Selective ligands for tau aggregates

Abstract

The present invention provides compounds of formula (I), or a pharmaceutically acceptable salt, ester, or carbamate thereof, or a salt of such an ester or carbamate, wherein R 1 is OH and R 2 is H or R 1 is H and R 2 is OH. The present invention further provides uses of compounds of formula (I) and compositions comprising compounds of formula (I), including the use of such compounds for the detection of tau deposits and the use of such compounds and compositions as diagnostic agents in diagnosing or monitoring the progression of a disease or disorder such as Alzheimer's disease, progressive supranuclear palsy and corticobasal degeneration, or for the prevention or treatment of a disease or disorder such as Alzheimer's disease, progressive supranuclear palsy and corticobasal degeneration. [Formula 1] JPEG2025540931000057.jpg34152

Description

Detailed Description of the Invention

[0001] [Technical field] The present invention relates to compounds of formula (I) and compositions comprising compounds of formula (I). The compounds of the present invention are useful in the diagnosis and treatment of neurodegenerative diseases, particularly tauopathies such as Alzheimer's disease.

[0002] (Introduction) Alzheimer's disease is a neurodegenerative disorder that causes symptoms including memory loss, difficulty thinking, problem-solving, speech and / or language, personality changes, hallucinations, delusions, and depression and anxiety. It is the most common cause of dementia. Alzheimer's is a progressive disease, and over time, more symptoms develop and the symptoms become more severe.

[0003] Protein deposits are a pathological hallmark of a wide range of neurodegenerative diseases, including Alzheimer's disease and corticobasal degeneration (CARoss, MA Poirier, Nat. Med. 2004, 10, 10-17). Small, hydrophobic ligands have been developed that are selective for protein aggregates with extensive cross-β-pleated sheet conformations and sufficient structural order. The most common ligands are derivatives of Congo Red or thioflavin, although various other molecular scaffolds have also been reported (KPR Nilsson, FEBS Lett. 2009, 583, 2593-2599). However, most of these ligands can only detect disease-related protein aggregates in general, but cannot detect specific disease-related protein aggregates composed of different proteins.

[0004] The microtubule-associated protein tau is one protein deposit that has been shown to cause neurodegeneration. Tau can form intracellular fibrillar deposits in neurons and glial cells, and these tau deposits are associated with a wide variety of disorders collectively known as tauopathies. Tauopathies include over 20 disorders, including Alzheimer's disease, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and Pick's disease. While it has been clearly demonstrated that tau dysfunction can cause neurodegeneration, the precise mechanisms by which tau contributes to neurodegenerative disorders remain poorly understood. Emerging cell biological concepts suggest that tau may play a role in regulating neuroplasticity in widespread neural networks. Furthermore, tau may be involved in regulating genomic stability (Arendt, T., et al., Brain Research Bulletin, 2016, 126, 238-292).

[0005] In Alzheimer's disease, the two major proteinaceous deposits are extracellular senile plaques composed of aggregated amyloid-β (Aβ) peptides and intraneuronal neurofibrillary tangles (NFTs) composed of aggregated tau (C.A. Ross, M.A. Poirier, Nat. Med. 2004, 10, 10-17; C. Ballatore, V.M.Y. Lee, J.Q. Trojanowski. Nat. Rev. Neurosci. 2007, 8, 663-672). The development of ligands that can specifically target Aβ or tau deposits is essential for the clinical diagnosis of Alzheimer's disease and for assessing the contribution of these respective aggregated species to the complex molecular pathology in the Alzheimer's disease brain. Molecular scaffolds have been proposed that allow visualization of Aβ deposits in humans with Alzheimer's disease by positron emission tomography (PET) imaging (W. E. Klunk, et al., Ann. Neurol. 2004, 55, 306-319; Y. Kudo, et al., J. Nucl. Med. 2007, 48, 553-561; and L. Yang, D., et al., N. Engl. J. Med. 2012, 367, 885-887). More recently, several molecular scaffolds have been identified that target tau deposits, another pathological hallmark of Alzheimer's disease (GW Small, et al., N. Eng. J. Med. 2006, 355, 2652-2663; Taghavi, et al., Alzheimers Dis. 2011, 27, 835-843; M. Fodero-Tavoletti, et al., Brain. 2011, 134, 1089-1100; W. Zhang, et al., Alzheimers Dis. 2012, 31, 601-612; M. Maruyama, et al., Neuron 2013, 79, 1094-1108; and C.F.Xia, et al., Alzheimers Dement. 2013, 9, 666-676).

[0006] Luminescent conjugated oligothiophenes (LCOs) have been utilized for fluorescent imaging of protein aggregates. Compared with conventional ligands, LCOs have been shown to detect a wider range of disease-related protein aggregates (A. Åslund, et al., ACS Chem. Biol. 2009, 4, 673-684; T. Klingstedt, et al., Org. Biomol. Chem. 2011, 9, 8356-8370; H. Shirani, et al., Chemistry 2015, 21, 15133-15137). Furthermore, LCOs with different chemical compositions can be utilized for the spectral characterization of different protein aggregates, such as Aβ or tau deposits in Alzheimer's disease (T. Klingstedt, et al., Chemistry 2013, 19, 10179-1019; T. Klingstedt, et al., Chemistry 2015, 21, 9072-9082). Recently, a thiophene-based tetrameric ligand, q-FTAA-CN, was identified that has significantly higher affinity for Aβ deposits than for aggregated species composed of tau (M. Back, et al., Chemistry 2016, 22, 18335-18338).

[0007] [ka] PBB3 is also known to be a tau-specific ligand (M. Maruyama, et al., Neuron 2013, 79, 1094-1108).

[0008] [ka] MK6240 is also known to be a tau-specific ligand (ED Hostetler, et al, J Nucl Med 2016, 57, 1599-1606).

[0009] [ka] However, different morphotypes of Aβ and tau aggregates have been reported (CL Maarouf, et al., Mol. Neurodegener. 2008, 3, 20; H. Levine, LC Walker, Neurobiol. Aging 2010, 31, 542-548; F. Clavaguera, et al., Proc. Natl. Acad. Sci. USA 2013, 110, 9535-9540; J. X Lu, et al., Cell 2013, 154, 1257-1268; W. Qiang, et al., Nature. 2017, 541, 217-221). The existence of different aggregate morphotypes has been suggested to explain the heterogeneous phenotypes reported for several neurodegenerative protein aggregation disorders. Therefore, various ligands are needed to accurately assess the diversity of pathological protein deposits present in neurodegenerative diseases such as Alzheimer's disease. Therefore, there is a need to develop additional small molecule ligands that target specific disease-associated protein aggregates, and in particular additional molecular scaffolds that allow visualization of tau deposits in humans with, for example, Alzheimer's disease (and other tauopathies).

[0010] Furthermore, it has been reported that the known tau-specific ligand PBB3 has the significant drawback of undergoing photoisomerization when exposed to fluorescent light (Hashimoto, H., et al., J Nucl Med (2014), Vol. 55, No. 9, pages 1532-1538). 11 After 1 minute of exposure of the C-PBB3 sample to the fluorescent light, 11 reported that the radiochemical purity of C-PBB3 decreased to 77% and that the radiochemical purity was approximately 50% between 10 and 60 minutes. 11We reported that an isomer of C-PBB3 showed much lower specific binding to tau in brain slices from Alzheimer's disease patients. This property makes PBB3 difficult to synthesize, radiolabel, store, and handle. This limits the practicality of using this tau ligand in in vitro experiments and in vivo acquisition (Saint-Aubert, L., et al., Molecular Neurodegeneration (2017), Vol. 12, No. 9: Tau PET imaging: present and future directions). [Summary of the Invention]

[0011] Summary of the Invention The present invention provides compounds of formula (I) or a pharmaceutically acceptable salt, ester, or carbamate thereof, or a salt of such an ester or carbamate:

[0012] [ka] wherein R 1 is OH and R 2 is H, or R 1 is H and R 2 But it is OH.

[0013] Thus, the present invention also provides a pharmaceutical composition comprising a compound of formula (I) together with a pharmaceutically suitable carrier.

[0014] The present invention also relates to a compound of formula (I): 3 H, 11 C. 13 C. 14 C. 13 N, 15 O. 18 F and 19 The present invention provides a compound of formula (I) or a composition comprising a compound of formula (I) for use as a diagnostic agent, comprising one or more radioisotopes selected from F.

[0015] The present invention also provides the use of a compound of formula (I) for the detection of tau deposits.

[0016] The present invention also relates to the treatment of Alzheimer's disease, corticobasal degeneration, Pick's disease, progressive supranuclear palsy, Parkinson's disease, Creutzfeldt-Jakob disease, familial Alzheimer's disease, argyrophilic granule disease, prion protein cerebral amyloid angiopathy, traumatic brain injury, amyotrophic lateral sclerosis, frontotemporal dementia and parkinsonism linked to chromosome 17, postencephalitic parkinsonism, Guadeloupe-type parkinsonism, glial microglobular tauopathy, age-related tauopathy, and the like. Strogliopathy, Guam Parkinsonism-dementia complex, Niemann-Pick disease type C, myotonic dystrophy, inclusion body myositis, chronic traumatic encephalopathy, Down syndrome, Gerstmann-Straussler-Scheinker syndrome, British dementia, familial Danish dementia, dementia pugilistica, neurofibrillary tangle-predominant senile dementia, Huntington's disease, Lewy body disease, prion disease, subacute sclerosing panencephalitis, subacute sclerosing panencephalitis, diffuse neurofibrillary tangle disease with calcifications, intracerebral Provided is a compound of formula (I) or a composition comprising a compound of formula (I) for use as a diagnostic agent in diagnosing or monitoring the progression of a disease or disorder selected from the group consisting of neurodegeneration with iron accumulation, mutations affecting sodium / proton exchange, cerebrotendinous xanthomatosis with the c.379C>T (p.R127W) mutation in the CYP27A1 gene, the TARDBP mutation ppIle383Val associated with semantic dementia, non-Guam man's motor neuron disease with neurofibrillary tangles, argyrophilic grain disease, Hallervorden-Spatz disease, multiple system atrophy, pallidopontine-nigral degeneration, progressive subcortical gliosis, neurofibrillary tangle dementia, myotonic dystrophy, taupanene cephalopathy, AD-like with astrocytic cells, Gerstmann-Straussler-Scheinker with tau, mutations in LRRK2, SLC9A6-associated mental retardation, and white matter tauopathy with intraglial microspherical inclusions.

[0017] The present invention also provides a method of diagnosing a patient or monitoring disease progression in a patient, comprising administering to the patient a compound of formula (I) or a composition comprising a compound of formula (I).

[0018] The present invention also provides a compound of formula (I) or a pharmaceutical composition comprising a compound of formula (I) for use as a medicine. [Brief explanation of the drawings]

[0019] [Figure 1] 1 shows the concentrations of Example Compound 1 in the plasma and brain of mice (NMRI, male, average n=3 per time point) following IV administration of Example Compound 1 at 1 mg / kg. DETAILED DESCRIPTION OF THE INVENTION

[0020] The compounds of formula (I) (also referred to herein as compounds of the present invention) have excellent binding affinity to tau deposits. The compounds of the present invention are also selective tau deposit ligands, i.e., they have excellent binding affinity to tau deposits and selectively bind to tau deposits over amyloid beta (Aβ) deposits.

[0021] Furthermore, the compounds of the present invention are not photosensitive because they do not have a photoisomerizable double bond in their structure. Therefore, the compounds have significant advantages over the known tau-selective ligand PBB3 in terms of their synthesis (including radiolabeling), storage, and handling, and can be appropriately used in in vitro experiments and in vivo acquisition.

[0022] A further advantage of the compounds of the present invention is that they bind to the four-repeat (4R) isomeric form of tau. The 4R form of tau is known to be present in various tauopathies, such as Alzheimer's disease, progressive supranuclear palsy, and corticobasal degeneration. This makes the compounds of the present invention particularly useful for the diagnosis and / or treatment or prevention of conditions associated with the 4R form of tau, such as Alzheimer's disease, progressive supranuclear palsy, and corticobasal degeneration.

[0023] A further advantage of the compounds of the present invention is that they are expected to have low binding affinity to MAO enzymes in the human brain. As reported in Murugan, NA, et al., Eur J Nucl Med Mol Imaging. (2019) doi:10.1007 / s00259-019-04305-8, the brain regions with the highest MAO-B concentrations overlap with the regions of tau pathology in tauopathies such as CBD and PSP. Therefore, it is undesirable for tau deposit ligands to have off-target binding to MAO, as such off-target effects would severely limit the use of tau deposit ligands for in vivo tau imaging. The compounds of the present invention are expected to be specific for tau accumulation in the brain and therefore have good specificity and sensitivity when used in vivo as tau imaging agents in all tauopathies, including CBD and PSP.

[0024] The compounds of the present invention cross the blood-brain barrier to a greater extent than previously disclosed compounds of similar properties, and once they cross the blood-brain barrier, they are well distributed across the brain.

[0025] For example, if a hydrogen atom is converted to a deuterium ( 2 H) or tritium ( 3 H) or the carbon atom is 13 C atoms are replaced by fluorine atoms 18Isotopic forms in which an F atom is substituted are included within the scope of the present invention. Certain isotopic forms may have beneficial biological properties, such as improved metabolic stability or enhanced therapeutic activity over other isotopic forms. Some particular isotopic forms may be useful for biological imaging purposes, for example, carbon-11 ( 11 C), nitrogen-13( 13 N), oxygen-15( 15 O) or fluorine-18( 18 F isotope variants can be used for positron emission tomography, and tritium (H 3 ) can be used for in vitro studies.

[0026] The present invention provides compounds of formula (I):

[0027] [ka] During the ceremony, R 1 is OH and R 2 is H, or R 1 is H and R 2 But it is OH. The compound of formula (I) can be a compound of formula (Ia) or a compound of formula (Ib).

[0028] [ka] Preferably, the compound of formula (I) has a structural formula selected from the following group:

[0029] [ka]

[0030] In the compounds of the present invention, one or more of the atoms may be an isotope. In the compounds of the present invention, one or more of the atoms may be a radiolabeled atom (also referred to as a radioisotope), for example, one, two or three of the atoms may be a radiolabeled atom. In particular, R1 , R 2 One or more of the atoms of the -O-CH3 substituent of the fluoropyridine ring, and / or the piperidine ring may be a radiolabeled atom. 3 H, 11 C. 13 C. 14 C. 13 N, 15 O. 18 F and 19 F, preferably 3 H, 11 C. 14 C. 13 N, 15 O. 18 F and 19 F, more preferably 3 H, 11 C. 13 N, 15 O and 18 F, even more preferably 3 H, 18 F and 11 C, and most preferably 3 H and 18 For example, R 1 , R 2 , one or more of the H atoms of the -O-CH3 substituents of the fluoropyridine ring, and / or the piperidine ring 3 H atoms, in particular one or more (e.g., one, two, or three) of the H atoms of the -O-CH3 substituents of the piperidine ring 3 Alternatively, or additionally, for example, the F atom of the fluoropyridine ring can be: 18 F or 19 F atoms, and preferably 18 It can be an F atom.

[0031] The compounds of the present invention may form esters, carbamates, and / or salts. Salts of the compounds of the present invention suitable for use in pharmaceuticals are those in which the counterion is pharmaceutically acceptable. However, salts having pharmaceutically unacceptable counterions are within the scope of the present invention, for example, for use as intermediates in the preparation of the compounds of the present invention, as well as their pharmaceutically acceptable salts and physiologically functional derivatives. The term "physiologically functional derivative" refers to a chemical derivative of the compounds of the present invention that has the same physiological function as the free compounds of the present invention, for example, by being convertible in the body. Esters and carbamates are examples of physiologically functional derivatives.

[0032] Suitable salts according to the invention include salts formed with organic or inorganic acids or bases. In particular, suitable salts formed with acids include those formed with mineral acids, strong organic carboxylic acids, such as alkanecarboxylic acids of 1 to 4 carbon atoms, which are unsubstituted or substituted, for example, by halogen, such as saturated or unsaturated dicarboxylic acids, such as hydroxycarboxylic acids, for example amino acids, or with organic sulfonic acids, such as (C1-C4)-alkyl- or aryl-sulfonic acids, which are unsubstituted or substituted, for example, by halogen. Pharmaceutically acceptable acid addition salts include those formed from hydrochloric, hydrobromic, hydroiodic, sulfuric, nitric, citric, tartaric, acetic, phosphoric, lactic, pyruvic, acetic, trifluoroacetic, succinic, perchloric, fumaric, maleic, glycolic, lactic, salicylic, oxaloacetic, methanesulfonic, ethanesulfonic, p-toluenesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic, benzenesulfonic, isethionic, ascorbic, malic, phthalic, aspartic, and glutamic acids, lysine, and arginine. Other acids, such as oxalic acid, while not themselves pharmaceutically acceptable, may be useful as intermediates in obtaining the compounds of the present invention and their pharmaceutically acceptable acid addition salts.

[0033] The compounds of the present invention may have suitable groups that are converted to esters or carbamates. Exemplary ester and carbamate groups formed from -OH in the compounds of the present invention include -OC(O)R h , -OC(O)NHR h , -OC(O)N(R h )2, and -OSO2R h (In the formula, each R h independently, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-8 Cycloalkyl and C 3-8 Cycloalkyl C 1-8 Alkyl, HaloC 1-8 Alkyl, dihalo C 1-8 Alkyl, trihalo C 1-8 Alkyl, phenyl and phenyl C 1-3 alkyl, more preferably R h is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, and C 3-8 Cycloalkyl C 1-6 alkyl).

[0034] Those skilled in the art of organic chemistry will understand that many organic compounds can form complexes with solvents with which they react or from which they are precipitated or crystallized. These complexes are known as "solvates." For example, a complex with water is known as a hydrate. A solvate, such as a hydrate, exists when a drug substance incorporates a solvent, such as water, into the crystal lattice in either stoichiometric or non-stoichiometric amounts. Drug substances are routinely screened for the presence of hydrates, as they may encounter solvent incorporation at any stage of the drug manufacturing process or during storage of the drug substance or dosage form. Solvates are discussed in detail in S. Byrn et al., Pharmaceutical Research 12(7), 1995, 954-954 and Water-Insoluble Drug Formulation, 2000, incorporated herein by reference. nd ed. R. Liu, CRC Press, page 553. Therefore, it will be understood by those skilled in the art that the compounds of the present invention, as well as their ester carbamates and / or salts, may therefore exist in the form of solvates. Solvates of the compounds of the present invention that are suitable for use in pharmaceuticals are those in which the associated solvent is pharmaceutically acceptable. For example, hydrates are an example of pharmaceutically acceptable solvates. However, solvates having associated solvents that are not pharmaceutically acceptable may find use as intermediates in the preparation of the compounds of the present invention, as well as their pharmaceutically acceptable ester carbamates, and / or their salts.

[0035] Compounds that can be converted into the compounds of the present invention or their active metabolites or residues as described above upon administration to a recipient are known as "prodrugs." For example, prodrugs can be converted into their active forms, which have medical effects, in the body, for example, by hydrolysis in the blood. Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the ACS Symposium Series (1976), "Design of Prodrugs" ed. H. Bundgaard, Elsevier, 1985, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, which are incorporated herein by reference.

[0036] Labeled Compounds of the Present Invention The compounds of the present invention can be labeled. A "label" (which can be a radiolabel or other detectable label, or a tag, marker, detectable marker, tracer, radiotracer, or equivalent) is any atom or group suitable for in vivo or in vitro imaging and / or assay (e.g., identification, imaging, diagnosis, evaluation, detection, and / or quantification), particularly imaging and diagnosis. Suitable labels include, for example, radioisotopes (which can also be referred to as "radiolabeled atoms"), radionuclides, isotopes, positron emitters, gamma emitters, fluorescent groups, luminescent groups, chromogenic groups, biotin (in combination with streptavidin conjugation), or photoaffinity groups. The type of label selected depends on the desired detection method. The position at which the label is incorporated into or attached to the compound of the present invention is not particularly limited.

[0037] Examples of isotopes (such as radioisotopes, radionuclides, positron emitters, and gamma emitters) that can be used to label the compounds of the invention include: 2 H, 3 H,11 C. 13 C. 14 C. 13 N, 15 O. 18 F and 19 F, preferably 2 H, 3 H, 11 C. 13 N, 15 O and 18 F, more preferably 3 H, 11 C. 13 N, 15 O and 18 F, and even more preferably 3 H, 11 C and 18 F, and most preferably 3 H and 18 Examples include, but are not limited to, F.

[0038] Preferred examples of the labeling compounds of the present invention are compounds of formula (I) having a structural formula selected from the following group:

[0039] [ka]

[0040] Even more preferred examples of the labeled compounds of the present invention are compounds of formula (I) having a structural formula selected from the group consisting of:

[0041] [ka]

[0042] Particularly preferred examples of the labelled compounds of the present invention are compounds of formula (I) having a structural formula selected from the group consisting of:

[0043] [ka]

[0044] Isotopic forms of the compounds of the present invention (which may also be referred to as "isotopic variants") can generally be prepared by conventional procedures, for example, by the methods described in the Examples section, using appropriate isotopic variants of suitable reagents that are commercially available or prepared by known synthetic techniques. Radioisotopes, radionuclides, positron emitters, and gamma emitters can be included in the compounds of the present invention by methods conventional in the art of organic chemistry. For example, they can be introduced by using correspondingly labeled starting materials when preparing the desired compounds of the present invention. Exemplary methods for introducing detectable labels are described, for example, in U.S. Patent Application Publication No. 2012 / 0302755.

[0045] In certain preferred embodiments, the compounds of the invention are labeled. In the compounds of the invention, one or more H, one or more C, one or more N, one or more O, and / or F are each 3 H; 11 C. 13 C or 14 C; 13 N; 15 O; 18 F or 19 Preferably, one or more H, one or more C, one or more N, one or more O, and / or F may be replaced by 3 H; 11 C or 14 C; 13 N; 15 O; 18 F or 19 F, and more preferably, 3 H, 11 C. 13 N, 15 O and 18 Even more preferably, one or more H, one or more C, and / or F may be replaced by 3 H, 11 C, and 18 Even more preferably, one or more H and / or F may be replaced by 3 H and 18 It can be replaced by F.

[0046] 11 C. 13 N, 15 O and 18F are radioactive isotopes. They decay primarily by positron emission. Thus, the inclusion of such atoms in the compounds of the present invention makes the compounds detectable by positron emission tomography. Thus, one or more 11 C. 13 N, 15 O or 18 The compounds of the invention that contain F are particularly useful as radiotracers, also called radioligands, for positron emission tomography (PET).

[0047] In the compounds of the present invention, one or more H is 3 H radioactive isotopes. Inclusion of such atoms in the compounds of the invention renders the compounds detectable by autoradiography or liquid scintillation counting. 3 The compounds of the invention that contain H are particularly useful as radiotracers for in vitro studies.

[0048] In certain preferred embodiments, the labeled compounds of the invention can be labeled so as to be detectable in vivo using in vivo magnetic resonance spectroscopy (MRS), magnetic resonance imaging, PET, single-photon SPECT, and combinations thereof. For example, the compounds of the invention can be labeled so as to be detectable in vivo using MRS / MRI. 19 F or 13 Can be labeled with C or C for PET imaging 11 , N 13 , O 15 or F 18 Preferably, the compounds of the present invention can be radiolabeled with C 11 , N 13 , O 15 and F 18 The compound comprises one or more radioisotopes selected from:

[0049] The compounds of the present invention contain a large number of C atoms. 11 C. For example, one C can be replaced by one 11 C is replaced by C, or two Cs are replaced by two 11 C is replaced by three Cs, 11 In certain preferred embodiments, one C is replaced by one 11 It can be replaced by C.

[0050] The compounds of the present invention contain three N atoms. One or more N atoms in the compounds of the present invention are 13 N. For example, one N can be 13 N or two Ns are replaced by two 13 N or three N's are replaced by three 13 In certain preferred embodiments, one N is replaced by 13 It is replaced by N.

[0051] The compounds of the present invention contain two O atoms. One or more O in the compound is 15 For example, one O can be replaced by 15 O or (two Os are replaced by two 15 In certain preferred embodiments, one O is replaced by 15 It is replaced by O.

[0052] The compounds of the present invention contain multiple H atoms. When one or more H atoms in the compounds of the present invention are 3 H. For example, one H can be replaced by one 3 H or two H are replaced by two 3 H or three H's are replaced by three 3 H or at least three H are replaced by at least three 3 In certain preferred embodiments, one H is replaced by one 3 H or two H are replaced by two 3H or three H are replaced by three 3 H, e.g., three Hs are replaced by three 3 It can be replaced by H.

[0053] The compounds of the present invention contain F atoms. In one preferred embodiment, the F atoms in the compounds of the present invention are F 18 can be replaced with

[0054] Uses of the Compounds of the Invention The present invention provides compounds that are selective tau deposit / aggregate ligands. As used herein, the terms "tau deposit ligand" and "tau aggregate ligand" are intended to encompass any moiety that binds to tau deposits (tau deposits may also be referred to as tau aggregates). For example, the compounds of the present invention may bind to one or more of pathologically aggregated tau, hyperphosphorylated tau, neurofibrillary tangles, paired helical filaments, straight filaments, neurotoxic soluble oligomers, polymers, and fibrils. The compounds of the present invention are particularly suitable for binding to various types of tau deposits (i.e., tau aggregates). In particular, the compounds of the present invention are suitable for binding to tau deposits containing the 4R isomeric form of tau (i.e., tau aggregates containing the 4R isomeric form of tau).

[0055] Preferred compounds of the present invention have excellent binding affinity to tau deposits. For example, preferably, the compounds of the present invention have an IC for tau deposits in a competitive binding assay of less than 100 nM, preferably less than 70 nM, preferably less than 60 nM, more preferably less than 55 nM, more preferably less than 50 nM, more preferably less than 40 nM, more preferably less than 30 nM, more preferably less than 25 nM, more preferably less than 20 nM, and even more preferably less than 15 nM, such as less than 13 nM, less than 10 nM, less than 8 nM, less than 6 nM, less than 5 nM, less than 4 nM, less than 3 nM, or less than 2 nM. 50 In one preferred embodiment, compounds of the invention have an IC for tau deposits of less than 70 nM in a competitive binding assay. 50In another preferred embodiment, compounds of the invention have an IC for tau deposits of less than 50 nM in a competitive binding assay. 50 In another preferred embodiment, compounds of the invention have an IC for tau deposits of less than 30 nM in a competitive binding assay. 50 In another preferred embodiment, compounds of the invention have an IC for tau deposits of less than 20 nM in a competitive binding assay. 50 In another preferred embodiment, compounds of the invention have an IC for tau deposits of less than 15 nM in a competitive binding assay. 50 In another preferred embodiment, compounds of the invention have an IC for tau deposits of less than 10 nM in a competitive binding assay. 50 In another preferred embodiment, compounds of the invention have an IC for tau deposits of less than 5 nM in a competitive binding assay. 50 In another preferred embodiment, compounds of the invention have an IC for tau deposits of less than 3 nM in a competitive binding assay. 50 Compounds of the invention have IC values ​​for tau deposits of less than 10 nM in a competitive binding assay. 50 It is particularly preferred that the value

[0056] Preferred compounds of the present invention have excellent binding affinity for tau deposits (e.g., bind to tau at levels described above in competitive binding assays) and are selective tau deposit ligands. "Selective," in this context, refers to any tau deposit ligand that binds to tau deposits preferentially over Aβ deposits. For example, preferably, compounds of the present invention have a binding affinity for tau that is at least 1.2-fold, more preferably at least 1.5-fold, more preferably at least 2-fold, more preferably at least 3-fold, more preferably at least 5-fold, more preferably at least 8-fold, more preferably at least 10-fold, more preferably at least 12-fold, and even more preferably at least 15-fold, e.g., at least 18-fold, at least 20-fold, at least 22-fold, at least 25-fold, at least 30-fold, at least 40-fold, at least 50-fold, at least 100-fold, or at least 150-fold greater than their binding affinity for Aβ. In one preferred embodiment, compounds of the present invention have a binding affinity for tau that is at least two-fold greater than their binding affinity for Aβ. In one preferred embodiment, compounds of the present invention have a binding affinity for tau that is at least three-fold greater than their binding affinity for Aβ. In another preferred embodiment, the compounds of the present invention have a binding affinity for tau that is at least 5-fold greater than its binding affinity for Aβ. In another preferred embodiment, the compounds of the present invention have a binding affinity for tau that is at least 10-fold greater than its binding affinity for Aβ. In another preferred embodiment, the compounds of the present invention have a binding affinity for tau that is at least 15-fold greater than its binding affinity for Aβ. In another preferred embodiment, the compounds of the present invention have a binding affinity for tau that is at least 20-fold greater than its binding affinity for Aβ. In another preferred embodiment, the compounds of the present invention have a binding affinity for tau that is at least 30-fold greater than its binding affinity for Aβ. In a particularly preferred embodiment, the compounds of the present invention have a binding affinity for tau that is at least 3-fold greater than its binding affinity for Aβ.

[0057] In certain highly preferred embodiments, compounds of the invention have a binding affinity for tau that is at least three times its binding affinity for Aβ, and an IC for tau deposits of less than 30 nM (more preferably less than 20 nM, and most preferably less than 10 nM) in a competitive binding assay. 50 It has a value.

[0058] It is also preferred that the compounds of the invention have a CLogP that is less than 7.0, preferably less than 6.5, preferably less than 5.0, more preferably less than 4.5, more preferably less than 4.0, more preferably less than 3.5, and more preferably less than 3.0, such as less than 2.8, less than 2.5, less than 2.3, less than 2.0, or less than 1.8.

[0059] The compounds of the invention find utility in the diagnosis and / or treatment or prevention of conditions associated with tau deposits. For example, the compounds of the invention may be used to treat tauopathies such as Alzheimer's disease, corticobasal degeneration (CBD), Pick's disease, progressive supranuclear palsy (PSP), Parkinson's disease, Creutzfeldt-Jakob disease, familial Alzheimer's disease, argyrophilic grain disease, prion protein cerebral amyloid angiopathy, traumatic brain injury, amyotrophic lateral sclerosis, frontotemporal dementia and parkinsonism linked to chromosome 17, postencephalitic parkinsonism, Guadeloupe-Cortez syndrome, and the like. Parkinsonism, glial globular tauopathy, age-related tau astrogliopathy, Guam Parkinsonism-dementia complex, Niemann-Pick disease type C, myotonic dystrophy, inclusion body myositis, chronic traumatic encephalopathy, Down syndrome, Gerstmann-Straussler-Scheinker syndrome, British dementia, familial Danish dementia, dementia pugilistica, neurofibrillary tangle-predominant senile dementia, Huntington's disease, Lewy body disease, Lyon disease, subacute sclerosing panencephalitis, subacute sclerosing panencephalitis, diffuse neurofibrillary tangle disease with calcifications, neurodegeneration with cerebral iron accumulation, mutations affecting sodium / proton exchange, cerebrotendinous xanthomatosis with C.379C>T(p.R127W) mutation in the CYP27A1 gene, TARDBP mutation p.Ile383Val associated with semantic dementia, non-Guam type motor neuron disease with neurofibrillary tangles, argyrophilic granule disease, Ha The compounds of the present invention find utility in the diagnosis and / or treatment or prevention of Lervorden-Spatz disease, multiple system atrophy, pallido-pontine-nigral degeneration, progressive subcortical gliosis, neurofibrillary tangle dementia, myotonic dystrophy, taupanene cephalopathy, astrocytic AD-like, Gerstmann-Straussler-Scheinker with tau, mutations in LRRK2, SLC9A6-associated mental retardation, and white matter tauopathies with glial microspheroid inclusions. The compounds of the present invention are particularly useful in the diagnosis and / or treatment (especially the diagnosis) of Alzheimer's disease, corticobasal degeneration, Pick's disease, Parkinson's disease, chronic traumatic encephalopathy, and progressive supranuclear palsy, and even more particularly Alzheimer's disease and corticobasal degeneration.

[0060] The compounds of the invention may be for use as therapeutic agents (or medicaments) in the treatment of diseases or disorders associated with tau deposits (ie, tauopathies), such as those listed above.

[0061] The present invention also provides a method for the treatment or prevention of a condition associated with a disease or disorder associated with tau deposits in a mammal (particularly in a human), comprising administering to the mammal a therapeutically effective amount of a compound according to the present invention, or a composition comprising a compound according to the present invention together with a pharmaceutically acceptable carrier. Clinical conditions mediated by tau deposits that can be treated by the method of the present invention are tauopathies, such as those listed above.

[0062] The present invention also provides the use of a compound according to the invention for the manufacture of a medicament for the treatment or prevention of a disease or disorder associated with tau deposits (i.e., a tauopathy), such as the conditions associated with a tauopathy listed above.

[0063] The compounds of the invention may also be used as diagnostic agents (for in vivo and / or in vitro diagnostic applications) for the detection of tau deposits.

[0064] The compounds of the present invention have the ability to target specific pathology (tau deposits) and can be detected at desired sites, so they can be used for diagnostic purposes.For example, the compounds of the present invention can detect the presence and level of tau deposits in patients with or suspected of having a disease or disorder associated with tau deposits (i.e., tauopathy), such as the tauopathies listed above.The compounds of the present invention are also particularly useful for diagnosing tauopathies, because they do not exhibit off-target MAO binding or inhibitory activity.Since MAO exists in the brain in areas that overlap with tau pathology in certain tauopathies, such off-target effects are undesirable in tau deposit ligands.

[0065] The compounds of the invention can bind to tau deposits both in vivo and in vitro. The compounds of the invention may be for use as diagnostic agents (for in vivo and / or in vitro diagnostic applications) in the diagnosis of diseases or disorders associated with tau deposits (i.e., tauopathies), such as those listed above.

[0066] The compounds of the present invention cross the blood-brain barrier to a greater extent than previously disclosed compounds of similar properties, and once they cross the blood-brain barrier, they are well distributed across the brain.

[0067] When used as a diagnostic agent, the compounds of the present invention may optionally be in a labeled form as described above. Thus, the present invention also provides the use of the compounds of the present invention in a labeled form for use as a diagnostic agent for the diagnosis of a condition associated with a disease or disorder associated with tau deposits (i.e., tauopathy). In such an embodiment, preferably, the compounds of the present invention in a labeled form are 3 H, 11 C. 13 C. 14 C. 13 N, 15 O. 18 F and 19 F, preferably 3 H, 11 C. 14 C. 13 N, 15 O. 18 F and 19 F, more preferably 3 H, 11 C. 13 N, 15 O and 18 F, and most preferably 3 H and 18 F. They are used as diagnostic agents (particularly for in vivo applications), and the compounds are, for example, 11 C. 13 N, 15 O or 18 F (preferably 18When radiolabeled with F, the compounds of the invention can be detected by positron emission tomography. 3 When radiolabeled with 3H, the compounds of the invention can be detected by autoradiography.

[0068] As described above, the compounds of the present invention can be used for diagnostic purposes because they have the ability to target specific pathologies (tau deposits) and detect them at desired sites. Therefore, when used as diagnostic agents, the compounds of the present invention are particularly useful as imaging agents. Imaging agents are compounds that enable imaging of specific organs, tissues, diseases, and physiological functions. Such imaging allows for disease diagnosis, monitoring of disease progression, and tracking of treatment responses.

[0069] The compounds of the invention, when used as diagnostic agents, particularly imaging agents, may be detected by radioscintigraphy, assay, chemiluminescence, electrochemiluminescence, near-infrared luminescence, fluorescence, spectroscopy, autoradiography, liquid scintillation counting, gamma imaging, magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), scintigraphy, single-photon emission computed tomography (SPECT), computed tomography (CT) scanning, and / or positron emission tomography (PET).

[0070] In embodiments of the present invention in which the compounds of the present invention are intended for use as diagnostic agents, particularly imaging agents, the type of detection instrument available is a major factor in determining whether a label is required and which label to select. For example, if imaging requires a detectable isotope, the type of detection instrument used will determine whether a label is required (i.e., whether the isotope is naturally occurring and, if so, in what amount), and if so, which isotope to use. In one aspect, the compounds of the present invention are labeled, and the selected form of label must have a type of decay that is detectable by a given type of instrument. Furthermore, when selecting an isotopic label for in vivo imaging, other considerations, such as the half-life of the radioisotope, are taken into account.

[0071] The compounds of the invention for use as diagnostic agents for in vivo imaging (particularly imaging and / or quantification of tau deposits) are preferably used in combination with non-invasive neuroimaging techniques, such as in vivo MRS, MRI, PET, SPECT and combinations thereof. For PET imaging, the compounds of the invention are 11 C. 13 N, 15 O or 18 F. Labeling may not be required for in vivo MRS or MRI, or the compound may be labeled with F for MRS or MRI. 13 It can be labeled with C.

[0072] The present invention also provides a method of diagnosing a patient or monitoring disease progression in a patient, comprising administering a compound of the present invention to the patient. The method may further comprise detecting the compound of the present invention in vivo at a site of interest (e.g., the brain) in the patient using PET or SPECT, or detecting the compound in a sample from the patient. Preferably, in such an embodiment, the compound of the present invention is 3 H, 11 C. 13 C. 14 C. 13N, 15 O. 18 F and 19 F, preferably 3 H, 11 C. 14 C. 13 N, 15 O. 18 F and 19 F, more preferably 3 H, 11 C. 13 N, 15 O or 18 F, and most preferably 3 H or 18 The compound of the present invention comprises one or more radioisotopes selected from F. The present invention also provides a method of diagnosing a patient or monitoring disease progression in a patient, comprising contacting a compound of the present invention with a sample taken from the patient.

[0073] The method may further comprise detecting the compound of the invention using radioscintigraphy, assay, chemiluminescence, electrochemiluminescence, autoradiography, near-infrared luminescence, fluorescence, spectroscopy, liquid scintillation counting, gamma imaging, scintigraphy, magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), single photon emission computed tomography (SPECT), or computed tomography (CT scan).

[0074] In the methods for diagnosing a disease or disorder associated with tau deposits described herein, the method comprises: i) administering to a subject a diagnostically effective amount of a compound of the invention; ii) distributing the compound of the invention to a tissue of interest (e.g., the brain or a body fluid such as cerebrospinal fluid (CSF)); iii) imaging the tissue of interest, wherein increased binding of the compound of the invention to the tissue of interest compared to normal or control binding levels indicates that the subject is suffering from or at risk of developing a disorder associated with tau deposits.

[0075] The compounds of the invention can be used to image tau deposits in any sample suspected of containing tau deposits or in specific body parts or regions of a patient. The compounds of the invention are particularly suitable for imaging tau deposits in the brain and body fluids such as cerebrospinal fluid (CSF).

[0076] Diagnosis of a disease or disorder associated with tau deposits in a patient may be achieved by detecting specific binding of a compound according to the invention to tau deposits in a sample or in situ; (a) contacting a sample or a specific body part or region (e.g., brain and / or CSF) suspected of containing tau deposits with a compound of the invention that binds to tau deposits; (b) binding a compound of the invention to tau deposits to form a compound / tau deposit complex; (c) detecting the formation of a compound / tau deposit complex; and (d) optionally correlating the presence or absence of the compound / tau deposit complex with the presence or absence of tau deposits in the sample or in a particular body part or region; (e) optionally, comparing the amount of the compound / tau deposit complex with a normal or control value, wherein an increased amount of the compound / tau deposit complex compared to the normal control value may indicate that the patient is suffering from or at risk of developing a tau-associated disorder.

[0077] After contacting the sample or a particular body part or region with a compound of the invention (e.g., brain and / or CSF), the compound is allowed to bind to tau deposits. The time required for binding depends on the type of test (e.g., in vitro or in vivo) and can be determined by one of ordinary skill in the art through routine experimentation.

[0078] The presence or absence of the compound / tau deposits is then optionally correlated with the presence or absence of tau deposits in the sample or in a particular body part or region. The amount of the compound / tau deposit complex can be compared to a normal or control value determined in the sample or in a particular body part or region of a healthy subject, and an increase in the amount of the compound / tau deposit complex compared to the normal or control value can indicate that the patient is suffering from or at risk of developing a disease or disorder associated with tau deposits (i.e., a tauopathy). The present invention also relates to a method for determining the amount of tau deposits in tissue and / or body fluids, the method comprising: (1) providing a sample representing the tissue and / or body fluid (e.g., brain and / or CSF) under investigation; (2) testing the sample for the presence of tau deposits using a compound of the invention; (3) determining the amount of compound bound to tau deposits; (4) calculating the amount of tau deposits in the tissue and / or body fluid.

[0079] A sample can be tested for the presence of tau deposits using a compound of the invention by contacting the sample with a compound of the invention, allowing the compound of the invention to bind to the tau deposits to form a compound / tau deposit complex, and detecting the formation of the compound / tau deposit as described above.

[0080] Monitoring minimal residual damage in a patient suffering from a disorder associated with tau deposits who has been treated with a therapeutic agent useful for the prevention or treatment of a disorder associated with tau deposits (e.g., one or more of those listed above or a therapeutic agent useful for the prevention or treatment of a tauopathy) can include: This may be achieved by performing steps (a)-(d) above, and (e) optionally comparing the amount of the compound / tau deposit complex with a normal or control value, where an increased amount of the complex compared to the normal or control value may indicate that the patient may still be afflicted with minimal residual disease. How steps (a) to (e) can be carried out has already been explained above.

[0081] Predicting the response of a patient suffering from a disorder associated with tau deposits and being treated with a therapeutic agent useful for preventing or treating the disorder associated with tau deposits includes: This can be achieved by performing steps (a)-(d) above, and (e) optionally comparing the amount of compound / tau deposit complexes to a normal or control value. How steps (a) to (e) can be carried out has already been explained above.

[0082] In methods for predicting responsiveness, the amount of compound / tau deposit complexes can optionally be compared at various time points during treatment, for example, before and after treatment begins, or at various time points after treatment begins. A change, particularly a decrease, in the amount of compound / tau deposit complexes can indicate that the patient is likely to be responsive to the respective treatment.

[0083] The compounds according to the invention can also be incorporated into test kits for detecting tau deposits. The test kit typically includes a container holding one or more compounds according to the invention and instructions for using the compounds to bind to tau deposits to form compound / tau deposit complexes, and detecting the formation of the compound / tau deposit complexes, such that the presence or absence of the compound / tau deposit complexes correlates with the presence or absence of tau deposits.

[0084] Administration Of course, the amount of a compound of the invention required to achieve a diagnostic or therapeutic effect will vary depending on the particular compound, the route of administration, the subject being treated (including the type, species, age, weight, sex, and condition of the subject), the subject's renal and hepatic function, and the particular disorder or disease being treated, diagnosed, or monitored, and its severity. An ordinarily skilled physician, veterinarian, or clinician can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of a condition, or to use to diagnose a condition or the progression of a condition.

[0085] When used as a diagnostic or therapeutic agent, the oral dosage of the present invention for an adult will be in the range of about 0.01 mg / kg / day to about 100 mg / kg / day, preferably 0.01 mg / kg / day to 10 mg / kg / day, and most preferably 0.1 to 5.0 mg / kg / day. For oral administration, the compositions are preferably provided as tablets or other presentation forms provided in discrete units containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, and 500 milligrams of the compound of the present invention for symptomatic adjustment of the dosage to the patient being treated. Medicaments typically contain about 0.01 mg to about 500 mg of the compound of the present invention, preferably about 1 mg to about 100 mg. Intravenously, the most preferred doses range from about 0.1 to about 10 mg / kg / min during a constant rate infusion. Advantageously, the compounds of the present invention can be administered in a single daily dose, or the total daily dosage can be administered in divided doses two, three, or four times daily. For diagnostic use, the compounds of the present invention are preferably administered in a single daily dose. Additionally, preferred compounds of the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes using transdermal skin patch formulations well known to those skilled in the art.

[0086] While it is possible for the compounds of the present invention to be administered alone, it is preferred that the active ingredient be present in a pharmaceutical formulation or composition. Thus, the present invention provides a pharmaceutical formulation or composition comprising a compound according to the present invention and a pharmaceutically acceptable diluent, excipient, or carrier. The pharmaceutical composition of the present invention may take the form of a pharmaceutical formulation as described below.

[0087] formulation As used herein, "pharmaceutical" does not necessarily mean therapeutic; for example, a pharmaceutical formulation may be used as a diagnostic agent, such as an imaging agent. Pharmaceutical formulations of the present invention include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous (bolus or infusion), and intra-articular), inhalation (including fine particle dusts or mists that may be generated by various types of metered dose pressurized aerosols), nebulizer or insufflator, rectal, intraperitoneal, and topical (including transdermal, buccal, sublingual, and ocular) administration, although the most suitable route may depend, for example, on the condition and disorder of the recipient being treated or diagnosed.

[0088] Preparation can be conveniently presented in unit dosage form, and can be prepared by any method well known in the field of pharmacy.All methods include the step of associating the compound of the present invention with a carrier that constitutes one or more accessory ingredients.Generally, preparation is prepared by uniformly and intimately associating the compound of the present invention with liquid carrier or finely divided solid carrier or both, and then, if necessary, shaping the product into desired preparation.

[0089] Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, pills, or tablets, each containing a predetermined amount of a compound of the invention; as a powder or granules; as a solution or suspension in an aqueous liquid or non-aqueous liquid, such as an elixir, tincture, suspension, or syrup, or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The compound of the present invention may also be presented as a bolus, electuary, or paste.

[0090] Preparations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats, and solutes that render the preparation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may contain suspending agents and thickening agents. The preparations may be presented in unit-dose or multi-dose containers, for example, sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) state, requiring only the addition of a sterile liquid carrier, for example, physiological saline or distilled water for injection, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets of the kind described above. Exemplary compositions for parenteral administration include injectable solutions or suspensions, which may contain, for example, a suitable non-toxic, parenterally acceptable diluent or solvent, such as mannitol, 1,3-butanediol, water, Ringer's solution, isotonic sodium chloride solution, or other suitable dispersing or wetting agent, and suspending agents including synthetic mono- or diglycerides, and fatty acids, including oleic acid or Cremaphor.

[0091] Exemplary compositions for nasal aerosol or inhalation administration include solutions in saline which may contain, for example, benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, and / or other solubilizing or dispersing agents such as those known in the art.

[0092] Formulations for topical administration in the oral cavity, e.g., buccal or sublingual, include lozenges comprising a compound of the invention in a flavored base such as sucrose and acacia or tragacanth, and pastilles comprising a compound of the invention in a base such as gelatin and glycerin or sucrose and acacia. An exemplary composition for topical administration comprises a topical carrier such as Plastibase (mineral oil gelled with polyethylene).

[0093] Preferred unit dosage formulations are those containing an effective dose, or an appropriate fraction thereof, of a compound of the present invention, as herein above recited.

[0094] It will be understood that in addition to the ingredients specifically mentioned above, the formulations of the present invention may include other agents commonly used in the art having regard to the type of formulation in question; for example, formulations suitable for oral administration may include flavoring agents.

[0095] The compounds of the present invention can be used in medicine as the sole active ingredient (i.e., the sole therapeutic agent or the sole diagnostic agent), but the compounds can also be used in combination with one or more additional active ingredients. For example, the compounds of the present invention can be used in a diagnostic composition as the sole diagnostic agent, or the compounds can be used in combination with one or more additional diagnostic agents and / or one or more therapeutic agents. Alternatively, the compounds of the present invention can be used in medicine as the sole diagnostic and / or therapeutic agent, or the compounds can be used in combination with one or more additional therapeutic agents and / or one or more diagnostic agents.

[0096] Thus, the present invention also provides a compound according to the present invention together with an additional diagnostic agent for simultaneous, sequential, or separate administration. Such additional diagnostic agents may be additional compounds according to the present invention, or they may be different diagnostic agents. The additional diagnostic agent may be an agent useful in diagnosing a tauopathy (e.g., a tauopathy listed above).

[0097] In certain preferred embodiments, the additional diagnostic agent can be an agent selective for Aβ deposits, which is useful for diagnosing Alzheimer's disease.The additional diagnostic agent can be detectable by radioscintigraphy, magnetic resonance imaging (MRI), assay, chemiluminescence, near-infrared luminescence, fluorescence, autoradiography, liquid scintillation counting, gamma imaging, scintigraphy, magnetic resonance imaging, magnetic resonance spectroscopy, SPECT, computed tomography (CT scan) and / or positron emission tomography (PET).Preferably, the additional diagnostic agent can be detectable by positron emission tomography.For example, the additional agent can be a PET ligand.

[0098] For example, the compounds of the present invention may be used in combination with an effective amount of one or more other diagnostic agents, such as luminescent conjugated oligothiophenes (e.g., q-FTAA-CN, p-FTAA-CN, h-FTAA-CN), Pittsburgh compound B (PiB), fludeoxyglucose F 18 (FDG), florbetapir, flutemetamol, NAV4694, PBB3, AT-100, 4G8, Congo red, thioflavin S, thioflavin T, ml-stilbene, chrysamine G, BF-277, TZDM, FDDNP, MeO-X-04, IMPY, NIAD-4, or the like. 3 HX-34 can be effectively administered in combination with (or used in vitro for in vitro diagnosis with) one or more diagnostic agents selected from the group consisting of: a luminescent conjugated polythiophene (e.g., polythiophene acetic acid (PTAA), tPTAA, POWT, tPOWT, POMT, tPOMY), and GTP1 (Genentech Tau Probe 1).

[0099] The present invention further provides compounds according to the invention together with additional therapeutic agents for simultaneous, sequential or separate administration. Such additional therapeutic agents may be additional compounds according to the invention or they may be different therapeutic agents, such as one or more of those listed above or agents useful in the prevention or treatment of tauopathies. For example, the compounds of the invention may be administered in combination with an effective amount of another agent, such as antibodies (e.g., active immunization (e.g., ACI-35 (AC Immune / Janssen), and AADvac1 (Axon Neuroscience)), passive immunization (e.g., BMS-986168 (IPN007, Bristol-Myers Squibb Company), C2N-8E12 (C2N / AbbVie), and RG6100 (RO7105705, AC Immune / Genentech; aducanumab; solanezumab; gantenerumab; and crenezumab), RG7345 (RO6926496, MAb86, F. Hoffmann-La Roche), PHF1, 4E6G7, 6B2G12), MK-8719 (Merck & Co.), TPI-287 (Cortice Biosciences), methylene blue (e.g., TRx 0327 and Rember), dopaminergic therapeutic agents (e.g., levodopa, caridopa, dopamine agonists (e.g., bromocriptine, perfolide, pramipexole, ropinirole)), cholinesterase inhibitors (e.g., tacrine, donepezil, rivastigmine, galantamine), monoamine oxidase inhibitors (e.g., selegiline), anthocolinergic agents (e.g., trihexyphenidin, In some embodiments, the medicament may be effectively administered in combination with one or more agents selected from the group consisting of benzodiazepines, benzocaine, benzophenone, benzocaine mesylate, benzodiazepines, benzocaine benzoate ...

[0100] The other diagnostic and therapeutic agents described above, when used in combination with the compounds of the present invention, may be used, for example, in amounts indicated in the Physicians' Desk Reference (PDR) or as otherwise determined by one of skill in the art.

[0101] The compounds of the present invention described above, optionally in labeled form, also find use as reference compounds in methods for identifying ligands for tau deposits. Accordingly, the present invention provides methods for identifying ligands for tau deposits, comprising the use of a compound of the present invention, or a labeled form of a compound of the present invention, as a reference compound. For example, such methods may involve competitive binding experiments in which the binding of a compound of the present invention to tau deposits is reduced by the presence of an additional compound having tau deposit-binding properties, e.g., stronger tau deposit-binding properties than the compound of the present invention of interest.

[0102] experiment General information All reagents and solvents used were of analytical grade and commercially available. Anhydrous solutions were routinely used for reactions. Reactions were typically carried out under an inert atmosphere of nitrogen (N).

[0103] 1 H and 13 C spectra were recorded on a Bruker 500 NMR spectrometer.

[0104] Mass spectra were recorded on a Waters Acquity QDa LSMS. The mass spectrometer was equipped with an electrospray ion source (ES) operated in positive or negative mode. The capillary voltage was 3.5 kV and the cone voltage was 30 V. The mass spectrometer was scanned from m / z 100 to 850 with a scan time of 0.5 seconds. The column temperature was set at 50 °C, and a linear gradient was used starting at 95% A (A: 10 mM NH4HCO3) and ending at 100% B (B: MeCN). The column used was an Acquity UPLC™ HSS C operated at 0.4 mL / min. 18It was 1.7 μm and 2.1 × 50 mm.

[0105] The HPLC used was an Agilent 1100 coupled to an Agilent 1290 Infinity DAD. The column used was an XBridge C operated at 0.8 mL / min. 18 The column temperature was set to 50°C, and a linear gradient was started from 98 to 2% A over 3.5 min (A: 10 mM NH4HCO3), followed by a 1.5 min hold at 98% B (B: MeCN).

[0106] The semi-preparative HPLC was a Gilson equipped with a 322 pump. The column used was Kromasil C87 μm, 20×250 mm.

[0107] Microwave heating was performed in a Biotage Initiator 2.0.

[0108] Chromatographic separations were performed using silica gel 60 (0.040-0.063 mm) in filter funnels or by using a Teledyne ISCO CombiFlash RF with Silicycle silica columns of various sizes (4-120 g). TLC plates were Merck silica gel 60F. 254 It was.

[0109] The term room temperature (rt) means, unless otherwise specified, a temperature between 16 and 25° C. The term reflux means, with respect to the solvent used, that a temperature at or slightly above the boiling point of the specified solvent is used, unless otherwise specified.

[0110] Example Compound 1: 2-{2-fluoro-6-[(3S)-3-methoxypiperidin-1-yl]pyridin-3-yl}-1H-indol-5-ol

[0111] [ka]

[0112] Method 1

[0113] [ka]

[0114] In a 20 mL microwave vial, t-butyl 2-(2,6-difluoropyridin-3-yl)-5-hydroxy-1H-indole-1-carboxylate (125 mg, 0.36 mmol, see WO2021074351(A1) for preparation) and 3-(S)-methoxypiperidine HCl (62 mg, 1.1 equiv.) were suspended in acetonitrile (4 mL). To the solution was added Hunig's base (160 μl, 2.5 equiv.), and the reaction was microwaved at 150° C. for 60 minutes.

[0115] The solvent was removed in vacuo, and the residue was taken up in ethyl acetate, washed with water, treated with brine, dried over MgSO4, and then filtered. The solvent was removed in vacuo to give the crude product.

[0116] The crude product was purified by ISCO (12 g silica, dichloromethane (DCM) loading, eluting with 20–40% ethyl acetate / hexanes over 8 min). DCM was added to the residue, and the solid was then filtered and washed with DCM to give 2-{2-fluoro-6-[(3S)-3-methoxypiperidin-1-yl]pyridin-3-yl}-1H-indol-5-ol (31 mg solid, 25% yield, HPLC Rf 2.92 min, MS m / z (M+1) 342.2, (M−1) 340.2, TLC: 40% ethyl acetate / hexanes Rf 0.15). 1H NMR(400MHz,DMSO)δ11.00(s,1H),8.69(s,1H),8.12(dd,J=10.7,8.6Hz,1H),7.23(dt, J=8.6,0.7Hz,1H),6.91(dd,J=8.6,2.1Hz,1H),6.87(d,J=2.3Hz,1H),6.65(dd,J=8.6,2 .3Hz,1H),6.60-6.53(m,1H),3.97(d,J=12.1Hz,1H),3.75(ddd,J=13.0,6.3,3.7Hz,1H) ,3.36(s,7H),2.08-1.91(m,1H),1.79(ddt,J=13.4,6.8,3.4Hz,1H),1.67-1.42(m,2H).

[0117] 13 C NMR(101MHz,DMSO)δ178.10,150.80,139.09,131.69,131.62,131.02,129.33,111.50,111.33,103.81,103.4 9,99.29,99.22,74.19,55.54,47.97,44.65,40.12,39.91,39.70,39.49,39.28,39.07,38.87,29.39,21.60.

[0118] 19 F NMR (377MHz, DMSO) δ-67.79,-67.82.

[0119] Method 2 Step (i) 2-fluoro-6-[(3S)-3-methoxypiperidin-1-yl]pyridine

[0120] [ka]

[0121] (S)-3-Methoxypiperidine HCl (1.0 g, 6.6 mmol) was slurried in dioxane (8 mL) and 2,6-difluoropyridine (660 μL, 1.1 equiv.) was added, followed by Hunig's base (3.0 mL, 2.6 equiv.). The reaction was heated to 100° C. for 5 h.

[0122] The cooled reaction mixture was taken up in ethyl acetate, washed with water, treated with brine, dried over MgSO4, and then filtered. The solvent was removed in vacuo to give a crude oil.

[0123] The crude oil was purified by ISCO (40 g silica, hexane application, elution with 5-20% ethyl acetate / hexane over 5 min) to give 2-fluoro-6-[(3S)-3-methoxypiperidin-1-yl]pyridine (1.03 g oil, HPLC Rf 2.90 min, 75% yield, MS m / z (M+1) 211.2 (very weak), TLC 10% ethyl acetate / hexane Rf 0.14).

[0124] 1 H NMR(500MHz,DMSO-d6)δ7.59(ddd,J=9.2,8.3,7.7Hz,1H),6.69-6.60(m,1H),6.16 (ddd,J=7.7,2.9,0.4Hz,1H),3.86(dq,J=11.0,1.3Hz,1H),3.64(dddt,J=13.2,5.6 ,3.9,0.9Hz,1H),3.25(s,3H),3.24-3.15(m,3H),1.95-1.84(m,1H),1.68(dddd,J =13.3,7.2,6.0,3.5Hz,1H),1.52-1.43(m,1H),1.39(dtt,J=13.2,9.2,3.7Hz,1H).

[0125] 13 C NMR(126MHz,DMSO-d6)δ163.41,161.56,158.28,158.15,142.90,142.83, 103.56,103.52,94.90,94.61,74.64,55.93,48.37,45.00,29.95,22.09.

[0126] Step (ii) 3-Bromo-2-fluoro-6-[(3S)-3-methoxypiperidin-1-yl]pyridine

[0127] [ka]

[0128] 2-Fluoro-6-[(3S)-3-methoxypiperidin-1-yl]pyridine (1.03 g, 4.9 mmol) was dissolved in acetonitrile (20 mL), cooled on an ice bath, and NBS (0.87 g, 1 equiv.) was added in two portions. The reaction was stirred at 0° C. for 5 min and then at room temperature for 30 min.

[0129] Ether was added to the mixture, and the solution was washed with water, treated with brine, dried over MgSO4, and then filtered. The solvent was removed in vacuo and stripped to give the crude product.

[0130] The crude product was purified by ISCO (40 g silica, hexane / DCM application, elution with 5-20% ethyl acetate / hexane over 5 min) to give 3-bromo-2-fluoro-6-[(3S)-3-methoxypiperidin-1-yl]pyridine (1.35 g oil, HPLC Rf 3.31 min, 96% yield, MS m / z (M+1) 289.0, 291.0, TLC 20% ethyl acetate / hexane Rf 0.19).

[0131] 1 H NMR(500MHz,DMSO-d6)δ7.75(dd,J=9.6,8.7Hz,1H),6.67(dd,J=8.8,1.9Hz,1H),3.78(ddt,J=12.9,3.2,1.1Hz,1H),3.57(ddd,J=13.3,6.7,3 .8Hz,1H),3.33-3.25(m,2H),3.24-3.19(m,1H),1.87(dqd,J=11.3,3. 8,1.9Hz,1H),1.72-1.61(m,1H),1.54-1.46(m,1H),1.43-1.34(m,1H).

[0132] 13 C NMR(126MHz,DMSO-d6)δ158.61,157.07,156.95,156.78,144.96,144.94, 106.04,106.01,85.85,85.54,74.51,55.98,48.40,45.16,29.70,21.85.

[0133] Step (iii) t-butyl 5-[(t-butyldimethylsilyl)oxy]-2-{2-fluoro-6-[(3S)-3-methoxypiperidin-1-yl]pyridin-3-yl}-1H-indole-1-carboxylate

[0134] [ka]

[0135] 3-Bromo-2-fluoro-6-[(3S)-3-methoxypiperidin-1-yl]pyridine (580 mg, 2 mmol) and {1-[(t-butoxy)carbonyl]-5-[(t-butyldimethylsilyl)oxy]-1H-indol-2-yl}boronic acid (1.1 g, 1.4 equiv.) were dissolved in dioxane (12 mL) in a 20 mL microwave vial. N was bubbled through the solution for 5 minutes, and then [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with dichloromethane (Pd(dppf)Cl2DCM; 82 mg, 5 mol%) was added, followed by the addition of 2 M K2CO3 (3 mL, 3 equiv.). N was again bubbled through the solution for 5 minutes, the cap was removed, and the mixture was placed in a preheated oil bath. The reaction was heated to 90 °C for 1 hour.

[0136] The aqueous fraction was removed from the cooled reaction, and the organic fraction was diluted with ethyl acetate, dried over MgSO4, and then filtered. The solvent was removed in vacuo to give the crude product.

[0137] The crude product was purified by ISCO (40 g silica, DCM applied, eluting with 5-15% ethyl acetate / hexanes over 6 min) to give t-butyl 5-[(t-butyldimethylsilyl)oxy]-2-{2-fluoro-6-[(3S)-3-methoxypiperidin-1-yl]pyridin-3-yl}-1H-indole-1-carboxylate (1.17 g foam, 98% yield, HPLC Rf 4.43 min, MS m / z (M+1) 556.7, TLC 20% ethyl acetate / hexanes Rf 0.35).

[0138] 1 H NMR(500MHz,DMSO-d6)δ7.92(dt,J=8.9,0.7Hz,1H),7.66(dd,J=10.2,8.3Hz,1H),7.01(dd,J=2.4,0.5Hz,1H),6.83( dd,J=8.9,2.5Hz,1H),6.76(dd,J=8.4,2.1Hz,1H),6.59(d,J=0.7Hz,1H),3.89(dd,J=13.1,3.3Hz,1H),3.67(ddd,J=1 3.2,6.4,3.8Hz,1H),3.62-3.52(m,4H),3.39-3.31(m,2H),3.27(s,3H),3.24(tt,J=7A,3.4Hz,1H),1.92(ddt,J=11.4 ,7.4,3.8Hz,1H),1.78-1.65(m,5H),1.53(dtd,J=12.5,8.3,3.9Hz,1H),1.45-1.36(m,1H),1.34(s,9H),0.95(s,9H).

[0139] 13 C NMR(126MHz,DMSO-d6)δ150.88,149.35,142.06,133.99,131.56,129.63,117.46,115.44,110.20,109.68,102. 72,102.44,102.19,83.27,74.16,67.01,55.57,48.08,44.84,29.53,27.18,25.63,25.12,21.57,17.98,-4.53.

[0140] Step (iv) t-butyl 2-{2-fluoro-6-[(3S)-3-methoxypiperidin-1-yl]pyridin-3-yl}-5-hydroxy-1H-indole-1-carboxylate

[0141] [ka]

[0142] t-Butyl 5-[(t-butyldimethylsilyl)oxy]-2-{2-fluoro-6-[(3S)-3-methoxypiperidin-1-yl]pyridin-3-yl}-1H-indole-1-carboxylate (1.1 g, 2.0 mmol) was dissolved in tetrahydrofuran (THF; 20 mL), cooled on an ice bath, and 1 M tetrabutylammonium fluoride (TBAF) solution (2.2 mL, 1.1 equiv.) was added. The reaction was stirred at 0° C. for 10 min.

[0143] The reaction was diluted with ethyl acetate, treated with brine, dried over MgSO4, and filtered. The solvent was removed in vacuo to give the crude product.

[0144] The crude product was purified by ISCO (40 g silica, DCM applied, eluted with 30-45% ethyl acetate / hexanes over 5 min) to give t-butyl 2-{2-fluoro-6-[(3S)-3-methoxypiperidin-1-yl]pyridin-3-yl}-5-hydroxy-1H-indole-1-carboxylate (0.84 g foam, HPLC 3.41 min, MS m / z (M+1) 442.2, (M-1) 440.2, 98% yield, TLC Rf 45% ethyl acetate / hexanes Rf 0.28).

[0145] 1H NMR(500MHz,DMSO-d6)δ9.18(s,1H),7.87(dt,J=8.8,0.7Hz,1H),7.63(dd,J=10.2,8.3Hz,1H),6.89(dd,J=2. 5,0.5Hz,1H),6.77(dd,J=8.9,2.5Hz,1H),6.72(dd,J=8.4,2.1Hz,1H),6.53(d,J=0.7Hz,1H),3.88(dd,J=13. 1,3.3Hz,1H),3.65(ddd,J=13.2,6.3,3.8Hz,1H),3.36-3.28(m,3H),3.22(tt,J=7.4,3.4Hz,1H),1.94-1.85( m,1H),1.69(dtt,J=13.4,6.9,3.5Hz,1H),1.52(tdd,J=12.5,7.7,3.9Hz,1H),1.45-1.35(m,1H),1.33(s,8H).

[0146] 13 C NMR(126MHz,DMSO-d6)δ170.31,159.27,157.41,157.17,157.04,153.33,149.4 5,142.00,141.97,133.62,133.58,130.25,129.71,115.39,113.35,109.69,10 4.99, 102.73, 102.67, 102.64, 102.49, 83.11, 82.96, 74.17, 59.75, 55.56, 48.11, 44.85, 30.96, 29.53, 27.20, 22.07, 21.57, 20.74, 20.04, 14.07, 13.95, 13.92.

[0147] Step (v) 2-{2-fluoro-6-[(3S)-3-methoxypiperidin-1-yl]pyridin-3-yl}-1H-indol-5-ol

[0148] [ka]

[0149] In a 20 mL microwave vial, t-butyl 2-{2-fluoro-6-[(3S)-3-methoxypiperidin-1-yl]pyridin-3-yl}-5-hydroxy-1H-indole-1-carboxylate (0.84 g, 1.9 mmL) was dissolved in methanol (15 mL), and the reaction was microwaved at 150° C. for 45 minutes.

[0150] The solvent was removed, the residue was stirred with DCM, and the solid was filtered to give 2-{2-fluoro-6-[(3S)-3-methoxypiperidin-1-yl]pyridin-3-yl}-1H-indol-5-ol (300 mg solid, HPLC 2.92 min, MS m / z (M+1) 342.2, (M-1) 340.2, 47% yield, TLC Rf 40% ethyl acetate / hexane Rf 0.15).

[0151] For spectral data see Example Compound 1, Method 1.

[0152] Example Compound 2: 2-{2-fluoro-6-[(3R)-3-methoxypiperidin-1-yl]pyridin-3-yl}-1H-indol-5-ol

[0153] [ka]

[0154] In a 20 mL microwave vial, t-butyl 2-(2,6-difluoropyridin-3-yl)-5-hydroxy-1H-indole-1-carboxylate (125 mg, 0.36 mmol, see WO2021074351(A1) for preparation) and 3-(R)-methoxypiperidine HCl (62 mg, 1.1 equiv.) were suspended in acetonitrile (4 mL). To the solution was added Hunig's base (160 μl, 2.5 equiv.), and the reaction was microwaved at 150° C. for 60 minutes.

[0155] The solvent was removed in vacuo, and the residue was taken up in ethyl acetate, washed with water, treated with brine, dried over MgSO4, and then filtered. The solvent was removed in vacuo to give the crude product.

[0156] The crude product was purified by ISCO (12 g silica, DCM applied, eluting with 20-40% ethyl acetate / hexanes over 8 min. DCM was added to the residue and the solid was filtered and then washed with DCM to give 2-{2-fluoro-6-[(3S)-3-methoxypiperidin-1-yl]pyridin-3-yl}-1H-indol-5-ol (24 mg solid, 25% yield, HPLC Rf 2.92 min, MS m / z (M+1) 342.2, (M-1) 340.2, TLC: 40% ethyl acetate / hexanes Rf 0.15).

[0157] Example Compound 3: 2-{2-fluoro-6-[(3S)-3-methoxypiperidin-1-yl]pyridin-3-yl}-1H-indol-6-ol

[0158] [ka]

[0159] Step (i) t-butyl 6-[(t-butyldimethylsilyl)oxy]-2-{2-fluoro-6-[(3S)-3-methoxypiperidin-1-yl]pyridin-3-yl}-1H-indole-1-carboxylate

[0160] [ka]

[0161] 3-Bromo-2-fluoro-6-[(3S)-3-methoxypiperidin-1-yl]pyridine (263 mg, 0.91 mmol, see Example Compound 1, Method 2, Step (ii) for preparation) and {1-[(t-butoxy)carbonyl]-6-[(t-butyldimethylsilyl)oxy]-1H-indol-2-yl}boronic acid (500 mg, 1.4 equiv.) were dissolved in dioxane (6 mL) in a 20 mL microwave vial. N was bubbled through the solution for 5 minutes, then Pd(dppf)Cl in DCM (40 mg, 5 mol %) was added, followed by 2 M KCO (1.4 mL, 3 equiv.). N was again bubbled through the solution for 5 minutes. The reaction was capped and then placed in a preheated oil bath. The reaction was heated to 90 °C for 1 hour.

[0162] The aqueous fraction was removed from the cooled reaction, and the organic fraction was diluted with ethyl acetate, dried over MgSO4, and then filtered. The solvent was removed in vacuo to give the crude product.

[0163] The crude product was purified by ISCO (40 g silica, DCM applied, eluted with 10–20% ethyl acetate / hexanes over 6 min) to give t-butyl 6-[(t-butyldimethylsilyl)oxy]-2-{2-fluoro-6-[(3S)-3-methoxypiperidin-1-yl]pyridin-3-yl}-1H-indole-1-carboxylate (329 mg foam, 66% yield, HPLC Rf 4.77 min, MS m / z (M+1) 556.3, TLC 20% ethyl acetate / hexanes Rf 0.25).

[0164] Step (ii) t-butyl 2-{2-fluoro-6-[(3S)-3-methoxypiperidin-1-yl]pyridin-3-yl}-6-hydroxy-1H-indole-1-carboxylate

[0165] [ka]

[0166] t-Butyl 6-[(t-butyldimethylsilyl)oxy]-2-{2-fluoro-6-[(3S)-3-methoxypiperidin-1-yl]pyridin-3-yl}-1H-indole-1-carboxylate (329 mg, 0.59 mmol) was dissolved in THF (10 mL), cooled on an ice bath, and 1 M TBAF solution (650 μL, 1.1 equiv.) was added. The reaction was stirred at 0° C. for 10 min.

[0167] The reaction was diluted with ethyl acetate, treated with brine, dried over MgSO4, and filtered. The solvent was removed in vacuo to give the crude product.

[0168] The crude product was purified by ISCO (12 g silica, applied DCM, eluted with 20–35% ethyl acetate / hexanes over 4 min) to give t-butyl 2-{2-fluoro-6-[(3S)-3-methoxypiperidin-1-yl]pyridin-3-yl}-6-hydroxy-1H-indole-1-carboxylate (242 mg film, HPLC 3.54 min, MS m / z (M+1) 442.2, (M−1) 440.2, 93% yield, TLC Rf 30% ethyl acetate / hexanes Rf 0.16).

[0169] Step (iii) 2-{2-fluoro-6-[(3S)-3-methoxypiperidin-1-yl]pyridin-3-yl}-1H-indol-6-ol

[0170] [ka]

[0171] In a 5 mL microwave vial, t-butyl 2-{2-fluoro-6-[(3S)-3-methoxypiperidin-1-yl]pyridin-3-yl}-6-hydroxy-1H-indole-1-carboxylate (0.24 g, 0.54 mmL) was dissolved in methanol (4 mL), and the reaction was microwaved at 150° C. for 60 minutes.

[0172] The solvent was removed in vacuo and the crude product was purified by ISCO (12 g silica, applied with DCM (poorly soluble), eluted with 40–50% ethyl acetate / hexanes over 3 min) to give 2-{2-fluoro-6-[(3S)-3-methoxypiperidin-1-yl]pyridin-3-yl}-1H-indol-6-ol (133 mg solid, HPLC 3.01 min, MS m / z (M+1) 342.2, (M−1) 340.1, 72% yield, TLC Rf 30% ethyl acetate / hexanes Rf 0.16).

[0173] Example Compound 4: 2-{2-fluoro-6-[(3R)-3-methoxypiperidin-1-yl]pyridin-3-yl}-1H-indol-6-ol

[0174] [ka]

[0175] Step (i) 2-fluoro-6-[(3R)-3-methoxypiperidin-1-yl]pyridine

[0176] [ka]

[0177] (R)-3-Methoxypiperidine HCl (0.73 g, 4.8 mmol) was slurried in dioxane (4 mL) and 2,6-difluoropyridine (530 μL, 1.2 equiv.) was added, followed by Hunig's base (2.2 mL, 2.6 equiv.). The reaction was heated to 100° C. overnight.

[0178] The cooled reaction mixture was taken up in ethyl acetate, washed with water, treated with brine, dried over MgSO4, and then filtered. The solvent was removed in vacuo to give a crude oil.

[0179] The crude oil was purified by ISCO (40 g silica, hexane application, elution with 5-20% ethyl acetate / hexane over 5 min) to give 2-fluoro-6-[(3R)-3-methoxypiperidin-1-yl]pyridine (0.85 g oil, HPLC Rf 2.90 min, 85% yield, MS m / z (M+1) 211.2 (very weak), TLC 10% ethyl acetate / hexane Rf 0.14).

[0180] Step (ii) 3-Bromo-2-fluoro-6-[(3R)-3-methoxypiperidin-1-yl]pyridine

[0181] [ka]

[0182] 2-Fluoro-6-[(3R)-3-methoxypiperidin-1-yl]pyridine (0.85 g, 4.0 mmol) was dissolved in acetonitrile (15 mL), cooled on an ice bath, and N-bromosuccinimide (NBS; 0.72 g, 1 equiv.) was added in two portions. The reaction was stirred at 0° C. for 5 min and then at room temperature for 30 min.

[0183] Diethyl ether was added to the mixture, and the solution was washed with water, treated with brine, dried over MgSO4, and then filtered. The solvent was removed in vacuo to give the crude product.

[0184] The crude product was purified by ISCO (40 g silica, hexane / DCM application, elution with 5-20% ethyl acetate / hexane over 5 min) to give 3-bromo-2-fluoro-6-[(3R)-3-methoxypiperidin-1-yl]pyridine (1.13 g oil, HPLC Rf 3.31 min, 97% yield, MS m / z (M+1) 289.0, 291.0, TLC 20% ethyl acetate / hexane Rf 0.19).

[0185] Step (iii) t-butyl 6-[(t-butyldimethylsilyl)oxy]-2-{2-fluoro-6-[(3R)-3-methoxypiperidin-1-yl]pyridin-3-yl}-1H-indole-1-carboxylate

[0186] [ka]

[0187] 3-Bromo-2-fluoro-6-[(3R)-3-methoxypiperidin-1-yl]pyridine (145 mg, 0.5 mmol) and {1-[(t-butoxy)carbonyl]-6-[(t-butyldimethylsilyl)oxy]-1H-indol-2-yl}boronic acid (300 mg, 1.5 equiv.) were dissolved in dioxane (3 mL) in a 20 mL microwave vial. N was bubbled through the solution for 5 minutes, then Pd(dppf)Cl in DCM (20 mg, 5 mol%) was added, followed by 2 M KCO (0.75 mL, 3 equiv.). N was again bubbled through the solution for 5 minutes. The reaction was capped and then placed in a preheated oil bath. The reaction was heated to 90 °C for 1 hour.

[0188] The aqueous fraction was removed from the cooled reaction, and the organic fraction was diluted with ethyl acetate, dried over MgSO4, and then filtered. The solvent was removed in vacuo to give the crude product.

[0189] The crude product was purified by ISCO (25 g silica, DCM applied, eluted with 10-15% ethyl acetate / hexanes over 5 min) to give t-butyl 6-[(t-butyldimethylsilyl)oxy]-2-{2-fluoro-6-[(3R)-3-methoxypiperidin-1-yl]pyridin-3-yl}-1H-indole-1-carboxylate (201 mg foam, 73% yield, HPLC Rf 4.84 min, MS m / z (M+1) 556.3, TLC 20% ethyl acetate / hexanes Rf 0.25).

[0190] Step (iv) t-butyl 2-{2-fluoro-6-[(3R)-3-methoxypiperidin-1-yl]pyridin-3-yl}-6-hydroxy-1H-indole-1-carboxylate

[0191] [ka]

[0192] t-Butyl 6-[(t-butyldimethylsilyl)oxy]-2-{2-fluoro-6-[(3R)-3-methoxypiperidin-1-yl]pyridin-3-yl}-1H-indole-1-carboxylate (201 mg, 0.36 mmol) was dissolved in THF (5 mL), cooled on an ice bath, and 1 M TBAF solution (400 μL, 1.1 equiv.) was added. The reaction was stirred at 0° C. for 10 min.

[0193] The reaction was diluted with ethyl acetate, treated with brine, dried over MgSO4, and filtered. The solvent was removed in vacuo to give the crude product.

[0194] The crude product was purified by ISCO (12 g silica, DCM applied, eluted with 20–35% ethyl acetate / hexanes over 4 min) to give t-butyl 2-{2-fluoro-6-[(3R)-3-methoxypiperidin-1-yl]pyridin-3-yl}-6-hydroxy-1H-indole-1-carboxylate (159 mg film, HPLC 3.63 min, MS m / z (M+1) 442.2, (M−1) 440.2, 99% yield, TLC Rf 30% ethyl acetate / hexanes Rf 0.16).

[0195] Step (v) 2-{2-fluoro-6-[(3R)-3-methoxypiperidin-1-yl]pyridin-3-yl}-1H-indol-6-ol

[0196] [ka]

[0197] In a 5 mL microwave vial, t-butyl 2-{2-fluoro-6-[(3R)-3-methoxypiperidin-1-yl]pyridin-3-yl}-6-hydroxy-1H-indole-1-carboxylate (159 mg, 0.36 mmL) was dissolved in methanol (3 mL), and the reaction was microwaved at 150° C. for 60 minutes.

[0198] A few drops of water were added to the clear solution and the solid was purified by a stream of N to give 2-{2-fluoro-6-[(3R)-3-methoxypiperidin-1-yl]pyridin-3-yl}-1H-indol-6-ol (82 mg solid, HPLC 3.02 min, MS m / z (M+1) 342.3, (M-1) 340.2, 67% yield, TLC Rf 30% ethyl acetate / hexane Rf 0.16).

[0199] Example Compound 5: 2-{2-fluoro-6-[3-methoxypiperidin-1-yl]pyridin-3-yl}-1H-indol-5-ol

[0200] [ka]

[0201] Step (i) 2-fluoro-6-[3-methoxypiperidin-1-yl]pyridine

[0202] [ka]

[0203] 3-Methoxypiperidine (1.1 g, 9.4 mmol) was dissolved in dioxane (8 mL) and 2,6-difluoropyridine (0.95 mL, 1.1 equiv.) was added, followed by Hunig's base (2.4 mL, 1.5 equiv.). The reaction was heated to 100° C. for 4 h.

[0204] The cooled reaction mixture was taken up in ethyl acetate, washed with water, treated with brine, dried over MgSO4, and then filtered. The solvent was removed in vacuo to give a crude oil.

[0205] The crude oil was purified by ISCO (40 g silica, hexane application, elution with 5-20% ethyl acetate / hexane over 5 min) to give 2-fluoro-6-[3-methoxypiperidin-1-yl]pyridine (1.29 g oil, HPLC Rf 2.85 min, 76% yield, MS m / z (M+1) 211.0 (very weak), TLC 10% ethyl acetate / hexane Rf 0.14).

[0206] Step (ii) 3-Bromo-2-fluoro-6-[3-methoxypiperidin-1-yl]pyridine

[0207] [ka]

[0208] 2-Fluoro-6-[3-methoxypiperidin-1-yl]pyridine (1.2 g, 6.1 mmol) was dissolved in acetonitrile (25 mL), cooled on an ice bath, and NBS (1.1 g, 1 equiv.) was added in two portions. The reaction was stirred at 0° C. for 5 min and then at room temperature for 30 min.

[0209] Diethyl ether was added to the mixture, and the solution was washed with water, treated with brine, dried over MgSO4, and then filtered. The solvent was removed in vacuo to give the crude product.

[0210] The crude product was purified by ISCO (40 g silica, hexane / DCM application, elution with 5-15% ethyl acetate / hexane over 3 min) to give 3-bromo-2-fluoro-6-[3-methoxypiperidin-1-yl]pyridine (1.62 g oil, HPLC Rf 3.31 min, 92% yield, MS m / z (M+1) 288.9, 290.9, TLC 20% ethyl acetate / hexane Rf 0.19).

[0211] Step (iii) t-butyl 5-[(t-butyldimethylsilyl)oxy]-2-{2-fluoro-6-[3-methoxypiperidin-1-yl]pyridin-3-yl}-1H-indole-1-carboxylate

[0212] [ka]

[0213] 3-Bromo-2-fluoro-6-[3-methoxypiperidin-1-yl]pyridine (145 mg, 0.5 mmol) and {1-[(t-butoxy)carbonyl]-5-[(t-butyldimethylsilyl)oxy]-1H-indol-2-yl}boronic acid (235 mg, 1.2 equiv.) were dissolved in dioxane (3 mL) in a 5 mL microwave vial. N was bubbled through the solution for 1.5 minutes, then Pd(dppf)Cl in DCM (20 mg, 5 mol%) was added, followed by 2 M KCO (0.75 mL, 3 equiv.). N was again bubbled through the solution for 5 minutes, the cap was removed, and the mixture was placed in a preheated oil bath. The reaction was heated to 90 °C for 1 hour.

[0214] The aqueous fraction was removed from the cooled reaction, and the organic fraction was diluted with ethyl acetate, dried over MgSO4, and then filtered. The solvent was removed in vacuo to give the crude product.

[0215] The crude product was purified by ISCO (25 g silica, DCM applied, eluted with 5-15% ethyl acetate / hexanes over 6 min) to give t-butyl 5-[(t-butyldimethylsilyl)oxy]-2-{2-fluoro-6-[3-methoxypiperidin-1-yl]pyridin-3-yl}-1H-indole-1-carboxylate (260 mg foam, 94% yield, HPLC Rf 4.42 min, MS m / z (M+1) 556.3, TLC 20% ethyl acetate / hexanes Rf 0.22).

[0216] Step (iv) t-butyl 2-{2-fluoro-6-[3-methoxypiperidin-1-yl]pyridin-3-yl}-5-hydroxy-1H-indole-1-carboxylate

[0217] [ka]

[0218] t-Butyl 5-[(t-butyldimethylsilyl)oxy]-2-{2-fluoro-6-[3-methoxypiperidin-1-yl]pyridin-3-yl}-1H-indole-1-carboxylate (260 mg, 0.47 mmol) was dissolved in THF (7 mL), cooled on an ice bath, and 1 M TBAF solution (0.51 mL, 1.1 equiv.) was added. The reaction was stirred at 0° C. for 10 min.

[0219] The reaction was diluted with ethyl acetate, treated with brine, dried over MgSO4, and filtered. The solvent was removed in vacuo to give the crude product.

[0220] The crude product was purified by ISCO (12 g silica, DCM applied, eluted with 20–35% ethyl acetate / hexanes over 5 min) to give t-butyl 2-{2-fluoro-6-[3-methoxypiperidin-1-yl]pyridin-3-yl}-5-hydroxy-1H-indole-1-carboxylate (204 mg oil, HPLC 3.46 min, MS m / z (M+1) 442.1, (M−1) 440.2, 99% yield, TLC Rf 50% ethyl acetate / hexanes Rf 0.49).

[0221] Step (v) 2-{2-fluoro-6-[3-methoxypiperidin-1-yl]pyridin-3-yl}-1H-indol-5-ol

[0222] [ka]

[0223] In a 5 mL microwave vial, t-butyl 2-{2-fluoro-6-[3-methoxypiperidin-1-yl]pyridin-3-yl}-5-hydroxy-1H-indole-1-carboxylate (204 mg, 0.46 mmL) was dissolved in methanol (5 mL), and the reaction was microwaved at 150° C. for 90 minutes.

[0224] A solid crystallized from the solution and was filtered off to give 2-{2-fluoro-6-[3-methoxypiperidin-1-yl]pyridin-3-yl}-1H-indol-5-ol (55 mg solid, HPLC 2.90 min, MS m / z (M+1) 342.1, (M-1) 340.0, 35% yield).

[0225] Example Compound 6: 2-{2-fluoro-6-[(3S)-3-( 3 H3) Methoxypiperidin-1-yl]pyridin-3-yl}-1H-indol-5-ol

[0226] [ka]

[0227] Step (i) t-butyl 5-hydroxy-2-{6-[(3S)-3-methoxypiperidin-1-yl]-2-nitropyridin-3-yl}-1H-indole-1-carboxylate

[0228] [ka]

[0229] To t-butyl (3S)-3-hydroxypiperidine-1-carboxylate (2.1 mg, 10.4 μmol) dissolved in DMF (0.5 mL) was added a 60% paraffin dispersion of sodium hydride (spatula tip), and the reaction was stirred at room temperature for 20 minutes. To this solution was added iodine ( 3 H3) Methane (74 mCi) was added and the reaction was stirred overnight.

[0230] The reaction was quenched with ammonium chloride solution, extracted with ethyl acetate, dried over sodium sulfate, filtered, and the solvent removed by a stream of N2.

[0231] The intermediate was purified on a silica column (Pasteur pipette), eluted with ethyl acetate / hexane 1:3, fractions containing activity were collected and the solvent was removed by a stream of N2.

[0232] The product was dissolved in dioxane (0.5 mL), cooled on an ice bath, and 4 M HCl in dioxane (0.5 mL) was added. The reaction was stirred at room temperature for 1 hour and then at 45° C. for 30 minutes. The solvent was removed by a stream of N to give (3S)-3-( 3 H3) Methoxypiperidine HCl was obtained, which was used directly in the next reaction.

[0233] Step (ii) 2-{2-fluoro-4-[(3S)-3-( 3 H3) Methoxypiperidin-1-yl]phenyl}-1H-indol-5-ol

[0234] [ka]

[0235] (3S)-3-( 3 H3) Methoxypiperidine HCl (from the above reaction) was dissolved in methanol (0.5 mL). To the solution was added t-butyl 2-(2,6-difluoropyridin-3-yl)-5-hydroxy-1H-indole-1-carboxylate (3.8 mg, 11 μmol, for preparation see WO2021074351(A1)) and Hunig's base (10 μL, excess), and the reaction was microwaved at 150° C. for 60 minutes.

[0236] The cooled reaction was evaporated and the residue was purified by HPLC (Kromasil C18, 250 x 10 mm, eluted with 70% acetonitrile in 0.1% TFA) to give 2-{2-fluoro-4-[(3S)-3-( 3H3) Methoxypiperidin-1-yl]phenyl}-1H-indol-5-ol (radiochemical concentration 71 MBq (1.9 mCi), molar activity 2.61 TBq / mmol (70 Ci, mmol), MS m / z (M+1) 348) was obtained.

[0237] Example Compound 7: 2-[2-( 18 F) Fluoro-6-[(3S)-3-methoxypiperidin-1-yl]pyridin-3-yl]-1H-indol-5-ol

[0238] [ka]

[0239] Step (i) 2-[(3S)-3-methoxypiperidin-1-yl]-6-nitropyridine

[0240] [ka]

[0241] 2-Chloro-6-nitropyridine (0.63 g, 4 mmol) and (S)-3-methoxypiperidine HCl (0.9 g, 1.5 equiv.) were slurried in dioxane (6 mL), followed by the addition of Hunig's base (2.9 mL, 1.5 equiv.), and the reaction was heated to 100° C. for 19 h.

[0242] The cooled reaction mixture was taken up in ethyl acetate, washed with water, treated with brine, dried over MgSO4, filtered, and the solvent was removed in vacuo to give a crude oil.

[0243] The crude product was purified by ISCO (40 g silica, hexane application, elution with 15–30% ethyl acetate / hexane over 8 min) to give 2-[(3S)-3-methoxypiperidin-1-yl]-6-nitropyridine (0.63 g oil, HPLC Rf 2.91 min, 67% yield, MS m / z (M+1) 238.2 (very weak), TLC 30% ethyl acetate / hexane Rf 0.22).

[0244] Step (ii) 3-bromo-6-[(3S)-3-methoxypiperidin-1-yl]-2-nitropyridine

[0245] [ka]

[0246] 2-[(3S)-3-Methoxypiperidin-1-yl]-6-nitropyridine (0.61 g, 2.6 mmol) was dissolved in acetonitrile (15 mL), cooled on an ice bath, and NBS (0.65 g, 1 equiv.) was added. The reaction was stirred at 0° C. for 5 min and then at room temperature for 60 min.

[0247] The reaction was taken up in ethyl acetate, treated twice with brine, dried over MgSO4, filtered, and the solvent was removed in vacuo to give the crude product.

[0248] The crude product was purified by ISCO (40 g silica, hexane / DCM application, elution with 15-30% ethyl acetate / hexane over 6 min) to give 3-bromo-6-[(3S)-3-methoxypiperidin-1-yl]-2-nitropyridine (0.74 g oil, HPLC Rf 3.27 min, 91% yield, MS m / z (M+1) 316.0, 318.0, TLC 60% ethyl acetate / hexane Rf 0.30).

[0249] Step (iii) t-butyl 5-[(t-butyldimethylsilyl)oxy]-2-{6-[(3S)-3-methoxypiperidin-1-yl]-2-nitropyridin-3-yl}-1H-indole-1-carboxylate

[0250] [ka]

[0251] 3-Bromo-6-[(3S)-3-methoxypiperidin-1-yl]-2-nitropyridine (316 mg, 1 mmol) and {1-[(t-butoxy)carbonyl]-5-[(t-butyldimethylsilyl)oxy]-1H-indol-2-yl}boronic acid (550 mg, 1.4 equiv.) were dissolved in dioxane (6 mL) in a 20 mL microwave vial. N was bubbled through the solution for 2 minutes, then Pd(dppf)Cl in DCM (41 mg, 5 mol%) was added, followed by 2 M KCO (31.5 mL, 3 equiv.). The solution was again bubbled with N for 5 minutes, capped, and then placed in a preheated oil bath. The reaction was operated at 90 °C for 1 hour.

[0252] The aqueous phase was removed from the cooled reaction mixture, after which the reaction mixture was diluted with ethyl acetate, dried over MgSO4, filtered, and the solvent removed in vacuo to give the crude product.

[0253] The crude product was purified by ISCO (40 g silica, DCM applied, eluted with 10–20% ethyl acetate / hexanes over 6 min) to give t-butyl 5-[(t-butyldimethylsilyl)oxy]-2-{6-[(3S)-3-methoxypiperidin-1-yl]-2-nitropyridin-3-yl}-1H-indole-1-carboxylate (334 mg foam, 57% yield, HPLC Rf 4.37 min, MS m / z (M+1) 583.4, TLC 20% ethyl acetate / hexanes Rf 0.16). 1 H NMR(400MHz,CDCI3)δ7.70(d,J=9.0Hz,1H),6.72(d,J=9.0Hz,1H),3.85(ddt,J=13.2,3.4,1.1Hz,1H),3.68(ddd,J=13.3,6.6,3.8Hz, 1H),3.52-3.31(m,6H),2.05-1.94(m,1H),1.88(ddp,J=14.2,7.3,3.6Hz,1H),1.69(ddt,J=12.8,8.7,3.9Hz,1H),1.61-1.48(m,1H). 13C NMR (101MHz, CDCI3) δ156.28,144.12,110.93,93.14,77.36,77.04,76.73,74.58,56.40,48.46,45.43,29.58,21.80. )

[0254] Step (iv) t-butyl 5-hydroxy-2-{6-[(3S)-3-methoxypiperidin-1-yl]-2-nitropyridin-3-yl}-1H-indole-1-carboxylate

[0255] [ka]

[0256] t-Butyl 5-[(t-butyldimethylsilyl)oxy]-2-{6-[(3S)-3-methoxypiperidin-1-yl]-2-nitropyridin-3-yl}-1H-indole-1-carboxylate (236 g, 0.40 mmol) was dissolved in THF (7 mL), cooled on an ice bath, and 1 M TBAF solution (450 μL, 1.1 equiv.) was added. The reaction was stirred at 0° C. for 10 min.

[0257] The reaction was diluted with ethyl acetate, treated with brine, dried over MgSO4, and filtered. The solvent was removed in vacuo to give the crude product.

[0258] The crude product was purified by ISCO (12 g silica, applied DCM, eluted with 25–40% ethyl acetate / hexanes over 5 min) to give t-butyl 5-hydroxy-2-{6-[(3S)-3-methoxypiperidin-1-yl]-2-nitropyridin-3-yl}-1H-indole-1-carboxylate (142 mg film, HPLC 3.43 min, MS m / z (M+1) 469.3, (M−1) 467.3, 75% yield, TLC Rf 40% ethyl acetate / hexanes Rf 0.16). 1H NMR(400MHz,CDCl3)δ8.03(d,J=8.9Hz,1H),7.56(d,J=8.6Hz,1H),6.91(d,J=2.5Hz,1H),6.88-6.81(m, 2H),6.35(d,J=0.7Hz,1H),3.95(dd,J=13.3,3.3Hz,1H),3.76(ddd,J=13.4,6.5,3.8Hz,1H),3.56(dd,J= 13.3,7.2Hz,1H),3.42(s,4H),3.37(tt,J=7.2,3.5Hz,1H),2.00(dq,J=11.6,3.6Hz,1H),1.88(dtt,J=13 .9,7.1,3.6Hz,1H),1.69(dtd,J=12.5,8.2,3.7Hz,1H),1.55(ddt,J=15.2,8.8,4.1Hz,1H),1.39(s,9H).

[0259] 13 C NMR(101MHz,CDCI3)δ156.82,151.78,149.82,142.77,134.69,131.55,130.02,116.72,113.52,111.46 ,110.10,109.35,105.52,83.70,77.36,77.04,76.72,74.81,56.41,48.38,45.46,29.85,27.80,21.99. )

[0260] Process (v)2-[2-( 18 F) Fluoro-6-[(3S)-3-methoxypiperidin-1-yl]pyridin-3-yl]-1H-indol-5-ol

[0261] [ka]

[0262] Non-carrier added 18 F]F - of, 18 O(p,n) 18 Generated via the F reaction (Scanditronix MC-17 cyclotron), [ 18O] in water and transferred to an automated radiosynthesizer (GE Tracerlab FX2N) in a lead-shielded hot cell. 18 F]F - The product was captured on a PS-HCO ion exchange column (Chromafix) and then eluted into a reaction vessel with KCO (1.37 mg, 10 μmol) and Kryptofix 2.2.2 (14 mg, 5 μmol) in water / methanol (10 / 90, 1 mL). The solvent was evaporated under vacuum and subsequently azeotropically dried with acetonitrile (1 mL) under a continuous stream of nitrogen. The precursor tert-butyl (S)-5-hydroxy-2-(6-(3-methoxypiperidin-1-yl)-2-nitropyridin-3-yl)-1H-indole-1-carboxylate (3 mg, 6.4 μmol) in DMSO (1 mL) was added, and the reactor was heated to 160 °C for 20 min. The reactor was cooled to 70 °C, methanol (2 mL) was added, and then the reaction vessel was heated to 130 °C for 20 min. The reactor was then cooled to 50°C, and the reaction mixture was diluted with acetonitrile:water (20:80) before being injected onto a reverse-phase HPLC column (LUNA 10 μm C18(2) 100 Å, 250 mm × 10 mm, Phenomenex). 18 F) Fluoro-6-[(3S)-3-methoxypiperidin-1-yl]pyridin-3-yl]-1H-indol-5-ol in acetonitrile-NH4CO2H aq Elution was carried out at a flow rate of 5 mL / min using a mobile phase of 2-[2-( 18 The retention time of F) fluoro-6-[(3S)-3-methoxypiperidin-1-yl]pyridin-3-yl]-1H-indol-5-ol was 14–16 min. The collected fractions were diluted with water (20 mL) and loaded onto a solid phase extraction (SPE) column (SepPak tC18, Waters). After washing the SPE column with water (10 mL), 2-[2-( 18F) Fluoro-6-[(3S)-3-methoxypiperidin-1-yl]pyridin-3-yl]-1H-indol-5-ol was eluted with ethanol (1 mL) and mixed with sterile saline (9 mL). Purity and molar activity were determined by reverse-phase HPLC (InfinityLab Poroshell 120 PFP, 4.6 × 150 mm, 2.7 μm, Agilent) with UV and gamma detectors in series. 2-[2-( 18 F) Fluoro-6-[(3S)-3-methoxypiperidin-1-yl]pyridin-3-yl]-1H-indol-5-ol was eluted with acetonitrile-NH4CO2H (0.05 M) (50 / 50, v / v) at a flow rate of 3 mL / min (retention time = 4.3-4.5 min). Radiochemical identity was confirmed by co-injection of an authentic sample of 2-{2-fluoro-6-[(3S)-3-methoxypiperidin-1-yl]pyridin-3-yl}-1H-indol-5-ol (Example Compound 1).

[0263] A summary of the structures of example compounds 1-7 and the CLogP of the compounds are provided in Table 1 below.

[0264] [Table 1]

[0265] Biological Testing Example (a): Biological Assay Methods and Results 3 H-THK5117 competitive binding to tau fibrils in vitro Preparation of recombinant 0N4R tau fibrils was performed as previously described in Morozova, OA, Biochemistry (2013), Vol., 52(40), pages 6960-6967. Competitive binding experiments against 0N4R tau fibrils were performed using increasing concentrations of [10 -10 ~10 -6M] Example compounds of the present invention, or known tau-specific ligand PBB3 (PBB3 was synthesized as previously described in M. Maruyama, et al., Neuron 2013, 79, 1094-1108) or MK6240 (Novandi Chemistry AB) were incubated with 3 nM of known tau ligand [ 3 The cells were incubated in the dark for 1 hour at 22°C in the presence of [H]-THK5117 (Novandi Chemistry) and 0.2 mM ON4R tau fibrils. The incubation was terminated by filtration through Whatman GF / B glass filters (Whatman International, Kent, UK) using a Brandel cell harvester. The filters were then rapidly washed four times with 3 mL of ice-cold wash buffer (5 mM Tris-HCl, 0.25 mM NaCl, 5% EtOH) and equilibrated for 1 hour in scintillation vials containing 5 mL of Ultima Gold scintillation fluid before analysis using a liquid scintillation analyzer.

[0266] The results are shown in Table 2, "Tau IC 50 For compounds that were subjected to competitive binding experiments more than once, the tau IC 50 Values ​​are the average of the results from each experiment.

[0267] Biological assay results

[0268] [Table 2]

[0269] The results in Table 2 show that the example compounds of the present invention have high affinity binding to recombinant 4R tau fibrils.

[0270] Example (b): Intravenous (IV) Pharmacokinetic Study of Example Compound 1 and Comparative Compound 1 in Mice with Bioanalysis Pharmacokinetic studies of plasma and brain exposure in mice after IV administration of Example Compound 1 or Comparative Compound 1 were carried out according to the protocol described in Loryan, I., et al., Pharm Res (2014) 31: 2203-2219. Comparative Compound 1 is 2-{2-fluoro-6-[4-(hydroxymethyl)piperidin-1-yl]pyridin-3-yl}-1H-indol-5-ol, which has the following structure:

[0271] [ka]

[0272] Comparative Example Compound 1 is Example Compound No. 48 disclosed in WO 2019 / 197502(A1) and was synthesized as described in that document.

[0273] Experimental Protocol and Bioanalysis Plasma and brain exposure in mice was measured according to the experimental protocol and bioanalysis described in Loryan, I., et al., Pharm Res (2014) 31:2203-2219. Table 3 below provides additional information regarding specific details of the mice, sampling, doses, formulations, methods, and experiments, and Table 4 below provides further information regarding sampling in the experiments. As can be seen in Table 4, n=3 mice per time point.

[0274] [Table 3]

[0275] [Table 4]

[0276] result No adverse events were observed in the mice during the study. Tables 5 and 6 below show a summary of the pharmacokinetic (PK) parameters measured for Example Compound 1 in plasma (Table 5) and brain (Table 6) after IV administration of Example Compound 1 at 1 mg / kg (mean, n=3).

[0277] [Table 5]

[0278] [Table 6]

[0279] Table 7 below shows the AUC in brain and plasma for total and unbound concentrations of Example Compound 1 and Comparative Example Compound 1, as well as the corresponding brain:plasma ratio for each compound.

[0280] [Table 7]

[0281] The total plasma and brain concentration versus time profiles following IV administration of Example Compound 1 are shown in FIG.

[0282] The data show that Example Compound 1 readily enters the brain after IV administration and is excreted with an elimination half-life of approximately 0.3 hours.

[0283] The total and unbound concentrations, and the brain:plasma ratio show that the unbound AUC in the brain of Comparative Example Compound 1 is only about 0.2% of the corresponding plasma AUC, indicating that the compound has limited brain penetration ability. In contrast, the unbound AUC of Example Compound 1 in the brain is about 56% of the plasma AUC. This indicates that Example Compound 1 has good brain penetration ability.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt, ester, or carbamate thereof, or a salt of such an ester or carbamate: 【Chemistry 1】 wherein R １ is OH and R ２ is H, or R １ is H and R ２ is OH, or a pharmaceutically acceptable salt, ester, or carbamate thereof, or a salt of such an ester or carbamate.

2. 2. The compound of claim 1, wherein the compound is a compound of formula (Ia) or (Ib). 【Chemistry 2】

3. 3. The compound of claim 1 or 2, wherein the compound has a structural formula selected from the group consisting of: 【Transformation 3】

4. The compound is ３ H. １１ C. １３ C. １４ C. １３ N. １５ O. １８ F and １９ 4. The compound of claim 1, comprising one or more radioisotopes selected from F.

5. The compound is １８ F and ３ 5. The compound of claim 4, comprising one or more radioisotopes selected from H.

6. 6. The compound of claim 5, wherein the compound has a structural formula selected from the group consisting of: 【Chemistry 4】

7. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6 together with a pharmaceutically suitable carrier.

8. 8. The pharmaceutical composition of claim 7, wherein the compound contains an additional active ingredient.

9. 9. The pharmaceutical composition of claim 8, wherein the additional active ingredient is an additional therapeutic agent or an additional diagnostic agent.

10. The compound is ３ H. １１ C. １３ C. １４ C. １３ N. １５ O. １８ F and １９ A compound according to any one of claims 1 to 6 or a composition according to any one of claims 7 to 9 for use as a diagnostic agent, comprising one or more radioisotopes selected from F.

11. Use of a compound according to any one of claims 1 to 6 for the detection of tau deposits.

12. Alzheimer's disease, corticobasal degeneration, Pick's disease, progressive supranuclear palsy, Parkinson's disease, Creutzfeldt-Jakob disease, familial Alzheimer's disease, argyrophilic granule disease, prion protein cerebral amyloid angiopathy, traumatic brain injury, amyotrophic lateral sclerosis, frontotemporal dementia and parkinsonism linked to chromosome 17, postencephalitic parkinsonism, Guadeloupe-type parkinsonism, glial microglobular tauopathy, age-related tau astrogliopathy, Guam-type parkinsonism-dementia complex, Niemann-Pick disease type C, myotonic dystrophy, inclusion body myositis, chronic traumatic encephalopathy, Down syndrome, Gerstmann-Straussler-Scheinker syndrome, British dementia, familial Danish dementia, dementia pugilistica, neurofibrillary tangle-predominant senile dementia, Huntington's disease, Lewy body disease, prion disease, subacute sclerosing panencephalitis, subacute sclerosing panencephalitis, diffuse neurofibrillary tangle disease with calcifications, neurodegeneration with cerebral iron accumulation, mutations affecting sodium / proton exchange, cerebrotendinous xanthomatosis with a C.379C>T (p.R127W) mutation in the CYP27A1 gene, TARDBP mutations associated with semantic dementia p.

11. The compound of any one of claims 1 to 6 or 10, or the composition of any one of claims 7 to 10, for use as a diagnostic agent in the diagnosis or monitoring the progression of a disease or disorder selected from the group consisting of Ile383Val, non-Guam human motor neuron disease with neurofibrillary tangles, argyrophilic grain disease, Hallervorden-Spatz disease, multiple system atrophy, pallido-pontine-nigral degeneration, progressive subcortical gliosis, dementia with neurofibrillary tangles, myotonic dystrophy, taupanene cephalopathy, AD-like with astrocytic cells, Gerstmann-Straussler-Scheinker with tau, mutations in LRRK2, SLC9A6-associated mental retardation, and white matter tauopathy with glial microspherical inclusions.

13. 10. A method of diagnosing a patient or monitoring disease progression in a patient, comprising administering to said patient a compound according to any one of claims 1 to 6 or a composition according to any one of claims 7 to 9.

14. The compound is ３ H. １１ C. １３ C. １４ C. １３ N. １５ O. １８ F and １９ 14. The method of diagnosing a patient or monitoring disease progression in a patient according to claim 13, comprising one or more radioisotopes selected from F.

15. 15. A method of diagnosis or progression monitoring according to claim 13 or 14, further comprising detecting said compound, for example using positron emission tomography.

16. A compound according to any one of claims 1 to 6 or a composition according to any one of claims 7 to 9 for use as a medicament.

17. Alzheimer's disease, corticobasal degeneration, Pick's disease, progressive supranuclear palsy, Parkinson's disease, Creutzfeldt-Jakob disease, familial Alzheimer's disease, argyrophilic granule disease, prion protein cerebral amyloid angiopathy, traumatic brain injury, amyotrophic lateral sclerosis, frontotemporal dementia and parkinsonism linked to chromosome 17, postencephalitic parkinsonism, Guadeloupe-type parkinsonism, glial microglobular tauopathy, age-related tau astrogliopathy, Guam-type parkinsonism-dementia complex, Niemann-Pick disease type C, myotonic dystrophy, inclusion body myositis, chronic traumatic encephalopathy, Down syndrome, Gerstmann-Straussler-Scheinker syndrome, British dementia, familial Danish dementia, dementia pugilistica, neurofibrillary tangle-predominant senile dementia, Huntington's disease, Lewy body disease, prion disease, subacute sclerosing panencephalitis, subacute sclerosing panencephalitis, diffuse neurofibrillary tangle disease with calcifications, neurodegeneration with cerebral iron accumulation, mutations affecting sodium / proton exchange, cerebrotendinous xanthomatosis with the c.379C>T (p.R127W) mutation in the CYP27A1 gene, TARDBP mutations p.

17. The compound or composition of claim 16 for use in the prevention or treatment of a disease or disorder selected from the group consisting of Ile383VaI, non-Guam human motor neuron disease with neurofibrillary tangles, argyrophilic grain disease, Hallervorden-Spatz disease, multiple system atrophy, pallido-pontine-nigral degeneration, progressive subcortical gliosis, dementia with neurofibrillary tangles, myotonic dystrophy, taupanene cephalopathy, AD-like with astrocytic disease, Gerstmann-Straussler-Scheinker with tau, mutations in LRRK2, SLC9A6-associated mental retardation, and white matter tauopathy with glial microspherical inclusions.

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