α-Synuclein binder and method of use

Abstract

The present invention relates to compounds represented by formula (I) or pharmaceutically acceptable salts thereof, which may be suitable for imaging α-synuclein pathologies. Accordingly, these compounds or pharmaceutically acceptable salts thereof are useful for binding and imaging α-synuclein aggregates in patients with Parkinson's disease. More specifically, the present invention relates to a method of using the compounds of the present invention as tracers in positron emission tomography (PET) imaging to study α-synuclein in the brain in vivo, in order to enable the diagnosis of Parkinson's disease and other neurodegenerative diseases characterized by α-synuclein pathologies. The present invention also relates to a method for measuring the clinical efficacy of therapeutic agents for Parkinson's disease and other neurodegenerative diseases characterized by α-synuclein pathologies.

Description

[Technical Field]

[0001] Cross-reference with related applications This application claims the benefit or priority of U.S. Provisional Application No. 63 / 488,652, filed on March 6, 2023, the disclosure thereof, which is incorporated herein by reference in its entirety. [Background technology]

[0002] Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease (PD), Huntington's disease, amyotrophic lateral sclerosis (ALS), and prion diseases are debilitating diseases that affect cognitive and / or muscle control. These diseases are a subset of protein misfolding diseases. Protein folding is an essential process for protein function in all living organisms, and conditions that disrupt protein folding threaten the viability of cells. In some cases, the above diseases arise because a particular protein becomes non-functional when it is misfolded. In other diseases, the pathological condition arises because misfolding occurs simultaneously with aggregation, and the underlying aggregates are harmful. Even though neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease are caused by different proteins, both involve the accumulation of insoluble fibrous protein deposits called amyloid. For example, Parkinson's disease (PD), Lewy body dementia (DLB), and multiple system atrophy (MSA), collectively known as "synucleinopathy," are associated with the accumulation of aggregated forms of α-synuclein protein in neurons in the brain (see "Nat. Rev. Neuro. 2013, 9, 13-24" and "J. Parkinson's Disease 2013, 3, 565-567"). Major neuropathological changes in PD include degeneration of dopaminergic neurons in the substantia nigra, as well as the formation of Lewy bodies (LBs) and Lewy neurites (LNs). To date, the pathogenesis of PD is not fully understood.

[0003] Alpha-synuclein is a presynaptic terminal protein consisting of 140 amino acids, playing crucial roles in the central nervous system, including synaptic vesicle recycling and synthesis, vesicle storage, and neurotransmitter release. It is specifically upregulated in individual populations of presynaptic terminals in the brain during synaptic rearrangement associated with acquisition. Alpha-synuclein is naturally highly soluble and exists in an unfolded state. Evidence suggests that in synucleinopathy, filamentous aggregates of alpha-synuclein accumulate on the presynaptic membrane, causing synaptic dysfunction and neuronal cell death, and that these filamentous aggregates may contribute to Parkinson's disease and DLB. Antibody immunohistochemical studies have identified alpha-synuclein aggregates as a major component of Lewy bodies, which are microscopic protein deposits in degraded nerve cells. The accumulation of misfolded fibrous α-synuclein in Lewy bodies (LBs) and Lewy neurites (LNs) is considered a characteristic feature of Parkinson's disease (PD).

[0004] The diagnosis of Parkinson's disease (PD) is primarily based on clinical symptoms such as resting tremor, bradykinesia, and rigidity, but these methods have limitations (see "J. Neurology 2019, 266, 1927-1936"). Current treatment goals for PD are to slow disease progression and minimize patient symptoms. Therefore, methods for diagnosing PD at a very early stage can greatly assist physicians in designing treatment paradigms accordingly and slowing disease progression. Improved diagnostic methods for identifying misfolded protein aggregates containing α-synuclein are still needed for early detection and continuous monitoring of PD in the population (see "J. Parkinson's Disease 2013, 3, 565-567").

[0005] Alpha-synuclein positron emission tomography (PET) tracers may be valuable non-invasive diagnostic biomarkers for spatial and temporal quantification of aggregated pathological alpha-synuclein in the human brain, serving as a Parkinson's disease biomarker. Furthermore, alpha-synuclein PET tracers may be useful for patient selection in PD clinical trials. In this manner, alpha-synuclein tracers can be developed as companion diagnostics for the co-registration of therapeutic agents. Moreover, alpha-synuclein PET tracers may be important disease-related tools for quantifying the stabilization or reduction of alpha-synuclein formation in relation to disease-modifying PD therapeutic agents.

[0006] Therefore, there is a need for neuroimaging radiotracers that enable in vivo imaging of α-synuclein pathology and thereby provide insights into the deposition of α-synuclein aggregates in the human brain. Successful neuroimaging radiotracers must cross the blood-brain barrier, be rapidly cleared from tissues and plasma, and possess high affinity and specificity for α-synuclein aggregates with higher selectivity than binding to β-amyloid and tau aggregate proteins, which are co-expressed in many PD patient populations (see "Biol Psychiatry 2015, 78, 672-683" and "J Neuropath Exper Neurol 2003, 62, 389-397"). While α-synuclein-binding ligands with reduced selectivity for aggregated β-amyloid have been described (WO2019 / 121661), compounds with high selectivity for aggregated proteins co-expressed in PD are needed to quantify α-synuclein-specific signals in in vivo imaging studies of PD patients. [Prior art documents] [Patent Documents]

[0007] [Patent Document 1] WO2019 / 121661 [Non-patent literature]

[0008] [Non-Patent Document 1] Nat. Rev. Neuro. 2013, 9, 13-24 [Non-Patent Document 2] J. Parkinson's Disease 2013, 3, 565-567 [Non-Patent Document 3] J. Neurology 2019, 266, 1927-1936 [Non-Patent Document 4] Biol Psychiatry 2015, 78, 672-683 [Non-Patent Document 5] J Neuropath Exper Neurol 2003, 62, 389-397 [Overview of the project] [Problems that the invention aims to solve]

[0009] The present invention advances these concerns by providing a compound represented by formula I as an aggregated α-synuclein binding ligand having higher selectivity than the binding of aggregated β-amyloid. The present invention further relates to a method of using the compound represented by formula I as a tracer in PET imaging to study α-synuclein deposition in the brain in vivo, in order to enable the diagnosis of neurodegenerative diseases characterized by α-synuclein pathology. The present invention further relates to a method of measuring the clinical efficacy of therapeutic agents targeting α-synuclein pathology. [Means for solving the problem]

[0010] The present invention relates to compounds represented by formula I, pharmaceutically salts thereof, pharmaceutical compositions containing them, diagnostic and therapeutic uses, and processes for producing such compounds. One embodiment of the present invention relates to a compound represented by formula I: [ka] Provided is a compound represented by or a pharmaceutically acceptable salt thereof, wherein in the above formula, …… may be absent or may represent a bond; R is H or -C , s , x , c , a , 1-6 , 2 , c , p , s , , 1-6 independently selected from alkyl, wherein the alkyl is -C 1-6 alkyl, OR a or may be optionally substituted with 1 to 3 groups from halo; R a is independently selected from H, -C 1-6 alkyl, -(CH2) p OR, -(CH2) p halo or -(CH2) p O(CH2) p halo; R b is independently selected from H, -C [[ID=​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​R 3 is -C 1-6 A molecule independently selected from alkyl, heteroaryl, or heterocyclyl, wherein the alkyl, heteroaryl, or heterocyclyl is an OR a or R b It may be arbitrarily substituted with 1 to 3 of the bases from; Ring A 1 This is selected from pyridinyl, imidazo-pyrimidinyl, triazinyl, pyrimidinyl, imidazo-pyrimidinyl, pyrazinyl, or pyridazinyl; Ring A 2 is selected from pyrimidinyl, pyridinyl, pyrazinyl or phenyl, where pyrimidinyl, pyridinyl, pyrazinyl or phenyl is -C 1-6 Alkyl, OR a Alternatively, it may be arbitrarily substituted with 1 to 3 elements from the halo; Ring A 3 This is selected from pyridinyl, pyrazinyl, pyrimidinyl, pyrrolopyrazinyl, triazinyl, indolyl, imidazolyl, oxadiazolyl, triazolyl, thiazolyl, isoxazolyl, oxazolyl, 3,4-dihydro-2H-pyrido[3,2,b][1,4]oxazine or phenyl; m is selected from 0, 1, or 2; n is selected from 1, 2, or 3; p is independently selected from 1, 2, or 3; r is selected from 1, 2, or 3; s is independently selected from 0, 1, 2, 3, 4, 5, or 6; t is independently selected from 0, 1, 2, 3, 4, 5, or 6; and, x is independently selected from 1, 2, 3, 4, 5, or 6.

[0011] The present invention also covers isotope-labeled compounds represented by formula I. Furthermore, the present invention provides pharmaceutical compositions comprising a compound represented by formula I and at least one pharmaceutically acceptable carrier.

[0012] The present invention relates to a compound represented by Formula I that can be useful for binding α-synuclein aggregated protein and / or tau aggregated protein, and is therefore useful for binding and imaging α-synuclein aggregated protein pathogenesis in patients with PD and non-PD synucleopathies, and aggregated tau protein pathogenesis in patients with Alzheimer's disease (AD) and non-AD tauopathy, by PET imaging techniques commonly known in the art (see "Nucl. Med. 2019, 60, 93-99 and 107-114"). The present invention further relates to a method of using the compound represented by Formula I to identify patients with abnormal levels of aggregated α-synuclein pathogenesis in the brain. The present invention further relates to a method of using the compound represented by Formula I to measure the progression of α-synuclein pathogenesis over time as a biomarker in the clinical evaluation of potential therapeutic agents that can modify the progression of Parkinson's disease.

[0013] The compounds of the present invention may also be useful for imaging and detection of other neurodegenerative diseases characterized by the deposition of α-synuclein aggregates, such as multiple system atrophy (MSA) and Lewy body dementia (DLB). [Brief explanation of the drawing]

[0014] [Figure 1] Saturation binding experiments for [3H]-105 in aggregated β-amyloid-rich AD tissue homogenates. [Figure 2] Specific binding of [3H]-2 to α-synucleinopathy in PD brain amygdala sections. [Figure 3] Coronal sections of PET images of [11C]-2 in the brain of rhesus monkeys (average values ​​from 30–90 minutes after injection, fused with MRI). [Modes for carrying out the invention]

[0015] The present invention provides novel compounds, synthesis methods for producing those compounds, pharmaceutical compositions containing them, isotope-labeled compounds, and methods for using those compounds as imaging agents.

[0016] In one embodiment, the present invention relates to formula I: [ka] A compound represented by or a pharmaceutically acceptable salt thereof is used as a control, where, ...may not exist, or can represent a combination; R is H or -C 1-6 Selected independently of alkyl, where the alkyl is -C 1-6 Alkyl, OR a Alternatively, it may be arbitrarily substituted with 1 to 3 elements from the halo; R a H, -C 1-6 Alkyl, -(CH2) p OR, -(CH2) p Halo or -O(CH2) p Selected independently from Halo; R b H, -C 1-6 Alkyl, heterocyclyl, heteroaryl, -(CH2) p OR, -CN, -(CH2) t Hello, -(CH2) s NR2 or -O(CH2) p Selected independently from Halo; R c This is H, halo, OR, or -C 1-6 Selected independently of alkyl, where the alkyl is -C 1-6 Alkyl, OR a Alternatively, it may be arbitrarily substituted with 1 to 3 elements from the halo; R 1 is, -(CH2) s OR, -(CH2) s NR2, -(CH2) s [O(R c 2) p ] x -Rc or -(CH2) s Selected from Halo; R 2 H, OR, CN, Halo, or C 1-6 Selected independently of alkyl, where the alkyl is -C 1-6 Alkyl, OR a Alternatively, it may be arbitrarily substituted with 1 to 3 elements from the halo; R 3 is -C 1-6 A molecule independently selected from alkyl, heteroaryl, or heterocyclyl, wherein the alkyl, heteroaryl, or heterocyclyl is an OR a or R b It may be arbitrarily substituted with 1 to 3 of the bases from; Ring A 1 This is selected from pyridinyl, imidazo-pyrimidinyl, triazinyl, pyrimidinyl, imidazo-pyrimidinyl, pyrazinyl, or pyridazinyl; Ring A 2 is selected from pyrimidinyl, pyridinyl, pyrazinyl or phenyl, where pyrimidinyl, pyridinyl, pyrazinyl or phenyl is -C 1-6 Alkyl, OR a Alternatively, it may be arbitrarily substituted with 1 to 3 elements from the halo; Ring A 3 This is selected from pyridinyl, pyrazinyl, pyrimidinyl, pyrrolopyrazinyl, triazinyl, indolyl, imidazolyl, oxadiazolyl, triazolyl, thiazolyl, isoxazolyl, oxazolyl, 3,4-dihydro-2H-pyrido[3,2,b][1,4]oxazine or phenyl; m is selected from 0, 1, or 2; n is selected from 1, 2, or 3; p is independently selected from 1, 2, or 3; r is selected from 1, 2, or 3; s is independently selected from 0, 1, 2, 3, 4, 5, or 6; t is independently selected from 0, 1, 2, 3, 4, 5, or 6; and, x is independently selected from 1, 2, 3, 4, 5, or 6.

[0017] A further embodiment of the present invention is a compound represented by formula IA:

Chemical formula

[0018] In a further embodiment, the present invention relates to formula IB: [ka] The subject is a compound represented by or a pharmaceutically acceptable salt thereof, wherein in the above formula, ...may not exist, or can represent a combination; R is H or -C 1-6 Selected independently of alkyl, where the alkyl is -C 1-6 Alkyl, OR a Alternatively, it may be arbitrarily substituted with 1 to 3 elements from the halo; R a H, -C 1-6 Alkyl, -(CH2) p OR, -(CH2) p Halo, halogen, or -(CH2) p O(CH2) p Selected independently from Halo; R b H, -C 1-6 Alkyl, heterocyclyl, heteroaryl, -(CH2) p OR, -CN, -(CH2) t Hello, -(CH2) s NR2 or -O(CH2) p Selected independently from Halo; R c This is H, halo, OR, or -C 1-6 Selected independently of alkyl, where the alkyl is -C 1-6 Alkyl, OR a Alternatively, it may be arbitrarily substituted with 1 to 3 elements from the halo; R 1b is -[O(R c 2) p ] x -R c Selected from OR, NR2, or Halo; R 2 H, OR, CN, Halo, or C 1-6 Selected independently of alkyl, where the alkyl is -C 1-6 Alkyl, OR a Alternatively, it may be arbitrarily substituted with 1 to 3 elements from the halo; R 3 is -C 1-6A alkyl, imidazolyl, morpholinyl, triazolyl, oxazolyl, triazinyl, pyrazolyl, thiazolyl, pyrazinyl, isoxazolyl, azetidinyl, pyrrolidinyl, tetrahydrotriazolopyradinyl, piperidinyl, or pyrimidinyl is independently selected from alkyl, imidazolyl, morpholinyl, triazolyl, oxazolyl, triazinyl, pyrazolyl, thiazolyl, pyrazinyl, isoxazolyl, azetidinyl, pyrrolidinyl, tetrahydrotriazolopyradinyl, piperidinyl, or pyrimidinyl is OR a or R b It may be arbitrarily substituted with 1 to 3 of the bases from; Ring A 1 This is selected from pyridinyl, imidazo-pyrimidinyl, triazinyl, pyrimidinyl, imidazo-pyrimidinyl, pyrazinyl, or pyridazinyl; Ring A 3 This is selected from pyridinyl, pyrazinyl, pyrimidinyl, pyrrolopyrazinyl, triazinyl, indolyl, imidazolyl, oxadiazolyl, triazolyl, thiazolyl, isoxazolyl, oxazolyl, 3,4-dihydro-2H-pyrido[3,2,b][1,4]oxazine or phenyl; m is selected from 0, 1, or 2; n is selected from 1, 2, or 3; p is independently selected from 1, 2, or 3; s is independently selected from 0, 1, 2, 3, or 4; t is independently selected from 0, 1, 2, 3, 4, 5, or 6; and, x is independently selected from 1, 2, 3, 4, 5, or 6.

[0019] In another embodiment, the present invention relates to formula IC: [ka] The subject is a compound represented by formula I having the structure represented by or a pharmaceutically acceptable salt thereof, wherein in the above formula, ...may not exist, or can represent a combination; R is H or -C 1-6 Selected independently of alkyl, where the alkyl is -C 1-6 Alkyl, OR a Alternatively, it may be arbitrarily substituted with 1 to 3 elements from the halo; R a H, -C 1-6 Alkyl, -(CH2) p OR, -(CH2) p Halo or -(CH2) p O(CH2) p Selected independently from Halo; R b H, -C 1-6 Alkyl, heterocyclyl, heteroaryl, -(CH2) p OR, -CN, -(CH2) t Hello, -(CH2) s NR2 or -O(CH2) p Selected independently from Halo; R c This is H, halo, OR, or -C 1-6 Selected independently of alkyl, where the alkyl is -C 1-6 Alkyl, OR a Alternatively, it may be arbitrarily substituted with 1 to 3 elements from the halo; R 1b is -[O(R c 2) p ] x -R c Selected from OR, NR2, or Halo; R 2 H, OR, CN, Halo, or C 1-6 Selected independently of alkyl, where the alkyl is -C 1-6 Alkyl, OR a Alternatively, it may be arbitrarily substituted with 1 to 3 elements from the halo; R 3 is -C 1-6A alkyl, imidazolyl, morpholinyl, triazolyl, oxazolyl, triazinyl, pyrazolyl, thiazolyl, pyrazinyl, isoxazolyl, azetidinyl, pyrrolidinyl, tetrahydrotriazolopyradinyl, piperidinyl, or pyrimidinyl is independently selected from alkyl, imidazolyl, morpholinyl, triazolyl, oxazolyl, triazinyl, pyrazolyl, thiazolyl, pyrazinyl, isoxazolyl, azetidinyl, pyrrolidinyl, tetrahydrotriazolopyradinyl, piperidinyl, or pyrimidinyl is OR a or R b It may be arbitrarily substituted with 1 to 3 of the bases from; Ring A 1 This is selected from pyridinyl, imidazo-pyrimidinyl, triazinyl, pyrimidinyl, imidazo-pyrimidinyl, pyrazinyl, or pyridazinyl; Ring A 3 This is selected from pyridinyl, pyrazinyl, pyrimidinyl, pyrrolopyrazinyl, triazinyl, indolyl, imidazolyl, oxadiazolyl, triazolyl, thiazolyl, isoxazolyl, oxazolyl, 3,4-dihydro-2H-pyrido[3,2,b][1,4]oxazine or phenyl; m is selected from 0, 1, or 2; n is selected from 1, 2, or 3; p is independently selected from 1, 2, or 3; s is independently selected from 0, 1, 2, 3, or 4; t is independently selected from 0, 1, 2, 3, 4, 5, or 6; and, x is independently selected from 0, 1, 2, 3, 4, 5, or 6.

[0020] In another embodiment, the present invention is defined by formula ID: [ka] The subject is a compound represented by formula I having the structure represented by or a pharmaceutically acceptable salt thereof, wherein in the above formula, ...may not exist, or can represent a combination; R is H or -C 1-6 independently selected from alkyl, where the alkyl is -C 1-6 alkyl, OR a and may be optionally substituted with 1 to 3 groups from alkyl, OR R a is H, -C<00​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​Independently selected from alkyl, imidazolyl, morpholinyl, triazolyl, oxazolyl, triazinyl, pyrazolyl, thiazolyl, pyrazinyl, isoxazolyl, azetidinyl, pyrrolidinyl, tetrahydrotriazolopyrazinyl, piperidinyl or pyrimidinyl, wherein said alkyl, imidazolyl, morpholinyl, triazolyl, oxazolyl, triazinyl, pyrazolyl, thiazolyl, pyrazinyl, isoxazolyl, azetidinyl, pyrrolidinyl, tetrahydrotriazolopyrazinyl, piperidinyl or pyrimidinyl is OR a or R b may be optionally substituted with 1 to 3 groups from; Ring A 1 is selected from pyridinyl, imidazo-pyrimidinyl, triazinyl, pyrimidinyl, imidazo-pyridinyl, pyrazinyl or pyridazinyl; Ring A 3 is selected from pyridinyl, pyrazinyl, pyrimidinyl, pyrrolopyrazinyl, triazinyl, indolyl, imidazolyl, oxadiazolyl, triazolyl, thiazolyl, isoxazolyl, oxazolyl, 3,4-dihydro-2H-pyrido[3,2,b][1,4]oxazine or phenyl; m is selected from 0, 1 or 2; n is selected from 1, 2 or 3; p is independently selected from 1, 2 or 3; s is independently selected from 0, 1, 2, 3 or 4; t is independently selected from 0, 1, 2, 3, 4, 5 or 6; and, x is independently selected from 0, 1, 2, 3, 4, 5 or 6.

[0021] In another embodiment, the present invention is directed to a compound of formula I having the structure represented by formula IE:

Chemical formula

[0022] In one embodiment, the present invention is expressed by formula IF: [ka] The compounds represented by and their pharmaceutically acceptable salts are subject to this study, where all substituents and variable parts are as defined above in Formula I.

[0023] In one embodiment, the present invention is based on formula IG: [ka] The compounds represented by and their pharmaceutically acceptable salts are subject to this study, where all substituents and variable parts are as defined above in Formula I.

[0024] In further embodiments, the present invention relates to a compound represented by formula I or a pharmaceutically acceptable salt thereof, wherein: Ring A 1 It is selected from pyrimidinyl or pyridinyl; Ring A 3 It is selected from pyridinyl, pyrazinyl, pyrimidinyl, or triazinyl; m is selected from 0 or 1; n is selected from 1 or 2; Furthermore, all other substituents and variable parts are as defined above in Formula I.

[0025] In one embodiment, the present invention relates to formulas I, IA, IB, IC, ID, IE, IF, or IG [wherein ring A 1 This provides compounds represented by [selected from pyridinyl, triazinyl, or pyrimidinyl]. In another embodiment, ring A 1 is pyridinyl or pyrimidinyl. In further embodiments, ring A 1 is pyridinyl. In further embodiments, ring A 1 is a triazinyl. In further embodiments, ring A 1 It is pyrimidinyl.

[0026] In one embodiment, the present invention relates to formula I, formula IF, or formula IG [wherein ring A 2 The present invention provides a compound represented by [a pyrimidinyl]. In another embodiment, ring A 2 is phenyl. In another embodiment, ring A 2 It is pyridinyl.

[0027] In one embodiment, the present invention provides a compound represented by formula I, formula IA, formula IB, formula IC, formula ID, formula IE, formula IF or formula IG [wherein ring A 3 is selected from pyridinyl, pyrimidinyl, pyrazinyl or triazinyl]. In another embodiment, ring A 3 is selected from pyridinyl or pyrimidinyl. In a further embodiment, ring A 3 is pyridinyl. In a further embodiment, ring A 3 is pyrimidinyl. In a further embodiment, ring A 3 is triazinyl.

[0028] In one embodiment, the present invention provides a compound represented by formula I, formula IA, formula IF or formula IG [wherein R 1 is -(CH2) s OR]. In one embodiment, the present invention provides a compound represented by formula I, formula IA, formula IF or formula IG [wherein R 1 is -(CH2) s [O(R c 2) p x -R c .

[0029] In one embodiment, the present invention provides a compound represented by formula I, formula IA, formula IB, formula IC, formula ID, formula IE, formula IF or formula IG [wherein R 3 is independently selected from -C 1-6 alkyl, imidazolyl, morpholinyl, triazolyl, oxazolyl, triazinyl, pyrazolyl or isoxazolyl, wherein the alkyl, imidazolyl, morpholinyl, triazolyl, oxazolyl, triazinyl, pyrazolyl or isoxazolyl is optionally substituted with 1 to 3 groups from OR a or R b . In a further embodiment, R 3 is independently selected from -C 1-6 alkyl, triazinyl or imidazolyl, wherein the alkyl, triazinyl and imidazolyl are optionally substituted with 1 to 3 groups from OR a or R b ​It may be optionally substituted with 1 to 3 of the following groups. In further embodiments, R 3 is -C 1-6 Independently selected from alkyl or imidazolyl, where the alkyl, pyrazolyl or imidazolyl is OR a or R b It may be optionally substituted with 1 to 3 of the following groups. In further embodiments, R 3 is independently selected from pyrazolyl or imidazolyl, where said pyrazolyl or imidazolyl is OR a or R b It may be optionally substituted with 1 to 3 of the following groups. In further embodiments, R 3 is pyrazolyl, where the pyrazolyl is OR a or R b It may be optionally substituted with 1 to 3 of the following groups. In further embodiments, R 3 is imidazolyl. Here, the imidazolyl is OR a or R b It may be arbitrarily substituted with 1 to 3 of the bases from.

[0030] Representative compounds of the present invention include those selected from the following: [Table 1] TIFF2026509241000012.tif236166TIFF2026509241000013.tif240166TIFF2026509241000014.tif239167TIFF2026509241000015.tif237167TIFF2026509241000016.tif236166TIFF2026509241000017.tif236167TIFF2026509241000018.tif140167The present invention relates to compounds represented by formula I for use as imaging agents.

[0031] One embodiment of the present invention comprises a compound selected from Examples No. 1, 2, 3, 4, 12, 13, 17, 29, 31, 32, 34, 38, 43, 44, 46, 48, 49, 51, or 52, or a pharmaceutically acceptable salt thereof. One embodiment of the present invention comprises a compound selected from Examples No. 1, 2, 3, 4, 12, 13, 17, 29, 31, 32, or 34, or a pharmaceutically acceptable salt thereof. A further embodiment of the present invention comprises a compound selected from Examples No. 38, 43, 44, 46, 48, 49, 51, or 52, or a pharmaceutically acceptable salt thereof. A further embodiment of the present invention comprises a compound selected from Examples No. 1, 2, 3, 12, 13, 29, or 32, or a pharmaceutically acceptable salt thereof. Further embodiments of the present invention include compounds selected from Examples No. 1, 2, 3, 12, 13, 29, 32, 38, 44, 46, or 52, or pharmaceutically acceptable salts thereof. Further embodiments of the present invention include compounds selected from Examples No. 2, 44, or 52, or pharmaceutically acceptable salts thereof.

[0032] Another aspect of the present invention is, 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 18 F, 35 S, 36 CL, 82 Br, 76 Br, 77 Br, 123 I, 124 I or 131 The present invention relates to compounds represented by formula I, labeled with an isotope selected from I, or pharmaceutically acceptable salts thereof. In a further aspect of the present invention, the compounds represented by formula I are 3 H, 11 C or 18 It is isotope-labeled with F. Examples of isotope-labeled compounds represented by formula I or their pharmaceutically acceptable salts include, but are not limited to, 3 H-2,3 H-29, 11 C-2, 18 F-3, 18 F-12, 18 F-13, 18 F-29, 18 F-38, 18 F-44, 18 F-46 and 18 Examples include the F-52.

[0033] Another aspect of the present invention is for use as an imaging agent, 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 18 F, 35 S, 36 CL, 82 Br, 76 Br, 77 Br, 123 I, 124 I or 131 The target is compounds represented by formula I, labeled with an isotope selected from I, or pharmaceutically acceptable salts thereof.

[0034] It is understood that references to "Formula I" also include compounds represented by Formula I', Formula IA, Formula IB, Formula IC, Formula ID, Formula IE, Formula IF, and Formula IG, unless otherwise indicated.

[0035] The compounds of the present invention may contain one or more chiral centers and therefore may exist as racemates and racemic mixtures, single enantiomers, diastereomer mixtures, and individual diastereomers. Depending on the properties of the various substituents of the molecule, additional chiral centers may be present. Each such chiral center independently produces two optical isomers, and all possible optical isomers and diastereomers in mixed state, as well as possible optical isomers and diastereomers as pure or partially purified compounds, are intended to be within the scope of the present invention. The present invention is intended to encompass all such isomeric forms of these compounds. Similarly, the present invention also encompasses tautomer forms of the compounds disclosed herein. Formula I shows the structure of the class of compounds without specific stereochemistry. At least some of the chemical names of the compounds of the present invention described in this application were automatically generated using commercially available chemical naming software programs and have not been independently verified.

[0036] The independent synthesis of these diastereomers or their chromatographic separation can be achieved by methods known in the art by appropriately modifying the methodologies disclosed herein. Their absolute stereochemistry can be confirmed by X-ray crystallography of crystalline products or intermediates derivatized with reagents containing chiral centers of known absolute configuration, if necessary. Absolute stereochemistry can also be elucidated by other techniques known in the art, such as cryo-electron microscopy. Relative stereochemistry can be determined by nuclear magnetic resonance using methods known in the art. Stereochemistry can be assigned by analogy with a set of isomers based on their relative biological activity, following the same trend established by similar stereochemically defined isomer groups. If necessary, the racemic mixture of the compound can be separated to isolate the individual enantiomers. This separation can be carried out by methods well known in the art, for example, by enantiomerically combining the racemic mixture of the compound with the pure compound to form a diastereomer mixture, and then separating the individual diastereomers by standard methods such as fractional crystallization or chromatography. The bonding reaction often involves forming a salt using an enantiomerically pure acid or base. The diastereomer derivative can then be converted back to the pure enantiomer by cleaving the added chiral residue. Racemic mixtures of the compounds can also be separated directly by chromatography using a chiral stationary phase, methods well known in the art. The compounds of the present invention can also be separated by supercritical fluid chromatography (SFC), reversed-phase HPLC, or silica gel chromatography. The isomers are named according to the order in which they are separated from the column (first eluted, second eluted, etc., or the first and second eluted isomers represented as "A" and "B" or "1" and "2"), for example, Example #A and Example #B according to the order in which they are eluted from the purification system.Those skilled in the art will understand that, in some cases, a peak may contain more than one isomer, and that splitting or further fractionating a peak may result in multiple fractions from a single peak, not representing a single isomer. Furthermore, some separations required multiple purification steps using the same purification method and / or alternative purification systems. Moreover, the mixture may be a mixture of 2 to 8 stereoisomers. Alternatively, any enantiomer of a compound can also be obtained by stereoselective synthesis using optically pure starting materials or reagents with known configurations, by methods well known in the art.

[0037] In one embodiment, the present invention provides a pharmaceutical composition comprising the compound of the present invention (for example, a compound represented by formula I) and at least one pharmaceutically active ingredient.

[0038] The compound represented by formula I is an inhibitor and / or binder of aggregated α-synuclein or tau protein. The compound represented by formula I and its isotopically labeled variants may be useful in the diagnosis and / or treatment of Parkinson's disease and / or Alzheimer's disease. Means for detecting the label are well known to those skilled in the art. For example, the isotopic label can be detected using imaging techniques, photographic film or a scintillation counter. In a preferred embodiment, the label is detected in vivo in the brain of a subject by imaging techniques, such as positron emission tomography (PET).

[0039] The compound represented by formula (I) may also form a component of a bifunctional compound that is a targeted proteolytic compound that binds to aggregated α-synuclein protein. Such a targeted α-synuclein proteolytic compound comprises a target protein-binding moiety formed from the compound represented by formula (I) and an E3 ubiquitin ligase-binding moiety. The targeted α-synuclein proteolytic compound typically contains a linker group that connects the α-synuclein protein-binding moiety and the E3 ubiquitin ligase-binding moiety. The E3 ubiquitin ligase-binding moiety in the α-synuclein targeted proteolytic compound may be, but are not limited to, a conjugate to the E3 ligase von Hipperrindau protein, a conjugate to the E3 ligase cereblon protein, or a conjugate to the MDM2 protein. Such compounds may be administered in pharmaceutical compositions to treat pathological conditions (which include, but are not limited to, the conditions disclosed herein).

[0040] In the following descriptions, conventional structural representations are used, and such representations include conventional stereochemical notations for specific chiral carbon centers.

[0041] Accordingly, the structural representation of the compounds of the present invention includes conventional stereochemical notations for some chiral carbon centers shown in the exemplary compounds. Thus, in such examples, a blacked-out “wedge” bond represents a bond protruding from the plane of the regeneration medium, a “finely engraved wedge” bond represents a bond descending into the plane of the regeneration medium, and a “wavy” line attached to a carbon having a double bond indicates that both possible cis and trans orientations are included. As in the conventional view, a plain solid line represents all spatial arrangements of the depicted bond. Therefore, where no specific stereochemical notation is given, the representation is intended to include all stereochemical and spatial orientations of the structural feature in question.

[0042] As shown in the examples of the present invention and as mentioned above, certain chiral carbon centers are structurally represented using the conventional “solid wedge” and “finely etched wedge” bonding representations. In most cases, the absolute configuration of the exemplary compounds has not been confirmed, but is assigned by analogy with specific exemplary compounds whose stereochemical configuration is known (confirmed by X-ray crystallography) and which were prepared using the same or similar reaction conditions and starting reagents and isolated under the same chromatographic conditions. Accordingly, the specific assignment of configurations structurally represented herein is intended to identify that a particular compound prepared has an excess of one particular stereoisomer, and is not necessarily stated herein as a description of the absolute determination of the stereochemical structure of the compound unless otherwise indicated in the presented data.

[0043] If an isomer mixture is obtained, it will be understood that the preparation of individual stereoisomers in significant enantiomer excess can be carried out, if desired, by separating the mixture using conventional methods (e.g., by chromatography or crystallization), by using stereochemically homogeneous starting materials for the described synthesis, or by stereoselective synthesis. In some cases, derivatization can be performed before separation of stereoisomers. Separation of a mixture of stereoisomers can be carried out at an intermediate stage during the synthesis of the compound represented by formula I, or it can be carried out on the final racemic product.

[0044] Where otherwise specified, absolute stereochemistry is determined by X-ray crystallography of the crystalline product or intermediate, where the crystalline product or intermediate is derivatized, if necessary, with a reagent containing a stereoisomer center of known configuration. Unless otherwise specified, the present invention encompasses all such isomers, salts, solvates (including hydrates), or solvated salts of such racemic compounds, enantiomers, or diastereomers.

[0045] When a wavy line terminates a conventional bond (rather than connecting two atoms within a structure), it indicates a bond point to the structure. For example, [ka] The tilde indicates that the secondary butyl moiety is bonded via a methylene group through a bond terminated by a wavy line. When alphabetical notation is used to represent a substitution, a dash is used to indicate the bond point to the indicated substrate. For example, -CH2-C(O)-CH2Cl indicates that the acetyl chloride moiety is bonded via the methylene moiety of that moiety.

[0046] If the compound represented by formula I is tautomerizable, all individual tautomers and mixtures thereof are included within the scope of the present invention.

[0047] Any variable part (e.g., R, R) 1 If any substituent (i.e., R, n, heteroaryl, alkyl, etc.) appears more than once in any component or in Formula I, the definition of that substituent in each appearance is independent of the definition of that substituent in all other appearances, unless otherwise specified at the time of the definition. Those skilled in the art will know that various substituents (i.e., R) as defined in the structural representation are independent of the definition of that substituent in all other appearances. 1 , R 2It will be recognized that the selection of combinations (such as) should be made in accordance with well-known principles of bonding and stability of chemical structures, and that combinations of substituents and / or variable parts are only permissible if such combinations result in a stable compound.

[0048] A “stable” compound is one that can be prepared and isolated, and whose structure and properties remain essentially unchanged or can be kept essentially unchanged for a period of time sufficient to enable the compound to be used for the purposes described herein (e.g., therapeutic administration to a subject). The compounds of the present invention are limited to stable compounds encompassed by Formula I.

[0049] Any variable part or substructure is in the form of a range (e.g., (-CH) 2- ) 1-4 When expressed as ), it includes not only the two extremes of the specified range (i.e., 1 and 4 in the example above), but also all integer values ​​in between (i.e., 2 and 3 in the example above).

[0050] Unless otherwise indicated, it is understood that references to "Formula I" also include compounds represented by Formulas IA, IB, and IC.

[0051] Where used herein, “alkyl” is intended to encompass both branched and linear saturated aliphatic hydrocarbon groups having a specified number of carbon atoms.

[0052] As used herein, "halogen" or "halo" means fluoro, chloro, bromo, and iodine.

[0053] Where used herein, “cycloalkyl” is intended to encompass a cyclic saturated aliphatic hydrocarbon group having a specified number of carbon atoms. Preferably, the cycloalkyl is C3-C 10It is a cycloalkyl compound. Examples of such cycloalkyl compounds include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0054] As used herein, “aryl” is intended to mean any stable monocyclic or bicyclic carbocyclic ring with up to seven members in each ring, wherein at least one ring is aromatic. Examples of such aryl components include phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl, or acenaphthyl. In one embodiment of the present invention, the aryl is phenyl or naphthyl. In a further embodiment, the aryl is phenyl.

[0055] The terms “heterocyclyl,” “heterocycle,” or “heterocyclic formula,” as used herein, refer to a stable 5-7 membered monocyclic heterocyclic ring or a stable 8-11 membered bicyclic heterocyclic ring, which is either saturated or unsaturated and consists of a carbon atom and 1-4 heteroatoms selected from the group consisting of N, O, and S, and encompass any bicyclic group formed by the condensation of any of the above-defined heterocyclic rings to a benzene ring. The heterocyclic ring may be bonded with any heteroatoms or carbon atoms resulting in a stable structure. The terms “heterocyclyl,” “heterocycle,” or “heterocyclic formula” may include a heteroaryl moiety when two rings are condensed with each other. Examples of heterocyclic components include, but are not limited to, azabicyclo[2.2.1]heptanil, azepanil, azetidinil, benzodioxolyl, chromanil, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranil, dihydrobenzothiopyranylsulfone, dihydro-pyrrolo[1,2-b]pyrazolyl, 1,3-dioxolanil, imidazolidinil, indolinil, isochromanil, isoindolinil, morpholinil, oxa-5-azabicyclo[2.2.1]heptanil, 2-oxopiperazinil, 2-oxopiperidinil, 2-oxopyrrolidinil, piperidyl, piperazinil, pyrazolidinil, pyrrolidinil, tetrahydrofuryl, tetrahydroisoquinolinil, tetrahydroquinolinil, and thiamorpholinil.

[0056] In one embodiment, the heterocyclil is selected from azabicyclo[2.2.1]heptanil, azepanil, azetidinil, dihydro-pyrrolo[1,2-b]pyrazolyl, morpholinil, oxa-5-azabicyclo[2.2.1]heptanil, piperidyl, piperazinil, pyrazolidinil, pyrrolidinil, pyrrolyl, and tetrahydrofuryl. In another embodiment, the heterocyclil is selected from azabicyclo[2.2.1]heptanil, azepanil, azetidinil, dihydro-pyrrolo[1,2-b]pyrazolyl, oxa-5-azabicyclo[2.2.1]heptanil, piperazinil, and pyrrolidinil.

[0057] The term "heteroaryl" is intended to mean any stable monocyclic or bicyclic carbocyclic ring with up to seven members in each ring, where at least one ring is aromatic and 1 to 4 carbon atoms are replaced by heteroatoms selected from the group consisting of N, O, and S. Examples of such heterocyclic components include, but are not limited to, azepinyl, furanyl, furyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoxazolyl, isoquinolinyl, isothiazolyl, naphthylidinyl, oxazolyl, oxadiazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyridadinyl, pyrimidinyl, 5H-pyrrolo[2,3-b]pyrazine, pyrrolyl, quinazolinyl, quinolinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, thiazolyl, thienofuryl, thienothienyl, thienyl, triazinyl, and triazolyl. In one embodiment, the heteroaryl is selected from furyl, imidazolyl, indolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridadinyl, pyrimidinyl, 5H-pyrrolo[2,3-b]pyradinyl, tetrazolyl, thiazolyl, thienyl, triazinyl, triazolyl, and the like.

[0058] When used in pharmaceuticals, salts of the compound represented by formula I are pharmaceutically acceptable salts. However, other salts may also be useful in the preparation of the compound or its pharmaceutically acceptable salt according to the present invention. When the compound of the present invention is acidic, a suitable "pharmaceutically acceptable salt" refers to a salt prepared from pharmaceutically acceptable, non-toxic bases, including inorganic and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganese salts, manganese, potassium, sodium, and zinc. Particularly preferred are ammonium salts, calcium salts, magnesium salts, potassium salts, and sodium salts. Salts derived from pharmaceutically acceptable, non-toxic organic bases include salts of primary, secondary, and tertiary amines, salts of substituted amines (including naturally occurring substituted amines), salts of cyclic amines, and basic ion exchange resins (e.g., arginine, betaine, caffeine, choline, N,N). 1 Examples include salts of dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydravamin, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc.

[0059] When the compound of the present invention is basic, the salt can be prepared from pharmaceutically acceptable, non-toxic acids, including inorganic and organic acids. Such acids include acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucoic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, and p-toluenesulfonic acid. Particularly preferred are citric acid, hydrobromic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid, and tartaric acid.

[0060] The preparation of the pharmaceutically acceptable salts described above and other typical pharmaceutically acceptable salts is described in more detail by Berg et al., “Pharmaceutical Salts,” J. Pharm. Sci., 1977:66:1-19.

[0061] When a compound represented by formula I contains both an acidic group and a basic group within its molecule, the present invention also includes zwitterions in addition to the salt forms described above.

[0062] The present invention further encompasses isotope-labeled compounds of the present invention that are structurally identical to those described herein, except that a statistically significant proportion of one or more atoms in the compound in its form are replaced by atoms having a different atomic mass or mass number than the most abundant isotope commonly found in nature, and therefore the naturally occurring amount of that isotope present in the compound of the present invention is altered. Another aspect of the present invention relates to the use of isotope-labeled compounds as neuroimaging radiotracers for in vivo imaging of the brain with respect to α-synuclein aggregates in the diagnosis, monitoring, and / or treatment of Parkinson's disease (PD). Another aspect of the present invention relates to the use of isotope-labeled compounds in PET, an in vivo analytical technique in the diagnosis, monitoring, and / or treatment of PD. 3 H, 11 C or 18 Compounds labeled with F can be used in in vitro and in vivo methods for measuring binding, receptor occupancy, and metabolic studies, including covalent labeling.

[0063] Another aspect of the present invention relates to the use of isotope-labeled compounds for screening new chemical substances. In particular, various isotope-labeled compounds find usefulness in magnetic resonance imaging, autoradiography, and other similar analytical tools. The present invention is intended to encompass all suitable isotope variants of the compound represented by formula I. Examples of isotopes that can be preferentially incorporated into the compounds of the present invention include, but are not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, iodine, fluorine, and chlorine. 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 18 F, 35 S, 36 Cl, 82 Br, 76 Br, 77 Br, 123 I, 124 I, 125 I or 131 Examples include substituted heterocyclic derivatives represented by formula I, which are isotope-labeled with I. It should be understood that other isotopes can also be incorporated by known means. In particular, the present invention relates to compounds represented by formula I. 11 C, 13 C, 14 C, 18 F, 15 O, 13 N, 35 S, 2 H and 3 The present invention relates to 1H isotopes, compositions, methods for preparing them, and their use as radiotracers or PET tracers in the diagnosis and measurement of the effects of compounds in the treatment of PD. In further embodiments, the present invention relates to 3 H, 11 C or 18The present invention relates to compounds represented by formula I, isotope-labeled with 1F, as well as compositions and methods for preparing them, and their use as PET tracers in the diagnosis and measurement of the effects of compounds in the treatment of PD. The present invention also relates to non-toxic α-synuclein protein-binding compounds that can rapidly cross the blood-brain barrier, have low nonspecific binding characteristics, and are rapidly removed from the system. This and other aspects of the present invention will be understood by examining the entire specification.

[0064] The isotope-enriched compounds contained in Formula I can be prepared without excessive experimentation by conventional techniques well known to those skilled in the art, or by processes similar to those described in the schemes and examples herein, using suitable isotope-enriched reagents and / or intermediates.

[0065] As described herein, the present invention encompasses the isotope-labeled compounds of the present invention. An “isotope-labeled” compound, a “radio-labeled” compound, a “tracer” compound, a “radio-tracer” compound, a “labeled tracer” compound, or a “radio-ligand” compound is a compound in which one or more atoms are replaced or substituted by atoms having atomic masses or mass numbers different from those commonly found in nature (i.e., naturally occurring). Suitable radionuclides (i.e., “detectable isotopes”) that can be incorporated into the compounds of the present invention include, but are not limited to, 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 18 F, 35 S, 36 Cl, 82 Br, 76 Br, 77 Br, 123 I, 124 I and 131Examples include I. The isotope-labeled compounds of the present invention are only required to be enriched with detectable isotopes to a degree or beyond that allows detection by techniques suitable for a particular application. The radionuclides incorporated into the radiolabeled compounds of the present invention depend on the specific application of the radiolabeled compound. In another embodiment of the present invention, the radionuclides are, 11 C, 13 C, 14 C, 18 F, 15 O, 13 N, 35 S, 2 H and 3 Represented by H, preferably, 11 C, 3 H and 18 It is represented by F.

[0066] The isotope-labeled compounds of the present invention are prepared by incorporating a selected isotope into a substrate molecule. This is achieved by using a reagent in which one or more atoms contained in the reagent have been radioactive, by placing the reagent in a radioactive source such as a nuclear reactor or cyclotron. Furthermore, 2 H2O, 3 H3CI, 14 C6H5Br, ClCH2 14 Many isotope-labeling reagents, such as COCl, are commercially available. Then, using standard organic chemical synthesis techniques, the isotope atoms are incorporated into the compound represented by formula I. The following scheme illustrates a method for producing the compound represented by formula I.

[0067] The present invention further relates to a pharmaceutical composition comprising an effective amount of at least one compound represented by formula I and a pharmaceutically acceptable carrier. The composition may, but is not limited to, contain one or more buffers, wetting agents, emulsifiers, suspending agents, lubricants, adsorbents, surfactants, preservatives, and the like. The composition may be formulated as a solid, liquid, gel, or suspension for oral administration (e.g., drench agents, bolus agents, tablets, powders, capsules, mouth sprays, emulsions), parenteral administration (e.g., subcutaneous injection, intramuscular injection, intravenous injection, epidural injection), topical application (e.g., creams, ointments, controlled-release patches, sprays), vaginal administration, rectal administration, transdermal administration, intraocular administration, or intranasal administration. In further embodiments, the pharmaceutical composition of the present invention may be formulated for parenteral administration (e.g., intravenous formulations).

[0068] The present invention provides radiolabeled compounds represented by formula I as α-synuclein imaging agents and synthetic precursor compounds for preparing them. The compounds represented by formula I bind to aggregated α-synuclein and potentially track the progression of age-related diseases such as PD, as well as other synucleinopathy and neurodegenerative diseases such as multiple system atrophy (MSA) and Lewy body dementia (DLB). The compounds of the present invention can also be used in combination with a wide range of cognitive deficit enhancement agents. Accordingly, in another embodiment of the present invention, a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or preparation containing a compound represented by formula (I), is administered concurrently, simultaneously, sequentially, or separately with another pharmaceutically active compound used in the treatment of AD / PD (which includes, for example, donepezil, memantine, tacrine, carbidopa, levodopa, MOA-B inhibitors, catechol O-methyltransferase (COMT) inhibitors, etc.) and their equivalents, pharmaceutically active isomers, and metabolites.

[0069] The object of the present invention is to provide a radiopharmaceutical agent (for example, an isotope-labeled compound represented by formula I) that is useful in α-synuclein imaging and has high specific radioactivity and high target tissue selectivity due to its high affinity for α-synuclein aggregates.

[0070] According to the present invention, a method for imaging α-synuclein deposits in a patient (where an isotope-labeled compound represented by formula I is used as the imaging agent) comprises the following steps: (a) positioning a human patient in a supine position inside a PET camera; (b) intravenously administering approximately 0.1 to approximately 10 mCi of the isotope-labeled compound represented by formula I to the patient; and (c) performing a radiographic scan of the cerebral region of the patient's head to identify α-synuclein aggregation in the patient's brain tissue. Techniques for performing radiographic scans of the head are well known to those skilled in the art. PET techniques are described in: Freeman et al., Freeman and Johnson's Clinical Radionuclide Imaging, 3rd. Ed. Vol. 1 (1984); Grune & Stratton, New York; Ennis et Q. Vascular Radionuclide Imaging: A Clinical Atlas, John Wiley & Sons, New York (1983).

[0071] The term “labeled tracer” refers to any molecule that can be used to track or detect defined activity in vivo. For example, a preferred tracer is one that accumulates in a region where α-synuclein aggregates may be found. Preferably, the labeled tracer is one that can be seen, for example, by positron emission tomography (PET) scans in living experimental animals, healthy humans, or patients (also referred to as subjects). Suitable labels include, but are not limited to, radioisotopes, fluorescent dyes, chemiluminescent compounds, pigments, and proteins (including enzymes).

[0072] The present invention also provides a method for confirming the in vivo activity of an enzyme or other molecule. In one embodiment, an isotope-labeled compound represented by formula I is used as a tracer to track the binding activity of aggregated α-synuclein protein in the brain and central nervous system.

[0073] Biomarkers of Parkinson's disease symptoms, prognosis, and progression are all useful not only for general diagnostic purposes but also for the clinical development planning of Parkinson's disease treatments. The compound represented by Formula I can be used to provide biomarker information to patients in clinical trials of novel symptomatic and disease-modifying Parkinson's disease therapies, and to assist in patient selection and cohort allocation. The present invention serves as one of the disease status biomarkers for enrolling eligible patients into appropriate PhIIb trial cohorts. In addition, the present invention can serve as one of the disease prognosis markers as an entry inclusion criterion to increase the probability of disease progression in the placebo group, a problem that has continued to plague Parkinson's disease clinical trials. Finally, the present invention can serve as one of the disease progression biomarkers for monitoring the clinical course of patients during treatment and can provide an independent biomarker index of therapeutic response to therapeutic drugs. The tracer can be selected according to a chosen detection method. Before carrying out the method of the present invention, a diagnostically effective amount of the labeled or unlabeled compound of the present invention is administered to a living organism (this includes humans).

[0074] The present invention also provides a method for measuring the clinical efficacy of a therapeutic agent useful for treating Parkinson's disease (PD), comprising the following steps: (a) administering an isotope-labeled compound represented by formula I to a patient diagnosed with PD before treatment with the therapeutic agent; (b) measuring the amount of α-synuclein aggregates formed in the patient's brain tissue; (c) administering an isotope-labeled compound represented by formula I to the patient after treatment with the therapeutic agent; (d) measuring the amount of α-synuclein aggregates formed in the patient's brain tissue after treatment; and (e) analyzing whether the therapeutic agent stopped or reduced the progression of α-synuclein aggregate formation in the patient's brain tissue.

[0075] The diagnostically effective amount of the labeled or unlabeled compound of the present invention to be administered before performing the in vivo procedure of the present invention is in the range of 0.1 ng to 100 mg per kg of body weight, preferably in the range of 1 ng to 10 mg per kg of body weight.

[0076] The compounds of the present invention are useful in the diagnosis, monitoring, and measurement of Parkinson's disease and other non-PD synuclein disorders (e.g., multiple system atrophy (MSA), Lewy body dementia (DLB), etc.).

[0077] In preferred embodiments, the compounds of the present invention are useful in the diagnosis, monitoring, or measurement of Parkinson's disease, non-PD synucleinopathy, neurodegenerative diseases, cognitive impairment, schizophrenia, pain disorders, and sleep disorders.

[0078] As used herein, the term “composition” is intended to encompass products containing specific components in predetermined amounts or proportions, and any products obtained directly or indirectly from specific combinations of specific components. In relation to pharmaceutical compositions, the term is intended to encompass products containing one or more active components and, if they constitute a support, inert components, and any products obtained directly or indirectly from any combination of two or more components, from complex formation or aggregation, from the dissociation of one or more components, or from another type of reaction or interaction of one or more components.

[0079] Generally, the pharmaceutical composition is prepared by uniformly and tightly combining the active ingredient with a liquid carrier, a micronized solid carrier, or both, and then, if necessary, molding the product into a desired formulation. In the pharmaceutical composition, the active compound (which is the compound represented by formula I) is present in an amount sufficient to produce a desired effect on the disease process or condition. Accordingly, the pharmaceutical compositions of the present invention encompass any composition produced by mixing the compound of the present invention with a pharmaceutically acceptable carrier.

[0080] Where used herein, “patient” (or alternatively, “subject”) refers to an animal, preferably a mammal, in particular a human, that requires evaluation via imaging studies. Where used herein, the terms “administer” and its variation (e.g., “administer” the compound) relating to the compound represented by Formula I mean providing the compound or a pharmaceutically acceptable salt thereof to a subject in need of treatment.

[0081] The present invention further provides a method for synthesizing compounds useful as intermediates in the preparation of the compounds of the present invention.

[0082] The compounds described herein can be prepared using appropriate materials and following the procedures of the following schemes and examples, and are further illustrated by the following specific examples. Deuterated versions of the compounds of the present invention can be prepared by replacing the non-isotope-labeled reagent with a suitable isotope-labeled reagent. However, the compounds illustrated in the examples should not be construed as forming the only genus considered as part of the present invention. The examples further illustrate details for the preparation of the compounds of the present invention. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparation procedures can be used to prepare these compounds. Reagents and starting materials for preparing intermediates and exemplary compounds are commercially available unless otherwise indicated. All temperatures are in degrees Celsius unless otherwise indicated. Mass spectra (MS) were measured by electrospray ion mass spectrometry (ESI). 1 1H NMR spectra were recorded at 300-500 MHz. [Table 2] TIFF2026509241000021.tif244170 The compounds described herein were synthesized as racemic mixtures unless otherwise indicated in the experimental procedure. The final product may be further modified, for example, by manipulating substituents. These manipulatives may include, but are not limited to, reduction, oxidation, alkylation, acylation, and hydrolysis reactions, which are generally known to those skilled in the art. The order in which the above reaction schemes are carried out may be changed to accelerate the reaction or avoid undesirable reaction products. The following schemes and examples are provided to allow for a better understanding of the present invention. These examples are merely illustrative and should not be construed as limiting the present invention.

[0083] General Scheme A [ka] Substitutive piperazine ( A-1 ) are heteroarylpiperazines or arylpiperazines obtained by a SNAr or Pd-mediated CN coupling reaction. A-2 It can be converted to an intermediate by deprotection followed by Pd-mediated CN coupling or SNAr coupling with a heteroaryl or aryl halogenate. A-3 This is obtained. By Suzuki coupling using vinyl equivalents, an intermediate is obtained. A-4 This can be obtained, and subsequently, by Heck coupling with a halogenated heteroaryl or halogenated aryl, the target molecule can be obtained. A-5 You can obtain this.

[0084] General Scheme B [ka] Substitutive piperazine ( B-1 ) are heteroarylpiperazines or arylpiperazines obtained by a SNAr or Pd-mediated CN coupling reaction. B-2 It can be converted to an intermediate by deprotection followed by Pd-mediated CN coupling or SNAr coupling with a heteroaryl or aryl halogenate. B-3 The target molecule is obtained by Heck coupling or Suzuki coupling with a substituted vinylized aromatic motif. B-4 You can obtain this.

[0085] General scheme C [ka] Substitutive piperazine ( C-1 ) are heteroarylpiperazines or arylpiperazines obtained by a SNAr or Pd-mediated CN coupling reaction. C-2 It can be converted to an intermediate by Heck coupling with a substituted vinylized aromatic motif. C-3The target molecule is obtained through deprotection followed by a SNAr or Pd-mediated CN coupling reaction. C-4 You can obtain this.

[0086] General Scheme D [ka] Substitutive piperazine ( D-1 ) are heteroarylpiperazines or arylpiperazines obtained by a SNAr or Pd-mediated CN coupling reaction. D-2 It can be converted to an intermediate by deprotection followed by Pd-mediated CN coupling or SNAr coupling with a heteroaryl or aryl halogenate. D-3 An intermediate is obtained by converting the aldehyde to an alkyne. D-4 This allows us to obtain the target molecule through subsequent Sonogoshira coupling with a heteroaryl halide or aryl halide. D-5 You can obtain this.

[0087] General scheme E [ka] Substitutive piperazine ( E-1 ) are heteroarylpiperazines or arylpiperazines obtained by a SNAr or Pd-mediated CN coupling reaction. E-2 It can be converted to an intermediate by converting an aldehyde to an alkyne. E-3 This can be obtained by Sonogoshira coupling with heteroaryl halides or aryl halides, which yields an intermediate. E-4 This can generate the target molecule through deprotection followed by a SNAr or Pd-mediated CN coupling reaction. E-5 You can obtain this.

[0088] General scheme F [ka] Substitutive piperazine ( F-1 ) are heteroarylpiperazines or arylpiperazines obtained by a SNAr or Pd-mediated CN coupling reaction. F-2 It can be converted to an intermediate by Sonogoshira coupling with a substituted acetylated aromatic motif. F-3 The target molecule is obtained through deprotection followed by a SNAr or Pd-mediated CN coupling reaction. F-4 You can obtain this.

[0089] General scheme G [ka] Substitutive piperazine ( G-1 ) are heteroarylpiperazines or arylpiperazines obtained by a SNAr or Pd-mediated CN coupling reaction. G-2 It can be converted to an intermediate by deprotection followed by Pd-mediated CN coupling or SNAr coupling with a heteroaryl or aryl halogenate. B-3 The target molecule is obtained through Sonogoshira coupling with a substituted acetylated aromatic motif. B-4 You can obtain this.

[0090] Preparation of intermediates Synthesis of intermediate A: 2-(1H-imidazole-1-yl)-5-vinylpyridine [ka] 1-1A solution of (40 g, 179 mmol) was dissolved in 1,4-dioxane (300 mL) and water (300 mL). Cesium carbonate (174 g, 536 mmol) was added at room temperature, and the mixture was degassed with argon for 20 minutes. Potassium vinyl trifluoroborate (35.9 g, 268 mmol) and dichlorobis(triphenylphosphine)palladium(II) (6.27 g, 8.93 mmol) were then added to the reaction mixture at room temperature. The resulting reaction mixture was stirred at 100 °C for 16 hours. The reaction mixture was quenched with water (500 mL) and extracted with pharmaceutically acceptable phosphate (2 × 500 mL). The organic layers were combined and washed with brine (500 mL), dehydrated with sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude compound was purified by silica gel column chromatography (100-200 mesh), and the compound was eluted using a gradient of 60% ethyl acetate in petroleum ether. The pure fraction was concentrated under reduced pressure. Int A This was obtained.

[0091] M / Z (ESI): 171.96 [M+H] + . Synthesis of intermediate B: (R)-(4-(5-bromopyrimidine-2-yl)-1-(pyrimidine-2-yl)piperazine-2-yl)methanol [ka] Synthesis of 2-2: tert-butyl (R)-3-(hydroxymethyl)-4-(pyrimidine-2-yl)piperazine-1-carboxylate 2-1 A solution of (15 g, 69.4 mmol) dissolved in NMP (150 mL) was stirred, and K2CO3 (19.17 g, 139 mmol) and 2-chloropyrimidine (7.94 g, 69.4 mmol) were added at room temperature. The reaction mixture was stirred at 80°C for 24 hours under a nitrogen atmosphere. The reaction mixture was quenched with ice-cold water (200 mL) and extracted with SiO2 (3 × 200 mL). The organic layers were combined and washed with ice-cold water (100 mL) and brine (100 mL), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by column chromatography using (100-200 mesh) silica gel, and the compound was eluted using a 50% SiO2 gradient in petroleum ether. The pure fraction was concentrated under reduced pressure. 2-2 This was obtained.

[0092] M / Z (ESI): 295.16 [M+H] + . Synthesis of 2-3: (R)-(1-(pyrimidine-2-yl)piperazin-2-yl)methanol 2-2 (9 g, 30.6 mmol) was dissolved in DCM (45 mL), and while stirring, 4N HCl (38.2 mL, 153 mmol) in 1,4-dioxane was added at 0°C. The reaction mixture was stirred under a nitrogen atmosphere at 25°C for 16 hours. The reaction mixture was concentrated under reduced pressure. The crude compound was ground with diethyl ether (20 mL). The resulting solid was filtered and dried under reduced pressure. 2-3 This was obtained.

[0093] M / Z (ESI): 195.06 [M+H] + . Synthesis of Int B: (R)-(4-(5-bromopyrimidine-2-yl)-1-(pyrimidine-2-yl)piperazine-2-yl)methanol 2-3 A solution of (3g, 13.00 mmol) dissolved in NMP (30 mL) was stirred, and K2CO3 (7.19 g, 52.0 mmol) and 5-bromo-2-chloropyrimidine (2.52 g, 13.00 mmol) were added at room temperature. The reaction mixture was stirred at 80°C for 16 hours under a nitrogen atmosphere. The reaction mixture was quenched with ice-cold water (100 mL) and extracted with SiO2 (3 × 100 mL). The organic layers were combined and washed with ice-cold water (100 mL) and brine (100 mL), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by column chromatography using (100-200 mesh) silica, and the compound was eluted using a 50% SiO2 gradient in petroleum ether. The pure fraction was concentrated under reduced pressure, and the resulting compound was further purified by Prep HPLC (conditions: mobile phase - 10 mM ammonium bicarbonate in H2O: MeCN, column - X-Bridge C18 (19×250) mm 5 μm, flow rate - 18 mL / min, gradient method - 0 / 45, 4 / 50, 10.5 / 50, 10.6 / 100, 11.9 / 100, 12 / 45, 15 / 45). The pure fraction was concentrated under reduced pressure and lyophilized. Int B This was obtained.

[0094] M / Z (ESI): 351.23 [M+H] + . Synthesis of intermediate C: (R)-5-bromo-2-(3-(methoxymethyl)-4-(pyrimidine-2-yl)piperazine-1-yl)pyrimidine [ka] Synthesis of 3-2: tert-butyl (R)-3-(hydroxymethyl)-4-(pyrimidine-2-yl)piperazine-1-carboxylate 3-1 (1 g, 4.62 mmol) was dissolved in dioxane (16 mL), and the solution was degassed with argon. Sodium tert-butoxide (1.333 g, 13.87 mmol), [(2-di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (BrettPhos Pd G3) (0.210 g, 0.231 mmol), and 2-bromopyrimidine (0.882 g, 5.55 mmol) were added at room temperature. The reaction mixture was stirred at 100 °C for 12 hours. The reaction mixture was quenched with ice water and extracted with ethyl acetate (50 mL x 2). The organic layers were combined, washed with brine solution, dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude compound was purified by 100 × 200 silica gel Biotage flash column chromatography (using 50% siRNA / petroleum ether as the eluent). The pure fraction was concentrated under reduced pressure to obtain the compound. 3-2 This was obtained.

[0095] M / Z (ESI): 295.19 [M+H] + . Synthesis of 3-3: tert-butyl (R)-3-(methoxymethyl)-4-(pyrimidine-2-yl)piperazine-1-carboxylate compound 3-2A solution of (800 mg, 2.72 mmol) dissolved in DMF (10 mL) was stirred, and methyl iodide (1929 mg, 13.59 mmol) and sodium hydride (98 mg, 4.08 mmol) were added at room temperature. The reaction mixture was stirred at 0°C for 2 hours. The reaction mixture was quenched with ice water and extracted with dimethyl phosphate (10 mL x 2). The organic layers were combined, washed with brine solution, dehydrated with anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to extract the compound. 3-3 This was obtained.

[0096] M / Z (ESI): 309.19 [M+H] + . Synthesis of 3-4: (R)-2-(2-(methoxymethyl)piperazin-1-yl)pyrimidine compound 3-3 A solution of (800 mg, 2.59 mmol) dissolved in DCM (9 mL) was stirred, and 4 M HCl (646 mg, 5.19 mmol) in 1,4-dioxane was added at 0°C and stirred at 25°C for 2 hours. The reaction mixture was evaporated under reduced pressure, co-distilled with toluene, washed with pentane, dried, and the compound was extracted. 3-4 This was obtained.

[0097] M / Z (ESI): 209.19 [M+H] + . Synthesis of Int C: (R)-5-bromo-2-(3-(methoxymethyl)-4-(pyrimidine-2-yl)piperazine-1-yl)pyrimidine compound 3-4 A solution of (700 mg, 2.86 mmol) dissolved in DMF (10 mL) was stirred, and potassium carbonate (0.813 mL, 14.30 mmol) was added at 0°C, followed by 5-bromo-2-fluoropyrimidine (607 mg, 3.43 mmol). The reaction mixture was stirred at 80°C for 12 hours. The reaction mixture was quenched with ice water, the resulting solid was filtered, and dried under reduced pressure to obtain the compound. Int C This was obtained.

[0098] M / Z (ESI): 365.06 [M+H] + . Synthesis of intermediate D: (R)-2-(3-(methoxymethyl)-4-(pyrimidine-2-yl)piperazine-1-yl)-5-vinylpyrimidine [ka] Int C A solution of (10 g, 27.4 mmol) was dissolved in 1,4-dioxane (80 mL) and water (14 mL). While stirring, Cs2CO3 (17.84 g, 54.8 mmol) and potassium vinyl trifluoroborate (7.33 g, 54.8 mmol) were added at room temperature, and the mixture was degassed with argon gas for 15 minutes. Next, PdCl2(dppf)-CH2Cl2 adduct (2.236 g, 2.74 mmol) was added to the reaction mixture at room temperature, and the resulting reaction mixture was stirred in a sealed tube under a nitrogen atmosphere at 100°C for 16 hours. The reaction mixture was quenched with water (50 mL) and extracted with SiO2 (2 × 200 mL). The organic layers were combined and washed with brine (50 mL), dehydrated with anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude compound was purified by column chromatography using silica gel (100-200 mesh), and the compound was eluted using a 30% siRNA gradient in petroleum ether. The pure fraction was concentrated under reduced pressure. Int D This was obtained.

[0099] M / Z (ESI): 313.63 [M+H] + . Synthesis of intermediate E: (R,E)-5-(2-(6-(1H-imidazole-1-yl)pyridine-3-yl)vinyl)-2-(3-(methoxymethyl)piperazine-1-yl)pyrimidine [ka] Synthesis of 4-2: tert-butyl (R)-4-(5-bromopyrimidine-2-yl)-2-(hydroxymethyl)piperazine-1-carboxylate tert-butyl 4-1A solution of (25 g, 116 mmol) and 5-bromo-2-chloropyrimidine (26.8 g, 139 mmol) was dissolved in DMF (250 mL). While stirring, K2CO3 (39.9 g, 289 mmol) was added at room temperature. The reaction mixture was stirred at 80 °C for 2 hours. The reaction mixture was diluted with ice water (100 mL) and extracted with siRNA (2 × 200 mL). The organic layers were combined and washed with brine solution (50 mL), dehydrated with anhydrous Na2SO4, filtered, dried, and concentrated under reduced pressure to obtain the crude compound. The crude compound was purified by silica column chromatography and eluted using 20% ​​siRNA in petroleum ether as a gradient. The pure fraction was concentrated under reduced pressure to obtain the compound. 4-2 This was obtained.

[0100] M / Z (ESI): 373.19 [M+H] + . Synthesis of 4-3: tert-butyl (R)-4-(5-bromopyrimidine-2-yl)-2-(methoxymethyl)piperazine-1-carboxylate compound 4-2 A solution of (25 g, 67.0 mmol) dissolved in DMF (250 mL) was stirred, and MeI (20.94 mL, 335 mmol) and NaH (5.36 g, 134 mmol) were added at 0°C. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (100 mL) and extracted with siRNA (2 × 200 mL). The organic layers were combined, washed with brine solution (50 mL), dehydrated with anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude compound. The crude compound was purified by silica column chromatography and eluted using 15% siRNA in petroleum ether as a gradient. The pure fraction was concentrated under reduced pressure to obtain the compound. 4-3 This was obtained.

[0101] M / Z (ESI): 387.14 [M+H] + . Synthesis of 4-4: tert-butyl (R,E)-4-(5-(2-(6-(1H-imidazole-1-yl)pyridine-3-yl)vinyl)pyrimidine-2-yl)-2-(methoxymethyl)piperazine-1-carboxylate compound 4-3 (1g, 2.58 mmol) was dissolved in toluene (10 mL) and the solution was stirred while adding the compound Int A(0.442 g, 2.58 mmol) and DIPEA (1.353 mL, 7.75 mmol) were added at room temperature, and the mixture was degassed with argon gas for 10 minutes. Subsequently, under a nitrogen atmosphere, Pd2(dba)3 (0.118 g, 0.129 mmol) and tri-tert-butylphosphonium tetrafluoroborate (0.075 g, 0.258 mmol) were added. The resulting reaction mixture was stirred at 120°C for 16 hours. The reaction mixture was filtered through a Celite pad, diluted with water (5 mL), and extracted with siRNA (2 × 10 mL). The organic layers were combined and washed with brine solution (5 mL), dehydrated with anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude compound. The crude compound was purified by silica column chromatography and eluted using a 5% MeOH gradient in DCM. The pure fraction was concentrated under reduced pressure to obtain the compound. 4-4 This was obtained.

[0102] M / Z (ESI): 478.35 [M+H] + . Synthesis of Int E: (R,E)-5-(2-(6-(1H-imidazole-1-yl)pyridine-3-yl)vinyl)-2-(3-(methoxymethyl)piperazine-1-yl)pyrimidine compound 4-4 A solution of (400 mg, 0.838 mmol) dissolved in DCM (5 mL) was stirred, and 4 M HCl (0.419 mL, 1.675 mmol) in 1,4-dioxane was added at 0°C. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the compound was extracted. Int E This was obtained.

[0103] M / Z (ESI): 378.23 [M+H] + . Synthesis of intermediate F: (R)-2-(2-(methoxymethyl)-4-(pyridine-2-yl)piperazine-1-yl)-5-vinylpyrimidine [ka] Synthesis of 5-2: tert-butyl (R)-2-(methoxymethyl)-4-(pyridine-2-yl)piperazine-1-carboxylate 5-1A solution of (1.50 g, 6.51 mmol) dissolved in toluene (60 mL) was stirred and purged with nitrogen for 10 minutes. 2-bromopyridine (0.932 mL, 9.77 mmol), sodium tert-butoxide (1.565 g, 16.28 mmol), and chloro(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (RuPhos Pd G2) (0.506 g, 0.651 mmol) were added, and the mixture was heated at 110°C with stirring for 18 hours. The reaction mixture was filtered through a Celite pad and washed with ELISA (3 × 20 mL). The filtrate was concentrated and purified by flash column chromatography (120 g Isco Gold column) using hexane:siRNA 100:0 → 50:50. The desired fraction was concentrated and the compound was purified. 5-2 This was obtained.

[0104] M / Z (ESI): 308.0 [M+H] + . Synthesis of 5-3: (R)-3-(methoxymethyl)-1-(pyridine-2-yl)piperazine hydrochloride 5-2 (1.97 g, 6.41 mmol) was dissolved in dichloromethane (5 mL) and MeOH (1 mL) to a solution, to which 4 M HCl (4.81 mL, 19.23 mmol) from dioxane was added, and the reaction mixture was aged at ambient temperature for 2 hours. The reaction mixture was evaporated under reduced pressure and dried under high vacuum to obtain the compound. 5-3 This was obtained.

[0105] M / Z (ESI): 208.0 [M+H] + Synthesis of 5-4: (R)-5-bromo-2-(2-(methoxymethyl)-4-(pyridine-2-yl)piperazine-1-yl)pyrimidine 5-3A solution of (1.86 g, 6.64 mmol), 5-bromo-2-fluoropyrimidine (2.350 g, 13.28 mmol), and potassium carbonate (2.75 g, 19.91 mmol) dissolved in DMF (25 mL) was heated at 70°C for 18 hours. The mixture was diluted with water (75 mL) and then extracted with Et2O (3 × 30 mL). The organic layers were combined, dehydrated with Na2SO4, filtered, and concentrated. The crude product was purified by flash column chromatography (120 g Isco Gold column) using hexane:siRNA 100:0 → 40:60 to obtain compound 5-4 This was obtained.

[0106] M / Z (ESI): 364.2, 366.2 [M+H] + . Synthesis of Int F: (R)-2-(2-(methoxymethyl)-4-(pyridine-2-yl)piperazine-1-yl)-5-vinylpyrimidine 5-4 A solution of (1.30 g, 3.57 mmol) potassium vinyl trifluoroborate (0.717 g, 5.35 mmol), cesium carbonate (3.49 g, 10.71 mmol), and dichlorobis(triphenylphosphine)palladium(II) (0.125 g, 0.178 mmol) dissolved in dioxane (13.38 mL) was purged with nitrogen and heated at 100 °C for 21 hours. The mixture was diluted with water (30 mL) and then extracted with pharmaceutically acceptable phosphate (3 × 30 mL). The organic layers were combined, dehydrated with Na₂SO₄, filtered, and concentrated. The crude product was purified by flash column chromatography (120 g Isco Gold column) using hexane:HCl 100:0 → 50:50 elution to obtain the compound. Int F This was obtained.

[0107] M / Z (ESI): 312.2 [M+H] + . Synthesis of intermediate G: ((E)-(2-(6-(1H-imidazole-1-yl)pyridine-3-yl)vinyl)boronic acid [ka] 5-bromo-2-(1H-imidazole-1-yl)pyridine ( 1-1A solution of (1.00 g, 4.46 mmol) and TEA (1.24 mL, 8.93 mmol) dissolved in toluene (44.6 mL) was purged with nitrogen for 15 minutes. Pinacol vinylboronic acid (1.14 mL, 6.69 mmol) and bis(tri-t-butylphosphine)palladium (0) (0.114 g, 0.223 mmol) were added, and the mixture was heated at 110°C for 16 hours. The mixture was filtered through a Celite pad, concentrated, and purified by flash column chromatography (40 g Isco Gold column) using hexane:SiO / EtOH (3:1) 100:0 → 0:100 to extract the compound. Int G This was obtained.

[0108] M / Z (ESI): 216.1 [M+H] + Synthesis of intermediate H: (R,E)-5-(2-(6-(1H-imidazole-1-yl)pyridine-3-yl)vinyl)-2-(2-((2-methoxyethoxy)methyl)piperazine-1-yl)pyrimidine dihydrochloride [ka] Synthesis of 6-2: tert-butyl (R)-4-(5-bromopyrimidine-2-yl)-3-(hydroxymethyl)piperazine-1-carboxylate 6-1 A solution of (2.74 g, 12.66 mmol) and 5-bromo-2-fluoropyrimidine (2.00 g, 11.30 mmol) and DIEA (19.7 mL, 113 mmol) dissolved in DMF (40 mL) was heated at 100 °C for 16 hours. The solution was poured into water (100 mL) and extracted with Et₂O (3 × 30 mL). The organic layers were combined, dehydrated with Na₂SO₄, filtered, and concentrated. The crude product was purified by flash column chromatography (120 g Isco Gold column) using hexane:SiO₂ 100:0 → 0:100 to extract the compound. 6-2 This was obtained.

[0109] M / Z (ESI): 373.0, 375.0 [M+H] + . Synthesis of 6-3: tert-butyl (R)-4-(5-bromopyrimidine-2-yl)-3-((2-methoxyethoxy)methyl)piperazine-1-carboxylate 6-2To a solution prepared by dissolving (1.02 g, 2.73 mmol) in THF (13.66 mL), sodium hydride (0.219 g, 5.47 mmol, 60 wt%) was added at ambient temperature, and the solution was stirred for 0.5 hours. Then, 1-bromo-2-methoxyethane (0.514 mL, 5.47 mmol) was added, and the solution was stirred at 50°C for 20 hours. The solution was poured into water (30 mL) and extracted with siRNA (3 × 30 mL). The organic layers were combined, dehydrated with Na₂SO₄, filtered, and concentrated. The crude product was purified by flash column chromatography (80 g Isco Gold column) using hexane:siRNA 100:0 → 0:100 to obtain the compound. 6-3 This was obtained.

[0110] M / Z (ESI): 431.3, 433.3 [M+H] + . Synthesis of 6-4: tert-butyl (R,E)-4-(5-(2-(6-(1H-imidazole-1-yl)pyridine-3-yl)vinyl)pyrimidine-2-yl)-3-((2-methoxyethoxy)methyl)piperazine-1-carboxylate 6-3 (200 mg, 0.464 mmol) Int G A solution of (150 mg, 0.696 mmol) and 1 M tripotassium phosphate (1391 μL, 1.391 mmol) dissolved in dioxane (4637 μL) was purged with nitrogen. Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (36.5 mg, 0.046 mmol) was added, and the solution was stirred at 80°C for 1.5 hours. The mixture was filtered through a Celite pad, concentrated, and purified by flash column chromatography (40 g Isco Gold column) with elution in hexane:siRNA 100:0 → 0:100 to obtain the compound. 6-4 This was obtained.

[0111] M / Z (ESI): 522.4 [M+H] + . Synthesis of Int H: (R,E)-5-(2-(6-(1H-imidazole-1-yl)pyridine-3-yl)vinyl)-2-(2-((2-methoxyethoxy)methyl)piperazine-1-yl)pyrimidine dihydrochloride 6-4(223 mg, 0.428 mmol) was dissolved in DCM (4275 μL) to which a solution of 4 M HCl in dioxane (1069 μL, 4.28 mmol) was added, and the solution was aged at ambient temperature for 2 hours. The mixture was concentrated and dried under high vacuum to extract the compound. Int H This was obtained.

[0112] M / Z (ESI): 422.3 [M+H] + . Synthesis of intermediate I: (R)-(4-(5-ethynylpyrimidine-2-yl)-1-(pyrimidine-2-yl)piperazine-2-yl)methanol [ka] Synthesis of 9-1: (R)-2-(3-(hydroxymethyl)-4-(pyrimidine-2-yl)piperazine-1-yl)pyrimidine-5-carbaldehyde compound 2-3 A solution of (3g, 13.0 mmol) was dissolved in DMF (45 mL). While stirring, potassium carbonate (8.99 g, 65.0 mmol) was added at room temperature, followed by 2-chloropyrimidine-5-carbaldehyde (1.854 g, 13.00 mmol) at room temperature. The resulting reaction mixture was stirred at 80°C for 2 hours. The reaction mixture was quenched with ice-cold water and extracted with HCl (30 mL). The organic layers were combined and separated, the aqueous layer was re-extracted with HCl (60 mL), then washed with brine, dehydrated with anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain the crude compound (4.5 g) as a brown solid. The crude compound was purified by 100-200 silica gel Biotage flash column chromatography and eluted using a 50% HCl / petroleum ether gradient. The pure fraction was concentrated under reduced pressure to obtain the compound. 9-1 This was obtained.

[0113] M / Z (LCMS) (M+H): 301.20. Synthesis of Int I: (R)-(4-(5-ethinylpyrimidine-2-yl)-1-(pyrimidine-2-yl)piperazine-2-yl)methanol compound 9-1A solution of (1.8 g, 5.99 mmol) dissolved in MeOH (20 mL) was stirred, and potassium carbonate (1.657 g, 11.99 mmol) and dimethyl (1-diazo-2-oxopropyl)phosphonate (Bestmann-Ohira reagent, 1.626 mL, 7.19 mmol) were added at 0°C. The reaction mixture was then stirred at room temperature for 16 hours. The reaction mixture was diluted with water (20 mL) and extracted with SiO2 (2 × 30 mL). The organic layers were combined and washed with brine solution (10 mL), dehydrated with anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude compound. The crude compound was purified by silica column chromatography, and the product was eluted using a gradient of 40% SiO2 in petroleum ether. The pure fraction was concentrated under reduced pressure to obtain the compound. Int I This was obtained.

[0114] M / Z (LCMS) (M+H): 297.25. Synthesis of intermediate J: (R)-5-((6-(1H-imidazole-1-yl)pyridine-3-yl)ethinyl)-2-(3-(methoxymethyl)piperazine-1-yl)pyrimidine hydrochloride [ka] Synthesis of 10-1: tert-butyl (R)-4-(5-formylpyrimidine-2-yl)-2-(hydroxymethyl)piperazine-1-carboxylate 4-1 A solution of (5g, 23.12 mmol) was dissolved in DMF (80 mL). While stirring, potassium carbonate (3.94 mL, 69.4 mmol) was added at room temperature, followed by 2-chloropyrimidine-5-carbaldehyde (4.28 g, 30.1 mmol) at room temperature. The resulting reaction mixture was stirred at 80°C for 12 hours. The reaction mixture was quenched with ice water and extracted with siRNA (50 mL x 2). The organic layers were combined, washed with brine, dehydrated with anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain the crude compound. The crude compound was purified by 100-200 silica gel Biotage flash column chromatography and eluted using a 20% siRNA / petroleum ether gradient. The pure fraction was concentrated under reduced pressure to obtain the compound. 10-1 This was obtained.

[0115] M / Z (LCMS) (M+H): 323.17. Synthesis of 10-2: tert-butyl (R)-4-(5-ethynylpyrimidine-2-yl)-2-(hydroxymethyl)piperazine-1-carboxylate compound 10-1 A solution of (6 g, 18.61 mmol) was dissolved in MeOH (75 mL). While stirring, potassium carbonate (5.14 g, 37.2 mmol) was added at room temperature, followed by dimethyl (1-diazo-2-oxopropyl)phosphonate (Bestmann-Ohira reagent; 5.36 mL, 22.33 mmol). The reaction mixture was stirred at 25°C for 4 hours. The reaction mixture was quenched with saturated NH4Cl solution and extracted with DCM (10 mL x 3). The organic layers were combined, washed with brine, dehydrated with anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain the crude compound. The crude compound was purified by 100-200 silica gel Biotage flash column chromatography and eluted using a 30% siRNA / petroleum ether gradient. The pure fraction was concentrated under reduced pressure to obtain the compound. 10-2 This was obtained.

[0116] M / Z (LCMS) (M+H): 319.22. Synthesis of 10-3: tert-butyl (R)-4-(5-((6-(1H-imidazole-1-yl)pyridine-3-yl)ethinyl)pyrimidine-2-yl)-2-(hydroxymethyl)piperazine-1-carboxylate compound 10-2A solution of (3.5 g, 10.99 mmol) was dissolved in ACN (40 mL) (degassed with argon), and while stirring, N,N-diisopropylethylamine (4.26 g, 33.0 mmol) was added, followed by chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.865 g, 1.099 mmol) and 5-bromo-2-(1H-imidazole-1-yl)pyridine (3.69 g, 16.49 mmol) at room temperature. The reaction mixture was stirred at 80°C for 1 hour. The reaction mixture was quenched with ice water and extracted with ELISA (50 mL). The organic layers were combined, washed with brine solution, dehydrated with anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain the crude compound as a brown solid. The crude compound was purified by 100-200 silica gel Biotage flash column chromatography and eluted using siRNA as a gradient. The pure fraction was concentrated under reduced pressure to obtain the compound. 10-3 This was obtained.

[0117] M / Z (LCMS) (M+H): 462.37. Synthesis of 10-4: tert-butyl (R)-4-(5-((6-(1H-imidazole-1-yl)pyridine-3-yl)ethinyl)pyrimidine-2-yl)-2-(methoxymethyl)piperazine-1-carboxylate compound 10-3 A solution of (2g, 4.33 mmol) dissolved in DMF (15 mL) was stirred, and methyl iodide (1.230 g, 8.67 mmol) was added at 0°C, stirred for 5 minutes at 0°C, and then sodium hydride (0.416 g, 17.33 mmol) was added at 0°C. The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was quenched with ice water and diluted with dimethyl phosphate (15 mL x 3). The organic layers were combined, washed with brine solution, dehydrated with anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain the crude compound. The crude compound was purified by 100-200 silica gel Biotage flash column chromatography (eluent 20% dimethyl phosphate / petroleum ether). All desired fractions (confirmed by TLC) were combined and concentrated under reduced pressure to obtain the compound. 10-4 This was obtained.

[0118] M / Z (LCMS) (M+H): 476.30. Synthesis of Int J: (R)-5-((6-(1H-imidazole-1-yl)pyridine-3-yl)ethinyl)-2-(3-(methoxymethyl)piperazine-1-yl)pyrimidine hydrochloride compound 10-4 A solution of (2 g, 4.21 mmol) dissolved in DCM (15 mL) was stirred, and 4 M HCl (1.048 g, 8.41 mmol) in 1,4-dioxane was added at 0°C. The resulting reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was evaporated under reduced pressure and distilled at low temperature using DCM. The resulting compound was washed with pentane and dried under reduced pressure to obtain the compound. Int J This was obtained.

[0119] M / Z (LCMS) (M+H): 376.30. [Examples]

[0120] Examples Example 1 (R,E)-(4-(5-(2-(6-(1H-imidazole-1-yl)pyridine-3-yl)vinyl)pyrimidine-2-yl)-1-(pyrimidine-2-yl)piperazine-2-yl)methanol [ka] Int B (1g, 2.85 mmol) was dissolved in toluene (10 mL), and the solution was purged with argon gas for 10 minutes. The reaction mixture was then... Int A (0.487 g, 2.85 mmol), DIPEA (1.492 mL, 8.54 mmol), Pd2(dba)3 (0.261 g, 0.285 mmol), and tri-tert-butylphosphonium tetrafluoroborate (0.165 g, 0.569 mmol) were added at room temperature, and the mixture was purged again with argon for another 10 minutes. The reaction mixture was stirred at 100°C for 16 hours. The reaction mixture was quenched with water (50 mL) and extracted with 10% MeOH in DCM (2 × 100 mL). The organic layers were combined and washed with brine (2 × 50 mL), dehydrated with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by column chromatography using (100-200 mesh) silica, and the compound was eluted using a gradient of 10% MeOH in DCM. The pure fraction was concentrated under reduced pressure. 1This was obtained.

[0121] M / Z (ESI): 442.33 [M+H] + ; 1 H NMR (DMSO-d6, 400 MHz): δ (ppm) 8.67 (s, 2H), 8.59 (d, J = 2.0 Hz, 1H), 8.55 (s, 1H), 8.39 (d, J = 4.4 Hz, 2H), 8.22 (dd, J = 8.6 Hz, 2.2 Hz, 1H), 7.96-8.0 (m, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.20-7.34 (m, 2H), 7.13 (s, 1H), 6.65 (t, J = 4.8 Hz, 1H), 4.71-4.84 (m, 3H), 4.41-4.55 (m, 2H), 3.40-3.53 (m, 2H), 3.18-3.30 (m, 3H). Example 2 (R,E)-5-(2-(6-(1H-imidazole-1-yl)pyridine-3-yl)vinyl)-2-(3-(methoxymethyl)-4-(pyrimidine-2-yl)piperazine-1-yl)pyrimidine [ka] compound Int C (300 mg, 0.821 mmol) and Int A A solution of (211 mg, 1.232 mmol) dissolved in 1,4-dioxane (5 mL) was stirred, and DIPEA (0.430 mL, 2.464 mmol) was added at room temperature. The reaction mixture was purged with argon for 5 minutes, followed by the addition of chloro[(tri-tert-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) (42.1 mg, 0.082 mmol), and the mixture was purged again with argon for 5 minutes. The reaction mixture was stirred at 120 °C for 16 hours. The reaction mixture was quenched with water (20 mL) and extracted with siRNA (2 × 30 mL). The organic layers were combined, washed with brine solution (10 mL), dehydrated with anhydrous Na₂SO₄, filtered, dried, and concentrated under reduced pressure to obtain the crude compound. The crude compound was purified by silica column chromatography and eluted using a 5% MeOH gradient in DCM. The pure fraction was concentrated under reduced pressure.2 was obtained.

[0122] M / Z (ESI): 456.39 [M+H] + . 1 H NMR (DMSO-d6, 400 MHz): δ (ppm) 8.69 (s, 2H), 8.60 (d, J = 2.4 Hz, 1H), 8.55 (s, 1H), 8.41 (d, J = 4.4 Hz, 2H), 8.23 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 7.98 (s, 1H), 7.85 (d, J = 8.8 Hz, 1H), 7.29 (d, J = 16.8 Hz, 1H), 7.24 (d, J = 16.4 Hz, 1H), 7.14 (s, 1H), 6.68 (t, J = 4.8 Hz, 1H), 4.89 - 4.96 (m, 1H), 4.79 (d, J = 13.2 Hz, 1H), 4.50 - 4.60 (m, 2H), 3.35 - 3.46 (m, 2H), 3.22 - 3.30 (m, 2H), 3.12 - 3.22 (m, 4H). Example 3 (R,E)-5-(2-(6-(1H-imidazole-1-yl)pyridine-3-yl)vinyl)-2-(3-((2-fluoroethoxy)methyl)-4-(pyrimidine-2-yl)piperazine-1-yl)pyrimidine [Chemical formula] 1A solution of (100 mg, 0.227 mmol) was dissolved in DMF (1 mL), and while stirring, 1-fluoro-2-iodoethane (79 mg, 0.453 mmol) was added at 0°C, followed by the addition of 60% NaH (18.12 mg, 0.453 mmol). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water (50 mL) and extracted with siRNA (3 × 50 mL). The organic layers were combined and dehydrated with Na₂SO₄, and concentrated under reduced pressure to obtain the crude compound. The crude compound was purified by prep HPLC (mobile phase - 10 mM ammonium bicarbonate in H2O: MeCN, column - YMC Triart C18 (25×250) mm 5u, flow rate - 7.0 mL / min, gradient method - 0 / 35, 2 / 35, 11 / 68, 11.05 / 100, 13 / 100, 13.05 / 35, 16 / 35), 3 This was obtained.

[0123] M / Z (ELSD) (M+H): 488.35. 1 H NMR (DMSO-d6, 400 MHz): δ (ppm) 8.68 (s, 2H), 8.60 (d, J = 2.0 Hz, 1H), 8.55 (s, 1H), 8.41 (d, J = 4.8 Hz, 2H), 8.23 ​​(dd, J = 8.6, 2.4 Hz, 1H), 7.98 (t, J = 1.4 Hz, 1H), 7.85 (d, J = 8.5 Hz, 1H), 7.20-7.33 (m, 2H), 7.14 (s, 1H), 6.68 (t, J = 4.8 Hz, 1H), 4.87-4.94 (m, 1H), 4.83 (br d, J = 13.3 Hz, 1H), 4.46-4.62 (m, 3H), 4.39 (ddd, J = 4.8, 3.3, 1.5 Hz, 1H), 3.65 (td, J = 4.1, 2.4 Hz, 1H), 3.44-3.61 (m, 3H), 3.32-3.35 (m, 1H), 3.13-3.29 (m, 2H). Example 4 (R,E)-5-(2-(6-(1H-imidazole-1-yl)pyridine-3-yl)vinyl)-2-(3-((fluoromethoxy)methyl)-4-(pyrimidine-2-yl)piperazine-1-yl)pyrimidine [ka] 1 A solution of (100 mg, 0.227 mmol) dissolved in THF (2 mL) was stirred, and fluoroiodomethane (72.4 mg, 0.453 mmol) and potassium tert-butoxide (50.8 mg, 0.453 mmol) were added at 0°C. The resulting reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was quenched with ice water and extracted with siRNA (50 mL x 2). The organic layers were combined, washed with brine solution, dehydrated with anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain the crude compound. The crude compound was purified by prep HPLC (Method: Mobile phase - 10 mM ammonium bicarbonate in H2O: MeCN, Column - X-Select C18 (19×250) mm 5u, Flow rate - 16 mL / min, Gradient method - 0 / 45, 2 / 45, 12 / 80, 12.05 / 99, 15 / 99, 15.05 / 45, 18 / 45), 4 This was obtained.

[0124] M / Z (ELSD) (M+H): 473.44. 1 H NMR (DMSO-d6, 400 MHz): δ (ppm) 8.69 (s, 2H), 8.60 (d, J = 2.0 Hz, 1H), 8.55 (s, 1H), 8.42 (d, J = 4.5 Hz, 2H), 8.23 ​​(dd, J = 8.8, 2.3 Hz, 1H), 7.98 (t, J = 1.3 Hz, 1H), 7.80-7.90 (m, 1H), 7.27 (d, J = 3.3 Hz, 2H), 7.14 (s, 1H), 6.70 (t, J = 4.6 Hz, 1H), 5.30-5.39 (m, 1H), 5.16-5.26 (m, 1H), 4.95-5.02 (m, 1H), 4.77-4.84 (m, 1H), 4.48-4.61 (m, 2H), 3.78-3.85 (m, 1H), 3.68-3.75 (m, 1H), 3.36 (br d, J = 4.3 Hz, 1H), 3.14-3.29 (m, 2H). Example 5 (R,E)-5-(2-(6-(4H-1,2,4-triazol-4-yl)pyridine-3-yl)vinyl)-2-(2-(methoxymethyl)-4-(pyridine-2-yl)piperazine-1-yl)pyrimidine [ka] Int F A solution of (10.0 mg, 0.032 mmol) of 5-bromo-2-(4H-1,2,4-triazol-4-yl)pyridine (14.6 mg, 0.065 mmol), N,N-dicyclohexylmethylamine (19.0 mg, 0.097 mmol), and dichlorobis(triphenylphosphine)palladium(II) (1.66 mg, 0.003 mmol) dissolved in dioxane (0.5 mL) was purged with nitrogen and heated at 120 °C for 18 hours. The mixture was diluted with DMF (0.8 mL), filtered, and purified by Gilson HPLC (10-100% ACN / H2O w / 0.1% NH4OH Gemini-NX column) to obtain compound 5 This was obtained.

[0125] M / Z (ESI): 456.21 [M+H] + . 1 H NMR (DMSO-d6, 500 MHz): δ (ppm) 9.31-9.26 (m, 2H), 8.78-8.58 (m, 3H), 8.31-8.24 (m, 1H), 8.14-8.08 (m, 1H), 7.88 (t, J = 9.0 Hz, 1H), 7.63-7.46 (m, 1H), 7.39-7.18 (m, 2H), 6.82 (t, J = 7.7 Hz, 1H), 6.71-6.55 (m, 1H), 4.97-4.89 (m, 1H), 4.73-4.45 (m, 1H), 4.39-4.30 (m, 1H), 4.27-4.17 (m, 1H), 3.47 (s, 3H), 3.35-3.26 (m, 1H), 3.25-3.18 (m, 2H), 3.17-3.09 (m, 1H), 3.01-2.91 (m, 1H). Example 6 (R,E)-5-(2-(6-(1H-imidazole-1-yl)pyridine-3-yl)vinyl)-2-(2-((2-methoxyethoxy)methyl)-4-(pyridine-2-yl)piperazine-1-yl)pyrimidine [ka] Int H A solution of (211 mg, 0.427 mmol) and 2-bromopyridine (52.9 μL, 0.555 mmol) and sodium tert-butoxide (205 mg, 2.134 mmol) dissolved in toluene (4268 μL) was stirred and purged with nitrogen for 10 minutes. Chloro(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (RuPhos Pd G2) (33.1 mg, 0.043 mmol) was added, and the mixture was heated at 110°C for 20 hours with stirring. The reaction mixture was filtered through a Celite pad and washed with ELISA (3 × 20 mL). The filtrate is concentrated and purified by flash column chromatography (40 g Isco Gold column) using hexane:siRNA 100:0 → 50:50 to extract the compound. 6 This was obtained.

[0126] M / Z (ESI): 499.4 [M+H] + . 1H NMR (CDCl3, 500 MHz): δ (ppm) 8.54-8.52 (m, 1H), 8.53 (s, 2H), 8.35 (s, 1H), 8.19 (d, J = 3.6 Hz, 1H), 7.94 (dd, J = 8.5 Hz, 2.2 Hz, 1H), 7.65 (s, 1H), 7.50 (t, J = 7.8 Hz, 1H), 7.35 (d, J = 8.5 Hz, 1H), 7.23 (d, J = 11.0 Hz, 1H), 6.95 (s, 2H), 6.76 (d, J = 8.5 Hz, 1H), 6.69-6.0 (m, 1H), 5.08-5.02 (m, 1H), 4.71-4.52 (m, 1H), 4.50-4.28 (m, 2H), 3.78-3.45 (m, 6H), 3.45-3.29 (m, 1H), 3.36 (s, 3H), 3.25 (dd, J = 13.1 Hz, 3.7 Hz, 1H), 3.16-2.96 (m, 1H). Examples 7 and 8 (R,E)-(2-(4-(5-(2-(6-(1H-imidazole-1-yl)pyridine-3-yl)vinyl)pyrimidine-2-yl)-2-(methoxymethyl)piperazine-1-yl)pyrimidine-5-yl)methanol and (R,E)-5-(2-(6-(1H-imidazole-1-yl)pyridine-3-yl)vinyl)-2-(4-(5-(fluoromethyl)pyrimidine-2-yl)-3-(methoxymethyl)piperazine-1-yl)pyrimidine [ka] Synthesis of 7-1: (R,E)-2-(4-(5-(2-(6-(1H-imidazole-1-yl)pyridine-3-yl)vinyl)pyrimidine-2-yl)-2-(methoxymethyl)piperazine-1-yl)pyrimidine-5-carbaldehyde Int E To a solution prepared by dissolving (2 g, 4.83 mmol) in DMF (20 mL), K2CO3 (4.01 g, 29.0 mmol) and 2-chloropyrimidine-5-carbaldehyde (0.827 g, 5.80 mmol) were added at room temperature, and the mixture was stirred at 80°C for 1 hour under an argon atmosphere. The reaction mixture was diluted with water (10 mL), stirred for 10 minutes, and the resulting solid precipitate was filtered and dried to obtain the crude compound. The crude compound was purified using biotage (48 g cartridge, 230-400 silica) and eluted using a 3% MeOH / DCM gradient. The pure fraction was concentrated under reduced pressure to obtain the compound. 7-1 This was obtained.

[0127] M / Z (ESI): 484.49 [M+H] + . Synthesis of Example 7: (R,E)-(2-(4-(5-(2-(6-(1H-imidazole-1-yl)pyridine-3-yl)vinyl)pyrimidine-2-yl)-2-(methoxymethyl)piperazine-1-yl)pyrimidine-5-yl)methanol Compound 7-1 A solution of (750 mg, 1.551 mmol) dissolved in MeOH (10 mL) was stirred, and NaBH4 (117 mg, 3.10 mmol) was added at 0°C and stirred at the same temperature for 30 minutes. The reaction mixture was quenched with water and extracted with dimethyl (3 × 50 mL). The organic layers were combined and washed with brine solution (50 mL), dehydrated with sodium sulfate, filtered, concentrated under reduced pressure, ground with ACN (3 × 10 mL), acetone (10 mL), and diethyl ether (10 mL), and washed with pentane (10 mL). 7 This was obtained.

[0128] M / Z (ESI): 486.37 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ (ppm) 8.68 (s, 2H), 8,59 (d, J = 2.0 Hz, 1H), 8.55 (s, 1H), 8.35 (s, 2H), 8.22 (dd, J = 2.4 Hz, 8.8 Hz, 1H), 7.97 (s, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.21-7.32 (m, 2H), 7.13 (s, 1H), 5.08 (t, J = 5.6 Hz, 1H), 4.89-4.98 (m, 1H), 4.79 (d, J = 13.6 Hz, 1H), 4.50-4.61 (m, 2H), 4.34 (d, J = 5.6 Hz, 2H), 3.36-3.46 (m, 2H), 3.10-3.30 (m, 6H). Synthesis of Example 8: (R,E)-5-(2-(6-(1H-imidazole-1-yl)pyridine-3-yl)vinyl)-2-(4-(5-(fluoromethyl)pyrimidine-2-yl)-3-(methoxymethyl)piperazine-1-yl)pyrimidine 7A solution of (500 mg, 1.030 mmol) was dissolved in DCM (10 mL), and while stirring, DAST (0.816 mL, 6.18 mmol) was added at 0°C under an argon atmosphere. The reaction mixture was stirred at 0°C for 30 minutes. The reaction mixture was quenched with water (10 mL), neutralized with saturated NaHCO3 solution (to adjust the pH to neutral), and extracted with DCM (3 × 50 mL). The organic layers were combined, washed with brine (30 mL), dehydrated with sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product (500 mg). The crude compound (150 mg) was purified by Prep HPLC, and the remaining amount was used in further steps. Prep HPLC conditions: Mobile phase - 10 mM ammonium bicarbonate in H2O: MeCN, Column - YMC ODS C18 (20 × 100), 3 μm, Flow rate - 18.0 mL / min, T / %B (0 / 55, 10.50 / 81.2, 10.55 / 100, 12.50 / 100, 12.55 / 55, 15.50 / 55). Pure fractions were collected under freezing and directly freeze-dried. 8 This was obtained.

[0129] M / Z (SFC-MS): 488.32 [M+H] + . 1 H NMR (DMSO-d6, 400 MHz): δ (ppm) 8.68 (s, 2H), 8.60 (d, J = 2.0 Hz, 1H), 8.55 (s, 1H), 8.52 (d, J = 2.0 Hz, 2H), 8.21-8.25 (m, 1H), 7.97 (s, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.29 (d, J = 16.8 Hz, 1H), 7.24 (d, J = 16.4 Hz, 1H), 7.13 (s, 1H), 5.29 (d, J = 48.8 Hz, 2H), 4.55-5.01 (m, 1H), 4.79 (d, J = 13.2 Hz, 1H), 4.57 (d, J = 10.4 Hz, 2H), 3.36-3.48 (m, 2H), 3.12-3.28 (m, 6H). Example 9 (R,E)-5-(2-(6-(1H-imidazole-1-yl)pyridine-3-yl)vinyl)-2-(2-(methoxymethyl)-4-(5-(methoxymethyl)pyrimidine-2-yl)piperazine-1-yl)pyrimidine [ka] Synthesis of Example 9: (R,E)-5-(2-(6-(1H-imidazole-1-yl)pyridine-3-yl)vinyl)-2-(2-(methoxymethyl)-4-(5-(methoxymethyl)pyrimidine-2-yl)piperazine-1-yl)pyrimidine 8-1 [Synthesized in the same manner as in Example 7] (300 mg, 0.618 mmol) was dissolved in DCM (4 mL) and, while stirring, DAST (0.163 mL, 1.236 mmol) was added dropwise at 0°C. The reaction mixture was stirred under a nitrogen atmosphere at 25°C for 2 hours. The reaction mixture was quenched with sodium bicarbonate solution (10 mL) and extracted with 10% MeOH (3 × 25 mL) in DCM. The organic layers were combined and washed with brine solution (2 × 40 mL), dehydrated with anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the intermediate benzyl fluoride as a yellow solid. The crude compound (280 mg) was purified by biotage using an 80 g cartridge silica (230-400 mesh) column and eluted using 5% MeOH in DCM as a gradient. The pure fraction was concentrated under reduced pressure and purified again by Prep HPLC (Method: Mobile phase - 10 mM ammonium bicarbonate in H2O: MeCN, Column - X-Bridge C18 (19×250), Flow rate - 12.0 mL / min, Gradient method: 0 / 40, 2 / 40, 12 / 65, 14 / 65, 14.1 / 95, 17 / 95, 17.01 / 40, 20 / 40), 9 This was obtained.

[0130] M / Z (LCMS) (M+H): 500.41. 1H NMR (chloroform-d, 400 MHz): δ (ppm) 8.69 (s, 2H), 8.55-8.60 (m, 2H), 8.37 (s, 2H), 8.23 ​​(dd, J = 2, 8.4 Hz, 1H), 7.97 (s, 1H), 7.85 (d, J = 8.8 Hz, 1H), 7.22-7.31 (m, 2H), 7.13 (s, 1H), 4.97-4.98 (m, 1H), 4.76 (d, J = 13.2 Hz, 1H), 4.54-4.59 (m, 2H), 4.25 (s, 1H), 3.36-3.45 (m, 2H), 3.15-3.26 (m, 8H), 3.08-3.14 (m, 1H). Example 10 (R)-(4-(5-((6-(1H-imidazole-1-yl)pyridine-3-yl)ethinyl)pyrimidine-2-yl)-1-(pyrimidine-2-yl)piperazine-2-yl)methanol [ka] compound Int I To a solution prepared by dissolving (1.1 g, 3.71 mmol) in ACN (30 mL), compound 5-bromo-2-(1H-imidazole-1-yl)pyridine (0.749 g, 3.34 mmol) and DIPEA (1.945 mL, 11.14 mmol) were added, and the mixture was degassed with argon for 5 minutes. Then, chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.292 g, 0.371 mmol) was added, and the mixture was stirred in a sealed tube at 80°C for 1 hour. The reaction mixture was evaporated under reduced pressure, the resulting precipitated solution was filtered and dried, and subjected to Prep HPLC purification (Method: Mobile phase - 10 mM ammonium bicarbonate in H2O: MeCN, Column - X-Bridge C18 (19×250), Flow rate - 15.0 mL / min, Gradient method - 0 / 40, 9.50 / 55, 9.55 / 98, 11.55 / 98, 11.60 / 40, 15.60 / 40), and then freeze-dried. 10 This was obtained.

[0131] M / Z (LCMS) (M+H): 440.33. 1 H NMR (DMSO-d6, 400 MHz): δ (ppm) 8.60-8.74 (m, 3H), 8.59 (s, 1H), 8.39 (d, J = 4.8 Hz, 2H), 8.16 (dd, J = 8.5, 2.3 Hz, 1H), 8.00 (t, J = 1.3 Hz, 1H), 7.91 (d, J = 8.5 Hz, 1H), 7.15 (s, 1H), 6.60-6.73 (m, 1H), 4.68-4.87 (m, 3H), 4.38-4.54 (m, 2H), 3.42-3.53 (m, 2H), 3.32-3.41 (m, 3H). Example 11 (R)-5-((6-(1H-imidazole-1-yl)pyridine-3-yl)ethinyl)-2-(3-(methoxymethyl)-4-(pyrimidine-2-yl)piperazine-1-yl)pyrimidine [ka] 10 To a solution prepared by dissolving (70 mg, 0.088 mmol) in DMF (0.7 mL), methyl iodide (7.05 μL, 0.113 mmol) and NaH (7 mg, 0.175 mmol) were added at 0°C. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with cold water (10 mL) and extracted with SiO2 (3 × 10 mL). The organic layers were combined, washed with brine solution (10 mL), dehydrated with Na2SO4, and concentrated under reduced pressure to obtain the crude compound. The crude compound was purified by Prep HPLC (Method: Mobile phase - 10 mM ammonium bicarbonate in H2O: MeCN, Column - Kromosil C18 (10 × 250) mm 5u, Flow rate - 8 mL / min, Gradient method - 0 / 50, 10 / 85, 10 / 10 / 98, 12 / 98, 12 / 10 / 50, 15 / 50), and then lyophilized. 11 This was obtained.

[0132] M / Z (LCMS) (M+H): 454.36. 1H NMR (DMSO-d6, 400 MHz): δ (ppm) 8.66 (dd, J = 2.3, 0.8 Hz, 1H), 8.64 (s, 2H), 8.59 (s, 1H), 8.41 (d, J = 4.8 Hz, 2H), 8.16 (dd, J = 8.5, 2.3 Hz, 1H), 8.00 (t, J = 1.4 Hz, 1H), 7.88-7.93 (m, 1H), 7.16 (s, 1H), 6.68 (t, J = 4.8 Hz, 1H), 4.87-4.98 (m, 1H), 4.72-4.82 (m, 1H), 4.48-4.60 (m, 2H), 3.33-3.41 (m, 3H), 3.14-3.27 (m, 5H). Example 12 (R)-5-((6-(1H-imidazole-1-yl)pyridine-3-yl)ethinyl)-2-(4-(6-fluoropyrimidine-4-yl)-3-(methoxymethyl)piperazine-1-yl)pyrimidine [ka] compound Int J A solution of (100 mg, 0.266 mmol) dissolved in DMF (1 mL) was stirred, and N,N-diisopropylethylamine (172 mg, 1.332 mmol) was added at room temperature, followed by 4,6-difluoropyrimidine (30.9 mg, 0.266 mmol) at room temperature. The reaction mixture was stirred at 50°C for 1 hour. The reaction mixture was quenched with ice water and extracted with siRNA (10 mL x 2). The organic layers were combined, washed with brine solution, dehydrated with anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain the crude compound. The crude compound was purified by prep HPLC (Method: Mobile phase - 10 mM ammonium bicarbonate in H2O: MeCN, Column - X-Select C18 (19×250), Flow rate - 18.0 mL / min, Gradient method: 0 / 50, 4 / 63, 9 / 63, 9.05 / 98, 11 / 98, 11.05 / 50, 15 / 50), and then lyophilized. 12 This was obtained.

[0133] M / Z (LCMS) (M+H): 472.43. 1H NMR (DMSO-d6, 400 MHz): δ (ppm) 8.64-8.65(m, 3H), 8.58(s, 1H), 8.35(d, J = 2.8 Hz, 1H), 8.16(dd, J = 2.4, 8.4 Hz, 1H), 8.00(s, 1H), 7.89(d, J = 8.4 Hz, 1H), 7.155(s, 1H), 6.58(s, 1H), 4.70-4.78(m, 2H), 4.50-4.52(m, 1H), 4.30(br s, 1H), 3.37-3.44(m, 3H), 3.24-3.29(m, 2H), 3.21 (s, 3H). The compounds included in Table 1 were synthesized using the same method as the synthesis procedure shown in the last column of Table 1. The following examples were prepared by substituting commercially available reagents as needed. [Table 3] TIFF2026509241000052.tif209170TIFF2026509241000053.tif209170TIFF2026509241000054.tif196170TIFF20265092410 00055.tif190170TIFF2026509241000056.tif204170TIFF2026509241000057.tif204170TIFF2026509241000058.tif147170 36 instances of implementation that are considered unusual. (R,E)-5-(5-(2-(2-(3-((2-fluoroethoxy)methyl)-4-(pyrimidine-2-yl)piperazin-1-yl)pyrimidine-5-yl)vinyl)pyridine-2-yl)oxazole [ka] Synthesis of 36-1: (R)-5-bromo-2-(3-((2-fluoroethoxy)methyl)-4-(pyrimidine-2-yl)piperazine-1-yl)pyrimidine Int BA solution of (250 mg, 0.712 mmol) dissolved in DMF (3 mL) was stirred, and 1-fluoro-2-iodoethane (0.115 mL, 1.424 mmol) and NaH (56.9 mg, 1.424 mmol) were added at 0°C. The reaction mixture was stirred at 25°C for 16 hours under a nitrogen atmosphere. The reaction mixture was quenched with water (40 mL) and extracted with siRNA (2 × 30 mL). The organic layers were combined and washed with brine (2 × 30 mL), dehydrated with anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude compound was purified by biotage in an 80 g silica (230-400 mesh) cartridge, and the compound was eluted with a 30% siRNA gradient in petroleum ether. The pure fraction was concentrated under reduced pressure. 36-1 This was obtained.

[0134] M / Z (ESI): 397.32 [M+H] + . Synthesis of 36-4: 5-(5-bromopyridine-2-yl)oxazole Tosylmethyl isocyanide (2 g, 10.24 mmol) was dissolved in MeOH (35 mL), and potassium carbonate (4.25 g, 30.7 mmol) was added to the solution while stirring at room temperature. Then, 5-bromopicoline aldehyde (2.096 g, 11.27 mmol) was added to the reaction mixture at room temperature. The reaction mixture was stirred at 80 °C for 16 hours. The reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (2 × 100 mL). The organic layers were combined and washed with brine (100 mL), dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude compound was purified by Biotage flash column chromatography using (100-200 mesh) silica gel, and the compound was eluted with a 50% ethyl acetate gradient in petroleum ether. The pure fraction was concentrated under reduced pressure. 36-4 This was obtained.

[0135] M / Z (ESI): 225.10 [M+2H] + . Synthesis of 36-2: 5-(5-vinylpyridine-2-yl)oxazole 36-4A solution of (1 g, 4.44 mmol) was dissolved in 1,4-dioxane (10 mL) and water (5 mL), and the solution was degassed with argon while stirring. Tribasic potassium phosphate (2.83 g, 13.33 mmol) was then added at room temperature. Next, 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (0.363 g, 0.444 mmol) and potassium vinyl trifluoroborate (1.190 g, 8.89 mmol) were added to the reaction mixture at room temperature. The reaction mixture was stirred at 100 °C for 12 hours. The reaction mixture was filtered through a Celite bed using a Buchner funnel, washed with HCl (100 mL), and concentrated under reduced pressure. The crude compound was purified by Biotage flash column chromatography on (100-200 mesh) silica gel, and the compound was eluted with a 50% HCl gradient in petroleum ether. The pure fraction is concentrated under reduced pressure. 36-2 This was obtained.

[0136] M / Z (ESI): 173.02 [M+H] + . Synthesis of 36: (R,E)-5-(5-(2-(2-(3-((2-fluoroethoxy)methyl)-4-(pyrimidine-2-yl)piperazin-1-yl)pyrimidine-5-yl)vinyl)pyridine-2-yl)oxazole 36-1 (120 mg, 0.302 mmol) dissolved in 1,4-dioxane (2 mL) solution, and while stirring, DIPEA (0.158 mL, 0.906 mmol) and 36-2(62.4 mg, 0.362 mmol) was added at room temperature. The reaction mixture was degassed using argon gas for 20 minutes. Then, chloro[(tri-tert-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) (15.48 mg, 0.030 mmol) was added to the reaction mixture at room temperature. The reaction mixture was stirred in a sealed tube under a nitrogen atmosphere at 100°C for 4 hours. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (2 × 20 mL). The organic layers were combined and washed with brine (20 mL), dehydrated with anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude compound was purified by biotage in a 40 g silica (230-400 mesh) cartridge, and the compound was eluted with a gradient of 3% MeOH in DCM. The pure fraction was concentrated under reduced pressure. 36 This was obtained.

[0137] M / Z (ESI): 489.36 [M+H] + . 1 H NMR (DMSO-d6, 400 MHz): δ (ppm) 8.76 (d, J = 1.6 Hz, 1H), 8.69 (s, 2H), 8.54 (s, 1H), 8.41 (d, J = 4.4 Hz, 2H), 8.11 (dd, J = 8.4 Hz, 2.0 Hz, 1H), 7.74-7.82 (m, 2H), 7.28 (q, J = 14.8 Hz, 2H), 6.68 (t, J = 4.8 Hz, 1H), 4.88-4.93 (m, 1H), 4.82 (d, J = 13.6 Hz, 1H), 4.49-4.60 (m, 3H), 4.37-4.41 (m, 1H), 3.62-3.68 (m, 1H), 3.45-3.60 (m, 3H), 3.13-3.30 (m, 3H). Example 37 (R,E)-5-(2-(6-(1-(2-fluoroethyl)-1H-pyrazole-4-yl)pyridine-3-yl)vinyl)-2-(3-(methoxymethyl)-4-(pyrimidine-2-yl)piperazine-1-yl)pyrimidine [ka] Synthesis of 37-1: (R)-2-(3-(methoxymethyl)-4-(pyrimidine-2-yl)piperazin-1-yl)-5-vinylpyrimidine Int CA solution of (10 g, 27.4 mmol) was dissolved in 1,4-dioxane (100 mL) and water (20 mL). While stirring, Cs2CO3 (17.84 g, 54.8 mmol) and potassium vinyl trifluoroborate (7.33 g, 54.8 mmol) were added at room temperature, and the mixture was degassed with argon gas for 15 minutes. Next, PdCl2(dppf)-CH2Cl2 adduct (2.236 g, 2.74 mmol) was added to the reaction mixture at room temperature. The reaction mixture was stirred in a sealed tube under a nitrogen atmosphere at 100°C for 16 hours. The reaction mixture was quenched with water (200 mL) and extracted with siRNA (2 × 200 mL). The organic layers were combined, washed with brine (200 mL), dehydrated with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified using a silica column, and the compound was eluted using a 30% siRNA gradient in petroleum ether. The pure fraction was concentrated under reduced pressure. 37-1 This was obtained.

[0138] M / Z (ESI): 313.38 [M+H] + . Synthesis of 37-2: (R,E)-5-(2-(6-bromopyridine-3-yl)vinyl)-2-(3-(methoxymethyl)-4-(pyrimidine-2-yl)piperazine-1-yl)pyrimidine 37-1 A solution of (4 g, 12.81 mmol) dissolved in 1,4-dioxane (50 mL) was stirred, and DIPEA (6.71 mL, 38.4 mmol) and 2-bromo-5-iodopyridine (18.18 g, 64.0 mmol) were added at room temperature, and the mixture was degassed with argon for 15 minutes. Then, tBu X-phos Pd G3 (1.017 g, 1.281 mmol) was added at room temperature. The reaction mixture was stirred in a sealed tube under a nitrogen atmosphere at 120 °C for 16 hours. The reaction mixture was quenched with water (50 mL) and extracted with dimethyl phosphate (2 × 200 mL). The organic layers were combined and washed with brine (50 mL), dehydrated with anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude compound was purified by silica column chromatography, and the compound was eluted using a 30% dimethyl phosphate gradient in petroleum ether. The pure fraction was concentrated under reduced pressure, and the resulting compound was further purified by Prep-HPLC. The pure fraction was concentrated under reduced pressure and freeze-dried. 37-2 This was obtained.

[0139] M / Z (ESI): 516.30 [M+H] + . 1 H NMR (DMSO-d6, 400 MHz): δ (ppm) 8.67 (s, 2H), 8.48 (d, J = 2.4 Hz, 1H), 8.40 (d, J = 4.8 Hz, 2H), 7.83 (d, J = 8.0 Hz, 1H), 7.71 (dd, J = 8.4 Hz, 2.4 Hz, 1H), 7.28 (d, J = 16.4 Hz, 1H), 7.14 (d, J = 16.4 Hz, 1H), 6.67 (t, J = 4.8 Hz, 1H), 4.89-4.96 (m, 1H), 4.78 (d, J = 13.2 Hz, 1H), 4.49-4.60 (m, 2H), 3.35-3.45 (m, 2H), 3.26 (d, J = 4.0 Hz, 1H), 3.11-3.25 (m, 5H). Synthesis of 37: (R,E)-5-(2-(6-(1-(2-fluoroethyl)-1H-pyrazole-4-yl)pyridine-3-yl)vinyl)-2-(3-(methoxymethyl)-4-(pyrimidine-2-yl)piperazine-1-yl)pyrimidine 37-2 (100 mg, 0.214 mmol) and 1-(2-fluoroethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (61.5 mg, 0.256 mmol) were dissolved in 1,4-dioxane (1 mL) and H2O (0.2 mL). Tripotassium phosphate (136 mg, 0.641 mmol) was added to the solution while stirring at room temperature. The reaction mixture was degassed and purged with argon gas for 5 minutes. Next, PdCl2(dppf)-CH2Cl2 adduct (17.44 mg, 0.021 mmol) was added to the reaction mixture at room temperature. The reaction mixture was stirred in a sealed tube under a nitrogen atmosphere at 80°C for 2 hours. The reaction mixture was diluted with water (10 mL) and extracted with ELISA (2 × 20 mL). The organic layers were combined, washed with brine (10 mL), dehydrated with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by prep-HPLC. The pure fractions were combined and freeze-dried. 37 This was obtained.

[0140] M / Z (ESI): 502.41 [M+H] + . Prep-HPLC purification conditions: Mobile phase - 10 mM ammonium bicarbonate in H2O: MeCN, Column - X-Bridge C18 (19×150), 5μ, Flow rate - 15.0 mL / min, Gradient method 0 / 40, 7 / 50, 9 / 56, 9.1 / 100, 11.9 / 100, 12 / 40, 15 / 40.

[0141] 1 H NMR (400 MHz, DMSO-d6) δ = 8.68 (s, 2H), 8.62 (d, J = 1.6 Hz, 1H), 8.41 (d, J = 4.6 Hz, 2H), 8.38 - 8.36 (m, 1H), 8.08 (s, 1H), 7.99 (dd, J = 8.4 Hz, 2.3 Hz, 1H), 7.68 (d, J = 8.1 Hz, 1H), 7.20 (s, 2H), 6.67 (t, J = 4.7 Hz, 1H), 4.95 - 4.85 (m, 2H), 4.82 - 4.73 (m, 2H), 4.58 - 4.50 (m, 3H), 4.45 (t, J = 4.7 Hz, 1H), 3.45 - 3.35 (m, 2H), 3.30 - 3.23 (m, 2H), 3.23 - 3.20 (m, 3H), 3.19 - 3.15 (m, 1H). Example 38 (R,E)-5-(5-(2-(2-(3-((2-(2-fluoroethoxy)ethoxy)methyl)-4-(1,3,5-triazin-2-yl)piperazin-1-yl)pyrimidine-5-yl)vinyl)pyridine-2-yl)oxazole [ka] Synthesis of 38-3: tert-butyl (R)-4-(4,6-dichloro-1,3,5-triazine-2-yl)-3-(hydroxymethyl)piperazine-1-carboxylate tert-butyl (R)-3-(hydroxymethyl)piperazine-1-carboxylate 38-1 A solution of ) (30 g, 139 mmol) dissolved in DCM (800 mL) was stirred, and DIPEA (72.7 mL, 416 mmol) was added at -45°C, and stirring was continued for 15 minutes. Then, to this reaction mixture, 2,4,6-trichloro-1,3,5-triazine (38-2 (38.4g, 208 mmol) was added at -45°C. The reaction mixture was stirred at -45°C for 20 minutes. The reaction mixture was diluted with water (500 mL) and then diluted with pharmaceutically acceptable phosphate (3 × 200 mL). The organic layers were combined, washed with water (2 × 200 mL), dehydrated with Na₂SO₄, and concentrated under reduced pressure. 38-3 This was obtained.

[0142] M / Z (ESI): 364.19 [M+H] + . Synthesis of 38-4: tert-butyl (R)-3-(hydroxymethyl)-4-(1,3,5-triazin-2-yl)piperazine-1-carboxylate 38-3 A solution of (20 g, 54.9 mmol) dissolved in EtOH (500 mL) was stirred, and sodium acetate (4.50 g, 54.9 mmol) and 10% Pd-C (5.84 g, 27.5 mmol) were added at room temperature. The reaction mixture was degassed and purged three times with nitrogen gas. The reaction mixture was stirred at 25°C for 16 hours under a H2 gas pressure of 60 psi. The reaction mixture was filtered through a Celite bed, washed with ELISA (500 mL), and concentrated under reduced pressure. 38-4 This was obtained.

[0143] M / Z (ESI): 296.34 [M+H] + . Synthesis of 38-5: (R)-(1-(1,3,5-triazin-2-yl)piperazin-2-yl)methanol hydrochloride 38-4 (15 g, 50.8 mmol) was dissolved in DCM (200 mL), and while stirring, HCl (6.03 mL, 50.8 mmol) from 1,4-dioxane was added at 0°C. The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was concentrated under reduced pressure. The crude compound was ground with diethyl ether (2 × 50 mL) and dried under reduced pressure. 38-5 This was obtained.

[0144] M / Z (ESI): 196.13 [M+H] + . Synthesis of 38-6: (R)-(4-(5-iodopyrimidine-2-yl)-1-(1,3,5-triazine-2-yl)piperazine-2-yl)methanol 38-5(9.5 g, 41.0 mmol) was dissolved in DMF (200 mL) and 2-chloro-5-iodopyrimidine (11.83 g, 49.2 mmol) and K2CO3 (17.00 g, 123 mmol) were added at room temperature while the solution was stirred. The reaction mixture was stirred at 80 °C for 16 hours. The reaction mixture was quenched with water (200 mL) and then quenched with siRNA (3 × 150 mL). The organic layers were combined, dehydrated with Na2SO4, and concentrated under reduced pressure. The crude compound was purified using a 300 g (100-200 mesh) silica gel cartridge, and the compound was eluted with 50% siRNA in petroleum ether. The pure fractions were combined and concentrated under reduced pressure. 38-6 This was obtained.

[0145] M / Z (ESI): 400.22 [M+H] + . Synthesis of 38-7: (R)-2-(2-((2,2-dimethoxyethoxy)methyl)-4-(5-iodopyrimidine-2-yl)piperazine-1-yl)-1,3,5-triazine 38-6 A solution of (2 g, 5.01 mmol) dissolved in DMF (30 mL) was stirred, and 60% NaH (0.401 g, 10.02 mmol) from the oil was added at 0°C. The reaction mixture was stirred at 0°C for 30 minutes. Next, 2-bromo-1,1-dimethoxyethane (3.39 g, 20.04 mmol) was added to this reaction mixture at 0°C. The reaction mixture was stirred at 50°C for 12 hours. The reaction mixture was diluted with water (100 mL) and extracted with ELISA (3 × 100 mL). The organic layers were combined, dehydrated with Na₂SO₄, and concentrated under reduced pressure. The crude compound was purified using a 100 g (100-200 mesh) silica gel cartridge, and the compound was eluted with 25% ELISA in petroleum ether. The pure fractions were combined and concentrated under reduced pressure. 38-7 This was obtained.

[0146] M / Z (ESI): 488.29 [M+H] + . Synthesis of 38-8: (R)-2-((4-(5-iodopyrimidine-2-yl)-1-(1,3,5-triazine-2-yl)piperazine-2-yl)methoxy)acetaldehyde 38-7(1.9 g, 3.90 mmol) was dissolved in 1,4-dioxane (30 mL), and while stirring, 50% HCl in water (1.281 mL, 15.60 mmol) was added at 0°C. The reaction mixture was stirred at 25°C for 2 hours. The reaction mixture was diluted with saturated NaHCO3 aqueous solution (100 mL) and extracted with SiO2 (3 × 100 mL). The organic layers were combined and dehydrated with Na2SO4, and concentrated under reduced pressure. 38-8 This was obtained.

[0147] M / Z (ESI): 442.22 [M+H] + . Synthesis of 38-9: (R)-2-((4-(5-iodopyrimidine-2-yl)-1-(1,3,5-triazine-2-yl)piperazine-2-yl)methoxy)ethane-1-ol 38-8 (1.2g, 2.72 mmol) was dissolved in MeOH (20 mL) and, while stirring, NaBH4 (0.206 g, 5.44 mmol) was added at 0°C. The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure and diluted with water (100 mL). The aqueous layer was extracted with SiO2 (3 × 150 mL). The organic layers were combined and dehydrated with Na2SO4, concentrated under reduced pressure, 38-9 This was obtained.

[0148] M / Z (ESI): 444.29 [M+H] + . Synthesis of 38-10: (R,E)-2-((4-(5-(2-(6-(oxazol-5-yl)pyridine-3-yl)vinyl)pyrimidine-2-yl)-1-(1,3,5-triazine-2-yl)piperazine-2-yl)methoxy)ethane-1-ol 38-9 (500 mg, 1.128 mmol) was dissolved in DMF (8 mL), and the solution was purged with argon gas for 10 minutes while stirring. Then, to this reaction mixture, 36-2(233 mg, 1.354 mmol), DIPEA (0.591 mL, 3.38 mmol), and chloro[(tri-tert-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) (57.8 mg, 0.113 mmol) were added at room temperature. The reaction mixture was purged again with argon for a further 10 minutes. The reaction mixture was stirred at 80°C for 12 hours. The reaction mixture was diluted with water (300 mL) and extracted with ethyl acetate (3 × 150 mL). The organic layers were combined, dehydrated with Na₂SO₄, and concentrated under reduced pressure. The crude compound was purified using a 100 g (100-200 mesh) silica gel cartridge, and the compound was eluted with 8% MeOH in DCM. The pure fractions were combined and concentrated under reduced pressure. 38-10 This was obtained.

[0149] M / z (ESI) = 488.36 [M+H] + Synthesis of 38: (R,E)-5-(5-(2-(2-(3-((2-(2-fluoroethoxy)ethoxy)methyl)-4-(1,3,5-triazin-2-yl)piperazin-1-yl)pyrimidine-5-yl)vinyl)pyridine-2-yl)oxazole 38-10 (350 mg, 0.718 mmol) was dissolved in DMF (4 mL) and, while stirring, 60% NaH (57.4 mg, 1.436 mmol) from the oil was added at 0°C. The reaction mixture was stirred at 0°C for 30 minutes. Next, 1-fluoro-2-iodoethane (500 mg, 2.87 mmol) was added to this reaction mixture at 0°C. The reaction mixture was stirred at 25°C for 12 hours. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (3 × 180 mL). The organic layers were combined, dehydrated with Na₂SO₄, and concentrated under reduced pressure. The crude compound was purified by prep HPLC. The pure fractions were combined and freeze-dried. 38 This was obtained.

[0150] M / z (ESI) = 534.31 [M+H] + . Purification: PREP HPLC method Mobile phase - 10 mM ammonium bicarbonate in H2O: MeCN Column - Princetonsphere (21.2 × 250 mm), 5 μm Flow rate - 19.0mL / min / Gradient method - 0 / 40, 8 / 45, 14 / 45, 14.05 / 100, 17 / 100, 17.05 / 40, 20 / 40.

[0151] 1 H NMR (400 MHz, DMSO-d6) δ = 8.76 (d, J = 1.8 Hz, 1H), 8.70 (s, 2H), 8.64 (s, 2H), 8.54 (s, 1H), 8.11 (dd, J = 2.1, 8.4 Hz, 1H), 7.83 - 7.76 (m, 2H), 7.35 - 7.22 (m, 2H), 5.02 - 4.96 (m, 1H), 4.83 - 4.77 (m, 1H), 4.65 - 4.38 (m, 4H), 3.63 - 3.44 (m, 8H), 3.35 - 3.33 (m, 1H), 3.30 (br s, 1H), 3.21 - 3.14 (m, 1H). Examples 39-A and 39-B 1-((2-((R)-4-(5-((E)-2-(6-(1H-imidazole-1-yl)pyridine-3-yl)vinyl)pyrimidine-2-yl)-2-(methoxymethyl)piperazine-1-yl)pyrimidine-5-yl)oxy)-3-fluoropropane-2-ol [ka] Synthesis of 39-2: (R)-2-chloro-5-(oxiran-2-ylmethoxy)pyrimidine 2-Chloropyrimidine-5-ol (2.0 g, 15.32 mmol) was dissolved in DMF (20 mL) and, while stirring, cesium carbonate (7.49 g, 22.98 mmol) and (R)-2-(chloromethyl)oxirane (7.09 g, 77 mmol) were added at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at 25 °C for 18 hours. The reaction mixture was concentrated under reduced pressure, diluted with 10% MeOH:DCM (20 mL), and filtered. The reaction mixture was concentrated under reduced pressure. The crude compound was purified by biotage column chromatography using a 25 g silica cartridge, and the compound was eluted using a gradient of 10% MeOH in DCM. The pure fraction was concentrated under reduced pressure. 39-2 This was obtained.

[0152] M / Z (ESI): 186.96 [M+H] + . Synthesis of 39-3: 1-((2-chloropyrimidine-5-yl)oxy)-3-fluoropropane-2-ol 39-2 (900 mg, 4.82 mmol) was mixed with triethylamine hydrofluoride (3 mL, 4.82 mmol) at room temperature. The reaction mixture was stirred at 80°C for 18 hours. The reaction mixture was cooled to room temperature. The reaction mixture was basicized with saturated NaHCO3 solution (pH approximately 8) and extracted with ethylethanol (100 mL). The organic layers were combined and washed with water (100 mL), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by biotage column chromatography using a 25 g silica (230-400 mesh) cartridge, and the compound was eluted with a gradient of 40% ethylethanol in petroleum ether. The pure fraction was concentrated under reduced pressure. 39-3 This was obtained.

[0153] M / Z (ESI): 207.02 [M+H] + . Synthesis of 39-4: 2-chloro-5-(3-fluoro-2-(methoxymethoxy)propoxy)pyrimidine 39-3( A solution of 0.3 g (1.452 mmol) was dissolved in THF (15 mL), and while stirring, sodium hydride (0.116 g, 2.90 mmol) was added at 0°C under a nitrogen atmosphere. Then, MOM-Cl (0.165 mL, 2.178 mmol) was added dropwise to the reaction mixture at 0°C. The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was quenched with ice water (20 mL) and extracted with ethyl acetate (20 mL). The organic layers were combined and washed with water (20 mL), dehydrated with Na₂SO₄, filtered, and concentrated under reduced pressure. The crude compound was purified by biotage column chromatography using a 25 g silica column (100-200 mesh) cartridge, and the compound was eluted with a gradient of 40% ethyl acetate in petroleum ether. The pure fraction was concentrated under reduced pressure. 39-4 This was obtained.

[0154] M / Z (ESI): 251.03[M+H] + . Synthesis of 39-5: 5-((E)-2-(6-(1H-imidazole-1-yl)pyridine-3-yl)vinyl)-2-((3R)-4-(5-(3-fluoro-2-(methoxymethoxy)propoxy)pyrimidine-2-yl)-3-(methoxymethyl)piperazine-1-yl)pyrimidine (R,E)-5-(2-(6-(1H-imidazole-1-yl)pyridine-3-yl)vinyl)-2-(3-(methoxymethyl)piperazine-1-yl)pyrimidine( Int E )(140mg, 0.371 mmol) and 39-4 A solution of (307 mg, 1.224 mmol) dissolved in 1,4-dioxane (10 mL) was stirred, and sodium tert-butoxide (143 mg, 1.484 mmol) was added at room temperature, and the mixture was degassed with nitrogen for 2 minutes. Then, under a nitrogen atmosphere, chloro(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (28.8 mg, 0.037 mmol) was added to the reaction mixture at room temperature. The reaction mixture was stirred at 150°C for 3 hours under microwave irradiation. The reaction mixture was quenched with water (10 mL) and extracted with ELISA (2 × 10 mL). The organic layers were combined, washed with water (20 mL), dehydrated with Na₂SO₄, filtered, and concentrated under reduced pressure. The crude compounds were mixed and purified by biotage column chromatography using a 12 g silica (100-200 mesh) cartridge, and the compounds were eluted with a gradient of 10% MeOH in DCM. The pure fraction was concentrated under reduced pressure, and the resulting compound was washed with diethyl ether (10 mL). 39-5 This was obtained.

[0155] M / Z (ESI): 592.45 [M+H] + . Synthesis of 39-A and 39-B: 1-((2-((R)-4-(5-((E)-2-(6-(1H-imidazole-1-yl)pyridine-3-yl)vinyl)pyrimidine-2-yl)-2-(methoxymethyl)piperazine-1-yl)pyrimidine-5-yl)oxy)-3-fluoropropane-2-ol 39-5 A solution of (40 mg, 0.068 mmol) dissolved in DCM (10 mL) was stirred, and 1,4-dioxane hydrochloride (0.017 mL, 0.068 mmol) was added at 0°C under a nitrogen atmosphere. The reaction mixture was stirred at 25°C for 3 hours. The reaction mixture was concentrated under reduced pressure. The crude compound was purified by SFC purification. The pure fraction was concentrated under reduced pressure and separately freeze-dried. 39-A (Peak -1) and 39-B (Peak -2) This was obtained.

[0156] M / Z (ESI): 548.37 [M+H] + . 1 H NMR (DMSO-d6, 400 MHz): δ (ppm) 8.68 (s, 2H), 8.54-8.63 (m, 2H), 8.26 (s, 2H), 8.20-8.25 (m, 1H), 8.01-8.13 (m, 1H), 7.98 (s, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.21-7.33 (m, 2H), 7.13 (s, 1H), 6.52 (s, 5H), 5.45 (d, J = 4.8 Hz, 1H), 4.79 (d, J = 11.2 Hz, 2H), 4.35-4.60 (m, 4H), 3.92-4.08 (m, 2H), 3.38-3.42 (m, 2H), 3.21-3.28 (m, 1H), 3.10-3.21 (m, 3H). Analytical NP-HPLC conditions: カラム / inch method: Chiralpak IA (250×4.6×5μ) Mobile phase: DCM:DIPA(80:20:0.2%) Flow rate: 0.5 mL / min Temperature: ambient temperature Wavelength: 340nm.

[0157] Preparative NP-HPLC conditions: カラム / inch method: Chiralpak IA (250×10×5μ) Mobile phase: DCM:DIPA(80:20:0.2%) Flow rate: 3.0 mL / min.

[0158] Example 40 (R,E)-2-(3-((2-fluoroethoxy)methyl)-4-(pyrimidine-2-yl)piperazine-1-yl)-5-(2-(6-(4-methyl-1H-imidazole-1-yl)pyridine-3-yl)vinyl)pyrimidine

change

[0159] M / Z (ESI): 237.98 [M+H] + . Synthesis of 40-2: 2-(4-methyl-1H-imidazole-1-yl)-5-vinylpyridine 40-1 A solution of (1 g, 4.20 mmol) was dissolved in 1,4-dioxane (10 mL) and water (10 mL). The solution was stirred, degassed, and purged with argon gas. Then, while stirring the degassed solution, tribasic potassium phosphate (2.67 g, 12.60 mmol), potassium vinyl trifluoroborate (1.125 g, 8.40 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.154 g, 0.210 mmol) were added at room temperature. The reaction mixture was stirred at 100 °C for 16 hours. The reaction mixture was quenched with ice water (10 mL) and extracted with dimethyl phosphate (2 × 10 mL). The organic layers were combined, washed with brine (10 mL), dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude compound was purified using a (100-200 mesh) silica gel column, and the compound was eluted with 100% siRNA. The pure fraction was concentrated under reduced pressure. 40-2 This was obtained.

[0160] M / Z (ESI): 186.02 [M+H] + . Synthesis of 40-3: (R)-5-bromo-2-(3-((2-fluoroethoxy)methyl)-4-(pyrimidine-2-yl)piperazine-1-yl)pyrimidine Int BA solution of (1 g, 2.85 mmol) dissolved in THF (10 mL) was stirred, and 1-fluoro-2-iodoethane (0.381 mL, 5.69 mmol) and sodium hydride (0.273 g, 11.39 mmol) were added at room temperature. The reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was quenched with ice water (10 mL), and the aqueous layer was extracted with ELISA (3 × 20 mL). The organic layers were combined and washed with brine (10 mL), dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude compound was purified by (100-200 mesh) silica gel column elution, and the compound was eluted with 50% ELISA in petroleum ether. The pure fractions were combined and concentrated under reduced pressure. 40-3 This was obtained.

[0161] M / Z (ESI): 399.13 [(M+2)+H] + . Synthesis of 40: (R,E)-2-(3-((2-fluoroethoxy)methyl)-4-(pyrimidine-2-yl)piperazine-1-yl)-5-(2-(6-(4-methyl-1H-imidazole-1-yl)pyridine-3-yl)vinyl)pyrimidine 40-2 A solution of (200 mg, 1.080 mmol) dissolved in 1,4-dioxane (5 mL) was stirred, degassed, and purged with argon gas. Then, N,N-diisopropylethylamine (0.581 mL, 3.24 mmol) was added to this reaction mixture. 40-3 (214 mg, 0.540 mmol) and chloro[(tri-tert-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) (27.7 mg, 0.054 mmol) were added at room temperature. The reaction mixture was stirred in a microwave oven at 150°C for 16 hours. The reaction mixture was quenched with ice water (10 mL), and the aqueous layer was extracted with ethyl acetate (3 × 5 mL). The organic layers were combined, washed with brine (10 mL), dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by prep HPLC. The pure fractions were combined and freeze-dried. 40 This was obtained.

[0162] M / Z (ESI): 502.39 [M+H] + . Prep HPLC conditions: Machine ID: ANL-MCL-5-PREP-021 Karaman name: X-SELECT C18(19×250)mm 5μ カラムNo#: X-SELECT C18(19×250)mm 5μ Mobile phase-A: 10mM ammonium bicarbonate in water Mobile Phase-B: Atomori Matching プログラム(T / %B): 0 / 50, 2 / 50, 11 / 74, 11.1 / 100, 13 / 100, 13., / 50, 16 / 50 Flow rate (mL / min): 19.

[0163] 1 H NMR (400 MHz, DMSO-d6) δ = 8.67 (s, 2H), 8.57 - 8.56 (m, 1H), 8.45 - 8.38 (m, 3H), 8.19 (dd, J = 8.8 Hz, 2.3 Hz, 1H), 7.77 (d, J = 8.6 Hz, 1H), 7.67 (s, 1H), 7.25 (d, J = 2.4 Hz, 2H), 6.68 (t, J = 4.7 Hz, 1H), 4.94 - 4.87 (m, 1H), 4.86 - 4.79 (m, 1H), 4.59 - 4.39 (m, 4H), 3.67 - 3.47 (m, 4H), 3.30 - 3.12 (m, 3H), 2.20 - 2.15 (m, 3H). Example 41 (R,E)-5-(5-(2-(2-(3-((2-fluoroethoxy)methyl)-4-(1,3,5-triazin-2-yl)piperazin-1-yl)pyrimidine-5-yl)vinyl)pyridine-2-yl)oxazole

change

[0164] M / Z (ESI): 446.19 [M+H] + . Synthesis of 41: (R,E)-5-(5-(2-(2-(3-((2-fluoroethoxy)methyl)-4-(1,3,5-triazin-2-yl)piperazin-1-yl)pyrimidine-5-yl)vinyl)pyridine-2-yl)oxazole 41-1 (80 mg, 0.151 mmol) was dissolved in ACN (1 mL), and the solution was purged with argon gas for 10 minutes while stirring. Then, into the stirring solution, 36-2 (51.9 mg, 0.301 mmol), DIPEA (0.105 mL, 0.603 mmol), and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (15.81 mg, 0.02 mmol) were added at room temperature, and the mixture was purged again with argon gas for another 10 minutes. The reaction mixture was stirred at 100°C for 12 hours. The reaction mixture was quenched with water (80 mL) and extracted with ELISA (3 × 80 mL). The organic layers were combined, dehydrated with anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude compound was purified by prep-HPLC (conditions: mobile phase - 10 mM ammonium bicarbonate in H2O: MeCN, column - X-Bridge C18 (19×250), flow rate - 18.0 mL / min, gradient method - 0 / 30, 7 / 42, 12 / 4 / 4 / 5, 12.05 / 100, 14 / 100, 14.05 / 30, 17 / 30). The pure fraction was concentrated under reduced pressure and freeze-dried.41 This was obtained.

[0165] M / Z (ESI): 490.42 [M+H] + . 1 H NMR (DMSO-d6, 400 MHz): δ (ppm) 8.76-8.75 (m, 1H), 8.70 (s, 2H), 8.64 (m, 2H), 8.54 (s, 1H), 8.11 (dd, J = 8.4Hz, 2.4Hz, 1H), 7.80-7.77 (m, 2H), 7.34-7.23 (m, 2H), 4.99-4.98 (m, 1H), 4.81 (d, J = 13.6 Hz, 1H), 4.62-4.56 (m, 2H), 4.50-4.36 (m, 2H), 3.66-3.64 (m, 1H), 3.58-3.56 (m, 3H), 3.34 (m, 1H), 3.27-3.26 (m, 1H), 3.20-3.17 (m, 1H). Example 42 (R,E)-5-(5-(2-(2-(3-((2-fluoroethoxy)methyl)-4-(pyrimidine-4-yl)piperazin-1-yl)pyrimidine-5-yl)vinyl)pyridine-2-yl)oxazole [ka] Synthesis of 42-2: tert-butyl (R)-3-(hydroxymethyl)-4-(pyrimidine-4-yl)piperazine-1-carboxylate 42-1 (2g, 6.08 mmol) was dissolved in MeOH (11 mL) and THF (11 mL). While stirring the solution, sodium acetate (0.998 g, 12.17 mmol) was added at room temperature. Then, 10% Pd / C (0.647 g, 6.08 mmol) was added to this reaction mixture at room temperature. The reaction mixture was stirred at 25°C for 16 hours under a hydrogen atmosphere. The reaction mixture was quenched with ice water (10 mL), and the solid was filtered through a Buchner funnel. The filtered solid was dried under reduced pressure. The crude compound was purified by Biotage flash column chromatography using a (100-200 mesh) silica gel column, and the compound was eluted with 10% ELISA in petroleum ether. The pure fractions were combined and concentrated under reduced pressure. 42-2 This was obtained.

[0166] M / Z (ESI): 295.11 [M+H] + Synthesis of 42-3: (R)-(1-(pyrimidine-4-yl)piperazin-2-yl)methanol 42-2 A solution of (1.5 g, 5.10 mmol) dissolved in DCM (20 mL) was stirred, and 4 M HCl (1.209 mL, 10.19 mmol) in 1,4-dioxane was added at room temperature. The reaction mixture was stirred at 25 °C for 4 hours. The reaction mixture was concentrated under reduced pressure and cold distilled using toluene. The crude compound was ground with pentane (5 mL) and dried under reduced pressure. 42-3 This was obtained.

[0167] M / Z (ESI): 195.10 [M+H] + Synthesis of 42-5: (R)-(4-(5-iodopyrimidine-2-yl)-1-(pyrimidine-4-yl)piperazine-2-yl)methanol 42-3 A solution of (1 g, 5.15 mmol) dissolved in DMF (25 mL) was stirred, and potassium carbonate (3.56 g, 25.7 mmol) and 2-chloro-5-iodopyrimidine (42-4) (1.238 g, 5.15 mmol) were added at room temperature. The reaction mixture was stirred at 80°C for 16 hours. The reaction mixture was quenched with ice water (20 mL) and extracted with ethyl acetate (3 × 20 mL). The organic layers were combined, washed with brine (10 mL), dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude compound was purified by Biotage flash chromatography using a (100-200 mesh) silica gel column, and the compound was eluted with 50% ethyl acetate in petroleum ether. The pure fractions were combined and concentrated under reduced pressure. 42-5 This was obtained.

[0168] M / Z (ESI): 399.13 [M+H] + Synthesis of 42-6: (R)-2-(3-((2-fluoroethoxy)methyl)-4-(pyrimidine-4-yl)piperazine-1-yl)-5-iodopyrimidine 42-5(5060079-0374-002) (500 mg, 1.256 mmol) was dissolved in THF (5 mL) and, while stirring, 1-fluoro-2-iodoethane (0.126 mL, 1.883 mmol) and sodium hydride (90 mg, 3.77 mmol) were added at room temperature. The reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was quenched with ice water (10 mL) and extracted with ethyl acetate (3 × 20 mL). The organic layers were combined, washed with brine (10 mL), dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude compound was purified by biotage using a (100-200 mesh) silica gel column, and the compound was eluted with 50% ethyl acetate in petroleum ether. The pure fractions were combined and concentrated under reduced pressure. 42-6 This was obtained.

[0169] M / Z (ESI): 445.12 [M+H] + Synthesis of 42: (R,E)-5-(5-(2-(2-(3-((2-fluoroethoxy)methyl)-4-(pyrimidine-4-yl)piperazin-1-yl)pyrimidine-5-yl)vinyl)pyridine-2-yl)oxazole 42-6 A solution of (100 mg, 0.225 mmol) dissolved in 1,4-dioxane (1 mL) was stirred, degassed, and purged with argon gas. Then, N,N-diisopropylethylamine (0.121 mL, 0.675 mmol) and 5-(5-vinylpyridine-2-yl)oxazole were added to this reaction mixture. 36-2 (46.5 mg, 0.270 mmol) and chloro[(tri-tert-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) (11.53 mg, 0.023 mmol) were added at room temperature. The reaction mixture was stirred at 100°C for 16 hours. The reaction mixture was quenched with ice water (10 mL) and extracted with ethyl acetate (3 × 10 mL). The organic layers were combined, washed with brine (5 mL), dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by prep HPLC. The pure fractions were combined and lyophilized. 42 This was obtained.

[0170] M / Z (ESI): 489.34 [M+H] + Prep HPLC purification conditions: Mobile phase - 10mM ammonium bicarbonate in H2O: MeCN カラム-LUNA C18(21.2×250)mm 5um Flow rate - 18 mL / min Matching - 0 / 38, 2 / 38, 15 / 40, 16 / 40.3, 16.05 / 100, 18.0 / 100, 18.05 / 38, 21.0 / 38.

[0171] 1 H NMR (400 MHz, DMSO-d6) δ = 8.76 (d, J = 1.8 Hz, 1H), 8.70 (s, 2H), 8.54 (s, 2H), 8.22 (d, J = 6.3 Hz, 1H), 8.11 (dd, J = 8.4 Hz, 2.1 Hz, 1H), 7.82 - 7.77 (m, 2H), 7.34 - 7.22 (m, 2H), 6.88 - 6.86 (m, 1H), 4.79 - 4.48 (m, 4H), 4.37 (br d, J = 4.1 Hz, 2H), 3.67 - 3.51 (m, 4H), 3.40 - 3.36 (m, 1H), 3.29 - 3.22 (m, 2H). Example 43 (R,E)-2-(2-((2-fluoroethoxy)methyl)-4-(5-(2-(2-(1-methyl-1H-pyrazole-4-yl)pyrimidine-5-yl)vinyl)pyrimidine-2-yl)piperazine-1-yl)-1,3,5-triazine

change

[0172] M / z (ESI) = 239.01 [M+H] + Synthesis of 43-3: 2-(1-methyl-1H-pyrazole-4-yl)-5-vinylpyrimidine 43-2 A solution of (1.00 g, 4.18 mmol) was dissolved in 1,4-dioxane (10 mL) and water (10 mL). While stirring, trifluoro(vinyl)-4-borane potassium salt (1.12 g, 8.37 mmol) and tripotassium phosphate (2.66 g, 12.5 mmol) were added at room temperature, and the mixture was degassed with argon at room temperature for 5 minutes. Then, PdCl2(dppf)-CH2Cl2 adduct (342 mg, 418 μmol) was added to the reaction mixture at room temperature. The reaction mixture was stirred at 100 °C for 16 hours. The reaction mixture was quenched with water (20 mL) and extracted with phenylethylamine (2 × 30 mL). The organic layers were combined and washed with brine (10 mL), dehydrated with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by biotage using a silica column, and the compound was eluted with 30% phenylethylamine in petroleum ether. The pure fractions are combined and concentrated under reduced pressure. 43-3 This was obtained.

[0173] M / Z (ESI): 187.00 [M+H] + . Synthesis of 43: (R,E)-2-(2-((2-fluoroethoxy)methyl)-4-(5-(2-(2-(1-methyl-1H-pyrazole-4-yl)pyrimidine-5-yl)vinyl)pyrimidine-2-yl)piperazin-1-yl)-1,3,5-triazine 41-1 (100 mg, 225 μmol) and 43-3 A solution of (50.2 mg, 270 μmol) dissolved in 1,4-dioxane (2 mL) was stirred, and DIPEA (117 μL, 674 μmol) was added at room temperature. The mixture was degassed with argon at room temperature for 5 minutes. Chloro(tri-t-butylphosphine)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (11.5 mg, 22.5 μmol) was then added to the reaction mixture at room temperature, and the mixture was again degassed with argon at room temperature for 5 minutes. The reaction mixture was stirred at 100 °C for 16 hours. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (2 × 20 mL). The organic layers were combined, washed with brine (10 mL), dehydrated with anhydrous sodium 2 SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by Prep HPLC (conditions: mobile phase - 10 mM ammonium bicarbonate in H2O: MeCN, column - X-Bridge C18 (19×250) mm, 5 μm, flow rate - 15.0 mL / min, gradient method: -0 / 28, 2 / 28, 11 / 59.4, 11.05 / 100, 13 / 100, 13.05 / 28, 16 / 28). The pure fractions were combined, concentrated under reduced pressure, and freeze-dried. 43 This was obtained.

[0174] M / Z (ESI): 504.39 [M+H] + . 1H NMR (400 MHz, DMSO-d6): δ (ppm) 8.91 (s, 2H), 8.68 (s, 2H), 8.64 (s, 2H), 8.38 (s, 1H), 8.03 (d, J = 0.4 Hz, 1H), 7.32 (d, J = 16.8 Hz, 1H), 7.16 (d, J = 16.4 Hz, 1H), 4.95-5.04 (m, 1H), 4.81 (d, J = 13.6 Hz, 1H), 4.55-4.67 (m, 2H), 4.33-4.52 (m, 2H), 3.91 (s, 3H), 3.63-3.69 (m, 1H), 3.58 (dd, J = 6.6 Hz, 3.0 Hz ,3H), 3.33-3.36 (m, 1H), 3.25-3.30 (m, 1H), 3.14-3.23 (m, 1H). Example 44 (R)-2-(2-((2-fluoroethoxy)methyl)-4-(5-((2-(1-methyl-1H-pyrazole-4-yl)pyrimidine-5-yl)ethinyl)pyrimidine-2-yl)piperazine-1-yl)-1,3,5-triazine [ka] Synthesis of 44-1: 2-(1-methyl-1H-pyrazole-4-yl)-5-((trimethylsilyl)ethynyl)pyrimidine 43-2 A solution of (2 g, 8.37 mmol) dissolved in ACN (24 mL) was stirred, and DIPEA (4.38 mL, 25.10 mmol) was added at room temperature. The reaction mixture was degassed and purged with argon gas for 15 minutes. Then, ethynyltrimethylsilane (1.786 mL, 12.55 mmol) and XPhos Pd G2 (0.658 g, 0.837 mmol) were added to the reaction mixture at room temperature. The reaction mixture was stirred in a sealed tube under a nitrogen atmosphere at 80°C for 16 hours. The reaction mixture was diluted with water (10 mL) and extracted with toluene (2 × 30 mL). The organic layers were combined, washed with brine (10 mL), dehydrated with anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude compound was purified using biotage with a 40 g (230-400 mesh) silica gel cartridge, and the compound was eluted with 30% phenylethylamine in petroleum ether. The pure fractions were combined and concentrated under reduced pressure. 44-1 This was obtained.

[0175] M / z (ESI) = 257.23 [M+H] + Synthesis of 44: (R)-2-(2-((2-fluoroethoxy)methyl)-4-(5-((2-(1-methyl-1H-pyrazole-4-yl)pyrimidine-5-yl)ethinyl)pyrimidine-2-yl)piperazine-1-yl)-1,3,5-triazine 41-1 (100 mg, 0.225 mmol) dissolved in DMF (1 mL) is stirred while adding to the solution. 44-1 (63.3 mg, 0.247 mmol) and potassium carbonate (93 mg, 0.674 mmol) were added at room temperature. The reaction mixture was degassed and purged with argon gas for 15 minutes. Then, X-Phos Pd G2 (17.67 mg, 0.022 mmol) was added to the reaction mixture at room temperature. The reaction mixture was stirred in a sealed tube under a nitrogen atmosphere at 80°C for 16 hours. The reaction mixture was diluted with water (10 mL) and extracted with pharmaceutically acceptable phosphate (2 × 30 mL). The organic layers were combined, washed with brine (10 mL), dehydrated with anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude compound was purified by prep HPLC (Method: Mobile phase - 10 mM ammonium bicarbonate in H2O: MeCN, Column - YMC HYDROSPHER C18 (20×250) mm, 5 μm, Flow rate - 18.0 mL / min, Gradient method 0 / 45, 10.5 / 66, 10.51 / 100, 13 / 100, 13.1 / 45, 16 / 45). The pure fractions were combined and freeze-dried. 44 This was obtained.

[0176] M / z (ESI) = 502.35 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ = 8.89 (s, 2H), 8.63 (d, J = 4.4 Hz, 4H), 8.42 (s, 1H), 8.05 (s, 1H), 4.98-4.96 (m, 1H), 4.80 (d, J = 13.6 Hz, 1H), 4.59-4.55 (m, 2H), 4.44 (dt, J = 4, 8.0 Hz, 2H), 3.92 (s, 3H), 3.65-3.55 (m, 4H), 3.40-3.36 (m, 1H), 3.29-3.20 (m, 2H). Example 45 (R)-5-((6-(4H-1,2,4-triazol-4-yl)pyridine-3-yl)ethinyl)-2-(4-(6-fluoropyrimidine-4-yl)-3-(methoxymethyl)piperazine-1-yl)pyrimidine [ka] Synthesis of 45-2: tert-butyl (R)-4-(6-fluoropyrimidine-4-yl)-3-(hydroxymethyl)piperazine-1-carboxylate 5 g, 23.12 mmol of tert-butyl (R)-3-(hydroxymethyl)piperazine-1-carboxylate was dissolved in 80 mL of DMF. While stirring, 3.22 g, 27.7 mmol of 4,6-difluoropyrimidine and 12.11 mL, 69.4 mmol of DIPEA were added at room temperature. The reaction mixture was stirred at 70°C for 16 hours under an argon atmosphere. The reaction mixture was diluted with 70 mL of water and extracted with SiO2 (3 × 70 mL). The organic layers were combined, washed with 70 mL of brine, dehydrated with anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was purified by biotage using a 120 g (230-400 mesh) silica gel cartridge, and the compound was eluted with 35% SiO2 in petroleum ether. The pure fractions were combined and concentrated under reduced pressure. 45-2 This was obtained.

[0177] M / z (ESI) = 313.31 [M+H] + . Synthesis of 45-3: tert-butyl (R)-4-(6-fluoropyrimidine-4-yl)-3-(methoxymethyl)piperazine-1-carboxylate 45-2 A solution of (5.5 g, 17.61 mmol) dissolved in DMF (70 mL) was stirred, and methyl iodide (2.202 mL, 35.2 mmol) was added at 0°C. Then, NaH (1.056 g, 26.4 mmol) was added to this reaction mixture in small amounts at 0°C. The reaction mixture was stirred at 25°C for 3 hours under an argon atmosphere. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (2 × 100 mL). The organic layers were combined and washed with brine (100 mL), dehydrated with anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography, and the compound was eluted with 15% ethyl acetate in petroleum ether. The pure fractions were combined and concentrated under reduced pressure. 45-3 This was obtained.

[0178] M / z (ESI) = 327.34 [M+H] + . Synthesis of 45-4: (R)-4-fluoro-6-(2-(methoxymethyl)piperazin-1-yl)pyrimidine 45-3 (4.5 g, 13.79 mmol) was dissolved in DCM (60 mL) and, while stirring, 4 M HCl (17.23 mL, 68.9 mmol) in 1,4-dioxane was added at room temperature. The reaction mixture was stirred under an argon atmosphere at 25°C for 16 hours. The reaction mixture was concentrated under reduced pressure. 45-4 This was obtained.

[0179] M / z (ESI) = 227.13 [M+H] + . Synthesis of 45-5: (R)-2-(4-(6-fluoropyrimidine-4-yl)-3-(methoxymethyl)piperazine-1-yl)-5-iodopyrimidine 45-4 A solution of (4.5 g, 17.13 mmol) dissolved in DMF (70 mL) was stirred, and 2-chloro-5-iodopyrimidine (4.53 g, 18.84 mmol) and DIPEA (14.96 mL, 86 mmol) were added at room temperature. The reaction mixture was stirred at 50°C for 16 hours under an argon atmosphere. The reaction mixture was diluted with water (200 mL). A precipitate formed, which was stirred at room temperature for 10 minutes. The solid was then filtered and dried under reduced pressure. The crude compound was purified by biotage using a 120 g (230-400 mesh) silica gel cartridge, and the compound was eluted with 35% siRNA in petroleum ether. The pure fractions were combined and concentrated under reduced pressure. 45-5 This was obtained.

[0180] M / z (ESI) = 431.14 [M+H] + . Synthesis of 45: (R)-5-((6-(4H-1,2,4-triazole-4-yl)pyridine-3-yl)ethinyl)-2-(4-(6-fluoropyrimidine-4-yl)-3-(methoxymethyl)piperazine-1-yl)pyrimidine 45-5 (200 mg, 0.465 mmol) dissolved in DMF (2 mL) is stirred while adding to the solution. 45-6(135 mg, 0.558 mmol), K2CO3 (193 mg, 1.395 mmol), and copper(I) iodide (9 mg, 0.047 mmol) were added at room temperature. The reaction mixture was degassed and purged with argon for 10 minutes. Next, davephos G2 palladacycle (33 mg, 0.047 mmol) was added to the reaction mixture at room temperature. The reaction mixture was stirred in a sealed tube at 80°C for 2 hours. The reaction mixture was diluted with cold water (10 mL), filtered through a Celite pad, washed with DCM (20 mL), and the organic layer was set aside. Next, the aqueous layer was extracted with DCM (2 × 20 mL). The organic layers were combined and washed with brine (20 mL), dehydrated with anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was ground with diethyl ether (10 mL), and the compound was purified by prep HPLC. The pure fractions are combined and freeze-dried. 45 This was obtained.

[0181] M / z (ESI) = 473.38 [M+H] + Prep HPLC purification: X-Bridge C18 PACK: Mobile phase - 10 mM ammonium bicarbonate in H2O: MeCN, Column - X-Bridge PACK, C18 (25×250) mm, 5 μm, Flow rate - 20.0 mL / min, Gradient method - 0 / 35, 4 / 35, 10.5 / 60, 10.51 / 100, 13 / 100, 13.05 / 35, 16 / 35.

[0182] 1H NMR (400 MHz, DMSO-d6) δ = 9.34 (s, 2H), 8.71 (d, J = 1.6 Hz, 1H), 8.65 (s, 2H), 8.36 (d, J = 2.6 Hz, 1H), 8.25 (dd, J = 2.1, 8.5 Hz, 1H), 7.97 (d, J = 8.5 Hz, 1H), 6.58 (s, 1H), 5.04 - 4.67 (m, 2H), 4.60 - 4.45 (m, 1H), 4.42 - 4.11 (m, 1H), 3.36 (br s, 4H), 3.30 - 3.28 (m, 1H), 3.20 (s, 3H). Example 46 (R)-2-(4-(5-((2-(1-(2-fluoroethyl)-1H-pyrazole-4-yl)pyrimidine-5-yl)ethinyl)pyrimidine-2-yl)-2-(methoxymethyl)piperazine-1-yl)-1,3,5-triazine [ka] Synthesis of 46-2: 1-(2-fluoroethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole( 46-1 A solution of (5g, 25.8 mmol) and 1-fluoro-2-iodoethane (8.96g, 51.5 mmol) was dissolved in THF (100 mL) and stirred. NaH (2.061 g, 51.5 mmol) was added in small amounts at 0°C under argon. The reaction mixture was stirred at 25°C for 24 hours. The reaction mixture was poured into crushed ice water (50 mL) and extracted with ELISA (2 × 50 mL). The organic layers were combined and washed with brine (100 mL), dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude compound was washed with diethyl ether (10 mL) and dried under reduced pressure. 46-2 This was obtained.

[0183] M / z (ESI) = 241.06 [M+H] + Synthesis of 46-4: 5-bromo-2-(1-(2-fluoroethyl)-1H-pyrazole-4-yl)pyrimidine 46-2600 mg, 2.499 mmol of (P) was dissolved in 1,4-dioxane (15 mL) and water (3 mL). 5-bromo-2-iodopyrimidine (783 mg, 2.75 mmol) was added to this solution at 25°C while stirring. The reaction mixture was degassed and purged with argon for 10 minutes. Then, Cs2CO3 (2443 mg, 7.50 mmol) and Pd(dppf)Cl2 (201 mg, 0.275 mmol) were added to the reaction mixture at 25°C. The reaction mixture was stirred at 130°C for 2 hours. The reaction mixture was partitioned between water (20 mL) and ethyl acetate (20 mL). The organic layer was dehydrated with sodium sulfate, filtered, and concentrated under reduced pressure. The crude compound was purified by biotage using a 12 g silica gel cartridge, and the compound was eluted with 50% ethyl acetate in petroleum ether. The pure fractions were combined and concentrated under reduced pressure to obtain 46-4.

[0184] M / z (ESI) = 271.18 [M+H] + Synthesis of 46-5: 2-(1-(2-fluoroethyl)-1H-pyrazole-4-yl)-5-((trimethylsilyl)ethynyl)pyrimidine 46-4 A solution of (180 mg, 0.664 mmol) dissolved in THF (6 mL) was stirred, degassed, and purged with argon for 5 minutes. Then, XPhos Pd G2 (52.2 mg, 0.066 mmol), DIPEA (0.348 mL, 1.992 mmol), copper(I) iodide (12.65 mg, 0.066 mmol), and trimethylsilylacetylene (100 mg, 1.018 mmol) were added to this reaction mixture at 25°C. The reaction mixture was stirred at 80°C for 12 hours. The reaction mixture was diluted with siRNA (20 mL) and washed with water (20 mL). The organic layer was dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude compound was purified by biotage using a 4 g silica gel cartridge, and the compound was eluted with 30% siRNA in petroleum ether. The pure fractions were combined and concentrated under reduced pressure. 46-5 This was obtained.

[0185] M / z (ESI) = 289.28 [M+H] + Synthesis of 46-6: (R)-2-(4-(5-iodopyrimidine-2-yl)-2-(methoxymethyl)piperazine-1-yl)-1,3,5-triazine 38-6 A solution of (1.00 g, 2.51 mmol) was dissolved in DMF (20 mL), and while stirring, NaH (90.2 mg, 3.76 mmol) was added at 0°C and the mixture was stirred for 30 minutes at 0°C. Then, methyl iodide (470 μL, 7.52 mmol) was added dropwise to the reaction mixture at 0°C. The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was quenched with cold water (50 mL) and extracted with ethyl acetate (2 × 50 mL). The organic layers were combined and washed with brine (100 mL), dehydrated with anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude compound was purified by biotage using a 120 g silica cartridge, and the compound was eluted with 15% ethyl acetate in hexane. The pure fractions were combined and concentrated under reduced pressure. 46-6 This was obtained.

[0186] M / Z (ESI): 414.10 [M+H] + . Synthesis of 46: (R)-2-(4-(5-((2-(1-(2-fluoroethyl)-1H-pyrazole-4-yl)pyrimidine-5-yl)ethinyl)pyrimidine-2-yl)-2-(methoxymethyl)piperazine-1-yl)-1,3,5-triazine 46-6 (200 mg, 0.484 mmol) dissolved in DMF (4 mL) is stirred while adding to the solution. 46-5 (100 mg, 0.347 mmol) was added at 25°C. The reaction mixture was degassed and purged with argon for 10 minutes. Then, K2CO3 (201 mg, 1.452 mmol) and davephos g2 palladacycle (34.1 mg, 0.048 mmol) were added to the reaction mixture at 25°C. The reaction mixture was stirred at 80°C for 3 hours. The reaction mixture was diluted with HCl (10 mL) and water (10 mL) and filtered through a Celite bed. The organic layer was dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude compound was purified by biotage using a 4 g silica gel cartridge, and the compound was eluted with 70% HCl in petroleum ether. The pure fractions were combined and concentrated under reduced pressure. The resulting compound was purified again by prep HPLC. The pure fractions were combined and lyophilized. 46 This was obtained.

[0187] M / z (ESI) = 502.29 [M+H] + Prep HPLC purification: X-Bridge: Mobile phase - 10 mM ammonium bicarbonate in H2O: MeCN Column - X-Bridge, C18 (10×250) mm, 5 μm, Flow rate - 19.0 mL / min Gradient method - 0 / 35, 2 / 35, 7.0, 40, 13.0 / 51, 1.1 / 100, 15.9 / 100, 16 / 35, 21 / 35 1 H NMR (400 MHz, DMSO-d6) δ = 8.91 (s, 2H), 8.74-8.68 (m, 4H), 8.50 (s, 1H), 8.13 (s, 1H), 5.02 - 4.97 (m, 1H), 4.89-4.85 (m, 1H), 4.79-4.73 (m, 2H), 4.61-4.46 (m, 4H), 3.44 (d, J = 6.8 Hz, 2H), 3.38-3.34 (m, 1H), 3.30-3.18 (m, 5H). Example 47 (R)-2-(4-(5-((6-(1-(2-fluoroethyl)-1H-pyrazole-4-yl)pyridine-3-yl)ethinyl)pyrimidine-2-yl)-2-(methoxymethyl)piperazine-1-yl)-1,3,5-triazine [ka] Synthesis of 47-2: 2-bromo-5-((trimethylsilyl)ethynyl)pyridine 2-bromo-5-iodopyridine ( 47-1A solution of (5g, 17.61 mmol) dissolved in THF (75 mL) was stirred and purged with argon gas for 10 minutes. Then, TEA (7.36 mL, 52.8 mmol), copper(I) iodide (0.168 g, 0.881 mmol), dichlorobis(triphenylphosphine)palladium(II) (1.236 g, 1.761 mmol) and trimethylsilylacetylene (1.903 g, 19.37 mmol) were added to this reaction mixture at room temperature, and the mixture was purged again with argon for another 10 minutes. The reaction mixture was stirred at 80°C for 3 hours. The reaction mixture was diluted with water (200 mL) and extracted with SiO2 (3 × 180 mL). The organic layers were combined and dehydrated with Na2SO4, and concentrated under reduced pressure. The crude compound was purified using a 100 g (100-200 mesh) silica gel cartridge, and the compound was eluted with 20% siRNA in petroleum ether. The pure fractions were combined and concentrated under reduced pressure. 47-2 This was obtained.

[0188] M / Z (ESI): 254.12 [M+H] + . Synthesis of 47-3: 5-Ethynyl-2-(1-(2-fluoroethyl)-1H-pyrazole-4-yl)pyridine 47-2A solution of (1.2 g, 4.72 mmol) dissolved in 1,4-dioxane (12 mL) and water (5 mL) was stirred and purged with argon gas for 10 minutes. Then, 1-(2-fluoroethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.680 g, 2.83 mmol), tribasic potassium phosphate (3.01 g, 14.16 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)] (0.345 g, 0.472 mmol) were added to this reaction mixture at room temperature, and the mixture was purged again with argon for another 10 minutes. The reaction mixture was stirred at 100 °C for 12 hours. The reaction mixture was diluted with water (100 mL) and extracted with SiO2 (3 × 100 mL). The organic layers were combined, dehydrated with Na2SO4, and concentrated under reduced pressure. The crude compound was purified using a 100 g (100-200 mesh) silica gel cartridge, and the compound was eluted with 20% siRNA in petroleum ether. The pure fractions were combined and concentrated under reduced pressure. 47-3 This was obtained.

[0189] M / Z (ESI): 216.23 [M+H] + . Synthesis of 47: (R)-2-(4-(5-((6-(1-(2-fluoroethyl)-1H-pyrazole-4-yl)pyridine-3-yl)ethynyl)pyrimidine-2-yl)-2-(methoxymethyl)piperazine-1-yl)-1,3,5-triazine 46-6 (600 mg, 1.452 mmol) was dissolved in DMF (5 mL), and the solution was purged with argon gas for 10 minutes while stirring. Then, to this reaction mixture, 47-3(344 mg, 1.597 mmol), K2CO3 (602 mg, 4.36 mmol), copper(I) iodide (27.7 mg, 0.145 mmol), and davephos g2 palladacycle (102 mg, 0.145 mmol) were added at room temperature, and the mixture was purged again with argon for another 10 minutes. The reaction mixture was stirred at 80°C for 12 hours. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 × 100 mL). The organic layers were combined, dehydrated with Na2SO4, and concentrated under reduced pressure. The crude compound was purified by 100 g (100-200 mesh) silica gel column, and the compound was eluted with 60% ethyl acetate in petroleum ether. The pure fractions were combined and concentrated under reduced pressure. The resulting compound was purified by prep HPLC. The pure fractions were combined and freeze-dried. 47 This was obtained.

[0190] M / Z (ESI): 501.35 [M+H] + . PREP HPLC method. Mobile phase - 10 mM ammonium bicarbonate in H2O: MeCN Column - X-Bridge C18 (19×250) Flow rate - 18.0mL / min Gradient method - 0 / 30, 7 / 42, 12 / 44 / 5, 12 / 05 / 100, 14 / 100, 14 / 05 / 30, 17 / 30.

[0191] 1H NMR (400 MHz, DMSO-d6) δ (ppm) = 8.88 - 8.57 (m, 5H), 8.42 (s, 1H), 8.12 (s, 1H), 7.91 (dd, J = 2.1, 8.3 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H), 5.03 - 4.95 (m, 1H), 4.89 - 4.73 (m, 3H), 4.64 - 4.54 (m, 2H), 4.54 - 4.43 (m, 2H), 3.44 (d, J = 7.0 Hz, 2H), 3.36 (br d, J = 4.4 Hz, 2H), 3.28 - 3.14 (m, 5H). Example 48 (R)-5-(5-((2-(3-((2-(2-fluoroethoxy)ethoxy)methyl)-4-(1,3,5-triazin-2-yl)piperazin-1-yl)pyrimidine-5-yl)ethinyl)pyridine-2-yl)oxazole [ka] Synthesis of 48-2: 5-(5-((trimethylsilyl)ethinyl)pyridine-2-yl)oxazole 48-1 A solution of (1.0 g, 4.44 mmol) dissolved in ACN (20 mL) was stirred, degassed, and purged with argon gas for 10 minutes. Next, DIPEA (2.328 mL, 13.33 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.350 g, 0.444 mmol) and ethinyltrimethylsilane (1.309 g, 13.33 mmol) were added to this reaction mixture at room temperature, and the mixture was purged again with argon gas for another 10 minutes. The reaction mixture was stirred at 80°C for 3 hours. The reaction mixture was diluted with water (200 mL) and extracted with ELISA (3 × 180 mL). The organic layers were combined, dehydrated with Na₂SO₄, and concentrated under reduced pressure. The crude compound was purified using a 100 g (100-200 mesh) silica gel cartridge, and the compound was eluted with 20% siRNA in petroleum ether. The pure fractions were combined and concentrated under reduced pressure. 48-2 This was obtained.

[0192] M / Z (ESI): 243.46 [M+H] + . Synthesis of 48-3: (R)-2-((4-(5-((6-(oxazol-5-yl)pyridine-3-yl)ethinyl)pyrimidine-2-yl)-1-(1,3,5-triazine-2-yl)piperazine-2-yl)methoxy)ethane-1-ol 38-9 (500 mg, 1.128 mmol) was dissolved in DMF (10 mL) and the solution was purged with argon gas for 10 minutes while stirring. Then, to this reaction mixture, 48-2 (328 mg, 1.354 mmol), K2CO3 (468 mg, 3.38 mmol), copper(I) iodide (21.48 mg, 0.113 mmol), and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (89 mg, 0.113 mmol) were added at room temperature. The reaction mixture was purged again with argon gas for another 10 minutes and stirred at 80°C for 12 hours. The reaction mixture was diluted with water (200 mL) and extracted with ELISA (3 × 150 mL). The organic layers were combined, dehydrated with Na2SO4, and concentrated under reduced pressure. The crude compound was ground with diethyl ether (2 × 50 mL) and concentrated under reduced pressure. 48-3 This was obtained.

[0193] M / Z (ESI): 486.35 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ (ppm) = 8.78 - 8.76 (m, 1H), 8.64 (s, 4H), 8.61 - 8.57 (m, 1H), 8.06 (dd, J = 2.1, 8.3 Hz, 1H), 7.88 (s, 1H), 7.82 (d, J = 8.1 Hz, 1H), 4.98 - 4.92 (m, 1H), 4.81 - 4.76 (m, 1H), 4.62 - 4.48 (m, 3H), 3.52 (d, J = 7.0 Hz, 2H), 3.42 - 3.36 (m, 5H), 3.30 - 3.15 (m, 2H). Synthesis of 48: (R)-5-(5-((2-(3-((2-(2-fluoroethoxy)ethoxy)methyl)-4-(1,3,5-triazin-2-yl)piperazin-1-yl)pyrimidine-5-yl)ethinyl)pyridine-2-yl)oxazole 48-3A solution of (50 mg, 0.103 mmol) dissolved in DMF (1 mL) was stirred, and 60% NaH (6.18 mg, 0.154 mmol) in oil was added at 0°C. The reaction mixture was stirred at 0°C for 30 minutes, and then 1-fluoro-2-iodoethane (35.8 mg, 0.206 mmol) was added at 0°C. The reaction mixture was stirred at 25°C for 24 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 × 80 mL). The organic layers were combined, dehydrated with Na₂SO₄, and concentrated under reduced pressure. The crude compound was purified by prep HPLC. The pure fractions were combined and freeze-dried. 48 This was obtained.

[0194] M / Z (ESI): 532.38 [M+H] + . Prep HPLC method Mobile phase - 10 mM ammonium bicarbonate in H2O: MeCN Column - X-Bridge C18 (19×250) Flow rate - 18.0mL / min Gradient method - 0 / 30, 7 / 42, 12 / 44 / 5, 12 / 05 / 100, 14 / 100, 14 / 05 / 30, 17 / 30.

[0195] 1 H NMR (400 MHz, DMSO-d6) δ (ppm) = 8.78 (s, 1H), 8.64 (s, 4H), 8.59 (s, 1H), 8.06 (dd, J = 1.8, 8.2 Hz, 1H), 7.88 (s, 1H), 7.83 (d, J = 8.3 Hz, 1H), 5.01 - 4.93 (m, 1H), 4.79 (br d, J = 13.4 Hz, 1H), 4.65 - 4.48 (m, 4H), 3.65 - 3.49 (m, 9H), 3.22 (br s, 2H). Example 49 (R)-2-(2-((2-fluoroethoxy)methyl)-4-(5-((2-(1-methyl-1H-pyrazole-3-yl)pyrimidine-5-yl)ethinyl)pyrimidine-2-yl)piperazine-1-yl)-1,3,5-triazine [ka] Synthesis of 49-2: 5-bromo-2-(1-methyl-1H-pyrazole-3-yl)pyrimidine 5-bromo-2-iodopyrimidine (500 mg, 1.755 mmol) was dissolved in 1,4-dioxane (10 mL) and water (2 mL). While stirring, 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (548 mg, 2.63 mmol) and K2CO3 (728 mg, 5.27 mmol) were added at room temperature. The reaction mixture was degassed and purged with argon gas for 15 minutes. Tetrakis(triphenylphosphine)palladium (203 mg, 0.176 mmol) was then added to the reaction mixture at room temperature. The reaction mixture was stirred in a sealed tube under a nitrogen atmosphere at 80°C for 2 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 × 20 mL). The organic layers were combined, washed with brine (10 mL), dehydrated with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by biotage using a silica gel column, and the compound was eluted with 40% siRNA in petroleum ether. The pure fractions were combined and concentrated under reduced pressure. 49-2 This was obtained.

[0196] M / Z (ESI): 238.92 [M+H] + . Synthesis of 49-3: 2-(1-methyl-1H-pyrazole-3-yl)-5-((trimethylsilyl)ethinyl)pyrimidine 49-2A solution of (350 mg, 1.464 mmol) dissolved in acetonitrile (5 mL) was stirred, and DIPEA (0.767 mL, 4.39 mmol) was added at room temperature. The reaction mixture was degassed and purged with argon gas for 15 minutes. Then, trimethylsilylacetylene (431 mg, 4.39 mmol) and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (115 mg, 0.146 mmol) were added to the reaction mixture at room temperature. The reaction mixture was stirred in a sealed tube under a nitrogen atmosphere at 80°C for 2 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 × 20 mL). The organic layers were combined, washed with brine (10 mL), dehydrated with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by biotage using a silica gel column, and the compound was eluted with 50% siRNA in petroleum ether. The pure fractions were combined and concentrated under reduced pressure. 49-3 This was obtained.

[0197] M / Z (ESI): 257.35 [M+H] + . Synthesis of 49: (R)-2-(2-((2-fluoroethoxy)methyl)-4-(5-((2-(1-methyl-1H-pyrazole-3-yl)pyrimidine-5-yl)ethinyl)pyrimidine-2-yl)piperazine-1-yl)-1,3,5-triazine 41-1 (130 mg, 0.292 mmol) dissolved in DMF (2 mL) is stirred while adding to the solution. 49-3(112 mg, 0.438 mmol), K2CO3 (121 mg, 0.876 mmol), and copper(I) iodide (5.56 mg, 0.029 mmol) were added at room temperature. The reaction mixture was degassed and purged with argon gas for 10 minutes. Next, davephos G2 palladacycle (20.54 mg, 0.029 mmol) was added to the reaction mixture at room temperature. The reaction mixture was stirred in a sealed tube at 80°C for 2 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (2 × 30 mL). The organic layers were combined, washed with brine (10 mL), dehydrated with anhydrous sodium 2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by prep-HPLC (conditions: mobile phase - 10 mM ammonium bicarbonate: MeCN, column - Betasil Phenyl hexyl C18 (20×250), 5 μm, flow rate - 18.0 mL / min, gradient method - 0 / 38, 2 / 38, 15.50 / 42, 15.60 / 100, 19.90 / 100, 20.0 / 38, 24.0 / 38). The pure fractions were combined and freeze-dried. 49 This was obtained.

[0198] M / Z (ESI): 502.22 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ (ppm)= 8.96 (s, 2H), 8.67 - 8.63 (m, 4H), 7.84 (d, J = 2.1 Hz, 1H), 6.94 (d, J = 2.3 Hz, 1H), 5.01 - 4.93 (m, 1H), 4.80 (br d, J = 13.6 Hz, 1H), 4.64 - 4.52 (m, 2H), 4.51 - 4.34 (m, 2H), 3.95 (s, 3H), 3.68 - 3.54 (m, 4H), 3.44 - 3.34 (m, 2H), 3.28 - 3.22 (m, 1H). Example 50 (R)-2-(2-((2-fluoroethoxy)methyl)-4-(5-((6-(1-methyl-1H-pyrazole-4-yl)pyridine-3-yl)ethinyl)pyrimidine-2-yl)piperazine-1-yl)-1,3,5-triazine [ka] Synthesis of 50-2: (R)-(4-(5-((6-(1-methyl-1H-pyrazole-4-yl)pyridine-3-yl)ethynyl)pyrimidine-2-yl)-1-(1,3,5-triazine-2-yl)piperazine-2-yl)methanol 38-6 (150 mg, 0.376 mmol) was dissolved in DMF (3 mL) and the solution was degassed while stirring, and then purged with argon gas for 10 minutes. Then, to this reaction mixture, 50-1 (Prepared in the same manner as in 44-3) (115 mg, 0.451 mmol), K2CO3 (156 mg, 1.127 mmol), copper(I) iodide (71.6 mg, 0.376 mmol), and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (29.6 mg, 0.038 mmol) were added at room temperature, and the mixture was purged again with argon gas for another 10 minutes. The reaction mixture was stirred at 80°C for 12 hours. The reaction mixture was quenched with water (40 mL) and extracted with ethyl acetate (3 × 30 mL). The organic layers were combined, dehydrated with anhydrous sodium (Na2SO4), filtered, and concentrated under reduced pressure. The crude compound was washed with diethyl ether (2 × 30 mL), dehydrated with Na₂SO₄, and concentrated under reduced pressure. The resulting compound was further purified by prep HPLC (conditions: mobile phase - 10 mM ammonium bicarbonate in H₂O: MeCN, column - X-Bridge C18 (19 × 250) mm, 5 μm, flow rate - 14.0 mL / min, gradient method - 0 / 25, 2 / 25, 11 / 60.9, 11.05 / 100, 17 / 100, 17.05 / 25, 20 / 25). The pure fractions were combined and concentrated under reduced pressure to obtain 50-2.

[0199] M / Z (ESI): 455.19 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ (ppm) = 8.58 - 8.68 (m, 5H), 8.34 (s, 1H), 8.04 (s, 1H), 7.90 (dd, J = 8.2 Hz, 2.2 Hz, 1H), 7.69 (d, J = 8.4 Hz, 1H), 4.89 (t, J = 5.0 Hz, 1H), 4.72 - 4.85 (m, 2H), 4.46 - 4.61 (m, 2H), 3.89 (s, 3H), 3.45 - 3.57 (m, 2H), 3.36 - 3.42 (m, 2H), 3.22 - 3.28 (m, 1H). Synthesis of 50: (R)-2-(2-((2-fluoroethoxy)methyl)-4-(5-((6-(1-methyl-1H-pyrazole-4-yl)pyridine-3-yl)ethinyl)pyrimidine-2-yl)piperazine-1-yl)-1,3,5-triazine 50-2 A solution of (70 mg, 0.154 mmol) dissolved in DMF (1 mL) was stirred, and 60% NaH (9.24 mg, 0.231 mmol) from the oil was added at 0°C. The reaction mixture was stirred at 0°C for 30 minutes. Next, 1-fluoro-2-iodoethane (53.6 mg, 0.308 mmol) was added to this reaction mixture at 0°C. The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was quenched with water (30 mL) and extracted with pharmaceutically acceptable ethyl acetate (3 × 40 mL). The organic layers were combined, dehydrated with anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude compound was purified by prep HPLC (conditions: mobile phase - 10 mM ammonium bicarbonate in H2O: MeCN, column - X-Bridge C18 (10 × 250 mm), 5 μm, flow rate - 7 mL / min, gradient method - 0 / 52, 2 / 52, 7.5 / 55.5, 10 / 55.5, 10.05 / 100, 12 / 100, 12.05 / 52, 16 / 52). The pure fractions were combined and concentrated under reduced pressure to obtain compound 50.

[0200] M / Z (ESI): 501.21 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ (ppm) = 8.63 (d, J = 10.8 Hz, 5H), 8.34 (s, 1H), 8.04 (s, 1H), 7.89 (dd, J = 8.2 Hz, 2.2 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H), 4.43 - 5.04 (m, 1H), 4.79 (d, J = 13.6 Hz, 1H), 4.54 - 4.67 (m, 2H), 4.43 (dt, J = 48.0 Hz, 4.0 Hz, 2H), 3.89 (s, 3H), 3.51 -3.60 (m, 4H), 3.35 - 3.43 (m, 2H), 3.18 - 3.26 (m, 1H). Example 51 (R)-2-(3-((2-fluoroethoxy)methyl)-4-(pyrimidine-2-yl)piperazine-1-yl)-5-((2-(1-methyl-1H-pyrazole-4-yl)pyrimidine-5-yl)ethinyl)pyrimidine [ka] Synthesis of 51: (R)-2-(3-((2-fluoroethoxy)methyl)-4-(pyrimidine-2-yl)piperazine-1-yl)-5-((2-(1-methyl-1H-pyrazole-4-yl)pyrimidine-5-yl)ethinyl)pyrimidine 40-3 (100 mg, 0.301 mmol) was dissolved in DMF (2 mL) to make a solution. 44-1(93 mg, 0.361 mmol) and tripotassium phosphate (383 mg, 1.805 mmol) were added at room temperature. The reaction mixture was degassed and purged with argon for 10 minutes. Then, chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (24 mg, 0.031 mmol) was added to the reaction mixture at room temperature. The reaction mixture was stirred in a sealed tube at 80°C for 2 hours. The reaction mixture was quenched with water (20 mL), filtered through a Celite pad, and washed with DCM (2 × 20 mL). The organic layers were combined and washed with brine (20 mL), dehydrated with anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The resulting compound was ground with diethyl ether (2 × 10 mL) and concentrated under reduced pressure. The obtained compound was purified by prep HPLC (conditions: mobile phase - 10 mM ammonium bicarbonate in H2O: MeCN, column - X-Bridge C18 (19×250), 5μ, flow rate - 15.0 mL / min, gradient method: 0 / 45, 2 / 45, 7 / 58, 12 / 58, 12.1 / 100, 15 / 100, 15.1 / 45, 18 / 45). The pure fractions were combined and concentrated under reduced pressure. 51 This was obtained.

[0201] M / Z (ESI): 501.21 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ = 8.89 (s, 2H), 8.63 (d, J = 4.4 Hz, 4H), 8.42 (s, 1H), 8.05 (s, 1H), 4.98-4.96 (m, 1H), 4.80 (d, J = 13.6 Hz, 1H), 4.59-4.55 (m, 2H), 4.44 (dt, J = 4, 8.0 Hz, 2H), 3.92 (s, 3H), 3.65-3.55 (m, 4H), 3.40-3.36 (m, 1H), 3.29-3.20 (m, 2H). Example 52 (R)-2-(3-((2-(2-fluoroethoxy)ethoxy)methyl)-4-(pyrimidine-2-yl)piperazine-1-yl)-5-((2-(1-methyl-1H-pyrazole-4-yl)pyrimidine-5-yl)ethinyl)pyrimidine [ka] TIFF2026509241000076.tif47143 Synthesis of 52-2: 5-bromo-2-((3R)-4-(pyrimidine-2-yl)-3-((2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)methyl)piperazine-1-yl)pyrimidine (R)-(4-(5-bromopyrimidine-2-yl)-1-(pyrimidine-2-yl)piperazine-2-yl)methanol( Int B To a solution prepared by dissolving (3 g, 8.54 mmol) in DMF (80 mL), 60% NaH (0.376 g, 9.40 mmol) in oil was added at 0°C and the mixture was stirred at 0°C for 30 minutes. Then, 2-(2-bromoethoxy)tetrahydro-2h-pyran (2.322 g, 11.10 mmol) was added to the reaction mixture at 0°C. The reaction mixture was stirred at 80°C for 16 hours. The reaction mixture was quenched with water (100 mL) and extracted with ELISA (3 × 100 mL). The organic layers were combined, dehydrated with Na₂SO₄, filtered, and concentrated under reduced pressure. The crude compound was purified by biotage using a 25 g silica gel cartridge, and the compound was eluted with 30% ELISA in petroleum ether. The pure fractions were combined and concentrated under reduced pressure. 52-2 This was obtained.

[0202] M / Z (ESI): 479.13 [M+H] + . Synthesis of 52-1: (R)-2-((4-(5-bromopyrimidine-2-yl)-1-(pyrimidine-2-yl)piperazine-2-yl)methoxy)ethane-1-ol 52-2 (2.5 g, 4.75 mmol) was dissolved in DCM (30 mL), and while stirring, 4M 1,4-dioxane hydrochloride (4.75 mL, 19.00 mmol) was added at 0°C. The reaction mixture was stirred at 25°C for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with NaHCO3 aqueous solution (100 mL) and extracted with SiO2 (3 × 100 mL). The organic layers were combined, dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by biotage using a 25 g silica gel cartridge, and the compound was eluted with 40% SiO2 in petroleum ether. The pure fractions were combined and concentrated under reduced pressure. 52-1 This was obtained.

[0203] M / Z (ESI): 395.24 [M+H] + . Synthesis of 52-3: (R)-2-((4-(5-((2-(1-methyl-1H-pyrazole-4-yl)pyrimidine-5-yl)ethinyl)pyrimidine-2-yl)-1-(pyrimidine-2-yl)piperazine-2-yl)methoxy)ethane-1-ol 52-1 (Prepared in the same manner as in 38-9) (200 mg, 0.506 mmol) dissolved in DMF (2 mL) to make a solution, 44-1 (130 mg, 0.506 mmol) and tripotassium phosphate (644 mg, 3.04 mmol) were added at room temperature. The reaction mixture was degassed and purged with argon gas for 10 minutes. Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (39.8 mg, 0.051 mmol) was then added to the reaction mixture, and the mixture was stirred in a sealed tube at 80°C for 2 hours. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (2 × 30 mL). The organic layers were combined and washed with brine (10 mL), dehydrated with anhydrous sodium 2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by prep-HPLC (conditions: mobile phase - 10 mM ammonium bicarbonate in H2O: MeCN, column - X-Bridge C18 (19×250), 5μ, flow rate - 15.0 mL / min, gradient method: 0 / 35, 2 / 35, 7 / 40, 11.7 / 40, 11.75 / 100, 14.95 / 100, 15 / 35, 18 / 35). The pure fractions were combined, concentrated under reduced pressure, and freeze-dried. 52-3 This was obtained.

[0204] M / Z (ESI): 499.16 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ = 8.89 (s, 2H), 8.62 (s, 2H), 8.37 - 8.44 (m, 3H), 8.05 (s, 1H), 6.91 (br s, 1H), 6.68 (t, J = 4.8 Hz, 1H), 4.78 - 4.96 (m, 2H), 4.48 - 4.59 (m, 2H), 3.92 (s, 3H), 3.35 - 3.53 (m, 7H), 3.20 - 3.30 (m, 2H). Synthesis of 52: (R)-2-(3-((2-(2-fluoroethoxy)ethoxy)methyl)-4-(pyrimidine-2-yl)piperazine-1-yl)-5-((2-(1-methyl-1H-pyrazole-4-yl)pyrimidine-5-yl)ethinyl)pyrimidine 52-3 To a solution prepared by dissolving (70 mg, 0.140 mmol) in DMF (1 mL), 1-fluoro-2-iodoethane (73.3 mg, 0.421 mmol) and NaH (11.23 mg, 0.281 mmol) were added at 0°C. The reaction mixture was stirred at room temperature for 48 hours. The reaction mixture was quenched with water (20 mL) and extracted with siRNA (2 × 30 mL). The organic layers were combined, washed with brine (10 mL), dehydrated with anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude compound was purified by Prep-HPLC (conditions: mobile phase - 10 mM ammonium bicarbonate in H2O: MeCN, column Name Betasil Phenyl Hexyl (21.2 × 250) MM, 5 μm, gradient method: 0 / 45, 5 / 50, 15 / 50, 15.05 / 100, 18.05 / 100, 18.10 / 45, 21 / 45). The pure fractions were combined and freeze-dried. 52 This was obtained.

[0205] M / Z (ESI): 545.26 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ = 8.89 (s, 2H), 8.63 (s, 2H), 8.38 - 8.44 (m, 3H), 8.05 (s, 1H), 6.68 (t, J = 4.8 Hz, 1H), 4.85 (br s, 1H), 4.77 - 4.85 (m, 1H), 4.38 - 4.60 (m, 4H), 3.92 (s, 3H), 3.61 -3.67 (m, 1H), 3.53 - 3.59 (m, 1H), 3.44 - 3.56 (m, 6H), 3.36-3.39 (m, 1H), 3.22 - 3.29 (m, 2H). Example 53 (R)-2-(3-((2-fluoroethoxy)methyl)-4-(pyrimidine-4-yl)piperazine-1-yl)-5-((2-(1-methyl-1H-pyrazole-4-yl)pyrimidine-5-yl)ethinyl)pyrimidine [ka] Synthesis of 53-1: (R)-2-(3-((2-fluoroethoxy)methyl)-4-(pyrimidine-4-yl)piperazine-1-yl)-5-iodopyrimidine 42-5 A solution of (2 g, 5.02 mmol) dissolved in DMF (30 mL) was stirred, and NaH (241 mg, 10 mmol) and 1-fluoro-2-iodoethane (2.62 g, 15.1 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was quenched with water (50 mL) and extracted with siRNA (2 × 75 mL). The organic layers were combined, washed with brine (2 × 30 mL), dehydrated with anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude compound was purified by biotage using an 80 g silica (230-400 mesh) cartridge, and the compound was eluted with 50% siRNA in petroleum ether. The pure fractions were combined and concentrated under reduced pressure. 53-1 This was obtained.

[0206] M / Z (ESI): 445.18 [M+H] + . Synthesis of 53: (R)-2-(3-((2-fluoroethoxy)methyl)-4-(pyrimidine-4-yl)piperazin-1-yl)-5-((2-(1-methyl-1H-pyrazole-4-yl)pyrimidine-5-yl)ethinyl)pyrimidine 53-1 (60 mg, 135 μmol) dissolved in DMF (1 mL) solution, stirring the solution, and then... 44-1(34.6 mg, 135 μmol), K2CO3 (56.0 mg, 405 μmol), and CuI (2.57 mg, 13.5 μmol) were added at room temperature. The reaction mixture was degassed and purged with argon gas for 15 minutes. XPhos Palladacycle (10.6 mg, 13.5 μmol) was then added to the reaction mixture at room temperature. The reaction mixture was stirred in a sealed tube at 100°C for 16 hours. The reaction mixture was quenched with aqueous saturated Na2CO3 (20 mL) and extracted with 10% MeOH in DCM (2 × 35 mL). The organic layers were combined, washed with brine (2 × 20 mL), dehydrated with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by prep-HPLC (conditions: mobile phase - 10 mM ammonium bicarbonate in H2O: MeCN, column - X-Bridge C18 (19×250) mm 5u, flow rate - 16 mL / min, gradient method - 0 / 35, 4 / 45, 8.6 / 45, 8.65 / 100, 11 / 100, 11.05 / 45, 14 / 45). The pure fractions were combined and concentrated under reduced pressure. 53 This was obtained.

[0207] M / Z (ESI): 501.33 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ (ppm) = 7.30-10.60 (m, 8H), 6.99 (br s, 1H), 4.55-4.87 (m, 2H), 4.19-4.56 (m, 4H), 3.92 (s, 3H), 3.49-3.71 (m, 4H), 3.42 (dd, J = 13.4 Hz, 3.8 Hz, 1H), 3.32 (s, 2H). Example 54 (R)-2-(1-(2-fluoroethyl)-1H-pyrazole-4-yl)-5-((2-(3-(methoxymethyl)-4-(pyrimidine-4-yl)piperazine-1-yl)pyrimidine-5-yl)ethinyl)pyrimidine [ka] Synthesis of 54-2: 5-bromo-2-(1-(2-fluoroethyl)-1H-pyrazole-4-yl)pyrimidine 5-bromo-2-(1H-pyrazole-4-yl)pyrimidine (54-1) (1 g, 3.82 mmol) was dissolved in DMF (15 mL) and 1-fluoro-2-iodoethane (2.66 g, 15.3 mmol) and Cs2CO3 (3.74 g, 11.5 mmol) were added at room temperature while stirring. The reaction mixture was stirred in a sealed tube under a nitrogen atmosphere at 50°C for 4 hours. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (2 × 25 mL). The organic layers were combined, washed with brine (2 × 20 mL), dehydrated with anhydrous sodium 2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by biotage using a 24 g silica (230-400 mesh) cartridge, and the compound was eluted with 50% ethyl acetate in hexane. The pure fractions were combined and concentrated under reduced pressure. 54-2 This was obtained.

[0208] M / Z (ESI): 273.00 [M+H] + . Synthesis of 54-3: 2-(1-(2-fluoroethyl)-1H-pyrazole-4-yl)-5-((trimethylsilyl)ethynyl)pyrimidine 54-2 A solution of (1 g, 3.69 mmol) dissolved in ACN (50 mL) was stirred, and ethynyl-trimethyl-silane (773 μL, 5.53 mmol) and DIPEA (1.29 mL, 7.38 mmol) were added at room temperature. The reaction mixture was degassed and purged with argon gas for 15 minutes. Then, XPhos Palladacycle (290 mg, 369 μmol) was added to the reaction mixture at room temperature. The reaction mixture was stirred in a sealed tube under a nitrogen atmosphere at 80°C for 16 hours. The reaction mixture was concentrated under reduced pressure. The crude compound was purified by biotage using a 40 g silica (230-400 mesh) cartridge, and the compound was eluted with 50% ethyl acetate in hexane. The pure fractions were combined and concentrated under reduced pressure. 54-3 This was obtained.

[0209] M / Z (ESI): 289.14 [M+H] + . Synthesis of 54-4: (R)-5-iodo-2-(3-(methoxymethyl)-4-(pyrimidine-4-yl)piperazine-1-yl)pyrimidine 42-5(5g, 12.6 mmol) was dissolved in DMF (50 mL), and while stirring, NaH (603 mg, 25.1 mmol) and methyl iodide (1.62 mL, 25.1 mmol) were added at 0°C. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with water (50 mL), the precipitated solid was filtered, washed with water, and dried under reduced pressure. 54-4 This was obtained.

[0210] M / Z (ESI): 413.18 [M+H] + . Synthesis of 54: (R,E)-2-(2-((2-fluoroethoxy)methyl)-4-(5-(2-(2-(1-methyl-1H-pyrazole-4-yl)pyrimidine-5-yl)vinyl)pyrimidine-2-yl)piperazine-1-yl)-1,3,5-triazine 54-3 (50 mg, 121 μmol) was dissolved in DMF (1 mL) and the solution was stirred while K2CO3 (50.3 mg, 364 μmol) was added to it. 54-4 (42 mg, 146 μmol) and CuI (2.31 mg, 12.1 μmol) were added at room temperature. The reaction mixture was degassed and purged with argon gas for 15 minutes. XPhos Palladacycle (9.54 mg, 12.1 μmol) was then added at room temperature. The reaction mixture was stirred in a sealed tube at 100°C for 16 hours. The reaction mixture was quenched with water (20 mL) and extracted with dimethyl phosphate (2 × 40 mL). The organic layers were combined, washed with brine (2 × 20 mL), dehydrated with anhydrous sodium 2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by prep-HPLC (conditions: mobile phase - 10 mM ammonium bicarbonate in H2O: MeCN, column - X-Bridge C18 (19×250) mm 5u, flow rate - 16 mL / min, gradient method - 0 / 35, 4 / 45, 8.6 / 45, 8.65 / 100, 11 / 100, 11.05 / 45, 14 / 45). The pure fractions were combined and concentrated under reduced pressure. 54 This was obtained.

[0211] M / Z (ESI): 501.34 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ (ppm) = 8.91 (s, 2H), 8.65 (s, 2H), 8.54 (br s, 1H), 8.50 (s, 1H), 8.26 (br s, 1H), 8.13 (s, 1H), 6.87 (s, 1H), 4.55 - 4.94 (m, 5H), 4.50 (t, J = 4.6 Hz, 2H), 4.30 (br s, 1H), 3.37 - 3.45 (m, 3H), 3.27 - 3.30 (m, 2H), 3.21 (s, 3H). Example 55 (R)-5-(5-((2-(3-((2-fluoroethoxy)methyl)-4-(1,3,5-triazine-2-yl)piperazin-1-yl)pyrimidine-5-yl)ethinyl)pyrimidine-2-yl)oxazole

Chem.

[0212] M / Z (ESI): 489.26 [M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ (ppm) 9.04 (s, 2H), 8.58-8.75 (m, 5H), 8.04 (s, 1H), 4.91-5.02 (m, 1H), 4.80 (d, J = 13.6 Hz, 1H), 4.54-4.64 (m, 2H), 4.30-4.52 (m, 2H), 3.54-3.69 (m, 4H), 3.40-3.45 (m, 1H), 3.22-3.30 (m, 2H). Example 56 (R)-2-(4-(5-((2-(1-(fluoromethyl)-1H-pyrazole-4-yl)pyrimidine-5-yl)ethinyl)pyrimidine-2-yl)-2-(methoxymethyl)piperazine-1-yl)-1,3,5-triazine [ka] Synthesis of 56-2: 5-bromo-2-(1-(fluoromethyl)-1H-pyrazole-4-yl)pyrimidine 5-Bromo-2-(1H-pyrazole-4-yl)pyrimidine ( 54-1 A solution of (1.00 g, 4.44 mmol) dissolved in anhydrous THF (20 mL) was prepared, and NaH (160 mg, 6.67 mmol) was added at 0°C. The reaction mixture was stirred at 0°C for 30 minutes. Then, fluoroiodomethane (330 μL, 4.89 mmol) was added dropwise to the reaction mixture at 0°C. The reaction mixture was stirred at 25°C for 3 hours. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (2 × 50 mL). The organic layers were combined, dehydrated with anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude compound was purified by biotage using a silica gel column, and the compound was eluted with 20% ethyl acetate in hexane. The pure fractions were combined and concentrated under reduced pressure. 56-2 This was obtained.

[0213] M / Z (ESI): 257.04 [M+H] + . Synthesis of 56-3: 2-(1-(fluoromethyl)-1H-pyrazole-4-yl)-5-((trimethylsilyl)ethinyl)pyrimidine 56-2A solution of (400 mg, 1.56 mmol) dissolved in acetonitrile (8 mL) was stirred, and DIPEA (542 μL, 3.11 mmol) was added at room temperature. The reaction mixture was stirred at room temperature and degassed with N2 gas at room temperature. Next, XPhos Palladacycle (122 mg, 156 μmol) and ethynyl-trimethyl-silane (326 μL, 2.33 mmol) were added to the reaction mixture at room temperature. The reaction mixture was stirred at 80 °C for 16 hours. The reaction mixture was filtered through a Celite pad, washed with ethyl acetate, and concentrated under reduced pressure. The residue was diluted with water (50 mL) and extracted with ethyl acetate (2 × 50 mL). The organic layers were combined, washed with brine (50 mL), dehydrated anhydrous, filtered with Na2SO4, and concentrated under reduced pressure. The crude compound was purified by biotage using a 120 g silica cartridge, and the compound was eluted with 15% ethyl acetate in hexane. The pure fractions are combined and concentrated under reduced pressure. 56-3 This was obtained.

[0214] M / Z (ESI): 275.02 [M+H] + . Synthesis of 56: (R)-2-(4-(5-((2-(1-(fluoromethyl)-1H-pyrazole-4-yl)pyrimidine-5-yl)ethinyl)pyrimidine-2-yl)-2-(methoxymethyl)piperazine-1-yl)-1,3,5-triazine 46-6 (150.0 mg, 363.0 μmol) and 56-3A solution of (99.60 mg, 363.0 μmol) dissolved in DMF (4 mL) was stirred, and K2CO3 (150.5 mg, 1.089 mmol) was added at room temperature. The mixture was then degassed with N2 gas at room temperature for 5 minutes. Next, copper(I) iodide (6.913 mg, 36.30 μmol) and 2-dicyclohexylphosphino-2-(N,N-dimethylamino)biphenyl(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (25.58 mg, 36.30 μmol) were added to the reaction mixture at room temperature. The reaction mixture was stirred at 100 °C for 5 hours. The reaction mixture was filtered through a Celite pad, washed with DCM, and concentrated under reduced pressure. The residue was diluted with water (50 mL) and extracted with ethyl acetate (2 × 50 mL). The organic layers were combined, washed with brine (50 mL), dehydrated with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by Biotage using an 80 g silica cartridge, and the compound was eluted with 8% MeOH in DCM. The pure fractions were combined and concentrated under reduced pressure, and the resulting compound was further purified by Prep HPLC (conditions: mobile phase - 10 mM ammonium bicarbonate in H2O: MeCN, column - X-Bridge C18 (19 × 250) mm, 5 μm, flow rate - 15.0 mL / min, gradient method - 0 / 42, 6 / 50, 10.45 / 50, 10.5 / 100, 14.5 / 100, 14.55 / 42, 17 / 42. APMS-008). The pure fractions were combined, concentrated under reduced pressure, and lyophilized. 56 This was obtained.

[0215] M / Z (ESI): 488.17 [M+H] + . 1H NMR (400 MHz, DMSO-d6): δ (ppm) 8.96 (s, 2H), 8.82 (s, 1H), 8.65 (d, J = 4.4 Hz, 4H), 8.28 (s, 1H), 6.23 (d, J = 52.4 Hz, 2H), 4.97-5.03 (m, 1H), 4.77 (d, J = 13.6 Hz, 1H), 4.55-4.63 (m, 2H), 3.45 (d, J = 7.2 Hz, 2H), 3.33-3.40 (m, 2H), 3.16-3.26 (m, 4H). Example 57 (R)-2-(4-(5-((6-(1H-imidazole-1-yl)pyridine-3-yl)ethinyl)-6-fluoropyrazine-2-yl)-2-(methoxymethyl)piperazine-1-yl)pyrimidine [ka] TIFF2026509241000082.tif152142 Synthesis of 57-2: 4-benzyl 1-(tert-butyl)(R)-2-(hydroxymethyl)piperazine-1,4-dicarboxylate 50 g, 231 mmol of tert-butyl (R)-2-(hydroxymethyl)piperazine-1-carboxylate (57-1) was dissolved in 700 mL of DCM. While stirring, 64.4 mL, 462 mmol of TEA and 49.5 mL, 347 mmol of Cbz-Cl were added at 0°C. The reaction mixture was stirred under a nitrogen atmosphere at room temperature for 16 hours. The reaction mixture was quenched with 250 mL of water and extracted with ethyl acetate (2 × 500 mL). The organic layers were combined and washed with saturated aqueous NaHCO3 (2 × 100 mL) and brine (2 × 100 mL), dehydrated with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by biotage using a 330 g silica (230-400 mesh) cartridge, and the compound was eluted with 20% ethyl acetate in petroleum ether. The pure fractions were combined and concentrated under reduced pressure to obtain 57-2.

[0216] 1H NMR (400 MHz, DMSO-d6) δ (ppm) = 7.28-7.42 (m, 5H), 5.09 (s, 2H), 4.81 (br s, 1H), 3.90-4.17 (m, 2H), 3.85 (d, J = 10.0 Hz, 1H), 3.73 (d, J = 10.8 Hz, 1H), 3.34-3.48 (m, 2H), 2.76-3.15 (m, 3H), 1.40 (s, 9H). Synthesis 57-3: 4-benzyl 1-(tert-butyl)(R)-2-(methoxymethyl)piperazine-1,4-dicarboxylate 57-2 A solution of (40 g, 114 mmol) dissolved in DMF (300 mL) was stirred, and NaH (9.13 g, 228 mmol) and MeI (21.41 mL, 342 mmol) were added at 0°C. The reaction mixture was stirred at 0°C for 2 hours under a nitrogen atmosphere. The reaction mixture was quenched with ice-cold water (250 mL) and extracted with pharmaceutically acceptable phosphate (2 × 650 mL). The organic layers were combined and washed with brine (2 × 150 mL), dehydrated with anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude compound was purified by biotage using a 330 g silica (230-400 mesh) cartridge, and the compound was eluted with 20% pharmaceutically acceptable phosphate in petroleum ether. The pure fractions were combined and concentrated under reduced pressure. 57-3 This was obtained.

[0217] M / Z (ESI): 309.17 [M+H] + (Mass excluding tert-butyl).

[0218] Synthesis of 57-4: tert-butyl (R)-2-(methoxymethyl)piperazine-1-carboxylate 57-3 (20g, 54.9 mmol) was dissolved in EtOH (200 mL) and, while stirring, Pd-C (5.84 g, 5.49 mmol) was added at room temperature. The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 18 hours. The reaction mixture was filtered through a Celite pad, and the residue was washed with ethyl acetate (2 × 200 mL). The filtrate was dehydrated with anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. 57-4 This was obtained.

[0219] M / Z (ESI): 231.16 [M+H] + . Synthesis of 57-5: tert-butyl (R)-4-(6-fluoropyrazine-2-yl)-2-(methoxymethyl)piperazine-1-carboxylate 57-4 A solution of (2 g, 8.68 mmol) dissolved in DMF (35 mL) was stirred, and K2CO3 (3.60 g, 26.1 mmol) and 2,6-difluoropyrazine (0.889 mL, 10.42 mmol) were added at room temperature. The reaction mixture was stirred at 80°C for 12 hours under a nitrogen atmosphere. The reaction mixture was quenched with water (100 mL) and extracted with siRNA (2 × 200 mL). The organic layers were combined, dehydrated with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by biotage using a 120 g silica (230-400 mesh) cartridge, and the compound was eluted with 30% siRNA in petroleum ether. The pure fractions were combined and concentrated under reduced pressure. 57-5 This was obtained.

[0220] M / Z (ESI): 327.25 [M+H] + . Synthesis of 57-6: tert-butyl (R)-4-(5-bromo-6-fluoropyrazine-2-yl)-2-(methoxymethyl)piperazine-1-carboxylate 57-5 (1.5 g, 4.60 mmol) was dissolved in ACN (45 mL), and while stirring, NBS (0.818 g, 4.60 mmol) was added at 0°C. The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 18 hours. The reaction mixture was quenched with water (50 mL) and extracted with HCl (2 × 100 mL). The organic layers were combined and washed with brine (2 × 50 mL), dehydrated with anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude compound was purified by biotage using an 80 g silica (230-400 mesh) cartridge, and the compound was eluted with 18% HCl in petroleum ether. The pure fractions were combined and concentrated under reduced pressure. 57-6 This was obtained.

[0221] M / Z (ESI): 405.09 [M+H] + . Synthesis of 57-8: 2-(1H-imidazole-1-yl)-5-((trimethylsilyl)ethynyl)pyridine 5-bromo-2-(1H-imidazole-1-yl)pyridine ( 57-11 A solution of (1 g, 4.46 mmol) dissolved in ACN (40 mL) was stirred, and DIPEA (2.339 mL, 13.39 mmol) and copper(I) iodide (0.085 g, 0.446 mmol) were added at 0°C. The reaction mixture was degassed and purged with argon gas for 20 minutes. Then, trimethylsilylacetylene (1.271 mL, 8.93 mmol) and bis-(triphenylphosphino)-palladium monochloride (0.297 g, 0.446 mmol) were added to the reaction mixture at 0°C. The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. The reaction mixture was quenched with water (50 mL) and extracted with pharmaceutically acceptable phosphate (2 × 100 mL). The organic layers were combined, washed with brine (2 × 50 mL), dehydrated with anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude compound was purified using Biotage with an 80 g silica (230-400 mesh) cartridge, and the compound was eluted with 60% ethyl acetate in petroleum ether. The pure fractions were combined and concentrated under reduced pressure. 57-8 This was obtained.

[0222] M / Z (ESI): 242.42 [M+H] + . Synthesis of 57-9: tert-butyl (R)-4-(5-((6-(1H-imidazole-1-yl)pyridine-3-yl)ethynyl)-6-fluoropyrazine-2-yl)-2-(methoxymethyl)piperazine-1-carboxylate 57-6 (1.5g, 3.70 mmol) dissolved in DMF (15 mL) solution, and while stirring, K2CO3 (1.535 g, 11.10 mmol) and 57-8(1.072 g, 4.44 mmol) was added at room temperature. The reaction mixture was degassed and purged with argon gas for 25 minutes. Then, XPhos Pd G2 (0.291 g, 0.370 mmol) was added to the reaction mixture at room temperature. The reaction mixture was stirred in a sealed tube under a nitrogen atmosphere at 80°C for 2 hours. The reaction mixture was quenched with water (60 mL) and extracted with pharmaceutically acceptable phosphate (2 × 85 mL). The organic layers were combined and washed with brine (2 × 30 mL), dehydrated with anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude compound was purified by biotage using an 80 g silica (230-400 mesh) cartridge, and the compound was eluted with 6% MeOH in DCM. The pure fractions were combined and concentrated under reduced pressure. 57-9 This was obtained.

[0223] M / Z (ESI): 494.45 [M+H] + . Synthesis of 57-10: (R)-2-((6-(1H-imidazole-1-yl)pyridine-3-yl)ethinyl)-3-fluoro-5-(3-(methoxymethyl)piperazine-1-yl)pyrazine 57-9 A solution of (750 mg, 1.520 mmol) dissolved in DCM (15 mL) was stirred, and 4 M HCl (0.760 mL, 3.04 mmol) in 1,4-dioxane was added at 0°C. The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 48 hours. The reaction mixture was concentrated under reduced pressure. The resulting compound was dissolved in 10% MeOH (50 mL) in DCM, and MP carbonate resin (2 g) was added for 20 minutes. The reaction mixture was filtered through a Celite pad and washed with 10% MeOH (2 × 20 mL) in DCM. The organic layers were combined, dehydrated with anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude compound was purified by biotage using an 80 g silica (230-400 mesh) cartridge, and the compound was eluted with 12% MeOH in DCM. The pure fractions were combined and concentrated under reduced pressure. 57-10 This was obtained.

[0224] M / Z (ESI): 394.21[M+H] + . Synthesis of 57: (R)-2-(4-(5-((6-(1H-imidazole-1-yl)pyridine-3-yl)ethinyl)-6-fluoropyrazine-2-yl)-2-(methoxymethyl)piperazine-1-yl)pyrimidine 57-10A solution of (100 mg, 0.254 mmol) dissolved in 1,4-dioxane (1.5 mL) was stirred, and 2-chloropyrimidine (87 mg, 0.763 mmol) and sodium tert-butoxide (73.3 mg, 0.763 mmol) were added at room temperature. The reaction mixture was degassed and purged with argon gas for 20 minutes. Then, RuPhos Pd G2 (19.74 mg, 0.025 mmol) was added to the reaction mixture at room temperature. The reaction mixture was stirred in a microwave oven at 150°C for 2 hours. The reaction mixture was quenched with water (25 mL) and extracted with siRNA (2 × 45 mL). The organic layers were combined, washed with brine (2 × 20 mL), dehydrated with anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude compound was purified using a 40 g silica (230-400 mesh) cartridge, and the compound was eluted with 4% MeOH in DCM. The pure fractions were combined and concentrated under reduced pressure. The resulting compound was purified again by prep-HPLC (conditions: mobile phase - 10 mM ammonium bicarbonate in H2O: MeCN, column - X-Bridge, C18 (10×250) mm, 5 μm, flow rate - 6.0 mL / min, gradient method: - 0 / 40, 5 / 55, 10.3 / 58, 10.4 / 100, 11.9 / 100, 12 / 40, 16 / 40). The pure fractions were combined, concentrated under reduced pressure, and lyophilized. 57 This was obtained.

[0225] M / Z (ESI): 472.11 [M+H] + 1H NMR (400 MHz, DMSO-d6) δ (ppm) = 8.68-8.73 (m, 1H), 8.60 (s, 1H), 8.42 (d, J = 4.8 Hz, 2H), 8.30 (d, J = 5.6 Hz, 1H), 8.21 (dd, J = 8.6 Hz, 2.2 Hz, 1H), 8.01 (t, J = 1.2 Hz, 1H), 7.92 (d, J = 8.8 Hz, 1H), 7.16 (s, 1H), 6.70 (t, J = 4.6 Hz, 1H), 4.85-4.99 (m, 1H), 4.40-4.54 (m, 2H), 4.27 (d, J = 12.0 Hz, 1H), 3.37-3.52 (m, 5H), 3.22 (s, 3H). Example 58 (R)-5-((6-(4H-1,2,4-triazol-4-yl)pyridine-3-yl)ethinyl)-4-fluoro-2-(3-(methoxymethyl)-4-(pyrimidine-4-yl)piperazine-1-yl)pyrimidine [ka] Synthesis of 58-2: tert-butyl (R)-3-(methoxymethyl)-4-(pyrimidine-4-yl)piperazine-1-carboxylate tert-butyl (R)-3-(hydroxymethyl)-4-(pyrimidine-4-yl)piperazine-1-carboxylate ( 58-1 A solution of (5.00 g, 17.0 mmol) dissolved in DMF (20 mL) was stirred, and MeI (3.19 mL, 51.0 mmol) and 60% NaH in oil (612 mg, 25.5 mmol) were added at 0°C. The reaction mixture was stirred at 25°C for 1 hour. The reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (2 × 100 mL). The organic layers were combined, washed with brine (2 × 50 mL), dehydrated with anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude compound was purified by biotage using an 80 g silica cartridge, and the compound was eluted with 20% ethyl acetate in petroleum ether. The pure fractions were combined and concentrated under reduced pressure. 58-2 This was obtained.

[0226] M / Z (ESI): 309.23 [M+H] + . Synthesis of 58-3: (R)-4-(2-(methoxymethyl)piperazin-1-yl)pyrimidine 58-2 (2.10 g, 6.81 mmol) was dissolved in DCM (20 mL) and, while stirring, 4 M hydrogen chloride in 1,4-dioxane (6.81 mL, 27.2 mmol) was added at 0°C. The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was concentrated under reduced pressure, the residue was washed with diethyl ether (2 × 10 mL), and dried under reduced pressure. 58-3 This was obtained.

[0227] M / Z (ESI): 209.18 [M+H] + . Synthesis of 58-8: 2,4-dichloro-5-(trimethylsilyl)pyrimidine 5-bromo-2,4-dichloropyrimidine (10.0 g, 43.9 mmol) was dissolved in THF (150 mL) and, while stirring, 2M isopropyl magnesium chloride (21.9 mL, 43.9 mmol) was added at -20°C. The reaction mixture was stirred at 0°C to 25°C for 3 hours. Then, TMS-Cl (16.7 mL, 132 mmol) was added to the reaction mixture at -20°C. The reaction mixture was then stirred under a nitrogen atmosphere at 0°C to 25°C for 16 hours. The reaction mixture was quenched with NH4Cl (100 mL) and extracted with ELISA (2 × 120 mL). The organic layers were combined, washed with brine (2 × 50 mL), dehydrated with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by biotage using a 120 g silica cartridge, and the compound was eluted with 10% ELISA in petroleum ether. The pure fractions are combined and concentrated under reduced pressure. 58-8 This was obtained.

[0228] M / Z (ESI): 220.97 [M+H] + . Synthesis of 58-4: (R)-4-chloro-2-(3-(methoxymethyl)-4-(pyrimidine-4-yl)piperazine-1-yl)-5-(trimethylsilyl)pyrimidine 58-3 (1.20g, 5.76 mmol) dissolved in DMF (30mL) is stirred while adding to the solution. 58-8(1.53 g, 6.91 mmol) and DIPEA (5.02 mL, 28.8 mmol) were added at room temperature. The reaction mixture was stirred at 25°C for 16 hours under a nitrogen atmosphere. The reaction mixture was quenched with water (100 mL) and extracted with dimethyl (2 × 100 mL). The organic layers were combined, washed with brine (2 × 50 mL), dehydrated with anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude compound was purified by biotage using a 40 g silica cartridge, and the compound was eluted with 20% dimethyl in petroleum ether. The pure fractions were combined and concentrated under reduced pressure. 58-4 This was obtained.

[0229] M / Z (ESI): 393.30 [M+H] + . Synthesis of 58-5: (R)-4-chloro-5-iodo-2-(3-(methoxymethyl)-4-(pyrimidine-4-yl)piperazine-1-yl)pyrimidine 58-4 800 mg (2.04 mmol) was dissolved in 20 mL of ACN and 5 mL of DCM, and while stirring, 197 μL (3.05 mmol) of iodine monochloride was added at -10°C to 0°C. The reaction mixture was stirred at 0°C for 1 hour under a nitrogen atmosphere. The reaction mixture was quenched with 80 mL of water and extracted with dimethyl phosphate (2 × 80 mL). The organic layers were combined, washed with brine (2 × 10 mL), dehydrated with anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude compound was purified by biotage using a 40 g silica cartridge, and the compound was eluted with 30% dimethyl phosphate in petroleum ether. The pure fractions were combined and concentrated under reduced pressure. 58-5 This was obtained.

[0230] M / Z (ESI): 446.98 [M+H] + . Synthesis of 58-6: (R)-5-((6-(4H-1,2,4-triazol-4-yl)pyridine-3-yl)ethinyl)-4-chloro-2-(3-(methoxymethyl)-4-(pyrimidine-4-yl)piperazine-1-yl)pyrimidine 58-5 (70.0 mg, 157 μmol) dissolved in DMF (1 mL) solution, stirring the solution, and then... 45-6(45.6 mg, 188 μmol), K2CO3 (65.0 mg, 470 μmol), and CuI (2.98 mg, 15.7 μmol) were added at room temperature, and the mixture was degassed with argon gas for 15 minutes. Then, XPhos Palladacycle (12.3 mg, 15.7 μmol) was added to this reaction mixture at room temperature. The reaction mixture was stirred in a sealed tube at 100°C for 16 hours. The reaction mixture was quenched with water (80 mL) and extracted with pharmaceutically acceptable phosphate (2 × 80 mL). The organic layers were combined, washed with brine (2 × 20 mL), dehydrated with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was washed with diethyl ether (2 × 10 mL) and dried under reduced pressure. The crude compound was purified by Prep HPLC (conditions: mobile phase - 10 mM ammonium bicarbonate in H2O: MeCN, column - X-Bridge C18 (19×250) mm 5u, flow rate - 16 mL / min, gradient method - 0 / 35, 4 / 45, 8.6 / 45, 8.65 / 100, 11 / 100, 11.05 / 45, 14 / 45). The pure fractions were combined, concentrated under reduced pressure, and freeze-dried. 58-6 This was obtained.

[0231] M / Z (ESI): 489.14 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ (ppm) = 9.34 (s, 2H), 8.64-8.78 (m, 2H), 8.54 (s, 1H), 8.19-8.31 ( m, 2H), 7.98 (d, J = 8.4 Hz, 1H), 6.86 (d, J = 6.0 Hz, 1H), 4.19-4.90 (m, 4H), 3.38-3.50 (m, 5H), 3.21 ( s, 3H). Synthesis of 58: (R)-5-((6-(4H-1,2,4-triazol-4-yl)pyridine-3-yl)ethinyl)-4-fluoro-2-(3-(methoxymethyl)-4-(pyrimidine-4-yl)piperazine-1-yl)pyrimidine 58-6(100.0 mg, 204.5 μmol) was dissolved in DMSO (2 mL), and potassium fluoride (38.32 μL, 1.636 mmol) was added to the solution while stirring at room temperature. The reaction mixture was stirred at 80°C for 16 hours under a nitrogen atmosphere. The reaction mixture was quenched with water (50 mL) and extracted with pharmaceutically acceptable ethyl acetate (2 × 50 mL). The organic layers were combined, washed with brine (2 × 20 mL), dehydrated with anhydrous sodium 2 SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by prep HPLC (conditions: mobile phase - 10 mM ammonium bicarbonate in H2O: MeCN column - X-Bridge C18 (19×250) mm 5u, flow rate - 16 mL / min, gradient method - 0 / 35, 4 / 45, 8.6 / 45, 8.65 / 100, 11 / 100, 11.05 / 45, 14 / 45). The pure fractions were combined, concentrated under reduced pressure, and freeze-dried. 58 This was obtained.

[0232] M / Z (ESI): 473.14 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ (ppm) = 9.35 (d, J = 3.6 Hz, 2H), 8.68-8.82 (m, 2H), 8.54 (s, 1H), 8.16-8.35 (m, 2H), 7.97 (d, J = 8.4 Hz, 1H), 6.86 (d, J = 6.0 Hz, 1H), 4.20-4.92 (m, 4H), 3.36-3.50 (m, 5H), 3.20 (s, 3H). Example 59 (R)-5-((6-(3-fluoro-4H-1,2,4-triazol-4-yl)pyridine-3-yl)ethinyl)-2-(3-(methoxymethyl)-4-(pyrimidine-2-yl)piperazine-1-yl)pyrimidine [ka] Synthesis of 59-2: 5-bromo-2-(3-chloro-4H-1,2,4-triazol-4-yl)pyridine 5-Bromo-2-(4H-1,2,4-triazol-4-yl)pyridine 59-1To a solution prepared by dissolving (3 g, 13.33 mmol) in ACN (50 mL), NCS (3 g, 22.47 mmol) was added at room temperature. The reaction mixture was stirred at 60°C for 16 hours under an argon atmosphere. The reaction mixture was concentrated under reduced pressure. The crude compound was purified by biotage using a 48 g silica (230-400 mesh) cartridge, and the compound was eluted with 45% phenylethylamine in petroleum ether. The pure fractions were combined and concentrated under reduced pressure. 59-2 This was obtained.

[0233] M / Z (ESI): 261.00 [M+H] + . Synthesis of 59: 2-(3-chloro-4H-1,2,4-triazol-4-yl)-5-((trimethylsilyl)ethynyl)pyridine 59-2 (2.5 g, 9.63 mmol) was dissolved in ACN (40 mL), and while stirring, DIPEA (5 mL, 28.6 mmol) was added at room temperature. The reaction mixture was degassed and purged with argon gas for 15 minutes. Then, ethynyltrimethylsilane (2.75 mL, 19.32 mmol) and XPhos Pd G2 (0.758 g, 0.963 mmol) were added to this reaction mixture at room temperature. The reaction mixture was stirred in a sealed tube at 80°C for 16 hours. The reaction mixture was concentrated under reduced pressure. The crude compound was purified by biotage using an 80 g silica (230-400 mesh) cartridge, and the compound was eluted with 50% ethyl acetate in petroleum ether. The pure fractions were combined and concentrated under reduced pressure. 59-3 This was obtained.

[0234] M / Z (ESI): 276.95 [M+H] + . Synthesis of 59-4: (R)-5-((6-(3-chloro-4H-1,2,4-triazole-4-yl)pyridine-3-yl)ethinyl)-2-(3-(methoxymethyl)-4-(pyrimidine-2-yl)piperazine-1-yl)pyrimidine 59-5 (Prepared in the same manner as Int C) (700 mg, 1.698 mmol) was dissolved in DMF (10 mL) to create a solution. 59-3(611 mg, 2.207 mmol) and tripotassium phosphate (2163 mg, 10.19 mmol) were added at room temperature. The reaction mixture was degassed and purged with argon gas for 10 minutes. Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (134 mg, 0.170 mmol) was then added to the reaction mixture at room temperature. The reaction mixture was stirred in a sealed tube at 80°C for 2 hours. The reaction mixture was quenched with water (50 mL), filtered through a Celite pad, and washed with DCM (50 mL). The aqueous layer was extracted with DCM (2 × 50 mL), the organic layers were combined and washed with brine (50 mL), dehydrated with Na₂SO₄, filtered, and concentrated under reduced pressure. The crude compound was purified using Biotage with a 48 g silica (230-400 mesh) cartridge, and the compound was eluted with 5% MeOH in DCM. The pure fractions were combined and concentrated under reduced pressure. 59-4 This was obtained.

[0235] M / Z (ESI): 489.20 [M+H] + . Synthesis of 59: (R)-5-((6-(3-fluoro-4H-1,2,4-triazole-4-yl)pyridine-3-yl)ethinyl)-2-(3-(methoxymethyl)-4-(pyrimidine-2-yl)piperazine-1-yl)pyrimidine 59-4 Potassium fluoride (119 mg, 2.045 mmol) was added to a solution prepared by dissolving (100 mg, 0.205 mmol) in DMSO (1 mL) at room temperature. The reaction mixture was stirred at 120 °C for 12 hours. The reaction mixture was quenched with ice-cold water (5 mL), filtered, and dried under reduced pressure. The crude compound was purified by prep-HPLC. The relatively pure fractions were combined and concentrated under reduced pressure. The resulting compound was re-purified by achiral SFC.

[0236] M / Z (ESI): 473.16 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ (ppm) = 9.05 (s, 1H), 8.75 (dd, J = 2.2 Hz, 0.6 Hz, 1H), 8.64 (s, 2H), 8.41 (d, J = 4.8 Hz, 2H), 8.25 (dd, J = 8.4 Hz, 2.4 Hz, 1H), 7.78 (d, J = 7.6 Hz, 1H), 6.68 (t, J = 4.8 Hz, 1H), 4.89-4.98 (m, 1H), 4.78 (d, J = 13.6 Hz, 1H), 4.48-4.61 (m, 2H), 3.39-3.45 (m, 3H), 3.20 (s, 5H). Prep-HPLC purification conditions: Equipment ID: ANL-MCL5-PREP-023 Column name: XBRIDGE ODS 19×250, 5um Column No.: XBRIDGE ODS 19×250, 5um Mobile phase-A: 10 mM ammonium bicarbonate in water Mobile phase-B: Acetonitrile Gradient program (T / %B) 0 / 48, 2 / 48, 10.20 / 65, 10.25 / 100, 13 / 100, 13.05 / 48, 17 / 48.

[0237] Achiral SFC purification conditions: Column: YMC DIOL (4.6 × 250 mm) 5 μm Co-solvent: methanol Total flow rate: 3mL / min CO2 %: 90 Cosolvent percentage: 10 ABPR: 1500 psi Temperature: 30℃.

[0238] The compounds included in Table 2 were synthesized using the same method as the synthesis procedure shown in the last column of Table 2. The following examples were prepared by substituting commercially available reagents as needed. [Table 4] TIFF2026509241000086.tif236170TIFF2026509241000087.tif219170TIFF2026509241000088.t if219170TIFF2026509241000089.tif238170TIFF2026509241000090.tif206170TIFF2026509241 000091.tif237170TIFF2026509241000092.tif213170TIFF2026509241000093.tif218170TIFF20 26509241000094.tif206170TIFF2026509241000095.tif201170TIFF2026509241000096.tif82170 Radioactive labeling procedure Synthesis of radioactive labeling precursors: Synthesis of 44-2: (R)-2-((4-(5-((2-(1-methyl-1H-pyrazole-4-yl)pyrimidine-5-yl)ethynyl)pyrimidine-2-yl)-1-(1,3,5-triazine-2-yl)piperazine-2-yl)methoxy)ethyl 4-methylbenzene sulfonate [ka] Synthesis of 44-2: (R)-2-((4-(5-((2-(1-methyl-1H-pyrazole-4-yl)pyrimidine-5-yl)ethynyl)pyrimidine-2-yl)-1-(1,3,5-triazine-2-yl)piperazine-2-yl)methoxy)ethyl 4-methylbenzene sulfonate 44-3 (Synthesized in the same manner as in 52-3) (500 mg, 1.001 mmol) was dissolved in DCM (5 mL) and, while stirring, TEA (0.419 mL, 3.00 mmol), DMAP (12.23 mg, 0.100 mmol), and p-toluenesulfonyl chloride (477 mg, 2.502 mmol) were added at 0°C. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (3 × 100 mL). The organic layers were combined, dehydrated with Na₂SO₄, filtered, and concentrated under reduced pressure. The crude compound was purified by prep-HPLC (conditions: mobile phase - 10 mM ammonium bicarbonate in H2O: MeCN, column - betasil phenyl hexyl (20 × 250) mm, 5 μm, flow rate - 18.0 mL / min, gradient method - 0 / 49, 16 / 52, 16.05 / 100, 19 / 100, 19.05 / 49, 23 / 49). The pure fractions were combined, concentrated under reduced pressure, and freeze-dried. 44-2 This was obtained.

[0239] M / Z (ESI): 654.35 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ (ppm) = 8.90 (s, 2H), 8.62 (d, J = 5.2 Hz, 4H), 8.42 (s, 1H), 8.06 (s, 1H), 7.75 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 8.0 Hz, 2H), 4.85-4.94 (m, 1H), 4.70 (d, J = 13.6 Hz, 1H), 4.48-4.64 (m, 2H), 4.03 (t, J = 4.4 Hz, 2H), 3.92 (s, 3H), 3.50-3.60 (m, 2H), 3.44 (d, J = 6.8 Hz, 2H), 3.36-3.40 (m, 1H), 3.18-3.27 (m, 2H), 2.40 (s, 3H). Synthesis of 46-7: (R)-2-(4-(5-((2-(3-(methoxymethyl)-4-(1,3,5-triazin-2-yl)piperazin-1-yl)pyrimidine-5-yl)ethynyl)pyrimidine-2-yl)-1H-pyrazole-1-yl)ethyl 4-methylbenzene sulfonate

change

[0240] M / Z (ESI): 270.90 [M+H] + . Synthesis of 46-10: (R)-2-(4-(5-iodopyrimidine-2-yl)-2-(methoxymethyl)piperazine-1-yl)-1,3,5-triazine 36-8 A solution of (1 g, 2.505 mmol) dissolved in DMF (10 mL) was stirred, and methyl iodide (0.711 g, 5.01 mmol) and 60% NaH in mineral oil (0.200 g, 5.01 mmol) were added at 0°C. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was quenched with water (8 mL) and extracted with ethyl acetate (2 × 50 mL). The organic layers were combined, washed with brine (10 mL), dehydrated with anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography, and the compound was eluted with 30% ethyl acetate in petroleum ether. The pure fractions were combined and concentrated under reduced pressure. 46-10 This was obtained.

[0241] M / Z (ESI): 414.18 [M+H]+ . Synthesis of 46-9: (R)-(R)-2-(2-(methoxymethyl)-4-(5-((trimethylsilyl)ethinyl)pyrimidine-2-yl)piperazine-1-yl)-1,3,5-triazine 46-10 A solution of (680 mg, 1.646 mmol) dissolved in ACN (7 mL) was stirred, and DIPEA (0.862 mL, 4.94 mmol) was added at room temperature. The reaction mixture was degassed and purged with argon for 20 minutes. Then, trimethylsilylacetylene (323 mg, 3.29 mmol) and XPhos Pd G2 (129 mg, 0.165 mmol) were added to the reaction mixture at room temperature. The reaction mixture was stirred at 80°C for 16 hours under a nitrogen atmosphere. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (2 × 50 mL). The organic layers were combined and washed with brine (2 × 10 mL), dehydrated with anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude compound was purified by biotage using a 100 g silica (100-200 mesh) cartridge, and the compound was eluted with 50% ethyl acetate in petroleum ether. The pure fractions are combined and concentrated under reduced pressure. 46-9 This was obtained.

[0242] M / Z (ESI): 384.32 [M+H] + . Synthesis of 46-11: (R)-2-(4-(5-((2-(3-(methoxymethyl)-4-(1,3,5-triazine-2-yl)piperazine-1-yl)pyrimidine-5-yl)ethinyl)pyrimidine-2-yl)-1H-pyrazole-1-yl)ethane-1-ol 46-9 (450 mg, 1.173 mmol) is dissolved in ACN (4 mL) and DMF (1.5 mL). While stirring the solution, add the following: 46-8(379 mg, 1.408 mmol) and tripotassium phosphate (747 mg, 3.52 mmol) were added at room temperature. The reaction mixture was degassed and purged with argon for 15 minutes. Then, XPhos Pd G2 (92 mg, 0.117 mmol) was added to the reaction mixture at room temperature. The reaction mixture was stirred in a sealed tube under a nitrogen atmosphere at 70°C for 18 hours. The reaction mixture was quenched with water (7 mL) and extracted with pharmaceutically acceptable phosphate (2 × 40 mL). The organic layers were combined and washed with brine (2 × 10 mL), dehydrated with anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude compound was purified by biotage using a 40 g silica (100-200 mesh) cartridge, and the compound was eluted with 10% MeOH in DCM. The pure fractions were combined and concentrated under reduced pressure. The obtained compound was further purified by prep-HPLC (conditions: mobile phase - 10 mM ammonium bicarbonate in H2O: MeCN, column - X-Bridge PACK, C18 (25×150) mm, 5 μm, flow rate - 20.0 mL / min, gradient method - 0 / 20, 9.5 / 47.3, 9.55 / 100, 12 / 100, 12.05 / 20, 15 / 20), 46-11 This was obtained.

[0243] M / Z (ESI): 500.25 [M+H] + . Synthesis of 46-7: (R)-2-(4-(5-((2-(3-(methoxymethyl)-4-(1,3,5-triazin-2-yl)piperazin-1-yl)pyrimidine-5-yl)ethynyl)pyrimidine-2-yl)-1H-pyrazole-1-yl)ethyl 4-methylbenzene sulfonate 46-11A solution of (120 mg, 0.240 mmol) dissolved in DCM (2 mL) was stirred, and TEA (0.100 mL, 0.721 mmol), DMAP (29.3 mg, 0.240 mmol), and Ts-Cl (114 mg, 0.601 mmol) were added at 0°C. The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The reaction mixture was quenched with water (40 mL) and extracted with siRNA (2 × 70 mL). The organic layers were combined, washed with brine (2 × 40 mL), dehydrated with anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude compound was purified by biotage using an 80 g silica (230-400 mesh) cartridge, and the compound was eluted with 3% MeOH in DCM. The pure fractions were combined and concentrated under reduced pressure. The obtained compound was further purified by pre-HPLC (conditions: mobile phase - 10 mM ammonium bicarbonate in H2O: MeCN, column - X-Bridge, C18 (19X150) mm, 5 μm, flow rate - 15.0 mL / min, gradient method - 0 / 45, 2 / 45, 12 / 80, 12.01 / 100, 15 / 100, 15.01 / 45, 18 / 45). The pure fractions were combined, concentrated under reduced pressure, and freeze-dried. 46-7 This was obtained.

[0244] M / Z (ESI): 654.18 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ (ppm) = 8.92 (s, 2H), 8.65 (d, J = 4.8 Hz, 4H), 8.35 (s, 1H), 7.99 (d, J = 0.4 Hz, 1H), 7.62 (d, J = 8.4 Hz, 2H), 7.30-7.39 (m, 2H), 4.95-5.06 (m, 1H), 4.77 (d, J = 13.6 Hz, 1H), 4.54-4.67 (m, 2H), 4.44 (q, J = 3.7 Hz, 4H), 3.45 (d, J = 7.2 Hz, 2H), 3.33-3.40 (m, 1H), 3.15-3.28 (m, 5H), 2.31 (s, 3H). Synthesis of 48-6: (R)-2-(2-((4-(5-((6-(oxazol-5-yl)pyridine-3-yl)ethynyl)pyrimidine-2-yl)-1-(1,3,5-triazine-2-yl)piperazine-2-yl)methoxy)ethoxy)ethyl 4-methylbenzene sulfonate [ka] Synthesis of 48-5: (R)-2-(2-((4-(5-((6-(Oxazol-5-yl)pyridine-3-yl)ethinyl)pyrimidine-2-yl)-1-(1,3,5-triazine-2-yl)piperazine-2-yl)methoxy)ethoxy)ethane-1-ol 48-4 (180 mg, 0.369 mmol) was dissolved in DMF (2 mL), and the solution was purged with argon gas for 10 minutes while stirring. Then, to this reaction mixture, 48-2 (107 mg, 0.443 mmol), K2CO3 (153 mg, 1.108 mmol), copper(I) iodide (7.03 mg, 0.037 mmol), and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (29.1 mg, 0.037 mmol) were added at room temperature. The reaction mixture was purged again with argon for 10 minutes. The reaction mixture was stirred at 80°C for 12 hours. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 × 100 mL). The organic layers were combined, dehydrated with Na2SO4, and concentrated under reduced pressure. The crude compound was ground with diethyl ether (2 × 30 mL) and dried under reduced pressure to obtain (5075688-0321-002) (160 mg, 0.275 mmol, 74.4% yield) as a pale yellow solid. From the obtained compound (5075688-0321-002) (160 mg), 30 mg was re-purified by SFC purification. The pure fractions were combined and freeze-dried. 48-5 This was obtained.

[0245] M / Z (ESI): 530.27 [M+H] + . [Table 5] 1H NMR (400 MHz, DMSO-d6) δ (ppm) = 8.77 (dd, J = 0.8, 2.4 Hz, 1H), 8.65 (s, 4H), 8.59 (s, 1H), 8.06 (dd, J = 2, 8.4 Hz, 1H), 7.88 (s, 1H), 7.83-7.81 (m, 1H), 4.96-4.94 (m, 1H), 4.78 (d, J = 13.6 Hz, 1H), 4.60-4.51 (m, 3H), 3.52 (d, J = 7.2 Hz, 2H), 3.49-3.44 (m, 2H), 3.43-3.39 (m, 5H), 3.36-3.31 (m, 2H), 3.26-3.25 (m, 1H), 3.26-3.16 (m, 1H). Synthesis of 48-6: (R)-2-(2-((4-(5-((6-(oxazol-5-yl)pyridine-3-yl)ethynyl)pyrimidine-2-yl)-1-(1,3,5-triazine-2-yl)piperazine-2-yl)methoxy)ethoxy)ethyl 4-methylbenzene sulfonate 48-5 A solution of (130 mg, 0.245 mmol) dissolved in DCM (1 mL) was stirred, and TEA (0.103 mL, 0.736 mmol), DMAP (3.00 mg, 0.025 mmol), and p-TsCl (140 mg, 0.736 mmol) were added at 0°C. The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was diluted with water (100 mL) and extracted with siRNA (3 × 100 mL). The organic layers were combined, dehydrated with Na₂SO₄, and concentrated under reduced pressure. The crude compound was purified by prep-HPLC. The pure fractions were combined and freeze-dried. 48-6 This was obtained.

[0246] M / Z (ESI): 684.20 [M+H] + . Prep HPLC method: Mobile phase - 10 mM ammonium bicarbonate in H2O: MeCN Column - X-Bridge C18 (10×250mm), 5μ Flow rate - 7mL / min Gradient method - 0 / 52, 2 / 52, 7.5 / 55.5, 10 / 55.5, 10.05 / 100, 12 / 100, 12.05 / 52, 16 / 52.

[0247] 1 H NMR (400 MHz, DMSO-d6) δ (ppm) = 8.79 - 8.76 (m, 1H), 8.63 (s, 4H), 8.59 (s, 1H), 8.06 (dd, J = 2.1, 8.3 Hz, 1H), 7.88 (s, 1H), 7.83 (dd, J = 0.8, 8.3 Hz, 1H), 7.79 - 7.75 (m, 2H), 7.45 (d, J = 8.0 Hz, 2H), 4.97 - 4.90 (m, 1H), 4.77 (br d, J = 13.5 Hz, 1H), 4.63 - 4.51 (m, 2H), 4.08 - 4.05 (m, 2H), 3.53 - 3.47 (m, 4H), 3.43 - 3.39 (m, 2H), 3.37 (br d, J = 2.4 Hz, 3H), 3.29 - 3.16 (m, 2H), 2.39 (s, 3H). Synthesis of 52-7: (R)-2-(2-((4-(5-((2-(1-methyl-1H-pyrazole-4-yl)pyrimidine-5-yl)ethynyl)pyrimidine-2-yl)-1-(pyrimidine-2-yl)piperazine-2-yl)methoxy)ethoxy)ethyl 4-methylbenzene sulfonate [ka] Synthesis of 52-4: 5-bromo-2-((3R)-4-(pyrimidine-2-yl)-3-((2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)ethoxy)methyl)piperazine-1-yl)pyrimidine 52-1 (2.0 g, 5.06 mmol) was dissolved in DMF (40 mL) and, while stirring, 60% NaH (0.304 g, 7.59 mmol) in the oil was added at 0°C and stirred for 30 minutes at 0°C. Then, 2-(2-bromoethoxy)tetrahydro-2h-pyran (2.116 g, 10.12 mmol) was added to the reaction mixture at 0°C. The reaction mixture was stirred at 80°C for 16 hours. The reaction mixture was quenched with water (150 mL) and extracted with ELISA (3 × 200 mL). The organic layers were combined, dehydrated with Na₂SO₄, filtered, and concentrated under reduced pressure. 52-4 This was obtained.

[0248] M / Z (ESI): 525.11 [M+H] + . Synthesis of 52-5: (R)-2-(2-((4-(5-bromopyrimidine-2-yl)-1-(pyrimidine-2-yl)piperazine-2-yl)methoxy)ethoxy)ethane-1-ol 52-4(2g, 3.82 mmol) was dissolved in DCM (30 mL), and while stirring, 4M 1,4-dioxane hydrochloride (3.82 mL, 15.28 mmol) was added at 0°C. The reaction mixture was stirred at 25°C for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with aqueous NaHCO3 solution and extracted with SiO2 (3 × 80 mL). The organic layers were combined, dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by biotage using 25 g silica gel, and the compound was eluted with 35% SiO2 in petroleum ether. The pure fractions were combined and concentrated under reduced pressure. 52-5 This was obtained.

[0249] M / Z (ESI): 439.07 [M+H] + . Synthesis of 52-6: (R)-2-(2-((4-(5-((2-(1-methyl-1H-pyrazole-4-yl)pyrimidine-5-yl)ethinyl)pyrimidine-2-yl)-1-(pyrimidine-2-yl)piperazine-2-yl)methoxy)ethoxy)ethane-1-ol 52-5 (800 mg, 1.821 mmol) dissolved in DMF (8 mL) is stirred while adding to the solution. 44-1 (607 mg, 2.367 mmol), K2CO3 (755 mg, 5.46 mmol), copper(I) iodide (34.7 mg, 0.182 mmol), and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (143 mg, 0.182 mmol) were added at room temperature, and the mixture was degassed with argon gas for 10 minutes at room temperature. The reaction mixture was stirred in a sealed tube under a nitrogen atmosphere at 80°C for 16 hours. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (2 × 50 mL). The organic layers were combined, washed with brine (2 × 30 mL), dehydrated with Na2SO4, filtered, and concentrated under reduced pressure. The crude compound was purified by biotage using a 100 g silica reverse-phase RP GOLD column, and the compound was eluted with 50% ACN in water. The pure fractions were combined and concentrated under reduced pressure. 52-6 This was obtained.

[0250] M / Z (ESI): 543.71 [M+H] + . Synthesis of 52-7: (R)-(R)-2-(2-((4-(5-((2-(1-methyl-1H-pyrazole-4-yl)pyrimidine-5-yl)ethynyl)pyrimidine-2-yl)-1-(pyrimidine-2-yl)piperazine-2-yl)methoxy)ethoxy)ethyl 4-methylbenzene sulfonate 52-6 A solution of (90 mg, 0.166 mmol) dissolved in DCM (1 mL) was stirred, and TEA (0.116 mL, 0.829 mmol), 4-dimethylaminopyridine (2.026 mg, 0.017 mmol), and p-TsCl (95 mg, 0.498 mmol) were added at 0°C. The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was quenched with water (40 mL) and extracted with siRNA (2 × 40 mL). The organic layers were combined, washed with brine (20 mL), dehydrated with anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude compound was purified by biotage using a 100 g silica reverse-phase RP GOLD column, and the compound was eluted with 70% ACN in water. The pure fractions were combined and concentrated under reduced pressure. 52-7 This was obtained.

[0251] M / Z (ESI): 697.37 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ = 8.89 (s, 2H), 8.61 (s, 2H), 8.36-8.47 (m, 3H), 8.05 (d, J = 0.4 Hz, 1H), 7.77 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.0 Hz, 2H), 6.67 (t, J = 4.8 Hz, 1H), 4.83-4.91 (m, 1H), 4.78 (d, J = 13.6 Hz, 1H), 4.47-4.57 (m, 2H), 4.08 (t, J = 4.4 Hz, 2H), 3.92 (s, 3H), 3.50-3.56 (m, 2H), 3.34-3.49 (m, 7H), 3.22-3.29 (m, 2H), 2.39 (s, 3H). The compounds included in Table 3 were synthesized using the same method as the synthesis procedure shown in the last column of Table 3. The following examples were prepared by substituting commercially available reagents as needed. [Table 6] [ 3 Synthesis of H-1000: [ 3 H]-(S)-6-(1H-imidazole-1-yl)-N-(2-(2-methyl-4-(pyridine-2-yl)piperazine-1-yl)pyrimidine-5-yl)nicotinamide [ka] Synthesis of intermediate ST-A: (S)-2-(2-methyl-4-(pyridine-2-yl)piperazine-1-yl)pyrimidine-5-amine [ka] Synthesis of 1000-2: (S)-tert-butyl 3-methyl-4-(5-nitropyrimidine-2-yl)piperazine-1-carboxylate (S)-tert-butyl 3-methylpiperazine-1-carboxylate 1000-1 To a solution prepared by dissolving 13.6 g (67.9 mmol) of the starting material in 150 mL of DMF, K2CO3 (14.08 g, 102 mmol) and 2-chloro-5-nitropyrimidine (12.46 g, 78 mmol) were added. The mixture was stirred under an N2 balloon at 25°C for 12 hours. TLC showed that the starting material was completely consumed. Water (450 mL) was added, and the mixture was stirred at 25°C (rt) for 30 minutes. The precipitated solid was collected by filtration, washed with water (100 mL x 3), and dried. 1000-2 It was obtained as a solid.

[0252] 1 ¹H NMR (500 MHz, chloroform-d): δ = 9.07 (s, 2H), 5.06 (br s, 1H), 4.67 (br s, 1H), 3.91~4.29 (m, 2H), 3.28~3.36 (m, 1H), 3.13 (br s, 1H), 2.83~3.01 (m, 1H), 1.45~1.52 (m, 9H), 1.26 (d, J = 6.5 Hz, 3H) Synthesis of 1000-3: (S)-2-(2-methylpiperazin-1-yl)-5-nitropyrimidine 1000-2(21 g, 64.9 mmol) was dissolved in DCM (160 mL), and TFA (40 mL) was added at 0°C. The mixture was stirred at 25°C for 2 hours. TLC showed that most of the starting material had been completely consumed. The mixture was concentrated under reduced pressure to obtain the crude product (S)-2-(2-methylpiperazin-1-yl)-5-nitropyrimidine (25 g, 78 mmol) as an oily substance. The product was diluted with DCM (200 mL) and H2O (160 mL). Then, Na2CO3 was added to the solution to adjust the pH to 7-8. The solution was extracted with DCM (200 mL x 2). The organic layer was dehydrated with Na2SO4, filtered, and concentrated. 1000-3 It was obtained as a solid.

[0253] 1 H NMR (400 MHz, DMSO-d6): δ = 9.44 (s, 1H), 8.92~9.10 (m, 1H), 5.13~5.24 (m, 1H), 4.82 (d, J = 14.4 Hz, 1H), 3.31~3.49 (m, 3H), 3.26 (d, J = 7.2 Hz, 1H), 3.06 (d, J = 8.8 Hz, 1H), 1.52 (s, 1H), 1.33 (d, J = 7.2 Hz, 3H). MS (ESI) m / z: 224.0 [M+H] + . Synthesis of 1000-4: (S)-2-(2-methyl-4-(pyridine-2-yl)piperazine-1-yl)-5-nitropyrimidine 1000-3To a solution prepared by dissolving (2.5 g, 11.20 mmol) in dioxane (50 mL), 2-bromopyridine (3.72 g, 23.52 mmol), Cs2CO3 (14.96 g, 45.9 mmol), and chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.968 g, 1.344 mmol) were added. The mixture was stirred under N2 balloon at 110°C for 12 hours. TLC showed that most of the starting material was completely consumed. The mixture was filtered and concentrated. The residue was extracted with ELISA (3 × 50 mL) and H2O (60 mL). The organic extracts were combined, washed with brine (100 mL), dehydrated with anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified using a silica gel column (eluted with 15-30% alkyl acetate / PE), 1000-4 It was obtained as a solid.

[0254] 1 H NMR (400 MHz, chloroform-d): δ = 9.10 (s, 2H), 8.17~8.24 (m, 1H), 7.47~7.59 (m, 1H), 6.62~6.71 (m, 2H), 5.11 (dt, J = 6.4, 3.2 Hz, 1H), 4.74 (dt, J = 13.6, 3.6 Hz, 1H), 4.24 (d, J = 12.8 Hz, 1H), 4.13 (d, J = 13.2 Hz, 1H), 3.53~3.63 (m, 1H), 3.37 (dd, J = 13.2, 4.0 Hz, 1H), 3.12 (td, J = 12.0, 3.6 Hz, 1H), 1.34 (d, J = 6.8 Hz, 3H). MS (ESI) m / z: 301.0 [M+H] + . Synthesis of (S)-2-(2-methyl-4-(pyridine-2-yl)piperazin-1-yl)pyrimidine-5-amine (Int ST-A) 1000-4To a solution of (2.5 g, 8.32 mmol) dissolved in MeOH (40 mL), Pd / C (0.2 g, 1.879 mmol) was added. The mixture was stirred under an H2 balloon at 25°C for 2 hours. TLC showed that most of the starting material was completely consumed. The mixture was filtered, and the filtered cake was washed with MeOH (3 × 200 mL). The organic extracts were combined and concentrated under reduced pressure. Int ST-A It was obtained as an oily substance.

[0255] 1 H NMR (400 MHz, chloroform-d): δ = 8.19 (dd, J = 4.8, 1.2 Hz, 1H), 8.01 (s, 2H), 7.45~7.50 (m, 1H), 6.66 (d, J = 8.8 Hz, 1H), 6.60 (dd, J = 6.8, 5.2 Hz, 1H), 4.76~4.85 (m, 1H), 4.32~4.40 (m, 1H), 4.19~4.26 (m, 1H), 4.10 (dt, J = 12.8, 2.0 Hz, 1H), 3.23~3.41 (m, 2H), 3.15 (s, 2H), 3.01~3.08 (m, 1H), 1.22 (d, J = 6.8 Hz, 3H). MS (ESI) m / z: 271.1 [M+H] + . Synthesis of compound 1000: (S)-6-(1H-imidazole-1-yl)-N-(2-(2-methyl-4-(pyridine-2-yl)piperazine-1-yl)pyrimidine-5-yl)nicotinamide [ka] Int ST-AA solution of (150 mg, 0.555 mmol) and 6-(1H-imidazole-1-yl)nicotinic acid (157 mg, 0.832 mmol) dissolved in THF (30 mL) was stirred, and TEA (0.193 mL, 1.387 mmol) and 1-propanephosphonic anhydride (0.495 mL, 0.832 mmol) were added at 25°C and stirred for 16 hours at 25°C. The reaction mixture was quenched with ice-cold water (10 mL), extracted with ethyl acetate (2 × 100 mL), combined with the organic layer and washed with brine solution (2 × 10 mL), dehydrated with sodium sulfate, filtered, concentrated under reduced pressure, and the crude compound was purified by Prep HPLC (mobile phase - 10 mM ammonium bicarbonate in H2O: MeCN, column - X-Select C18 (19 × 250) mm 5u, flow rate - 18 mL / min, gradient method - 0 / 45, 6.9 / 76, 6.95 / 100, 9 / 100, 9.05 / 45, 12 / 45). The pure fraction was concentrated and lyophilized. 1000 It was obtained as a pale yellow solid.

[0256] M / Z (ESI): 442.14 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ: 10.43 (s, 1H), 9.04 (d, J=2.0 Hz, 1H), 8.71 (s, 2H), 8.66 (s, 1H), 8.52 (dd, J=8.7, 2.3 Hz, 1H), 8.12 (dd, J=4.9, 1.2 Hz, 1H), 8.06 (t, J=1.2 Hz, 1H), 8.01 (d, J=8.6 Hz, 1H), 7.55 (ddd, J=8.6, 7.0, 2.2 Hz, 1H), 7.18 (s, 1H), 6.86 (d, J=8.8 Hz, 1H), 6.60-6.67 (m, 1H), 4.85 (dt, J=6.4, 3.2 Hz, 1H), 4.41-4.49 (m, 1H), 4.17-4.31 (m, 2H), 3.28 (br d, J=3.7 Hz, 1H), 3.19 (br dd, J=13.1, 3.8 Hz, 1H), 2.90-3.01 (m, 1H), 1.16 (d, J=6.6 Hz, 3H). In a glove box, compound 1000 (1.33 mg, 3.0 μmol) was dissolved in CPME (75 μL) and NMP (25 μL). Nickel pre-catalyst ( ipcADI)NiBr2 (6.73 mg) was dissolved in CPME (670 μL), treated with NaHBEt3 (1 M, 25 μL) in toluene, and then stirred for 5 minutes. The substrate solution (100 μL) was combined with the activated catalyst solution (200 μL, 3.5 μmol) in a tritiation vessel and fixed with a portable Swagelok® valve. The valve was attached to a Trisorber, and after two freeze-pump-thaw cycles, 102 ml of tritium gas was introduced. The reaction mixture was thawed and then placed in an oil bath at 45°C and stirred overnight. After capturing spent tritium in the waste liquid bed, the reaction mixture was transferred to a vial containing 10 mL of saturated aqueous sodium bicarbonate. The mixture was extracted three times with dichloromethane. The organic layers were combined, dehydrated with sodium sulfate, and evaporated. The residue was dissolved in EtOH for LSC and radio-HPLC analysis. Crude yield: 120 mCi; RCP: 67%. This substance was purified by HPLC. The collected fraction was diluted with an equal volume of water, concentrated in a pair of C18 cartridges, and eluted with EtOH. Yield: approximately 20 mL ethanol solution @ 3.18 mCi / mL. The specific activity was determined to be 44.9 Ci / mmol by mass spectrometry.

[0257] C 23 H 17 MW [M+H] for T7N9O + : 456.3, Measured value: 456.0. HPLC analysis conditions Method: 10-95% B over 12 minutes, hold for 3 minutes, re-equilibrium for 6 minutes. Column: Gemini NX C18, 4.6×50mm, 3.5mm @ 40℃ Flow rate: 1mL / min Injection volume: 1.0μL Detection: UV @ 294nm Mobile phase A: 0.05M pH10 TEAA in H2O Mobile phase B: CH3CN Product elution time: 6.32 minutes.

[0258] HPLC preliminary separation conditions Method: Isocratic (A:B=65:35) Column: Gemini NX C18, 10×250mm @ 40℃ Flow rate: 5mL / min Injection volume: 0.5mL Detection: UV @ 295nm Mobile phase A: 0.05M pH10 TEAA in H2O Mobile phase B: CH3CN.

[0259] [ 3 Synthesis of H]-2: [ 3 H]-(R,E)-5-(2-(6-(1H-imidazole-1-yl)pyridine-3-yl)vinyl)-2-(3-(methoxymethyl)-4-(pyrimidine-2-yl)piperazine-1-yl)pyrimidine [ka] Ex.No.1 (4.55 mg, 10 μmol) was combined with dimethylacetamide (0.1 mL) in a 1 mL crimp-seal V vial under nitrogen. When sodium pentoxide (1.4 M, 6.9 μL, 9.7 μmol) was added, the yellow suspension darkened to orange, but the solid did not completely dissolve. After stirring at room temperature for 30 minutes, the suspension was transferred under nitrogen to another 1 mL crimp-seal V vial containing 50 mCi of methyl [3H]nosylate (0.6 μmol). This vial was heated overnight in an oil bath. The reaction product was partitioned between saturated aqueous solution NaHCO3 and CH2Cl2. The aqueous phase was extracted three more times with CH2Cl2. The organic extracts were combined, dehydrated with Na2SO4, and evaporated to obtain a crude product (24.5 mCi) with a radiochemical purity of 57% as determined by RP-HPLC analysis. [ 3 H]-2 The radioactive material was purified by semi-preparative HPLC. The recovered fraction was diluted with an equal volume of water, concentrated in a pair of C18 cartridges, and eluted with EtOH. Yield: 20 mL ethanol solution @ 0.28 mCi / mL. The specific activity was determined to be 63.0 Ci / mmol by mass spectrometry.

[0260] C 24 H 23 MW [M+H] for T3N9O +: 462.2, Measured value: 462.0. HPLC analysis conditions Method: 10-95% B over 12 minutes, hold for 3 minutes, re-equilibrium for 6 minutes. Column: Gemini NX C18, 4.6×50mm, 3.5mm @ 40℃ Flow rate: 1mL / min Injection volume: 3.0μL Detection: UV @ 335nm Mobile phase A: 0.1% TFA in H2O Mobile phase B: 0.1%TFA CH3CN Product elution time: 4.43 minutes.

[0261] HPLC preliminary separation conditions Method: Isocratic (A:B=55:45) Column: Gemini NX C18, 10×250mm @ 40℃ Flow rate: 5mL / min Injection volume: 0.6mL Detection: UV @ 340nm Mobile phase A: 0.05M pH10 TEAA in H2O Mobile phase B: CH3CN.

[0262] Assay procedure Acquisition of human postmortem tissue samples for in vitro binding assays Frozen human brain tissue from PD patients was purchased from Analytic Biological Services Inc. The samples were postmortem tissue from donors clinically diagnosed with late-stage PD. Alpha-synuclein, tau, and amyloid loadings were determined by a combination of immunohistochemistry of frozen thin coronal sections and quantification based on α-Lisa protein levels in surfactant-insoluble protein fractions. One temporal cortical tissue sample, derived from a single donor, was identified as having a moderate to high alpha-synuclein loading, low amyloid content, and minimal tau pathology. The surfactant-insoluble fraction of the temporal cortex from this patient was used to support homogenate-binding studies.

[0263] Preparation of surfactant-insoluble fractions of human brain tissue for in vitro binding studies. Gray matter was extracted from the temporal cortical tissue using a dissecting knife and finely chopped with thin dissecting scissors. To prepare the insoluble fraction, the minced tissue was homogenized in ice-cold TBS-TX buffer (50 mM Tris + 150 mM NaCl + 1% Triton X100 + 1 mM EDTA + 1 tablet / 10 mL of complete protease inhibitor + 1 tablet / 10 mL of PHOSSTOP phosphatase inhibitor tablet) using a glass Dounce tissue grinder. The homogenate was centrifuged at 100,000 × g for 45 minutes. The pellet was resuspended in TBS-TX buffer using a Polytron at the highest setting for 30 seconds at 4°C. The homogenate was centrifuged at 100,000 × g for 45 minutes, and the pellet was resuspended in TBS-TX buffer. The final homogenate was subjected to a BCA protein assay to measure the protein concentration. The homogenate was divided into equal portions of 0.5 mL / tube and stored at -70°C until use.

[0264] Procedure for the α-synuclein tissue homogenate binding assay (Assay 1) For the substitution α-synuclein binding assay, the compound and control were dissolved in dimethyl sulfoxide (DMSO) and transferred to designated wells of a uniquely barcoded 96-well V-bottom low-binding polypropylene microplate (Thermo Scientific, 249946) using focused ultrasonic energy with an Echo 655 liquid handling instrument (Beckman Coulter, Indianapolis, IN). Compound dose-response curves were prepared in the form of 10 points of 3-fold dilution from high to low compound concentrations in columns 2–11 of the microplate. Starting at 1 mM, the final assay concentrations in the dose-response curves ranged from 1.2 μM to 0.061 nM (DMSO final assay concentration 0.12%, 270 nL / well). For the minimum effective signal, an inhibitor-free control (DMSO only) was dispensed into wells A1-D1 and A12-D12. For the maximum effective signal, 1000 units of compound at a final assay concentration of 12 μM were dispensed into wells E1-H1 and E12-H12. The liquid handling step for dispensing the insoluble fraction of PD brain homogenate and the radioligand was performed using a Bravo automated liquid handling platform (Agilent Technologies, Santa Clara, CA) equipped with a 96LT disposable tip head. The insoluble fraction of PD brain homogenate was diluted to 50 μg / mL in assay buffer, and 200 μL was dispensed into the assay plate to a final concentration of 10 μg / well. 25 μL of (9×)[ 3[H]-1000 was dispensed into assay plates to a final assay concentration of 3.0 nM. The sealed assay plates were incubated at room temperature for 90 minutes with gentle agitation. Incubation was terminated by rapid filtration using a FilterMate Harvester (PerkinElmer) through a UniFilter-96 GF / C microplate (pre-treated with 0.2% polyethyleneimine at 4°C for 30 minutes). The microplates were then washed four times with 3.75 mL of ice-cold Dulbecco's Phosphate-Buffered Saline (DPBS, Gibco 14190136) and dried in a vacuum oven (Fisher Scientific Isotemp 285A) at 47°C for 90 minutes or dried overnight at room temperature. After sealing the bottom of each UniFilter-96 GF / C microplate with adhesive (PerkinElmer 6005199), 50 μL of MicroScint-20 liquid scintillation cocktail (PerkinElmer 6013621) was added to each well. Then, a clear adhesive seal (TopSeal-A PLUS, PerkinElmer 6050185) was applied to the top of each microplate, and MicroBeta 2 The counting was performed at 1 minute / well using the system (PerkinElmer, model: 2450-0120). The data was analyzed using IDBS ActivityBase XE Runner (version 9.6.0.148) to determine the Ki values ​​shown in Table 1 (K d (Value 0.90 nM, ligand concentration 3.0 nM).

[0265] Competitive binding of radioactive ligands to pathologically aggregated β-amyloid in AD tissue (Assay 2): Frozen human brain samples from Alzheimer's disease (AD) were purchased from Analytic Biological Services Inc. The samples were postmortem tissue from a clinically diagnosed AD donor, and a large portion of the white matter was excised from the frontal cortex to concentrate the gray matter tissue preparation. A gray matter-rich frontal cortex brain homogenate was prepared by homogenizing the tissue in ice-cold phosphate-buffered saline (PBS) (pH 7.4) with 80 mg of wet tissue per mL at 4°C for 45 seconds using a Polytron set to 16. The homogenate was further diluted with ice-cold PBS to 30 mg of wet tissue per mL and homogenized for another minute as described above. The homogenate was divided into 5 mL / tube portions and stored at -70°C until use.

[0266] Radiating ligand [ 3 H]-105 was prepared in this assay as described in "ACS Med. Chem. Lett., Vol. 2, pages 498-502". [ka] In the hot saturation binding assay, various concentrations of radioactive ligands are used. [ 3 H]-105 The assay was prepared in assay buffer (PBS + 0.1% BSA) with 20% DMSO to a concentration range of 3.9–500 nM. 25 μL of radioactive ligand was added to 200 μL of crude brain homogenate (diluted to 0.5 mg / mL with assay buffer) to achieve a final radioactive ligand concentration in the range of 0.39–50 nM, resulting in a final crude brain homogenate at 100 μg wet weight / assay well (incubation, filtration, and measurement of the amount of radioactive ligand used in the assay are described below). Nonspecific binding was measured using self-blocking with an unlabeled compound. Saturation data were analyzed using GraphPad / Prism software. Figure 1 shows the results for AD tissue homogenate rich in aggregated β-amyloid pathology. [ 3 H]-105This represents a high-affinity saturated bond. Figure 1 shows, [ 3 H]-105 This shows an example of hot saturated binding, where the radioactive ligand exhibits high affinity for aggregated β-amyloid (abeta) in AD brain homogenate, with a measured dissociation constant of 11 nM. This data supports the use of this ligand in radioactive ligand binding assays for screening binding to aggregated β-amyloid.

[0267] In Assay 2, the unlabeled test compound was dissolved in DMSO at 10 mM. Dilution of the test compound to various concentrations was performed in 100% DMSO at a concentration 1000 times the final assay concentration, and 0.225 μL aliquots were dispensed into assay plates. The brain homogenate was diluted from its original 30 mg / mL volume in assay buffer to 0.5 mg / mL, and 200 μL was added to the assay plate to obtain a final concentration of 100 μg wet weight / assay well. [ 3 H]-105 The assay solution was prepared in assay buffer + 20% DMSO to a 10-fold final concentration, and 25 μL was added to the assay plate to achieve a final assay concentration of 3.0 nM. The plate was incubated at 37°C for 90 minutes. Unbound and bound ligands were analyzed. The bound material was filtered using a Packard Filtermate on a GF / B filter plate (pre-treated with 0.1% PEI for 30 minutes), and the unbound material was washed with 2.5 mL of ice-cold 5 mM Tris (pH 7.4) to separate it. The filter plate was dried at 57°C for 1 hour, and 50 μL of Microscint was added to each well of the plate. The plate was counted for 3H cpm for 1 minute per well using a PerkinElmer TopCount. The data were analyzed using the IDBS Activity Base, and the K values ​​are shown in Table 1 below. i The value was determined (K d (Value 11.0 nM, ligand concentration 3.5 nM). [Table 7] TIFF2026509241000109.tif244159TIFF2026509241000110.tif243159TIFF2026509241000111.tif101159 In human PD brain tissue (sections and homogenates) [ 3 In vitro binding of H]-2 To assess the presence of α-synucleinopathy (Lewy bodies (LB) and Lewy neurites (LN)) in the subject human brain samples, adjacent human PD brain sections were used for autoradiography (ARG) and immunohistochemistry (IHC) studies. ARG was performed using radiolabeled compounds that bind to LB and LN in PD brain sections. IHC was performed using antibodies against LB and LN (LB509), Aβ (6E10), and p-tau (AT8). Binding to tissue homogenates was performed using human PD brain homogenates from the cerebral cortex. In the same study, human brains from donors without neurological disease were used as controls.

[0268] Procedure for in vitro autoradiography: Frozen human brain samples from Parkinson's disease (PD) patients were provided by Banner Sun Health Institute (USA) and Sydney Brain Bank (Australia) through collaboration with the Michael J Fox Foundation (MJFF). Additional PD and non-PD brain samples were purchased from vendors "Analytic Biological Services Inc., ABS" and "Discovery Life Science, DLS". Frozen brain sections (14 μm thick) were prepared using a cryostat (Leica CM3050) and stored in order. Tissue sections were placed on Superfrost Plus glass slides (Cat.# 5075-FR, Brain Research Laboratories, USA), dried at room temperature, and stored in a slide box at -70°C prior to use. [ 3 H]-2It was synthesized by Merck's Radio Compound Labelling Synthesis Group. [ 3 H]-2 The specific activity of was 62.95 Ci / mmol. The final concentration of the radioactive ligand for in vitro autoradiography was 3 nM. On the day of the binding experiment, adjacent sections were selected from the region of interest of each brain sample for the in vitro autoradiography study and designated for total binding and non-substitutive binding (NDB). These sections were thawed in a biosafety hood at room temperature for 15 minutes. In this study, [ 3 H]-2 A single concentration was applied. Total binding of the radioactive ligand in brain sections was defined in the absence of competing substances, and non-substitutable binding (NDB) was measured in the presence of a competing substance (1.0 μM unlabeled self-blocking). Brain sections were first pre-incubated in pH 7.4 PBS buffer at room temperature for 15 minutes. The sections were then transferred to fresh buffer containing the radioactive ligand or radioactive ligand + competing substance as described above and incubated at room temperature for 90 minutes. Incubation was completed by washing the sections three times with ice-cold (4°C) wash buffer (PBS, pH 7.4). Each wash was performed for 3 minutes. After washing, the sections were lightly rinsed with ice-cold (4°C) deionized water and then completely dried with an air blower at room temperature. The sections were placed against Fuji Phosphor Image Plates (TR2025) in a sealed set for exposure at room temperature. After 3 weeks of exposure, the plates were scanned with an Amersham Typhoon Imager, and the scan images were analyzed using MCID 7.1 software. For the quantification of radioligand binding density, [ 3 [H]-microscale (Amersham Biosciences, GE) was used. All section-binding assays were performed in laboratories designated for human tissue studies.

[0269] Figure 2 shows the relationship between α-synucleinopathy and PD brain amygdala sections. [ 3 H]-2This shows specific binding. Based on the immunoreactivity (IR) of LB509 (α-syn) and AT8 (tau) in IHC studies, this figure shows that in region A, LB509 IR is positive and AT8 IR is minimal. In contrast, in region B of Figure 2, AT8 IR is positive and LB509 IR is minimal. [ 3 H]-2 The combined autoradiography image matches only the clear LB509 IR pattern of region A in the IHC, and not the AT8 IR pattern of region B. This indicates that [ 3 H]-2 This shows that it specifically binds to alpha-synucleinopathy in the brain of Parkinson's disease (PD).

[0270] Procedure for tissue homogenate binding: Frozen human brain samples from Parkinson's disease (PD) patients were provided by Banner Sun Health Institute (USA) and Sydney Brain Bank (Australia) through collaboration with the Michael J Fox Foundation (MJFF). Additional PD and non-PD brain samples were purchased from vendors "Analytic Biological Services Inc., ABS" and "Discovery Life Science, DLS." These were postmortem tissues from donors clinically diagnosed with PD or non-PD. Cortical brain homogenates were prepared by homogenizing the cortex in ice-cold phosphate-buffered saline (PBS) (pH 7.4) at 4°C for 30 seconds using a Polytron set to 6. The final concentration of the brain homogenate was 30 mg of moist tissue per 1 mL of buffer. The homogenates were divided into 1 mL / tube portions and stored at -70°C prior to use.

[0271] [ 3 H]-2 It was synthesized by Merck's Radio Compound Labelling Synthesis Group. [ 3H]-2 The specific activity of the compound is 62.95 Ci / mmol. For the hot saturated binding assay, radioligands of varying concentrations ranging from 20 nM to 0.2 nM were used. Brain homogenates were diluted from their original 30 mg / mL volume with assay buffer (Tris, pH 7.5, 0.1% BSA) to a final concentration of 2.2 mg / mL, with 250 μL per assay tube used in the assay. Unlabeled test compounds were dissolved in DMSO at 1 mM. Dilutions of the test compounds to various concentrations were performed using assay buffer containing 2% DMSO. Total binding was defined in the absence of competing compounds, and unsubstitutable binding was measured in the presence of 1 μM of unlabeled self-blocking. A 10-fold dilution of the compound was added to an assay tube containing 200 μL of diluted brain homogenate (25 μL each, separately) and the tube was pre-incubated at room temperature for 30 minutes. Then, a 10-fold dilution of the radioactive ligand was added to the assay tube (25 μL each, separately) to a final volume of 250 μL per tube. Incubation was performed at 37°C for 120 minutes. The assay samples were then filtered onto a GF / C filter using a Skatron 12-well harvester and washed with ice-cold buffer (Tris, pH 7.5) at a setting of 5-5-5 (approximately 3 × 2 ml). The GF / C filter paper for the Skatron harvester was pre-soaked in 0.1% BSA at room temperature for 1 hour before use. The filters were punched into scintillation vials. Liquid scintillation solution (2 mL of Ultima Gold) was added to each vial, filtered for 4 hours, and counted for 1 minute using a Perkin Elmer Tri-Carb 2900TR. Data analysis was performed using Prism software. All assays were performed in 2 or 3 replicates, depending on the assay setup, in laboratories designated for human tissue studies. [Table 8] [ 11 Radiochemical synthesis of C-2 [ka] Sodium tert-butoxide 2.5M (1.3 μL, 3.3 μmol) in dimethylformamide (50 μL) was slowly added to Ex. No. 1 (0.41 mg, 0.93 μmol) in dimethylformamide (250 μL) under argon at room temperature. After 15 minutes, the reaction mixture was heated at room temperature, [ 11 [C] Methyl iodide was passed through the solution. The solution was maintained at room temperature for 3 minutes, water (700 μL) was added, and the crude product was injected into a semi-preparative HPLC column. The product was purified at a flow rate of 5 mL / min using a Luna, 5u, C18, 250 × 10 mm (Phenomenex) column. The mobile phase was 20% to 50% acetonitrile / 0.1% formic acid over 15 minutes. The radioactive fraction eluted between 10 and 11 minutes was collected, diluted with 20 mL of sterile water for injection, and loaded into a Waters Sep-Pak Classic C18 cartridge (Waters, Milford, MA, USA). The Sep-Pak was rinsed with 10 mL of water, then eluted with ethanol (0.5 mL), and placed in a 10 mL sterile vial to dilute to the desired formulation. The final product was tested for chemical and radiochemical purity using an analytical HPLC system (Agilent) with a Gemini, 5μ, C18, 150×4.6 mm (Phenomenex) at a flow rate of 1 mL / min. The mobile phase was a mixture of acetonitrile / 0.1% trifluoroacetic acid in water (from 5% to 90% in 7 minutes). The concentration of Ex. No. 2 was measured using an ultraviolet detector (254 nm). The identity of the product was determined by simultaneous injection of a sample of Ex. No. 2, and the radiochemical purity was determined using a sodium iodide detector (Bioscan). 11 The retention time for C-2 was 5.9 minutes.

[0272] In rhesus macaques [ 11 Image of C-2 A fasted rhesus monkey (7-11 kg) is anesthetized with ketamine IM (15 mpk), and then placed on a PET camera bed. An IV catheter is inserted into the right saphenous vein. The right thigh is aseptically prepared for arterial blood collection, an arterial catheter is inserted, and the area is secured with sutures.

[0273] Subsequent anesthesia is maintained with propofol. The induction dose is 5 mg / kg IV, followed by infusion at 0.4–0.6 mg / kg / min throughout the scanning procedure. The animal is intubated and positioned supine with its head first in the camera gantry. The animal is maintained under ventilation with medical-grade air:oxygen gas mixture at approximately 23 breaths per minute throughout the study. The ventilation I / E ratio, respiratory volume, and rate are adjusted to maintain a CO2 level of approximately 40 mmHg and an SpO2 level of 95–100%. A temperature probe, pulse oximeter, non-invasive blood pressure cuff, and end-tidal CO2 monitor are connected. Body temperature is maintained by placing K-module heating pads dorsally and ventrally on the animal. Systemic fluid therapy is maintained throughout the scanning procedure with IV Ringer's lactate solution at 10 mL / kg / hour. For sampling, another line is placed downstream of the saphenous artery and connected to an automated blood sampling system from Instech. [ 11 C]-2 The aliquot is injected intravenously via a syringe pump over 2 minutes, and positron emission tomography (POSTOCE) is started at the time of injection and continues for 90 minutes.

[0274] To measure radioactivity in whole blood and plasma, whole blood samples are collected into heparinized tubes via arterial catheters. The samples are centrifuged, and 20 μL of whole blood and plasma are counted 20, 40, 80, 100, 120, and 150 seconds after PET ligand injection. Blood samples (0.8 mL) are collected at 3, 5, 15, 30, 60, and 90 minutes for radioactivity measurements and metabolite correction in plasma and whole blood.

[0275] Figure 3 shows the brain of a rhesus monkey. [ 11 C]-2This shows a coronal section of a PET image. This image was averaged over 30-90 minutes after injection and superimposed onto a brain MRI template. This is in the brain of a rhesus monkey. [ 11 C]-2 This shows an appropriate distribution.

[0276] [ 18 Radiochemical synthesis of [F]-ligand [ 18 Radiochemical synthesis of F]-38 [ka] Before use, the anion exchange resin is pre-treated by flushing it with EtOH (10 mL), followed by flushing it with 0.5 M K3PO4 (10 mL) and H2O (10 mL) in H2O. 18 [F] Fluoride was concentrated.

[0277] [ 18 An anion exchange resin containing [F] fluoride was eluted in a vented 2.5 mL V-shaped vial with tetrabutylammonium mesylate (6.8 mg, 20 μmol) in CH3CN / H2O 1:1 (1.0 mL), followed by elution with CH3CN (0.5 mL), and dried under an argon stream using conventional heating at 100 °C. Additional aliquot CH3CN (2 × 0.5 mL) was added for azeotropic drying. The dried [ 18 In a vial containing F]Bu4NF, 38-20A solution of (0.9 mg, 1.3 μmol) dissolved in DMSO (0.5 mL) was added. The reaction mixture was heated at 100°C for 10 minutes, and then transferred to a vial containing H2O (0.8 mL) at room temperature for dilution, mixing, and injection into a semi-preparative HPLC column. The product was purified using a Gemini C6-PhenylHexyl, 5 μm, 250 × 10 mm HPLC column (Phenomonex) [flow rate 5 mL / min, mobile phase 37% CH3CN / 10 mM Na2HPO4 pH 7.4]. The radioactive fraction eluted between 20.6 and 21.6 minutes was collected in a round-bottom flask containing 10% Captisol in H2O (0.5 mL), evaporated under negative pressure to remove CH3CN, and transferred to a sterile vial of 10 mL. The final product was tested for chemical and radiochemical purity using an analytical HPLC system (Agilent) employing a Luna PFP(2), 3 μm, 150 × 3.0 mm HPLC column (Phenomonex) [flow rate 0.7 mL / min, mobile phase CH3CN / H2O (40-50% gradient)]. [ 18 F]38 The concentration was measured using an ultraviolet detector (254 nm). Product identity was determined by the compound. 38 The samples were co-injected and confirmed, and the radiochemical purity was measured using a sodium iodide detector (Bioscan). [ 18 F]38 The holding time was 5.4 minutes.

[0278] [ 18 Radiochemical synthesis of F44 [ka] [ 18 [F]Fluoride was concentrated using an anion exchange resin and eluted before use. 18An anion exchange resin containing [F] fluoride was eluted with Kryptofix 222 (7 mg, 19 μmol) and K2CO3 (2.1 mg, 15 μmol) in acetonitrile / water (80 / 20, 0.7 mL) and transferred to a vented 4 mL vial. The fluoride was dried under an argon stream at 90°C. Additional aliquot acetonitrile (2 × 0.5 mL) was added for azeotropic drying at 90°C.

[0279] 44-2 (0.51 mg, 0.78 μmol) was dissolved in CH3CN (0.5 mL) and the solution was dried [ 18 The reaction mixture was added to a 4 mL vial containing [F] fluoride, the vent line was removed, and the reaction mixture was heated at 90°C (60 W) for 15 minutes. After cooling to below 50°C, the reaction mixture was diluted with HPLC eluent (approximately 2 mL), mixed, and injected into a semi-preparative HPLC column. The product was purified using a Gemini, C6-Phenyl, 110A, 150 × 10 mm (Phenomenex) column at a flow rate of 5 mL / min. The mobile phase was acetonitrile-10% H2O / Na2HPO4 (10 mM), increasing from 30% to 70% in 15 minutes.

[0280] The radioactive fraction eluted between 15 and 16 minutes was collected in a flask containing 1 mL of 30% β-cyclodextrin solution, evaporated under negative pressure, diluted with physiological saline, and transferred to a sterile container. The final product was tested for chemical and radiochemical purity using an analytical HPLC system (Agilent) with an ONYX Monolithic, 5 μm, C18, 100 × 3 mm (Phenomenex) at a flow rate of 1.5 mL / min. The mobile phase was a mixture of 5% to 90% acetonitrile / 0.1% formic acid in water over 7 minutes. [ 18 F]44 The concentration was measured using an ultraviolet detector (254 nm). Product identity was determined by the compound. 44 The samples were co-injected and confirmed, and the radiochemical purity was measured using a sodium iodide detector (Bioscan). [ 18 F]44The retention time was 4.1 minutes.

[0281] [ 18 Radiochemical synthesis of F46 [ka] [ 18 An anion exchange resin containing [F] fluoride was eluted in a vented 2.5 mL V-shaped vial with tetrabutylammonium bicarbonate (4.2 mg, 22 μmol) in CH3CN / H2O 1:1 (1.0 mL), followed by elution with CH3CN (0.5 mL), and then dried under an argon stream using conventional heating at 100°C. 18 In a vial containing F]Et4NF, 46-21 A solution of (1.0 mg, 1.4 μmol) dissolved in DMSO (0.5 mL) was added. The reaction mixture was heated at 100°C for 10 minutes, and then transferred to a vial containing H2O (0.8 mL) at room temperature for dilution, mixing, and injection into a semi-preparative HPLC column. The product was purified using a Gemini C6-PhenylHexyl, 5 μm, 250 × 10 mm HPLC column (Phenomonex) [flow rate 5 mL / min, mobile phase 35% CH3CN / 10 mM Na2HPO4 pH 7.4]. The radioactive fraction eluted between 24.1 and 24.6 minutes was collected in a round-bottom flask containing 10% Captisol in H2O (0.5 mL), evaporated under negative pressure to remove CH3CN, and transferred to a sterile vial of 10 mL. The final product was tested for chemical and radiochemical purity using an analytical HPLC system (Agilent) employing a Luna PFP(2), 3 μm, 150 × 3.0 mm HPLC column (Phenomonex) [flow rate 1.0 mL / min, mobile phase CH3CN / H2O (40-50% gradient)]. [ 18 F]46 The concentration was measured using an ultraviolet detector (254 nm). Product identity was determined by the compound. 46 The samples were co-injected and confirmed, and the radiochemical purity was measured using a sodium iodide detector (Bioscan).[ 18 F]46 The retention time was 4.8 minutes.

[0282] The compounds included in Table 4 were synthesized using the same methods and precursors as described above. The following examples were prepared by substituting commercially available reagents as needed.

[0283] Common method: [ 18 [F] fluoride was concentrated with an anion exchange resin and eluted before use. Unless otherwise specified, [ 18 An anion exchange resin containing [F] fluoride was eluted with Kryptofix 222 (7 mg, 19 μmol) and K2CO3 (2.1 mg, 15 μmol) in acetonitrile / water (80 / 20, 0.7 mL) and transferred to a vented 4 mL vial. The fluoride was dried under an argon stream at 90°C. Additional aliquot acetonitrile (2 × 0.5 mL) was added for azeotropic drying at 90°C.

[0284] Column description: Column 1: Phenomenex Gemini 5μm C6-Phenyl 110A 250×10mm Column 2: Onyx Monolithic C18 100×3.0mm Column 3: Agilent Zorbax Eclipse XDB-C18 9.4 x 250 mm 5μ Column 4: Phenomenex Gemini 5μ C18 150 x 4.6 mm [Table 9] TIFF2026509241000118.tif117169 The present invention has been described and illustrated with reference to specific embodiments thereof, but those skilled in the art will understand that various adaptations, changes, modifications, substitutions, deletions or additions to the procedures and protocols may be made without departing from the spirit and scope of the invention. Accordingly, the present invention is defined by the claims that follow below, and such claims are intended to be interpreted as broadly as reasonable.

Claims

1. Formula I: 【Chemistry 1】 [During the ceremony, ...may not exist, or can represent a combination; R is H or -C １－６ Selected independently of alkyl, where the alkyl is -C １－６ Alkyl, OR ａ Alternatively, it may be arbitrarily substituted with 1 to 3 groups from the halo; R ａ is independently selected from H, -C １－６ alkyl, -(CH ２ ) ｐ OR, -(CH ２ ) ｐ halo or -(CH ２ ) ｐ O(CH ２ ) ｐ halo; R ｂ H, -C １－６ Alkyl, heterocyclyl, heteroaryl, -(CH ２ ) ｐ OR, -CN, -(CH ２ ) ｔ Hello, - (CH ２ ) ｓ NR ２ or -O(CH ２ ) ｐ Selected independently from Halo; R ｃ is H, halo, OR, or -C １－６ Selected independently of alkyl, where the alkyl is -C １－６ Alkyl, OR ａ Alternatively, it may be arbitrarily substituted with 1 to 3 groups from the halo; R １ is, -(CH ２ ) ｓ OR, -(CH ２ ) ｓ NR ２ ,-(CH ２ ) ｓ [O(R ｃ ２ ) ｐ ] ｘ -R ｃ or - (CH ２ ) ｓ Selected from Halo; R ２ is H, OR, CN, Halogen or C １－６ Selected independently of alkyl, where the alkyl is -C １－６ Alkyl, OR ａ Alternatively, it may be arbitrarily substituted with 1 to 3 groups from the halo; R ３ is, -C １－６ A molecule independently selected from alkyl, heteroaryl, or heterocyclyl, wherein the alkyl, heteroaryl, or heterocyclyl is OR ａ or R ｂ It may be arbitrarily substituted with 1 to 3 of the following; Ring A １ This is selected from pyridinyl, imidazo-pyrimidinyl, triazinyl, pyrimidinyl, imidazo-pyrimidinyl, pyrazinyl, or pyridazinyl; Ring A ２ is selected from pyrimidinyl, pyridinyl, pyrazinyl or phenyl, where pyrimidinyl, pyridinyl, pyrazinyl or phenyl is -C １－６ Alkyl, OR ａ Alternatively, it may be arbitrarily substituted with 1 to 3 groups from the halo; Ring A ３ This is selected from pyridinyl, pyrazinyl, pyrimidinyl, pyrrolopyrazinyl, triazinyl, indolyl, imidazolyl, oxadiazolyl, triazolyl, thiazolyl, isoxazolyl, oxazolyl, 3,4-dihydro-2H-pyrido[3,2,b][1,4]oxazine or phenyl; m is selected from 0, 1, or 2; n is selected from 1, 2, or 3; p is selected independently from 1, 2, or 3; r is selected from 1, 2, or 3; s is independently selected from 0, 1, 2, 3, 4, 5, or 6; t is independently selected from 0, 1, 2, 3, 4, 5, or 6; and, x is independently selected from 1, 2, 3, 4, 5, or 6. A compound represented by or a pharmaceutically acceptable salt thereof.

2. Formula IA: 【Chemistry 2】 [During the ceremony, ...may not exist, or can represent a combination; R is H or -C １－６ Selected independently of alkyl, where the alkyl is -C １－６ Alkyl, OR ａ Alternatively, it may be arbitrarily substituted with 1 to 3 groups from the halo; R ａ H, -C １－６ Alkyl, -(CH ２ ) ｐ OR, -(CH ２ ) ｐ Halo or - (CH ２ ) ｐ O(CH ２ ) ｐ Selected independently from Halo; R ｂ H, -C １－６ Alkyl, heterocyclyl, heteroaryl, -(CH ２ ) ｐ OR, -CN, -(CH ２ ) ｔ Hello, - (CH ２ ) ｓ NR ２ or -O(CH ２ ) ｐ Selected independently from Halo; R ｃ is H, halo, OR, or -C １－６ Selected independently of alkyl, where the alkyl is -C １－６ Alkyl, OR ａ Alternatively, it may be arbitrarily substituted with 1 to 3 groups from the halo; R １ is selected from -(CH ２ ), -(CH ｓ ), -(CH ２ ), -(CH ｓ NR ２ ), -(CH ２ ), -(CH ｓ )[O(R ｃ ２ ), -(CH ｐ ), -R ｘ or -(CH ｃ ); selected from halo; ２ ), -(CH ｓ ), -(CH R ２ is H, OR, CN, Halogen or C １－６ Selected independently of alkyl, where the alkyl is -C １－６ Alkyl, OR ａ Alternatively, it may be arbitrarily substituted with 1 to 3 groups from the halo; R ３ is, -C １－６ A molecule independently selected from alkyl, heteroaryl, or heterocyclyl, wherein the alkyl, heteroaryl, or heterocyclyl is OR ａ or R ｂ It may be arbitrarily substituted with 1 to 3 of the following; X １ is N or CH; X ２ is N or CH; Ring A １ This is selected from pyridinyl, imidazo-pyrimidinyl, triazinyl, pyrimidinyl, imidazo-pyrimidinyl, pyrazinyl, or pyridazinyl; Ring A ３ This is selected from pyridinyl, pyrazinyl, pyrimidinyl, pyrrolopyrazinyl, triazinyl, indolyl, imidazolyl, oxadiazolyl, triazolyl, thiazolyl, isoxazolyl, oxazolyl, 3,4-dihydro-2H-pyrido[3,2,b][1,4]oxazine or phenyl; m is selected from 0, 1, or 2; n is selected from 1, 2, or 3; p is selected independently from 1, 2, or 3; r is selected from 1, 2, or 3; s is independently selected from 0, 1, 2, 3, 4, 5, or 6; t is independently selected from 0, 1, 2, 3, 4, 5, or 6; and, x is independently selected from 1, 2, 3, 4, 5, or 6. A compound according to claim 1 or a pharmaceutically acceptable salt thereof having the structure represented by .

3. Formula IB: 【Transformation 3】 [During the ceremony, ...may not exist, or can represent a combination; R is H or -C １－６ Selected independently of alkyl, where the alkyl is -C １－６ Alkyl, OR ａ Alternatively, it may be arbitrarily substituted with 1 to 3 groups from the halo; R ａ H, -C １－６ Alkyl, -(CH ２ ) ｐ OR, -(CH ２ ) ｐ Halo or - (CH ２ ) ｐ O(CH ２ ) ｐ Selected independently from Halo; R ｂ H, -C １－６ Alkyl, heterocyclyl, heteroaryl, -(CH ２ ) ｐ OR, -CN, -(CH ２ ) ｔ Hello, - (CH ２ ) ｓ NR ２ or -O(CH ２ ) ｐ Selected independently from Halo; R ｃ is H, halo, OR, or -C １－６ Selected independently of alkyl, where the alkyl is -C １－６ Alkyl, OR ａ Alternatively, it may be arbitrarily substituted with 1 to 3 groups from the halo; R １ｂ is -[O(R ｃ ２ ) ｐ ] ｘ -R ｃ OR, NR ２ Or selected from Halo; R ２ is H, OR, CN, Halogen or C １－６ Selected independently of alkyl, where the alkyl is -C １－６ Alkyl, OR ａ Alternatively, it may be arbitrarily substituted with 1 to 3 groups from the halo; R ３ is, -C １－６ A alkyl, imidazolyl, morpholinyl, triazolyl, oxazolyl, triazinyl, pyrazolyl, thiazolyl, pyrazinyl, isoxazolyl, azetidinyl, pyrrolidinyl, tetrahydrotriazolopyradinyl, piperidinyl, or pyrimidinyl is independently selected from the above, wherein the alkyl, imidazolyl, morpholinyl, triazolyl, oxazolyl, triazinyl, pyrazolyl, thiazolyl, pyrazinyl, isoxazolyl, azetidinyl, pyrrolidinyl, tetrahydrotriazolopyradinyl, piperidinyl, or pyrimidinyl is OR ａ or R ｂ It may be arbitrarily substituted with 1 to 3 of the following; Ring A １ This is selected from pyridinyl, imidazo-pyrimidinyl, triazinyl, pyrimidinyl, imidazo-pyrimidinyl, pyrazinyl, or pyridazinyl; Ring A ３ This is selected from pyridinyl, pyrazinyl, pyrimidinyl, pyrrolopyrazinyl, triazinyl, indolyl, imidazolyl, oxadiazolyl, triazolyl, thiazolyl, isoxazolyl, oxazolyl, 3,4-dihydro-2H-pyrido[3,2,b][1,4]oxazine or phenyl; m is selected from 0, 1, or 2; n is selected from 1, 2, or 3; p is selected independently from 1, 2, or 3; s is independently selected from 0, 1, 2, 3, or 4; t is independently selected from 0, 1, 2, 3, 4, 5, or 6; and, x is independently selected from 1, 2, 3, 4, 5, or 6. A compound according to claim 1 or a pharmaceutically acceptable salt thereof having the structure represented by .

4. Formula IC: 【Chemistry 4】 [During the ceremony, ...may not exist, or can represent a combination; R is H or -C １－６ Selected independently of alkyl, where the alkyl is -C １－６ Alkyl, OR ａ Alternatively, it may be arbitrarily substituted with 1 to 3 groups from the halo; R ａ H, -C １－６ Alkyl, heterocyclyl, heteroaryl, -(CH ２ ) ｐ OR, -(CH ２ ) ｐ Halo or - (CH ２ ) ｐ O(CH ２ ) ｐ Selected independently from Halo; R ｂ H, -C １－６ Alkyl, -(CH ２ ) ｐ OR, -CN, -(CH ２ ) ｔ Hello, - (CH ２ ) ｓ NR ２ or -O(CH ２ ) ｐ Selected independently from Halo; R ｃ is H, halo, OR, or -C １－６ Selected independently of alkyl, where the alkyl is -C １－６ Alkyl, OR ａ Alternatively, it may be arbitrarily substituted with 1 to 3 groups from the halo; R １ｂ is -[O(R ｃ ２ ) ｐ ] ｘ -R ｃ OR, NR ２ Or selected from Halo; R ２ is H, OR, CN, Halogen or C １－６ Selected independently of alkyl, where the alkyl is -C １－６ Alkyl, OR ａ Alternatively, it may be arbitrarily substituted with 1 to 3 groups from the halo; R ３ is, -C １－６ A alkyl, imidazolyl, morpholinyl, triazolyl, oxazolyl, triazinyl, pyrazolyl, thiazolyl, pyrazinyl, isoxazolyl, azetidinyl, pyrrolidinyl, tetrahydrotriazolopyradinyl, piperidinyl, or pyrimidinyl is independently selected from the above, wherein the alkyl, imidazolyl, morpholinyl, triazolyl, oxazolyl, triazinyl, pyrazolyl, thiazolyl, pyrazinyl, isoxazolyl, azetidinyl, pyrrolidinyl, tetrahydrotriazolopyradinyl, piperidinyl, or pyrimidinyl is OR ａ or R ｂ It may be arbitrarily substituted with 1 to 3 of the following; Ring A １ This is selected from pyridinyl, imidazo-pyrimidinyl, triazinyl, pyrimidinyl, imidazo-pyrimidinyl, pyrazinyl, or pyridazinyl; Ring A ３ This is selected from pyridinyl, pyrazinyl, pyrimidinyl, pyrrolopyrazinyl, triazinyl, indolyl, imidazolyl, oxadiazolyl, triazolyl, thiazolyl, isoxazolyl, oxazolyl, 3,4-dihydro-2H-pyrido[3,2,b][1,4]oxazine or phenyl; m is selected from 0, 1, or 2; n is selected from 1, 2, or 3; p is selected independently from 1, 2, or 3; s is independently selected from 0, 1, 2, 3, or 4; t is independently selected from 0, 1, 2, 3, 4, 5, or 6; and, x is independently selected from 0, 1, 2, 3, 4, 5, or 6. A compound according to claim 1 or a pharmaceutically acceptable salt thereof having the structure represented by .

5. Ring A １ is selected from pyrimidinyl or pyridinyl; Ring A ３ is selected from pyridinyl, pyrazinyl, pyrimidinyl, or triazinyl; m is selected from 0 or 1; and, n is selected from 1 or 2; The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

6. Ring A １ is pyridinyl or pyrimidinyl; The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

7. Ring A ２ It is pyrimidinyl; The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

8. Ring A ３ This is selected from pyridinyl, pyrimidinyl, pyrazinyl, or triazinyl; The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

9. R １ is, -(CH ２ ) ｓ OR or - (CH ２ ) ｓ [O(R ｃ ２ ) ｐ ] ｘ -R ｃ It is; The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

10. R ３ is, -C １－６ A alkyl, imidazolyl, morpholinyl, triazolyl, oxazolyl, triazinyl, pyrazolyl or isoxazolyl is independently selected from alkyl, imidazolyl, morpholinyl, triazolyl, oxazolyl, triazinyl, pyrazolyl or isoxazolyl OR ａ or R ｂ It may be arbitrarily substituted with 1 to 3 of the following: The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

11. The following compounds can be selected: Table 1

12. A compound according to claim 11 or a pharmaceutically acceptable salt thereof, selected from Examples No. 1, 2, 3, 4, 12, 13, 17, 29, 31, 32, 34, 38, 43, 44, 46, 48, 49, 51 and 52.

13. A compound according to claim 11 or a pharmaceutically acceptable salt thereof, selected from Examples No. 1, 2, 3, 12, 13, 29, 32, 38, 44, 46, or 52.

14. ２ H, ３ H, １１ C, １３ C, １４ C, １３ N, １５ N, １５ O, １７ O, １８ O, １８ F, ３５ S, ３６ Cl, ８２ Br, ７６ Br, ７７ Br, １２３ I, １２４ I or １３１ A compound according to claim 1 or 11, or a pharmaceutically acceptable salt thereof, labeled with an isotope selected from I.

15. ３ H, １１ C or １８ A compound according to claim 1 or 11, or a pharmaceutically acceptable salt thereof, isotope-labeled with F.

16. A pharmaceutical composition comprising the compound described in claim 1 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

17. A method for imaging α-synuclein deposits in human patients, wherein the compound described in claim 14 or a pharmaceutically acceptable salt thereof is used as an imaging agent, and the following steps are performed: (a) The step of positioning a human patient in a supine position inside the PET camera; (b) The step of administering the compound according to claim 14 to a patient in an amount of about 0.1 to about 10 mCi; and, (c) A step in which a radiographic scan of the cerebral region of the patient's head is performed to identify and distinguish α-synuclein aggregates in the patient's brain tissue; A method that includes

18. A method for measuring the clinical efficacy of a drug for treating Parkinson's disease, comprising the following steps: (a) The step of administering to a patient diagnosed with PD an isotope-labeled compound represented by formula I as described in claim 14, prior to treatment with the therapeutic agent; (b) A step of measuring the amount of α-synuclein aggregates formed in the patient's brain tissue; (c) After treatment with the therapeutic agent, administer to the patient an isotope-labeled compound represented by formula I as described in claim 14; (d) A step of measuring the amount of α-synuclein aggregates formed in the brain tissue of the patient after treatment, (e) A step of analyzing whether the therapeutic agent stopped or reduced the progression of α-synuclein aggregate formation in the patient's brain tissue; A method that includes

19. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, for use as an imaging agent.

20. A compound according to claim 14 or a pharmaceutically acceptable salt thereof, for use as an imaging agent.

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