Step 5 NH3 / MeOH (7 M, 7.33 mL) was added to a mixture of 1-(5-isopropoxypyrazolo[3,4-c]pyridin-1-yl)acetone (7.5 g, 34 mmol) in MeOH (100 mL). The mixture was stirred at 25 °C for 16 hours and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-50% ethyl acetate / petroleum ether) to give 5-isopropoxy-1H-pyrazolo[3,4-c]pyridine (5.3 g, 87%) as a yellow solid.

[0262] Step 6 Potassium hydroxide (6.71 g, 0.12 mol) and iodine (12 mL, 60 mmol) were added to a solution of 5-isopropoxy-1H-pyrazolo[3,4-c]pyridine (5.3 g, 30 mmol) in DMF (50 mL), and the solution was stirred at 25 °C for 1 hour. The reaction mixture was diluted with saturated sodium thiosulfate solution (50 mL) and extracted with ethyl acetate (2 × 30 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-30% ethyl acetate / petroleum ether) to give 3-iodo-5-isopropoxy-1H-pyrazolo[3,4-c]pyridine (7 g, 77%) as a yellow solid.

[0263] Step 7 Sodium hydride (1.39 g, 35 mmol, 60%) was added to a solution of 3-iodo-5-isopropoxy-1H-pyrazolo[3,4-c]pyridine (7.0 g, 23 mmol) in DMF (50 mL). The solution was stirred at 0 °C for 0.5 h, and then triphenylmethyl chloride (7.73 g, 28 mmol) was added. The reaction mixture was stirred at 25 °C for 2 h, then diluted with water (50 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with brine (20 mL × 3), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-6% ethyl acetate / petroleum ether) to give 3-iodo-5-isopropoxy-1-triphenylmethyl-pyrazolo[3,4-c]pyridine (7 g, 56%) as an off-white solid.

[0264] Step 8 Pd(dppf)Cl2 (268.3 mg, 0.4 mmol) and potassium acetate (1.08 g, 11 mmol) were added to a solution of 3-iodo-5-isopropoxy-1-triphenylmethyl-pyrazolo[3,4-c]pyridine (2 g, 4 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1,3,2-dioxacyclopentaborane (1.86 g, 7 mmol) in dioxane (20 mL). The mixture was stirred at 100 °C for 16 hours under a nitrogen atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give 5-isopropoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1-triphenylmethyl-pyrazolo[3,4-c]pyridine (2. g, crude product), which was used directly in the next step. MS (ESI) m / z: 464.1 [M-81] + .

[0265] Step 9 Sodium carbonate (1.17 g, 11 mmol) and Pd(dppf)Cl2 (268.3 mg, 0.4 mmol) were added to a solution of 5-isopropoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1-triphenylmethyl-pyrazolo[3,4-c]pyridine (2 g, 4 mmol) and 4,6-dichloropyrimidine (819 mg, 6 mmol) in dioxane (20 mL) and water (4 mL). The mixture was stirred at 100 °C for 1 hour under a nitrogen atmosphere, then filtered and concentrated under reduced pressure. The residue was diluted with water (20 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic phase was washed with water, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0 to 30% ethyl acetate / petroleum ether) to give 3-(6-chloropyrimidin-4-yl)-5-isopropoxy-1-triphenylmethyl-pyrazolo[3,4-c]pyridine (1.1 g, 56%) as a grayish-white solid.

[0266] Step 10 DIEA (1.08 mL, 6 mmol) was added to a solution of piperazine-1-carboxylic acid tert-butyl ester (578 mg, 3 mmol) and 3-(6-chloropyrimidin-4-yl)-5-isopropoxy-1-triphenylmethyl-pyrazolo[3,4-c]pyridine (1.1 g, 2 mmol) in DMSO (10 mL). The mixture was stirred at 100 °C for 1 hour under a nitrogen atmosphere, then diluted with water (40 mL) and extracted with ethyl acetate (3 × 40 mL). The combined organic phases were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0 to 30% ethyl acetate / petroleum ether) to give tert-butyl 4-[6-(5-isopropoxy-1-triphenylmethyl-pyrazolo[3,4-c]pyridin-3-yl)pyrimidin-4-yl]piperazine-1-carboxylate (1.3 g, 92%) as a yellow solid.

[0267] Step 11 HCl / dioxane (2 M, 10 mL) was added to a solution of tert-butyl 4-[6-(5-isopropoxy-1-triphenylmethyl-pyrazolo[3,4-c]pyridin-3-yl)pyrimidin-4-yl]piperazine-1-carboxylate (1.22 g, 1.8 mmol) in MeOH (8 mL). The mixture was stirred at 40 °C for 16 h under a nitrogen atmosphere and then diluted with water (10 mL). The pH of the mixture was adjusted to 13 with sodium hydroxide and then extracted with ethyl acetate (40 mL × 3). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 5-isopropoxy-3-(6-piperazine-1-ylpyrimidin-4-yl)-1H-pyrazolo[3,4-c]pyridine (0.6 g, 99%) as a red solid, which was used directly in the next step.

[0268] Step 12 Acetic acid (16.9 μL, 0.29 mmol) was added to a solution of 5-isopropoxy-3-(6-piperazin-1-ylpyrimidin-4-yl)-1H-pyrazolo[3,4-c]pyridine (100 mg, 0.29 mmol) and 4-[[1-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazol-5-yl]-4-piperidinyl]oxy]cyclohexaneformaldehyde (138 mg, 0.29 mmol) in dichloromethane (10 mL). The mixture was stirred at 0 °C for 30 min, and then sodium triacetoxyborohydride (156.1 mg, 0.74 mmol) was added. The mixture was stirred at 0 °C for 12 h and filtered. The filtrate solution was concentrated. The residue was purified by preparative HPLC (0%–34% acetonitrile / water (TFA), over 20 min), and the crude product was further purified by preparative HPLC (0%–32% acetonitrile / water (formic acid), over 20.5 min) to give compound 20 (104.7 mg, 45%) as a grayish-white solid. MS (ESI) m / z: 792.4 [M+H] + .

[0269] Exemplary synthesis of compound 21: Step 1 Acetic anhydride (13.6 mL, 145 mmol) was added to a mixture of 6-methoxy-4-methylpyridin-3-amine (10 g, 72 mmol) and triethylamine (25.18 mL, 181 mmol) in dichloromethane (100 mL). The mixture was stirred at 25 °C for 16 h, then diluted with water (60 mL) and extracted with ethyl acetate (60 mL × 3). The combined organic phases were washed with brine (60 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-100% ethyl acetate / petroleum ether) to give N-(6-methoxy-4-methyl-3-pyridinyl)acetamide (12 g, 92%) as a yellow gel. MS (ESI) m / z: 180.9 [M+H] + .

[0270] Step 2 Acetic anhydride (28.8 mL, 306 mmol) and potassium acetate (9.80 g, 100 mmol) were added to a solution of N-(6-methoxy-4-methyl-3-pyridyl)acetamide (12.0 g, 66 mmol) in toluene (20 mL). The solution was heated to 80 °C, followed by dropwise addition of isoamyl nitrite (35.9 mL, 266 mmol). The reaction mixture was stirred at 80 °C for 16 hours, then filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0–13% ethyl acetate / petroleum ether) to give 1-(5-methoxypyrazolo[3,4-c]pyridin-1-yl)acetone (8.2 g, 64%) as a yellow solid. MS (ESI) m / z: 192.0 [M+H] + .

[0271] Step 3 NH3 / MeOH (7 M, 12.3 mL) was added to a mixture of 1-(5-methoxypyrazolo[3,4-c]pyridin-1-yl)acetone (8.2 g, 43 mmol) in MeOH (100 mL). The mixture was stirred at 25 °C for 16 hours and then concentrated under reduced pressure. The residue was ground with methyl tert-butyl ether: petroleum ether (1:1) to give 5-methoxy-1H-pyrazolo[3,4-c]pyridine (6.3 g, 98%) as a yellow solid. MS (ESI) m / z: 150.0 [M+H] + .

[0272] Step 4 Iodine (16.8 mL, 83 mmol) was added to a mixture of 5-methoxy-1H-pyrazolo[3,4-c]pyridine (6.2 g, 41 mmol) and potassium hydroxide (9.33 g, 166 mmol) in DMF (50 mL). The mixture was stirred at 25 °C for 16 hours. The reaction mixture was diluted with saturated sodium thiosulfate solution (50 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (3 × 40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was ground with methyl tert-butyl ether:acetonitrile (5:1) to give 3-iodo-5-methoxy-1H-pyrazolo[3,4-c]pyridine (8.2 g, 72%) as a yellow solid. MS (ESI) m / z: 275.8 [M+H] + .

[0273] Step 5 Sodium hydride (1.64 g, 41 mmol, 60%) was added to a mixture of 3-iodo-5-methoxy-1H-pyrazolo[3,4-c]pyridine (7.5 g, 27 mmol) in DMF (30 mL) at 0 °C. The mixture was stirred at 25 °C for 1 h under a nitrogen atmosphere, followed by the addition of triphenylmethyl chloride (9.12 g, 33 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 15 h, then diluted with water (50 mL) and extracted with ethyl acetate (60 mL × 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-14% ethyl acetate / petroleum ether) to give 3-iodo-5-methoxy-1-triphenylmethyl-pyrazolo[3,4-c]pyridine (7.2 g, 51%) as a yellow solid.

[0274] Step 6 Pd(dppf)Cl2 (282.9 mg, 0.4 mmol) and potassium acetate (1.14 g, 12 mmol) were added to a mixture of 3-iodo-5-methoxy-1-triphenylmethyl-pyrazolo[3,4-c]pyridine (2 g, 4 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1,3,2-dioxacyclopentaborane (1.47 g, 6 mmol) in dioxane (10 mL) under a nitrogen atmosphere. The mixture was stirred at 100°C for 16 hours under a nitrogen atmosphere, then filtered and concentrated under reduced pressure to give 5-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1-triphenylmethyl-pyrazolo[3,4-c]pyridine (2 g, 75%, 75% purity) as a black solid, which was used directly in the next step. MS (ESI) m / z: 436.2 [M-81+H] + .

[0275] Step 7 Pd(dppf)Cl2 (282.8 mg, 0.4 mmol) and sodium carbonate (1.23 g, 12 mmol) were added to a mixture of 5-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)-1-triphenylmethyl-pyrazolo[3,4-c]pyridine (2 g, 4 mmol) and 4,6-dichloropyrimidine (748.6 mg, 5 mmol) in dioxane (50 mL) and water (5 mL) under a nitrogen atmosphere. The mixture was stirred at 100 °C for 2 hours under nitrogen, then filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-17% ethyl acetate / petroleum ether) to give 3-(6-chloropyrimidine-4-yl)-5-methoxy-1-triphenylmethyl-pyrazolo[3,4-c]pyridine (680 mg, 35%) as a yellow solid. MS (ESI) m / z: 504.1 [M+H] + .

[0276] Step 8 DIEA (260 μL, 1.5 mmol) was added to a mixture of 3-(6-chloropyrimidin-4-yl)-5-methoxy-1-triphenylmethyl-pyrazolo[3,4-c]pyridine (250 mg, 0.5 mmol) and piperazine-1-carboxylic acid tert-butyl ester (120 mg, 0.6 mmol) in DMSO (5 mL). The mixture was stirred at 100 °C for 1 hour, then diluted with water (60 mL) and extracted with ethyl acetate (60 mL × 3). The combined organic phases were washed with brine (60 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0–23% ethyl acetate / petroleum ether) to give tert-butyl 4-[6-(5-methoxy-1-triphenylmethyl-pyrazolo[3,4-c]pyridin-3-yl)pyrimidin-4-yl]piperazine-1-carboxylate (250 mg, 77%) as a yellow solid. MS (ESI) m / z: 654.4 [M+H] + .

[0277] Step 9 To a mixture of 4-[6-(5-methoxy-1-triphenylmethyl-pyrazolo[3,4-c]pyridin-3-yl)pyrimidin-4-yl]piperazine-1-carboxylic acid tert-butyl ester (250 mg, 0.4 mmol) in MeOH (5 mL), HCl / dioxane (2 M, 10 mL) was added. The mixture was stirred at 40 °C for 1 hour, and then sodium hydroxide was added to adjust the pH to 14. The resulting mixture was concentrated under reduced pressure. The residue was suspended in dichloromethane:MeOH (10:1), filtered, and the filtrate was concentrated under reduced pressure to give 5-methoxy-3-(6-piperazine-1-ylpyrimidin-4-yl)-1H-pyrazolo[3,4-c]pyridine (110 mg, 83%) as a pink solid. MS (ESI) m / z 312.2 [M+H] + .

[0278] Step 10 Acetic acid (60.68 μL, 1.1 mmol) was added in a single batch to a mixture of 5-methoxy-3-(6-piperazin-1-ylpyrimidin-4-yl)-1H-pyrazolo[3,4-c]pyridine (110 mg, 0.35 mmol) and 4-[[1-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazol-5-yl]-4-piperidinyl]oxy]cyclohexaneformaldehyde (165.5 mg, 0.35 mmol) in dichloromethane (5 mL). The mixture was stirred for 1 hour, and then sodium triacetoxyborohydride (149.8 mg, 0.7 mmol) was added. The reaction mixture was stirred for 3 hours, then filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (0%–30% acetonitrile / water (formic acid), over 20.5 min) to give compound 21 (93.7 mg, 33%, formate) as a white solid. MS (ESI) m / z: 764.6 [M+H] + .

[0279] Exemplary synthesis of compound 22: Step 1 To 5-chloro-1H-pyrazolo[3,4-c]pyridine (1.0 g, 7 mmol), cyclobutyronitrile (1.58 g, 19 mmol) and {( R A solution of palladium(II) methanesulfonate (602 mg, 0.7 mmol) in THF (20 mL) was prepared by adding lithium bis(trimethylsilyl)amide (1 M, 16.3 mL). The mixture was stirred at 80 °C for 12 h, then slowly diluted at 0 °C with saturated ammonium chloride solution (100 mL) and extracted with ethyl acetate (100 mL × 2). The combined organic phases were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-30% ethyl acetate / petroleum ether) to give 1-(1H-pyrazolo[3,4-c]pyridin-5-yl)cyclobutyronitrile (1.2 g, 93%) as a yellow solid. MS (ESI) m / z: 199.1 [M+H] + .

[0280] Step 2 Iodine (1 mL, 5 mmol) was added to a solution of 1-(1H-pyrazolo[3,4-c]pyridin-5-yl)cyclobutyronitrile (0.5 g, 2 mmol) and potassium hydroxide (566 mg, 10 mmol) in DMF (10 mL). The mixture was stirred at 25 °C for 2 h, then slowly diluted with saturated ammonium chloride solution (100 mL) and extracted with ethyl acetate (100 mL × 2). The combined organic phases were washed with brine (100 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-30% THF / petroleum ether) to give 1-(3-iodo-1H-pyrazolo[3,4-c]pyridin-5-yl)cyclobutyronitrile (0.55 g, 67%) as a brown solid. MS (ESI) m / z: 325.0 [M+H] + .

[0281] Step 3 Sodium hydride (81.4 mg, 2 mmol, 60%) was added to a solution of 1-(3-iodo-1H-pyrazolo[3,4-c]pyridin-5-yl)cyclobutyronitrile (0.55 g, 1.7 mmol) in DMF (10 mL) at 0 °C under a nitrogen atmosphere. The mixture was stirred at 0 °C for 30 min, then triphenylmethyl chloride (567.7 mg, 2 mmol) was added, and the mixture was heated to 25 °C and stirred at a nitrogen atmosphere for 3 h. The reaction mixture was slowly diluted with a saturated ammonium chloride solution (100 mL) and extracted with ethyl acetate (100 mL × 2). The combined organic phases were washed with brine (100 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was ground with petroleum ether / methyl tert-butyl ether (10 mL / 1 mL) to give 0.8 g, 77%, a brown solid of 1-(3-iodo-1-triphenylmethyl-pyrazolo[3,4-c]pyridin-5-yl)cyclobutyronitrile. MS (ESI) m / z: 567.1 [M+H] + .

[0282] Step 4 The mixture of 1-(3-iodo-1-triphenylmethyl-pyrazolo[3,4-c]pyridin-5-yl)cyclobutyronitrile (0.4 g, 0.7 mmol), 4-(6-bromopyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (218 mg, 0.6 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1,3,2-dioxacyclopentaborane (179.3 mg, 0.7 mmol) and cesium fluoride (536 mg, 3.5 mmol) in MeOH (10 mL) was degassed and purged with nitrogen several times. A solution of palladium(II) acetate (15.9 mg, 71 μmol) and bis(1-adamantyl)-butylphosphine (50.6 mg, 0.1 mmol) in toluene (5 mL) was then added to the mixture, and the mixture was further degassed and purged with nitrogen. The reaction mixture was stirred at 70 °C for 2 hours under a nitrogen atmosphere, then filtered and concentrated under reduced pressure. The residue was diluted with water (100 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with brine (150 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-20% THF / petroleum ether) to give tert-butyl 4-[6-[5-(1-cyanocyclobutyl)-1-triphenylmethyl-pyrazolo[3,4-c]pyridin-3-yl]pyrimidin-4-yl]piperazine-1-carboxylate (220 mg, 39%, 88% purity) as a pale yellow solid. MS (ESI) m / z: 703.4 [M+H] + .

[0283] Step 5 TFA (4 mL) was added to a solution of 200 mg (0.3 mmol) of 4-[6-[5-(1-cyanocyclobutyl)-1-triphenylmethyl-pyrazolo[3,4-c]pyridin-3-yl]pyrimidin-4-yl]piperazine-1-carboxylic acid tert-butyl ester (3 mL) in dichloromethane. The mixture was stirred at 25 °C for 2 hours and then concentrated under reduced pressure to give 200 mg (crude product, 3 TFA salt) of 1-[3-(6-piperazine-1-ylpyrimidin-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl]cyclobutyronitrile as a brown oil. MS (ESI) m / z: 361.2 [M+H] + .

[0284] Step 6 Acetic acid (0.5 mL, 9 mmol) was added to a solution of 1-[3-(6-piperazin-1-ylpyrimidin-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl]cyclobutyronitrile (100 mg, 0.28 mmol) and 4-[[1-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazol-5-yl]-4-piperidinyl]oxy]cyclohexylcarbaldehyde (65.0 mg, 0.14 mmol) in dichloromethane (10 mL), followed by the addition of sodium triacetoxyborohydride (88.2 mg, 0.42 mmol). The reaction mixture was stirred at 0 °C for 12 hours, then filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (0%–36% acetonitrile / water (TFA), over 20.5 min) to give a pale yellow solid (60 mg, 94% purity), which was further purified by preparative HPLC (30%–70% acetonitrile / water (ammonium bicarbonate), over 25 min) to give compound 22 (32.2 mg, 13% formate) as a white solid. MS (ESI) m / z: 813.4 [M+H] + .

[0285] Exemplary synthesis of compound 23: Step 1 Under an argon atmosphere, lithium bis(trimethylsilyl)amide (1 M, 29.3 mL) and {( R 1-[(sp)-2-(dicyclohexylphosphino)ferrocene]ethyl di-tert-butylphosphine}[2-(2'-amino-1,1'-diphenyl)]palladium(II) methanesulfonate (1.08 g, 1 mmol) was stirred at 80 °C for 12 h under an argon atmosphere. The reaction mixture was diluted with saturated ammonium chloride solution at 0 °C and extracted with ethyl acetate (60 mL × 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-30% ethyl acetate / petroleum ether) to give 1-(1H-pyrazolo[3,4-c]pyridin-5-yl)cyclopropaneformitrile (1.9 g, 88%) as a pale yellow solid. MS (ESI) m / z: 185.1 [M+H] + .

[0286] Step 2 Potassium hydroxide (2.31 g, 41 mmol) and iodine (3.1 mL, 15 mmol) were added to a solution of 1-(1H-pyrazolo[3,4-c]pyridin-5-yl)cyclopropanecarboxynitrile (1.9 g, 10 mmol) in DMSO (20 mL). The mixture was stirred at 25 °C for 2 h, then diluted with water (50 mL) and extracted with ethyl acetate (40 mL × 3). The combined organic layers were washed with brine (30 mL × 3), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-100% ethyl acetate / petroleum ether) to give 1-(3-iodo-1H-pyrazolo[3,4-c]pyridin-5-yl)cyclopropanecarboxynitrile (3 g, 94%) as a pale yellow solid.

[0287] Step 3 Sodium hydride (464 mg, 12 mmol, 60%) was added to a solution of 1-(3-iodo-1H-pyrazolo[3,4-c]pyridin-5-yl)cyclopropanecarboxylonitrile (3.0 g, 10 mmol) in DMF (70 mL) at 0 °C under a nitrogen atmosphere. The mixture was stirred at 0 °C for 0.5 h under a nitrogen atmosphere, and then triphenylmethyl chloride (3.24 g, 12 mmol) was added. The reaction mixture was stirred at 25 °C for 2 h under a nitrogen atmosphere, then diluted with water (100 mL) and extracted with ethyl acetate (80 mL × 3). The combined organic layers were washed with brine (70 mL × 3), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was ground with petroleum ether (30 mL) and methyl tert-butyl ether (30 mL) to give 1-(3-iodo-1-triphenylmethyl-pyrazolo[3,4-c]pyridin-5-yl)cyclopropaneformitrile (3 g, 50%) as a pale yellow solid. MS (ESI) m / z: 553.1 [M+H] + .

[0288] Step 4 Potassium acetate (693 mg, 7 mmol) and Pd(dppf)Cl2 (137.8 mg, 0.2 mmol) were added to a solution of 1-(3-iodo-1-triphenylmethyl-pyrazolo[3,4-c]pyridin-5-yl)cyclopropanecarboxylonitrile (1.3 g, 2 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1,3,2-dioxacyclopentaborane (956 mg, 4 mmol) in dioxane (50 mL). The mixture was stirred at 110 °C for 12 hours under a nitrogen atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give 1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1-triphenylmethyl-pyrazolo[3,4-c]pyridin-5-yl]cyclopropanecarboxynitrile (3 g, crude product) as a brown solid, which was used directly in the next step. MS (ESI) m / z: 471.2 [M-81+H] + .

[0289] Step 5 Sodium carbonate (719 mg, 7 mmol) and Pd(dppf)Cl2 (139 mg, 0.2 mmol) were added to a solution of 1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1-triphenylmethyl-pyrazolo[3,4-c]pyridin-5-yl]cyclopropanecarboxynitrile (1.5 g, 3 mmol) and 4,6-dichloropyrimidine (445 mg, 3 mmol) in dioxane (50 mL) and water (10 mL). The mixture was stirred at 100 °C for 4 hours under a nitrogen atmosphere. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (40 mL × 3). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-20% ethyl acetate / petroleum ether) to give 1-[3-(6-chloropyrimidin-4-yl)-1-triphenylmethyl-pyrazolo[3,4-c]pyridin-5-yl]cyclopropaneformitrile (1.5 g, 54%, 53% purity) as a colorless oil. MS (ESI) m / z: 539.3 [M+H] + .

[0290] Step 6 DIEA (1.5 mL, 8 mmol) was added to a solution of 1-[3-(6-chloropyrimidin-4-yl)-1-triphenylmethyl-pyrazolo[3,4-c]pyridin-5-yl]cyclopropanecarboxylonitrile (1.5 g, 3 mmol) and piperazine-1-carboxylic acid tert-butyl ester (777 mg, 4 mmol) in DMSO (30 mL), and the mixture was stirred at 90 °C for 8 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (40 mL × 3). The combined organic layers were washed with brine (40 mL × 3), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-28% ethyl acetate / petroleum ether) to give tert-butyl 4-[6-[5-(1-cyanocyclopropyl)-1-triphenylmethyl-pyrazolo[3,4-c]pyridin-3-yl]pyrimidin-4-yl]piperazine-1-carboxylate (0.8 g, 38%) as a white solid.

[0291] Step 7 TFA (3.8 mL) was added to a solution of tert-butyl piperazine-1-carboxylate (250 mg, 0.4 mmol) in dichloromethane (3 mL). The reaction solution was stirred at 25 °C for 4 hours and then concentrated under reduced pressure to give a yellow gel-like substance, 1-[3-(6-piperazin-1-ylpyrimidin-4-yl)-1H-pyrazoline-5-yl]cyclopropanecarboxylate (210 mg, 70%, 56% purity, TFA salt), which was used in the next step without further purification. MS (ESI) m / z: 347.1 [M+H] + .

[0292] Step 8 A solution of 1-[3-(6-piperazin-1-ylpyrimidin-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl]cyclopropanecarboxylonitrile (77.63 mg, 0.22 mmol) in dichloromethane (15 mL) was added at -10 °C. The solution contained acetic acid (8.55 μL, 0.15 mmol) and 4-[[1-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazol-5-yl]-4-piperidinyl]oxy]cyclohexylcarbaldehyde (70 mg, 0.15 mmol). The mixture was stirred for 1 hour, followed by the addition of sodium triacetoxyborohydride (79.16 mg, 0.37 mmol). The reaction mixture was stirred at -10 °C for 4 hours, then filtered and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (26%–66% acetonitrile / water (ammonium bicarbonate), over 25 minutes) to give compound 23 (81.3 mg, 68%) as a white solid. MS (ESI) m / z: 799.4 [M / 2+H] + .

[0293] Exemplary synthesis of compound 24: Step 1 In an argon atmosphere at 25 °C, [bis(trimethylsilyl)amino]lithium (1 M, 23 mL) and {( R )-1-[(sp)-2-(dicyclohexylphosphino)ferrocene]ethyl di-tert-butylphosphine}[2-(2'-amino-1,1'-diphenyl)]palladium(II) methanesulfonate (863 mg, 0.9 mmol). The mixture was stirred at 80 °C for 12 hours under an argon atmosphere. The reaction mixture was diluted with saturated ammonium chloride solution (60 mL) at 0 °C and extracted with ethyl acetate (60 mL × 3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-30% ethyl acetate / petroleum ether) to give a crude product (1.7 g). The above material was ground with methyl tert-butyl ether (20 mL) to give 5-(1H-pyrazolo[3,4-c]pyridin-5-yl)spiro[2,3]hexane-5-carboxynitrile (750 mg, 36%) as a pale yellow solid. MS (ESI) m / z: 225.1 [M+H] + .

[0294] Step 2 Potassium hydroxide (562.9 mg, 10 mmol) and iodine (1 mL, 5 mmol) were added to a solution of 5-(1H-pyrazolo[3,4-c]pyridin-5-yl)spiro[2,3]hexane-5-carboxynitrile (0.75 g, 3 mmol) in DMSO (15 mL). The reaction mixture was stirred at 25 °C for 2 h, then diluted with water (50 mL) and extracted with ethyl acetate (40 mL × 3). The combined organic layers were washed with brine (40 mL × 3), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was ground with methyl tert-butyl ether (20 mL) to give 5-(3-iodo-1H-pyrazolo[3,4-c]pyridin-5-yl)spiro[2,3]hexane-5-carboxynitrile (1.1 g, 94%) as a white solid. MS (ESI) m / z: 351.0 [M+H] + .

[0295] Step 3 NaH (188.5 mg, 5 mmol, 60%) was added to a solution of 5-(3-iodo-1H-pyrazolo[3,4-c]pyridin-5-yl)spiro[2,3]hexane-5-carboxylonitrile (1.1 g, 3 mmol) in DMF (30 mL) at 0 °C under a nitrogen atmosphere. The mixture was stirred at 0 °C for 0.5 h, followed by the addition of triphenylmethyl chloride (1.14 g, 4 mmol). The reaction mixture was stirred at 25 °C for 2 h under a nitrogen atmosphere and then suspended in water (100 mL). The mixture was filtered, and the filter cake was washed with methyl tert-butyl ether (70 mL) and dried to give 5-(3-iodo-1-triphenylmethyl-pyrazolo[3,4-c]pyridin-5-yl)spiro[2,3]hexane-5-carboxylonitrile (1.8 g, 97%) as a white solid. MS (ESI) m / z: 593.1 [M+H] + .

[0296] Step 4 Add Pd(dppf)Cl2 (178 mg, 0.2 mmol) and potassium acetate (894.51 mg, 9 mmol) to a solution of 5-(3-iodo-1-triphenylmethyl-pyrazolo[3,4-c]pyridin-5-yl)spiro[2,3]hexane-5-carboxynitrile (1.8 g, 3 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1,3,2-dioxacyclopentaborane (1.16 g, 5 mmol) in dioxane (30 mL). The reaction mixture was stirred at 110 °C for 12 hours under a nitrogen atmosphere, then filtered and concentrated under reduced pressure to give 5-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)-1-triphenylmethyl-pyrazolo[3,4-c]pyridin-5-yl]spiro[2,3]hexane-5-carboxynitrile (2.1 g, 85%, 73% purity) as a brown solid. MS (ESI) m / z: 511.2 [M-81+H] + .

[0297] Step 5 Pd(dppf)Cl2 (178 mg, 0.2 mmol) and sodium carbonate (708 mg, 7 mmol) were added to a solution of 4,6-dichloropyrimidine (452.6 mg, 3 mmol) and 5-[3-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)-1-triphenylmethyl-pyrazolo[3,4-c]pyridin-5-yl]spiro[2,3]hexane-5-carboxynitrile (1.8 g, 3 mmol) in dioxane (30 mL) and water (5 mL). The mixture was stirred at 90 °C for 4 hours under a nitrogen atmosphere. The reaction mixture was diluted with water (80 mL) and extracted with ethyl acetate (60 mL × 3). The combined organic layers were washed with brine (60 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0–12% ethyl acetate / petroleum ether) to give 5-[3-(6-chloropyrimidin-4-yl)-1-triphenylmethyl-pyrazolo[3,4-c]pyridin-5-yl]spiro[2,3]hexane-5-carboxynitrile (1.2 g, 68%) as a pale yellow solid. MS (ESI) m / z: 579.2 [M+H] + .

[0298] Step 6 DIEA (1.8 mL, 10 mmol) was added to a solution of 5-[3-(6-chloropyrimidin-4-yl)-1-triphenylmethyl-pyrazolo[3,4-c]pyridin-5-yl]spiro[2,3]hexane-5-carboxylonitrile (1.2 g, 2 mmol) and piperazine-1-carboxylic acid tert-butyl ester (579 mg, 3 mmol) in DMSO (30 mL), and the mixture was stirred at 90 °C for 6 hours. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (40 mL × 4), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-17% ethyl acetate / petroleum ether) to give tert-butyl 4-[6-[5-(5-cyanospiro[2.3]hex-5-yl)-1-triphenylmethyl-pyrazolo[3,4-c]pyridin-3-yl]pyrimidin-4-yl]piperazine-1-carboxylate (1.2 g, 79%) as a pale yellow solid.

[0299] Step 7 TFA (6 mL) was added to a solution of 0.5 g (0.7 mmol) of tert-butyl piperazine-1-carboxylate in dichloromethane (3 mL). The reaction solution was stirred at 25 °C for 2 h and then concentrated under reduced pressure to give a white solid of 5-[3-(6-piperazin-1-ylpyrimidin-4-yl)-1H-pyrazolone[3,4-c]pyridin-5-yl]spiro[2.3]hexane-5-carboxylonitrile (0.52 g, 78%, 75% purity, 3 TFA salt), which was used in the next step without further purification. MS (ESI) m / z: 387.2 [M+H] + .

[0300] Step 8 A solution of 5-[3-(6-piperazin-1-ylpyrimidin-4-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl]spiro[2,3]hexane-5-carboxynitrile (123.7 mg, 320 μmol) in dichloromethane (15 mL) was added at -10 °C to a solution of 5-[3-(6-piperazinyl-1-ylpyrimidinyl)-1H-pyrazolo[3,4-c]pyridinyl]oxy]cyclohexylcarbaldehyde (0.1 g, 0.2 mmol) in dichloromethane (5 mL). The mixture was stirred for 1 hour, and then sodium triacetoxyborohydride (90.47 mg, 0.43 mmol) was added. The reaction mixture was stirred for 4 hours, then filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (0%–38% acetonitrile / water (TFA), over 20 min), and the crude product was further purified by preparative HPLC (38%–78% acetonitrile / water (ammonium bicarbonate), over 25 min) to give compound 24 (61.1 mg, 34%) as a white solid. MS (ESI) m / z: 420.4 [M / 2+H] + .

[0301] Exemplary synthesis of compound 25: Step 1 Sodium tert-butoxide (20.7 g, 215 mmol) was added to a solution of cyclohexane-1,4-diol (5.0 g, 43 mmol) and 4-chloropyridine (14.2 g, 95 mmol, HCl salt) in DMSO (150 mL), and the reaction mixture was stirred at 80 °C for 10 h. The mixture was cooled to 25 °C, diluted with water (100 mL), and extracted with ethyl acetate (200 mL × 3). The combined organic phases were washed with brine (200 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0–4% methanol / dichloromethane) to give 4-[4-(4-pyridyloxy)cyclohexyloxy]pyridine (8.73 g, 75%) as a brown solid. MS (ESI) m / z: 271.2 [M+H] + .

[0302] Step 2 Over 15 hours, toluene (40 mL) containing bromotoluene (5.1 mL, 43 mmol) was added dropwise to a solution of 4-[4-(4-pyridyloxy)cyclohexyloxy]pyridine (7.73 g, 29 mmol) in toluene (400 mL). The mixture was stirred at 80 °C for 36 hours. The reaction mixture was filtered, and the filter cake was washed with petroleum ether (500 mL) and dried to give a white solid of 1-benzyl-4-[4-(4-pyridyloxy)cyclohexyloxy]pyridine-1-cation (11.52 g, crude product), which was used directly in the next step. MS (ESI) m / z: 361.1 [M+H] + .

[0303] Step 3 Sodium borohydride (3.8 g, 0.1 mol) was added to a solution of 4-[4-[(1-benzyl-4-pyridinyl)oxy]cyclohexyloxy]pyridine (11.52 g, 28 mmol, 89% purity) in EtOH (120 mL) at 0 °C under a nitrogen atmosphere. The mixture was stirred at 0 °C for 1 hour, then diluted with water (200 mL) and extracted with ethyl acetate (300 mL × 3). The combined organic phases were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 4-[4-[(1-benzyl-3,6-dihydro-2H-pyridin-4-yl)oxy]cyclohexyloxy]pyridine (9.97 g, 68%, 71% purity) as a yellow oil, which was used directly in the next step. MS (ESI) m / z: 365.1 [M+H] + .

[0304] Step 4 To a solution of 4-[4-[(1-benzyl-3,6-dihydro-2H-pyridin-4-yl)oxy]cyclohexyloxy]pyridine (9.97 g, 24 mmol) in EtOH (200 mL), 10% palladium / carbon (2.5 g), 20% palladium hydroxide (2.5 g), and di-tert-butyl dicarbonate (10.9 mL, 48 mmol) were added. The suspension was degassed and purged several times with hydrogen. The mixture was stirred at 60 °C for 12 hours under hydrogen (50 psi). The reaction mixture was filtered and concentrated to give 4-[4-(4-piperidinyloxy)cyclohexyloxy]pyridine (7.09 g, crude product) as a white gel, which was used directly in the next step. MS (ESI) m / z: 277.1 [M+H] + .

[0305] Step 5 Di-tert-butyl dicarbonate (8.8 mL, 38 mmol) was added to a solution of 4-[4-(4-piperidinoxy)cyclohexyloxy]pyridine (7.09 g, 26 mmol), DIEA (4.5 mL, 26 mmol), and DMAP (313 mg, 2.6 mmol) in dichloromethane (140 mL). The mixture was stirred at 25 °C for 12 h and then concentrated under reduced pressure. The residue was purified by rapid column chromatography (0-52% ethyl acetate / petroleum ether) to give 4-[4-(4-pyridinoxy)cyclohexyloxy]piperidine-1-carboxylic acid tert-butyl ester (4.37 g, 37%, 82% purity) as a yellow solid. MS (ESI) m / z: 377.2 [M+H] + .

[0306] Step 6 Benzyl bromide (1.8 mL, 15 mmol) was added to a solution of 4-[4-(4-pyridyloxy)cyclohexyloxy]piperidine-1-carboxylic acid tert-butyl ester (4.37 g, 12 mmol) in toluene (160 mL). The mixture was stirred at 80 °C for 12 hours. The reaction mixture was filtered, and the filter cake was washed with petroleum ether (250 mL) and dried to give 4-[4-(1-benzylpyridin-1-cation-4-yl)oxycyclohexyloxy]piperidine-1-carboxylic acid tert-butyl ester (5.27 g, 78%) as a white solid. MS (ESI) m / z: 467.2 [M+H] + .

[0307] Step 7 Sodium borohydride (1.18 g, 31 mmol) was added to a solution of 4-[4-(1-benzylpyridin-1-cation-4-yl)oxycyclohexyloxy]piperidine-1-carboxylic acid tert-butyl ester (5.27 g, 9 mmol, 89% purity) in EtOH (50 mL) at 0 °C under a nitrogen atmosphere. The mixture was stirred at 0 °C for 1 h, then diluted with water (50 mL) and extracted with ethyl acetate (70 mL × 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (5% - 43% acetonitrile / water (formic acid), within 22 min). The collected fractions were combined, sodium carbonate was added to adjust the pH to 9, and the mixture was extracted with dichloromethane / MeOH (10 / 1). The organic phase was concentrated under reduced pressure to give tert-butyl 4-[4-[(1-benzyl-3,6-dihydro-2H-pyridin-4-yl)oxy]cyclohexyloxy]piperidine-1-carboxylate (2.92 g, 70%) as a white solid. MS (ESI) m / z: 471.7 [M+H] + .

[0308] Step 8 Under a nitrogen atmosphere, a solution of tert-butyl piperidine-1-carboxylate (200 mg, 0.4 mmol) in tert-butanol (10 mL) was supplemented with 10% palladium / carbon (40 mg) and 20% palladium hydroxide (40 mg). The suspension was degassed and purged several times with hydrogen. The mixture was stirred at 60 °C for 36 hours under hydrogen (50 psi), then filtered and concentrated to give tert-butyl piperidine-1-carboxylate (116.2 mg, 71%) as a white solid. MS (ESI) m / z: 383.5 [M+H] + .

[0309] Step 9 Sodium hydride (15.85 g, 0.4 mol, 60%) was added to a solution of 5-bromo-3-methyl-1H-benzimidazol-2-one (15 g, 66 mmol) in THF (400 mL) at 0 °C and stirred for 0.5 h. The mixture was then heated to 65 °C. A solution of 3-bromopiperidin-2,6-dione (38.05 g, 0.2 mol) in THF (200 mL) was then added dropwise, and the resulting mixture was stirred at 65 °C for 2 h. The reaction mixture was poured into a 1 M sulfuric acid aqueous solution (400 mL) at 0 °C, diluted with a saturated sodium bicarbonate aqueous solution (150 mL), and extracted with dichloromethane (500 mL × 2). The combined organic layers were washed with brine (300 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was ground with MeOH / THF (300 mL / 30 mL) at 25 °C for 12 hours and filtered to give 14 g (63%) of 3-(5-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione as a gray solid. MS (ESI) m / z: 339.9 [M+H] + .

[0310] Step 10 At 0 °C, Ruphos Pd G2 (50.8 mg, 65 μmol) and lithium (trimethylsilyl)amide (1 M, 6.5 mL) were added dropwise to a mixture of tert-butyl 4-[4-(4-piperidinyloxy)cyclohexyloxy]piperidine-1-carboxylate (0.5 g, 1 mmol), 3-(5-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (663 mg, 2 mmol), and RuPhos (30.5 mg, 65 μmol) in toluene (7 mL). The mixture was stirred at 100 °C for 3 hours under a nitrogen atmosphere. The reaction solution was cooled to 25 °C and poured into an aqueous solution of acetic acid at 0 °C (acetic acid / water = 2 mL / 20 mL). The mixture was diluted with a saturated aqueous solution of sodium bicarbonate to adjust the pH to 8–9. The mixture was extracted with ethyl acetate (100 mL × 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (0-80% THF / petroleum ether) to give tert-butyl 4-[4-[[1-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazol-5-yl]-4-piperidinyl]oxy]cyclohexyloxy]piperidine-1-carboxylic acid (300 mg, 36%) as a white solid. MS (ESI) m / z: 640.4 [M+H]+ .

[0311] Step 11 HCl / dioxane (2 M, 10 mL) was added to a solution of 0.3 g (0.5 mmol) of 4-[4-[[1-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazol-5-yl]-4-piperidinyl]oxy]cyclohexyloxy]piperidin-1-carboxylic acid tert-butyl ester in dichloromethane (5 mL). The reaction solution was stirred at 25 °C for 2 h and then concentrated under reduced pressure to give 3-[3-methyl-2-oxo-5-[4-[4-(4-piperidinyloxy)cyclohexyloxy]-1-piperidinyl]benzimidazol-1-yl]piperidin-2,6-dione (300 mg, crude product, 2HCl salt) as a gray solid. MS (ESI) m / z: 540.3 [M+H] + .

[0312] Step 12 DIEA (144 μL, 0.83 mmol) was added to a solution of 3-(6-chloropyrimidin-4-yl)-5-(1-methylcyclopropoxy)-1H-pyrazolo[3,4-c]pyridine (50 mg, 0.17 mmol) and 3-[3-methyl-2-oxo-5-[4-[4-(4-piperidinyloxy)cyclohexyloxy]-1-piperidinyl]benzimidazol-1-yl]piperidin-2,6-dione (89.4 mg, 0.17 mmol) in DMSO (5 mL). The resulting mixture was heated to 80 °C and stirred for 2 hours. The reaction mixture was cooled to 25°C, filtered, and the filtrate was purified by preparative HPLC (0%–40% acetonitrile / water (formic acid), over 25 minutes). The crude product was further purified by preparative HPLC (28%–68% acetonitrile / water (sodium bicarbonate), over 25 minutes) to give compound 25 (57.1 mg, 42%) as a white solid. MS (ESI) m / z 805.3 [M+H] + .

[0313] Exemplary synthesis of compound 26: Step 1 Propyl-2-amine (3.91 mL, 45 mmol) and potassium carbonate (12.56 g, 91 mmol) were added to a solution of 4-bromo-2-fluoro-1-nitrobenzene (10 g, 45 mmol) in DMF (100 mL). The mixture was stirred at 25 °C for 12 h, then diluted with water (100 mL) and extracted with ethyl acetate (150 mL × 2). The combined organic phases were washed with brine (150 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0–1% ethyl acetate / petroleum ether) to give 5-bromo-N-isopropyl-2-nitrobenzene (11.3 g, 96%) as an orange solid. MS (ESI) m / z: 259.0 [M+H] + .

[0314] Step 2 Iron (12.18 g, 0.2 mol) and ammonium chloride (23.33 g, 0.4 mol) were added to a solution of 5-bromo-N-isopropyl-2-nitrobenzene (11.3 g, 44 mmol) in EtOH (100 mL) and water (100 mL). The mixture was stirred at 80 °C for 5 hours, then filtered and washed with MeOH. The filtrate was concentrated under reduced pressure. The residue was diluted with water (200 mL) and extracted with ethyl acetate (200 mL × 2). The combined organic phases were washed with brine (400 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-20% ethyl acetate / petroleum ether) to give 4-bromo-nitrogen atmosphere-isopropylbenzene-1,2-diamine (9.8 g, 98%) as a purple solid. MS (ESI) m / z: 229.0 [M+H] + .

[0315] Step 3 Carbonyl diimidazole (10.4 g, 64 mmol) was added to a solution of 4-bromo-nitrogen-isopropylbenzene-1,2-diamine (9.8 g, 43 mmol) in THF (100 mL). The mixture was stirred at 60 °C for 12 h, then diluted with water (100 mL) and extracted with ethyl acetate (150 mL × 2). The combined organic phases were washed with brine (150 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-40% ethyl acetate / petroleum ether) to give 5-bromo-3-isopropyl-1H-benzimidazole-2-one (10.5 g, 96%) as a gray solid. MS (ESI) m / z: 257.0 [M+H] + .

[0316] Step 4 Sodium hydride (9.88 g, 0.2 mol, 60%) was added to a solution of 5-bromo-3-isopropyl-1H-benzimidazol-2-one (10.5 g, 41 mmol) in 200 mL THF at 0 °C and stirred for 0.5 h. The mixture was heated to 65 °C and 3-bromopiperidin-2,6-dione (23.71 g, 0.1 mol) in 200 mL THF was added dropwise. The mixture was stirred at 65 °C for 3 h. The reaction mixture was poured into 250 mL of 1 M sulfuric acid aqueous solution at 0 °C and diluted with 150 mL of saturated sodium bicarbonate aqueous solution. The mixture was extracted with dichloromethane (500 mL × 2). The combined organic layers were washed with brine (300 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was ground with isopropanol / THF (200 mL / 20 mL) to give 9.7 g (54%, 84% purity) of 3-(5-bromo-3-isopropyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione as a grayish-white solid. MS (ESI) m / z: 368.3 [M+H] + .

[0317] Step 5 At 0 °C, Ruphos Pd G2 (20.3 mg, 26 μmol) and lithium (trimethylsilyl)amide (1 M, 2.6 mL) were added dropwise to a mixture of tert-butyl 4-[4-(4-piperidinyloxy)cyclohexyloxy]piperidine-1-carboxylate (200 mg, 0.5 mmol), 3-(5-bromo-3-isopropyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (287.2 mg, 0.8 mmol), and RuPhos (12.2 mg, 26 μmol) in toluene (5 mL). The mixture was stirred at 100 °C for 3 hours under a nitrogen atmosphere. The reaction mixture was cooled to 25 °C and poured into an aqueous solution of acetic acid at 0 °C (acetic acid / water = 2 mL / 20 mL), and then a saturated aqueous solution of sodium bicarbonate was added to adjust the pH to 8–9. The mixture was extracted with ethyl acetate (100 mL × 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (0–60% THF / petroleum ether) to give tert-butyl 4-[4-[[1-[1-(2,6-dioxo-3-piperidinyl)-3-isopropyl-2-oxo-benzimidazol-5-yl]-4-piperidinyl]oxy]cyclohexyloxy]piperidine-1-carboxylate (110 mg, 20%, 65% purity) as a pale yellow solid. MS (ESI) m / z: 668.3 [M+H] + .

[0318] Step 6 HCl / dioxane (2 M, 4 mL) was added to a solution of tert-butyl piperidine-1-carboxylate (110 mg, 0.2 mmol) in dichloromethane (3 mL). The mixture was stirred at 25 °C for 2 hours and then concentrated under reduced pressure to give 100 mg, crude product, HCl salt, as a pale yellow solid. MS (ESI) m / z: 568.3 [M+H] + .

[0319] Step 7 DIEA (144 μL, 0.83 mmol) was added to a solution of 3-(6-chloropyrimidin-4-yl)-5-(1-methylcyclopropoxy)-1H-pyrazolo[3,4-c]pyridine (50 mg, 0.17 mmol) and 3-[3-isopropyl-2-oxo-5-[4-[4-(4-piperidinyloxy)cyclohexyloxy]-1-piperidinyl]benzimidazol-1-yl]piperidin-2,6-dione (94.1 mg, 0.17 mmol) in DMSO (6 mL). The mixture was stirred at 80 °C for 2 h, then filtered and the filtrate was purified by preparative HPLC (4%–44% acetonitrile / water (formic acid), within 25 min) to give compound 26 (29.7 mg, 21%) as a grayish-white solid. MS (ESI) m / z 833.4 [M+H] + .

[0320] Exemplary synthesis of compound 27: DIEA (151 μL, 0.87 mmol) was added to a solution of 3-(6-chloropyrimidin-4-yl)-5-isopropoxy-1H-indazole (prepared in a manner similar to that described for compound 20, 50 mg, 0.17 mmol) and 3-[3-methyl-2-oxo-5-[4-[4-(4-piperidinyloxy)cyclohexyloxy]-1-piperidinyl]benzimidazol-1-yl]piperidin-2,6-dione (for the synthesis described for compound 25, 99.8 mg, 0.17 mmol, HCl) in DMSO (5 mL). The mixture was stirred at 80 °C for 2 h, filtered, and the resulting filtrate was purified by preparative HPLC (0%–40% acetonitrile / water (formic acid), within 25 min) to give compound 27 (62.6 mg, 43%) as a grayish-white solid. MS (ESI) m / z 792.4 [M+H] + .

[0321] Exemplary synthesis of compound 28: To a solution of 3-(6-chloropyrimidin-4-yl)-5-isopropoxy-1H-pyrazolo[3,4-c]pyridine (prepared in a manner similar to the synthesis described for compound 20, 50 mg, 0.17 mmol) and 3-[3-methyl-2-oxo-5-[4-[4-(4-piperidinyloxy)cyclohexyloxy]-1-piperidinyl]benzimidazol-1-yl]piperidin-2,6-dione (for the synthesis described for compound 25, 93.1 mg, 0.17 mmol) in DMSO (5 mL), DIEA (150 μL, 0.86 mmol) was added, and the mixture was heated to 80 °C and stirred for 2 h. The reaction mixture was filtered, and the filtrate was purified by preparative HPLC (2%–42% acetonitrile / water (formic acid), within 25 min) to give compound 28 (38.2 mg, 27%) as a brown solid. MS (ESI) m / z 793.4 [M+H] + .

[0322] Exemplary synthesis of compound 29: Step 1 Triphenylphosphine (5.8 g, 22 mmol) was added to a solution of tert-butyl piperidine-1-carboxylate (5.0 g, 18 mmol) and pyridine-4-ol (2.10 g, 22 mmol) in THF (50 mL). The mixture was stirred at 0 °C for 30 min, and then diisopropyl azodicarbonate (4.3 mL, 22 mmol) was added dropwise under nitrogen atmosphere at 0 °C. The reaction mixture was stirred at 50 °C for 12 h under nitrogen atmosphere, and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-34% ethyl acetate / petroleum ether), and the crude product was further ground with methyl tert-butyl ether (5 mL × 2) to give tert-butyl piperidine-1-carboxylate (7.43 g, 96%) as a yellow oil. MS (ESI) 349.2 [M+H] + .

[0323] Step 2 Platinum oxide (IV) (3.56 g, 16 mmol) was added to a solution of tert-butyl piperidine-1-carboxylate (7.43 g, 20 mmol) and acetic acid (4.49 mL, 78 mmol) in EtOH (80 mL). The suspension was degassed and purged several times with hydrogen. The mixture was stirred at 60 °C for 12 hours under hydrogen (50 psi.), then filtered through diatomaceous earth and washed with EtOH (60 mL × 5) and ethyl acetate (60 mL × 5). The filtrate was concentrated under reduced pressure. The residue was dissolved in dichloromethane (30 mL), and triethylamine (6.0 mL, 43 mmol) and benzyl chloroformate (4.2 mL, 29 mmol) were added to the mixture at 0 °C under a nitrogen atmosphere. The reaction mixture was stirred at 25 °C for 2 hours under a nitrogen atmosphere. Add saturated sodium bicarbonate solution to the mixture to adjust the pH to 7-8. Extract the mixture with ethyl acetate (20 mL × 3). Wash the combined organic phases with brine (20 mL × 2), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Purify the residue by silica gel chromatography (0-87% ethyl acetate / petroleum ether) to give 2.74 g (29%) of benzyl 4-[3-[(1-tert-butoxycarbonyl-4-piperidinyl)oxy]cyclobutoxy]piperidine-1-carboxylate as a colorless oil. MS (ESI) 389.1 [M-100+H] + .

[0324] Step 3 Add 10% palladium / carbon (312.5 mg) to a solution of 4-[3-[(1-tert-butoxycarbonyl-4-piperidinyl)oxy]cyclobutoxy]piperidine-1-carboxylic acid benzyl ester (2.87 g, 6 mmol) in EtOH (15 mL) and ethyl acetate (15 mL). Degas the suspension and purge it several times with hydrogen. Stir the mixture at 50 °C for 12 hours under hydrogen (50 psi). Filter the reaction mixture through diatomaceous earth and wash the filter cake with MeOH (100 mL × 5) and ethyl acetate (100 mL × 5). [The filtrate solution...] In a vacuum Concentrate to obtain tert-butyl 4-[3-(4-piperidinyloxy)cyclobutoxy]piperidine-1-carboxylate (2.06 g, 99%) as a colorless oil.

[0325] Step 4 RuPhos (32.91 mg, 70 μmol) and [2-(2-aminophenyl)phenyl]chloro-palladium;dicyclohexyl-[2-(2,6-diisopropoxyphenyl)phenyl]phosphine (54.78 mg, 70 μmol) were added dropwise to a mixture of 3-(5-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (620 mg, 1.8 mmol) and 4-[3-(4-piperidinyloxy)cyclobutoxy]piperidine-1-carboxylic acid tert-butyl ester (500 mg, 1.4 mmol) in toluene (5 mL). Lithium bis(trimethylsilyl)amide (1 M, 7.1 mL) was added dropwise to the mixture at 0 °C under a nitrogen atmosphere. The mixture was stirred at 100 °C for 2 hours under a nitrogen atmosphere. The reaction mixture was poured into acetic acid (4 mL) and water (40 mL) at 0 °C, and then diluted with saturated sodium bicarbonate aqueous solution (40 mL). The mixture was extracted with ethyl acetate (50 mL × 2). The combined organic layers were washed with brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (0-60% ethyl acetate / petroleum ether) to give tert-butyl 4-[3-[[1-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazol-5-yl]-4-piperidinyl]oxy]cyclobutoxy]piperidine-1-carboxylic acid (450 mg, 52%) as a grayish-white solid. MS (ESI) 612.3 [M+H + .

[0326] Step 5 HCl / dioxane (2 M, 6 mL) was added to a solution of tert-butyl piperidine-1-carboxylate (250 mg, 0.4 mmol) in dichloromethane (2 mL). The mixture was stirred at 25 °C for 3.5 h and then concentrated under reduced pressure to give 240 mg, crude product, HCl salt, as a grayish-white solid of 3-[3-methyl-2-oxo-5-[4-[3-(4-piperidinyloxy)cyclobutoxy]-1-piperidinyl]benzimidazol-1-yl]piperidine-2,6-dione. MS (ESI) 512.2 [M+H + .

[0327] Step 6 DIEA (191 μL, 1.1 mmol) was added to a solution of 3-[3-methyl-2-oxo-5-[4-[3-(4-piperidinyloxy)cyclobutoxy]-1-piperidinyl]benzimidazol-1-yl]piperidin-2,6-dione (205.8 mg, 402 μmol) and 3-(6-chloropyrimidin-4-yl)-5-(1-methylcyclopropoxy)-1H-indazole (110 mg, 366 μmol) in DMSO (4 mL). The mixture was stirred at 70 °C for 12 h, then cooled to 25 °C, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (2%–42% acetonitrile / water (TFA), over 29 min), and the crude product was further purified by preparative HPLC (0%–60% acetonitrile / water (formic acid), over 20 min) to give compound 20 (98.8 mg, 35%) as a grayish-white solid. MS (ESI) m / z 776.4 [M+H] + .

[0328] Exemplary synthesis of compound 30: DIEA (191 μL, 1.1 mmol) was added to a solution of 3-[3-methyl-2-oxo-5-[4-[3-(4-piperidinyloxy)cyclobutoxy]-1-piperidinyl]benzimidazol-1-yl]piperidin-2,6-dione (for the synthesis described for compound 29, 205.8 mg, 402 μmol) and 3-(6-chloropyrimidin-4-yl)-5-(1-methylcyclopropoxy)-1H-indazole (110 mg, 366 μmol) in DMSO (4 mL). The mixture was stirred at 70 °C for 12 h, then cooled to 25 °C, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (2%–42% acetonitrile / water (TFA), over 20 minutes), and the crude product was further purified by preparative HPLC (0%–60% acetonitrile / water (formic acid), over 20 minutes) to give compound 30 (98.8 mg, 35%) as a grayish-white solid. MS (ESI) m / z 776.4 [M+H] + .

[0329] Exemplary synthesis of compound 31: DIEA (108 μL, 0.6 mmol) was added to a solution of 3-[3-methyl-2-oxo-5-[4-[3-(4-piperidinyloxy)cyclobutoxy]-1-piperidinyl]benzimidazol-1-yl]piperidin-2,6-dione (for the synthesis described for compound 29, 137.7 mg, 269 μmol) and 3-(6-chloropyrimidin-4-yl)-5-isopropoxy-1H-pyrazolo[3,4-c]pyridine (60.0 mg, 207 μmol) in DMSO (5 mL). The mixture was stirred at 80 °C for 2 h, then cooled to 25 °C, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (4%–44% acetonitrile / water (TFA), over 25 min), and the crude product was further purified by preparative HPLC (2%–42% acetonitrile / water (formic acid), over 20.5 min) to give compound 31 (39.9 mg, 25% y) as a white solid. MS (ESI) m / z 765.3 [M+H] + .

[0330] Exemplary synthesis of compound 32: Step 1 Under a nitrogen atmosphere at 0°C, chloro(trimethyl)silane (16.1 mL, 0.1 mol) and triethylamine (19.3 mL, 0.1 mol) were added to a solution of methyl 3-hydroxycyclobutane carboxylate (15 g, 0.1 mol) in THF (150 mL). The mixture was stirred at 25°C for 1 hour under a nitrogen atmosphere. The reaction mixture was filtered and concentrated under reduced pressure. Under a nitrogen atmosphere at -70°C, triethylsilane (27.6 mL, 0.2 mol) and trimethylsilyl trifluoromethanesulfonate (11.5 mL, 63 mmol) were added dropwise to a stirred solution of the above residue and 4-oxopiperidinyl-1-carboxylate (27.5 mL, 0.1 mol) in dichloromethane (150 mL). The reaction mixture was stirred at 0°C for 2 hours under a nitrogen atmosphere. The mixture was diluted with water (200 mL) and extracted with dichloromethane (200 mL × 3). The combined organic layers were washed with brine (200 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-30% ethyl acetate / petroleum ether) to give benzyl 4-(3-methoxycarbonylcyclobutoxy)piperidine-1-carboxylate (21.39 g, 53%) as a colorless oil. MS (ESI) 370.2 [M+23] + .

[0331] Step 2 Palladium / carbon (3.28 g) was added to a solution of 4-(3-methoxycarbonylcyclobutoxy)piperidine-1-carboxylate (21.4 g, 61 mmol) and di-tert-butyl dicarbonate (42.4 mL, 185 mmol) in MeOH (200 mL). The suspension was degassed and purged several times with hydrogen. The mixture was stirred at 50 °C for 12 hours under hydrogen (50 psi). The reaction mixture was filtered through diatomaceous earth, washed with MeOH (100 mL × 5) and ethyl acetate (100 mL × 5), and the filtrate solution was... In a vacuum middle Concentration. The residue was purified by silica gel chromatography (0-30% ethyl acetate / petroleum ether) to give tert-butyl 4-(3-methoxycarbonylcyclobutoxy)piperidine-1-carboxylate (17.57 g, 91%) as a colorless oil.

[0332] Step 3 Lithium aluminum chloride (2.5 M, 1.3 mL) was added dropwise to a mixture of tert-butyl piperidine-1-carboxylate (1 g, 3 mmol) in THF (10 mL) under a nitrogen atmosphere at 0 °C. The mixture was stirred at 0 °C under a nitrogen atmosphere for 2 h. The reaction mixture was diluted with water (0.12 mL), followed by dilution with 15% sodium hydroxide aqueous solution (0.12 mL) and water (0.36 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and washed with THF (40 mL × 4). The combined filtrate solutions were concentrated under reduced pressure to give tert-butyl piperidine-1-carboxylate (900 mg, crude product) as a colorless oil, which was used directly in the next step. MS (ESI) 230.2 [M-55+H] + .

[0333] Step 4 4-chloropyridine hydrochloride (3.39 g, 23 mmol) was added to a solution of sodium tert-butoxide (5.79 g, 60 mmol) in DMSO (50 mL), and the mixture was stirred at 40 °C for 0.5 h. Then, tert-butyl 4-[3-(hydroxymethyl)cyclobutoxy]piperidine-1-carboxylate (4.3 g, 15 mmol) was added. The reaction mixture was stirred at 80 °C for 12 h, then cooled to 0 °C and diluted with saturated ammonium chloride solution (100 mL). The mixture was extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with brine (100 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-77% ethyl acetate / petroleum ether) to give tert-butyl 4-[3-(4-pyridyloxymethyl)cyclobutoxy]piperidine-1-carboxylate (3.26 g, 60%) as a white solid. MS (ESI) 363.0 [M+H] + .

[0334] Step 5 Platinum oxide (IV) (1.63 g, 7 mmol) was added to a solution of tert-butyl piperidine-1-carboxylate (3.26 g, 9 mmol) and acetic acid (1.54 mL, 27 mmol) in EtOH (30 mL). The suspension was degassed and purged several times with hydrogen. The mixture was stirred at 50 °C for 16 hours under hydrogen (50 psi). The reaction mixture was filtered through diatomaceous earth and washed with EtOH (50 mL × 5) and ethyl acetate (50 mL × 5). The filtrate was concentrated to give tert-butyl piperidine-1-carboxylate (5 g, crude product) as a colorless oil, which was used directly in the next step. MS (ESI) 369.6 [M+H] + .

[0335] Step 6 Triethylamine (3.74 mL, 27 mmol) and benzyl chloroformate (1.92 mL, 13 mmol) were added to a solution of tert-butyl piperidine-1-carboxylate (3.3 g, 9 mmol) in dichloromethane (40 mL) under a nitrogen atmosphere at 0 °C. The mixture was stirred at 25 °C for 2 hours under a nitrogen atmosphere, then cooled to 0 °C and diluted with a saturated aqueous sodium bicarbonate solution (60 mL). The mixture was extracted with ethyl acetate (60 mL × 3). The combined organic phases were washed with brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-25% ethyl acetate / petroleum ether) to give 1.19 g, 26%, of benzyl 4-[[3-[(1-tert-butoxycarbonyl-4-piperidinyl)oxy]cyclobutyl]methoxy]piperidine-1-carboxylic acid benzyl ester as a colorless oil. MS (ESI) 403.3 [M-100+H] + .

[0336] Step 7 Add 10% palladium / carbon (102.7 mg) to a solution of 4-[[3-[(1-tert-butoxycarbonyl-4-piperidinyl)oxy]cyclobutyl]methoxy]piperidin-1-carboxylic acid benzyl ester (970 mg, 2 mmol) in EtOH (10 mL) and ethyl acetate (10 mL). Degas the suspension and purge it several times with hydrogen. Stir the mixture at 50 °C for 12 hours under hydrogen (50 psi). Filter the reaction mixture through diatomaceous earth and wash with MeOH (50 mL × 5) and ethyl acetate (50 mL × 5). Filter the filtrate solution... In a vacuum Concentrate to obtain tert-butyl 4-[3-(4-piperidinyloxymethyl)cyclobutoxy]piperidine-1-carboxylate (750 mg, crude product), a colorless oil, which was used directly in the next step. MS (ESI) 369.2 [M+H] + .

[0337] Step 8 To a mixture of tert-butyl piperidine-1-carboxylate (550 mg, 1.5 mmol) and 3-(5-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (1.31 g, 4 mmol) in toluene (10 mL), RuPhos (69.6 mg, 0.1 mmol) and RuPhos Pd G2 (115.9 mg, 0.15 mmol) were added dropwise at 0 °C under a nitrogen atmosphere for 15 minutes. The mixture was stirred at 100 °C for 12 hours under a nitrogen atmosphere. The reaction mixture was poured into acetic acid (0.5 mL) and water (5 mL) at 0 °C. The resulting mixture was diluted with saturated sodium bicarbonate aqueous solution (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. The residue was purified by silica gel chromatography (0-50% THF / petroleum ether) to give tert-butyl 4-[3-[[1-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazol-5-yl]-4-piperidinyl]oxymethyl]cyclobutoxy]piperidine-1-carboxylic acid (250 mg, 24%) as a green solid. MS (ESI) 626.6 [M+H] + .

[0338] Step 9 To a solution of tert-butyl piperidine-1-carboxylate (250 mg, 0.4 mmol) in dichloromethane (4 mL), HCl / dioxane (2 M, 12 mL) was added. The reaction mixture was stirred at 25 °C for 6 hours and then concentrated under reduced pressure to give a brown solid of 3-[3-methyl-2-oxo-5-[4-[[3-(4-piperidinyloxy)cyclobutyl]methoxy]-1-piperidinyl]benzimidazol-1-yl]piperidine-2,6-dione (250 mg, crude product, HCl salt). MS (ESI) 526.3 [M+H + .

[0339] Step 10 DIEA (86.6 μL, 0.5 mmol) was added to a solution of 3-[3-methyl-2-oxo-5-[4-[[3-(4-piperidinyloxy)cyclobutyl]methoxy]-1-piperidinyl]benzimidazol-1-yl]piperidin-2,6-dione (87.1 mg, 0.16 mmol) and 3-(6-chloropyrimidin-4-yl)-5-(1-methylcyclopropoxy)-1H-pyrazolo[3,4-c]pyridine (50 mg, 0.16 mmol) in DMSO (5 mL). The mixture was stirred at 80 °C for 2 hours, then cooled to 25 °C, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (2%–42% acetonitrile / water (TFA), over 20 minutes), and the crude product was further purified by preparative HPLC (0%–60% acetonitrile / water (formic acid), over 20 minutes) to give compound 32 (33.5 mg, 26%) as a grayish-white solid. MS (ESI) m / z 396.5 [M / 2+H] + .

[0340] Exemplary synthesis of compound 33: DIEA (122 μL, 0.7 mmol) was added to a solution of 3-[3-methyl-2-oxo-5-[4-[[3-(4-piperidinyloxy)cyclobutyl]methoxy]-1-piperidinyl]benzimidazol-1-yl]piperidin-2,6-dione (for compounds 32, 122 mg, 0.2 mmol as described in the synthesis) and 3-(6-chloropyrimidin-4-yl)-5-(1-methylcyclopropoxy)-1H-indazole (70 mg, 0.2 mmol) in DMSO (4 mL). The mixture was stirred at 70 °C for 12 h, then cooled to 25 °C, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (0%–40% acetonitrile / water (TFA), within 20 min), and the crude product was further purified by preparative HPLC (0%–60% acetonitrile / water (formic acid), within 20 min) to give compound 33 (36.2 mg, 19%) as a grayish-white solid. MS (ESI) m / z 789.3 [M+H] + .

[0341] Exemplary synthesis of compound 34: Step 1 HCl / dioxane (2 M, 22.7 mL) was added to a solution of tert-butyl piperidine-1-carboxylate (2.7 g, 9 mmol) in dichloromethane (7 mL). The mixture was stirred at 25 °C for 12 hours and then concentrated under reduced pressure to give [3-(4-piperidinoxy)cyclobutyl]methanol (2.05 g, crude product, HCl salt) as a white solid, which was used directly in the next step.

[0342] Step 2 Triethylamine (3.9 mL, 28 mmol) was added to a solution of [3-(4-piperidinoxy)cyclobutyl]methanol (2.05 g, 9 mmol, HCl) in dichloromethane (20 mL) at 0 °C, followed by dropwise addition of dichloromethane (5 mL) containing benzyl chloroformate (2.0 mL, 14 mmol) under a nitrogen atmosphere at 0 °C. The reaction mixture was stirred at 25 °C for 2 hours under a nitrogen atmosphere and then cooled to 0 °C. The mixture was diluted with saturated aqueous sodium bicarbonate solution (60 mL) and extracted with ethyl acetate (60 mL × 3). The combined organic phases were washed with brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-80% methyl tert-butyl ether / petroleum ether) to give 4-[3-(hydroxymethyl)cyclobutoxy]piperidin-1-carboxylate (1.55 g, 52%) as a colorless oil. MS (ESI) 320.1 [M+H] + .

[0343] Step 3 Under a nitrogen atmosphere at 0°C, chloro(trimethyl)silane (656 μL, 5 mmol) and triethylamine (784 μL, 6 mmol) were added to a solution of 4-[3-(hydroxymethyl)cyclobutoxy]piperidine-1-carboxylate (1.5 g, 5 mmol) in THF (20 mL). The mixture was stirred under a nitrogen atmosphere at 25°C for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. Under a nitrogen atmosphere at -70°C, triethylsilane (1.13 mL, 7 mmol) and trimethylsilyl trifluoromethanesulfonate (467 μL, 2.6 mmol) were added dropwise to a stirred solution of the above residue and 4-oxopiperidinidine-1-carboxylate tert-butyl ester (2.81 g, 14 mmol) in dichloromethane (20 mL). The reaction mixture was stirred at 0°C for 2 hours under a nitrogen atmosphere, then diluted with water (20 mL) and extracted with dichloromethane (20 mL × 3). The combined organic layers were washed with brine (20 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0 -23% THF / petroleum ether) to give tert-butyl 4-[[3-[(1-benzyloxycarbonyl-4-piperidinyl)oxy]cyclobutyl]methoxy]piperidine-1-carboxylic acid (320 mg, 14%) as a yellow oil. MS (ESI) 403.2 [M-100+H] + .

[0344] Step 4 Add 10% palladium / carbon (33.9 mg) to a solution of 4-[[3-[(1-benzyloxycarbonyl-4-piperidinyl)oxy]cyclobutyl]methoxy]piperidin-1-carboxylic acid tert-butyl ester (320 mg, 0.6 mmol) in EtOH (5 mL) and ethyl acetate (5 mL). Degas the suspension and purge it several times with hydrogen. Stir the mixture at 50 °C for 12 hours under hydrogen (50 psi). Filter the reaction mixture through diatomaceous earth, wash with MeOH (50 mL × 5) and ethyl acetate (50 mL × 5), and exist In a vacuum Concentrate to obtain tert-butyl 4-[[3-(4-piperidinyloxy)cyclobutyl]methoxy]piperidine-1-carboxylate (210 mg, 75%, 84% purity), a yellow oil. MS (ESI) 369.3 [M+H] + .

[0345] Step 5 To a mixture of tert-butyl piperidine-1-carboxylate (150 mg, 0.4 mmol) and 3-(5-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (151 mg, 0.4 mmol) in toluene (5 mL), RuPhos (9.5 mg, 20 μmol) and RuPhos Pd G2 (15.8 mg, 20 μmol) were added dropwise, followed by the dropwise addition of lithium bis(trimethylsilyl)amide (1 M, 2 mL) at 0 °C under a nitrogen atmosphere. The mixture was stirred at 100 °C for 2 hours under a nitrogen atmosphere. The reaction mixture was then poured into acetic acid (0.3 mL) and water (5 mL) at 0 °C, diluted with saturated sodium bicarbonate aqueous solution (10 mL), and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (0-54% THF / petroleum ether) to give tert-butyl 4-[[3-[[1-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazol-5-yl]-4-piperidinyl]oxy]cyclobutyl]methoxy]piperidine-1-carboxylic acid tert-butyl ester (110 mg, 23%, 53% purity) as a yellow solid. MS (ESI) 626.4 [M+H] + .

[0346] Step 6 4-[[3-[[1-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazol-5-yl]-4-piperidinyl]oxy]cyclobutyl]methoxy]piperidin-1-carboxylic acid tert-butyl ester (110 mg, 0.2 mmol) was added to a solution of dichloromethane (4 mL) and HCl / dioxane (2 M, 4 mL) was added. The solution was stirred at 25 °C for 1 hour. The reaction solution was concentrated under reduced pressure and used directly in the next step.

[0347] Step 7 DIEA (153.1 μL, 0.9 mmol) was added to DMSO (10 mL) containing the crude product from step 6 above and 3-(6-chloropyrimidin-4-yl)-5-(1-methylcyclopropoxy)-1H-pyrazolo[3,4-c]pyridine (53.04 mg, 0.17 mmol). The resulting solution was stirred at 70 °C for 16 h, then diluted with water (20 mL) and extracted with dichloromethane (2 × 30 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (dichloromethane:methanol = 10:1) to give 100 mg of crude product as a yellow gel, which was further purified by preparative HPLC (2%-42% acetonitrile / water (formic acid), within 20 min) to give compound 34 (24.2 mg, 17%) as a white solid. MS (ESI) m / z 791.4 [M+H] + .

[0348] Exemplary synthesis of compound 35: Step 1 A solution of tert-butyl 4-[3-(hydroxymethyl)cyclobutoxy]piperidine-1-carboxylate (2 g, 7 mmol) in dichloromethane (35 mL) was added to a solution of Dess-Martin periodinane (3.26 mL, 10 mmol), and the mixture was stirred at 25 °C for 1 hour. The reaction mixture was diluted with saturated sodium bicarbonate solution to pH 8, saturated sodium thiosulfate solution (80 mL) was added, and the resulting mixture was extracted with dichloromethane (60 mL × 3). The combined organic layers were washed with brine (80 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl 4-(3-formylcyclobutoxy)piperidine-1-carboxylate (1.74 g, 88%) as a colorless oil.

[0349] Step 2 A solution of benzyl piperazine-1-carboxylate (1.78 mL, 9 mmol) in dichloromethane (20 mL) containing acetic acid (351 μL, 6. mmol) and tert-butyl 4-(3-formylcyclobutoxy)piperidine-1-carboxylate (1.74 g, 6 mmol) was added to dichloromethane at 0 °C under a nitrogen atmosphere. The solution was stirred at 0 °C for 0.5 h, and then sodium triacetoxyborohydride (3.90 g, 18 mmol) was added. The reaction mixture was stirred at 0 °C for 2 h under a nitrogen atmosphere. The mixture was diluted with saturated sodium bicarbonate solution to pH 8, and the resulting mixture was extracted with dichloromethane (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-90% ethyl acetate / petroleum ether) to give 4-[[3-[(1-tert-butoxycarbonyl-4-piperidinyl)oxy]cyclobutyl]methyl]piperazine-1-carboxylic acid benzyl ester (1.94 g, 65%) as a colorless gel.

[0350] Step 3 TFA (4 mL) was added to a solution of 4-[[3-[(1-tert-butoxycarbonyl-4-piperidinyl)oxy]cyclobutyl]methyl]piperazine-1-carboxylate (0.8 g, 2 mmol) in dichloromethane (4 mL). The reaction solution was stirred at 25 °C for 1 h, and then concentrated under reduced pressure. The residue was diluted with saturated sodium carbonate solution to adjust the pH to 12, and the mixture was extracted with dichloromethane (40 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 4-[[3-(4-piperidinyloxy)cyclobutyl]methyl]piperazine-1-carboxylate (0.6 g, 94%) as a pale yellow gel. MS (ESI) m / z: 388.3 [M+H] + .

[0351] Step 4 To a solution of 4-[[3-(4-piperidinyloxy)cyclobutyl]methyl]piperazine-1-carboxylate (0.54 g, 1.4 mmol) and 3-(5-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidin-2,6-dione (518 mg, 1.5 mmol) in toluene (30 mL), RuPhos (32.5 mg, 70 μmol), Ruphos Pd G2 (54.1 mg, 70 μmol), and lithium bis(trimethylsilyl)amide (1 M, 7 mL) were added, and the mixture was stirred at 100 °C for 2 hours under a nitrogen atmosphere. The reaction mixture was slowly poured into acetic acid (40 mL) at 0 °C and then diluted with a saturated aqueous sodium bicarbonate solution until pH 8. The mixture was extracted with dichloromethane (40 mL × 2). The combined organic layers were washed with brine (50 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0–7% methanol / dichloromethane) to give a white solid, benzyl 4-[[3-[[1-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazol-5-yl]-4-piperidinyl]oxy]cyclobutyl]methyl]piperazine-1-carboxylate (150 mg, 13%, 75% purity). MS (ESI) m / z: 645.3 [M+H] + .

[0352] Step 5 A solution of 4-[[3-[[1-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazol-5-yl]-4-piperidinyl]oxy]cyclobutyl]methyl]piperazine-1-carboxylic acid benzyl ester (0.14 g, 0.2 mmol) in TFA (3.5 mL) was stirred at 70 °C for 1 hour, and then concentrated under reduced pressure to give a pale yellow gel, 3-[3-methyl-2-oxo-5-[4-[3-(piperazine-1-ylmethyl)cyclobutoxy]-1-piperidinyl]benzimidazol-1-yl]piperidin-2,6-dione (0.2 g, 81%, 55% purity, TFA salt). MS (ESI) m / z: 511.3 [M+H] + .

[0353] Step 6 DIEA (2.0 mL, 12 mmol) was added to a solution of 3-[3-methyl-2-oxo-5-[4-[3-(piperazin-1-ylmethyl)cyclobutoxy]-1-piperidinyl]benzimidazol-1-yl]piperidin-2,6-dione (0.1 g, 0.2 mmol, TFA) and 3-(6-chloropyrimidin-4-yl)-5-(1-methylcyclopropoxy)-1H-pyrazolo[3,4-c]pyridine (53 mg, 0.2 mmol) in DMSO (5 mL). The reaction mixture was stirred at 70 °C for 12 hours, then filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (0%–32% acetonitrile / water (TFA), over 20 min) followed by further purification by preparative HPLC (22%–62% acetonitrile / water (ammonium bicarbonate), over 25 min) to give compound 35 (19.3 mg, 15%) as a white solid. MS (ESI) m / z: 776.4 [M+H] + .

[0354] Exemplary synthesis of compound 36: Step 1 10% palladium / carbon (218 mg) was added to a stirred solution of 4-[[3-[(1-tert-butoxycarbonyl-4-piperidinyl)oxy]cyclobutyl]methyl]piperazine-1-carboxylic acid benzyl ester (0.5 g, 1 mmol) in EtOH (15 mL). The suspension was degassed and purged several times with hydrogen, and then stirred at 40 °C for 4 hours under hydrogen (40 psi). The reaction mixture was filtered and concentrated under reduced pressure to give 4-[3-(piperazine-1-ylmethyl)cyclobutoxy]piperidin-1-carboxylic acid tert-butyl ester (0.32 g, 88%) as a gray gel.

[0355] Step 2 Under a nitrogen atmosphere at 25 °C, Ruphos Pd G2 (33 mg, 42 μmol), RuPhos (19.8 mg, 42 μmol), and lithium bis(trimethylsilyl)amide (1 M, 4.24 mL) were added to a solution of 4-[3-(piperazin-1-ylmethyl)cyclobutoxy]piperidine-1-carboxylate tert-butyl ester (0.3 g, 0.8 mmol) and 3-(5-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (301 mg, 0.9 mmol) in toluene (20 mL). The mixture was stirred at 100 °C for 2 hours under a nitrogen atmosphere. The reaction mixture was slowly poured into acetic acid (40 mL) at 0 °C and diluted with saturated sodium bicarbonate aqueous solution until pH 8. The mixture was extracted with dichloromethane (40 mL × 2). The combined organic layers were washed with brine (50 mL × 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0–7% methanol / dichloromethane) to give tert-butyl 4-[3-[[4-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazol-5-yl]piperazin-1-yl]methyl]cyclobutoxy]piperidine-1-carboxylate (240 mg, 46%) as a pale yellow solid.

[0356] Step 3 HCl / dioxane (2 M, 5 mL) was added to a solution of 0.2 g (0.3 mmol) of 4-[3-[[4-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazol-5-yl]piperazin-1-yl]methyl]cyclobutoxy]piperidine-1-carboxylic acid tert-butyl ester in dichloromethane (5 mL). The reaction solution was stirred at 25 °C for 3 h and then concentrated under reduced pressure to give 170 mg (92%, HCl salt) of 3-[3-methyl-2-oxo-5-[4-[[3-(4-piperidinyloxy)cyclobutyl]methyl]piperazin-1-yl]benzimidazol-1-yl]piperidine-2,6-dione as a white solid. MS (ESI) m / z: 511.3 [M+H] + .

[0357] Step 4 DIEA (346 μL, 2 mmol) was added to a solution of 3-[3-methyl-2-oxo-5-[4-[[3-(4-piperidinyloxy)cyclobutyl]methyl]piperazin-1-yl]benzimidazol-1-yl]piperidin-2,6-dione (141 mg, 0.26 mmol, HCl) and 3-(6-chloropyrimidin-4-yl)-5-(1-methylcyclopropoxy)-1H-pyrazolo[3,4-c]pyridine (60 mg, 0.2 mmol) in DMSO (3 mL). The reaction mixture was stirred at 80 °C for 2 h, then filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (22%–62% acetonitrile / water (ammonium bicarbonate), within 25 min) to give compound 36 (35.1 mg, 22%) as a white solid. MS (ESI) m / z: 776.3 [M+H] + .

[0358] Exemplary synthesis of compound 37: Step 1 Cesium fluoride (4.04 g, 27 mmol) and Pd 118 (578 mg, 0.9 mmol) were added to a solution of 3-(5-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidin-2,6-dione (3 g, 9 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (2.74 g, 9 mmol) in dioxane (30 mL) and water (1.5 mL) under a nitrogen atmosphere. The mixture was stirred at 90 °C for 12 hours under a nitrogen atmosphere. The reaction mixture was cooled to 25 °C, filtered, and concentrated under reduced pressure. The residue was ground with THF (10 mL) to give tert-butyl 4-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazol-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (2 g, 51%) as a gray solid. MS (ESI) m / z: 441.2 [M+H] + .

[0359] Step 2 Add 10% palladium / carbon (0.2 g) and 20% palladium hydroxide (0.2 g) to a solution of 4-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazol-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1 g, 2 mmol) in ethyl acetate (20 mL) and DMF (10 mL). Degas the suspension and purge it several times with hydrogen. Stir the mixture at 40 °C for 12 hours under hydrogen (30 psi). Cool the mixture to 25 °C, filter, and In a vacuum Concentration was performed to give tert-butyl 4-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazol-5-yl]piperidin-1-carboxylate (0.9 g, 90%) as a white solid. MS (ESI) m / z: 387.2 [M-56+H] + .

[0360] Step 3 To a solution of 0.9 g (2 mmol) of 4-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazol-5-yl]piperidin-1-carboxylic acid tert-butyl ester in dichloromethane (10 mL), HCl / dioxane (2 M, 10 mL) was added. The reaction solution was stirred at 25 °C for 2 h, and then concentrated under reduced pressure to give 0.8 g (crude product, HCl salt) of 3-[3-methyl-2-oxo-5-(4-piperidinyl)benzimidazol-1-yl]piperidin-2,6-dione as a white solid, which was used directly in the next step. MS (ESI) m / z: 343.1 [M+H] + .

[0361] Step 4 DIEA (1.27 mL, 7 mmol) was added to a solution of 3-[3-methyl-2-oxo-5-(4-piperidinyl)benzimidazol-1-yl]piperidin-2,6-dione (500 mg, 1.5 mmol) and 4-[3-(trifluoromethanesulfonyloxy)cyclobutoxy]piperidin-1-carboxylic acid tert-butyl ester (589 mg, 1.5 mmol) in acetonitrile (10 mL) and DMSO (2 mL). The mixture was stirred at 35 °C for 12 hours, then cooled to 25 °C and poured into water (100 mL). The mixture was extracted with ethyl acetate (100 mL × 2). The combined organic phases were washed with brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-80% THF / petroleum ether) to give tert-butyl 4-[3-[4-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1-piperidinyl]cyclobutoxy]piperidine-1-carboxylate (290 mg, 27%, 82% purity), as a pale yellow solid. MS (ESI) m / z: 596.3 [M+H] + .

[0362] Step 5 HCl / dioxane (2 M, 8 mL) was added to a solution of 0.29 g (0.5 mmol) of 4-[3-[4-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazol-5-yl]-1-piperidinyl]cyclobutoxy]piperidin-1-carboxylic acid tert-butyl ester in dichloromethane (4 mL). The reaction solution was stirred at 25 °C for 1 hour and then concentrated under reduced pressure to give 3-[3-methyl-2-oxo-5-[1-[3-(4-piperidinyloxy)cyclobutyl]-4-piperidinyl]benzimidazol-1-yl]piperidin-2,6-dione (300 mg, crude product, HCl salt) as a grayish-white solid. MS (ESI) m / z: 496.4 [M+H] + .

[0363] Step 6 DIEA (257.9 mg, 347.5 μL, 2.00 mmol) was added to a solution of 3-(6-chloropyrimidin-4-yl)-5-(1-methylcyclopropoxy)-1H-indazole (60 mg, 0.2 mmol) and 3-[3-methyl-2-oxo-5-[1-[3-(4-piperidinyloxy)cyclobutyl]-4-piperidinyl]benzimidazol-1-yl]piperidin-2,6-dione (98.9 mg, 0.2 mmol) in DMSO (10 mL). The mixture was stirred at 80 °C for 2 hours, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (34%–74% acetonitrile / water (ammonium bicarbonate), over 25 minutes), and the crude material was further purified by preparative HPLC (0%–38% acetonitrile / water (formic acid), over 25 minutes) to give compound 37 (30.4 mg, 20%) as a white solid. MS (ESI) m / z: 760.3 [M+H] + .

[0364] The remaining compounds were prepared using a procedure similar to that described in the examples above, as follows: Compound 10 was prepared in a manner similar to that of compound 7. Compound 11 was prepared in a manner similar to that of compound 7. Compound 13 was prepared in a manner similar to that of compound 7. Compound 14 was prepared in a manner similar to that of compound 2. Compound 15 was prepared in a manner similar to that of compounds 7 and 8. Compound 17 was prepared in a manner similar to that of compounds 5 and 16. Compounds 38-41 were prepared in a manner similar to that of compound 13. Compounds 42-45 were prepared in a manner similar to that of compounds 3 and 13. Compound 46 was prepared in a manner similar to that of compounds 1 and 9. Compound 47 was prepared in a manner similar to that of compounds 1 and 8. Compound 48 was prepared in a manner similar to that of compounds 1 and 14. Compounds 49, 50, 54-57, 60, and 61 were prepared in a manner similar to that of compound 6. Compound 51 was prepared in a manner similar to that of compounds 1 and 2. Compounds 52, 53, 66, and 67 were prepared in a manner similar to that of compound 1. Compound 58 was prepared in a manner similar to that of compound 19. Compound 59 was prepared in a manner similar to that of compound 20. Compound 62 was prepared in a manner similar to that of compound 22. Compound 63 was prepared in a manner similar to that of compound 23. Compounds 64-66 were prepared in a manner similar to that of compound 23. Compound 69 was prepared in a manner similar to that of compounds 3 and 10. Compound 70 was prepared in a manner similar to that of compounds 3 and 11.

[0365] Characterization data of the compounds disclosed herein are presented in Table 1 below.

[0366] Table 1. Bioassay Exemplary assay for testing LRRK2 degradation driven by an exemplary heterobifunctional compound designed to target LRRK2. The assay measured the degradation of LRRK2 in cells, with the C-terminus (3') of the endogenous gene labeled with a HiBit sequence in HEK293 cells. The cells also expressed firefly luciferase, which was expressed from a cytomegalovirus promoter and introduced into HiBit-labeled cells for stable expression. Nano-Glo was used to measure the degradation. ® Dual-luciferase reporter assay system (Promega™, Madison, Wisconsin).

[0367] Day 1 - Preparation of Compounds and Assay Plates Prepare two sets of plates: three replicates for the HiBit assay in white 384-well plates and three replicates for the Alamar Blue cell viability assay in black 384-well plates. Briefly, aspirate the growth medium (DMEM + Glutamax - 10% fetal bovine serum - 1% penicillin - streptomycin) from two T128 flasks. Wash the cells with Dulbecco's Phosphate Buffered Saline (dPBS) and aspirate. Add trypsin (3 mL per flask) and incubate for 2–3 minutes.

[0368] Ten mL of OptiMEM-10% fetal bovine-1% penicillin-streptomycin (hereinafter referred to as "OptiMEM medium") was added to the flask and cells, and transferred to 50 mL conical tubes. Cell counting was performed (25 μL of cells into an Effendorf vial + 25 μL of trypan blue staining solution), and the cell density was adjusted to 15,000 cells / 45 µL / well (3.33 × 10^5 / mL) in OptiMEM medium.

[0369] Forty-five microliters of cell suspension (15,000 cells) were aliquoted into each well of a white 384-well plate. The plate was incubated at room temperature for 10 minutes, then placed in a 37°C + 5% CO2 incubator overnight.

[0370] Day 2 - Compound treatment. Exemplary compounds were prepared at a starting concentration of 1 mM and serially diluted 1:3 for use in 11-point CRC preparations and stored in a refrigerator. The master compound plate was thawed overnight at room temperature. DMSO (20 µL) was added to column 24 of the master compound plate as a negative control, and 20 µL of 300 µM compound 4 was added to column 23 as a positive control.

[0371] Intermediate compound with OptiMEM medium containing 4% DMSO. Add DMSO to warm OptiMEM medium to obtain a 4% DMSO solution (approximately 50 mL / plate). Dispense 100 μL of OptiMEM-4% DMSO into each well of a 384-well deep-well microplate.

[0372] Rotate the main compound plate and intermediate compound plate downwards.

[0373] Transfer one µL of the compound from the master compound plate to the intermediate plate (1:100 dilution). Combine the diluted mixture and transfer 5 µL to the assay plate (1:10 dilution) to achieve a final starting concentration of 1 µM. Incubate the treated assay plate at 37 °C + 5% CO2 for 24 hours. Seal the master compound plate and store it at room temperature for use in a second run within one week.

[0374] Day 3 - HiBit measurement. Add 5 μL of Almar Blue to each well of a black 384-well plate. Incubate the plate in an incubator (37°C + 5% CO2) for 2 hours, followed by incubation at room temperature for 1 hour. Read the fluorescence of each plate using a microplate reader to determine the Almar Blue activity.

[0375] Heat a set of white test plates to room temperature (45 minutes).

[0376] Prepare the One Glo luciferase mixture. Aspirate culture medium from a white 384-well assay plate. Add 25 µL of One Glo luciferase mixture to each well of the assay plate. Incubate the plate on a benchtop (room temperature) for 45 minutes, including 10 minutes of shaking at 700 rpm. Read the luminescence of each plate using a microplate reader.

[0377] Add 1:100 DLR substrate and 1:100 LgBiT protein dilution to the Promega Stop and Glo buffer, and mix just before adding to the assay plate. Add 25 μL of the Stop and Glo mixture to each well. Incubate the assay plate for at least 45 minutes, including 10 minutes of shaking at 700 rpm. Read the luminescence of each plate on a microplate reader.

[0378] Analysis of LRRK2 HiBit screening assay. As described above, the plates were run in triplicate and the assays were repeated twice (a total of 6 replicates for the exemplary compound). For each treatment, the number of firefly luciferase cells, cell viability (Almar Blue), and LRRK2-HiBit quantification of Nanoluc were measured.

[0379] The LRRK2 HiBit and Almar Blue signals were normalized relative to the median DMSO value for each plate. Curve fitting was performed for each compound, repeated across three plates.

[0380] Data on the compounds disclosed in this paper are provided in Table 2.

[0381] Table 2. NT = Untested As shown in Table 3 below, the variables (L) attached to the described compounds are included. n Some compounds with the 3-(3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione group exhibit improved activity compared to the following direct comparatives, particularly those having the 3-(4-methoxy-1-oxoisoindoline-2-yl)piperidine-2,6-dione group. For example, when compared to Comparative Example 1, Compound 1 shows WT LRRK2 DC 50 The activity increased more than 40-fold, and the comparative example included variables (L). nThe 3-(4-methoxy-1-oxoisoindoline-2-yl)piperidine-2,6-dione group. Compounds 6, 12, 14, and 48 all showed similar trends when compared to comparative examples 2, 4, 5, and 6, respectively. These data, along with additional data presented in Table 3, demonstrate the improved activity resulting from the use of the 3-(3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione group.

[0382] Table 3. The subject matter disclosed is not limited in scope to the specific embodiments and examples described herein. In fact, various modifications to this disclosure, in addition to those described, will become apparent to those skilled in the art from the foregoing description and drawings. Such modifications are intended to fall within the scope of the appended claims.

[0383] All references cited herein (e.g., publications, patents, or patent applications) are incorporated herein by reference in their entirety for all purposes, as if each individual reference (e.g., publications, patents, or patent applications) were specifically or individually indicated to be incorporated herein by reference in their entirety for all purposes. Other embodiments are within the scope of the following claims.

Claims

1. A compound of formula (Ia): Or its pharmaceutically acceptable salt. in: X 1 For CR 1 Or N; X 2 For H, C 1-3 Alkyl or O; R 1 R 2 R 3 R 4 and R 5 Each is independently selected from H, acetyl, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl, OC 3-6 cycloalkyl and C 1-6 Alkoxy, wherein the C 3-10 cycloalkyl, OC 3-6 cycloalkyl and C 1-6 The alkoxy group is optionally surrounded by 1 or 2 carbon atoms. 1-6 Alkyl or cyano substitution; R 6 Halogenated or C 1-3 alkyl; R 7 For H or C 1-3 alkyl; one It is a double bond, and one It is a single bond; the condition is that when R 4 N When C is a double bond, then R 4 It does not exist; and the condition is that when X 2 When it is O, C X 2 It is a double bond; Each L is independently selected from C 1-6 Alkyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, O, C 3-11 Cycloalkyl and 4-12 membered heterocyclic alkyl groups, wherein C 3-11 Cycloalkyl and 4-12 membered heterocyclic alkyl groups are optionally substituted with 1, 2 or 3 R groups. L Replace, where each R L Independently selected from halogenated, CN and C 1-6 alkyl; n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; m can be 0, 1, or 2.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 7 It can be H or -CH3.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein m is 0 or 1, and R 6 When present, it is halogenated.

4. The compound according to claim 1, wherein the compound has formula (I): ； Or its pharmaceutically acceptable salt, wherein: X 1 For CR 1 Or N; X 2 It is H or O; R 1 R 2 R 3 R 4 and R 5 Each is independently selected from H, acetyl, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl, OC 3-6 cycloalkyl and C 1-6 Alkoxy, wherein the C 3-6 cycloalkyl, OC 3-6 cycloalkyl and C 1-6 The alkoxy group is optionally surrounded by 1 or 2 carbon atoms. 1-6 Alkyl substitution; one It is a double bond, and one It is a single bond; the condition is that when R 4 N When C is a double bond, then R 4 It does not exist; and the condition is that when X 2 When it is O, C X 2 It is a double bond; Each L is independently selected from C 1-6 Alkyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, O, C 3-11 Cycloalkyl and 4-12 membered heterocyclic alkyl groups, wherein C 3-11 Cycloalkyl and 4-12 membered heterocyclic alkyl groups are optionally substituted with 1, 2 or 3 R groups. L Replace, where each R L Independently selected from halogenated, CN and C 1-6 Alkyl; and n can be 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein: X 1 For CR 1 Or N; X 2 It is H or O; R 1 R 2 R 3 R 4 and R 5 Each is independently selected from H, halogenated, C 1-6 Alkyl, C 3-6 cycloalkyl, OC 3-6 cycloalkyl and C 1-6 Alkoxy, where C 3-6 cycloalkyl, OC 3-6 cycloalkyl and C 1-6 The alkoxy group is optionally surrounded by 1 or 2 carbon atoms. 1-6 Alkyl substitution; Each L is independently selected from C 1-6 Alkyl, C 2-6 alkynyl group, C 1-6 Alkoxy, O, C 3-11 Cycloalkyl and 4-12-membered heterocyclic alkyl groups, wherein the 4-12-membered heterocyclic alkyl group is optionally substituented by one or two R groups. L Replace, where each R L Independently selected from halogenated, CN and C 1-6 Alkyl; and n can be 1, 2, 3, 4, 5, 6, 7 or 8.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein: X 1 For CH or N; X 2 It is H or O; R 2 R 3 R 4 and R 5 Each is independently selected from H and C. 1-6 Alkyl, OC 3-6 cycloalkyl and C 1-6 Alkoxy, of which OC 3-6 cycloalkyl and C 1-6 The alkoxy group is optionally surrounded by 1 or 2 carbon atoms. 1-4 Alkyl substitution; Each L is independently selected from C 1-6 Alkyl, C 2-6 alkynyl group, C 1-6 Alkoxy, O, C 3-11 Cycloalkyl and 4-12-membered heterocyclic alkyl groups, wherein the 4-12-membered heterocyclic alkyl group is optionally substituented by one or two R groups. L Replace, where each R L Halogenated or C 1-6 Alkyl; and n can be 1, 2, 3, 4, 5, or 6.

7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein: X 1 For CH or N; X 2 It is H or O; R 3 R 4 and R 5 Each independently is H or C 1-6 alkyl; R 2 To be optionally bounded by 1 or 2 C 1-4 Alkyl-substituted OC 3-6 cycloalkyl; Each L is independently selected from C 1-6 Alkyl, C 2-6 alkynyl group, C 1-6 Alkoxy, O, C 3-11 Cycloalkyl and 4-12-membered heterocyclic alkyl groups, wherein the 4-12-membered heterocyclic alkyl group is optionally substituented by one or two R groups. L Replace, where each R L Halogenated or C 1-6 Alkyl; and n can be 1, 2, 3, 4, 5, or 6.

8. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R 3 For H.

9. The compound according to any one of claims 1 to 8, wherein the compound is a compound of formula (II): ， Or its pharmaceutically acceptable salt.

10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R 4 N C is a double bond; X 2 For H; and R 4 It does not exist.

11. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein... X 2 C is a double bond; and X 2 It is O.

12. The compound according to any one of claims 1 to 9 and 11, wherein the compound is a compound of formula (IIA): ， Or its pharmaceutically acceptable salt.

13. The compound according to any one of claims 1 to 10, wherein the compound is a compound of formula (IIB): ， Or its pharmaceutically acceptable salt.

14. The compound according to any one of claims 1 to 5 and 8 to 12, or a pharmaceutically acceptable salt thereof, wherein R 1 For H.

15. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 and 8 to 14, wherein R 2 C 1-4 Alkoxy, C 3-8 cycloalkyl or OC 3-5 cycloalkyl, wherein the C 3-8 cycloalkyl and OC 3-5 Each cycloalkyl group is optionally surrounded by one or two C atoms. 1-4 Alkyl or cyano substitution.

16. The compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein R 2 To be optionally bounded by 1 or 2 C 1-4 Alkyl-substituted OC 3-5 Cycloalkyl.

17. The compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R 2 For optional use by C 1-3 Alkyl-substituted OC 3-5 Cycloalkyl.

18. The compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein R 2 for .

19. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 and 8 to 15, wherein R 2 For -OCH3, -OCH2CH3, -OCH(CH3)2, -OC(CH3)3, , , , or .

20. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, 11, 12 and 14 to 19, wherein R 4 For H, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 3-10 cycloalkyl, wherein the C 3-10 The cycloalkyl group is optionally surrounded by 1 or 2 Cs 1-6 Alkyl or cyano substitution.

21. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, 11, 12 and 14 to 20, wherein R 4 C 1-3 alkyl.

22. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, 11, 12 and 14 to 21, wherein R 4 It is -CH3.

23. The compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein R 5 For H, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 3-10 cycloalkyl, wherein the C 3-10 The cycloalkyl group is optionally surrounded by 1 or 2 Cs 1-6 Alkyl or cyano substitution.

24. The compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein R 5 For H.

25. The compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, wherein each L is independently selected from C 1-6 Alkyl, C 2-6 alkynyl group, C 1-6 Alkoxy, O, C 3-11 Cycloalkyl and 4-12-membered heterocyclic alkyl groups, wherein the 4-12-membered heterocyclic alkyl group is optionally substituented by one or two R groups. L Replace, where R L C 1-6 alkyl.

26. The compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, wherein n is 2, 3, 4, 5, 6, 7, or 8, and at least two L are 4-12-membered heterocyclic alkyl groups, wherein the 4-12-membered heterocyclic alkyl group is optionally substituted by one or two R groups. L Replace, where R L C 1-6 alkyl.

27. The compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, wherein n is 3, 4, 5, 6, 7, or 8, and at least three L are 4-12-membered heterocyclic alkyl groups, wherein the 4-12-membered heterocyclic alkyl group is optionally substituted by one or two R groups. L Replace, and where R L C 1-6 alkyl.

28. The compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein each L is independently selected from C 1-6 Alkyl, C 2-4 alkynyl group, C 1-6 Alkoxy, O, C 3-7 Cycloalkyl and 6-8-membered heterocycloalkyl, wherein the 6-8-membered heterocycloalkyl is optionally substituent by one or two R groups. L Replace, and where R L C 1-3 alkyl.

29. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 28, wherein n is 4, 5 or 6.

30. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 26, 27 and 28, wherein n is 5, and each L together forms a linker selected from (4-12 membered heterocyclic alkyl)-(C 1-6 alkyl)-(4-12 membered heterocyclic alkyl)-(C 1-6 (alkyl)-(4-12-membered heterocyclic alkyl); (4-12-membered heterocyclic alkyl)-(C 1-6 alkyl)-(C 3-12 (4-12-membered heterocyclic alkyl)-(O)-(4-12-membered heterocyclic alkyl)-(C 1-6 alkyl)-(4-12 membered heterocyclic alkyl)-(C 1-6 alkoxy)-(C 3-6 (alkynyl); and (4-12 membered heterocyclic alkyl)-(C 1-6 alkyl)-(4-12 membered heterocyclic alkyl)-(O)-(C 3-6 (alkynyl), wherein each 4-12 membered heterocyclic alkyl group is optionally substituent by 1 or 2 substituents R. L Replace, where R L C 1-6 alkyl.

31. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 26 and 28 to 30, wherein n is 5, and each L together forms a linker selected from (5-6 membered heterocyclic alkyl)-(C 1-6 alkyl)-(5-6 membered heterocyclic alkyl)-(C 1-6 (alkyl)-(5-6 membered heterocyclic alkyl); (5-6 membered heterocyclic alkyl)-(C 1-6 alkyl)-(C 5-6 (5-6 membered heterocyclic alkyl)-(O)-(5-6 membered heterocyclic alkyl)-(C 1-6 alkyl)-(5–6-membered heterocyclic alkyl)-(C 1-6 alkoxy)-(C 3-6 (alkynyl); and (5-6 membered heterocyclic alkyl)-(C 1-6 alkyl)-(5-6 membered heterocyclic alkyl)-(O)-(C 3-6 (alkynyl), wherein each 5-6 membered heterocyclic alkyl group is optionally substituent by 1 or 2 substituents R. L Replace, where R L C 1-6 alkyl.

32. The compound according to any one of claims 1 to 26 and 28 to 30, wherein the compound is a compound of formula (IIAa): ， Or its pharmaceutically acceptable salt. in: Each ring A is independently selected from piperidinyl, hexahydropyridinyl, hexahydropyrimidinyl, and piperidinyl, wherein each ring A is optionally substituent R by one or two substituents. L Replace, where R L C 1-6 alkyl; Ring B is selected from cyclohexyl, piperidinyl, hexahydropyridinyl, hexahydropyrimidinyl, and piperazinyl, wherein each ring B is optionally substituent R by one or two substituents. L Replace, where R L C 1-6 Alkyl; and Each Y is independently O, C 1-6 Alkyl or C 1-6 Alkyl group.

33. The compound according to any one of claims 1 to 26 and 28 to 30, wherein the compound is a compound of formula (IIAb): ， Or its pharmaceutically acceptable salt. in: Each ring A is independently selected from piperidinyl, hexahydropyridinyl, hexahydropyrimidinyl, and piperidinyl, wherein each ring A is optionally substituent R by one or two substituents. L Replace, where R L C 1-6 alkyl; Ring B is selected from cyclohexyl, piperidinyl, hexahydropyridinyl, hexahydropyrimidinyl, and piperazinyl, wherein each ring B is optionally substituent R by one or two substituents. L Replace, where R L C 1-6 Alkyl; and Each Y is independently O, C 1-6 Alkyl or C 1-6 Alkyl group.

34. The compound according to any one of claims 1 to 26 and 28 to 30, wherein the compound is a compound of formula (IIBa): ， Or its pharmaceutically acceptable salt. in: Each ring A is independently selected from piperidinyl, hexahydropyridazinyl, hexahydropyrimidinyl, and piperazinyl; Y 1 C 1-6 alkyl; Y 2 For O or C 1-6 alkoxy groups; and Z is a C3-6 acetylene group.

35. The compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, wherein (L) n Selected from:

36. The compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, wherein (L) n Selected from:

37. The compound according to claim 1, wherein the compound is a compound of formula (III): (III); Or its pharmaceutically acceptable salt, wherein R 4 C 1-3 alkyl; L 1 and L 3 Each is independently a 5- to 6-membered heterocyclic group; and L 2 C 3-6 Cycloalkyl.

38. The compound according to claim 37, wherein the compound is a compound of formula (IIIa): (IIIa); Or its pharmaceutically acceptable salt.

39. The compound according to claim 37 or 38, wherein the compound is a compound of formula (IIIb): (IIIb); Or its pharmaceutically acceptable salt.

40. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 37 to 39, wherein L 1 It is piperazine-based.

41. The compound according to any one of claims 37 to 40, or a pharmaceutically acceptable salt thereof, wherein L 3 It is piperidinyl.

42. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 37 to 41, wherein L 2 It is a cyclohexyl group.

43. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from any of compounds 1-70.

44. A pharmaceutical composition comprising a compound according to any one of claims 1 to 43 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

45. The pharmaceutical composition of claim 44, wherein the pharmaceutical composition further comprises an additional bioactive agent.

46. ​​The pharmaceutical composition of claim 45, wherein the additional bioactive agent is an anti-inflammatory agent, a chemotherapeutic agent, or an immunomodulator.

47. A method for treating a disease, condition, or symptom causally related to LRRK2, the method comprising administering to a subject an effective amount of a compound according to any one of claims 1 to 43 or a pharmaceutical composition according to claim 44.

48. The method of claim 47, wherein the disease or condition is idiopathic Parkinson's disease (PD), LRRK2 mutation-associated Parkinson's disease (PD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Lewy body dementia, Crohn's disease, leprosy with type 1 inflammatory response, neuroinflammation, Kennedy's disease, TDP-43 ALS, c9orfALS, Huntington's disease, Alzheimer's disease, Pick's disease, multiple system atrophy, systemic lupus erythematosus (SLE), acute kidney injury, rhabdomyolysis, lipofuscinosis, Fabry's disease, or batten's disease. Diseases including ulcerative colitis, irritable bowel syndrome, Kufor–Rakeb syndrome, Gaucher disease, frontotemporal dementia, spinocerebellar ataxia (SCA) 1, 2, 3, 6, 7 and 17 and / or dentate nucleus, globus pallidus, and Lewy body atrophy (DRPLA).

49. The method of claim 47 or 48, wherein the disease or condition is idiopathic PD.

50. The method of claim 47 or 48, wherein the disease or condition is LRRK2 mutation-related PD.

51. The method according to claim 47 or 48, wherein the disease or condition is progressive supranuclear palsy (PSP).

52. The method according to claim 47 or 48, wherein the disease or condition is systemic lupus erythematosus (SLE).

53. A method for treating Parkinson's disease, the method comprising administering to a subject an effective amount of the compound according to any one of claims 1 to 43 or the pharmaceutical composition according to claim 44.

54. The method of claim 53, wherein the Parkinson's disease is LRRK2 mutation-associated Parkinson's disease.

55. A method for treating progressive supranuclear palsy (PSP), the method comprising administering to a subject an effective amount of the compound according to any one of claims 1 to 43 or the pharmaceutical composition according to claim 44.

56. A method for treating systemic lupus erythematosus (SLE), the method comprising administering to a subject an effective amount of the compound according to any one of claims 1 to 43 or the pharmaceutical composition according to claim 44.

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