As a PET radioactive tracer 18 F]-labeled imidazopyridine derivative

Abstract

The present disclosure relates to an [¹⁸F]-labeled imidazopyridine derivative or a salt thereof, as a positron emission tomography (PET) radiotracer, which is suitable for imaging of the stress signal non-receptor tyrosine kinase c-abl, and its use in in vivo diagnosis, pre-clinical and clinical imaging, patient stratification based on the c-abl mutation status, and assessment of response to treatment. The present disclosure also relates to the use of an [¹⁸F]-labeled imidazopyridine derivative as a PET radiotracer. The present disclosure also provides a method for radiosynthesizing an [¹⁸F]-labeled imidazopyridine derivative.

Description

[0001] Cross - reference to related applications

[0002] This application claims priority to U.S. Patent Application No. 63 / 068,476, filed on August 21, 2020. The entire disclosure of this application as determined in this paragraph is incorporated herein by reference. Technical Field

[0003] The present disclosure generally relates to fluorine-18 labeled imidazopyridine compounds as positron emission tomography (PET) tracers for imaging enzyme inhibitory activity, including such compounds and methods of using such compounds for diagnosis and imaging. Background Art

[0004] Positron emission tomography (PET) is a nuclear imaging method that detects pairs of gamma rays indirectly emitted by radionuclides that produce positrons. Radioactive tracers are used as diagnostic tools in PET and image the tissue concentration of molecules of interest.

[0005] The development of molecular imaging biomarkers is closely related to the development of therapeutic agents. Among potential targets, tyrosine kinase c-abl is a tightly regulated non-receptor protein tyrosine kinase that is involved in a wide range of cellular processes, including growth, survival, and stress responses (Nat Rev Mol Cell Biol, 2004, 5:33-44) and c-abl is involved in the regulation of multiple cellular processes and participates in the development of the central nervous system by controlling neurogenesis. More recently, increasing evidence from various experimental model systems also indicates that c-abl is activated in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Niemann-Pick type C disease, and Tau protein diseases. (Human Molecular Genetics, 2014, Vol. 23, No. 11)

[0006] The stress-signaling non-receptor tyrosine kinase c-abl links parkin to the sporadic form of Parkinson's disease through tyrosine phosphorylation. Tyrosine phosphorylation of parkin by c-abl is a major post-translational modification that leads to loss of parkin function and disease progression in sporadic Parkinson's disease. Inhibition of c-abl provides a new therapeutic opportunity to block the progression of Parkinson's disease. (Journal of Neuroscience, 2011, 31(1):157-163) Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive death of motor neurons. Knockdown of c-abl with small interfering RNA (siRNA) can also rescue ALS motor neuron degeneration. (Imamura et al., Sci. Transl. Med. 9, 2017) Multiple system atrophy (MSA) is a rare and rapidly progressive neurodegenerative disease for which there is no treatment. In MSA, α-synuclein accumulates in neurons and oligodendrocytes in the substantia nigra, striatum, olivopontocerebellar structures, and spinal cord. (J Neural Trans Vienna Austria 1996.2016; 123(6))

[0007] In transgenic and lentiviral gene transfer models, administration of the tyrosine kinase inhibitor nilotinib reduced c-abl activity and improved autophagic clearance of α-synuclein. Activation of c-abl in the mouse forebrain induced neurodegeneration in the hippocampus and striatum. Thus, increased c-abl activity through phosphorylation may be associated with α-synuclein pathology detected in Parkinson's disease and other neurodegenerative diseases (Hum Mol Genet. August 15, 2013).

[0008] c-abl is a potential therapeutic target for α-synucleinopathies, Parkinson's disease, Alzheimer's disease, ALS, dementia with Lewy bodies, and MSA. Recent studies have revealed a key role for c-abl in Parkinson's disease (PD), such as inducing α-synuclein aggregation through its direct phosphorylation, parkin inactivation, and induction of neuroinflammation. The expression levels of total c-abl and activated c-abl measured by the phosphorylated forms of Y412 and Y214 are upregulated in various animal models, and more importantly, in human specimens, such as postmortem whole brain or striatal samples from PD patients, in the pathogenesis of PD.

[0009] However, no one has yet investigated whether c-abl levels are upregulated in the substantia nigra or striatum of living PD patients. It will be crucial to investigate the c-abl expression levels in the brains of PD patients to understand the pathophysiological role of c-abl in PD and its functional link to disease stage and symptom status.

[0010] The present invention provides a novel fluorine-18 radiolabeled compound that can selectively target c-abl as a PET tracer for in vitro and in vivo imaging studies.

[0011] The IC of c-abl catalytic inhibition for each cold compound, Formula IIA and IIB 50 ’ is in the range of 0.59 nM to 10 nM. We synthesized the 18 F radiolabeled tracer for PET using the corresponding cold compound. SUMMARY OF THE INVENTION

[0012] The present disclosure provides compounds having c-abl kinase inhibitory activity, compositions comprising the compounds, and methods useful for treating neurodegenerative diseases.

[0013] In one embodiment, the compound is a compound represented by formula (I):

[0014]

[0015] wherein R 1 and R 2 are defined as follows.

[0016] In another embodiment, the present invention provides enantiomers, diastereomers or racemates of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof.

[0017] In another example, the present disclosure provides a method for visualizing brain abnormalities, cell death and nerve injury by using the compound through different landscapes of neuroimaging. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 is the HPLC chromatogram of Example 1 using HPLC method 1, UV at 254 nm (retention time = 9.504 minutes).

[0019] Figure 2 is the HPLC chromatogram of the precursor of Compound 5 using HPLC method 1, UV at 254 nm (RT = 29.876 minutes).

[0020] Figure 3 is the HPLC chromatogram of diastereomer A of Example 1 using HPLC method 1, UV at 254 nm (RT = 11.690 minutes).

[0021] Figure 4 is the HPLC chromatogram of diastereomer B of Example 1 using HPLC method 1, UV at 254 nm (RT = 11.684 minutes).

[0022] Figure 5 Is the prepared one obtained by using HPLC method 1 18 F] HPLC chromatogram of Example 1 (RT = 9.633 minutes).

[0023] Figure 6 Is the HPLC chromatogram of Example 3 (RT = 8.987 minutes) using HPLC method 1 with UV at 254 nm.

[0024] Figure 7 Is the HPLC chromatogram of the precursor, Compound 8 (RT = 27.502 minutes) using HPLC method 1 with UV at 254 nm.

[0025] Figure 8 Is the HPLC chromatogram of diastereomer A of Example 3 (RT = 10.988 minutes) using HPLC method 1 with UV at 254 nm.

[0026] Figure 9 Is the HPLC chromatogram of diastereomer B of Example 3 (RT = 10.993 minutes) using HPLC method 1 with UV at 254 nm.

[0027] Figure 10 Is the prepared one obtained by using HPLC method 1 18 F] HPLC chromatogram of Example 3 (RT = 9.199 minutes).

[0028] Figure 11 Is the HPLC chromatogram of Example 1 (RT = 10.710 minutes) using HPLC method 2 with UV at 254 nm.

[0029] Figure 12 Is the HPLC chromatogram of precursor Compound 5 (RT = 12.392 minutes) using HPLC method 2 with UV at 254 nm.

[0030] Figure 13 Is the HPLC chromatogram of diastereomer A of Example 1 (RT = 11.114 minutes) using HPLC method 2 with UV at 254 nm.

[0031] Figure 14 Is the HPLC chromatogram of diastereomer B of Example 1 (RT = 11.116 minutes) using HPLC method 2 with UV at 254 nm.

[0032] Figure 15 Is the HPLC chromatogram of Example 3 (RT = 10.637 minutes) using HPLC method 2 with UV at 254 nm.

[0033] Figure 16 This is the HPLC chromatogram of precursor compound 8 (RT = 12.331 minutes) using HPLC method 2 with UV detection at 254 nm.

[0034] Figure 17 This is the HPLC chromatogram of diastereomer A of Example 3 (RT = 11.019 minutes) using HPLC method 2 with UV detection at 254 nm.

[0035] Figure 18 This is the HPLC chromatogram of diastereomer B of Example 3 (RT = 11.011 minutes) using HPLC method 2 with UV detection at 254 nm. Detailed Description

[0036] The following description is merely exemplary in nature and is not intended to limit the present disclosure, application, or uses.

[0037] Definitions

[0038] As used herein, the term "pharmaceutically acceptable" means suitable for pharmaceutical formulations, generally considered safe for such uses, officially approved for such uses by a regulatory agency of a national or state government, or listed in the United States Pharmacopeia or other generally recognized pharmacopeias for animals, particularly humans.

[0039] As used herein, the term "pharmaceutically acceptable carrier" means a diluent, adjuvant, excipient, or vehicle, or other components that are pharmaceutically acceptable and administered together with the compounds of the present invention.

[0040] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that enhances the desired pharmacological activity. Examples of pharmaceutically acceptable salts include acid addition salts formed with inorganic or organic acids, metal salts, and amine salts. Examples of acid addition salts formed with inorganic acids include salts formed with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Examples of salts formed with organic acids such as acetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, o-(4-hydroxy-benzoyl)-benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, 4-methyl-bicyclo[2,2,2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis(3-hydroxy-2-naphthoic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxy-naphthoic acid, salicylic acid, stearic acid, and mucic acid. Examples of metal salts include salts formed with sodium, potassium, calcium, magnesium, aluminum, iron, and zinc ions. Examples of amine salts include salts formed with ammonia and organic nitrogen-containing bases that are strong enough to form salts with carboxylic acids.

[0041] As used herein, the term "therapeutically effective amount" is intended to mean an amount of a compound that, when applied to a compound of the present invention, is sufficient to ameliorate, alleviate, stabilize, reverse, slow, or delay the progression of a disease, or the symptoms of a disease. In one embodiment, the methods of the present invention provide for the administration of a combination of compounds. In such a case, a "therapeutically effective amount" is the amount of the compounds of the present invention in the combination that is sufficient to elicit the desired biological effect.

[0042] As used herein, the term "treatment" or "treating" refers to ameliorating or reversing the progression or severity of a disease or disorder, or ameliorating or reversing one or more symptoms or side effects of such a disease or disorder. As used herein, "treatment" or "treating" also refers to inhibiting or blocking, such as delaying, preventing, inhibiting, hindering the progression of a disease or disorder, condition, or state. For the purposes of the present invention, "treatment" or "treating" also refers to a method of obtaining a beneficial or desired clinical outcome, where "beneficial or desired clinical outcome" includes, but is not limited to, alleviation of symptoms, diminishment of the degree of a disorder or disease, stabilization (i.e., not worsening) of a disease or disorder state, delay or slowing of a disease or disorder state, amelioration or palliation of a disease or disorder state, and partial or total remission of a disease or disorder.

[0043] In another embodiment, the compound represented by formula (I) is used to modulate the activity of protein kinase c-abl.

[0044] As used herein, the term "modulate" refers to altering the catalytic activity of a protein kinase. Modulation particularly refers to activating or inhibiting the catalytic activity of a protein kinase, depending on the concentration of the compound or salt to which the protein kinase is exposed, or more preferably, modulation refers to inhibiting the catalytic activity of a protein kinase. The term "catalytic activity" as used herein refers to the rate of phosphorylation of tyrosine, serine, or threonine directly or indirectly affected by a protein kinase.

[0045] Pharmacological inhibitors of kinase activity are mainly divided into three categories: (1) Type I or "DFG-in" ATP-competitive inhibitors, which directly compete with ATP at the ATP-binding site (i.e., dual SRC ABL inhibitor, dasatinib), (2) Type II or "DFG-out" ATP-competitive inhibitors, which in addition to binding to the ATP-binding site, also bind to an adjacent hydrophobic binding site that is only accessible when the kinase is in an inactivated conformation (i.e., the orientation of the activation loop is in a conformation that would prevent substrate binding) (i.e., imatinib, nilotinib), and (3) non-ATP-competitive inhibitors, which bind to a site outside the ATP-binding site that affects kinase activity (i.e., GNF-2).

[0046] As used herein, the phrase "one or more compounds of the present disclosure" includes any compound represented by formula (I), as well as its inclusion compounds, hydrates, solvates, or polymorphs. Also, even if the term "one or more compounds of the present disclosure" does not mention its pharmaceutically acceptable salts, the term includes its salts. In one embodiment, the compounds of the present disclosure include stereochemically pure compounds, e.g., those that are substantially free (e.g., greater than 85% ee, greater than 90% ee, greater than 95% ee, greater than 97% ee, or greater than 99% ee) of other stereoisomers. That is, if the compound or its salt represented by formula (I) according to the present disclosure is a tautomer and / or stereoisomer (e.g., geometric isomers and conformational isomers), then such isolated isomers and their mixtures are also included within the scope of the present disclosure. If the compounds or their salts of the present disclosure have asymmetric carbons in their structures, their active enantiomers and their racemic mixtures are also included within the scope of the present disclosure.

[0047] As used herein, the term "polymorph" refers to a solid crystalline form of a compound of the present disclosure or its complex. Different polymorphs of the same compound can exhibit different physical, chemical, and / or spectroscopic properties.

[0048] Different physical properties include, but are not limited to, stability (e.g., stability to heat or light), compressibility and density (important in formulation and product manufacture), and dissolution rate (which affects bioavailability). Differences in stability may be caused by changes in chemical reactivity (e.g., different oxidation such that one dosage form discolors faster when composed of one polymorph than when composed of another), or mechanical properties (e.g., tablets crumbling during storage as the kinetically favored polymorph converts to the thermodynamically more stable polymorph), or both (e.g., tablets of one polymorph are more likely to decompose at high humidity). The different physical properties of polymorphs affect their processing. For example, due to, e.g., the shape or size distribution of their particles, one polymorph may be more likely to form a solvate than another or may be more difficult to filter or wash to remove impurities than another.

[0049] As used herein, the term "solvate" refers to a compound or a salt thereof according to the present disclosure, which further includes a solvent that is bound by stoichiometric or non-stoichiometric non-covalent intermolecular forces. Preferred solvents are volatile, non-toxic and / or acceptable for administration to humans in trace amounts.

[0050] As used herein, the term "hydrate" refers to a compound or a salt thereof according to the present disclosure, which further includes stoichiometric or non-stoichiometric water that is bound by non-covalent intermolecular forces.

[0051] As used herein, the term "inclusion compound" refers to a compound or a salt thereof in lattice form, which includes a space (e.g., a channel) in which a guest molecule (e.g., a solvent or water) is trapped.

[0052] Compounds of the present disclosure

[0053] The present disclosure provides a compound according to formula (I):

[0054]

[0055] or a pharmaceutically acceptable salt thereof, wherein R 2 is -H, R 1 is -CH 2 CH 2 18 F or -OCH 2 CH 2 18 F, or when R 2 is -F, R 1 is -CH 2 CH 2 18 F or -OCH 2 CH 2 18 F.

[0056] In one embodiment, the compound of formula (I) is selected from the compounds of formula (IIA) and their pharmaceutically acceptable salts:

[0057]

[0058] wherein R 2 is -H or -F.

[0059] In one embodiment, the compound of formula (I) is selected from the compounds of formula (IIB) and their pharmaceutically acceptable salts:

[0060]

[0061] wherein R 2 is -H or -F.

[0062] In another embodiment, there is provided a pharmaceutical composition comprising a therapeutically effective amount of the compound of formula (I) or its pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier.

[0063] In another embodiment, there is provided a method of treating a neurodegenerative disease or disorder, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or its pharmaceutically acceptable salt. That is, there is provided the medical use of the compound of formula (I) or its pharmaceutically acceptable salt, wherein the compound of formula (I) or its pharmaceutically acceptable salt is used as an active agent. In some embodiments, the neurodegenerative disease is selected from α-synucleinopathy, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy (MSA), Alzheimer's disease, and amyotrophic lateral sclerosis (ALS).

[0064] In one embodiment, the present disclosure relates to a fluorine-18 labeled imidazopyridine compound as a positron emission tomography (PET) tracer for imaging the enzyme inhibitory activity of a composition containing the compound, and methods of diagnosis and imaging using the compound. In one embodiment, there is provided a method of treating a neurodegenerative disease, comprising: administering to a subject in need thereof a therapeutically effective amount of the above compound or its pharmaceutically acceptable salt.

[0065] In another embodiment, a method for determining enzyme inhibitory activity is provided, the method comprising: applying the above compound to a biological sample; and imaging the compound to determine enzyme inhibitory activity. In various embodiments, the compound is used as a positron emission tomography (PET) tracer. The method can be a PET imaging method. In addition, the method can be used in an AD-induced mouse AD model or an α-synuclein PFF-induced mouse PD model. The method can be used to determine c-abl upregulation or activation in the brain. In some embodiments, the method is used for companion diagnostics of c-abl therapy or other disease alleviating agents as predictive biomarkers. The method can be used for patients suffering from neurodegenerative diseases.

[0066] Examples

[0067] Hereinafter, the present disclosure is described in considerable detail by way of examples to assist those skilled in the art in understanding the present disclosure. However, the following examples are provided by way of illustration and are not intended to limit the scope of the present invention. Obviously, various changes can be made without departing from the spirit and scope of the present invention or sacrificing all of its material advantages.

[0068] Synthesis of the compound represented by formula (IIA)

[0069] The exemplary compounds of the present disclosure are described in Scheme 1.

[0070]

[0071] Scheme 1

[0072] Example 1 (1S,2S)-2-Fluoro-N-(6-(3-fluoro-2-(2-(fluoro- 18 F)ethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)cyclopropane-1-carboxamide

[0073] Step 1) 2-(2-Bromo-6-fluorophenoxy)ethan-1-ol

[0074] To a solution of compound 1 (5 g, 26.18 mmol, 1 eq), 2-bromoethanol (6.54 g, 52.36 mmol, 3.72 mL, 2 eq) in MeCN (50 mL) was added K 2 CO 3 (7.60 g, 54.97 mmol, 2.1 eq). The mixture was stirred at 80 °C for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (SiO 2 , petroleum ether:ethyl acetate = 1:0 to 10:1). Compound 2 (6.0 g, 25.53 mmol, 97.51% yield) was obtained as a yellow oil.

[0075] 1 1H NMR (400 MHz, DMSO-d 6 ) δ 7.46 (td, J = 1.5, 8.1 Hz, 1H), 7.33 (ddd, J = 1.4, 8.4, 11.0 Hz, 1H), 7.10 (dt, J = 5.5, 8.3 Hz, 1H), 4.83 - 4.60 (m, 2H), 4.39 - 4.24 (m, 2H); LCMS (electrospray) m / z 236.05 (M + H)+.

[0076] Step 2) (1S,2S)-2-Fluoro-N-(6-(3-fluoro-2-(2-hydroxyethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)cyclopropane-1-carboxamide

[0077] Under N 2 atmosphere, to a solution of Compound 2 (1 g, 4.25 mmol, 1 eq) and Compound 3 (1.76 g, 5.11 mmol, 1.2 eq) in dioxane (0.4 mL) and H 2 O (0.1 mL) was added Na 2 CO 3 (901.84 mg, 8.51 mmol, 2 eq) and Pd(dppf)Cl 2 (155.65 mg, 212.72 μmol, 0.05 eq). The mixture was stirred at 80 °C for 12 h under N 2 atmosphere. The reaction mixture was diluted with 200 mL of water and extracted with ethyl acetate (200 mL * 2). The combined organic layers were washed with 100 mL of brine, dried over Na 2 SO 4 filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (SiO 2 , petroleum ether:ethyl acetate = 1:0 to 0:1). Compound 4 was obtained as a yellow solid (770 mg, 2.06 mmol, 48.48% yield).

[0078] 1 1H NMR (400 MHz, DMSO-d 6)δ 11.03 (s, 1H), 8.83 (s, 1H), 8.09 (s, 1H), 7.51 - 7.41 (m, 2H), 7.35 - 7.26 (m, 2H), 7.25 - 7.16 (m, 1H), 5.06 - 4.84 (m, 1H), 4.82 - 4.73 (m, 1H), 3.93 (t, J = 4.9 Hz, 2H), 3.55 (q, J = 4.4 Hz, 2H), 2.21 - 2.08 (m, 1H), 1.74 - 1.58 (m, 1H), 1.21 - 1.07 (m, 1H); LCMS (electrospray) m / z 374.35 (M + H)+.

[0079] Step 3) 2-(2-Fluoro-6-(2-((1S,2S)-2-fluorocyclopropane-1-carbonylamino)imidazo[1,2-a]pyridin-6-yl)phenoxy)ethyl 4-methylbenzenesulfonate

[0080] To a solution of compound 4 (690 mg, 1.85 mmol, 1 eq) in THF (20 mL) was added TEA (467.52 mg, 4.62 mmol, 643.09 μL, 2.5 eq), DMAP (22.58 mg, 184.81 μmol, 0.1 eq) and TsCl (704.68 mg, 3.70 mmol, 2 eq). The mixture was stirred at 25 °C for 12 h under N 2 atmosphere. The reaction mixture was concentrated under reduced pressure, diluted with 200 mL of water and extracted with ethyl acetate (200 mL × 2). The combined organic layers were washed with 100 mL of brine, dried over Na 2 SO 4 and filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (SiO 2 , petroleum ether:ethyl acetate = 1:0 to 85:15). Compound 5 was obtained as a yellow solid (470 mg, 890.93 μmol, 48.21% yield).

[0081] 1 1H NMR (400 MHz, DMSO-d 6) δ 11.06 (s, 1H), 8.65 (d, J = 0.6 Hz, 1H), 8.11 (s, 1H), 7.59 (d, J = 8.3 Hz, 2H), 7.43 - 7.38 (m, 1H), 7.36 - 7.28 (m, 4H), 7.28 - 7.19 (m, 2H), 5.06 - 4.82 (m, 1H), 4.16 - 4.05 (m, 4H), 2.37 (s, 3H), 2.21 - 2.12 (m, 1H), 1.74 - 1.62 (m, 1H), 1.22 - 1.13 (m, 1H); LCMS (electrospray) m / z 528.54 (M + H)+.

[0082] Step 4) (1S,2S)-2-Fluoro-N-(6-(3-fluoro-2-(2-(fluoro- 18 F)ethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)cyclopropane-1-carboxamide

[0083] 18 F]fluoride is produced in an IBA 18 / 9 cyclotron using 18 O]H 2 O liquid target via the 18 O(p,n) 18 F nuclear reaction. After irradiation, the target water is passed through a Chromafix 45 mg PS-HCO 3 - 18 F separation column. The trapped 18 F]fluoride is eluted with water. K 2 SO 4 solution (500 μL, 0.1 M) is placed in a vial containing DMF (850 μL). A DMF solution of N,N-bis(trifluoromethylsulfonyl)aniline (150 μL, 0.1 M) is added and the temperature is set to 40 °C. The formed 18 F]trifluoromethanesulfonic acid is distilled through a drying column (P 2 O 5 ) into a vial containing DCB (850 μL) and K 222 / K 2 CO 3 solution (12 μmol K 222 and 12 μmol K 2 CO 3 ) in 100 μL MeCN to obtain free 18 F]fluoride. The distillate receiver vial is cooled to -5 °C to effectively trap 18 ​F]Trifluoromethanesulfonyl fluoride. Distillation was completed in about 5 minutes. Then, a solution of precursor compound 5 (0.5 mg) in DCB (50 μL) was added. The mixture was heated at 120 °C for 10 minutes, then cooled, and then diluted with pentane (1.5 ml). The diluted mixture was flushed through a silica column (Sep-Pak silica light cartridge, Waters) to remove DCB and capture the unreacted 18 F]F−. The product was eluted with MeCN (1 ml) and diluted with water (1 ml), and then purified by semi-preparative HPLC on an Altima C18 5 μm column using an isocratic 40% aqueous MeCN solution containing 0.1% TFA at a flow rate of 4 ml / min for 30 minutes. Under these conditions, 18 F]

[0084] Example 1 was separated with an RCY (d.c.) of 3.4% ± 1.0% (n = 3) and an Am of 99 ± 35 GBq / μmol (n = 3). The separated portion of Example 1 was diluted with water (50 ml), and the product was captured on a tC18 column (Sep-Pak tC18 plus short column, Waters). EtOH was removed by a He flow (15 ml / min) under vacuum at 80 °C for 10 minutes. The residue was cooled and then re-formulated in an appropriate volume of EtOH / saline for animal studies. The total synthesis time including radiolabeling, purification, separation, and re-formulation was 59 - 65 minutes.

[0085] 1 1H NMR (400 MHz, DMSO-d 6 ) δ 11.04 (s, 1H), 8.73 (s, 1H), 8.10 (s, 1H), 7.53 - 7.20 (m, 5H), 5.13 - 4.77 (m, 1H), 4.60 - 4.44 (m, 2H), 4.20 - 4.07 (m, 2H), 2.21 - 2.10 (m, 1H), 1.75 - 1.57 (m, 1H), 1.16 (tdd, J = 6.0, 9.1, 12.2 Hz, 1H).; LCMS (electrospray) m / z 375.35 (M + H)+.

[0086] Example 2 (1S,2S)-2-Fluoro-N-(6-(2-(2-(fluoro- 18 F)ethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)cyclopropane-1-carboxamide

[0087] The synthesis method was the same as that of Example 1

[0088]

[0089] 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.02 (s, 1H), 8.67 (t, J = 1.4 Hz, 1H), 8.07 (s, 1H), 7.44 - 7.35 (m, 4H), 7.16 (d, J = 8.0 Hz, 1H), 7.10 - 7.06 (m, 1H), 5.01 - 4.82 (m, 1H), 4.72 (dt, J = 47.8, 3.8 Hz, 2H), 4.29 (dt, J = 29.7, 3.8 Hz, 2H), 2.15 - 2.12 (m, 1H), 1.68 - 1.62 (m, 1H), 1.18 - 1.13 (m, 1H).; LCMS (electrospray) m / z 357.36 (M + H)+.

[0090] Synthesis of the compound shown in formula (IIB)

[0091] The exemplary compounds of the present disclosure are described in Scheme 2.

[0092]

[0093] Scheme 2

[0094] Example 3 (1S,2S)-2-Fluoro-N-(6-(2-(2-(fluoro- 18 F)ethyl)phenyl)imidazo[1,2-a]pyridin-2-yl)cyclopropane-1-carboxamide

[0095] Step 1) (1S,2S)-2-Fluoro-N-(6-(2-(2-hydroxyethyl)phenyl)imidazo[1,2-a]pyridin-2-yl)cyclopropane-1-carboxamide

[0096] Under N 2 atmosphere, to a solution of compound 6 (2.54 g, 7.36 mmol, 1 eq) and compound 3 (1.48 g, 7.36 mmol, 1 eq) in dioxane (4 mL) and H 2 O (16 mL) was added Na 2 CO 3 (1.56 g, 14.7 mmol, 2 eq) and Pd(dppf)Cl 2 (538 mg, 0.74 mmol, 0.1 eq). The mixture was stirred at 80 °C for 12 h under N 2 atmosphere. The reaction mixture was filtered and diluted with water (20 mL), then extracted with ethyl acetate (40 mL * 3). The combined organic layers were dried over Na 2 SO 4It was dried, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (SiO 2 , petroleum ether: ethyl acetate = 1:4) to obtain the compound 7 as a brown solid (990 mg, 2.92 mmol, 39.6% yield).

[0097] 1 1H NMR (400 MHz, DMSO-d 6 ) δ 11.02 (s, 1H), 8.53 (s, 1H), 8.10 (s, 1H), 7.46 (d, J = 9.17 Hz, 1H), 7.39 - 7.33 (m, 2H), 7.31 - 7.24 (m, 2H), 7.21 - 7.19 (m, 2H), 5.01 - 4.93 (m, 1H), 4.61 (t, J = 5.3 Hz, 1H), 3.52 - 3.47 (m, 2H), 2.74 (t, J = 7.27 Hz, 2H), 2.17 - 2.13 (m, 1H), 1.70 - 1.62 (m, 1H), 1.19 - 1.13 (m, 1H); LCMS (electrospray) m / z 340.10 (M+H)+.

[0098] Step 2) 2-(2-((1S,2S)-2-fluorocyclopropane-1-carbonylamino)imidazo[1,2-a]pyridin-6-yl)phenethyl 4-methylbenzenesulfonate

[0099] Under N 2 atmosphere, at 0 °C, TsCl (3.17 g, 16.62 mmol, 6 eq), TEA (1.96 g, 19.39 mmol, 2.70 mL, 7 eq) and DMAP (101.52 mg, 830.97 μmol, 0.3 eq) were added to a mixture of compound 7 (940.00 mg, 2.77 mmol, 1 eq) in DCM (80 mL) in one portion. Then the mixture was stirred at 0 °C for 10 minutes, then heated to 20 °C and stirred for 4 hours. The reaction mixture was quenched by adding H 2 O 20 mL at 0 °C, and then washed with NaHCO 3 (40 mL * 2). The organic layer was washed with 40 mL of saturated NaCl solution, dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 4 / 1 to 1 / 3). The compound 8 as a white solid was obtained (860 mg, 1.74 mmol, 62.91% yield).

[0100] 1 1H NMR (400 MHz, DMSO-d6 ) δ 11.08 (s, 1H), 8.42 (s, 1H), 8.08 (s, 1H), 7.53 (d, J = 8.3 Hz, 2H), 7.42 (d, J = 9.2 Hz, 1H), 7.34 - 7.32 (m, 3H), 7.27 - 7.24 (m, 3H), 7.04 (dd, J = 1.5, 9.2 Hz, 1H), 5.03 - 4.85 (m, 1H), 4.09 (t, J = 6.8 Hz, 2H), 2.91 (t, J = 6.8 Hz, 2H), 2.37 (s, 3H), 2.19 - 2.16 (m, 1H), 1.72 - 1.65 (m, 1H), 1.20 - 1.15 (m, 1H); LCMS (e electrospray) m / z 494.10 (M + H)+.

[0101] Step 3) (1S,2S)-2-Fluoro-N-(6-(2-(2-(fluoro- 18 F)ethyl)phenyl)imidazo[1,2-a]pyridin-2-yl)cyclopropane-1-carboxamide

[0102] 18 F] fluoride is produced in an IBA 18 / 9 cyclotron using 18 O]H 2 O liquid target via the 18O(p,n) 18 F nuclear reaction. After irradiation, the target water is passed through a Chromafix 45 mg PS-HCO 3 - 18 F separation column. The trapped 18 F] fluoride is eluted with water. K 2 SO 4 solution (500 μL, 0.1 M) is placed in a vial containing DMF (850 μL). A DMF solution of N,N-bis(trifluoromethylsulfonyl)aniline (150 μL, 0.1 M) is added, and the temperature is set to 40 °C. The formed 18 F] trifluoromethanesulfonic acid is distilled through a drying column (P 2 O 5 ) into a vial containing MeCN (900 μL) and K 222 / K 2 CO 3 solution (12 μmol K 222 and 12 μmol K 2 CO 3 ) in 100 μL MeCN to obtain free 18 ​F]Fluoride. The temperature of the distillate receiving flask was 20 °C. Distillation was completed in about 5 minutes. Then, precursor compound 8 (1 mg) in MeCN (100 μL) was added. The mixture was heated at 80 °C for 10 minutes, then cooled, and then diluted with water (1 mL) before purification. The diluted mixture was purified by semi-preparative HPLC on Luna C18 5 μm using a 20 mM NH 4 OAc (pH 4) solution. Under these conditions, 18 F]Example 3 was isolated with an RCY (d.c.) of 6.7% ± 3.5% (n = 4) and an Am of 132 ± 60 GBq / μmol (n = 4). The isolated fraction was diluted with water (60 mL), and the product was captured on a tC18 column (Sep-Pak tC18 plus short column, Waters). The column was washed with water (25 mL) and 18 F]Example 3 was eluted with EtOH (1 mL). EtOH was removed under He flow (15 mL / min) at 80 °C under vacuum for 10 minutes. The residue was cooled and then re-formulated in an appropriate volume of EtOH / saline for animal studies. The total synthesis time including radiolabeling, purification, isolation, and re-formulation was 62 - 68 minutes.

[0103] 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.03 (s, 1H), 8.52 (s, 1H), 8.10 (s, 1H), 7.49 - 7.42 (m, 2H), 7.39 (dt, J = 1.7, 7.3 Hz, 1H), 7.36 - 7.28 (m, 2H), 7.19 (dd, J = 1.7, 9.1 Hz, 1H), 5.04 - 4.80 (m, 1H), 4.63 - 4.46 (m, 2H), 3.06 - 2.91 (m, 2H), 2.21 - 2.08 (m, 1H), 1.74 - 1.59 (m, 1H), 1.16 (tdd, J = 6.2, 9.2, 12.3 Hz, 1H).; LCMS (e electrospray) m / z 341.10 (M + H)+.

[0104] Example 4 (1S, 2S)-2-Fluoro-N-(6-(3-fluoro-2-(2-(fluoro- 18 F)ethyl)phenyl)imidazo[1,2-a]pyridin-2-yl)cyclopropane-1-carboxamide

[0105] The synthesis method was the same as that of Example 3.

[0106]

[0107] 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.05 (s, 1 H), 8.56 (s, 1 H), 8.11 (s, 1 H), 7.48 (t, J = 9.1 Hz, 1 H), 7.43 - 7.24 (m, 2H), 7.22 - 7.14 (m, 2H), 5.03 - 4.82 (m, 1 H), 4.50 (dt, J = 46.9, 6.5 Hz, 2H), 3.02 (dt, J = 22.0, 6.3 Hz, 2H), 2.18 - 2.11 (m, 1 H), 1.71 - 1.60 (m, 1 H), 1.20 - 1.12 (m, 1 H).; LCMS (electrospray) m / z 359.35 (M + H)+.

[0108] Analytical HPLC chromatogram

[0109] Two analytical HPLC methods were established; an isocratic (HPLC method 1) and a gradient (HPLC method 2). HPLC method 1 was used to determine A of the tracer example m . Table 1 shows the conditions of HPLC method 1 and the retention times of Example 1, Example 3 and the isomers. The HPLC chromatogram (UV and radioactive detection) is as Figures 1 - 10 shown.

[0110] Table 1. HPLC Isocratic Conditions and Retention Times of Analytes

[0111] Chromatographic column Altima C18 5μm (250 x 4.6 mm) Eluent <![CDATA[Isocratic; 40% MeCN in H 2 O with (0.1%)]]> Flow rate 1 ml / min UV detection 254 nm Analyte Retention time (min) Example 1 9.504 Precursor, Compound 5 29.876 Diastereomer A of Example 1 11.690 Diastereomer B of Example 1 11.684 Example 3 8.987 Precursor, Compound B 27.502 Diastereomer A of Example 3 10.988 Diastereomer B of Example 3 10.993

[0112] Table 2 shows the conditions of HPLC method 2 and the retention times of Example 1, Example 3 and the isomers. The HPLC chromatogram (UV and radioactive detection) is as Figures 11 - 18 shown.

[0113] Table 2. HPLC Gradient Conditions and Retention Times of Analytes

[0114]

[0115]

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof: where R 2 is -H, R1 is -CH 2 CH 2 18 F or -OCH 2 CH 2 18 F, or When R 2 is -F, R 1 is -CH 2 CH 2 18 F or -OCH 2 CH 2 18 F.

2. The compound according to claim 1, wherein, it is a compound of formula (IIA) or a pharmaceutically acceptable salt thereof: wherein R 2 is -H or -F.

3. The compound according to claim 1, wherein, it is a compound of formula (IIB) and a pharmaceutically acceptable salt thereof: wherein R 2 is -H or -F.

4. The compound or a pharmaceutically acceptable salt thereof according to claim 1, which is selected from: (1S,2S)-2-Fluoro-N-(6-(3-fluoro-2-(2-(fluoro 18 F)ethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(2-(2-(fluoro- 18 F)ethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)cyclopropane-1-carboxamide; (1S,2S)-2-Fluoro-N-(6-(2-(2-(fluoro- 18 F)ethyl)phenyl)imidazo[1,2-a]pyridin-2-yl)cyclopropane-1-carboxamide; and (1S,2S)-2-Fluoro-N-(6-(3-fluoro-2-(2-(fluoro- 18 F)ethyl)phenyl)imidazo[1,2-a]pyridin-2-yl)cyclopropane-1-carboxamide.

5. A pharmaceutical composition comprising a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof as claimed in claim 1, and a pharmaceutically acceptable carrier.

6. Use of a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof as claimed in claim 1 in the preparation of a medicament for treating neurodegenerative diseases.

7. The use according to claim 6, wherein, the neurodegenerative disease is selected from α-synucleinopathy, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy (MSA), Alzheimer's disease and amyotrophic lateral sclerosis (ALS).

8. Use of the compound as claimed in claim 1 in the preparation of a preparation for determining enzyme inhibitory activity.

9. The use according to claim 8, wherein, the preparation is a positron emission tomography (PET) tracer.

10. The use according to claim 8, wherein, it is a PET imaging method.

11. The use according to claim 8, wherein, for an AD-induced mouse AD model or an α-synuclein PFF-induced mouse PD model.

12. The use according to claim 8, wherein, for determining c-abl upregulation or activation in the brain.

13. The use according to claim 8, wherein, for the companion diagnosis of c-abl therapy or other disease remitters as predictive biomarkers.

14. The use according to claim 8, wherein, for patients suffering from neurodegenerative diseases.

Images