Selective ligands for tau aggregates

Abstract

The present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, ester or carbamate thereof, or a salt of such an ester or carbamate wherein: R1 is OH and R2 is H; or R1 is H, and R2 is OH. The invention also provides uses of compounds of formula (I) and compositions comprising compounds of formula (I), including uses of such compounds for detecting tau deposits, and the use of such compounds and compositions as diagnostic agents in the diagnosis or monitoring of the progression of diseases or disorders such as Alzheimer's disease, progressive suprakaryotic paralysis and corticobasal node degeneration, or for the prevention or treatment of diseases or disorders such as Alzheimer's disease, progressive suprakaryotic paralysis and corticobasal node degeneration. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to compounds of formula (I) and compositions comprising compounds of formula (I). The compounds of the present invention can be used for the diagnosis and treatment of neurodegenerative diseases, and in particular tauopathies, such as Alzheimer's disease. Background Art

[0002] Alzheimer's disease is a neurodegenerative disorder that causes symptoms including: memory loss, difficulties with thinking, problem-solving, speech and / or language, personality changes, hallucinations, delusions, low mood, and anxiety. Alzheimer's disease is the most common cause of dementia. Alzheimer's disease is a progressive disease, and over time, more symptoms appear and the symptoms become more severe.

[0003] Protein deposits are pathological hallmarks of a wide range of neurodegenerative diseases (C.A. Ross, M.A. Poirier, Nat. Med. 2004, 10, 10–17), which include Alzheimer's disease and corticobasal degeneration. Small hydrophobic ligands have been developed that are selective for protein aggregates with a wide cross-β-sheet conformation and sufficient structural regularity. The most common ligands are derivatives of Congo red or thioflavin, and various other molecular scaffolds have also been reported (K.P.R. Nilsson, FEBS Lett. 2009, 583, 2593-2599). However, most of these ligands can generally only detect disease-related protein aggregates, and the ligands cannot detect specific disease-related protein aggregates composed of different proteins.

[0004] The microtubule-associated protein tau is a 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 variety of disorders (collectively referred to as tauopathies). Tauopathies include more than 20 disorders, including Alzheimer's disease, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and Pick's disease. Although the dysfunction of tau has clearly been shown to be able to cause neurodegeneration, the exact mechanism by which tau is involved in neurodegenerative disorders is still not well understood. According to current emerging cell biological concepts, tau may play a role in the regulation of neuronal plasticity in a large number of neuronal networks. In addition, it may be involved in the regulation of genomic stability (Arendt, T., et al., Brain Research Bulletin, 2016, 126, 238-292).

[0005] In Alzheimer's disease, two major proteinaceous deposits are extracellular senile plaques composed of aggregated β-amyloid (Aβ) peptides and intracellular 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). 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 aggregates to the complex molecular pathology in the Alzheimer's disease brain. Molecular scaffolds have been proposed for visualizing Aβ deposits in individuals 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 that target other pathological hallmarks (tau deposits) in Alzheimer's disease have also been identified (G. W. Small, et al., N. Engl. J. Med. 2006, 355, 2652–2663; Taghavi, et al., Alzheimers Dis. 2011, 27, 835-843; M. T. 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 AlzheimersDement. 2013, 9, 666–676).

[0006] Luminescent conjugated oligothiophenes (LCOs) have been used for fluorescence imaging of protein aggregates. Compared with conventional ligands, LCOs have been shown to detect a broader range of disease-related protein aggregates (A. 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). In addition, LCOs with different chemical compositions can be used for spectral evaluation 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 tetramer ligand q - FTAA - CN was identified, which has a significantly higher affinity for Aβ deposits compared to aggregates composed of tau (M. et al., Chemistry. 2016, 22, 18335 - 18338).

[0007]

[0008] PBB3 is also known to be a tau - specific ligand (M. Maruyama, et al., Neuron 2013, 79, 1094 - 1108).

[0009]

[0010] MK6240 is also known to be a tau - specific ligand (E. D. Hostetler, et al., J Nucl Med 2016, 57, 1599 - 1606).

[0011]

[0012] However, different morphotypes of Aβ and tau aggregates have been reported (C.L. Maarouf, et al., Mol. Neurodegener. 2008, 3, 20; H. Levine, L.C. 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 proposed to explain the heterogeneous phenotypes reported for several neurodegenerative protein aggregation diseases. Thus, multiple ligands are needed to achieve an accurate assessment of the diversity of pathological protein deposits present in neurodegenerative diseases such as Alzheimer's disease. Accordingly, there is a need to develop additional small molecule ligands that target specific disease-related protein aggregates in individuals with Alzheimer's disease (and other tauopathies), and in particular additional molecular scaffolds that enable visualization of tau deposits.

[0013] In addition, the known tau-specific ligand PBB3 has been reported to have the significant drawback of undergoing photoisomerization when exposed to fluorescence (Hashimoto, H., et al., J Nucl Med (2014), Vol. 55, No. 9, pp. 1532-1538). Hashimoto et al. reported that 11 at 1 min after a sample of [11C]-PBB3 was exposed to fluorescence, 11 the radiochemical purity of [11C]-PBB3 decreased to 77%, and at 10 min to 60 min, the radiochemical purity was approximately 50%. Hashimoto et al. also reported that the 11 isomers of [11C]-PBB3 exhibited much less specific binding to tau in brain slices from Alzheimer's disease patients. This property makes it difficult to synthesize, radiolabel, store, and handle PBB3. This limits the utility of this tau ligand in in vitro experiments and in vivo acquisitions (Saint-Aubert, L., et al., Molecular Neurodegeneration (2017), Vol. 12, No. 9: Tau PET imaging: present and future directions). SUMMARY OF THE INVENTION

[0014] The present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, ester, or carbamate thereof, or a salt of such an ester or carbamate,

[0015]

[0016] Wherein:

[0017] R 1 is OH, and R 2 is H; or

[0018] R 1 is H, and R 2 is OH.

[0019] The present invention also provides a pharmaceutical composition, which comprises a compound of formula (I) and a pharmaceutically suitable carrier.

[0020] The present invention also provides a compound of formula (I) or a composition comprising a compound of formula (I) for use as a diagnostic agent, wherein the compound of formula (I) comprises one or more radioisotopes selected from the following: 3 H, 11 C, 13 C, 14 C, 13 N, 15 O, 18 F and 19 F.

[0021] The present invention also provides the use of a compound of formula (I) for detecting tau deposits.

[0022] The present invention also provides 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: Alzheimer's disease, corticobasal degeneration, Pick's disease, progressive supranuclear palsy, 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 with parkinsonism linked to chromosome 17, postencephalitic parkinsonism, Guadeloupean-type parkinsonism, globular glial 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-type dementia, familial Danish dementia, pugilistic dementia, tangle-predominant dementia, Huntington's disease, Lewy body disorder, prion disease, subacute sclerosing panencephalitis, subacute sclerosing panencephalitis, diffuse neurofibrillary tangles with calcification, neurodegeneration with brain iron accumulation, mutations affecting sodium / proton exchanger, 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 grain disease, Hallervorden-Spatz disease, multiple system atrophy, pallidopontine nigral degeneration, progressive subcortical gliosis, tangle-only dementia, myotonic dystrophy, tau panencephalopathy, AD-like with astrocytes, Gerstmann-Straussler-Scheinker disease regarding tau, mutations in LRRK2, SLC9A6-related mental retardation, and white matter tauopathy with globular glial inclusions.

[0023] The present invention also provides a method for diagnosing a patient or monitoring the progression of a disease in a patient, the method comprising administering to the patient a compound of formula (I) or a composition comprising a compound of formula (I).

[0024] The present invention also provides a compound of formula (I) or a composition comprising a compound of formula (I) for use as a medicament. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 Shows the concentration of Example Compound 1 in plasma and brain of mice (NMRI, male, mean n = 3 / time point) after administration of Example Compound 1 at 1 mg / kg IV. DETAILED DESCRIPTION

[0026] The compounds of formula (I) (also referred to herein as the compounds of the present invention) have excellent binding affinity for tau deposits. The compounds of the present invention are also selective tau deposit ligands, i.e., in addition to having excellent binding affinity for tau deposits, the compounds preferentially bind to tau deposits over β-amyloid (Aβ) deposits.

[0027] Furthermore, the compounds of the present invention are not photosensitive because they do not have photoisomerizable double bonds in their structures. Thus, 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 feasibly used in in vitro experiments and in vivo acquisitions.

[0028] Another advantage of the compounds of the present invention is that the compounds bind to the four-repeat (4R) isoform 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 diagnosing and / or treating or preventing conditions associated with the 4R form of tau, such as Alzheimer's disease, progressive supranuclear palsy, and corticobasal degeneration.

[0029] Another advantage of the compounds of the present invention is that the compounds are expected to have low binding affinity for MAO enzymes in the human brain. As reported by Murugan, N.A. et al., Eur J Nucl Med Mol Imaging. (2019) doi:10.1007 / s00259-019-04305-8, the brain regions with the highest concentration of MAO-B overlap with the regions of tau proteinopathy in tauopathies such as CBD and PSP. Thus, off-target binding of tau deposit ligands to MAO is not desirable because such off-target effects 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 aggregation in the brain and thus have good specificity and sensitivity when used as in vivo tau imaging agents in all tauopathies, including CBD and PSP.

[0030] The compounds of the present invention cross the blood-brain barrier to a greater extent than previously disclosed compounds with similar properties, and furthermore, once they cross the blood-brain barrier, they are well distributed throughout the brain.

[0031] Isotope forms (e.g., where a hydrogen atom is replaced by deuterium ( 2 H) or tritium ( 3 H), or a carbon atom is replaced by 13 C atoms, or a fluorine atom is replaced by 18Substitutions with F atoms are included within the present invention. Certain isotopic forms may have beneficial biological properties, such as improved metabolic stability or enhanced therapeutic activity compared to other isotopic forms. Some specific isotopic forms can be used for bioimaging purposes, such as 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.

[0032] The present invention provides compounds of formula (I):

[0033]

[0034] Wherein:

[0035] R 1 is OH, and R 2 is H; or

[0036] R 1 is H, and R 2 is OH.

[0037] The compounds of formula (I) can be compounds of formula (Ia) or compounds of formula (Ib):

[0038]

[0039] Preferably, the compounds of formula (I) have a structural formula selected from the group consisting of:

[0040]

[0041] In the compounds of the present invention, one or more atoms in the atoms can be isotopes. In the compounds of the present invention, one or more atoms in the atoms can be radiolabeled atoms (which can also be referred to as radioactive isotopes), for example, one, two, or three atoms in the atoms can be radiolabeled atoms. In particular, R 1 , R 2 , the fluoropyridine ring and / or one or more atoms in the atoms of the -O-CH3 substituent of the piperidine ring can be radiolabeled atoms. The radiolabeled atoms can be selected from the group consisting of: 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 F. For example, one or more H atoms of R 1 , R 2 , the fluoro-pyridine ring and / or the -O-CH3 substituent of the piperidine ring can be 3 H atoms, and in particular, one or more (e.g., one, two or three) H atoms of the H atoms of the -O-CH3 substituent of the piperidine ring can be 3 H atoms. Alternatively or in addition, for example, the F atom of the fluoro-pyridine ring can be 18 F atom or 19 F atom, and is preferably 18 F atom.

[0042] The compounds of the present invention can form esters, carbamates and / or salts. The salts of the compounds of the present invention suitable for use in medicine are those in which the counterion is pharmaceutically acceptable. However, salts with non-pharmaceutically acceptable counterions are within the scope of the present invention, for example, used as intermediates for preparing the compounds of the present invention and their pharmaceutically acceptable salts and physiological function derivatives. The term "physiological function derivative" means a chemical derivative of a compound of the present invention having the same physiological function as the free compound of the present invention, for example, formed by being convertible in vivo. Esters and carbamates are examples of physiological function derivatives.

[0043] Suitable salts according to the invention include salts formed from organic or inorganic acids or bases. In particular, suitable salts formed with acids include salts formed with mineral acids, strong organic carboxylic acids (such as alkanoic acids having 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, such as amino acids) or with organic sulfonic acids (such as unsubstituted or substituted, for example, by halogen, (C1 to C4)-alkyl- or aryl-sulfonic acids). Pharmaceutically acceptable acid addition salts include salts formed from: hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, citric acid, tartaric acid, acetic acid, phosphoric acid, lactic acid, pyruvic acid, acetic acid, trifluoroacetic acid, succinic acid, perchloric acid, fumaric acid, maleic acid, glycolic acid, lactic acid, salicylic acid, oxaloacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, hydroxyethanesulfonic acid, ascorbic acid, malic acid, phthalic acid, aspartic acid and glutamic acid, lysine and spermidine. Other acids, although not themselves pharmaceutically acceptable, may be used as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts.

[0044] The compounds of the invention may have suitable groups which can be converted into esters or carbamates. Typical ester groups and carbamate groups formed from -OH in the compounds of the invention include -OC(O)R h , -OC(O)NHR h , -OC(O)N(R h )2 and -OSO2R h , where each R h is independently selected from the group consisting of: C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl and 3-8 cycloalkylC 1-8 alkyl, haloC 1-8 alkyl, dihaloC 1-8 alkyl, trihalo 1-8 alkyl, phenyl and phenylC 1-3 alkyl; more preferably, R h is selected from the group consisting of: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl and C 3-8 cycloalkylC 1-6 alkyl.

[0045] Those skilled in the art of organic chemistry will appreciate that many organic compounds can form complexes with solvents in which they react or from which they precipitate or crystallize. These complexes are referred to as "solvates". For example, a complex with water is called a hydrate. Solvates (such as hydrates) are present when a drug substance incorporates a solvent (such as water) in a stoichiometric or non-stoichiometric amount in the crystal lattice. Since hydrates can be encountered at any stage of the drug preparation process or when storing the drug substance or dosage form, routine screening of the drug substance is carried out to determine the presence of hydrates. Solvates are described in the following documents: S. Byrn et al., Pharmaceutical research 12(7), 1995, 954 - 954 and Water-Insoluble Drug Formulation, 2nd Edition, R. Liu, CRC Press, page 553, which are incorporated herein by reference. Thus, those skilled in the art will understand that the compounds of the present invention, as well as their esters, carbamates and / or salts, can accordingly exist in the form of solvates. Solvates of the compounds of the present invention that are suitable for use in drugs are those in which the associated solvent is pharmaceutically acceptable. For example, hydrates are examples of pharmaceutically acceptable solvates. However, solvates having a non-pharmaceutically acceptable associated solvent can be used as intermediates in the preparation of the compounds of the present invention and their pharmaceutically acceptable esters, carbamates and / or salts.

[0046] A compound that, when administered to a recipient, is capable of being converted into a compound of the present invention or its active metabolite or residue as described above is called a "prodrug". A prodrug can be converted, for example, in vivo, such as by hydrolysis in the blood, into an active form having a medical effect. Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the A.C.S Symposium Series (1976); "Design of Prodrugs", edited by H. Bundgaard, Elsevier, 1985; and Edward B. Roche, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, which are incorporated herein by reference.

[0047] Labeled compound of the present invention

[0048] 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, assessment, detection and / or quantification) and particularly suitable for imaging and diagnosis. Suitable labels include, for example, radioisotopes (which may also be referred to as "radiolabeled atoms"), radionuclides, isotopes, positron emitters, γ emitters, fluorophores, luminophores, chromophores, biotin (which binds to streptavidin complexes) or photoaffinity groups. The type of label selected will depend on the desired detection method. The position at which the label is incorporated or attached to the compounds of the present invention is not particularly limited.

[0049] Examples of isotopes (such as radioisotopes, radionuclides, positron emitters and γ emitters) that can be used to label the compounds of the present invention include, but are not limited to: 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 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; even more preferably 3 H, 11 C and 18 F; and most preferably 3 H and 18 F.

[0050] Preferred examples of the labeled compounds of the present invention are compounds of formula (I) having a structural formula selected from the following group:

[0051]

[0052] Even more preferred examples of the labeled compounds of the present invention are compounds of formula (I) having a structural formula selected from the following group:

[0053]

[0054]

[0055] Particularly preferred examples of the labeled compounds of the present invention are compounds of formula (I) having a structural formula selected from the following group:

[0056]

[0057] Isotopic forms (also referred to as "isotope variants") of the compounds of the present invention can generally be prepared by conventional procedures such as by the methods described in the Examples section, using appropriate isotopic variant forms of commercially available or prepared by known synthetic techniques suitable reagents. Radioactive isotopes, radionuclides, positron emitters, and gamma emitters can be incorporated into the compounds of the present invention by conventional methods in the field of organic chemistry. For example, they can be introduced by using the corresponding labeled starting materials in the preparation of the desired compounds of the present invention. Exemplary methods for introducing detectable labels are described, for example, in US2012 / 0302755.

[0058] In certain preferred embodiments, the compounds of the present invention are labeled. In the compounds of the present invention, one or more H, one or more C, one or more N, one or more O, and / or F can be respectively 3 H; 11 C, 13 C or 14 C; 13 N; 15 O; 18 F or 19 F substituted. Preferably, one or more H, one or more C, one or more N, one or more O, and / or F can be respectively 3 H; 11 C or 14 C; 13 N; 15 O; 18 F or 19 F substituted; and more preferably respectively by 3 H, 11 C, 13 N, 15 O and 18 F substituted. Even more preferably, one or more H, one or more C, and / or F can be respectively 3 H, 11 C and 18 F substituted. Even more preferably, one or more H and / or F can be respectively 3 H and 18 F substituted.

[0059] 11 C, 13 N, 15 O and 18FAre radioactive isotopes. They decay mainly by positron emission. Thus, inclusion of such atoms in the compounds of the present invention renders the compounds detectable by positron emission tomography. Accordingly, compounds of the present invention containing one or more 11 C, 13 N, 15 O or 18 F are particularly useful as radiotracers, also known as radioligands, for positron emission tomography (PET).

[0060] In the compounds of the present invention, one or more H may be replaced by 3 H radioactive isotopes. Inclusion of such atoms in the compounds of the present invention renders the compounds detectable by autoradiography or liquid scintillation counting. Compounds of the present invention containing one or more 3 H are particularly useful as radiotracers for in vitro studies.

[0061] In certain preferred embodiments, the labeled compounds of the present invention may be labeled such that they are 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 present invention may be labeled with 19 F or 13 C for MRS / MRI; or they may also be radiolabeled with C 11 , N 13 , O 15 or F 18 for PET imaging. Preferably, the compounds of the present invention contain one or more radioisotopes selected from C 11 , N 13 , O 15 and F 18 .

[0062] The compounds of the present invention contain multiple C atoms. One or more C in the compounds of the present invention may be replaced by 11 C. For example, one C is replaced by one 11 C; or two C are replaced by two 11 C; or three C are replaced by three 11 C. In certain preferred embodiments, one C is replaced by one 11 C.

[0063] The compounds of the present invention contain three N atoms. One or more N in the compounds of the present invention may be replaced by 13 N. For example, one N is replaced by 13 N; or two N are replaced by two 13 N; or three N are replaced by three 13N substitution. In certain preferred embodiments, one N is 13 substituted by N.

[0064] The compounds of the present invention contain two O atoms. One or more O in the compounds can be 15 substituted by O. For example, one O is substituted by 15 O; or (two O are substituted by two 15 O. In certain preferred embodiments, one O is substituted by 15 O.

[0065] The compounds of the present invention contain multiple H atoms. One or more H in the compounds of the present invention can be 3 substituted by H. For example, one H is substituted by one 3 H; or two H are substituted by two 3 H; or three H are substituted by three 3 H, or at least three H are substituted by at least three 3 H. In certain preferred embodiments, one H is substituted by one 3 H; or two H are substituted by two 3 H; or three H are substituted by three 3 H; for example, three H are substituted by three 3 H.

[0066] The compounds of the present invention contain F atoms. In certain preferred embodiments, the F atoms in the compounds of the present invention are replaced by F 18 substitution.

[0067] Use of the compound of the present invention

[0068] The present invention provides compounds as selective tau deposit / aggregate ligands. As used herein, the terms "tau deposit ligand" and "tau aggregate ligand" are intended to cover 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 can bind to one or more of the following: 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 isoform of tau (i.e., tau aggregates containing the 4R isoform of tau).

[0069] The preferred compounds of the present invention have excellent binding affinity for tau deposits. For example, preferably, the compounds of the present invention have an IC for tau deposits in a competitive binding assay 50a value that is 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. In a preferred embodiment, the compounds of the present invention have an IC 50 value against tau aggregates that is less than 70 nM in a competitive binding assay. In another preferred embodiment, the compounds of the present invention have an IC 50 value against tau aggregates that is less than 50 nM in a competitive binding assay. In another preferred embodiment, the compounds of the present invention have an IC 50 value against tau aggregates that is less than 30 nM in a competitive binding assay. In another preferred embodiment, the compounds of the present invention have an IC 50 value against tau aggregates that is less than 20 nM in a competitive binding assay. In another preferred embodiment, the compounds of the present invention have an IC 50 value against tau aggregates that is less than 15 nM in a competitive binding assay. In another preferred embodiment, the compounds of the present invention have an IC 50 value against tau aggregates that is less than 10 nM in a competitive binding assay. In another preferred embodiment, the compounds of the present invention have an IC 50 value against tau aggregates that is less than 5 nM in a competitive binding assay. In another preferred embodiment, the compounds of the present invention have an IC 50 value against tau aggregates that is less than 3 nM in a competitive binding assay. Particularly preferably, the compounds of the present invention have an IC 50 value against tau aggregates that is less than 10 nM in a competitive binding assay.

[0070] Preferred compounds of the present invention and those having excellent binding affinity for tau deposits (e.g., binding to tau at the levels described above in a competitive binding assay) are selective tau deposit ligands. In this context, "selective" means any tau deposit ligand that binds to tau deposits preferentially over Aβ deposits. For example, preferred compounds of the present invention have a binding affinity for tau that is at least 1.2 times, and more preferably at least 1.5 times, more preferably at least 2 times, more preferably at least 3 times, more preferably at least 5 times, more preferably at least 8 times, more preferably at least 10 times, more preferably at least 12 times, and even more preferably at least 15 times, such as at least 18 times, at least 20 times, at least 22 times, at least 25 times, at least 30 times, at least 40 times, at least 50 times, at least 100 times, or at least 150 times, the binding affinity for Aβ. In a preferred embodiment, the compounds of the present invention have a binding affinity for tau that is at least 2 times the binding affinity for Aβ. In a preferred embodiment, the compounds of the present invention have a binding affinity for tau that is at least 3 times the 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 times the 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 times the 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 times the 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 times the 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 times the 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 times the binding affinity for Aβ.

[0071] In certain very preferred embodiments, the compounds of the present invention have a binding affinity for tau (which is at least 3 times the binding affinity for Aβ) in a competitive binding assay and have an IC 50 value for tau deposits of less than 30 nM (and more preferably less than 20 nM, and most preferably less than 10 nM).

[0072] Also preferably, the compounds of the present invention have a CLogP of 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 even 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.

[0073] The compounds of the present invention can be used for diagnosing and / or treating or preventing conditions associated with tau deposits. For example, the compounds of the present invention can be used for diagnosing and / or treating or preventing 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 with parkinsonism linked to chromosome 17, postencephalitic parkinsonism, Guadeloupean type parkinsonism, globular glial 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-type dementia, familial Danish dementia, pugilistic dementia, tangle-predominant dementia, Huntington's disease, Lewy body disease, prion disease, subacute sclerosing panencephalitis, subacute sclerosing panencephalitis, diffuse neurofibrillary tangles with calcification, neurodegeneration with brain iron accumulation, mutations affecting sodium / proton exchanger, 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 grain disease, Hallervorden-Spatz disease, multiple system atrophy, pallido-pontine-nigral degeneration, progressive subcortical gliosis, tangle-only dementia, myotonic dystrophy, tau panencephalopathy, AD-like with astrocytes, Gerstmann-Straussler-Scheinker disease regarding tau, mutations in LRRK2, SLC9A6-related mental retardation, and white matter tauopathy with globular glial inclusions. The compounds of the present invention can be particularly used for diagnosing and / or treating (especially diagnosing) Alzheimer's disease, corticobasal degeneration, Pick's disease, Parkinson's disease, chronic traumatic encephalopathy, and progressive supranuclear palsy; and even more particularly for Alzheimer's disease and corticobasal degeneration.

[0074] The compounds of the present invention can be used as a therapeutic agent (or drug) for treating diseases or disorders associated with tau deposits (i.e., tauopathies), such as the tauopathies listed above.

[0075] The present invention also provides a method for treating or preventing a condition associated with a disease or disorder (associated with tau deposits) (i.e., tauopathy) in a mammal, particularly in a human, the method 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 and a pharmaceutically acceptable carrier. The tau deposit-mediated clinical conditions that can be treated by the method of the present invention are tauopathies, such as the tauopathies listed above.

[0076] The present invention also provides the use of a compound according to the present invention for the manufacture of a medicament for treating or preventing a condition associated with a disease or disorder (associated with tau deposits) (i.e., tauopathy) (such as the tauopathies listed above).

[0077] The compounds of the present invention can also be used as diagnostic agents (for in vivo and / or in vitro diagnostic use) for detecting tau deposits.

[0078] The compounds of the present invention can be used for diagnostic purposes because they have the ability to target specific lesions (tau deposits) and can be detected at the desired site. For example, the compounds of the present invention can detect the presence and level of tau deposits in patients suffering from or suspected of suffering from 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 tauopathy because the compounds of the present invention do not exhibit off-target MAO binding or inhibitory activity. Since MAO is present in the brain in regions that overlap with tau lesions in certain tauopathies, such off-target effects are not desired in tau deposit ligands.

[0079] The compounds of the present invention can bind to tau deposits both in vivo and in vitro. The compounds of the present invention can be used as diagnostic agents (for in vivo and / or in vitro diagnostic use) for diagnosing a disease or disorder associated with tau deposits (i.e., tauopathy), such as the tauopathies listed above.

[0080] The compounds of the present invention cross the blood-brain barrier to a greater extent than previously disclosed compounds with similar properties, and furthermore, once they cross the blood-brain barrier, they are well distributed throughout the brain.

[0081] When used as a diagnostic agent, the compounds of the present invention may optionally be in a labeled form as described above. Accordingly, the present invention also provides the use of a compound of the present invention in a labeled form as a diagnostic agent for diagnosing a condition associated with a disease or disorder (associated with tau deposits) (i.e., tauopathy). In such embodiments, preferably, the compound of the present invention in a labeled form comprises one or more radioisotopes selected from the following: 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. When used as a diagnostic agent (especially for in vivo use) and radiolabeled with, for example, 11 C, 13 N, 15 O or 18 F (preferably 18 F), the compounds of the present invention can be detected by positron emission tomography. When used as a diagnostic agent (especially for in vitro use) and radiolabeled with, for example, 3 H, the compounds of the present invention can be detected by autoradiography.

[0082] As described above, the compounds of the present invention can be used for diagnostic purposes because they have the ability to target specific lesions (tau deposits) and can be detected at the desired site. Thus, the compounds of the present invention are particularly useful as imaging agents when used as diagnostic agents. An imaging agent is a compound that allows imaging of specific organs, tissues, diseases, and physiological functions. Such imaging allows diagnosis of diseases, monitoring of disease progression, and tracking of treatment response.

[0083] When the compounds of the present invention are used as diagnostic agents and particularly as imaging agents, they can be detected by the following means: radioisotope scanning, determination, 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 scan), and / or positron emission tomography (PET).

[0084] In embodiments of the present invention where the compounds of the present invention are used as diagnostic agents and particularly as imaging agents, the type of detection instrument available is a major factor in selecting whether a label is needed and what label to use. For example, in cases where imaging requires detection of an isotope, the type of detection instrument used will guide whether a label is needed (i.e., whether the isotope is naturally occurring and, if so, its abundance) and, if so, what isotope to use. In one aspect, the compounds of the present invention are labeled, and the selected form of the label must have a decay type that can be detected by a given instrument type. Additionally, when selecting an isotope label for in vivo imaging, other considerations are taken into account, such as the half-life of the radioisotope.

[0085] The compounds of the present invention used as diagnostic agents for in vivo imaging, particularly for imaging and / or quantifying tau deposits, are preferably used in conjunction with non-invasive neuroimaging techniques such as in vivo MRS, MRI, PET, SPECT, and combinations thereof. The compounds of the present invention can be labeled with 11 C, 13 N, 15 O, or 18 F for PET imaging. Labeling may not be required for in vivo MRS or MRI, or the compound can be labeled with 13 C for MRS or MRI.

[0086] The present invention also provides a method for diagnosing a patient or monitoring the progression of a disease in a patient, the method 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 in the patient (such as the brain) using PET or SPECT, or detecting the compound in a sample from the patient. Preferably, in such embodiments, the compound of the present invention comprises one or more radioisotopes selected from the group consisting of 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, or 18 F, and most preferably 3 H, or 18 F. The present invention also provides a method for diagnosing a patient or monitoring the progression of a disease in a patient, the method comprising contacting a compound of the present invention with a sample taken from the patient.

[0087] The method may further comprise detecting the compound of the present invention using: radioisotope scintigraphy, 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).

[0088] In a method for diagnosing a disease or disorder associated with tau deposits as described herein, the method may comprise:

[0089] i) administering to a subject a diagnostically effective amount of a compound of the present invention;

[0090] ii) distributing the compound of the present invention into a tissue of interest (such as the brain, or a body fluid such as cerebrospinal fluid (CSF)); and

[0091] iii) imaging the tissue of interest, wherein an increase in the binding of the compound of the present invention to the tissue of interest compared to normal or control binding levels indicates that the subject has a disorder associated with tau deposits or is at risk of developing such a disorder.

[0092] The compounds of the present invention can be used to image tau deposits in any sample or a specific body part or body region of a patient suspected of containing tau deposits. The compounds of the present invention are particularly suitable for imaging tau deposits in the brain and in body fluids (such as cerebrospinal fluid (CSF)).

[0093] Diagnosis of a disease or disorder associated with tau deposits in a patient can be achieved by detecting specific binding of a compound according to the present invention to tau deposits in a sample or in situ, which includes:

[0094] (a) Contacting a sample suspected of containing tau deposits, or a particular body part or body region (such as the brain and / or CSF), with a compound of the invention that binds to tau deposits.

[0095] (b) Binding the compound of the invention to tau deposits to form a compound / tau deposit complex.

[0096] (c) Detecting the formation of the compound / tau deposit complex.

[0097] (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 the particular body part or region, and

[0098] (e) Optionally comparing the amount of the compound / tau deposit complex with a normal or control value, wherein an increase in the amount of the compound / tau deposit complex compared to the normal control value may indicate that the patient has a tau-related disorder or is at risk of developing such a tau-related disorder.

[0099] After a sample or a particular body part or body region (such as the brain and / or CSF) has been contacted with a compound of the invention, the compound is bound to tau deposits. The amount of time required for binding will depend on the type of test (e.g., in vitro or in vivo) and can be determined by those skilled in the art through routine experimentation.

[0100] Then, optionally, the presence or absence of the compound / tau deposit is correlated with the presence or absence of tau deposits in the sample or the particular body part or region. The amount of the compound / tau deposit complex can be compared with a normal or control value that has been determined in a sample or a particular body part or body region of a healthy subject, wherein an increase in the amount of the compound / tau deposit complex compared to the normal or control value may indicate that the patient has a disease or disorder associated with tau deposits (i.e., a tauopathy) or is at risk of developing such a disease or disorder. The invention also relates to a method for determining the amount of tau deposits in a tissue and / or a body fluid. This method comprises the following steps:

[0101] (1) Providing a sample representative of the tissue and / or body fluid under study (such as the brain and / or CSF);

[0102] (2) Testing the sample with a compound of the invention for the presence of tau deposits;

[0103] (3) Determining the amount of the compound that binds to tau deposits; and

[0104] (4) Calculating the amount of tau deposits in the tissue and / or body fluid.

[0105] The compounds of the present invention can be used to test a sample for the presence of tau deposits by: contacting the sample with a compound of the present invention, binding the compound of the present invention to the tau deposits to form a compound / tau deposit complex, and detecting the formation of the compound / tau deposit complex as explained above.

[0106] Monitoring of minimal residual disorders in patients suffering from a disorder associated with tau deposits, who have been treated with a therapeutic agent useful for preventing or treating a disorder associated with tau deposits (e.g., a therapeutic agent useful for preventing or treating one or more of the above-listed or tauopathies), can be achieved by:

[0107] Performing steps (a) to (d) above; and (e) optionally comparing the amount of the compound / tau deposit complex with a normal or control value, wherein an increase in the amount of the complex compared to the normal or control value can indicate that the patient may still be suffering from minimal residual disease.

[0108] How to perform steps (a) to (e) has been explained above.

[0109] Predicting the responsiveness of a patient suffering from a disorder associated with tau deposits and being treated with a therapeutic agent useful for preventing or treating a disorder associated with tau deposits can be achieved by

[0110] Performing steps (a) to (d) above; and (e) optionally comparing the amount of the compound / tau deposit complex with a normal or control value.

[0111] How to perform steps (a) to (e) has been explained above.

[0112] In the method for predicting responsiveness, the amount of the compound / tau deposit complex can optionally be compared at various time points during treatment, e.g., before and after the start of treatment or at various time points after the start of treatment. A change in the amount of the compound / tau deposit complex, especially a decrease, can indicate a high likelihood that the patient will respond to the corresponding treatment.

[0113] The compounds according to the invention can also be incorporated into a test kit for detecting tau deposits. The test kit generally comprises a container holding one or more compounds according to the invention and instructions for using the compound for binding to tau deposits to form a compound / tau deposit complex and detecting the formation of the compound / tau deposit complex such that the presence or absence of the compound / tau deposit complex is correlated with the presence or absence of tau deposits.

[0114] Administration

[0115] Of course, the amount of the compounds of the present invention required to achieve a diagnostic or therapeutic effect will vary with the particular compound, the route of administration, and the subject being treated, including the type, species, age, weight, sex and medical condition of the subject, as well as the renal and hepatic function of the subject, and the particular disorder or disease being treated, diagnosed or monitored and its severity. A physician, veterinarian or clinician of ordinary skill can readily determine and prescribe an effective amount of the drug required to prevent, counteract or arrest the progression of a condition or for diagnosing a condition or the progression of a condition.

[0116] When used as a diagnostic or therapeutic agent, for adults, the oral dosage range of the compounds of the present invention will be between about 0.01 mg per kg body weight per day (mg / kg / day) and about 100 mg / kg / day, preferably from 0.01 mg per kg body weight per day (mg / kg / day) to 10 mg / kg / day, and most preferably from 0.1 mg / kg / day to 5.0 mg / kg / day. For oral administration, the composition is preferably provided in the form of tablets or other presentation forms provided in discrete units, the discrete units containing 0.01 mg, 0.05 mg, 0.1 mg, 0.5 mg, 1.0 mg, 2.5 mg, 5.0 mg, 10.0 mg, 15.0 mg, 25.0 mg, 50.0 mg, 100 mg and 500 mg of the compounds of the present invention for symptom adjustment in a dose for the patient to be treated. The medicament generally contains from about 0.01 mg to about 500 mg of the compounds of the present invention, preferably from about 1 mg to about 100 mg of the compounds of the present invention. During a constant rate infusion, intravenously, the most preferred dosage range is from about 0.1 to about 10 mg / kg / minute. Advantageously, the compounds of the present invention may be administered in a single daily dose, or the total daily dose may be administered in two, three or four divided doses per day. For diagnostic use, preferably, the compounds of the present invention may be administered in a single daily dose. In addition, those forms of transdermal skin patches well known to those of ordinary skill in the art may be used, and the preferred compounds of the present invention may be administered intranasally by topical use of a suitable intranasal carrier, or by the transdermal route.

[0117] Although the compounds of the present invention may be administered alone, preferably the compounds of the present invention are present in a pharmaceutical formulation or composition. Accordingly, 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 compositions of the present invention may take the form of pharmaceutical formulations as described below.

[0118] Formulation

[0119] As used herein, "pharmaceutical" does not necessarily mean a therapeutic agent. For example, a pharmaceutical formulation can be used as a diagnostic agent, such as an imaging agent. Pharmaceutical formulations useful in accordance with 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 generated by various types of metered dose pressurized sprays), nebulizer or insufflator, rectal, intraperitoneal and topical (including dermal, oral, sublingual and intraocular) administration, but the most suitable route may depend, for example, on the condition and disorder of the recipient to be treated or diagnosed.

[0120] The formulations can conveniently be presented in unit dosage form and can be prepared by any methods well known in the art of pharmacy. All methods include the step of bringing the compound of the present invention into association with a carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing the compound of the present invention into association with a liquid carrier or a finely divided solid carrier or both and then, if necessary, shaping the product into the desired formulation.

[0121] Formulations of the present invention suitable for oral administration may be presented in the form of discrete units such as capsules, sachets, pills or tablets each containing a predetermined amount of the compound of the present invention; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids, such as elixirs, tinctures, suspensions or syrups; or oil-in-water liquid emulsions or water-in-oil liquid emulsions. The compounds of the present invention may also be presented in the form of boluses, lozenges or pastes.

[0122] Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostatic agents and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may contain suspending agents and thickening agents. The formulations 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) condition which requires only the addition of a sterile liquid carrier (such as saline or water for injection) immediately prior to use. Temporary injection solutions and suspensions may be prepared from the sterile powders, granules and tablets of the foregoing kind. 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 agents and suspending agents, including synthetic mono- or di-glycerides of fatty acids and fatty acids (including oleic acid or Cremophor).

[0123] Exemplary compositions for nasal aerosol or inhalation administration include solutions in saline which may contain, for example, benzyl alcohol or other suitable preservatives, absorption promoters for enhancing bioavailability, and / or other solubilizers or dispersants known in the art.

[0124] Formulations for topical administration in the mouth (e.g., buccally or sublingually) include lozenges comprising the compounds of the present invention in a flavoring matrix such as sucrose and gum acacia or tragacanth, and soft lozenges comprising the compounds of the present invention in a matrix such as gelatin and glycerol or sucrose and gum acacia. Exemplary compositions for topical administration comprise a topical carrier such as Plastibase (mineral oil gelled with polyethylene).

[0125] Preferred unit dose formulations are those containing an effective dose of the above-described compounds of the present invention or suitable fractions thereof.

[0126] It should be understood that with respect to the type of formulation under discussion, in addition to the ingredients specifically mentioned above, the formulations of the present invention may contain other conventional reagents in the art. For example, formulations suitable for oral administration may contain flavoring agents.

[0127] Although the compounds of the present invention may be used as the sole active ingredient in a medicament (i.e., the sole therapeutic or the sole diagnostic agent), the compounds may also be used in combination with one or more additional active ingredients. For example, the compounds of the present invention may be used as the sole diagnostic agent in a diagnostic composition, or the compounds may also 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 may be used as the sole diagnostic and / or sole therapeutic agent in a medicament, or the compounds may also be used in combination with one or more additional therapeutic agents and / or one or more diagnostic agents.

[0128] Accordingly, the present invention also provides a compound according to the present invention for administration simultaneously with, sequentially with, or separately from an additional diagnostic agent. Such additional diagnostic agents may be additional compounds according to the present invention, or they may be different diagnostic agents. The additional diagnostic agents may be agents useful for diagnosing tauopathies (such as the tauopathies listed above).

[0129] In certain preferred embodiments, the additional diagnostic agent can be an agent selective for Aβ deposits and useful for diagnosing Alzheimer's disease. The additional diagnostic agent can be detected by, for example, radio-scintigraphy, 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 detected by positron emission tomography. For example, the additional agent can be a PET ligand.

[0130] For example, the compounds of the present invention can be effectively administered in combination with an effective amount of one or more other diagnostic agents (which can also be used in vitro for in vitro diagnosis in combination with the one or more other diagnostic agents), and the one or more other diagnostic agents are, for example, one or more diagnostic agents selected from the group consisting of: luminescent conjugated oligothiophenes (such as q-FTAA-CN, p-FTAA-CN, h-FTAA-CN), Pittsburgh Compound B (PiB), fluorodeoxyglucose F18 (FDG), florbetapir, flutemetamol, NAV4694, PBB3, AT-100, 4G8, congo red, thioflavin S, thioflavin T, m-l-stilbene, coriamyrtin G, BF-277, TZDM, FDDNP, MeO-X-04, IMPY, NIAD-4 3 H-X-34, luminescent conjugated polythiophenes (such as polythiopheneacetic acid (PTAA), tPTAA, POWT, tPOWT, POMT, tPOMY), and GTP1 (Genentech tau probe 1).

[0131] The invention also provides a compound according to the invention for administration simultaneously with, sequentially or separately from another therapeutic agent. Such other therapeutic agents may be additional compounds according to the invention or they may be different therapeutic agents, such as agents useful for the prevention or treatment of one or more of the tauopathies listed above. For example, the compounds of the invention may be effectively administered in combination with an effective amount of other agents, which other agents are, for example, one or more agents selected from the group consisting of: antibodies (such as active immunizations (such as ACI-35 (AC Immune / Janssen) and AADvac1 (Axon Neuroscience)), passive immunizations (such as tau antibodies, such as BMS-986168 (IPN007, Bristol-Myers Squibb), 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 (such as TRx 0327 and Rember), dopaminergic therapeutics (such as levodopa, caridopa, dopamine agonists (such as bromocriptine, pergolide, pramipexole, ropinirole)), anticholinesterase agents (such as tacrine, donepezil, rivastigmine, galantamine), monoamine oxidase inhibitors (such as selegiline), anticholinergic agents (such as trihexyphenidyl, benztropine mesylate, biperiden, procyclidine), antihistamines (such as diphenhydramine), tranquilizers, painkillers, anti-inflammatory agents, riluzole, non-steroidal anti-inflammatory drugs, caffeine A2A receptor antagonists, CERE-120 (adeno-associated virus serotype 2-neuregulin), amantadine, tolcapone, entacapone, ethosuximide, trazodone, and dibenzoylmethane).

[0132] When used in combination with the compounds of the present invention, the other diagnostic and therapeutic agents described above can be used, for example, in the amounts indicated in the Physicians' Desk Reference (PDR) or as otherwise determined by one of ordinary skill in the art.

[0133] The compounds of the present invention, optionally in labeled form, as described above can also be used as reference compounds in a method for identifying tau deposit ligands. Accordingly, the present invention provides a method for identifying a ligand for tau deposits, the method comprising using a compound of the present invention or a compound of the present invention in labeled form as a reference compound. For example, such a method can involve a competitive binding experiment in which the binding of a compound of the present invention to tau deposits is reduced due to 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 being considered).

[0134] Experiment

[0135] General information

[0136] All reagents and solvents used were of analytical grade and commercially available. Anhydrous reactions were used for the reactions as a matter of routine. The reactions were generally run under an inert atmosphere of nitrogen (N2).

[0137] 1 H and 13 13C spectra were recorded on a Bruker 500 NMR spectrometer.

[0138] Mass spectra were recorded on a Waters Acquity QDa LSMS. The mass spectrometer was equipped with an electrospray ionization source (ES) operating in positive or negative mode. The capillary voltage was 3.5 kV and the cone voltage was 30 V. The mass spectrometer was scanned between m / z 100 and 850 with a scan time of 0.5 s. The column temperature was set at 50 °C. The linear gradient started at 95% A (A: 10 mM NH4HCO3) and ended at 100% B (B: MeCN). The column used was an Acquity UPLC TM HSS C 18 1.7 μm, 2.1×50 mm, which was run at 0.4 ml / min.

[0139] The HPLC used was an Agilent 1100 coupled to an Agilent 1290 Infinity DAD. The column used was an XBridge C 183.5 μm, 3.0 × 50 mm, running at 0.8 ml / min. The column temperature was set at 50 °C, with a linear gradient starting from 98 - 2% A for 3.5 min (A: 10 mM NH4HCO3), then holding at 98% B (B: MeCN) for 1.5 min.

[0140] The semi - preparative HPLC was a Gilson with a 322 pump. The column used was a Kromasil C8 7 μm, 20 × 250 mm.

[0141] Microwave heating was performed in a Biotage Initiator 2.0.

[0142] Chromatographic separation was performed using silica gel 60 (0.040 mm to 0.063 mm) in a filtering funnel or by using a Teledyne ISCO CombiFlash Rf with Silicycle silica gel columns of different sizes (4 g to 120 g). The TLC plates were Merck silica gel 60F 254 。

[0143] Unless otherwise specified, the term room temperature (rt) means a temperature between 16 °C and 25 °C. Unless otherwise stated, the term reflux means using the adopted solvent at a temperature equal to or slightly higher than the boiling point of the specified solvent.

[0144] Example Compound 1: 2-{2-Fluoro-6-[(3S)-3-methoxypiperidin-1-yl]pyridin-3-yl}-1H-indol-5-ol

[0145]

[0146] Method 1

[0147]

[0148] In a 20 ml microwave vial, tert - butyl 2 - (2,6 - difluoropyridin - 3 - yl) - 5 - hydroxy - 1H - indole - 1 - carboxylate (125 mg, 0.36 mmol, for the manufacturing method, see WO2021074351 A1) and 3 - (S) - methoxypiperidine HCl (62 mg, 1.1 eq) were suspended in acetonitrile (4 ml). Hunig's base (160 μl, 2.5 eq) was added to the solution, and the reaction was subjected to microwave treatment at 150 °C for 60 min.

[0149] The solvent was removed under vacuum, the residue was taken up in ethyl acetate, washed with water, treated with brine, dried over MgSO4, and then filtered. The solvent was removed under vacuum to obtain the crude product.

[0150] The crude product was purified on ISCO (12 g silica gel, eluted with dichloromethane (DCM), eluted with 20%-40% ethyl acetate / hexane for 8 min). DCM was added to the residue, and then the solid was filtered and washed with DCM to obtain 2-{2-fluoro-6-[(3S)-3-methoxypiperidin-1-yl]pyridin-3-yl}-1H-indol-5-ol (31 mg solid, yield 25%, HPLC Rf 2.92 min, MS m / z (M+1) 342.2, (M-1) 340.2, TLC: 40% ethyl acetate / hexane Rf 0.15), 1 H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 8.69 (s, 1H), 8.12 (dd, J = 10.7, 8.6 Hz, 1H), 7.23 (dt, J = 8.6, 0.7 Hz, 1H), 6.91 (dd, J = 8.6, 2.1 Hz, 1H), 6.87 (d, J = 2.3 Hz, 1H), 6.65 (dd, J = 8.6, 2.3 Hz, 1H), 6.60–6.53 (m, 1H), 3.97 (d, J = 12.1 Hz, 1H), 3.75 (ddd, J = 13.0, 6.3, 3.7 Hz, 1H), 3.36 (s, 7H), 2.08–1.91 (m, 1H), 1.79 (ddt, J = 13.4, 6.8, 3.4 Hz, 1H), 1.67–1.42 (m, 2H).

[0151] 13 C NMR (101 MHz, DMSO) δ 178.10, 150.80, 139.09, 131.69, 131.62, 131.02, 129.33, 111.50, 111.33, 103.81, 103.49, 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.

[0152] 19 F NMR (377 MHz, DMSO) δ -67.79, -67.82.

[0153] Method 2

[0154] Step (i) 2-Fluoro-6-[(3S)-3-methoxypiperidin-1-yl]pyridine

[0155]

[0156] (S)-3-Methoxypiperidine HCl (1.0 g, 6.6 mmol) was suspended in dioxane (8 ml), 2,6-difluoropyridine (660 μl, 1.1 eq) was added, and then Hunig's base (3.0 ml, 2.6 eq) was added. The reaction was heated to 100 °C for 5 h.

[0157] 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.

[0158] The crude oil was purified on ISCO (40 g silica gel, eluted with hexane, eluted with 5%-20% ethyl acetate / hexane for 5 min) to give 2-fluoro-6-[(3S)-3-methoxypiperidin-1-yl]pyridine (1.03 g of oil, HPLC Rf 2.90 min, yield 75%, MS m / z (M+1) 211.2 (very weak), TLC 10% ethyl acetate / hexane Rf 0.14).

[0159] 1 1H NMR (500 MHz, DMSO-d6) δ 7.59 (ddd, J = 9.2, 8.3, 7.7 Hz, 1H), 6.69–6.60 (m, 1H), 6.16 (ddd, J = 7.7, 2.9, 0.4 Hz, 1H), 3.86 (dq, J = 11.0, 1.3 Hz, 1H), 3.64 (dddt, J = 13.2, 5.6, 3.9, 0.9 Hz, 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, 3.5 Hz, 1H), 1.52–1.43 (m, 1H), 1.39 (dtt, J = 13.2, 9.2, 3.7 Hz, 1H).

[0160] 13 13C NMR (126 MHz, DMSO-d6) δ 163.41, 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.

[0161] Step (ii) 3-Bromo-2-fluoro-6-[(3S)-3-methoxypiperidin-1-yl]pyridine

[0162]

[0163] 2-Fluoro-6-[(3S)-3-methoxypiperidin-1-yl]pyridine (1.03 g, 4.9 mmol) was dissolved in acetonitrile (20 ml), cooled in an ice bath, and NBS (0.87 g, 1 eq) was added in two portions. The reaction was stirred at 0 °C for 5 min and then at room temperature for 30 min.

[0164] Ether was added to the mixture, the solution was washed with water, treated with brine, dried over MgSO4, and then filtered. The solvent was removed in vacuo and the residue was stripped to give the crude product.

[0165] The crude product was purified on ISCO (40 g silica gel, eluted with hexane / DCM, eluted with 5%-20% ethyl acetate / hexane for 5 min) to give 3-bromo-2-fluoro-6-[(3S)-3-methoxypiperidin-1-yl]pyridine (1.35 g as an oil, HPLC Rf 3.31 min, yield 96%, MS m / z (M+1) 289.0, 291.0, TLC 20% ethyl acetate / hexane Rf 0.19).

[0166] 1 H NMR (500 MHz, DMSO-d6) δ 7.75 (dd, J = 9.6, 8.7 Hz, 1H), 6.67 (dd, J = 8.8, 1.9 Hz, 1H), 3.78 (ddt, J = 12.9, 3.2, 1.1 Hz, 1H), 3.57 (ddd, J = 13.3, 6.7, 3.8 Hz, 1H), 3.33–3.25 (m, 2H), 3.24–3.19 (m, 1H), 1.87 (dqd, J = 11.3, 3.8, 1.9 Hz, 1H), 1.72–1.61 (m, 1H), 1.54–1.46 (m, 1H), 1.43–1.34 (m, 1H).

[0167] 13 C NMR (126 MHz, DMSO-d6) δ 158.61, 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.

[0168] Step (iii) 5-[(tert-Butyldimethylsilyl)oxy]-2-{2-fluoro-6-[(3S)-3-methoxypiperidin- 1-yl]pyridin-3-yl}-1H-indole-1-carboxylic acid tert-butyl ester

[0169]

[0170] In a 20 ml microwave vial, 3-bromo-2-fluoro-6-[(3S)-3-methoxypiperidin-1-yl]pyridine (580 mg, 2 mmol) and {1-[(tert-butoxy)carbonyl]-5-[(tert-butyldimethylsilyl)oxy]-1H-indol-2-yl}boronic acid (1.1 g, 1.4 eq) were dissolved in dioxane (12 ml). The solution was bubbled with N2 for 5 min, then [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with dichloromethane (Pd(dppf)Cl2 DCM; 82 mg, 5 mol%) was added, followed by 2 M K2CO3 (3 ml, 3 eq). The solution was bubbled with N2 again for 5 min, capped, and then placed in a preheated oil bath. The reaction was heated to 90 °C for 1 h.

[0171] 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.

[0172] The crude product was purified on an ISCO (40 g silica gel, eluted with DCM, eluted with 5%-15% ethyl acetate / hexane for 6 min) to give tert-butyl 5-[(tert-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 / hexane Rf 0.35).

[0173] 11H NMR (500 MHz, DMSO-d6) δ 7.92 (dt, J = 8.9, 0.7 Hz, 1H), 7.66 (dd, J = 10.2, 8.3 Hz, 1H), 7.01 (dd, J = 2.4, 0.5 Hz, 1H), 6.83 (dd, J = 8.9, 2.5 Hz, 1H), 6.76 (dd, J = 8.4, 2.1 Hz, 1H), 6.59 (d, J = 0.7 Hz, 1H), 3.89 (dd, J = 13.1, 3.3 Hz, 1H), 3.67 (ddd, J = 13.2, 6.4, 3.8 Hz, 1H), 3.62–3.52 (m, 4H), 3.39–3.31 (m, 2H), 3.27 (s, 3H), 3.24 (tt, J = 7.4, 3.4 Hz, 1H), 1.92 (ddt, J = 11.4, 7.4, 3.8 Hz, 1H), 1.78–1.65 (m, 5H), 1.53 (dtd, J = 12.5, 8.3, 3.9 Hz, 1H), 1.45–1.36 (m, 1H), 1.34 (s, 9H), 0.95 (s, 9H).

[0174] 13 13C NMR (126 MHz, DMSO-d6) δ 150.88, 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.

[0175] Step (iv) 2-{2-Fluoro-6-[(3S)-3-methoxypiperidin-1-yl]pyridin-3-yl}-5-hydroxy-1H-indole- 1- Carboxylic acid tert-butyl ester

[0176]

[0177] tert-Butyl 5-[(tert-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 in an ice bath, and 1 M tetrabutylammonium fluoride (TBAF) solution (2.2 ml, 1.1 eq) was added. The reaction was stirred at 0 °C for 10 min.

[0178] The reaction was diluted with ethyl acetate, treated with brine, dried over MgSO4, and then filtered. The solvent was removed in vacuo to give the crude product.

[0179] The crude product was purified on ISCO (40 g silica gel, eluted with DCM, eluted with 30%-45% ethyl acetate / hexane for 5 min) to obtain tert-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, yield 98%, TLC Rf 45% ethyl acetate / hexane Rf 0.28).

[0180] 1 H NMR (500 MHz, DMSO-d6) δ 9.18 (s, 1H), 7.87 (dt, J = 8.8, 0.7 Hz, 1H), 7.63 (dd, J = 10.2, 8.3 Hz, 1H), 6.89 (dd, J = 2.5, 0.5 Hz, 1H), 6.77 (dd, J = 8.9, 2.5 Hz, 1H), 6.72 (dd, J = 8.4, 2.1 Hz, 1H), 6.53 (d, J = 0.7 Hz, 1H), 3.88 (dd, J = 13.1, 3.3 Hz, 1H), 3.65 (ddd, J = 13.2, 6.3, 3.8 Hz, 1H), 3.36–3.28 (m, 3H), 3.22 (tt, J = 7.4, 3.4 Hz, 1H), 1.94–1.85 (m, 1H), 1.69 (dtt, J = 13.4, 6.9, 3.5 Hz, 1H), 1.52 (tdd, J = 12.5, 7.7, 3.9 Hz, 1H), 1.45–1.35 (m, 1H), 1.33 (s, 8H).

[0181] 13 C NMR (126 MHz, DMSO-d6) δ 170.31, 159.27, 157.41, 157.17, 157.04, 153.33, 149.45, 142.00, 141.97, 133.62, 133.58, 130.25, 129.71, 115.39, 113.35, 109.69, 104.99, 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。

[0182] Step (v) 2-{2-Fluoro-6-[(3S)-3-methoxypiperidin-1-yl]pyridin-3-yl}-1H-indol-5-ol

[0183]

[0184] In a 20 ml microwave vial, tert-butyl 2-{2-fluoro-6-[(3S)-3-methoxypiperidin-1-yl]pyridin-3-yl}-5-hydroxy-1H-indole-1-carboxylate (0.84 g, 1.9 mmol) was dissolved in methanol (15 ml). The reaction was subjected to microwave treatment at 150 °C for 45 min.

[0185] The solvent was removed, the residue was stirred with DCM, and the solid was filtered to obtain 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, yield 47%, TLC Rf 40% ethyl acetate / hexane Rf 0.15).

[0186] For spectral data, see Example Compound 1, Method 1.

[0187] Example Compound 2: 2-{2-Fluoro-6-[(3R)-3-methoxypiperidin-1-yl]pyridin-3-yl}-1H-indol-5-ol

[0188]

[0189]

[0190] In a 20 ml microwave vial, tert-butyl 2-(2,6-difluoropyridin-3-yl)-5-hydroxy-1H-indole-1-carboxylate (125 mg, 0.36 mmol, for the manufacturing method, see WO2021074351 A1) and 3-(R)-methoxypiperidine HCl (62 mg, 1.1 eq) were suspended in acetonitrile (4 ml). Hunig's base (160 μl, 2.5 eq) was added to the solution, and the reaction was subjected to microwave treatment at 150 °C for 60 min.

[0191] The solvent was removed in vacuo, 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 obtain the crude product.

[0192] The crude product was purified on an ISCO (12 g silica gel, eluted with DCM, eluted with 20%-40% ethyl acetate / hexane for 8 min). DCM was added to the residue, the solid was filtered, and then washed with DCM to obtain 2-{2-fluoro-6-[(3S)-3-methoxypiperidin-1-yl]pyridin-3-yl}-1H-indol-5-ol (24 mg solid, yield 25%, HPLC Rf 2.92 min, MS m / z (M+1) 342.2, (M-1) 340.2, TLC: 40% ethyl acetate / hexane Rf 0.15).

[0193] Example Compound 3: 2-{2-Fluoro-6-[(3S)-3-methoxypiperidin-1-yl]pyridin-3-yl}-1H-indol-6-ol

[0194]

[0195] Step (i) 6-[(tert-Butyldimethylsilyl)oxy]-2-{2-fluoro-6-[(3S)-3-methoxypiperidin-1- yl]pyridin-3-yl}-1H-indole-1-carboxylic acid tert-butyl ester

[0196]

[0197] In a 20 ml microwave vial, 3-bromo-2-fluoro-6-[(3S)-3-methoxypiperidin-1-yl]pyridine (263 mg, 0.91 mmol, for the manufacturing method, see Example Compound 1, Method 2, Step (ii)) and {1-[(tert-butoxy)carbonyl]-6-[(tert-butyldimethylsilyl)oxy]-1H-indol-2-yl}boronic acid (500 mg, 1.4 eq) were dissolved in dioxane (6 ml). The solution was bubbled with N2 for 5 min, then Pd(dppf)Cl2 DCM (40 mg, 5 mol%) was added, followed by 2 M K2CO3 (1.4 ml, 3 eq). The solution was bubbled with N2 again for 5 min. The reaction was capped and then placed in a preheated oil bath. The reaction was heated to 90 °C for 1 h.

[0198] 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 obtain the crude product.

[0199] The crude product was purified on an ISCO (40 g silica gel, eluted with DCM, eluted with 10%-20% ethyl acetate / hexane for 6 min) to obtain tert-butyl 6-[(tert-butyldimethylsilyl)oxy]-2-{2-fluoro-6-[(3S)-3-methoxypiperidin-1-yl]pyridin-3-yl}-1H-indole-1-carboxylate (329 mg foam, yield 66%, HPLC Rf 4.77 min, MS m / z (M+1) 556.3, TLC 20% ethyl acetate / hexane Rf 0.25).

[0200] Step (ii) 2-{2-Fluoro-6-[(3S)-3-methoxypiperidin-1-yl]pyridin-3-yl}-6-hydroxy-1H-indole- 1-carboxylic acid tert-butyl ester

[0201]

[0202] Dissolve tert-butyl 6-[(tert-butyldimethylsilyl)oxy]-2-{2-fluoro-6-[(3S)-3-methoxypiperidin-1-yl]pyridin-3-yl}-1H-indole-1-carboxylate (329 mg, 0.59 mmol) in THF (10 ml), cool on an ice bath, and add 1 M TBAF solution (650 μl, 1.1 eq). Stir the reaction at 0 °C for 10 min.

[0203] Dilute the reaction with ethyl acetate, treat with brine, dry over MgSO4, and then filter. Remove the solvent in vacuo to obtain the crude product.

[0204] Purify the crude product on ISCO (12 g silica gel, eluting with DCM, eluting with 20%-35% ethyl acetate / hexane over 4 min) to obtain tert-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, yield 93%, TLC Rf 30% ethyl acetate / hexane Rf 0.16).

[0205] Step (iii) 2-{2-Fluoro-6-[(3S)-3-methoxypiperidin-1-yl]pyridin-3-yl}-1H-indol-6-ol

[0206]

[0207] In a 5 ml microwave vial, dissolve tert-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) in methanol (4 ml). Subject the reaction to microwave treatment at 150 °C for 60 min.

[0208] Remove the solvent in vacuo and purify the crude product on ISCO (12 g silica gel, eluting with DCM (poor solubility), eluting with 40%-50% ethyl acetate / hexane over 3 min) to obtain 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, yield 72%, TLC Rf 30% ethyl acetate / hexane Rf 0.16).

[0209] Example Compound 4: 2-{2-Fluoro-6-[(3R)-3-methoxypiperidin-1-yl]pyridin-3-yl}-1H-indol-6-ol

[0210]

[0211] Step (i) 2-Fluoro-6-[(3R)-3-methoxypiperidin-1-yl]pyridine

[0212]

[0213] (R)-3-Methoxypiperidine HCl (0.73 g, 4.8 mmol) was suspended in dioxane (4 ml), 2,6-difluoropyridine (530 μl, 1.2 eq) was added, followed by Hunig's base (2.2 ml, 2.6 eq). The reaction was heated to 100 °C overnight.

[0214] 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.

[0215] The crude oil was purified on an ISCO (40 g silica gel, eluting with hexanes, using 5%-20% ethyl acetate / hexanes over 5 min) to give 2-fluoro-6-[(3R)-3-methoxypiperidin-1-yl]pyridine (0.85 g as an oil, HPLC Rf 2.90 min, 85% yield, MS m / z (M+1) 211.2 (very weak), TLC 10% ethyl acetate / hexanes Rf 0.14).

[0216] Step (ii) 3-Bromo-2-fluoro-6-[(3R)-3-methoxypiperidin-1-yl]pyridine

[0217]

[0218] 2-Fluoro-6-[(3R)-3-methoxypiperidin-1-yl]pyridine (0.85 g, 4.0 mmol) was dissolved in acetonitrile (15 ml), cooled in an ice bath, and N-bromosuccinimide (NBS; 0.72 g, 1 eq) was added in 2 portions. The reaction was stirred at 0 °C for 5 min and then at room temperature for 30 min.

[0219] Diethyl ether was added to the mixture, 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.

[0220] The crude product was purified on an ISCO (40 g silica gel, eluting with hexanes / DCM, using 5%-20% ethyl acetate / hexanes over 5 min) to give 3-bromo-2-fluoro-6-[(3R)-3-methoxypiperidin-1-yl]pyridine (1.13 g as an oil, HPLC Rf 3.31 min, 97% yield, MS m / z (M+1) 289.0, 291.0, TLC 20% ethyl acetate / hexanes Rf 0.19).

[0221] Step (iii) 6-[(tert-Butyldimethylsilyl)oxy]-2-{2-fluoro-6-[(3R)-3-methoxypiperidin- 1-yl]pyridin-3-yl}-1H-indole-1-carboxylic acid tert-butyl ester

[0222]

[0223] In a 20 ml microwave vial, 3-bromo-2-fluoro-6-[(3R)-3-methoxypiperidin-1-yl]pyridine (145 mg, 0.5 mmol) and {1-[(tert-butoxy)carbonyl]-6-[(tert-butyldimethylsilyl)oxy]-1H-indol-2-yl}boronic acid (300 mg, 1.5 eq) were dissolved in dioxane (3 ml). The solution was bubbled with N2 for 5 min, then Pd(dppf)Cl2 DCM (20 mg, 5 mol%) was added, followed by 2M K2CO3 (0.75 ml, 3 eq). The solution was bubbled with N2 again for 5 min. The reaction was capped and then placed in a preheated oil bath. The reaction was heated to 90 °C for 1 h.

[0224] 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.

[0225] The crude product was purified on an ISCO (25 g silica gel, eluted with DCM, eluted with 10%-15% ethyl acetate / hexane for 5 min) to give tert-butyl 6-[(tert-butyldimethylsilyl)oxy]-2-{2-fluoro-6-[(3R)-3-methoxypiperidin-1-yl]pyridin-3-yl}-1H-indole-1-carboxylate (201 mg foam, yield 73%, HPLC Rf 4.84 min, MS m / z (M+1) 556.3, TLC 20% ethyl acetate / hexane Rf 0.25).

[0226] Step (iv) 2-{2-Fluoro-6-[(3R)-3-methoxypiperidin-1-yl]pyridin-3-yl}-6-hydroxy-1H-indole -1- Carboxylic acid tert-butyl ester

[0227]

[0228] tert-Butyl 6-[(tert-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 in an ice bath, and 1M TBAF solution (400 μl, 1.1 eq) was added. The reaction was stirred at 0 °C for 10 min.

[0229] The reaction was diluted with ethyl acetate, treated with brine, dried over MgSO4, and then filtered. The solvent was removed in vacuo to give the crude product.

[0230] The crude product was purified on ISCO (12 g silica gel, eluted with DCM, eluted with 20%-35% ethyl acetate / hexane for 4 min) to obtain tert-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, yield 99%, TLC Rf 30% ethyl acetate / hexane Rf 0.16).

[0231] Step (v) 2-{2-Fluoro-6-[(3R)-3-methoxypiperidin-1-yl]pyridin-3-yl}-1H-indol-6-ol

[0232]

[0233] In a 5 ml microwave vial, tert-butyl 2-{2-fluoro-6-[(3R)-3-methoxypiperidin-1-yl]pyridin-3-yl}-6-hydroxy-1H-indole-1-carboxylate (159 mg, 0.36 mmol) was dissolved in methanol (3 ml). The reaction was subjected to microwave treatment at 150 °C for 60 min.

[0234] A few drops of water were added to the clear solution, and a solid was obtained with a N2 stream to obtain 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, yield 67%, TLC Rf 30% ethyl acetate / hexane Rf 0.16).

[0235] Example Compound 5: 2-{2-Fluoro-6-[3-methoxypiperidin-1-yl]pyridin-3-yl}-1H-indol-5-ol

[0236]

[0237] Step (i) 2-Fluoro-6-[3-methoxypiperidin-1-yl]pyridine

[0238]

[0239] 3-Methoxypiperidine (1.1 g, 9.4 mmol) was dissolved in dioxane (8 ml), 2,6-difluoropyridine (0.95 ml, 1.1 eq) was added, and then Hunig's base (2.4 ml, 1.5 eq) was added. The reaction was heated to 100 °C for 4 h.

[0240] 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 obtain a crude oil.

[0241] The crude oil was purified on ISCO (40 g silica gel, eluted with hexane, eluted with 5%-20% ethyl acetate / hexane for 5 min) to obtain 2-fluoro-6-[3-methoxypiperidin-1-yl]pyridine (1.29 g oil, HPLC Rf 2.85 min, yield 76%, MS m / z (M+1) 211.0 (very weak), TLC 10% ethyl acetate / hexane Rf 0.14).

[0242] Step (ii) 3-Bromo-2-fluoro-6-[3-methoxypiperidin-1-yl]pyridine

[0243]

[0244] 2-Fluoro-6-[3-methoxypiperidin-1-yl]pyridine (1.2 g, 6.1 mmol) was dissolved in acetonitrile (25 ml), cooled in an ice bath, and NBS (1.1 g, 1 eq) was added in two portions. The reaction was stirred at 0 °C for 5 min and then at room temperature for 30 min.

[0245] Diethyl ether was added to the mixture, the solution was washed with water, treated with brine, dried over MgSO4, and then filtered. The solvent was removed in vacuo to obtain the crude product.

[0246] The crude product was purified on ISCO (40 g silica gel, eluted with hexane / DCM, eluted with 5%-15% ethyl acetate / hexane for 3 min) to obtain 3-bromo-2-fluoro-6-[3-methoxypiperidin-1-yl]pyridine (1.62 g oil, HPLC Rf 3.31 min, yield 92%, MS m / z (M+1) 288.9, 290.9, TLC 20% ethyl acetate / hexane Rf 0.19).

[0247] Step (iii) tert-Butyl 5-[(tert-butyldimethylsilyl)oxy]-2-{2-fluoro-6-[3-methoxypiperidin-1-yl] pyridin-3-yl}-1H-indole-1-carboxylate

[0248]

[0249] In a 5 ml microwave vial, 3-bromo-2-fluoro-6-[3-methoxypiperidin-1-yl]pyridine (145 mg, 0.5 mmol) and {1-[(tert-butoxy)carbonyl]-5-[(tert-butyldimethylsilyl)oxy]-1H-indol-2-yl}boronic acid (235 mg, 1.2 eq) were dissolved in dioxane (3 ml). The solution was bubbled with N2 for 1.5 min, then Pd(dppf)Cl2 DCM (20 mg, 5 mol%) was added, followed by 2M K2CO3 (0.75 ml, 3 eq). The solution was bubbled with N2 again for 5 min, capped, and then placed in a preheated oil bath. The reaction was heated to 90 °C for 1 h.

[0250] 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 afford the crude product.

[0251] The crude product was purified on ISCO (25 g silica gel, eluted with DCM, eluted with 5%-15% ethyl acetate / hexane for 6 min) to give tert-butyl 5-[(tert-butyldimethylsilyl)oxy]-2-{2-fluoro-6-[3-methoxypiperidin-1-yl]pyridin-3-yl}-1H-indole-1-carboxylate (260 mg foam, yield 94%, HPLC Rf 4.42 min, MS m / z (M+1) 556.3, TLC 20% ethyl acetate / hexane Rf 0.22).

[0252] Step (iv) tert-Butyl 2-{2-fluoro-6-[3-methoxypiperidin-1-yl]pyridin-3-yl}-5-hydroxy-1H-indole-1-carboxylate tert-Butyl

[0253]

[0254] tert-Butyl 5-[(tert-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 in an ice bath, and 1 M TBAF solution (0.51 ml, 1.1 eq) was added. The reaction was stirred at 0 °C for 10 min.

[0255] The reaction was diluted with ethyl acetate, treated with brine, dried over MgSO4, and then filtered. The solvent was removed in vacuo to afford the crude product.

[0256] The crude product was purified on ISCO (12 g silica gel, eluted with DCM, eluted with 20%-35% ethyl acetate / hexane for 5 min) to give tert-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, yield 99%, TLC Rf 50% ethyl acetate / hexane Rf 0.49).

[0257] Step (v) 2-{2-fluoro-6-[3-methoxypiperidin-1-yl]pyridin-3-yl}-1H-indol-5-ol

[0258]

[0259] In a 5 ml microwave vial, tert-butyl 2-{2-fluoro-6-[3-methoxypiperidin-1-yl]pyridin-3-yl}-5-hydroxy-1H-indole-1-carboxylate (204 mg, 0.46 mmol) was dissolved in methanol (5 ml). The reaction was subjected to microwave irradiation at 150 °C for 90 min.

[0260] The solid was crystallized from the solution, and the solution was filtered to obtain 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, yield 35%).

[0261] Example Compound 6: 2-{2-Fluoro-6-[(3S)-3-( 3 piperidin-1-yl)methoxy]pyridin-3-yl}-1H-indole- 5-ol

[0262]

[0263] Step (i) tert-Butyl 5-hydroxy-2-{6-[(3S)-3-methoxypiperidin-1-yl]-2-nitropyridin-3-yl}-1H-indole- 1-carboxylate

[0264]

[0265] To (3S)-tert-butyl 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 (scraper tip), and the reaction was stirred at room temperature for 20 min. To the solution was added iodine dissolved in DMF (0.2 ml) 3 H3) methane (74 mCi), and the reaction was stirred overnight.

[0266] The reaction was quenched with ammonium chloride solution, extracted with ethyl acetate, dried over sodium sulfate, filtered, and the solvent was removed by a stream of N2.

[0267] The intermediate was purified on a silica gel column (Pasteur pipette), eluted with ethyl acetate / hexane 1:3, and the fractions containing activity were collected, and the solvent was removed by a stream of N2.

[0268] The product was dissolved in dioxane (0.5 ml), cooled in an ice bath, and a solution of 4 M HCl in dioxane (0.5 ml) was added. The reaction was stirred at room temperature for 1 h and then at 45 °C for 30 min. The solvent was removed by a stream of N2 to obtain (3S)-3-( 3 H3)methoxypiperidine HCl, which was used as such in the next reaction.

[0269] Step (ii) 2-{2-fluoro-4-[(3S)-3-( 3 H 3 ) methoxypiperidin-1-yl]phenyl}-1H-indol-5-ol

[0270]

[0271] Dissolve (3S)-3-( 3 H3)methoxypiperidine HCl (from the above reaction) in methanol (0.5 ml). Add tert-butyl 2-(2,6-difluoropyridin-3-yl)-5-hydroxy-1H-indole-1-carboxylate (3.8 mg, 11 μmol, for the manufacturing method, see WO2021074351 A1) and Hunig's base (10 μl, in excess) to this solution, and subject the reaction to microwave treatment at 150 °C for 60 min.

[0272] Cool the reacted mixture and evaporate it, and purify the residue on HPLC (Kromasil C18, 250x10 mm, eluting with 0.1% TFA containing 70% acetonitrile) to obtain 2-{2-fluoro-4-[(3S)-3-( 3 H3)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).

[0273] Example Compound 7: 2-[2-( 18 F)fluoro-6-[(3S)-3-methoxypiperidin-1-yl]pyridin-3-yl]-1H-indole -5-ol

[0274]

[0275] Step (i) 2-[(3S)-3-Methoxypiperidin-1-yl]-6-nitropyridine

[0276]

[0277] Suspend 2-chloro-6-nitropyridine (0.63 g, 4 mmol) and (S)-3-methoxypiperidine HCl (0.9 g, 1.5 eq) in dioxane (6 ml), and then add Hunig's base (2.9 ml, 1.5 eq). Heat the reaction to 100 °C for 19 h.

[0278] Incorporate the cooled reaction mixture into ethyl acetate, wash with water, treat with brine, dry over MgSO4, and filter. Remove the solvent in vacuo to obtain a crude oil.

[0279] Purify the crude product on ISCO (40 g silica gel, eluting with hexane, eluting with 15%-30% ethyl acetate / hexane over 8 min) to obtain 2-[(3S)-3-methoxypiperidin-1-yl]-6-nitropyridine (0.63 g of oil, HPLC Rf 2.91 min, yield 67%, MS m / z (M+1) 238.2 (very weak), TLC 30% ethyl acetate / hexane Rf 0.22).

[0280] Step (ii) 3-Bromo-6-[(3S)-3-methoxypiperidin-1-yl]-2-nitropyridine

[0281]

[0282] Dissolve 2-[(3S)-3-methoxypiperidin-1-yl]-6-nitropyridine (0.61 g, 2.6 mmol) in acetonitrile (15 ml), cool in an ice bath, and add NBS (0.65 g, 1 eq). Stir the reaction at 0 °C for 5 min, then at room temperature for 60 min.

[0283] Incorporate the reaction into ethyl acetate, treat twice with brine, dry over MgSo4, and filter. Remove the solvent in vacuo to obtain the crude product.

[0284] Purify the crude product on ISCO (40 g silica gel, eluted with hexane / DCM, eluted with 15%-30% ethyl acetate / hexane for 6 min) to obtain 3-bromo-6-[(3S)-3-methoxypiperidin-1-yl]-2-nitropyridine (0.74 g oil, HPLC Rf 3.27 min, yield 91%, MS m / z (M+1) 316.0, 318.0, TLC 60% ethyl acetate / hexane Rf 0.30).

[0285] Step (iii) tert-Butyl 5-[(tert-butyldimethylsilyl)oxy]-2-{6-[(3S)-3-methoxypiperidin-1- yl]-2-nitropyridin-3-yl}-1H-indole-1-carboxylate

[0286]

[0287] In a 20 ml microwave vial, dissolve 3-bromo-6-[(3S)-3-methoxypiperidin-1-yl]-2-nitropyridine (316 mg, 1 mmol) and {1-[(tert-butoxy)carbonyl]-5-[(tert-butyldimethylsilyl)oxy]-1H-indol-2-yl}boronic acid (550 mg, 1.4 eq) in dioxane (6 ml). Bubble the solution with N2 for 2 min, then add Pd(dppf)Cl2DCM (41 mg, 5 mol%), then add 2M K2CO3 (31.5 ml, 3 eq). Bubble the solution with N2 again for 5 min, cap, and then place in a preheated oil bath. Run the reaction at 90 °C for 1 h.

[0288] Remove the aqueous phase from the cooled reaction mixture, and then dilute the reaction mixture with ethyl acetate, dry over MgSO4, and filter. Remove the solvent in vacuo to obtain the crude product.

[0289] The crude product was purified on ISCO (40 g silica gel, eluted with DCM, eluted with 10%-20% ethyl acetate / hexane for 6 min) to obtain tert-butyl 5-[(tert-butyldimethylsilyl)oxy]-2-{6-[(3S)-3-methoxypiperidin-1-yl]-2-nitropyridin-3-yl}-1H-indole-1-carboxylate (334 mg foam, yield 57%, HPLC Rf 4.37 min, MS m / z (M+1) 583.4, TLC 20% ethyl acetate / hexane Rf 0.16, 1 H NMR (400 MHz, CDCI3) δ 7.70 (d, J = 9.0 Hz, 1H), 6.72 (d, J = 9.0 Hz, 1H), 3.85 (ddt, J = 13.2, 3.4, 1.1 Hz, 1H), 3.68 (ddd, J = 13.3, 6.6, 3.8 Hz, 1H), 3.52–3.31 (m, 6H), 2.05–1.94 (m, 1H), 1.88 (ddp, J = 14.2, 7.3, 3.6 Hz, 1H), 1.69 (ddt, J = 12.8, 8.7, 3.9 Hz, 1H), 1.61–1.48 (m, 1H). 13 C NMR (101 MHz, CDCI3) δ 156.28, 144.12, 110.93, 93.14, 77.36, 77.04, 76.73, 74.58, 56.40, 48.46, 45.43, 29.58, 21.80).

[0290] Step (iv) tert-Butyl 5-hydroxy-2-{6-[(3S)-3-methoxypiperidin-1-yl]-2-nitropyridin-3-yl}-1H-ind ole-1-carboxylate

[0291]

[0292] tert-Butyl 5-[(tert-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 in an ice bath, and 1 M TBAF solution (450 μl, 1.1 eq) was added. The reaction was stirred at 0 °C for 10 min.

[0293] The reaction was diluted with ethyl acetate, treated with brine, dried over MgSO4, and filtered. The solvent was removed in vacuo to obtain the crude product.

[0294] The crude product was purified on ISCO (12 g silica gel, eluted with DCM, eluted with 25%-40% ethyl acetate / hexane for 5 min) to obtain tert-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, yield 75%, TLC Rf 40% ethyl acetate / hexane Rf 0.16, 1 H NMR (400 MHz, CDCl3) δ 8.03 (d, J = 8.9 Hz, 1H), 7.56 (d, J = 8.6 Hz, 1H), 6.91 (d, J = 2.5 Hz, 1H), 6.88–6.81 (m, 2H), 6.35 (d, J = 0.7 Hz, 1H), 3.95 (dd, J = 13.3, 3.3 Hz, 1H), 3.76 (ddd, J = 13.4, 6.5, 3.8 Hz, 1H), 3.56 (dd, J = 13.3, 7.2 Hz, 1H), 3.42 (s, 4H), 3.37 (tt, J = 7.2, 3.5 Hz, 1H), 2.00 (dq, J = 11.6, 3.6 Hz, 1H), 1.88 (dtt, J = 13.9, 7.1, 3.6 Hz, 1H), 1.69 (dtd, J = 12.5, 8.2, 3.7 Hz, 1H), 1.55 (ddt, J = 15.2, 8.8, 4.1 Hz, 1H), 1.39 (s, 9H).

[0295] 13 C NMR (101 MHz, CDCI3) δ 156.82, 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).

[0296] Step (v) 2-[2-( 18 F)fluoro-6-[(3S)-3-methoxypiperidin-1-yl]pyridin-3-yl]-1H-indol-5-ol

[0297]

[0298] Via 18 O(p,n) 18 F reaction (Scanditronix MC-17 cyclotron) to produce carrier-free 18 F]F - and use it in 18Transfer to an automated radiochemistry synthesizer (GE Tracerlab FX2N) in a lead-shielded hot cell in water. 18 F]F - was trapped on a PS-HCO3 ion exchange column (Chromafix), and then eluted with water / methanol (10 / 90, 1 mL) containing K2CO3 (1.37 mg, 10 μmol) and Kryptofix 2.2.2 (14 mg, 5 μmol) into the reaction vessel. The solvent was evaporated under vacuum and then co-dried with acetonitrile (1 mL) under a continuous nitrogen stream. The precursor (S)-tert-butyl 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, and methanol (2 mL) was added, then heated to 130 °C for 20 min. Then the reactor was cooled to 50 °C, and the reaction mixture was diluted with acetonitrile:water (20:80) and then injected into a reverse-phase HPLC column (LUNA 10 μm C18(2) 250 mm × 10 mm, Phenomenex). 2-[2-( 18 F)fluoro-6-[(3S)-3-methoxypiperidin-1-yl]pyridin-3-yl]-1H-indol-5-ol was eluted with a mobile phase of acetonitrile-NH4CO2H aq (0.05 M) (45 / 55, v / v) at a flow rate of 5 mL / min. The retention time of 2-[2-( 18 F)fluoro-6-[(3S)-3-methoxypiperidin-1-yl]pyridin-3-yl]-1H-indol-5-ol was 14 min to 16 min. The collected fractions were diluted with water (20 mL) and loaded onto a solid-phase extraction (SPE) column (SepPak tC18, Waters). The SPE column was washed with water (10 mL), and then 2-[2-( 18 F)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 120PFP, 4.6 × 150 mm, 2.7 μm, Agilent), where the UV and γ detectors were connected in series. 2-[2-( 18F) 2-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 min to 4.5 min). The radiochemical identity was confirmed by co-injecting an authentic sample of 2-{2-fluoro-6-[(3S)-3-methoxypiperidin-1-yl]pyridin-3-yl}-1H-indol-5-ol (Example Compound 1).

[0299] The structures of Example Compound 1 to Example Compound 7 and a summary of the CLogP of the compounds are provided in Table 1 below.

[0300] Table 1 :

[0301]

[0302] Biological Tests

[0303] Example (a): Biological Assay Method and Results

[0304] 3 In vitro competitive binding of H-THK5117 to tau fibrils

[0305] The preparation of recombinant 0N4R tau fibrils was carried out as previously described in Morozova, O.A., Biochemistry (2013), Vol. 52(40), pp. 6960-6967. The competitive binding experiment with 0N4R tau fibrils was carried out by: in the presence of 3 nM of the known tau ligand 3 [3H]-THK5117 (Novandi Chemistry) and 0.2 mM 0N4R tau fibrils, in binding buffer (50 mM Tris-HCl, pH 7.4, 0.1% BSA), in the dark and at 22 °C, increasing concentrations [10 -10 M to 10 -6The exemplary compounds of the present invention or the known tau-specific ligand PBB3 (PBB3 has been synthesized as previously described in M. Maruyama, et al., Neuron 2013, 79, 1094 - 1108) or MK6240 (Novandi Chemistry AB) were incubated for 1 h. The incubation was terminated by filtration through a Whatman GF / B glass filter (Whatman International, Kent, UK) using a Brandel cell harvester. The filter was then washed four times quickly with 3 mL of ice-cold wash buffer (5 mM Tris-HCl, 0.25 mM NaCl, 5% EtOH) and equilibrated for 1 h in a scintillation vial containing 5 mL of Ultima Gold scintillation fluid, and then analyzed using a liquid scintillation analyzer.

[0306] The results are shown in Table 2 in the column labeled "tauIC 50 ". For compounds that were run more than once in the competitive binding experiment, the tauIC 50 values in Table 2 are the average of the results for each experiment.

[0307] Biological Assay Results

[0308] Table 2 :

[0309] Example Compound Number <![CDATA[tauIC 50 (nM)]]> 1 1.7 2 31.8 3 n.d 4 n.d 5 n.d 6 n.d

[0310] n.d = not determined.

[0311] The results in Table 2 indicate that the exemplary compounds of the present invention have high-affinity binding to recombinant 4R tau fibrils.

[0312] Example (b): Intravenous (IV) Pharmacokinetic Study and Bioanalysis of Example Compound 1 and Comparative Compound 1 in Mice Bioanalysis

[0313] Pharmacokinetic studies of plasma and brain exposure in mice after IV administration of Example Compound 1 or Comparative Example Compound 1 were conducted according to the protocol described in Loryan, I. et al., Pharm Res (2014) 31:2203 - 2219. Comparative Example Compound 1 is 2-{2-fluoro-6-[4-(hydroxymethyl)piperidin-1-yl]pyridin-3-yl}-1H-indol-5-ol and has the following structure:

[0314]

[0315] Comparative Example Compound 1 is Example Compound No. 48 as disclosed in WO2019 / 197502A1 and was synthesized as described in that document.

[0316] Experimental Protocol and Bioanalysis

[0317] Mouse plasma and brain exposures were measured according to the experimental protocol and bioanalysis described in Loryan, I. et al., Pharm Res (2014) 31:2203 - 2219. Table 3 below provides specific details of mouse, sampling, dose, formulation, method, and additional information about the experiment, and Table 4 below provides further information about sampling in the experiment. As can be seen from Table 4, n = 3 mice at each time point.

[0318] Table 3 :

[0319]

[0320]

[0321] Table 4 :

[0322]

[0323]

[0324] x - Whole blood serial sampling of plasma via the tail vein

[0325] X - Terminal whole blood sampling of plasma via the tail vein and, in addition, brain sampling.

[0326] Results

[0327] No adverse events were observed in the mice during the study. Tables 5 and 6 below show a summary (mean, n = 3) of the pharmacokinetic (PK) parameters measured for Example Compound 1 in plasma (Table 5) and brain (Table 6) after administration of Example Compound 1 at 1 mg / kg IV.

[0328] Table 5 :

[0329] PK Parameters Unit Results <![CDATA[t 1 / 2 > hr 0.4 <![CDATA[T max > hr 0.03 <![CDATA[C max > ng / mL 781.7 <![CDATA[AUC last > hr*ng / mL 263.5 <![CDATA[AUC inf > hr*ng / mL 267.1 Cl mL / min / kg 62.4 Vd L / kg 1.2 MRT hr 0.3 <![CDATA[C0]]> ng / mL 883.8

[0330] Table 6 :

[0331]

[0332]

[0333] Table 7 below shows the AUCs in brain and plasma for the total and unbound concentrations of Example Compound 1 and Comparative Compound 1, as well as the corresponding brain:plasma ratios for each compound.

[0334] Table 7 :

[0335]

[0336] Figure 1 The total concentration-time profiles in plasma and brain following IV administration of Example Compound 1 are shown.

[0337] The data indicate that Example Compound 1 readily enters the brain following IV administration and is eliminated with an elimination half-life of approximately 0.3 hours.

[0338] The total and unbound concentration brain:plasma ratios indicate that for Comparative Example Compound 1, the ability of the compound to penetrate the brain is limited, as the unbound AUC in the brain is only approximately 0.2% of the corresponding plasma AUC. In contrast, the unbound AUC in the brain for Example Compound 1 is approximately 56% of the plasma AUC. This indicates that Example Compound 1 has good brain penetration.

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, wherein: R 1 is OH, and R 2 is H; or R 1 is H, and R 2 is OH.

2. The compound according to claim 1, wherein the compound is a compound of formula (Ia) or formula (Ib):

3. The compound according to claim 1 or claim 2, wherein the compound has a structural formula selected from the following group:

4. A compound according to any one of the preceding claims, wherein the compound comprises one or more radioisotopes selected from the following: 3 H, 11 C, 13 C, 14 C, 13 N, 15 O, 18 F and 19 F.

5. The compound according to claim 4, wherein the compound comprises one or more radioisotopes selected from 18 F and 3 H.

6. The compound according to claim 5, wherein the compound has a structural formula selected from the following group:

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

8. The pharmaceutical composition according to claim 7, wherein the composition contains an additional active ingredient.

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

10. 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, wherein the compound comprises one or more radioisotopes selected from the following: 3 H, 11 C, 13 C, 14 C, 13 N, 15 O, 18 F and 19 F.

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

12. The compound according to any one of claims 1 to 6 or 10 or the composition according to any one of claims 7 to 10, which is used as a diagnostic agent in diagnosing or monitoring the progression of a disease or disorder selected from the group consisting of: Alzheimer's disease, corticobasal degeneration, Pick's disease, progressive supranuclear palsy, 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 with parkinsonism linked to chromosome 17, postencephalitic parkinsonism, Guadeloupean type parkinsonism, globular glial 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 type dementia, familial Danish dementia, pugilistic dementia, tangle-predominant Alzheimer's disease, Huntington's disease, Lewy body disease, prion disease, subacute sclerosing panencephalitis, subacute sclerosing panencephalitis, diffuse neurofibrillary tangles with calcification, neurodegeneration with brain iron accumulation, mutations affecting the sodium / proton exchanger, cerebrotendinous xanthomatosis with the C.379C>T (p.R127W) mutation in the CYP27A1 gene, the TARDBP mutation p.Ile383VaI associated with semantic dementia, non-Guam type motor neuron disease with neurofibrillary tangles, argyrophilic grain disease, Hallervorden-Spatz disease, multiple system atrophy, pallidopontine nigral degeneration, progressive subcortical gliosis, tangle-only dementia, myotonic dystrophy, tau panencephalopathy, AD-like with astrocytes, Gerstmann-Straussler-Scheinker disease regarding tau, mutations in LRRK2, SLC9A6-related mental retardation, and white matter tauopathy with globular glial inclusions.

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

14. A method of diagnosing a patient or monitoring the progression of a disease in a patient according to claim 13, wherein the compound comprises one or more radioisotopes selected from the following: 3 H, 11 C, 13 C, 14 C, 13 N, 15 O, 18 F, and 19 F.

15. The method for diagnosing or monitoring progression according to claim 13 or 14, the method further comprising detecting the 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. The compound or composition according to claim 16, for use in the prevention or treatment of a disease or disorder selected from the group consisting of: Alzheimer's disease, corticobasal degeneration, Pick's disease, progressive supranuclear palsy, Parkinson's disease, Creutzfeldt-Jakob disease, familial Alzheimer's disease, argentophilic grain disease, prion protein cerebral amyloid angiopathy, traumatic brain injury, amyotrophic lateral sclerosis, frontotemporal dementia with parkinsonism linked to chromosome 17, postencephalitic parkinsonism, Guadeloupean type parkinsonism, globular glial tauopathy, aging-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-type dementia, familial Danish dementia, pugilistic dementia, tangle-predominant senile dementia, Huntington's disease, Lewy body dementia, prion disease, subacute sclerosing panencephalitis, subacute sclerosing panencephalitis, diffuse neurofibrillary tangles with calcification, neurodegeneration with brain iron accumulation, mutations affecting sodium / proton exchangers, cerebrotendinous xanthomatosis with the c.379C>T (p.R127W) mutation in the CYP27A1 gene, the TARDBP mutation p.Ile383VaI associated with semantic dementia, non-Guam type motor neuron disease with neurofibrillary tangles, argentophilic grain disease, Hallervorden-Spatz disease, multiple system atrophy, pallidopontine nigral degeneration, progressive subcortical gliosis, tangle-only dementia, myotonic dystrophy, tau panencephalopathy, AD-like with astrocytes, Gerstmann-Straussler-Scheinker disease with respect to tau, mutations in LRRK2, SLC9A6-related mental retardation, and white matter tauopathy with globular glial inclusions.

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