Novel compounds for tau imaging

Abstract

The present disclosure provides novel compounds of the formula: wherein R1, R2, and R3 are as described herein, methods of preparing the same, pharmaceutical compositions the same, tau imaging formulations, and methods of using the compounds for tau imaging.

Description

[14] In some embodiments, the present disclosure provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula Ic: Formula Ic.

[15] In some embodiments, the present disclosure provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula Id: Formula Id.

[16] In some embodiments, the present disclosure provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula Ie: Formula Ie.

[17] In some embodiments, the present disclosure provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein: R1 is H, iodine, -OH, or -OCH3; R2 is H, bromine, iodine, or -CH=CH2; R3 is phenyl, pyrrolidyl, or piperidyl, wherein the phenyl, pyrrolidyl, or piperidyl is substituted with one or more R3a; and each R3a independently is F, 18F, Ci alkyl, C2 alkyl, C3 alkyl, or azetidinyl, wherein the Ci alkyl, C2 alkyl, C3 alkyl, or azetidinyl is substituted with F or 18F; provided that the compound is not F                       F

[18] In some embodiments, R1 is H.

[19] In some embodiments, R1 is-OH.

[20] In some embodiments, R1 is -OCH3.

[21] In some embodiments, R2 is H.

[22] In some embodiments, R2 is halogen.

[23] In some embodiments, R2 is bromine or iodine. In some embodiments, R2 is bromine. In some embodiments, R2 is iodine.

[24] In some embodiments, R2 is -CH=CH2.

[25] In some embodiments, R3 is phenyl substituted with one or more R3a. In some embodiments, R3 is phenyl substituted with one R3a.

[26] In some embodiments, R3 is 3- to 6-membered heterocycloalkyl substituted with one or more R3a. In some embodiments, R3 is 3-membered heterocycloalkyl substituted with one or more R3a. In some embodiments, R3 is 4-membered heterocycloalkyl substituted with one or more R3a. In some embodiments, R3 is 5-membered heterocycloalkyl substituted with one or more R3a. In some embodiments, R3 is 6membered heterocycloalkyl substituted with one or more R3a.

[27] In some embodiments, R3 is 3- to 6-membered heterocycloalkyl substituted with one R3a. In some embodiments, R3 is 3-membered heterocycloalkyl substituted with one R3a. In some embodiments, R3 is 4-membered heterocycloalkyl substituted with one R3a. In some embodiments, R3 is 5-membered heterocycloalkyl substituted with one R3a. In some embodiments, R3 is 6-membered heterocycloalkyl substituted with one R3a.

[28] In some embodiments, R3 is 3- to 5-membered heterocycloalkyl substituted with one or more R3a. In some embodiments, R3 is 3- to 5-membered heterocycloalkyl substituted with one R3a.

[29] In some embodiments, R3 is azetidinyl substituted with one or more R3a. In some embodiments, R3 is azetidinyl substituted with one R3a.

[30] In some embodiments, R3 is pyrrolidinyl substituted with one or more R3a. In some embodiments, R3 is pyrrolidinyl substituted with one R3a.

[31] In some embodiments, R3 is piperidinyl substituted with one or more R3a. In some embodiments, R3 is piperidinyl substituted with one R3a.

[32] In some embodiments, R3a is F or 18F.

[33] In some embodiments, R3a is Ci alkyl, C2 alkyl, or C3 alkyl, wherein the Ci alkyl, C2 alkyl, or C3 alkyl is substituted with F or 18F. In some embodiments, R3a is Ci alkyl substituted with F or 18F. In some embodiments, R3a is C2 alkyl substituted with F or 18F. In some embodiments, R3a is C3 alkyl substituted with F or 18F.

[34] In some embodiments, R3a is azetidinyl is substituted with F or 18F.

[35] In some embodiments, the leaving group is methanesulfonate (i.e., mesylate) or 4-methylbenzenesulfonate (i.e., tosylate). In some embodiments, the leaving group is methanesulfonate (i.e., mesylate). In some embodiments, the leaving group is 4-methylbenzenesulfonate (i.e., tosylate).

[36] In some embodiments, the present disclosure provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound represented in Table 1. Table 1. Compounds

[37] In some embodiments, the present disclosure provides a compound, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound represented in Table 2. Table 2. Compounds

[38] In some embodiments, the present disclosure provides a compound, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound represented in Table 3. Table 3. Compounds Comp. No. Structure

[39] In some embodiments, the present disclosure provides precursor compounds that can be converted into compounds for tau imaging. In some embodiments, the precursor compounds themselves may be useful for tau imaging. The present disclosure provides a compound, or a pharmaceutically acceptable salt thereof, of formula (II): wherein, R1 is H, -OH, or Ci-Ce alkoxyl; R2 is H; R3 is Ce-Cio aryl or 3- to 6-membered heterocycloalkyl, wherein the Ce-Cio aryl or 3- to 6-membered heterocycloalkyl is substituted with one or more R3a; and each R3a independently is a leaving group, Ci-Ce alkyl, or 3- to 6-membered heterocycloalkyl, wherein the Ci-Ce alkyl or 3- to 6-membered heterocycloalkyl is substituted with a leaving group.

[40] In some embodiments, the compound of Formula (II) is a precursor compound for making radiolabeled compounds. In some embodiments, the precursor compound may be useful for imagin.

[41] In some embodiments, the compound, or pharmaceutically acceptable salt thereof, of the compound of formula (II) is: Comp. No. Structure 16 "do C / / 0^0 z o o 17 ,,     / =\              o lr\ / ^n \ N                u 18 19 20 21 N                                   , or 22 / =\    / -_      O / ^N )__ >-N         #

[42] The compounds of the present disclosure were prepared in radiolabeled and nonradiolabeled forms. For example, each of Compound Nos. 1-15, as represented in Table 1, were prepared with a naturally occurring F and a radiolabeled 18F. The notation “F(18F)” is understood to disclose the compound with naturally occurring F, and with the 18F radioisotope. It is to be understood, unless otherwise specified, that any reference to a compound, by number (e.g., Compound No. 1, Compound No. 2, etc. or Comp. No. 1, Comp. No. 2, etc.) or by structure, encompasses both its naturally occurring isotope (e.g., Comp. No. 1(F)) and its radiolabeled isotope (e.g., Compound No. 1(18F)).

[43] In yet other forms, the present disclosure provides a pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt thereof according to Formula I above as described in the various forms above and one or more of a pharmaceutically acceptable carrier, diluent, or stabilizer. Examples of pharmaceutical compositions and processes for their preparation can be found in “Remington: The Science and Practice of Pharmacy”, Loyd, V., et al. Eds., 22nd Ed., Mack Publishing Co., 2012.

[44] In another form, the present disclosure provides a pharmaceutical composition comprising a compound according to Formula I, or a pharmaceutically acceptable salt thereof, as described in the various forms above wherein the carrier comprises ethanol, water, and a buffer suitable for injection into a patient. In some embodiments, the composition includes sodium chloride in an amount to provide a formulation suitable for injection into a patient.

[45] In this form, the buffer may comprise sodium chloride, sodium phosphate, or sodium ascorbate.

[46] Examples of diluents includes water for injection and saline. The diluent can be included in the pharmaceutical composition in an amount sufficient to provide a concentration of the radiolabeled embodiment of a compound of Formula I, or a pharmaceutically acceptable salt thereof, suitable to facilitate the diagnosis of a patient at risk for or suffering from dementia or AD.

[47] Examples of stabilizers, in particular radiolytic stabilizers, include ethanol, ascorbic acid, monothioglycerol, vitamin E, and cysteine.

[48] The compounds of the present disclosure may be formulated as pharmaceutical compositions that are administered for intravenous use in a patient (e.g., in humans). Such pharmaceutical compositions and processes for preparing the compositions are known in the art. See, e.g., Remington: The Science and Practice of Pharmacy (P.P. Gerbino, 21st ed., Lippincott Williams & Wilkins, 2006). Methods of using tau imaging agents for PET imaging of tau are known to those of skill in the art. See e.g. [(18)F]T807, a novel tau positron emission tomography imaging agent for Alzheimer's disease. Xia CF, et al., Alzheimer’s Dement. 2013 Nov; 9(6):666-76.). [(18)F]T807 is also known as [18F]AV-1451.

[49] In another aspect the invention provides a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, for imaging tau. The tau imaging formulation may be formulated for use in mammals (e.g., humans). In one embodiment, the tau imaging formulation includes a compound according to Formula I, or a pharmaceutically acceptable salt thereof, formulated in 10% EtOH (v / v), 0.45% (w / v) sodium ascorbate in 0.9% sodium chloride.

[50] The present disclosure also provides methods of imaging tau comprising introducing into a patient a detectable quantity of a compound of Formula I, or a pharmaceutically acceptable salt thereof. In another form the present disclosure provides methods of imaging tau comprising introducing into a patient a pharmaceutical composition comprising a detectable quantity of a compound of Formula I, or a pharmaceutically acceptable salt thereof.

[51] The present disclosure provides a method of imaging tau comprising introducing into a mammal a detectable quantity of a pharmaceutical composition as described according to the embodiments herein and allowing sufficient time for said pharmaceutical composition to become associated with tau; and detecting the radiolabeled compound. The method for detecting the radiolabeled compound may be PET.

[52] In some embodiments, the present disclosure provides a method of imaging aggregated tau in a mammal, the method comprising: introducing into a mammal a detectable quantity of a compound of Formula I or a pharmaceutical composition comprising a compound of Formula I and one or more pharmaceutically acceptable excipient; wherein said compound or pharmaceutical composition has an 18F substituent; allowing sufficient time for said compound or said pharmaceutical composition to become associated with aggregated tau; and detecting said compound or said pharmaceutical composition.

[53] In some embodiments, the present disclosure provides a method of imaging aggregated tau in a mammal, wherein the mammal is a human.

[54] In some embodiments, the present disclosure provides a method of imaging aggregated tau in a mammal, wherein the mammal is a human and is suspected of having a neurological disease or disorder.

[55] In some embodiments, the neurological disease or disorder is Alzheimer’s Disease.

[56] In some embodiments, the neurological disease or disorder is progressive supranuclear palsy (PSP), cortical basal degeneration (CBD), Pick’s disease (PiD), atypical Alzheimer’s disease, chronic traumatic encephalopathy (CTE), or frontotemporal dementia (FTD).

[57] In some embodiments, the human is suspected of having early Alzheimer’s disease tau.

[58] In some embodiments, the human is suspected of having non-Alzheimer’s disease tau.

[59] The present disclosure provides the use of compounds of Formula I or pharmaceutically acceptable salts thereof. Further, the present disclosure also provides that the compounds (or pharmaceutically acceptable salts) of Formula I may be used, for the manufacture of a radiopharmaceutical agent for imaging tau in a patient (e.g., humans).

[60] The present disclosure provides a process of making a compound according to Formula I with a 18F radiolabel. In certain embodiments, the present disclosure provides methods of preparing a compound of Formula I, or a pharmaceutically acceptable salt thereof, from a precursor compound outlined herein.

[61] In some embodiments, the present disclosure provides a method of preparing a compound of Formula (I), comprising contacting a compound of Formula (II) with a fluorinating agent. In some embodiments, the fluorinating agent is radiolabeled or not radiolabeled.

[62] As used herein, the term “alkoxy” or “alkoxyl” includes substituted and unsubstituted alkyl groups covalently linked to an oxygen atom. Examples of alkoxy groups or alkoxyl radicals include, but are not limited to, methoxy, ethoxy, isopropyloxy, propoxy, butoxy and pentoxy groups. Examples of substituted alkoxy groups include halogenated alkoxy groups. The alkoxy groups can be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moi eties. Examples of halogen substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, di chloromethoxy and trichloromethoxy.

[63] As used herein, “alkyl”, “Ci, C2, C3, C4, C5 or C6 alkyl” or “Ci-C6 alkyl” is intended to include Ci, C2, C3, C4, Cs or Ce straight chain (linear) saturated aliphatic hydrocarbon groups and C3, C4, Cs or Ce branched saturated aliphatic hydrocarbon groups. For example, Ci-Ce alkyl is intended to include Ci, C2, C3, C4, Cs and Ce alkyl groups. Examples of alkyl include, moieties having from one to six carbon atoms, such as, but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl or n-hexyl. In some embodiments, a straight chain or branched alkyl has six or fewer carbon atoms (e.g., Ci-Ce for straight chain, C3-Ce for branched chain), and in another embodiment, a straight chain or branched alkyl has four or fewer carbon atoms. When the term is used with the term halogen or specifically an F atom or an 18F atom, the halogen or F(18F) atom replaces any one of the hydrogen atoms on the carbon chain. In some embodiments, the F or 18F atom is attached to the terminal carbon atom of the chain.

[64] As used herein, the term “alkenyl” includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double bond. For example, the term “alkenyl” includes straight chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl), and branched alkenyl groups. In some embodiments, a straight chain or branched alkenyl group has six or fewer carbon atoms in its backbone (e.g., C2-C6 for straight chain, C3-C6 for branched chain). The term “C2-C4” includes alkenyl groups containing two to four carbon atoms. The term “C2-C6” includes alkenyl groups containing two to six carbon atoms. The term “Cs-Ce” includes alkenyl groups containing three to six carbon atoms. Depending upon the substituents attached to the two carbons of the double bond the geometry about the double bond can be described in as either a cis or trans double bond. When the term is used with a halogen or specifically an F atom or an 18F atom, the halogen or F(18F) atom can be attached replacing one of the hydrogen atoms attached to the carbon backbone of the alkenyl chain.

[65] As used herein, the term “aryl” includes groups with aromaticity, including “conjugated,” or multicyclic systems with one or more aromatic rings and do not contain any heteroatom in the ring structure. The term aryl includes both monovalent species and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl and the like.

[66] As used herein, the term “halo” or “halogen” refers to fluorine, chlorine, bromine, and iodine.

[67] As used herein, the term “heterocycloalkyl” refers to a saturated or partially unsaturated 3-8 membered monocyclic, 7-12 membered bicyclic (fused, bridged, or spiro rings), or 11-14 membered tricyclic ring system (fused, bridged, or spiro rings) having one or more heteroatoms (such as O, N, S, P, or Se), e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or e.g., 1, 2, 3, 4, 5, or 6 heteroatoms, independently selected from the group consisting of nitrogen, oxygen, and sulfur, unless specified otherwise. Examples of heterocycloalkyl groups include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, 1,2,3,6-tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiopyranyl, 1,4-diazepanyl, 1,4-oxazepanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, l,4-dioxa-8-azaspiro[4.5]decanyl, l,4-dioxaspiro[4.5]decanyl, l-oxaspiro[4.5]decanyl, l-azaspiro[4.5]decanyl, 3'H-spiro[cyclohexane-l,l'-isobenzofuran]-yl, 7'H-spiro[cyclohexane-l,5'-furo[3,4-b]pyridin]-yl, 3'H-spiro[cyclohexane-l,l'-furo[3,4-c]pyridin]-yl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexan-3-yl, l,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, 3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidinyl, 4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridinyl, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl, 2-azaspiro[3.3]heptanyl, 2-methyl-2-azaspiro[3.3]heptanyl, 2-azaspiro[3.5]nonanyl, 2-methyl-2-azaspiro[3.5]nonanyl, 2-azaspiro[4.5]decanyl, 2-methyl-2-azaspiro[4.5]decanyl, 2-oxa-azaspiro[3.4]octanyl, 2-oxa-azaspiro[3.4]octan-6-yl, and the like. In the case of multicyclic heterocycloalkyl, only one of the rings in the heterocycloalkyl needs to be non-aromatic (e.g., 4,5,6,7-tetrahydrobenzo[c]isoxazolyl).

[68] The term “leaving group” (LG) refers to a halogen (e.g., Cl, Br, or I), a trialkyl ammonium, alkyl sulfonate, trifluoroalkyl sulfonate, or aryl sulfonate. Alkyl sulfonates of the present disclosure include C1-C4 alkyl sulfonate. Aryl sulfonates of the present disclosure include phenyl sulfonate, wherein the phenyl group is optionally substituted once with C1-C4 alkyl, halogen or nitro. In some embodiments, the leaving group is an alkyl sulfonate (e.g., methanesulfonate (mesylate) or ethanesulfonate). In some embodiments, the leaving group is an aryl sulfonate (e.g., benzenesulfonate, 4-methylbenzenesulfonate (tosylate), 4-bromobenzenesulfonate, or 4-nitrobenzenesulfonate).

[69] The term “radiolabeled compound” refers to one of the compounds described below that includes an 18F atom.

[70] The term “pharmaceutically acceptable salt” as used herein refers to a salt of a compound of the invention considered to be acceptable for clinical and / or veterinary use. Examples of pharmaceutically acceptable salts and common methodology for preparing them can be found in “Handbook of Pharmaceutical Salts: Properties, Selection and Use” P. Stahl, et al., 2nd Revised Edition, Wiley-VCH, 2011 and S.M. Berge, et aL, "Pharmaceutical Salts", Journal of Pharmaceutical Sciences, 1977, 66(1), 1-19.

[71] As used herein, the term “effective amount” refers to an amount that is a dosage, which is effective in imaging tau. The attending physician, as one skilled in the art, can readily determine an effective amount by the use of conventional techniques and by observing results obtained under analogous circumstances. In determining an effective amount or dose of a compound, a number of factors are considered, including, but not limited to whether the compound or its salt, will be administered; the co-administration of other agents, if used; the species of mammal; its size, age, and general health; the degree of involvement or the severity of the disorder; the response of the individual patient; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of other concomitant medication; and other relevant circumstances.

[72] As used herein, the term "patient" refers to a mammal. In some embodiments, the patient is a human or companion mammal, such as, a dog or cat; or other domesticated mammal, such as, a cow, pig, horse, sheep, rabbit, mouse, rat, and goat.

[73] A treating physician, veterinarian, or other medical person will be able to determine an effective amount of the compound for treatment of a patient in need. In some embodiments, pharmaceutical compositions are formulated as an injectable solution. The solution can include a compound of the present disclosure in an amount effective for treating a patient in need of treatment.

[74] The compounds of Formula I have been discovered to be advantageous for tau imaging, including, for example, in human clinical imaging. The compounds of Formula I possess a combination of useful properties for tau imaging, including high affinity for tau. In vivo, some of the compounds of Formula I demonstrate advantageous tissue distribution and pharmacokinetics. Ex vivo and / or in vitro, some of the compounds demonstrate high affinity binding to tau, and label tau containing tissue samples from AD brain with high selectivity with respect to Ap and / or non-tau binding.

[75] The abbreviations used herein are defined according to Daub G.H., et al., “The Use of Acronyms in Organic Chemistry” Aldrichimica Acta, 1984, 17(1), 6-23. Other terms as used herein, the following terms have the meanings indicated: “AD” refers to Alzheimer’s disease; “Boc” or “BOC” refers to tert-butoxy carbonyl; “cat amt” refers to catalytic amount; “CT” or “CAT” refers to computer tomography; “DMAP” refers to 4-(dimethylamino)pyridine; “DMF” refers to dimethylformamide; “DMPAO” refers to (2,6-Dimethylanilino)(oxo)acetic acid; “DMSO” refers to dimethylsulfoxide; “EOS” refers to end of synthesis; “ESI” refers to electrospray ionization; “EtOH” refers to ethanol; “HPLC” refers to high performance liquid chromatography; “hr” or “h” refers to hour; “HRMS” refers to high resolution mass spectrometry; “LCMS” refers to liquid chromatography mass spectrometry; “mCT” refers to Micro-Computed Tomography; “MeOH’ refers to methanol; “min” refers to minutes; “mPET” refers to Micro-Positron Emission Tomography; “MS” refers to mass spectroscopy; “OMs” refers to 0-mesyl”; “OTs” refers to O-tosyl; “PBS” refers to phosphate-buffered saline; “PET” refers to Positron Emission Tomography; “PHF” refers to paired helical filament; “Prec” refers to precursor; “Prep” refers to preparations compounds; “RCP” refers to radiochemical purity; “RT” refers to room temperature; “SM” refers to starting material; “TAC” refers to Time Activity Curves; “OTMS” refers to O-trimethylsilyl; “WFI” refers to water for injection. EXAMPLES

[76] The following Schemes, preparations, precursors, and examples are provided to better elucidate the practice of the present disclosure. Suitable reaction conditions for the steps of these schemes, preparations, precursors and examples are known in the art and appropriate modification of reaction conditions, including substitution of solvents and coreagents are within the ability of the skilled artisan.

[77] Furthermore, the skilled artisan will appreciate that in some circumstances, the order in which moieties are introduced is not critical. The particular order of steps required to produce a compound of Formula I is dependent upon the particular compound being synthesized, the starting compound, and the relative lability of the substituted moieties, as is well appreciated by the skilled chemist. The skilled artisan will appreciate that not all substituents are compatible with all reaction conditions. These compounds may be protected or modified at a convenient point in the synthesis by methods well known in the art. The intermediates and final products of the present disclosure may be further purified, if desired by common techniques such as recrystallization or chromatography over solid supports such as silica gel or alumina.

[78] The compounds of the present disclosure, or salts thereof, may be prepared by a variety of procedures known in the art, some of which are illustrated in the schemes, preparations, precursors, and examples below. The specific synthetic steps for each of the routes described may be combined in different ways, or in conjunction with steps from different schemes, to prepare compounds or salts of the present disclosure. The products of each step in the schemes below can be recovered by conventional methods well known in the art, including extraction, evaporation, precipitation, chromatography, filtration, trituration, and crystallization. In the schemes below, all substituents unless otherwise indicated, are as previously defined. The reagents and starting materials are readily available to one of ordinary skill in the art.

[79] All reactions are run under a nitrogen atmosphere unless otherwise noted. Reagents, solvents, and supplies are purchased from commercial sources unless otherwise indicated. Compounds are purified using an automated Teledyne Isco Flash Chromatography System. HRMS data is obtained on a Waters QT of mass spectrometer using an electrospray ionization positive scan mode. Nominal resolution MS data are obtained on a Waters Micromass ZQ mass spectrometer using an ESI positive ionization scan mode. Radiolabeling Procedures

[80] Radiolabeling synthesis was performed using a GE TRACERlab FXF-N automated radiosynthesizer with starting activity in the range of 0.1 Ci - 2.4 Ci. The range of averaged synthesis time was 60 ± 10 minutes and the range of averaged decay-corrected yield was 12-54%.

[81] [18F]Fluoride activity was retained on a Sep-Pak Accell Plus QMA Carbonate Plus Light Cartridge (Waters, 40 mg Sorbent per Cartridge, 40 pm Particle Size) and eluted into the reaction vessel using 0.8 mL of Cryptand 2.2.2-K2CO3 solution [Cryptand 2.2.2 (7 mg) and potassium carbonate (0.75 mg) in H2O (0.4 mL) and acetonitrile (0.4 mL)].

[82] The eluted activity was dried by heating at 70 °C under inert gas flow and vacuum for ~5 minutes. The temperature was raised to 100 °C under vacuum for 5 minutes to afford anhydrous Cryptand 2.2.2-K2CO3 [18F]fluoride. A solution of precursor [0.5 mg to 2.0 mg in DMSO (1-2 mL)] was added to the reaction vessel containing the anhydrous Cryptand 2.2.2-K2CO3 [18F]fluoride and the resulting mixture was kept at an elevated temperature (100-150 °C) for 10-20 minutes. The crude reaction was cooled (50-65 °C) and H2O (2.5-3 mL) was added for dilution. The diluted crude reaction was loaded onto a semi-preparative HPLC column for purification using isocratic elution (Agilent ZORBAX Eclipse XDB-C18 9.4 x 250 mm; flow rate of 4 mL / minutes, see Table 4 for details). The isolated fraction from the HPLC column contained the radiolabeled compound as identified in Table 4.

[83] The Examples listed in Table 4 below were prepared essentially according to the radiolabeling procedure as generally described above. 18F-Comp. No.: Retention time Mobile Phase 2 15-16 70% 10 mM NH4OAc in H2O / 30% MeCN 8 19-20 60% 20 mM NH4OAc in H2O / 40% MeCN 10 16-17 70% 10 mM NH4OAc in H2O / 30% MeCN 11 11-12 65% 10 mM NH4OAc in H2O / 35% MeCN 12 17-18 80% 10 mM NH4OAc, 0.1% (w / v) NaAsc in H2O / 20% MeCN 13 21-22 70% 10 mM NH4OAc in H2O / 30% MeCN, pH = 8.5 adjusted with NH40H 14 28-29 80% 10 mM NH4OAc in H2O / 20% MeCN, pH = 8.5 adjusted with NH40H 84] The other compounds discloser herein were prepared in their radiolabeled forms (i.e., 18F) essentially according to the radiolabeling procedure as generally described above. Example 1 Synthesis of 2-(4-(3-fluoropropyl)piperidin-l-yl)-8-methoxybenzo[4,5]imidazo[l,2-a]pyrimidine (Comp. No. 1).

[85] Step 1: Synthesis of 2-bromo-8-methoxybenzo[4,5]imidazo[l,2-a]pyrimidine. £ L

[86] The synthesis of 2-bromo-8-methoxybenzo[4,5]imidazo[l,2-a]pyrimidine was performed following the procedure cited for 2-bromobenzo[4,5]imidazo[l,2-a]pyrimidine in Bioorganic & Medicinal Chemistry Letters 24 (2014) 254-257. MS (m / z): 278.0 / 280.0 (M+H).

[87] Step 2: Synthesis of 2-(4-(3-fluoropropyl)piperidin-1 -yl)-8-methoxybenzo[4,5]imidazo[l,2-a]pyrimidine.

[88] A solution of 2-bromo-8-methoxybenzo[4,5]imidazo[l,2-a]pyrimidine (0.057 g, 0.23 mmol), 4-(3-fluoropropyl)piperidine hydrogen chloride (0.05 g, 0.28 mmol), and cesium carbonate (0.22 g, 0.69 mmol) in anhydrous dimethylformamide (3 mL) was heated at 100 °C under nitrogen for 2 hours. The reaction was determined to be complete by TLC. The reaction mixture was cooled to room temperature, concentrated and purified on silica gel using a gradient of 0 to 20% methanol in dichoromethane as eluent. The title compound was obtained as a yellow solid (36.8 mg, 47%). ES / MS m / z 343.5 (M+H); 'H NMR (400 MHz, CDC13) 8 ppm: 8.17 (d, J= 7.7 Hz, 1H), 7.42 (d, J= 8.8 Hz, 1H), 7.21 (d, J= 2.3 Hz, 1H), 6.80 (dd, J= 2.4, 8.7 Hz, 1H), 6.39 (d, J= 7.8 Hz, 1H), 4.52-4.37 (dt, J=6.0, 47Hz, 2H), 3.89 (s, 3H), 3.04-2.97 (m, 2H), 1.86-1.80 (m, 8H). Example 2 Synthesis of 2-(3-(fluoromethyl)pyrrolidin-l-yl)-8-methoxybenzo[4,5]imidazo[l,2-a]pyrimidine (Comp. No. 2).

[89] Step 1: Synthesis of (l-(8-methoxybenzo[4,5]imidazo[l,2-a]pyrimidin-2- yl)pyrrolidin-3-yl)methanol.

[90] A solution of 2-bromo-8-methoxybenzo[4,5]imidazo[l,2-a]pyrimidine (200 mg, 0.72 mmol), pyrroli din-3-ylmethanol (8.7 mg, 0.86 mmol), and cesium carbonate (704 mg, 2.16 mmol) in anhydrous dimethylformamide (5 mL) was heated at 100 °C for 1 hour. The reaction was determined to be complete by LCMS and cooled to room temperature. The reaction mixture was concentrated and purified on silica gel using a gradient of 0 to 10% methanol in dichoromethane as eluent. The title compound was obtained as a yellow solid (189 mg, 88%). ES / MS m / z 299.2 (M+H).

[91] Step 2: Synthesis of (l-(8-methoxybenzo[4,5]imidazo[l,2-a]pyrimidin-2- yl)pyrrolidin-3-yl)methyl 4-methylbenzenesulfonate.

[92] A solution of (l-(8-methoxybenzo[4,5]imidazo[l,2-a]pyrimidin-2-yl)pyrrolidin-3-yl)methanol (109 mg, 0.36 mmol),p-toluenesulfonyl chloride (412 mg, 2.16 mmol), and triethylamine (500 pL, 364 mg, 3.6 mmol) in methylene chloride (6 mL) was stirred at room temperature overnight. The reaction mixture was concentrated, combined with additional crude material from a previous reaction, and purified on silica gel using a gradient of 0 to 20% methanol in dichoromethane as eluent. The product obtained as a dark red vicous oil was determined by NMR to be the tosylate salt of the desired compound (347 mg). ES / MS m / z 607.6 (M+C7H7O2S). To verify structure, a portion of the material (120 mg, 0.18 mmol) was dissolved in methylene chloride (4 mL) and washed with IN sodium hydroxide (3x3 mL) and water (1x1 mL). The organic layer was dried over sodium sulfate, filtered, concentrated, and purified on silica gel using a gradient of 0 to 4% methanol in dichoromethane as eluent to afford the monotosylated compound as a tan solid (30 mg, 82%). ES / MS m / z 453.4 (M+H) 'H NMR (400 MHz, CDC13) 8 ppm: 8.20 (d, J= 7.6 Hz, 1H), 7.81-7.78 (m, 2H), 7.45 (d, J= 8.7 Hz, 1H), 7.35 (d, J= 7.9 Hz, 2H), 7.22 (d, J= 2.3 Hz, 1H), 6.82 (dd, J= 2.4, 8.7 Hz, 1H), 6.15 (d, J= 7.6 Hz, 1H), 4.19-4.12 (m, 2H), 3.89 (s, 3H), 3.68-3.32 (m, 2H), 2.85-2.82 (m, 2H), 2.44 (s, 3H), 2.29-2.27 (m, 1H), 1.52 (m, 2H).

[93] Step 3: Synthesis of (l-(8-methoxybenzo[4,5]imidazo[l,2-a]pyrimidin-2-yl)pyrrolidin-3-yl)methyl 4-methylbenzenesulfonate.

[94] The ditosylated material prepared above, (l-(8-methoxybenzo[4,5]imidazo[l,2-a]pyrimidin-2-yl)pyrrolidin-3-yl)methyl 4-methylbenzenesulfonate, (220 mg, 0.36 mmol) was dissolved in THF (5mL) and tetra-n-butylammonium fluoride (IM TBAF in THF, 1.44 mL, 1.44 mmol) was added. The reaction was heated at 65 °C for 2 hours and then treated with saturated sodium bicarbonate (3 mL). Methylene chloride (5 mL) was added and the layers were separated. The organic layer was washed with water (2x5 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified on silica gel using a gradient of 0 to 4% methanol in dichoromethane as eluent. The fractions containing the product were combined, concentrated and redissolved in 1 mL of 4:1 acetonitrile methanol, and purified ona5.5 gC18 reverse phase column using a gradient of 95% to 85% water in acetonitrile with 0.1% trifluoroacetic acid as the gradient. The purification was repeated using 4:1 water:acetonitrile as the loading solvent. The fractions containing product were combined and concentrated to remove acetonitrile. Saturated sodium bicarbonate solution (10 mL) was added and the aqueous solution was extracted with methylene chloride (2x15 mL). The organic layers were dried over sodium sulfate, filtered, and concentrated. The title compound was obtained as a white solid (10 mg, 9%). ES / MS m / z 301.3 (M+H); 'HNMR (400 MHz, CDC13) 6 ppm: 8.21 (d, J= 7.7 Hz, 1H), 7.44 (d, J= 8.7 Hz, 1H), 7.21 (m, 1H), 6.81 (dd, J= 2.4, 8.7 Hz, 1H), 6.21-6.18 (m, 1H), 4.60-4.58 (m, 2H), 3.89 (s, 3H), 3.73-3.30 (m, 2H),2.88-2.85 (m, 1H), 2.30-2.27 (m, 2H), 1.60-1.58 (m, 2H). Example 3 Synthesis of 2-(4-(2-fluoroethyl)piperidin-l-yl)-8-methoxybenzo[4,5]imidazo[l,2- a]pyrimidine (Comp. No. 3).

[95] A solution of 2-bromo-8-methoxybenzo[4,5]imidazo[l,2-a]pyrimidine (0.1 g, 0.36 mmol), 4-(2-fluoroethyl)piperidine trifluoroacetic acid (0.166 g, 0.72 mmol), and cesium carbonate (0.703 g, 2.16 mmol) in anhydrous dimethylformamide (2 mL) was heated at 100 °C for 2 hours. The reaction was determined to be complete by TLC and cooled to room temperature. The reaction mixture was concentrated and purified on silica gel using a gradient of 0 to 15% methanol in dichoromethane as eluent. The title compound was obtained as an off-white solid (103.5 mg, 88%). ES / MS m / z 329.6 (M+H); 'HNMR (400 MHz, CDCI3) 8 ppm: 8.17 (d, J= 7.7 Hz, 1H), 7.42 (d, J= 8.7 Hz, 1H), 7.21 (d, J= 2.3 Hz, 1H), 6.80 (dd, J= 2.4, 8.7 Hz, 1H), 6.39 (d, J= 7.7 Hz, 1H), 4.64-4.48 (dt, J=6.0, 47Hz, 2H), 3.89 (s, 3H), 3.06-2.99 (m, 2H), 1.90-1.82 (m, 7H), 1.35-1.26 (m, 2H). Example 4 Synthesis of 7-bromo-2-(4-(2-fluoroethyl)piperidin-l-yl)benzo[4,5]imidazo[l,2-a]pyrimidine (Comp. No. 4).

[96] Step 1: Synthesis of 2-[4-(2-fluoroethyl)piperidin- l-yl]pyrimido[ 1,2-A]benzimidazole.

[97] This material was synthesized as described in Bioorganic & Medicinal Chemistry Letters 24 (2014) 254-257. Step 2: Synthesis of 7-bromo-2-(4-(2-fluoroethyl)piperidin-l-yl)benzo[4,5]imidazo[l,2-a]pyrimidine.

[98] To a stirred solution of 2-[4-(2-fluoroethyl)piperidin-l-yl]pyrimido[l,2-A]benzimidazole (150 mg, 0.5 mmol) in 10% methanol in methylene chloride (50 mL), was added dropwise a solution of N-bromosuccinimide (98 mg, 0.55 mmol) in methylene chloride (10 mL). The reaction was stirred at room temperature for 4-5 hours. The mixture was purified on silica gel using a gradient of 0 to 10% methanol in ethyl acetate as eluent. The title compound was obtained as a solid (180 mg, 95%). ES / MS m / z (79Br / 81Br): 377.2 / 379.2 (M+H); 'H NMR (400 MHz, CDC13): 5 ppm: 8.16 (d, J= 7.7 Hz, 1H), 7.69 (d, J= 1.6 Hz, 1H), 7.57 (d, J= 8.6 Hz, 1H), 7.44-7.46 (m, 1H), 6.45 (d, J= 7.8 Hz, 1H), 4.61-4.46 (m, 4H), 3.08-3.01 (m, 2H), 1.92-1.83 (m, 3H), 1.74-1.63 (m, 2H), 1.36-1.28 (m, 2H); 19F NMR (376 MHz, CDC13) 5 ppm: -218.8. Example 5 Synthesis of 2-(4-(2-fluoroethyl)piperidin-l-yl)benzo[4,5]imidazo[l,2-a]pyrimidin-7-ol (Comp. No. 5).

[99] Step 1: Synthesis of 2-bromobenzo[4,5]imidazo[l,2-a]pyrimidin-8-ol.

[100] A solution of 2-bromo-8-methoxybenzo[4,5]imidazo[l,2-a]pyrimidine (195 mg, 0.7 mmol) in di chloromethane was cooled to -78 °C and treated with boron tribromide (4.2 mL, 4.2 mmol) in di chloromethane. The reaction was allowed to warm to room temperature with stirring overnight and then stirred an additional 24 hours at room temperature. The reaction was quenched with sodium bicarbonate, extracted with 10% methanol in ethyl acetate, dried over magnesium sulfate, filtered, and concentrated. The resulting crude material was purified on silica gel using a gradient of 0 to 20% methanol in dichoromethane as eluent to afford the title compound (150 mg, 82%). ES / MS m / z 264.1 / 266.1 (M+H).

[101] Step 2: Synthesis of 2-(4-(2-fluoroethyl)piperidin-l-yl)benzo[4,5]imidazo[l,2-a]pyrimidin-7-ol.

[102] A solution of 2-bromo-8-methoxybenzo[4,5]imidazo[l,2-a]pyrimidine (26.4 mg, 0.1 mmol), 4-(2-fluoroethyl)piperidine hydrogen chloride (65 mg, 0.2 mmol), and cesium carbonate (330 mg, 1.0 mmol) in anhydrous dimethylformamide (1 mL) was heated at 100 °C for 1-2 hours. The reaction mixture was cooled to room temperature, concentrated and purified on silica gel using a gradient of 0 to 20% methanol in dichoromethane as eluent to afford the title compound (6 mg, 19%). ES / MS m / z 315.4 (M+H); 'H NMR (400 MHz, CDC13) 8 ppm: 8.19 (d, J= 7.7 Hz, 1H), 7.40 (d, J= 8.7 Hz, 1H), 7.06 (d, J= 2.2 Hz, 1H), 6.76 (dd, J= 2.3, 8.6 Hz, 1H), 6.42 (d, J= 7.7 Hz, 1H), 4.62-4.57 (m, 4H), 3.42-3.40 (m, 2H), 3.07-3.01 (m, 2H), 1.78-1.76 (m, 2H), 1.45-1.34 (m, 3H). 19F NMR (376 MHz, CDCI3) 6 ppm: -218.8. Example 6 Synthesis of 2-(4-(2-fluoroethyl)piperidin-l-yl)-7-iodobenzo[4,5]imidazo[l,2-a]pyrimidine (Comp. No. 6).

[103] To a stirred solution of 2-[4-(2-fluoroethyl)piperidin-l-yl]pyrimido[l,2-A]benzimidazole (0.29 g, 1.0 mmol) and N-iodosuccinimide (0.55 g, 2.4 mmol) in acetonitrile (10 mL), was added glacial acetic acid (5 drops). The reaction was stirred at room temperature for 3 hours and then heated at reflux overnight. The mixture was diluted with water and aqueous sodium thiosulfate. The nearly colorless aqueous layer was extracted with 10% methanol in di chloromethane. The combined organic layers were concentrated and the residue was purified by preparative HPLC. The title compound was obtained as a solid (90 mg, 22%). Regiochemistry was confirmed by NOESY NMR. ES / MS m / z 424.9 (M+H); XHNMR (400.13 MHz, CDC13) 8 ppm: 8.44, (d, J=7.7Hz, 1H), 7.99 (s, 1H), 7.58 (dd, J=1.5, 8.4Hz, 1H), 7.37 (d, J=8.6Hz, 1H), 6.67 (d, J=8.0Hz, 1H), 5.48 (dt, J= 5.6, 47.3Hz, 2H), 3.03 (m, 3H), 1.86 (m, 4H), 1.63 (dq, J=5.6, 27.4Hz, 2H), 1.23 (dq, J=4.2, 12.1Hz, 2H). Example 7 Synthesis of 2-(4-(2-fluoroethyl)piperidin-l-yl)-7-vinylbenzo[4,5]imidazo[l,2-a]pyrimidine (Comp. No. 7).

[104] A 2 mL vial was charged with 7-bromo-2-(4-(2-fluoroethyl)piperidin-l-yl)benzo[4,5]imidazo[l,2-a]pyrimidine (30 mg, 0.08 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (25 mg, 0.16 mmol), [ 1,1 '-Bis(di-tert- butylphosphino)ferrocene]dichloropalladium( / 7) (5 mg, 0.008 mmol), and sodium carbonate (0.2 mL of a 2M aqueous solution, 0.4 mmol) in dioxane (0.8 mL). The reaction was heated at 100 °C for 6 hours, determined to be complete by LCMS, and 30 cooled to room temperature. The reaction mixture was diluted with 10 mL methylene chloride / methanol, adhered to 3 g silica gel, and concentrated. The crude product was purified on silica gel using a gradient of 0 to 5% methanol in dichoromethane as eluent to afford the title compound as a yellow solid (10 mg, 39%). ES / MS m / z 325.4 (M+H); 'H NMR (400 MHz, CDC13) 8 ppm: 8.19 (d, J= 7.7 Hz, 1H), 7.63 (d, J= 8.4 Hz, 1H), 7.54 (d, J= 1.3 Hz, 1H), 7.46-7.43 (m, 1H), 6.81 (dd, J= 10.9, 17.5 Hz, 1H), 6.37 (d, J= 7.7 Hz, 1H), 5.71 (dd, J= 0.7, 17.5 Hz, 1H), 5.20-5.17 (m, 1H), 4.60-4.57 (m, 2H), 4.48-4.45 (m, 1H), 3.03-2.25 (m, 4H), 1.92-1.81 (m, 4H), 1.73-1.65 (m, 2H). Example 8 Synthesis of 2-(4-(3-fluoroazetidin-l-yl)phenyl)benzo[4,5]imidazo[l,2-a]pyrimidine (Comp. No. 8).

[106] A slurry of 1,4-dibromobenzene (1000 mg, 4.2 mmol), 3-fluoroazetidine hydrochloride (520 mg, 4.7 mmol) and sodium tert-butoxide (1.222 g, 6.4 mL, 2 M, 12.7 mmol) in 1,4-dioxane (10.6 mL) was bubbled with nitrogen for 10 minutes. Xantphos (491 mg, 848 pmol) and tris(dibenzylideneacetone)dipalladium(0)N(388 mg, 424 pmol) were introduced, the vial was capped and the mixture heated to 60 °C overnight. Product was determined to be present by LCMS. The mixture was cooled to room temperature and concentrated over silica gel. Purification by column chromatography on silica gel using a gradient of 0 to 20% ethyl acetate in hexanes as eluent afforded 1-(4-bromophenyl)-3-fluoroazetidine (457 mg, 46.9 %) as a light yellow solid. ES / MS m / z (79Br / 81Br) 229.9 / 231.9 (M+H); XH NMR (400.13 MHz, CDCI3) 6 ppm: 7.31 (d, J=8.8Hz, 2H), 6.34 (d, J=8.8Hz, 2H), 5.40 (m, 1H), 4.16 (m, 2H), 3.93 (m, 2H); 19F NMR (376.45 MHz, CDCI3) 6 ppm: -180.08.

[107] Step 2: Synthesis of 3-fluoro-l-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)azetidine. F

[108] A slurry of l-(4-bromophenyl)-3-fluoroazetidine (257 mg, 1.1 mmol), bis(pinacolato)diborane (284 mg, 1.1 mmol) and potassium acetate (329 mg, 3.4 mmol) in 1,4-dioxane (2 mL) was bubbled with nitrogen for 10 minutes. To this was added l,T-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (82 mg, 112 pmol) and the reaction mixture was heated at 80 °C for 2 h. Product was determined to be present by LCMS. The mixture was cooled to room temperature, filtered through Celite (rinsed with ethyl acetate), and concentrated over silica gel. Column chromatography on silica gel using a gradient of 0 to 30% ethyl acetate in hexanes afforded 3-fluoro-1-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)azetidine as an off-white solid. ES / MS m / z TT&2 (M+H); 'HNMR (400.13 MHz, CDC13) 8 ppm: 7.69 (d, J=8.6Hz, 2H), 6.44 (d, J=8.7Hz, 2H), 5.42 (m, 1H), 4.21 (m, 2H), 3.99 (m, 2H), 1.32 (s, 12H); 19F NMR (376.45 MHz, CDCI3) 6 ppm: -180.13.

[109] Step 3: Synthesis of 2-(4-(3-fluoroazetidin-l-yl)phenyl)benzo[4,5]imidazo[l,2-a]pyrimidine.

[110] A slurry of 3-fluoro-l-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)azetidine (142 mg, 514 pmol), 2-bromobenzo[4,5]imidazo[l,2-a]pyrimidine (85.0 mg, 343 pmol), l,T-bis(diphenylphosphino)ferrocene-palladium(II) di chloride (25 mg, 34 pmol) in a mixture of 1,4-dioxane (3.5 mL), ethanol (0.5 mL) and aqueous sodium carbonate (109 mg, 514 pL, 2 molar, 1.03 mmol) was capped and heated at 80 °C for 3 hours. The reaction was determined to be complete by LCMS. The reaction mixture was concentrated over silica gel, dried under high vac, and then purified by column chromatography using a gradient of 0 to 10% methanol in methylene chloride as eluent to afford 2-(4-(3-fluoroazetidin-l-yl)phenyl)benzo[4,5]imidazo[l,2-a]pyrimidine (84 mg, 77 %) as a light brown solid. ES / MS m / z 319.2 (M+H); 1H NMR (400.13 MHz, DMSO-d6) 8 ppm: 9.39 (d, J=7.2 Hz, 1H), 8.23 (m, 3H), 7.77 (dt, J=0.8, 8.1Hz, 1H), 7.69 (d, J=7.2Hz, 1H), 7.49 (ddd, J=1.2, 7.2, 8.2Hz, 1H), 7.36, (ddd, J=1.0, 7.2, 8.2Hz, 1H), 6.63 (d, J=8.9Hz, 2H), 5.56 (m, 1H), 4.31 (m, 2H), 4.06 (m, 2H); 19F NMR (376.45 MHz, DMSO-de) 6 ppm: -179.26. Example 9 Synthesis of 2-(3-(2-fluoroethyl)pyrrolidin-l-yl)-8-methoxybenzo[4,5]imidazo[l,2-a]pyrimidine (Comp. No. 9). [Hl] A solution of 2-bromo-8-methoxybenzo[4,5]imidazo[l,2-a]pyrimidine (68.6 mg, 0.3 mmol), 3-(2-fluoroethyl)pyrrolidine hydrogen chloride (48 mg, 0.3 mmol), and cesium carbonate (361 mg, 1.1 mmol) in anhydrous dimethylformamide (3 mL) was heated at 100 °C for 2 hours. The reaction mixture was cooled to room temperature, concentrated, and purified on silica gel using a gradient of 0 to 20% methanol in dichoromethane as eluent. The title compound was obtained as a light yellow solid (66.0 mg, 85%). ES / MS m / z 315.4 (M+H); 'HNMR (400 MHz, CDC13) 6 ppm: 8.18 (d, J= 7.5 Hz, 1H), 7.43 (d, J= 8.7 Hz, 1H), 7.21 (d, J= 2.4 Hz, 1H), 6.80 (dd, J= 2.4, 8.7 Hz, 1H), 6.20-6.17 (m, 1H), 4.63-4.49 (dt, J=6.0, 47Hz, 2H), 4.25-3.77 (m, 4H), 3.89-3.88 (m, 3H), 2.59-2.56 (m, 2H), 1.96-1.89 (m, 2H), 1.82-1.81 (m, 1H). Example 10 Synthesis of 2-(3-(2-fluoroethyl)pyrrolidin-l-yl)benzo[4,5]imidazo[l,2-a]pyrimidine (Comp. No. 10).

[112] A solution of 2-bromobenzo[4,5]imidazo[l,2-a]pyrimidine (50 mg, 0.2 mmol), 3-(2-fluoroethyl)pyrrolidine hydrogen chloride (37 mg, 0.2 mmol), and cesium carbonate (326 mg, 1.0 mmol) in anhydrous dimethylformamide (1 mL) was heated at 100 °C for 2 hours. The reaction was determined to be complete by LCMS, cooled to room temperature, and concentrated. The reaction mixture was purified on silica gel using a gradient of 0 to 10% methanol in dichoromethane as eluent. The title compound was obtained as a solid (45 mg, 79%). ES / MS m / z 285.4 (M+H); 'HNMR (400 MHz, d6-DMSO) 5 ppm: 8.94 (d, J= 7.6 Hz, 1H), 7.94-7.92 (m, 1H), 7.51-7.49 (m, 1H), 7.31-7.27 (m, 1H), 7.17-7.13 (m, 1H), 6.53 (d, J= 7.6 Hz, 1H), 4.64 (t, J= 6.0 Hz, 1H), 4.52 (t, J= 6.0 Hz, 1H), 3.98-3.95 (m, 2H), 3.55-3.49 (m, 1H), 3.26-3.18 (m, 2H), 2.27-2.25 (m, 2H), 1.93-1.87 (m, 3H). Example 11 Synthesis of 2-(4-(fluoromethyl)piperidin-1 -yl)-8-methoxybenzo[4,5]imidazo[ 1,2- a]pyrimidine (Comp. No. 11).

[113] A solution of 2-bromo-8-methoxybenzo[4,5]imidazo[l,2-a]pyrimidine (100 mg, 0.4 mmol), 4-(fluoromethyl)piperidine hydrogen chloride (68 mg, 0.4 mmol), and cesium carbonate (703 mg, 2.2 mmol) in anhydrous dimethylformamide (2 mL) was heated at 100 °C for 2 hours. The reaction was determined to be complete by LCMS, cooled to room temperature, and concentrated. The reaction mixture was purified on silica gel using a gradient of 0 to 15% methanol in dichoromethane as eluent. The title compound was obtained as a yellow solid (108.4 mg, 96%). ES / MS m / z 315.6 (M+H); 'HNMR (400 MHz, CDC13) 8 ppm: 8.19 (d, J= 7.7 Hz, 1H), 7.43 (d, J= 8.6 Hz, 1H), 7.21 (d, J= 2.3 Hz, 1H), 6.81 (dd, J= 2.4, 8.7 Hz, 1H), 6.40 (d, J= 7.7 Hz, 1H), 4.37-4.24 (dt, J=6.0, 47Hz, 2H), 3.89 (s, 3H), 3.05 (td, J= 12.9, 2.4 Hz, 2H), 2.12-2.08 (m, 1H), 1.90-1.86 (m, 2H), 1.64-1.61 (m, 2H), 1.38 (qd, J= 12.5, 4.3 Hz, 2H). Example 12 Synthesis of 2-(4-(3-fluoropropyl)piperidin-l-yl)benzo[4,5]imidazo[l,2-a]pyrimidine (Comp. No. 12).

[114] Step 1: Synthesis of tert-butyl 4-(2-fluoroethyl)piperidine-l-carboxylate.

[115] To a solution of tert-butyl 4-(2-hydroxyethyl)piperidine-l-carboxylate (2.0 g, 8.2 mmol) in dichloromethane (150 mL) at 0 °C was added diethylaminosulfur trifluoride (DAST, 4.3 mL, 32.9 mmol) in di chloromethane (5 mL) dropwise. The resulting mixture was stirred at room temperature for 6 hours. Ice water was added and the reaction was made basic by the addition of saturate aqueous sodium bicarbonate. The phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried, filtered, and concentrated. The crude material was purified on silica gel using a gradient of 10 to 100% ethyl acetate in hexanes as eluent. The title compound was obtained as a light yellow oil (1.49 g, 74%). 'H NMR (400 MHz, CDCh) 5 ppm: 4.50-4.35 (dt, J=6.0, 47Hz, 2H), 4.13-4.06 (m, 2H), 2.68 (t, J= 12.0 Hz, 2H), 1.781.72 (m, 4H), 1.45 (s, 9H), 1.41-1.34 (m, 3H), 1.15-1.05 (m, 2H). Step 2: Synthesis of 4-(3-fluoropropyl)piperidine.

[116] To a solution of tert-butyl 4-(2-fluoroethyl)piperidine-l-carboxylate (0.8 g, 3.3 mmol) in dioxane (10 mL) at 0 °C was added dropwise 4N HC1 in dioxane (20.4 mL, 81.5 mmol). The reaction was stirred at room temperature for 2-3 hours and determined to be complete by TLC (KMnO4 stain). The material was concentrated and triturated in diethyl ether. The desired 4-(3-fluoropropyl)piperi dine hydrogen chloride was obtained as a white solid (0.5 g, 85%). 'HNMR (400 MHz, CD3OD) 5 ppm: 4.50-4.35 (dt, J=6.0, 47Hz, 2H), 3.39-3.34 (m, 2H), 2.96 (td, J= 12.9, 3.1 Hz, 2H), 1.96 (dd, J= 1.5, 14.4 Hz, 2H), 1.79-1.73 (m, 3H), 1.44-1.36 (m, 4H).

[117] Step 3: Synthesis of 2-(4-(3-fluoropropyl)piperidin-l-yl)benzo[4,5]imidazo[l,2-a]pyrimidine.

[118] A solution of 2-bromobenzo[4,5]imidazo[l,2-a]pyrimidine (0.1 g, 0.4 mmol), 4-(3-fluoropropyl)piperidine hydrogen chloride (0.095 g, 0.5 mmol), and cesium carbonate (0.788 g, 2.4 mmol) in anhydrous dimethylformamide (4 mL) was heated at 100 °C for 23 hours. The reaction was cooled to room temperature and determined to be complete by TLC. The reaction mixture was concentrated and purified on silica gel using methanol in dichoromethane as eluent. The title compound was obtained as a yellow solid (99.0 mg, 79%). ES / MS m / z 313.5 (M+H); 'HNMR (400 MHz, CDCI3) 8 ppm: 8.23 (d, J= 7.7 Hz, 1H), 7.73-7.71 (m, 1H), 7.55 (d, J= 7.9 Hz, 1H), 7.38-7.34 (m, 1H), 7.20-7.16 (m, 1H), 6.42 (d, J= 7.7 Hz, 1H), 4.52-4.37 (dt, J=6.0, 47Hz, 2H), 3.05-2.98 (m, 2H), 1.87-1.79 (m, 7H), 1.43-1.37 (m, 2H), 1.31-1.24 (m, 2H). Example 13 Synthesis of 2-(4-(fluoromethyl)piperidin-l-yl)benzo[4,5]imidazo[l,2-a]pyrimidine (Comp. No. 13).

[119] A solution of 2-bromobenzo[4,5]imidazo[l,2-a]pyrimidine (0.025 g, 0.1 mmol), 4-(fluoromethyl)piperidine hydrogen chloride (0.0185 g, 0.12 mmol), and cesium carbonate (0.197 g, 0.6 mmol) in anhydrous dimethylformamide (1 mL) was heated at 100 °C for 2 hours. The reaction was cooled to room temperature, filtered through celite, washed with ethyl acetate, and the filtrate concentrated. The crude material was purified on silica gel using a gradient of 5 to 10% methanol in dichoromethane as eluent. The title compound was obtained as an off-white solid (26.2 mg, 91%). ES / MS m / z 285.4 (M+H); 'HNMR (400.13 MHz, CDC13) 8 ppm: 8.26 (d, J=7.7Hz, 1H), 7.73 (ddd, J=0.9, 0.9, 8.2Hz, 1H), 7.57 (ddd, J=1.0, 1.0, 8.0Hz, 1H), 7.38 (ddd, J=1.1, 7.2, 8.3 Hz, 1H), 7.20 (ddd, J=1.1, 7.5, 8.2 Hz, 1H), 6.44 (d, J=7.7Hz, 1H), 4.70-4.64 (m, 2H), 4.31 (dd, J=6.0, 43.7Hz, 2H), 3.07 (ddd, J=2.7, 13.1, 13.1Hz, 2H), 2.13-2.02 (m, 1H), 1.89 (dd, J=2.2, 13.1Hz, 2H), 1.40 (ddd, J=4.4, 12.2, 12.2Hz, 2H). Example 14 Synthesis of (S)-2-(3-fluoropyrrolidin-l-yl)benzo[4,5]imidazo[l,2-a]pyrimidine (Comp. No. 14).

[120] A solution of 2-bromobenzo[4,5]imidazo[l,2-a]pyrimidine (0.1 g, 0.4 mmol), (S)-3-fluoropyrrolidine hydrogen chloride (0.0658 g, 0.5 mmol), and cesium carbonate (0.788 g, 2.4 mmol) in anhydrous dimethylformamide (3-4 mL) was heated at 100 °C for 2-3 hours. The reaction was determined to be complete by TLC, cooled to room temperature, concentrated and purified on silica gel using a gradient of 0 to 10% methanol in dichoromethane as eluent. The title compound was obtained as a white solid (36.7 mg, 36%). ES / MS m / z 257.3 (M+H); 'HNMR (400.13 MHz, CDCI3) 5 ppm: 8.29 (d, J=7.6Hz, 1H), 7.59 (d, J=8.0Hz, 1H), 7.39 (ddd, J=1.1, 7.5, 8.3Hz, 1H), 7.21 (ddd, J=1.0, 7.5, 8.4Hz, 1H), 6.25 (bd, J=6.2Hz, 1H), 5.41 (bd, J=52.2Hz, 1H), 3.91-3.71 (bm, 2H), 2.51-2.47 (m, 1H), 2.30-2.15 (bm, 1H), 1.62-1.46 (bm, 2H). Example 15 Synthesis of 2-(4-(2-fluoroethyl)piperidin-l-yl)-8-iodobenzo[4,5]imidazo[l,2-a]pyrimidine (Comp. No. 15).

[121] To a stirred solution of 2-[4-(2-fluoroethyl)piperidin-l-yl]pyrimido[l,2-A]benzimidazole (1.16 g, 3.9 mmol) and iodine (0.75 g, 3.0 mmol) in dichloromethane (50mL) was added diacetoxyiodo)benzene (2.5 g, 7.8 mmol). Trifluoroacetic acid (3 mL) was added and the reaction was stirred at room temperature for 1.5 hours. The reaction was quenched with water. Aqueous sodium thiosulfate was added and the bright yellow aqueous layer was extracted with methylene chloride and then 10% methanol in di chloromethane (2 x 50 mL). The organic layers were combined and concentrated. The material was purified on silica gel using a gradient of 0 to 30% methanol in dichoromethane as eluent. The title compound was obtained as a solid (240 mg, 15%). ES / MS m / z 424.9 (M+H); 'HNMR (400.13 MHz, CDC13) 8 ppm: 8.57 (d, J=8.0Hz, 1H), 8.00 (d, J=1.2Hz, 1H), 7.50 (dd, J=1.5, 8.4Hz, 1H), 7.31 (d, J=8.4Hz, 1H), 6.77 (d, J=7.8Hz, 1H), 4.47 (dt, J=5.7, 47.3Hz, 2H), 3.32-2.96 (m, 3H), 1.88-1.79 (m, 4H), 1.671.56 (m, 2H), 1.21 (q, J=11.0Hz, 2H). Example 16 Synthesis of l-(4-(benzo[4,5]imidazo[l,2-a]pyrimidin-2-yl)phenyl)azetidin-3-yl 4- methylbenzenesulfonate (Comp. No. 16).

[122] Step 1: Synthesis of l-(4-bromophenyl)azetidin-3-ol. OH Br

[123] A slurry of 1,4-dibromobenzene (1000 mg, 4.24 mmol), azetidin-3-ol hydrochloride (511 mg, 4.7 mmol) and sodium tert-butoxide (6.4 mL, 2 molar, 12.7 mmol) in 1,4-dioxane (10.6 mL) was bubbled with nitrogen for 10 min. Xantphos (490.6 mg, 848 pmol) and Pd2(dba)3 (388.2 mg, 424 pmol) were introduced, the vial was capped and heated at 90 °C overnight. The reaction was cooled to room temperature and product determined to be present by LCMS. The mixture was concentrated over silica gel, dried under high vacuum, and purified by column chromatography on silica gel using a gradient of 0 to 30% ethyl acetate in hexanes as eluent to afford 1-(4- bromophenyl)azetidin-3-ol as an off-white solid (627 mg, 64.8 %). ES / MS m / z (79Br / 81Br) 227.9 / 229.9 (M+H); ^NMR (400.13 MHz, CDC13) 8 ppm: 7.28 (d, J=8.9Hz, 2H), 6.33 (d, J=8.9Hz, 2H), 4.74 (m, 1H), 4.14 (m, 2H), 3.64 (m, 2H).

[124] Step 2: Synthesis of 1-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)azetidin-3-ol. OH A slurry of l-(4-bromophenyl)azetidin-3-ol (237 mg, 1.0 mmol), bis(pinacolato)diborane (264 mg, 1.0 mmol) and potassium acetate (306 mg, 3.1 mmol) in 1,4-dioxane (1.5 mL) was bubbled with nitrogen for 10 minutes. To the mixture was then added 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (76.0 mg, 104 pmol). The vial was capped and the mixture heated at 80 °C for 2 hours. Product was determined to be present by LCMS. The mixture was cooled to room temperature, filtered through Celite, washed with ethyl acetate, and concentrated over silica gel. Column chromatography on silica gel using a gradient of 0 to 50% ethyl acetate in hexanes afforded 1-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)azetidin-3-ol as an off-white solid (134 mg, 46.9 %). ES / MS m / z 276.1 (M+H); 1HNMR (400.13 MHz, DMSO-d6) 5 ppm: 7.46 (d, J=8.7Hz, 2H), 6.37 (d, J=8.7Hz, 2H), 5.59 (d, J=6.6Hz, 1H), 4.57 (m, 1H), 4.08 (dd, J=6.6, 8.4Hz, 2H), 3.54 (dd, J=4.8, 8.6Hz, 2H), 1.25 (s, 12H).

[125] Step 3: Synthesis of l-(4-(benzo[4,5]imidazo[l,2-a]pyrimidin-2-yl)phenyl)azetidin-3-ol.

[126] A mixture of 1-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)azetidin-3-ol (221 mg, 804 pmol), 2-bromobenzo[4,5]imidazo[l,2-a]pyrimidine (133 mg, 536 pmol) and sodium carbonate (170 mg, 804 pL, 2 molar, 1.6 mmol) in 1,4-dioxane (5.4 mL) was bubbled with nitrogen for 10 minutes. The 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (39.2 mg, 53.6 pmol) was added and the reaction mixture was stirred at 80 °C overnight. Product was determined to be present by LCMS. The reaction mixture was concentrated over silica gel and purified by column chromatography on silica gel using a gradient of 0 to 20% methanol in methylene chloride as eluent to afford l-(4-(benzo[4,5]imidazo[l,2-a]pyrimidin-2-yl)phenyl)azeti din-3-ol as an orange foam (97 mg, 57 %). ES / MS m / z 317.1 (M+H); 1H NMR (400.13 MHz, DMSO-d6) 5 ppm: 9.36 (d, J=7.2Hz, 1H), 8.22 (m, 3H), 7.76 (d, J=8.0Hz, 1H), 7.67 (d, J=7.3Hz, 1H), 7.49 (m, 1H), 7.35 (m, 1H), 6.56 (d, J=8.9Hz, 2H), 5.68 (d, J=6.5Hz, 1H), 4.64 (m, 1H), 4.21 (dd, J=6.7, 8.4Hz, 2H), 3.69 (dd, J=4.8, 8.8Hz, 2H).

[127] Step 4: Synthesis of l-(4-(benzo[4,5]imidazo[l,2-a]pyrimidin-2-yl)phenyl)azetidin-3-yl 4-methylbenzenesulfonate.

[128] A dilute solution of l-(4-(benzo[4,5]imidazo[l,2-a]pyrimidin-2-yl)phenyl)azeti din-3-ol (30 mg, 95 pmol), DMAP (1.2 mg, 9.5 pmol), 4-methylbenzenesulfonic anhydride (93 mg, 0.28 mmol) and triethylamine (58 mg, 79 pL, 0.57 mmol) in dichloromethane (4.7 mL) was stirred at room temperature for 3 days. LCMS showed conversion to the di-tosylate. The reaction mixture was treated with 2 mL 40 of IM KOH (aq) and stirred vigorously for 2 hours. LCMS showed conversion to the mono-tosylate. The reaction mixture was diluted with water and extracted with methylene chloride (x3). The combined organics were dried over sodium sulfate, filtered, and concentrated over silica gel. Column chromatography on silica gel using a gradient of 0 to 10% methanol in methylene chloride as eluent afforded l-(4-(benzo[4,5]imidazo[l,2-a]pyrimidin-2-yl)phenyl)azetidin-3-yl 4-methylbenzenesulfonate as an orange foam (18 mg, 40 %). ES / MS m / z 471.3 (M+H); 'HNMR (400.13 MHz, DMSO-d6) 8 ppm: 9.39 (d, J=7.3Hz, 1H), 8.23 (d, J=8.0Hz, 1H), 8.20 (d, J=9.0 Hz, 2H), 7.87 (d, J=8.4 Hz, 2H), 7.76 (d, J=8.0Hz, 1H), 7.68 (d, J=7.3Hz, 1H), 7.53 (d, J=8.0Hz, 2H), 7.49 (ddd, J=1.3, 7.3, 7.5Hz, 1H), 7.35 (ddd, J=1.0, 7.2, 8.0Hz, 1H), 6.58 (d, J=8.9Hz, 2H), 5.31 (m, 1H), 4.26 (m, 2H), 3.93 (m, 2H), 2.46 (s, 3H). Example 17 Synthesis of (l-(8-methoxybenzo[4,5]imidazo[l,2-a]pyrimidin-2-yl)piperidin-4-yl)methyl methanesulfonate (Comp. No. 17).

[129] Step 1: Synthesis of (l-(8-methoxybenzo[4,5]imidazo[l,2-a]pyrimidin-2-yl)piperidin-4-yl)methanol.

[130] A solution of 2-bromo-8-methoxybenzo[4,5]imidazo[l,2-a]pyrimidine (0.21 g, 0.8 mmol), piperidin-4-ylmethanol (0.130 g, 1.1 mmol), and cesium carbonate (0.738 g, 2.3 mmol) in anhydrous dimethylformamide (3 mL) was heated at 100 °C for 2 hours. The reaction was determined to be complete by LCMS, cooled to room temperature, concentrated and purified on silica gel using a gradient of 0 to 40% methanol in dichoromethane as eluent. The title compound was obtained as a yellow solid (0.12 g, 51%). ES / MS m / z 313.5 (M+H).

[131] Step 2: Synthesis of (l-(8-methoxybenzo[4,5]imidazo[l,2-a]pyrimidin-2-yl)piperidin-4-yl)methyl methanesulfonate.

[132] A solution of (l-(8-methoxybenzo[4,5]imidazo[l,2-a]pyrimidin-2-yl)piperidin-4-yl)methanol (0.083 g, 0.3 mmol), methanesulfonyl chloride (61 pL, 0.8 mmol), and triethylamine (0.22 mL, 1.6 mmol) in dichloromethane (50 mL) was stirred at room temperature for 1 hour. Aqueous saturated sodium bicarbonate was added (10-20 mL) and the mixture was stirred at room temperature for 25 minutes. The layers were separated and the aqueous layer was extracted with 10% methanol in di chloromethane. The organic layers were combined, washed with saturated sodium bicarbonate, brine, and water, dried, filtered, and concentrated to afford the title compound as an off-white solid (0.11 g). ES / MS m / z 391.4 (M+H); 'HNMR (400.13 MHz, CDC13) 8 ppm: 8.21 (d, J=7.6Hz, 1H), 7.44 (d, J=8.7Hz, 1H), 7.22 (d, J=2.3 Hz, 1H), 6.81 (dd, J=2.3, 8.7Hz, 1H), 6.40 (d, J=7.7Hz, 1H), 4.66 (bd, J=11.8Hz, 2H), 4.10 (d, J=6.5Hz, 2H), 3.89 (s, 3H), 3.04 (ddd, J=2.6, 13.0, 13.0Hz, 2H), 3.01 (s, 3H), 2.18-2.09 (m, 1 H), 1.92 (bd, J=13.0Hz, 2H), 1.441.33 (m, 2H). Example 18 Synthesis of 2-(l-(benzo[4,5]imidazo[l,2-a]pyrimidin-2-yl)pyrrolidin-3-yl)ethyl methanesulfonate (Comp. No. 18).

[133] Step 1: Synthesis of 2-(l-(benzo[4,5]imidazo[l,2-a]pyrimidin-2-yl)pyrrolidin-3-yl)ethan-l-ol.

[134] A mixture of 2-bromobenzo[4,5]imidazo[l,2-a]pyrimidine (248 mg, 1.0 mmol), 2-(pyrrolidin-3-yl)ethan-l-ol (140 mg, 1.2 mmol), and cesium carbonate (815 mg, 2.5 mmol) in anhydrous dimethylformamide (5 mL) was heated at 100 °C for 3 hours. The reaction was determined to be complete by LCMS, cooled to room temperature, concentrated, and purified on silica gel using a gradient of 0 to 20% methanol in dichoromethane as eluent. The title compound was obtained as a solid (229 mg, 81%). ES / MS m / z 283.3 (M+H).

[135] Step 2: Synthesis of 2-(l-(benzo[4,5]imidazo[l,2-a]pyrimidin-2-yl)pyrrolidin-3-yl)ethyl methanesulfonate.

[136] To a stirred suspension of 2-(l-(benzo[4,5]imidazo[l,2-a]pyrimidin-2-yl)pyrrolidin-3-yl)ethan-l-ol (50 mg, 0.2 mmol) and triethylamine (0.3 mL, 2.0 mmol) in di chloromethane (50 mL) was added methanesulfonyl chloride (103 mg, 0.9 mmol) in di chloromethane (3 mL). The reaction mixture was stirred at room temperature for 1-2 hours and determined to be complete by LCMS and TLC. The reaction mixture was washed with aqueous saturated sodium bicarbonate and brine, dried over sodium sulfate, filtered, and concentrated. The material was purified on silica gel using a gradient of 0 to 10% methanol in dichoromethane as eluent to afford the title compound as a solid (50 mg, 77%). ES / MS m / z 361.3 (M+H); 'HNMR (400 MHz, CDC13) 8 ppm: 8.27 (d, J= 7.6 Hz, 1H), 7.72-7.69 (m, 1H), 7.59-7.54 (m, 1H), 7.40-7.36 (m, 1H), 7.23-7.18 (m, 1H), 6.24 (d, J= 7.6 Hz, 1H), 4.37-4.32 (m, 2H), 3.46-3.42 (m, 4H), 3.06 (s, 3H), 2.62-2.60 (m, 2H), 2.01-1.99 (m, 3H). Example 19 Synthesis of (R)-1 -(benzo[4,5]imidazo[ 1,2-a]pyrimidin-2-yl)pyrrolidin-3-yl methanesulfonate (Comp. No. 19).

[137] Step 1: Synthesis of (R)-l-(benzo[4,5]imidazo[l,2-a]pyrimidin-2-yl)pyrrolidin-3-ol.

[138] A mixture of 2-bromobenzo[4,5]imidazo[l,2-a]pyrimidine (0.2 g, 0.8 mmol), (R)-pyrrolidin-3-ol (98pL, 1.2 mmol), and cesium carbonate (1.05 g, 3.2 mmol) in anhydrous dimethylformamide (3 mL) was heated at 100 °C for 2 hours. The reaction was cooled to room temperature, filtered through celite, and washed several times with methanol. The combined filtrate and washes were concentrated and purified on silica gel using a gradient of 0 to 20% methanol in dichoromethane as eluent. The title compound was obtained as a light yellow solid (51.1 mg, 25%). ES / MS m / z 255.2 (M+H).

[139] Step 2: Synthesis of (R)-l-(benzo[4,5]imidazo[l,2-a]pyrimidin-2-yl)pyrrolidin-3-yl methanesulfonate.

[140] To a stirred suspension of (R)-l-(benzo[4,5]imidazo[l,2-a]pyrimidin-2-yl)pyrrolidin-3-ol (0.1 g, 0.4 mmol) and triethylamine (0.55 mL, 3.9 mmol) in di chloromethane was added methanesulfonyl chloride (92 pL, 1.2 mmol). The reaction mixture was stirred at room temperature and a total of 7 additional equivalents of methanesulfonyl chloride were added to drive the reaction to completion. The reaction mixture was diluted with water and methylene chloride and the layers were separated. The organic layer was washed with aqueous saturated sodium bicarbonate and brine, dried over sodium sulfate, filtered, and concentrated. The material was purified by preparative silica TLC using 10% methanol in dichoromethane as eluent to afford the title compound as an off-white solid (73.5 mg, 56%). ES / MS m / z 333.2 (M+H); 'H NMR (400.13 MHz, CDC13) 8 ppm: 8.31 (d, J=7.3Hz, 1H), 7.75 (dt, J=0.7, 8.2 Hz, 1H), 7.60 (dt, J=0.9, 8.0Hz, 1H), 7.4 (ddd, J=l. 1, 7.3, 8.3Hz, 1H), 7.23 (ddd, J=1.1, 7.5, 8.2Hz, 1H), 6.25 (bd, J=6.7Hz, 1H), 5.48 (bs, 1H), 3.91 (bd, J=ll.lHz, 1H), 3.80 (bs, 1H), 3.07 (s, 3H), 2.52 (bs, 1H), 2.40-2.30 (bm, 1H), 1.64 (bs, 2H). Example 20 Synthesis of (l-(8-methoxybenzo[4,5]imidazo[l,2-a]pyrimidin-2-yl)pyrrolidin-3-yl)methyl 4-methylbenzenesulfonate (Comp. No. 20).

[141] A solution of (l-(8-methoxybenzo[4,5]imidazo[l,2-a]pyrimidin-2-yl)pyrrolidin-3-yl)methyl 4-methylbenzenesulfonate (120 mg, 0.18 mmol) in methylene chloride (4 mL) was washed with IN sodium hydroxide (3x3 mL) and water (1x1 mL). The organic layer was dried over sodium sulfate, filtered, concentrated, and purified on silica gel using a gradient of 0 to 4% methanol in dichoromethane as eluent to afford the title compound as a tan solid (30 mg, 82%). ES / MS m / z 453.5 (M+H); 'H NMR (400 MHz, CDC13) 8 ppm: 8.20 (d, J= 7.6 Hz, 1H), 7.81-7.78 (m, 2H), 7.45 (d, J= 8.7 Hz, 1H), 7.35 (d, J= 7.9 Hz, 2H), 7.22 (d, J= 2.3 Hz, 1H), 6.82 (dd, J= 2.4, 8.7 Hz, 1H), 6.15 (d, J= 7.6 Hz, 1H), 4.19-4.12 (m, 2H), 3.89 (s, 3H), 3.68-3.32 (m, 2H), 2.85-2.82 (m, 2H), 2.44 (s, 3H), 2.292.27 (m, 1H), 1.52 (m, 2H). Example 21 Synthesis of 3-(l-(benzo[4,5]imidazo[l,2-a]pyrimidin-2-yl)piperidin-4-yl)propyl methanesulfonate (Comp. No. 21).

[142] Step 1: Synthesis of 3-(l-(benzo[4,5]imidazo[l,2-a]pyrimidin-2-yl)piperidin-4-yl)propan-l-ol.

[143] A solution of 2-bromobenzo[4,5]imidazo[l,2-a]pyrimidine (0.2 g, 0.8 mmol), 3-(piperidin-4-yl)propan-l-ol (0.173 g, 1.2 mmol), and cesium carbonate (0.788 g, 2.4 mmol) in anhydrous dimethylformamide (2-3 mL) was heated at 100 °C for 2 hours. The reaction was determined to be complete by LCMS and TLC and cooled to room temperature. The reaction mixture was filtered, concentrated, and purified on silica gel using a gradient of 0 to 20% methanol in dichoromethane as eluent. The title compound was obtained as a solid (0.257 g). ES / MS m / z 311.3 (M+H); 'H NMR (400 MHz, CDC13) 5 ppm: 8.24 (d, J= 7.7 Hz, 1H), 7.72 (d, J= 8.1 Hz, 1H), 7.56 (d, J= 7.9 Hz, 1H), 7.397.35 (m, 1H), 7.21-7.17 (m, 1H), 6.43 (d, J= 7.7 Hz, 1H), 4.77-4.75 (m, 1H), 4.23 (t, J= 6.5 Hz, 2H), 3.00 (m, 4H), 1.86-1.81 (m, 9H).

[144] Step 2: Synthesis of 3-(l-(benzo[4,5]imidazo[l,2-a]pyrimidin-2-yl)piperidin-4-yl)propyl methanesulfonate.

[145] Procedure: To a solution of 3-(l-(benzo[4,5]imidazo[l,2-a]pyrimidin-2-yl)piperidin-4-yl)propan-l-ol (0.14 g, 0.5 mmol), and triethylamine (0.63 mL, 4.5 mmol) in dichloromethane (40-50 mL) was added methanesulfonyl chloride (105 pL, 1.4 mmol). The reaction was stirred at room temperature for 1 hour. A total of 5 additional equivalents methanesulfonyl chloride were added to drive the reaction to completion. The reaction mixture was diluted with dichloromethane and quenched with water. The organic layer was washed with saturated sodium bicarbonate, brine, and water, dried over sodium sulfate, filtered, and concentrated. The material was purified by preparative silica TLC using 5% methanol in di chloromethane as eluent to afford the title compound (109 mg, 63%). ES / MS m / z 389.6 (M+H); 'H NMR (400 MHz, CDCI3) 8 ppm: 8.24 (d, J= 7.7 Hz, 1H), 7.72 (d, J= 8.1 Hz, 1H), 7.56 (d, J= 7.9 Hz, 1H), 7.39-7.35 (m, 1H), 7.21-7.17 (m, 1H), 6.43 (d, J= 7.7 Hz, 1H), 4.23 (t, J= 6.5 Hz, 2H), 3.00 (s, 5H), 1.86-1.81 (m, 4H), 1.71-1.67 (m, 1H), 1.44-1.37 (m, 2H), 1.32-1.23 (m, 2H). Example 22 Synthesis of (l-(benzo[4,5]imidazo[l,2-a]pyrimidin-2-yl)piperidin-4-yl)methyl methanesulfonate (Comp. No. 22).

[146] Step 1: Synthesis of (l-(benzo[4,5]imidazo[l,2-a]pyrimidin-2-yl)piperidin-4-yl)methanol.

[147] A solution of 2-bromobenzo[4,5]imidazo[l,2-a]pyrimidine (0.3mg, 1.2 mmol), piperidin-4-ylmethanol (209 mg, 1.8 mmol), and cesium carbonate (1.576 g, 4.8 mmol) in anhydrous dimethylformamide (3 mL) was heated at 100 °C for 2 hours. The reaction was cooled to room temperature, filtered through a glass filter, and the solids washed several times with methanol. The filtrate was concentrated and purified on silica gel using a gradient of methanol in dichoromethane as eluent. The title compound was obtained as a solid (287 mg, 84%). ES / MS m / z 283.4 (M+H).

[148] Step 2: Synthesis of (l-(benzo[4,5]imidazo[l,2-a]pyrimidin-2-yl)piperidin-4-yl)methyl methanesulfonate.

[149] To a solution of (l-(benzo[4,5]imidazo[l,2-a]pyrimidin-2-yl)piperidin-4-yl)methanol (0.16 g, 0.6 mmol), and triethylamine (0.79 mL, 5.7 mmol) in di chloromethane (50 mL) was added methanesulfonyl chloride (132 pL, 1.7 mmol). The reaction was stirred at room temperature. A total of 4 additional equivalents methanesulfonyl chloride were added to drive the reaction to completion. The reaction mixture was concentrated and the material was purified by preparative silica TLC using 10% methanol in di chloromethane as eluent to afford the title compound as an off-white solid (110 mg, 54 %). ES / MS m / z 361.4 (M+H); 'HNMR (400.13 MHz, CDC13) 8 ppm: 8.42 (d, J=7.8Hz, 1H), 7.86 (d, J=8.1Hz, 1H), 7.63 (d, J=8.2Hz, 1H), 7.42 (ddd, J=0.9, 7.5, 8.2Hz, 1H), 7.254 (ddd, J=1.0, 7.6, 8.3Hz, 1H), 6.60 (d, J=7.8Hz, 1H), 4.68 (bs, 1H), 4.12 (d, J=6.4Hz, 2H), 3.09 (t, J=12.8Hz, 1H), 3.03 (s, 3H), 2.20-2.10 (m, 1H), 1.95 (bd, J=14.6Hz, 2H), 1.39 (ddd, J=4.4, 12.2, 12.2Hz, 2H), 0.90-0.82 (m, 2H). Example 23 Autoradiography Determination for the Binding of the compound of Compound No. 8(18F) to nonAD tau aggregates in Human PSP and CBD Brain Tissue

[150] Autoradiography was employed in the determination of the compound of Compound No. 8(18F) binding to native tau-aggregates on human PSP and CBD brain sections that have been characterized using anti-tau immunostaining according to methods known to the skilled artisan (See e.g. [(18)F]T807, a novel taupositron emission tomography imaging agent for Alzheimer's disease. Xia CF, et al., Alzheimer’s Dement. 2013 Nov; 9(6):666-76), (Zhang, J. (2012), “A highly selective and specific PET tracer for imaging of tau pathologies ” J Alzheimers Dis., 31(3):601). The experiment uses 10 um adjacent sections from cases clinically diagnosed with AD, PSP or CBD confirmed as tau positive by IHC employing AT8 or AT 100 antibody using standard techniques or control tissue defined as amyloid and tau negative by IHC. Sections are covered with Compound No. 8(18F) (40 pCi / ml in binding buffer (2.5% dimethylsulfoxide + 2.5% ethanol in IX PBS, pH 7.4). After a 60 min incubation at room temperature, unbound ligand is removed through successive wash cycles (2 minutes in IX PBS, 2 minutes 30% ethanol in IX PBS, 2 minutes in 70% ethanol in IX PBS, 2 minutes in IX PBS). After drying under the hood, the sections are exposed overnight to a phosphorimaging screen. The autoradiography signal recorded on the phosphorimaging screen is read using an Amersham Typhoon Bio-Imaging System. Individual tissue samples are compared to adjacent slices which have been stained with either AT8 or AT 100. A positive correlation with tau antibody indicates binding to the non-AD tau being studied (PSP or CBD).

[151] Autoradiography from the compound of Compound No. 8(18F) on PSP brain sections (16 cases, 1-4 regions per case) for determination of binding is shown in FIG. 1. Autoradiography from the compound of Compound No. 8 (18F) on CBD brain sections (5 cases, 3-6 regions per case) for determination of binding is shown in FIG. 2. The presence of ARG signal for the compound of Compound No. 8(18F), which correlates to tau positive regions of PSP and CBD human tissues indicates this compound binds non-AD tau. Both figures include the binding of the compound of Compound No. 8(18F) to human AD tissue indicating strong binding to AD tau. Therefore, PET imaging with the compound of Compound No. 8(18F) and examination of the imaging pattern, would be useful to detect the presence of AD and non-AD tau in patients, and could confirm a diagnosis of AD or non-AD tauopathies.

Claims

1. A compound, or a pharmaceutically acceptable salt thereof, of the formula:wherein,R1 is H, halogen, -OH, or Ci-Ce alkoxyl;R2 is H, halogen, or C2-C6 alkenyl;R3 is Ce-Cio aryl or 3- to 6-membered heterocycloalkyl, wherein the Ce-Cio aryl or 3- to 6-membered heterocycloalkyl is substituted with one or more R3a; andeach R3a independently is F, 18F, Ci-Ce alkyl, or 3- to 6-membered heterocycloalkyl, wherein the Ci-Ce alkyl or 3- to 6-membered heterocycloalkyl is substituted with a leaving group, F, or 18F;provided that the compound is not2. A compound, or a pharmaceutically acceptable salt thereof, of formula (I):wherein,R1 is H, halogen, -OH, or Ci-Ce alkoxyl;R2 is H, halogen, or C2-C6 alkenyl;R3 is Ce-Cio aryl or 3- to 5-membered heterocycloalkyl, wherein the Ce-Cio aryl or3- to 6-membered heterocycloalkyl is substituted with one or more R3a; andeach R3a independently is F, 18F, Ci-Ce alkyl, or 3- to 6-membered heterocycloalkyl, wherein the Ci-Ce alkyl or 3- to 6-membered heterocycloalkyl is substituted with F or 18F.

3. The compound, or a pharmaceutically acceptable salt thereof, of claim 1 or 2,wherein the compound is of formula4. The compound, or a pharmaceutically acceptable salt thereof, of claim 1 or 2,wherein the compound is of formula5. The compound, or a pharmaceutically acceptable salt thereof, of any one of claims1-4, wherein the compound is of formula6. The compound, or a pharmaceutically acceptable salt thereof, of claim 1 or 2,wherein the compound is of formula7. The compound, or a pharmaceutically acceptable salt thereof, of claim 1, wherein the compound is of formula8. The compound, or a pharmaceutically acceptable salt thereof, of claim 1, wherein the compound is9. The compound, or a pharmaceutically acceptable salt thereof, of claim 1, wherein the compound isComp. No. Structure 1 1 !L / X"N                 f(18f) 2 XX         F(18F) I 3 5 XN\__ / \-F(18F) j X 7 / -A    / -F(18F) II         / =\ J \__ / XxX y-N r-X X N 8 n / r\ / 9 XNCX XX / ^-N O        N               T(18F) 10 N XNCX ( X       L N          X18F)10. The compound, or a pharmaceutically acceptable salt thereof, of any claim 2, wherein the compound is11. A pharmaceutical composition comprising the compound, or a pharmaceutically acceptable salt thereof, of any one of claims 1-10, and one or more pharmaceutically acceptable carrier or diluent.

12. The pharmaceutical composition of claim 11, wherein the carrier comprises ethanol, water, and a buffer suitable for injection into a patient.

13. A method of imaging aggregated tau in a mammal, the method comprising: introducing into a mammal a detectable quantity of(a) the compound of any one of claims 1-10, or(b) the pharmaceutical composition of claim 11 or 12,wherein said compound or pharmaceutical composition has an 18F substituent; and further comprising detecting said compound or said pharmaceutical composition in association with aggregated tau.

14. The method of claim 13, wherein the mammal is a human.

15. The method of claim 13, wherein the mammal is a human and is suspected of having a neurological disease or disorder.

16. The method of claim 15, wherein the neurological disease or disorder is Alzheimer’s disease.

17. The method of claim 15, wherein the human is suspected of having progressive supranuclear palsy (PSP), cortical basal degeneration (CBD), Pick’s disease (PiD), atypical Alzheimer’s disease, chronic traumatic encephalopathy (CTE), frontotemporal dementia (FTD), or argyrophilic grains disease (AGD).

18. The method of claim 15, wherein the human is suspected of having early Alzheimer’s disease tau or primary age-related tauopathy (PART).

19. The method of claim 15, wherein the human is suspected of having nonAlzheimer’s disease tau.

20. The method of claim 13, wherein the compound or pharmaceutical composition is detected using positron emission tomography (PET) imaging.

21. The compound of any one of claims 1-10, wherein the compound is a radiolabeled compound, wherein the radiolabeled compound comprises an 18F.

22. A compound, or a pharmaceutically acceptable salt thereof, of the formula:wherein,R1 is H, -OH, or Ci-Ce alkoxyl;R2 is H;R3 is Ce-Cio aryl or 3- to 6-membered heterocycloalkyl, wherein the Ce-Cio aryl or 3- to 6-membered heterocycloalkyl is substituted with one or more R3a; andeach R3a independently is a leaving group, Ci-Ce alkyl, or 3- to 6-membered heterocycloalkyl, wherein the Ci-Ce alkyl or 3- to 6-membered heterocycloalkyl is substituted with a leaving group.

23. The compound, or a pharmaceutically acceptable salt thereof, of claim 22, wherein the leaving group is methanesulfonate or 4-methylbenzenesulfonate.

24. The compound, or a pharmaceutically acceptable salt thereof, of claim 22, wherein the leaving group is methanesulfonate.

25. The compound, or a pharmaceutically acceptable salt thereof, of claim 22, wherein the leaving group is 4-methylbenzenesulfonate.

26. The compound, or a pharmaceutically acceptable salt thereof, of claim 22,wherein the compound is22 [lT\ / ^n  \ vL >-n    — 6'

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