Substituted heterocyclic compounds as imaging agents for neurofibrillary tangles

Abstract

Disclosed are substituted heterocyclic compounds of formula (I) and pharmaceutically acceptable salts thereof, which may be suitable for imaging tau aggregates, b-sheet aggregates, beta-amyloid aggregates or alpha-synuclein aggregates, and hence are useful in binding and imaging tau aggregates in Alzheimer's patients. More specifically, this invention relates to a method of using the compounds of formula (I) as tracers in positron emission tomography (PET) imaging to study tau deposits in brain in vivo to allow diagnosis of Alzheimer's disease and other neurodegenerative diseases characterized by tau pathology. The disclosure further relates to a method of measuring clinical efficacy of therapeutic agents for Alzheimer's disease and other neurodegenerative diseases characterized by tau pathology.

Description

SUBSTITUTED HETEROCYCLIC COMPOUNDS AS IMAGING AGENTS FOR NEUROFIBRILLARY TANGLESCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application Serial No. 63 / 724,429 filed November 25, 2024, the entire contents of which are incorporated by reference herein.FIELD

[0002] The disclosure is directed to novel substituted heterocyclic compounds, their salts, pharmaceutical compositions comprising them, and therapeutic uses and processes for making such compounds. The present disclosure also relates to novel substituted heterocyclic compounds which may be suitable for imaging tau aggregates, B-sheet aggregates, B-amyloid aggregates, a- synuclein aggregates or trans-active response DNA binding protein 43kDa and hence are useful in binding and imaging tau aggregates in patients with neurodegenerative diseases characterized by tau pathology. More specifically, this disclosure relates to a method of using the compounds of this disclosure as tracers in PET imaging to study tau deposits in brain in vivo to allow diagnosis of neurodegenerative diseases characterized by tau pathology. The disclosure further relates to a method of measuring clinical efficacy of therapeutic agents targeting tau pathology.BACKGROUND

[0003] Furthermore, it is Alzheimer’s disease (AD) is a common neurodegenerative disease affecting the elderly, resulting in progressive memory impairment, loss of language and visuospatial skills, and behavior deficits. Characteristics of the disease include degeneration of cholinergic neurons in the cerebral cortex, hippocampus, basal forebrain, and other regions of the brain, neurofibrillary tangles, and accumulation of the amyloid B peptide (AB).

[0004] In AD, two main proteins form abnormal polymers (aggregates) in the brain that are believed to result from misfolding during aggregation of one of twenty nonhomologous human proteins. The intracellular neurofibrillary tangles-(NFT’s) are made from the microtubule- associated protein (tau protein) and the extracellular “amyloid” plaques consist mainly of polymerized AB-peptide. Both are toxic to the brain neurons and are the result of fibers formed from the subunit protein by stacking of beta strands. See B. Bulic, E. Mandelkow et al.Angewandte Chemie International Edition, Vol. 48, Issue 10, pgs. 1740-1752, 2009 and B. Bulic, et al. J. Med. Chem 2013 June 13; 56(11):4135-55.

[0005] Tau is a microtubule associate protein that is thought to play a critical role in the etiology of AD based on several lines of evidence. First, NFTs are invariably found in the brains of patients with AD and several other neurodegenerative diseases. Second, the extent of NFTs pathology in the brain of AD patients is closely correlated with cognitive function. Finally, while mutations in tau have not been shown to cause AD, such mutations do cause another form of dementia known as frontotemporal dementia with parkinsonism (FTDP). Therefore, approaches aimed at reducing NFTs and / or hyperphosphorylated tau represent potential disease modifying treatments for tauopathies.

[0006] A tau PET tracer would be a valuable non-invasive diagnostic biomarker for spatial and temporal quantification of NFTs in human brain. Additionally, a tau PET tracer could be useful for patient selection for AD clinical trials, and as a critical disease-relevant tool for quantifying a stabilization or decrease of NFT formation for disease-modifying AD therapeutics. In this mode, a tau PET tracer could be developed as a companion diagnostic for co-regi strati on. In addition to AD, there are other neurodegenerative diseases characterized by the deposition of tau aggregates (frontotemporal dementia (FTD), progressive supranuclear palsy (PSP) corticobasal degeneration (CBD), chronic traumatic encephalopathy (CTE), Pick’s disease, etc.).

[0007] Therefore, a need exists for neuroimaging radiotracers that would allow in vivo imaging of tau pathology thereby providing insight into the deposition of tau aggregates in the human brain. The successful neuroimaging radiotracer must cross the blood-brain barrier and possess high affinity and specificity for tau aggregates and therefore must have appropriate lipophilicity (logD 1-3) and low molecular weight (<450), show rapid clearance from blood and low nonspecific binding.SUMMARY OF THE DISCLOSURE

[0008] The disclosure is directed to a class of substituted heterocyclic compounds of formula I, their salts, pharmaceutical compositions comprising them, diagnostic and therapeutic uses and processes for making such compounds. In particular, the disclosure is directed to a class of heterocyclic compounds of formula I which may be useful for binding and imaging tau aggregates, B-sheet aggregates, beta-amyloid aggregates or alpha-synuclein aggregates, TDP-43 and hence are useful in binding and imaging tau aggregated protein pathology in AD and non- AD tauopathy patients. This disclosure also relates to use of the compounds as an imaging tool to improve diagnosis of patients likely to develop tauopathies by determining if said patients present with abnormal levels of tau aggregates in the brain. This disclosure further relates to finding an imaging tool that will be used to diagnosis and monitor the progression of AD andnon-AD tauopathies. This disclosure also relates use of the substituted heterocyclic compound to monitor and measure treatment when an anti-tau aggregate drug becomes available. This disclosure also may be useful for imaging and detecting for other neurodegenerative diseases characterized by the deposition of tau aggregates such as frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), chronic traumatic encephalopathy (CTE), Pick’s disease, etc. This disclosure further relates to a pharmaceutical composition containing a compound of formula I and a pharmaceutically acceptable carrier.

[0009] Also included are isotopically labeled compounds of this disclosure. Another aspect of the disclosure relates to use of the isotopically labeled compounds as neuroimaging radiotracers for in vivo imaging of the brain for tau aggregates in the diagnosis, monitoring, and / or treatment of AD. Another aspect of the disclosure is use of the isotopically labeled compounds in PET, which is an in vivo analysis technique in the diagnosis, monitoring, and / or treatment of AD. The14C and3H labeled compounds can be used in in vitro and in vivo methods for the determination of binding, receptor occupancy and metabolic studies including covalent labeling. Another aspect of the disclosure relates to the use of the isotopically labeled compounds to screen for new chemical matter. In particular, various isotopically labeled compounds find utility in magnetic resonance imaging, autoradiography and other similar analytical tools. Thus, another aspect is further directed to H, H, C, C, C, N, N, O, O, O, F, S, Cl, Br, Br, Br, 123 124 125 131I, I, I and I isotopically labeled substituted heterocyclic derivative compounds of formula I. In particular, the present disclosure is directed tonC,13C,14C,18F,15O,13N,35S,2H, and3H isotopes of substituted heterocyclic compounds, compositions and methods of their preparation and use as radiotracers or PET tracers in diagnosing and measuring the effects of a compound in the treatment of AD. The present disclosure also relates to non-toxic tau protein binding compounds that can rapidly cross the blood brain barrier, have low non-specific binding properties and are rapidly cleared from the system. This and other aspects will be realized upon review of the specification in its entirety.BRIEF DESCRIPTION OF THE DRAWINGS

[0010] Figure 1 : Saturation binding of [3H]-5 in AD brain homogenates

[0011] Figure 2: Displacement binding of [3H]-1 in AD brain homogenatesDETAILED DESCRIPTION

[0012] The present disclosure is directed to compounds of formula I:V, W2, W4, and X independently represent C(R) or N;W1and W3independently represent C or N;Z is S, C(R), N(R) or N;ZHs S, C(R), or N;Z2and Z3independently are absent or selected from C(H) or N;Z4is absent or represents C(R5) or N;R represents hydrogen, halogen, -Cj.6alkyl, or -OC|_6alkyl said alkyl optionally substituted with 1 to 3 groups of halogen;R1is absent or is selected from -Cj.6alkyl, -(CH2)nOR, -OCH2CH(OH)CH2F, -C5.10heterocyclyl, -O(CH2)nhalogen and -(CH2)nhalogen; said alkyl and heterocyclyl optionally substituted with 1 to 3 groups selected from halogen, OH, -Cj.6alkyl, -OC|_6alkyl, C1.3haloalkyl, and -OC1.3haloalkyl;R is absent or represents halogen, -Cj.6alkyl, -OC|_6alkyl, -(CH2)nOR, C1.3haloalkyl, or OC^3haloalkyl;26090R3and R5are independently selected from -Cj.6alkyl, -(CH2)nhalogen, -O(CH2)nhalogen, -C i- shaloalkyl, -OC i-shaloalkyl, -(CH2)nN(R)2, -OC^g alkyl, and -(CH2)nOR, said alkyl optionally substituted with 1 to 3 groups of halogen;R4, when present, is hydrogen, or -C^alkyl; n represents an integer from 0-4, and m represents 0 or 1, provided that only one of Z2, Z3and Z4 is absent.

[0013] In one aspect of the compounds of formula I, it is provided that only one of Z2, Z3, and Z4is absent. In another aspect, at least two of Z2, Z3, and Z4are present. In another aspect, each of Z2, Z3, and Z4is present. In another aspect, at exactly two of Z2, Z3, and Z4are present.

[0014] An aspect of the disclosure is realized when one or more available hydrogen atoms in R, R1, R2, R3and / or R4may be exchanged for deuterium. A sub-aspect of the disclosure is realized when one to three, one to two, or one hydrogen atom(s) in R, R1, R2, R3and / or R4may be exchanged for deuterium. Deuterated versions of all of the embodiments of the compounds described herein are contemplated as being withing the scope of the invention.

[0015] An aspect of the disclosure is realized when n is 0. Another aspect of the disclosure is realized when n is 1. Another aspect of the disclosure is realized when n is 2. Another aspect of the disclosure is realized when n is 3. Still another aspect of the disclosure is realized when n is 4.

[0016] An aspect of the compounds of formula I is realized when m is 0. Another aspect is realized when m is 1.

[0017] An aspect of the disclosure is realized when W1and W4are C and -C(H), respectively.

[0018] Another aspect of the disclosure is realized when W1and W4are C and N, respectively.

[0019] Another aspect of the disclosure is realized when W1, W2, W3and W4, respectively are selected from the group consisting of:1) C, N, C, C(H);2) C, C(H), N, C(H);3) N, C(H), C, C(H); and4) N, N, C, C(H).

[0020] Another aspect of the disclosure is realized when W1, W2, W3and W4, respectively are C, N, C, and C(H). A subembodiment of this aspect of the disclosure is realized when W1, W2, W3and W4, respectively are C, N, C, and C(H); X is N and V is C(H). Another subembodimentof this aspect of the disclosure is realized when W1, W2, W3and W4, respectively are C, N, C, and C(H); X is CH and V is N.

[0021] Another aspect of the disclosure is realized when W1, W2, W3and W4, respectively are C, C(H), N, and C(H). A subembodiment of this aspect of the disclosure is realized when W1, W2, W3and W4, respectively are C, C(H), N, and C(H); X is N and V is C(H). Another subembodiment of this aspect of the disclosure is realized when W1, W2, W3and W4, respectively are C, C(H), N, and C(H); X is C(H) and V is N.

[0022] Another aspect of the disclosure is realized when W1, W2, W3and W4, respectively are N, C(H), C, and C(H). A subembodiment of this aspect of the disclosure is realized when W1, W2, W3and W4, respectively are N, C(H), C, and C(H); X is N and V is C(H). Another subembodiment of this aspect of the disclosure is realized when W1, W2, W3and W4, respectively are N, C(H), C, and C(H); X is C(H) and V is N.

[0023] Another aspect of the disclosure is realized when W1, W2, W3and W4, respectively are N, N, C, and C(H). A subembodiment of this aspect of the disclosure is realized when W1, W2, W3and W4, respectively are N, N, C, and C(H); X is N and V is CH. Another subembodiment of this aspect of the disclosure is realized when W1, W2, W3and W4, respectively are N, N, C, and C(H); X is C(H) and V is N.

[0024] Another aspect of the disclosure is realized when Z is S. Another aspect of the disclosure is realized when Z is C(R). Another aspect of the disclosure is realized when Z is N(R). Another aspect of the disclosure is realized when Z is N.

[0025] Another aspect of the disclosure is realized when Z1is S. Another aspect of the disclosure is realized when Z1is C(R). Another aspect of the disclosure is realized when Z1is N.

[0026] Another aspect of the disclosure is realized when Z2is absent. Another aspect of the disclosure is realized when Z2is C(H). Another aspect of the disclosure is realized when Z2is N.

[0027] Another aspect of the disclosure is realized when Z3is absent. Another aspect of the disclosure is realized when Z3is C(H). Another aspect of the disclosure is realized when Z3is N.

[0028] Another aspect of the disclosure is realized when Z4is absent. Another aspect of the disclosure is realized when Z4is C(R5)Another aspect of the disclosure is realized when Z4is N.

[0029] Another aspect of the disclosure is realized when Z, Z1, Z2, Z3, and Z4together form a ring selected from optionally substituted pyridine, pyrimidine, pyrazole, thiazole, isothiazole, oxazole, oxadiazole and pyrazine.

[0030] Another aspect of the disclosure is realized when Z, Z1, Z2, Z3, and Z4together form an optionally substituted pyridine. Another subembodiment of this aspect of the disclosure is realized when the pyridine is formed when Z1is N and Z, Z2, Z3, and Z4are all C(H). Anothersubembodiment of this aspect of the disclosure is realized when the pyridine is formed when Z2is N and Z, Z1, Z3, and Z4are all C(H). Another subembodiment of this aspect of the disclosure is realized when the pyridine is formed when Z4is N and Z, Z1, Z3, and Z2are all C(H). Another subembodiment of this aspect of the disclosure is realized when the pyridine is formed when Z is N and Z4, Z1, Z3, and Z2are all C(H). Another subembodiment of this aspect of the disclosure is realized when the pyridine is formed when Z3is N and Z4, Z1, Z, and Z2are all C(H).

[0031] Another aspect of the disclosure is realized when Z, Z1, Z2, Z3, and Z4together form an optionally substituted pyrimidine. Another subembodiment of this aspect of the disclosure is realized when the pyrimidine is formed when Z and Z2are both N and Z1, Z3, and Z4are all C(H). Another subembodiment of this aspect of the disclosure is realized when the pyrimidine is formed when Z3and Z4are both N and Z, Z1, and Z2are all C(H).

[0032] Another aspect of the disclosure is realized when Z, Z1, Z2, Z3, and Z4together form an optionally substitututed pyrazole. Another subembodiment of this aspect of the disclosure is realized when the pyrazole is formed when Z and Z3are both N, Z1and Z2are both C(H), and Z4is absent. Another subembodiment of this aspect of the disclosure is realized when the pyrazole is formed when Z and Z2are both N and Z1and Z3are both C(H) and Z4is absent.

[0033] Another aspect of the disclosure is realized when Z, Z1, Z2, Z3, and Z4together form an optionally substituted thiazole. Another subembodiment of this aspect of the disclosure is realized when the thiazole is formed when Z is N, Z1is S, Z2and Z3are both C(H), and Z4is absent. Another subembodiment of this aspect of the disclosure is realized when the thiazole is formed when Z3is N, Z1is S, Z and Z2are both C(H) and Z4is absent. Another subembodiment of this aspect of the disclosure is realized when the thiazole is formed when Z2is N, Z is S, Z1and Z3are both C(H) and Z4is absent.

[0034] Another aspect of the disclosure is realized when Z, Z1, Z2, Z3, and Z4together form an optionally substituted oxazole.

[0035] Another aspect of the disclosure is realized when Z, Z1, Z2, Z3, and Z4together form an optionally substituted oxadiazole.

[0036] Another aspect of the disclosure is realized when Z, Z1, Z2, Z3, and Z4together form na n optionally substituted pyrazine. Another subembodiment of this aspect of the disclosure is realized when the pyrazine is formed when Z, Z1and Z4are all C(H), and Z2and Z3are both N. Another subembodiment of this aspect of the disclosure is realized when the pyrazine is formed when Z2, Z3and Z4are all C(H), and Z and Z1are both N.

[0037] Still another aspect of this disclosure is realized when R is hydrogen.

[0038] Still another aspect of this disclosure is realized when R is halogen.26090

[0039] Yet another aspect of this disclosure is realized when R is optionally substituted -Cj.6alkyl. A subembodiment of this aspect of the disclosure is realized when the alkyl is optionally substituted methyl, ethyl, butyl, or pentyl. Another aspect of this disclosure is realized when R is -C|_6alkyl substituted to 1 to 3 fluoro groups.

[0040] Yet another aspect of this disclosure is realized when R is optionally substituted -OC^6alkyl. A subembodiment of this aspect of the disclosure is realized when the alkyl is optionally substituted methyl, ethyl, butyl, or pentyl. Another aspect of this disclosure is realized when R is -OC|_6alkyl substituted to 1 to 3 fluoro groups.

[0041] An aspect of this disclosure is realized when R1is absent.

[0042] An aspect of this disclosure is realized when R1is optionally substituted -C^alkyl. A subembodiment of this aspect of the disclosure is realized when the alkyl is substituted with 1 to 3 groups selected from OH, -OCH3, -O(CH2)2F, and -OCF3.

[0043] Another aspect of this disclosure is realized when R1is -(CH2)nOR. An embodiment of this aspect of the disclosure is realized when R is hydrogen and n is 1. An embodiment of this aspect of the disclosure is realized when R is hydrogen and n is 0. Another embodiment of this aspect of the disclosure is realized when R is -C|_6alkyl and n is 0. A subembodiment of this aspect of the disclosure is realized when R is -C|_6alkyl selected from methyl, ethyl, and butyl. Another subembodiment of this aspect of the disclosure is realized when R is optionally substituted methyl, ethyl, and butyl. An embodiment of this aspect of the disclosure is realized when R1is selected from the group consisting of -CH2OH, OCH3, OH, OCH2F, and OCH2(CH(OH)CH2F.

[0044] Another embodiment of the disclosure is realized when R1is -O(CH2)nhalogen or - (CH2)nhalogen. A subembodiment of this aspect of the disclosure is realized when the halogen is fluorine. Another subembodiment of this aspect of the disclosure is realized when the halogen is chlorine.

[0045] Another aspect of this disclosure is realized when R1is optionally substituted -C5.10heterocyclyl. A subembodiment of this aspect of the disclosure is realized when the heterocyclyl is optionally substituted piperidinyl.2

[0046] An aspect of this disclosure is realized when R is absent.2

[0047] An aspect of this disclosure is realized when R is -C^alkyl, -OC|_6alkyl, -or (CH2)nOR. A subembodiment of this aspect of the disclosure is realized when the alkyl is CH3.2

[0048] An aspect of this disclosure is realized when R is C1.3haloalkyl, or OC1.3haloalkyl. A subembodiment of this aspect of the disclosure is realized when the halo in haloalkyl is fluorine.

[0049] Yet another aspect of this disclosure is realized when R2is halogen. A subembodiment of this aspect of the disclosure is realized when R2is fluorine. Another subembodiment of this aspect of the disclosure is realized when R2is bromine. Another subembodiment of this aspect of the disclosure is realized when R2is chlorine. Another subembodiment of this aspect of the disclosure is realized when R2is iodine.

[0050] Another aspect of this disclosure is realized when R3is -C^alkyl, said alkyl optionally substituted with 1 to 3 groups of halogen. A subembodiment of this aspect of the disclosure is realized when R3is CH3 or CF3.

[0051] Another aspect of this disclosure is realized when R3is -(CH2)nhalogen. A subembodiment of this aspect of the disclosure is realized when the halogen is fluorine. A subembodiment of this aspect of the disclosure is realized when the halogen is chlorine. Still another embodiment of this aspect of the disclosure is realized when n is 0, 1 or 2.

[0052] Another aspect of this disclosure is realized when R3is -O(CH2)nhalogen. A subembodiment of this aspect of the disclosure is realized when the halogen is fluorine. A subembodiment of this aspect of the disclosure is realized when the halogen is chlorine. Still another embodiment of this aspect of the disclosure is realized when n is 1 or 2.

[0053] Another aspect of this disclosure is realized when R3is -C i-3haloalkyl.

[0054] Another aspect of this disclosure is realized when R3is -OC i-3haloalkyl.

[0055] Another aspect of this disclosure is realized when R3is -(CH2)nN(R)2. A subembodiment of this aspect of this disclosure is realized when one R is hydrogen and the other is -C|_6alkyl such as methyl, ethyl and butyl, preferably methyl. Another subembodiment of this aspect of this disclosure is realized when both Rs are hydrogen. Still another aspect of the disclosure is realized when R3is selected from the group consisting of NH2, NHCH3, NCH3(CH2)nF, and NH(CH2)nF. A subembodiment of this aspect of the disclosure is realized when R3is NH2. A subembodiment of this aspect of the disclosure is realized when R3is NHCH3. A subembodiment of this aspect of the disclosure is realized when R3is NCH3(CH2)nF. A subembodiment of this aspect of the disclosure is realized when R3is NH(CH2)2F.

[0056] Another aspect of this disclosure is realized when R3is -(CH2)nOR. . A subembodiment of this aspect of this disclosure is realized when one R is hydrogen. Another subembodiment of this aspect of this disclosure is realized when R is -Chalky! and n is 0.

[0057] Another subembodiment of this aspect of this disclosure is realized when R is -C j _6al ky 1 optionally substituted with 1 to 3 groups of halogen and n is 0. Another subembodiment of this aspect of the disclosure is realized when the alkyl is selected from the group consisting of optionally substituted methyl, ethyl, and butyl, preferably methyl and ethyl. Another subembodiment of this aspect of the disclosure is realized when the alkyl is substituted with at least one halogen, preferably fluorine. Still another aspect of the disclosure is realized when R3is selected from the group consisting of CH2OH, OCH3, O(CH2)2F, and OCH2CH3. Another aspect of the disclosure is realized when R3is OCH3. Another aspect of the disclosure is realized when R3is O(CH2)2F. Another aspect of the disclosure is realized when R3is OCH2CH3.

[0058] Another aspect of this disclosure is realized when R3is halogen. A subembodiment of this aspect of the disclosure is realized when the halogen is fluorine. A subembodiment of this aspect of the disclosure is realized when the halogen is chlorine.

[0059] Another aspect of the disclosure is realized when m is 1 and R4is -C^alkyl.

[0060] Another aspect of the disclosure is realized when m is 1 and R4is hydrogen.

[0061] Yet another aspect is when m is 0.

[0062] Another aspect of the disclosure is realized when the compounds of formula I are isotopically labeled with 2H, 3H, HC, 13c, 14c, 13N, 15N, 15Q, 1?O, 18(3, 18F, 35S, 36CL, 82Br, 76Br, 77Br, 1231, 124i and 1311.

[0063] Still another aspect of this disclosure is realized with the compound of structural formula la:la or a pharmaceutically acceptable salt thereof, wherein R, R2, R3, and R4 are as described herein. Another subembodiment of formula la is realized when R2is absent. Another subembodiment of formula la is realized when R2is present. A further subembodiment of R2is realized when it is halogen, preferably fluorine. Another subembodiment of the disclosure of formula la is realized when Z1is N and Z2is C(H). Another subembodiment of the disclosure of formula la is realized when Z1is C(H) and Z2is N. Another subembodiment of formula la is realized when R3is selected from the group consisting of fluorine, CH3, (CH2)nOH, CF3, NH2, NHCH3, NH(CH2)nF,26090OCH3, O(CH2)nF, and OCH2CH3. Still a further subembodiment of formula la is realized when R3is NHCH3. A further subembodiment of formula la is realized when R3is OCH3. An aspect of the disclosure of formula la is realized when one or more available hydrogen atoms in R, R2, R3and / or R4may be exchanged for deuterium. A sub-aspect of the disclosure is realized when one to three, one to two, or one available hydrogen atom(s) in R, R2, R3and / or R4may be exchanged for deuterium.

[0064] Still another aspect of this disclosure is realized with the compound of structural formula lb:lb or a pharmaceutically acceptable salt thereof, wherein R, Rl, R2, R3, and R4 are as described herein. A subembodiment of formula lb is realized when R1is absent. Another subembodiment of formula lb is realized when R1is selected from the group consisting of CH2OH, OH, -OCH3, - OCH2F, -O(CH2)2F, -OCF3, and OCH2CH(OH)CH2F. Another subembodiment of formula lb is realized when R2is absent. Another subembodiment of formula lb is realized when R2is present. A further subembodiment of R2is realized when it is halogen, preferably fluorine. Another subembodiment of formula lb is realized when R3is selected from the group consisting of fluorine, CH3, (CH2)nOH, CF3, NH2, NHCH3, NH(CH2)nF, OCH3, O(CH2)nF, and OCH2CH3. Still a further subembodiment of formula lb is realized when R3is NHCH3. A further subembodiment of formula lb is realized when R3is OCH3. An aspect of the disclosure of formula lb is realized when one or more available hydrogen atoms in R, Rl, R2, R3and / or R4may be exchanged for deuterium. A sub-aspect of the disclosure is realized when one to three, one to two, or one available hydrogen atom(s) in R, R2, R3and / or R4may be exchanged for deuterium.

[0065] Still another aspect of this disclosure is realized with the compound of structural formula Ic:26090or a pharmaceutically acceptable salt thereof, wherein R, Rl, R2, R3, and R4 are as described herein. A subembodiment of formula Ic is realized when R1is absent. Another subembodiment of formula Ic is realized when R1is selected from the group consisting of CH2OH, OH, -OCH3, - OCH2F, -O(CH2)2F, -OCF3, and OCH2CH(OH)CH2F. Another subembodiment of formula Ic is realized when R2is absent. Another subembodiment of formula Ic is realized when R2is present. A further subembodiment of R2is realized when it is halogen, preferably fluorine.

[0066] Another subembodiment of formula Ic is realized when Z3is N, Z is N(R), Z1and Z2are C(H) and a double bond is present between Z1and Z2. Another subembodiment of formula Ic is realized when Z2is N, Z is N(R), Z1and Z3are C(H) and a double bond is present between Z1and Z2. Another subembodiment of formula Ic is realized when Z2is C(H), Z is N, Z1is S and Z3is C(H) and a double bond is present between Z and Z2. Another subembodiment of formula Ic is realized when Z2is C(H), Z is C(R), Z1is S and Z3is N and a double bond is present between Z and Z2. Another subembodiment of formula Ic is realized when Z2is N, Z is S, Z1and Z3both are C(H) and a double bond is present between Z1and Z2. Another subembodiment of formula Ic is realized when R3is selected from the group consisting of fluorine, CH3, (CH2)nOH, CF3, NH2, NHCH3, NH(CH2)nF, OCH3, O(CH2)nF, and OCH2CH3. Still a further subembodiment of formula Ic is realized when R3is NHCH3. A further subembodiment of formula Ic is realized when R3is OCH3. An aspect of the disclosure of formula Ic is realized when one or more available hydrogen atoms in R, Rl, R2, R3and / or R4may be exchanged for deuterium. A subaspect of the disclosure is realized when one to three, one to two, or one available hydrogen atom(s) in R, R2, R3and / or R4may be exchanged for deuterium.

[0067] The compounds of the present disclosure may have asymmetric centers, chiral axes and chiral planes, and occur as racemates, racemic mixtures, and as individual diastereomers, with all possible isomers, including optical isomers, being included in the present disclosure. (See E.L. Eliel and S.H. Wilen Stereochemistry of Carbon Compounds (John Wiley and Sons, New York 1994), in particular pages 1119-1190)

[0068] When any variable (e.g., aryl, heterocycle, Rl, R^ etc.) occurs more than one time in any constituent, its definition on each occurrence is independent at every other occurrence. Also,26090 combinations of substituents / or variables are permissible only if such combinations result in stable compounds.

[0069] As used herein, "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms; "alkoxy" represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge.

[0070] "Halogen" or "halo" as used herein means fluoro, chloro, bromo and iodo.

[0071] As used herein, "cycloalkyl" is intended to include cyclic saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. Preferably, cycloalkyl is C3- C10 cycloalkyl. Examples of such cycloalkyl elements include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

[0072] The term "haloalkyl" refers to an alkyl group in which one or more of the hydrogen atoms on one or more carbon atoms have been replaced (i.e., substituted) with a halogen (i.e., F, Cl, Br and / or I). Thus, for example, “-C1-6 haloalkyl” (or “-Ci-Cg haloalkyl”) refers to a -Cl to Cg linear or branched alkyl group as defined above with one or more halogen substituents; particularly 1-6 halogen substituents; and more particularly 1-3 halogen substituents. The term “fluoroalkyl” has an analogous meaning except that the halogen substituents are restricted to fluoro.

[0073] As used herein, "aryl" is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic. Examples of such aryl elements include phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl.

[0074] The term heterocyclyl, heterocycle or heterocyclic, as used herein, represents a stable 5- to 7-membered monocyclic or stable 8- to 11 -membered bicyclic heterocyclic ring which is either saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O, and S, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. The term heterocyclyl, heterocycle or heterocyclic includes heteroaryl moieties.Examples of such heterocyclic elements include, but are not limited to, azepinyl, benzodi oxolyl, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzotriazolyly, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, 1,3-dioxolanyl, furyl, furopyridinyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl,26090 indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, 2-oxopiperazinyl, 2- oxopiperdinyl, 2-oxopyrrolidinyl, piperidyl, piperazinyl, pyridyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyrazolopyridinyl, pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, pyrrolopyridinyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiazolyl, thiazolinyl, thi enofuryl, thi enothienyl, thienyl, and triazolyl.

[0075] Preferably, heterocyclyl is selected from furopyridinyl, imidazolyl, indolyl, isoquinolinylisothiazolyl, morpholinyl, naphthyridinyl, piperidyl, piperazinyl, pyridyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyrazolopyridinyl, pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, pyrrolopyridinyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiazolinyl, thienofuryl, thi enothienyl, thienyl, and triazolyl.

[0076] "Heteroaryl" is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic and wherein from one to four carbon atoms are replaced by heteroatoms selected from the group consisting of N, O, and S. Examples of such heteroaryl elements include, but are not limited to, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiazolyl, thienofuryl, thi enothienyl, thienyl, triazolyl and the like.

[0077] Examples of an "effective amount" include amounts that enable imaging of NFTs in vivo, that yield acceptable toxicity and bioavailability levels for pharmaceutical use, and / or prevent cell degeneration and toxicity associated with fibril formation.

[0078] For use in medicine, the salts of the compounds of formula I will be pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds according to the disclosure or of their pharmaceutically acceptable salts. When the compound of the present disclosure is acidic, suitable “pharmaceutically acceptable salts” refers to salts prepared form pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as arginine, betaine26090 caffeine, choline, N,N'-dibenzylethylenediamine, diethylamin, 2-diethylaminoethanol, 2- dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine tripropylamine, tromethamine and the like.

[0079] When the compound of the present disclosure is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p- toluenesulfonic acid and the like. Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric and tartaric acids.

[0080] The preparation of the pharmaceutically acceptable salts described above and other typical pharmaceutically acceptable salts is more fully described by Berg et al., “Pharmaceutical Salts,” J. Pharm. Sci., 1977:66: 1-19.

[0081] As indicated herein the present disclosure includes isotopically labeled compounds of the disclosure. An "isotopically-labeled", "radio-labeled", “tracer”, “radiotracer”, “labeled tracer” or “radioligand” compound, is a compound where one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (i.e., naturally occurring). Suitable radionuclides (i.e., "detectable isotopes") that may be incorporated in compounds of the present disclosure include 1 i - - J AT3TT H -, 13 / -, 14„ 13,T15,T15 „ 17„ 18„ 18^ 35 36„f82„ 76 „ 77„ but are not limited to H, H, C, C, C, N, N, O, O, O, F, S, Cl, Br, Br, Br,123I,124I,125I and131I.The isotopically labeled compounds of the disclosure need only to be enriched with a detectable isotope to, or above, the degree which allows detection with a technique suitable for the particular application. The radionuclide that is incorporated in the instant radiolabeled compounds will depend on the specific application of that radiolabeled compound. In another embodiment of the disclosure the radionuclides are represented bynC,13C,14C,18F,15O,13N,35S,2H, and3H, preferablynC, and18F. For example, deuterium, when introduced into a compound at levels at least 5x above natural abundance, can also be considered a substituent for purposes of describing the compounds herein. Note that because deuterium is an isotope of hydrogen that does not substantially change the shape of the molecule, deuterium is exempt from the typical numerical limitations placed on numbers of substituents: deuterium (D) can be included in place of hydrogen (H) in addition to other substituents and should not be counted in the numerical limitations that apply to other substituents. Different isotopic forms of26090 hydrogen (H) include protium (1H) and deuterium (2H). Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples. Isotopically-enriched compounds within generic Formulas (I), (la), (lb), and (Ic) can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and / or intermediates.

[0082] As used herein, “deuterated version” refers to a compound in which at least one hydrogen atom is enriched in the isotope deuterium beyond the natural rate of deuterium occurrence. Typically, the hydrogen atom is enriched to be at least 50% deuterium, frequently at least 75% deuterium, and often at least about 90% deuterium. Optionally, more than one hydrogen atom can be replaced by deuterium. For example, a methyl group can be deuterated by replacement of one hydrogen with deuterium (i.e., it can be -CHzD), or it can have all three hydrogen atoms replaced by deuterium (i.e., it can be -CD3). In each case, D signifies that at least 50% of the corresponding H is present as deuterium.

[0083] This disclosure further relates to a pharmaceutical composition comprising an effective amount of at least one compound of formula I and a pharmaceutically acceptable carrier. The composition may comprise, but is not limited to, one or more buffering agents, wetting agents, emulsifiers, suspending agents, lubricants, adsorbents, surfactants, preservatives and the like. The composition may be formulated as a solid, liquid, gel or suspension for oral administration (e.g., drench, bolus, tablet, powder, capsule, mouth spray, emulsion); parenteral administration (e.g., subcutaneous, intramuscular, intravenous, epidural injection); topical application (e.g., cream, ointment, controlled-released patch, spray); intravaginal, intrarectal, transdermal, ocular, or nasal administration.

[0084] This disclosure provides radiolabeled and isotopically stable substituted heterocylic derivatives as tau imaging agents and synthetic precursor compounds from which they are prepared. The compounds of formula I are active against age-related diseases such as AD, as well as other tauopathies and neurodegenerative diseases, such as PSP, CTE, FTD, Pick’s disease, corticobasal degeneration, etc. The compounds of this disclosure may also be used in combination with a broad range of cognition deficit enhancement agents. Thus, in another embodiment of this disclosure a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or formulation comprising a compound of formula I is administered concurrently, simultaneously, sequentially or separately with another26090 pharmaceutically active compound or compounds used in AD therapies including for example donepezil, memantine, tacrine and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.

[0085] This disclosure further relates to a method of treating or preventing a tau-related pathology in a patient comprising administering a therapeutically effective amount of a compound of formula I. This disclosure also provides a method for treating neurodegenerative disorders such as dementia, Cognitive Deficit in Schizophrenia, Mild Cognitive Impairment, Age Associated Memory Impairment, Age-Related Cognitive Decline, and the like.

[0086] An ultimate objective of the present disclosure is to provide a radiopharmaceutical agent, useful in tau imaging that has high molar activity and high target tissue selectivity by virtue of its high affinity for tau aggregates. The tissue selectivity is capable of further enhancement by coupling this highly selective radiopharmaceutical with targeting agents, such as microparticles.

[0087] In accordance with the present disclosure, the most preferred method for imaging tau deposits in a patient, wherein an isotopically labeled novel substituted heterocyclic derivative is employed as the imaging agent, comprises the following steps: the patient is placed in a supine position in the PET camera, and a sufficient amount (< 10 mCi) of an isotopically labeled substituted heterocyclic derivative is administered to the brain tissue of the patient. An emission scan of the cerebral region is performed. The technique for performing an emission scan of the head is well known to those of skilled in the art. PET techniques are described in Freeman et al., Freeman and Johnson's Clinical Radionuclide Imaging. 3rd. Ed. Vol. 1 (1984); Grune & Stratton, New York; Ennis et Q. Vascular Radionuclide Imaging: A Clinical Atlas, John Wiley & Sons, New York (1983).

[0088] The term "labeled tracer" refers to any molecule which can be used to follow or detect a defined activity in vivo, for example, a preferred tracer is one that accumulates in the regions where tau aggregates may be found. Preferably, the labeled tracer is one that can be viewed in a living experimental animal, healthy human or patient (referred to as a subject), for example, by PET scanning. Suitable labels include, but are not limited to radioisotopes, fluorochromes, chemiluminescent compounds, dyes, and proteins, including enzymes.

[0089] The present disclosure also provides methods of determining in vivo activity of an enzyme or other molecule. More specifically, a tracer, which specifically tracks the targeted activity, is selected and labeled. In a preferred embodiment, the tracer tracks binding activity of tau protein in the brain and central nervous system. The tracer provides the means to evaluate various neuronal processes, including, regulation of neurotransmitter release, and long-term26090 potentiation. Biomarkers of AD disease state, prognosis and progression will all be useful for general diagnostic utilities as well as for clinical development plans for therapeutic agents for AD. Compounds of formula I may provide biomarker information as patients are enrolled in clinical trials for new AD treatments to assist in patient selection and assignment to cohorts. Compounds of formula I may serve as one of the biomarkers of disease state in order to get the correct patients into the proper Phllb trial cohort. In addition, compounds of formula I may serve as one marker of disease prognosis as an entry inclusion criterion in order to enhance the probability that the disease will progress in the placebo treatment arm, an issue that has plagued recent AD clinical trials. Finally, the compounds of formula I could serve as one biomarker of disease progression to monitor the clinical course of patients on therapy and could provide an independent biomarker measure of treatment response by a therapeutic drug.

[0090] Compounds within this disclosure are inhibitors and / or binders of aggregated tau protein. Compounds of formula I, and isotopically labeled variants thereof, may be useful for the diagnosis and / or treatment of Alzheimer's disease, depression, schizophrenia, or Parkinson's disease. Means of detecting labels are well known to those skilled in the art. For example, isotopic labels may be detected using imaging techniques, photographic film or scintillation counters. In a preferred embodiment, the label is detected in vivo in the brain of the subject by imaging techniques, for example PET.

[0091] The labeled compound of formula I preferably contains at least one radionuclide as a label. Positron-emitting radionuclides are all candidates for usage. In the context of this disclosure the radionuclide is preferably selected fromnC,13C,14C,18F,15O,13N,35S,2H, and3H, more preferably fromnC, and18F.

[0092] The tracer can be selected in accordance with the detection method chosen. Before conducting the method of the present disclosure, a diagnostically effective amount of a labeled or unlabeled compound of the disclosure is administered to a living body, including a human.

[0093] The diagnostically effective amount of the labeled or unlabeled compound of formula I to be administered before conducting the present in-vivo method is within a range of from 0.1 ng to 100 mg per kg body weight, preferably within a range of from 1 ng to 10 mg per kg body weight.

[0094] The isotopically labeled compounds of this disclosure are prepared by incorporating an isotope such asnC,13C,14C,18F,15O,13N,35S,2H, and3H into the substrate molecule. This is accomplished by utilizing reagents that have had one or more of the atoms contained therein made radioactive by placing them in a source of radioactivity such as a nuclear reactor, a cyclotron and the like. Additionally many isotopically labeled reagents, such as2H20,3H3CI,2609014C6HsBr, C1CH214COC1 and the like, are commercially available. The isotopically labeled reagents are then used in standard organic chemistry synthetic techniques to incorporate the isotope atom, or atoms, into a compound of formula I, la, lb, or Ic as described below. The following Schemes illustrate how to make the compounds of formulae I, la, lb, and Ic.

[0095] The compounds of formula I have utility in diagnosing, monitoring, and measuring Alzheimer’s disease and other non- D tauopathies such as frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), chronic traumatic encephalopathy (CTE), Pick’s disease, etc. Other conditions that may be diagnosed by the compounds of the disclosure include Parkinson’s Disease, pulmonary hypertension, chronic obstructive pulmonary disease (COPD), asthma, urinary incontinence, glaucoma, schizophrenia, Trisomy 21 (Down Syndrome), cerebral amyloid angiopathy, degenerative dementia, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type (HCHWA-D), Creutzfeld-Jakob disease, prion disorders, amyotrophic lateral sclerosis, head trauma, stroke, pancreatitis, inclusion body myositis, other peripheral amyloidoses, diabetes, autism and atherosclerosis.

[0096] In preferred embodiments, the compounds of formula I are useful in diagnosing, monitoring or measuring Alzheimer’s Disease, non- AD tauopathies, neurodegenerative disease, cognitive disorders, schizophrenia, pain disorders and sleep disorders. For example, the compounds may be useful for the prevention of dementia of the Alzheimer’s type, as well as for the treatment of early stage, intermediate stage or late stage dementia of the Alzheimer’s type.

[0097] The term "composition" as used herein is intended to encompass a product comprising specified ingredients in predetermined amounts or proportions, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. This term in relation to pharmaceutical compositions is intended to encompass a product comprising one or more active ingredients, and an optional carrier comprising inert ingredients, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.

[0098] In general, pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient 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. In the pharmaceutical composition the active compound, which is a compound of formulae I, la, lb, and Ic, is included in an amount sufficient to produce the desired effect upon the process or condition of diseases. Accordingly, the pharmaceutical compositions of the present disclosure encompass26090 any composition made by admixing a compound of the present disclosure and a pharmaceutically acceptable carrier.

[0099] The present disclosure also provides a method for the synthesis of compounds useful as intermediates in the preparation of compounds of the disclosure.

[0100] The compounds described herein can be prepared according to the procedures of the following schemes and examples, using appropriate materials and are further exemplified by the following specific examples. Deuterated versions of the compounds of the disclosure can be prepared by substituting an appropriate isotopically labeled reagent for a non-isotopically labeled reagent. The compounds illustrated in the examples are not, however, to be construed as forming the only genus that is considered as the disclosure. The examples further illustrate details for the preparation of the compounds of the present disclosure. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. All temperatures are degrees Celsius unless otherwise noted. Mass spectra (MS) were measured by electrospray ion-mass spectroscopy (ESI). 'H NMR spectra were recorded at 300-500 MHz. Compounds described herein were synthesized as a racemic mixture unless otherwise stated in the experimental procedures.

[0101] In some cases the final product may be further modified, for example, by manipulation of substituents. These manipulations may include, but are not limited to, reduction, oxidation, alkylation, acylation, and hydrolysis reactions which are commonly known to those skilled in the art. In some cases the order of carrying out the foregoing reaction schemes may be varied to facilitate the reaction or to avoid unwanted reaction products. The following examples are provided so that the disclosure might be more fully understood. These examples are illustrative only and should not be construed as limiting the disclosure in any way.List of AbbreviationsAnal. = analytical calc. = calculatedDEA = diethylamineDIPEA = A,A-diisopropylethylamineDMF = dimethylformamideDCM = dichloromethaneTFA = trifluoroacetic acidTBAF = tert-butylammonium fluorideTBSC1 = tert-butyldimethylsilyl chlorideDMSO = dimethyl sulfoxide26090DMP Dess-Martin periodinaneDMA dimethylacetamideEtOAc ethyl acetateEtOH ethanolHPLC high-pressure liquid chromatographyIPA / .w-propyl alcoholIP Ac / .w-propyl acetateKF Karl-Fischer titration (to determine water content)MeCN acetonitrileMeOH methyl alcoholMS mass spectroscopyMTBE methyl tert-butyl etherNHS normal human serumNMR nuclear magnetic resonance spectroscopyPd / C palladium on carbon rt room temperature h hour(s)TLC thin-layer chromatographyTHF tetrahydrofuran wt% percentage by weightEt3N triethylamineTFA trifluoroacetic acidTBSC1 tert-butyldimethylsilyl chlorideAcOH acetic acidTBAF tetrabutylammonium fluorideDMSB dimethylsulfide boraneEt2O ethoxy ethane aq. aqueousPhMe tolueneP(OEt)3triethyl phosphitePd(PPh3)4tetrakis(triphenylphosphine)palladium(O)Pd(PPh3)2Cl2bis(triphenylphosphine)palladium(II) dichlorideTEAA triethylammonium acetate260902nd generation XPhos precatalyst = 2ndgeneration 2-dicyclohexylphosphino-2’,4’,6’- triisopropyl- 1,1’ -biphenyl

[0102] The following examples are provided to illustrate the disclosure and are not to be construed as limiting the scope of the disclosure in any manner.EXAMPLE 1(2-(5-((6-(methylamino)pyridin-3-yl)ethynyl)pyridin-2-yl)imidazo[L2-a1pyridin-6-yl)methanolStep A: (2-(5-bromopyri din-2 -yl)imidazo[L2-a1pyridin-6-yl)methanol

[0103] To a solution of (6-aminopyri din-3 -yl)methanol (222 mg, 1.79 mmol) in EtOH (17 ml) was added 2-bromo-l-(5-bromopyridin-2-yl)ethanone (500 mg, 1.79 mmol). The reaction was heated at reflux for 12 h, cooled to rt at which point the product crashed out of solution. The product was collected by filtration, and rinsed with cold EtOH to get the crude product (2-(5- bromopyri din-2 -yl)imidazo[l,2-a]pyridin-6-yl)methanol as a solid, which was used for the next step directly without further purification. ESI-MS m / z [M + H]: 303.0Step B: tert-butyl methyl(5-((trimethylsilyl)ethynyl)pyridin-2-yl)carbamate

[0104] To a solution of tert-butyl (5-bromopyri din-2 -yl)(methyl)carbamate (5000 mg, 17.41 mmol) in DMF (87 ml) was added trimethyl silyl acetylene (7.4 ml, 52.2 mmol), 2nd generation XPhos precatalyst (1370 mg, 1.74 mmol), and EtsN (7.3 ml, 52.2 mmol). The reaction was sealed and heated at 80DC for 12 h, quenched with water, extracted with EtOAc, concentreated and chromatographed (0-5% MeOH: DCM, 40 g silica gel column) to give tert-butyl methyl(5- ((trimethylsilyl)ethynyl)pyridin-2-yl)carbamate as a solid. ESI-MS m / z [M + H]: 305.2Step C: tert-butyl (5-ethynylpyridin-2-yl)(methyl)carbamate26090

[0105] K2CO3 (7.8 g, 56.1 mmol) was added to a solution of tert-butyl methyl(5- ((trimethylsilyl)ethynyl)pyridin-2-yl)carbamate (5.7 g, 18.7 mmol) in MeOH (187 ml). The reaction was stirred at rt for 12 h, quenched with water, extracted with EtOAc, concentrated, and chromatographed (0-20% EtOAc: hexanes, 40 g silica gel column) to give tert-butyl (5- ethynylpyridin-2-yl)(methyl)carbamate as a solid. ESI-MS m / z [M + H]: 233.1Step D: tert-butyl (5-((6-(6-(hydroxymethyl)imidazorE2-a]pyridin-2-yl)pyridin-3- yl)ethynyl)pyridin-2-yl)(methyl)carbamate

[0106] To a solution of (2-(5-bromopyridin-2-yl)imidazo[l,2-a]pyridin-6-yl)methanol (39 mg, 0.13 mmol) and tert-butyl (5-ethynylpyridin-2-yl)(methyl)carbamate (30 mg, 0.13 mmol) in DMF (650 pl) was added 2nd generation XPhos precatalyst (10 mg, 0.01 mmol), and EtiN (54 pl, 0.39 mmol). The reaction was sealed and heated at 80°C for 3 h, and concentrated to give tertbutyl (5-((6-(6-(hydroxymethyl)imidazo[l,2-a]pyridin-2-yl)pyridin-3-yl)ethynyl)pyridin-2- yl)(methyl)carbamate as an oil which was used for the next step directly without further purification. ESI-MS m / z [M + H]: 456.2Step E: (2-(5-((6-(methylamino)pyridin-3-yl)ethynyl)pyridin-2-yl)imidazo[E2-a1pyridin-6- yDmethanol

[0107] To a solution of tert-butyl (5-((6-(6-(hydroxymethyl)imidazo[l,2-a]pyridin-2-yl)pyridin- 3-yl)ethynyl)pyridin-2-yl)(methyl)carbamate (59 mg, 0.13 mmol) in DCM (1 ml) was added TFA (50 pl, 0.65 mmol). The reaction was stirred at rt for 2 h, concentrated, and chromatographed using HPLC purification (30 cm x 100cm Cl 8, 30 min 0-95% acetonitrile- water gradient, 0.05% TFA added) to give (2-(5-((6-(methylamino)pyridin-3-yl)ethynyl)pyridin- 2-yl)imidazo[l,2-a]pyridin-6-yl)methanol as a solid. 'H NMR (500 MHz, DMSO-t / 6) 6: 8.86 (d, 2 H, J= 5.0 Hz), 8.74 (s, 1 H), 8.28 (m, 1 H), 8.15 (m, 2 H), 7.80 (d, 1 H, J= 10 Hz), 7.69 (m, 2 H), 6.65 (d, 1 H, J= 10 Hz), 4.64 (s, 2 H), 2.86 (s, 3 H); ESI-MS m / z [M + H]: 356.2EXAMPLE 2(2-(5-((2-((2-fluoroethyl)amino)pyrimidin-5-yl)ethynyl)pyridin-2-yl)imidazo[L2-a1pyridin-6- yDmethanol26090Step A: 2- 5- trimethylsilyl)ethynyl)pyridin-2-yl)imidazo[E2-a1pyridin-6-yl)methanol

[0108] To a solution of (2-(5-bromopyridin-2-yl)imidazo[l,2-a]pyridin-6-yl)methanol (500 mg, 1.64 mmol) in DMF (8.2 ml) was added trimethyl silyl acetylene (700 pl, 4.93 mmol), 2nd generation Xphos precatalyst (129 mg, 0.164 mmol), and Et3N (680 p 1, 4.93 mmol). The reaction was sealed and heated at 80°C for 12 h, quenched with water, extracted with EtOAc, concentrated and chromatographed (0-5% MeOH: DCM, 24 g silica gel column) to give (2-(5- ((trimethylsilyl)ethynyl)pyridin-2-yl)imidazo[l,2-a]pyridin-6-yl)methanol as a solid. ESI-MS m / z [M + H]: 322.2Step B: (2-(5-ethynylpyridin-2-yl)imidazolE2-a1pyridin-6-yl)methanol

[0109] K2CO3 (335 mg, 2.43 mmol) was added to a solution of (2-(5- ((trimethylsilyl)ethynyl)pyridin-2-yl)imidazo[l,2-a]pyridin-6-yl)methanol (260 mg, 0.81 mmol) in MeOH (8.0 ml). The reaction was stirred at rt for 12 h, quenched with water, extracted with EtOAc, concentrated, and chromatographed (0-5% MeOH: DCM, 12 g silica gel column) to give (2-(5-ethynylpyri din-2 -yl)imidazo[l,2-a]pyridin-6-yl)m ethanol as a solid. ESI-MS m / z [M + H]: 250.1Step C: 5-bromo-N-(2-fluoroethyl)pyrimidin-2-amine

[0110] To a solution of 5-bromo-2-fluoropyrimidine (750 mg, 4.24 mmol) and 2- fluoroethanamine hydrochloride (506 mg, 5.09 mmol) in MeCN (21 ml) was added Hunig's base (2220 pl, 12.7 mmol). The reaction was sealed and heated for 12 h, concentrated and chromatographed (silica gel 40 g, 0-5% MeOH: DCM) to give 5-bromo-N-(2- fluoroethyl)pyrimidin-2-amine as a solid. ESI-MS m / z [M + H]: 221.0Step D: (2-(5-((2-((2-fluoroethyl)amino)pyrimidin-5-yl)ethynyl)pyridin-2-yl)imidazo[E2- a1pyridin-6-yl)methanol26090

[0111] To a solution of (2-(5-ethynylpyridin-2-yl)imidazo[l,2-a]pyridin-6-yl)methanol (26 mg, 0.10 mmol) and 5-bromo-N-(2-fluoroethyl)pyrimidin-2-amine (24 mg, 0.11 mmol) in DMF (525 p 1) was added 2nd generation XPhos precatalyst (8.2 mg, 0.01 mmol), and Et3N (44 p 1, 0.31 mmol). The reaction was sealed and heated to 80°C for 3 h, and chromatographed using HPLC purification (30 cm x 100cm C18, 30 min 0-95% acetonitrile-water gradient, 0.05% TFA added) to give (2-(5-((2-((2-fluoroethyl)amino)pyrimidin-5-yl)ethynyl)pyridin-2-yl)imidazo[l,2- a]pyridin-6-yl)methanol as a solid.XH NMR (500 MHz, DMSO-t / 6) 6: 8.82 (m, 2 H), 8.68 (s, 1 H), 8.56 (s, 1 H), 8.23 (m, 1 H), 8.13 (m, 2 H), 7.98 (m, 1 H), 7.74 (d, 1 H, J= 10 Hz), 4.60 (s, 2 H), 4.5 l(t, 2 H, J= 5 Hz), 3.64 (m, 2 H); ESI-MS m / z [M + H]: 389.2.EXAMPLE 3(2-(5-((6-(methylamino)pyridin-3-yl)ethynyl)pyridin-2-yl)imidazolL2-a1pyridin-8-yl)methanol3Step A: (2-(5-bromopyri din-2 -yl)imidazolL2-a1pyridin-8-yl)methanol

[0112] To a suspension of pyri din-3 -ylmethanol (1.37 g, 12.57 mmol) in EtOH (125 ml) was added 2-bromo-l -(5 -brom opyri din-2 -yl)ethanone (4.21 g, 15.10 mmol). The reaction was heated to 115°C for 12 h, and cooled to rt causing the product to crash out of solution. The solid was filtered, washed with cold EtOH to give (2-(5 -brom opyri din-2 -yl)imidazo[l, 2-a]pyridin-8- yl)methanol as a solid. ESI-MS m / z [M + H]: 304.0.Step B: 2-(5-bromopyridin-2-yl)-8-(((tert-butyldimethylsilyl)oxy)methyl)imidazolL2-a1pyridine

[0113] To a solution of (2-(5-bromopyridin-2-yl)imidazo[l,2-a]pyridin-8-yl)methanol (2.5 g, 8.2 mmol) in DMF (40 ml) was added TBSC1 (1.5 g, 9.9 mmol) and imidazole (670 mg, 9.9 mmol). The reaction was stirred at rt for 2 h, quenched with water, extracted with EtOAc, concentrated, and chromatographed (40 g silica gel, 0-5% MeOH: DCM) to give 2-(5- bromopyri din-2 -yl)-8-(((tert-butyldimethylsilyl)oxy)methyl)imidazo[l,2-a]pyri dine as a solid. ESI-MS m / z [M + H]: 418.1.Step C: tert-butyl (5-((6-(8-(((tert-butyldimethylsilyl)oxy)methyl)imidazo[ 1,2-alpyri din-2 - yl)pyridin-3-yl)ethynyl)pyridin-2-yl)(methyl)carbamate

[0114] To a purged vial containing give 2-(5-bromopyridin-2-yl)-8-(((tert- butyldimethylsilyl)oxy)methyl)imidazo[l,2-a]pyridine (1.0 g, 2.4 mmol), tert-butyl (5- ethynylpyridin-2-yl)(methyl)carbamate (1.1 g, 4.8 mmol), and chloro(2-dicyclohexylphosphino- 2',4',6'-triisopropyl-l,r-biphenyl)[2-(2'-amino-l,r-biphenyl)]palladium(II) (188 mg, 0.24 mmol) was added DMF (12 ml) followed by EtiN (1.0 ml, 7.2 mmol). The reaction was heated to 80 °C for 6 h, quenched with water, extracted with EtOAc, concentrated and chromatographed (24 g silica gel, 0-5% MeOH: DCM) to give tert-butyl (5-((6-(8-(((tert- butyldimethylsilyl)oxy)methyl)imidazo[l,2-a]pyridin-2-yl)pyridin-3-yl)ethynyl)pyridin-2- yl)(methyl)carbamate as a solid. ESI-MS m / z [M + H]: 570.3.Step D: (2-(5 -((6-(m ethylamino)pyri din-3 -yl)ethynyl)pyridin-2-yl)imidazo[ l,2-a1pyridin-8- yDmethanol

[0115] To a solution of tert-butyl (5-((6-(8-(((tert-butyldimethylsilyl)oxy)methyl)imidazo[l,2- a]pyridin-2-yl)pyridin-3-yl)ethynyl)pyridin-2-yl)(methyl)carbamate (1.3 g, 2.3 mmol) in DCM (22 ml) was added TFA (525 p 1, 6.84 mmol). The reaction was stirred at rt for 2 h, concentrated and chromatographed using HPLC purification (19 cm x 150cm C18, 30 min 0-95% acetonitrile- water gradient, 0.05% TFA added) to yield (2-(5-((6-(methylamino)pyridin-3-yl)ethynyl)pyridin- 2-yl)imidazo[l,2-a]pyridin-8-yl)methanol as a solid. 'H NMR (500 MHz, DMSO-t / 6) 6: 8.70 (d, 1 H, J= 5.0 Hz), 8.53 (s, 1 H), 8.48 (d, 1 H, J= 5.0 Hz), 8.25 (d, 1 H, J= 5.0 Hz), 8.13 (d, 1H, J = 5.0 Hz), 7.97 (m, 1 H), 7.56 (m, 1 H), 7.30 (d, 1 H, J= 5.0 Hz), 7.05 (m, 1 H), 6.96 (t, 1 H, J =5.0 Hz), 6.50 (d, 2 H, J= 5.0 Hz), 4.90 (d, 2 H, J= 5.0 Hz), 3.17 (d, 1 H, J= 5.0 Hz), 2.82 (d, 3 H, J= 5.0 Hz); ESI-MS m / z [M + H]: 356.2.EXAMPLE 4(2-(5-((2-(methylamino)pyrimidin-5-yPethynyPpyridin-2-yl)imidazorL2-a]pyridin-6- yDmethanolStep A: (2-(5-((2-(methylamino)pyrimidin-5-yl)ethynyl)pyridin-2-yl)imidazc>ri,2-a]pyridin-6- yDmethanol

[0116] To a solution of (2-(5-ethynylpyridin-2-yl)imidazo[l,2-a]pyridin-6-yl)methanol (22 mg, 0.12 mmol) and 5-bromo-N-methylpyrimidin-2-amine (26 mg, 0.11 mmol) in DMF (525 p 1) was added chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-l,l'-biphenyl)[2-(2'-amino-l,l'- biphenyl)]palladium(II) ((8.2 mg, 0.01 mmol), and Et3N (44 p 1, 0.31 mmol). The reaction was sealed and heated to 80°C for 3 h, and chromatographed using HPLC purification (30 cm x 100cm C18, 30 min 0-95% acetonitrile-water gradient, 0.05% TFA added) to give (2-(5-((2- (methylamino)pyrimidin-5-yl)ethynyl)pyridin-2-yl)imidazo[l,2-a]pyridin-6-yl)methanol as a solid. 'HNMR (500 MHz, DM SO-6 / 6) 8: 8.82 (m, 2 H), 8.68 (s, 1 H), 8.56 (m, 1 H), 8.23 (m, 1 H), 8.13 (m, 2 H), 7.74 (d, 1 H, J= 10 Hz), 7.61 (m, 1 H), 4.62 (s, 2 H), 2.86 (d, 3 H, J= 5.0 Hz); ESI-MS m / z [M + H]: 357.2.EXAMPLE 5(2-(6-((6-(m ethylamino)pyri din-3 -yl)ethynyl)pyri din-3 -yl)imidazorL2-a1pyridin-8-yl)methanolStep A: 2 -bromo- 1 -(6-bromopyri din-3 -yl)ethan- 1 -one26090

[0117] To a solution of 2-bromo-5-(l-ethoxyvinyl)pyridine (8.03 g, 35.2 mmol) in THF (150 ml) and water (15 ml) was added 1 -bromopyrrolidine-2, 5-dione (6.27 g, 35.2 mmol) at ambient temperature. After stirring at ambient temperature for 10 min the reaction was taken into the next step directly without working up.Step B: (2-(6-brom opyri din-3 -yl)imidazo[L2-a]pyridin-8-yl)m ethanol

[0118] To a suspension of pyri din-3 -ylmethanol (785 mg, 7.2 mmol) in THF (100 ml) and water (10 ml) was added 2-bromo-l-(6-bromopyridin-3-yl)ethanone (2.0 g, 7.2 mmol). The reaction was stirred at rt for 12, concentrated and chromatographed (silica gel, 0-5% MeOH: DCM) to give (2-(6-bromopyri din-3 -yl)imidazo[l,2-a]pyridin-8-yl)m ethanol as a solid. ESI-MS m / z [M + H]: 303.8.Step C: (2-(6-((6-(methylamino)pyri din-3 -yl)ethynyl)pyri din-3 -yl)imidazo[ 1,2-alpyri din-8- yDmethanol

[0119] A solution of (2-(6-bromopyri din-3 -yl)imidazo[l,2-a]pyridin-8-yl)m ethanol (96 mg, 0.316 mmol), 5-ethynyl-N-methylpyridin-2-amine (50.1 mg, 0.379 mmol), copper(I) iodide (6.01 mg, 0.032 mmol), triethylamine (96 mg, 0.947 mmol) and Pd(PPh3)2Ch (11.08 mg, 0.016 mmol) in DMF (30 ml) were stirred for 3 h at 50°C. The mixture was cooled to ambient temperature, diluted with ethyl acetate (200 ml), washed with brine (3 x 200 ml), dried over anhydrous Na2SC>4, and filtered. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with to (2-10%) methanol in di chloromethane to afford (2-(6-((6-(m ethylamino)pyri din-3 -yl)ethynyl)pyri din-3 - yl)imidazo[l,2-a]pyridin-8-yl)methanol as a solid.1H NMR. (300 MHz, DMSO-t / 6) 6: 9.16 (s, 1 H), 8.58 (s, 1 H), 8.45 (d, 1 H, J= 6.6 Hz), 8.32 (m, 2 H), 7.62 (m, 2 H), 7.29 (d, 1 H, J= 6.3 Hz), 7.11 (m, 1 H), 6.96 (t, 1 H, J= 6.9 Hz), 6.50 (d, 1 H, J= 9.0 Hz), 5.41 (d, 2 H, J= 5.7 Hz), 2.82 (d, 3 H, J= 4.8 Hz); ESI-MS m / z [M + H]: 356.2.EXAMPLE 6260906-methoxy-l -methyl-2-(5-((l -methyl- lH-pyrazol-3-yl)ethynyl)pyridin-2-yl)-lH- benzoldlimidazole6Step A: tert-butyl (5-methoxy-2-nitrophenyl)(methyl)carbamate

[0120] To a solution of tert-butyl (5-methoxy-2-nitrophenyl)carbamate (4.5 g, 16.77 mmol) in DMF (100 ml) was added NaH (0.805 g, 20.13 mmol) at 0 °C. The reaction was warmed to rt and stirred for 40 min, followed by the addition of Mel (2.62 g, 18.45 mmol). The reaction was stirred at rt for 3 h. The reaction was quenched with aq. NF Cl (100 ml), diluted with water (300 ml), extracted with EtOAc (3 x 200 ml), concentrated, and chromatographed (silica gel, 2% to 10% EtOAc: petrolium ether) to afford tert-butyl (5-methoxy-2-nitrophenyl)(methyl)carbamate as a solid. ESI-MS m / z [M + H]: 183.1.Step B: tert-butyl (2-amino-5-methoxyphenyl)(methyl)carbamate ill „ 'B°cNH2

[0121] To a solution of tert-butyl (5-methoxy-2-nitrophenyl)(methyl)carbamate (4.5 g, 15.94 mmol) in MeOH (100 ml) and EtOAc (15 ml) was added palladium on charcoal (0.848 g, 0.797 mmol, 10% w / w). The resulting mixture was kept under a hydrogen atmosphere (1 atm.) for 3 hours at 40 °C. The mixture was filtered and concentrated to afford tert-butyl (2-amino-5- methoxyphenyl)(methyl)carbamate as a solid. ESI-MS m / z [M + H]: 197.1.Step C: tert-butyl (2-(5-bromopicolinamido)-5-methoxyphenyl)(methyl)carbamate

[0122] To a solution of tert-butyl (2-amino-5-methoxyphenyl)(methyl)carbamate (4 g, 15.85 mmol) in DMF (100 ml) was added 5 -bromopicolinic acid (3.84 g, 19.02 mmol), EtsN (4.81 g, 47.6 mmol) and HATU (18.08 g, 47.6 mmol). The reaction was stirred at rt for 16 h. The reaction26090 was diluted with water (500 ml), extracted with EtOAc (3 x 100 ml), and concentrated to afford tert-butyl (2-(5-bromopicolinamido)-5-methoxyphenyl)(methyl)carbamate as a solid. ESI-MS m / z [M + H]: 436.1.Step D: 6-methoxy-l-methyl-2-(5-((trimethylsilyl)ethynyl)pyri din-2 -yl)-lH-benzo[d1imidazole

[0123] A solution of tert-butyl (2-(5-bromopicolinamido)-5-methoxyphenyl)(methyl)carbamate (6.5 g, 14.90 mmol) in AcOH (100 ml) and TFA (20 ml) was stirred at 115°C for 2h. The mixture was cooled to rt, concentrated and dissolved in EtOAc (200 ml). The pH value of the mixture was adjusted to 9 by ammonia, diluted with water (300 ml), extracted with EtOAc (3 x 200 ml), concentrated chromatographed (silica gel, 4% to 25% EtOAc: petrolium ether) to afford 2-(5-bromopyridin-2-yl)-6-methoxy-l-methyl-lH-benzo[d]imidazole as a solid. ESI-MS m / z [M + H]: 318.0.Step E: 6-methoxy-l -methyl-2-(5-((trimethylsilyl)ethynyl)pyri din-2 -yl)-lH-benzo[d1imidazole

[0124] To a slurry of Pd(PPh3)2Ch (0.221 g, 0.314 mmol), copper(I) iodide (0.060 g, 0.314 mmol) and 2-(5-bromopyridin-2-yl)-6-methoxy-l-methyl-lH-benzo[d]imidazole (1 g, 3.14 mmol) in EtsN (20 ml), was added ethynyltrimethylsilane (0.617 g, 6.29 mmol). The reaction was heated to 50°C for 16 h. The reaction was concentrated, and chromatographed (silica gel, 0 to 15% EtOAc: petrolium ether) to afford 6-methoxy-l -methyl-2-(5- ((trimethylsilyl)ethynyl)pyridin-2-yl)-lH-benzo[d]imidazole as a solid. ESI-MS m / z [M + H]: 336.0.Step F: 2-(5-ethynylpyridin-2-yl)-6-methoxy-l-methyl-lH-benzord1imidazole

[0125] To a stirred solution of 6-methoxy-l -methyl-2-(5-((trimethylsilyl)ethynyl)pyri din-2 -yl)- lH-benzo[d]imidazole (500 mg, 1.490 mmol) in MeOH (20 ml) was added K2CO3 (309 mg, 2.236 mmol). After stirring for 1 h at rt, the mixture was evaporated under reduced pressure to give a residue, which was chromatographed (silica gel, 1 to 3% MeOH: DCM) to give 2-(5- ethynylpyridin-2-yl)-6-methoxy-l -methyl- lH-benzo[d]imidazole as a solid. ESI-MS m / z [M + H]: 264.0.26090Step G: 6-methoxy-l-methyl-2-(5-((l-methyl-lH-pyrazol-3-yl)ethynyl)pyridin-2-yl)-lH- benzordlimidazole

[0126] 3-iodo-l-methyl-lH-pyrazole (33.2 mg, 0.160 mmol), bis(triphenylphosphine)palladium(II) chloride (9.33 mg, 0.013 mmol), copper(I) iodide (2.53 mg, 0.013 mmol) and EtsN (0.056 ml, 0.399 mmol) were added into the solution of 2-(5- ethynylpyridin-2-yl)-6-methoxy-l -methyl- lH-benzo[d]imidazole (35 mg, 0.133 mmol) in DMF (2 ml). The mixture was stirred at 30 °C for 16 h and diluted with EtOAc (100 ml). The mixture was washed with water (3 x 10 ml), brine (1 x 10 ml), concentrated and chromatographed (Cl 8, 19x150 mm, 10-50% water / 0.05% NH4HCO3: MeCN) to give 6-methoxy-l-methyl-2-(5-((l- methyl-lH-pyrazol-3-yl)ethynyl)pyridin-2-yl)-lH-benzo[d]imidazole as a solid. 'HNMR (400 MHz, DM SO-6 / 6) 8: 8.86 (s, 1 H), 8.30 (d, 1 H, J= 8.0 Hz), 8.11 (d, 1 H, J= 10 Hz), 7.83 (s, 1 H), 7.61 (d, 1 H, J= 8.8 Hz), 7.20 (s, 1 H), 6.92 (m, 1 H), 6.00 (s, 1 H), 4.23 (s, 3 H), 3.90 (s, 3 H), 3.87 (s, 3 H); ESI-MS m / z [M + H]: 344.2.EXAMPLE 76-methoxy-2-(5-((l-methyl-lH-pyrazol-3-yl)ethynyl)pyridin-2-yl)-lH-benzo[d1imidazoleStep A: tert-butyl (2-amino-5-methoxyphenyl)carbamate

[0127] To a solution of tert-butyl (5-methoxy-2-nitrophenyl)carbamate (3.0 g, 11.18 mmol) in MeOH (100 ml) was added Pd-C (0.119 g, 0.112 mmol) at rt. The resulting slurry was sitted under EE (2 atm.) for 3 h. The mixture was filtered, washing with MeOH (100 ml), concentrated to afford tert-butyl (2-amino-5-methoxyphenyl)carbamate which was used without further purification. ESI-MS m / z [M + H]: 239.2.Step B: tert-butyl (2-(5-bromopicolinamido)-5-methoxyphenyl)carbamate26090Boc

[0128] To a solution of tert-butyl (2-amino-5-methoxyphenyl)carbamate (2.1 g, 8.81 mmol) in pyridine (100 ml) was added 5-bromopicolinoyl chloride (1.943 g, 8.81 mmol). The mixture was stirred at 25 °C for 12 h. The reaction was concentrated, and chromatographed (silica gel, 1 to 10% MeOH: DCM to afford tert-butyl (2-(5-bromopicolinamido)-5-methoxyphenyl)carbamate as a solid. ESI-MS m / z [M + H]: 423.9.Step C: 2-(5-bromopyridin-2-yl)-6-methoxy-lH-benzo[d1imidazole

[0129] To a solution of tert-butyl (2-(5-bromopicolinamido)-5-methoxyphenyl)carbamate (3.5 g, 8.29 mmol) in AcOH (150 ml) was added TFA (2.84 g, 24.87 mmol). The reaction was stirred at 90°C for 3 h. The reaction mixture was allowed to cool down to rt. The pH was adjusted to 9 by aq. ammonia, concentrated, and chromatographed (silica gel, 1 to 5% MeOH: DCM) to afford 2-(5-bromopyridin-2-yl)-6-methoxy-lH-benzo[d]imidazole as a solid. ESI-MS m / z [M + H]: 305.9.Step D: 6-methoxy-2-(5-((trimethylsilyl)ethynyl)pyridin-2-yl)-lH-benzord]imidazole

[0130] To a solution of 2-(5-bromopyridin-2-yl)-6-methoxy-lH-benzo[d]imidazole (440 mg, 1.447 mmol) and EtsN (1.008 ml, 7.23 mmol) in DMF (30 ml) was added ethynyltrimethylsilane (284 mg, 2.89 mmol), copper(I) iodide (27.6 mg, 0.145 mmol), and Pd(PPh3)2Ch (102 mg, 0.145 mmol). The reaction was heated under an N2 atm at 50 °C for 6 h. The reaction was allowed to cool to rt, concentrated, and chromatographed (silica gel, 10 to 50% EtOAc: petroleum ether) to afford the 6-methoxy-2-(5-((trimethylsilyl)ethynyl)pyri din-2 -yl)-lH-benzo[d]imidazole as a solid. ESI-MS m / z [M + H]: 322.0.Step E: 2-(5-ethynylpyri din-2 -yl)-6-methoxy-lH-benzo[d]imidazole26090

[0131] To a solution of 6-methoxy-2-(5-((trimethylsilyl)ethynyl)pyridin-2-yl)-lH- benzo[d]imidazole (320 mg, 0.995 mmol) in DCM (50 ml) was added TBAF (1 M, 1.991 ml, 1.991 mmol). The reaction was stirred at rt for 2 h, concentrated, and chromatographed (silica gel, 1 to 10% MeOH: DCM) to afford 2-(5-ethynylpyridin-2-yl)-6-methoxy-lH-benzo[d]imidazole as a solid. ESI-MS m / z [M + H]: 250.0.Step F: 6-methoxy-2-(5-((l -methyl- lH-pyrazol-3-yl)ethynyl)pyri din-2 -yl)-lH- benzoldlimidazole

[0132] To a solution of 2-(5-ethynylpyridin-2-yl)-6-methoxy-lH-benzo[d]imidazole (150 mg, 0.602 mmol) and 3-iodo-l-methyl-lH-pyrazole (125 mg, 0.602 mmol) in DMF (30 ml) was added EtsN (0.419 ml, 3.01 mmol), copper(I) iodide (11.46 mg, 0.060 mmol) and Pd(PPh3)2Ch (42.2 mg, 0.060 mmol). The reaction was heated and stirred under an N2 atm at 70°C for 3 h, cooled to rt, concentrated, and chromatographed (silica gel column, 3 to 10% EtOAc: petroleum ether) to afford the 6-methoxy-2-(5-((l-methyl-lH-pyrazol-3-yl)ethynyl)pyridin-2-yl)-lH- benzo[d]imidazole as a solid. 'H NMR (300 MHz, DMSO-t / 6) 6: 13.11 (brs, 1H), 8.86 (s, 1 H), 8.27 (s, 1 H), 8.10 (d, 1 H, J= 8.1 Hz), 7.83 (s, 1 H), 7.55 (brs, 1 H), 7.05 (brs, 1 H), 6.87 (d, 1 H, J= 8.4 Hz), 6.60 (s, 1 H), 3.90 (s, 3 H), 3.81 (s, 3 H); ESI-MS m / z [M + H]: 330.1.EXAMPLE 8(2-(6-((6-(methylamino)pyridin-3-yl)ethynyl)pyridin-3-yl)-2H-indazol-7-yl)methanolStep A: 2 -nitroisophthalic acid26090

[0133] To a solution of dimethyl 2-nitroisophthalate (9.0 g, 38 mmol) in THF: H2O (10: 1, 60 ml) was added LiOH (1.8 g, 75 mmol). The reaction was stirred for 16 hours at 50°C, cooled to rt, and acidified to pH 4 with HC1 (3 M) causing the product to crash out of solution. The product was collected by filtration and washed with HC1 (3 M), and dried in a oven in vacuo to afford 2- nitroisophthalic acid as a solid. 'HNMR (300 MHz, DM SO-6 / 6) 6: 14.17 (brs, 2H), 8.19 (d, 2 H, J= 7.8 Hz), 7.82 (t, 1 H, J= 7.8 Hz).Step B: (2 -nitro- 1 , 3 -phenylene)dimethanol

[0134] To a stirred solution of 2-nitroisophthalic acid (7.3g, 35 mmol) in THF (10 ml) was added DMSB (51.9 ml, 104 mmol) dropwise at 0°C over 1 h. The reaction was allowed to warm slowly to rt and stirred for 36 h .The reaction was slowly quenched with methanol (40 ml), and the mixture was filtered and evaporated. The residue was dissolved in EtOAc (100 ml), washed with water (20ml), dried, filtered, concentrated, and chromatographed (silica gel, 20 to 40% EtOAc: petroleum ether) to afford (2-nitro-l,3-phenylene)dimethanol as a solid. 'H NMR. (300 MHz, DM SO-6 / 6) 8: 7.56 (m, 3H), 5.54 (brs, 2 H), 4.53 (s, 4 H).Step C: (3-(((tert-butyldimethylsilyl)oxy)methyl)-2-nitrophenyl)methanol

[0135] To a solution of (2-nitro-l,3-phenylene)dimethanol (3.2 g, 17 mmol) in DCM (80 ml) was added EtsN (2.1 g, 21 mmol) and tert-butylchlorodimethylsilane (2.8 g, 18 mmol). The reaction was stirred for 24 hours at rt. The reaction was washed water (3 x 10 ml), dried, filtered, concentrated, and chromatographed (silica gel, 10 to 30% EtOAc: petroleum ether to afford (3- (((tert-butyldimethylsilyl)oxy)methyl)-2-nitrophenyl)methanol as a solid. 'H NMR (300 MHz, DM SO-6 / 6) 6: 7.54 (m, 3H), 5.48 (t, 1 H, J= 5.7 Hz), 4.75 (s, 2 H), 4.53 (d, 2 H, J= 5.7 Hz), 0.85 (s, 9 H), 0.04 (s, 6 H).Step D: 3 -('(Ttert-butyldimethylsilyl (oxy (methyl )-2-nitrobenzaldehvde26090

[0136] To a solution of (3-(((tert-butyldimethylsilyl)oxy)methyl)-2-nitrophenyl)methanol (1.7g,5.7 mmol) in DCM (80 ml) was added DMP (3.6 g, 8.6 mmol). The reaction was stirred for 2 h, quenched with aq NaHCOs and NaS2Os. The resulting mixture was extracted with Et2O (2 x 50 ml), dried, filtered, concentrated, and chromatographed (silica gel, 5% to 10% EtOAc: petroleum ether) to afford 3-(((tert-butyldimethylsilyl)oxy)methyl)-2 -nitrobenzaldehyde as a solid. 'H NMR (300 MHz, DMSO-t / 6) 8: 9.99 (s, 1 H), 8.03 (m, 1H), 7.95 (m, 1 H), 7.87, (m, 1 H), 4.79 (s, 2 H), 4.53 (d, 2 H, J= 5.7 Hz), 0.87 (s, 9 H), 0.06 (s, 6 H).Step E: (E)-N-(6-bromopyridin-3-yl)-l-(3-(((tert-butyldimethylsilyl)oxy)methyl)-2- nitrophenyDmethanimine

[0137] To a stirred solution of 3-(((tert-butyldimethylsilyl)oxy)methyl)-2-nitrobenzaldehyde (1.2 g, 4.1 mmol) in PhMe (60 ml) was added 6-bromopyri din-3 -amine (0.78 g, 4.5 mmol) and 4- methylbenzenesulfonic acid (0.035 g, 0.20 mmol). The reaction was stirred for 16 h at 120°C, cooled to rt, and concentrated afford (E)-6-bromo-N-(3-(((tert-butyldimethylsilyl)oxy)methyl)-2- nitrobenzylidene)pyridin-3-amine as a solid. ESI-MS m / z [M + H]: 452.1.Step F: 2-(6-bromopyridin-3-yl)-7-(((tert-butyldimethylsilyl)oxy)methyl)-2H-indazole

[0138] A stirred mixture of (E)-6-bromo-N-(3-(((tert-butyldimethylsilyl)oxy)methyl)-2- nitrobenzylidene)pyridin-3-amine (1.5g, 2.7 mmol) in P(OEt)s (8.0 ml, 2.7 mmol) was heated to 150 °C for 2 hours, cooled to rt, and quenched with water (40 ml). The resulting mixture was extracted with EtOAc (3 x 80 ml), washed with brine (4 x 20 ml), dried, concentrated, and chromatographed (silica gel column chromatography, 5 to 15% EtOAc: petroleum ether) to afford 2-(6-bromopyridin-3-yl)-7-(((tert-butyldimethylsilyl)oxy)methyl)-2H-indazole as a solid. ESI-MS m / z [M + H]: 417.9.Step G: (2-(6-bromopyridin-3-yl)-2H-indazol-7-yl)methanol26090

[0139] To a solution of 2-(6-bromopyridin-3-yl)-7-(((tert-butyldimethylsilyl)oxy)methyl)-2H- indazole (500 mg, 1.20 mmol) in DCM (50 ml) was added HC1 (0.59 M in MeOH, 2ml). The reaction was stirred for 3 h at rt causing the product to crash out. The solid was collected by filtration, washed with water (30 ml) to afford (2-(6-bromopyridin-3-yl)-2H-indazol-7- yl)methanol as a solid. ESI-MS m / z [M + H]: 304.0.Step H: (2-(6-((6-(methylamino)pyridin-3-yl)ethynyl)pyridin-3-yl)-2H-indazol-7-yl)methanol

[0140] To a solution of (2-(6-bromopyridin-3-yl)-2H-indazol-7-yl)methanol (100 mg, 0.329 mmol) in 1,4-di oxane (30 ml) was added 5-ethynyl-N-methylpyridin-2-amine (65.2 mg, 0.493 mmol), EtsN (100 mg, 0.986 mmol), Cu(I)I (6.3 mg, 0.033 mmol) and Pd(PPhs)4 (38.0 mg, 0.033 mmol). The reaction was stirred for 1.5 h at 80°C, cooled to rt, and concentrated. The residue was chromatographed (silica gel, 1 to 5% MeOH: DCM) to afford (2-(6-((6- (methylamino)pyridin-3-yl)ethynyl)pyridin-3-yl)-2H-indazol-7-yl)methanol as a solid. 'HNMR (300 MHz, DM SO-6 / 6) 8: 9.33 (d, 1 H, J= 2.4 Hz), 9.24 (s, 1 H), 8.50 (m, 1 H), 8.30 (s, 1 H), 7.78 (d, 1 H, J= 8.4 Hz), 7.62 (m, 2 H), 7.35 (d, 1 H, J= 5.7 Hz), 7.14 (m, 2 H), 6.51 (d, 1 H, J = 8.7 Hz), 5.26 (t, 1 H, J= 5.4 Hz), 4.94 (d, 2 H, J= 5.7), 2.82 (d, 3 H, J= 4.8 Hz); ESI-MS m / z [M + H]: 356.2.EXAMPLE 92-(6-fluoro-5-((l -methyl- lH-pyrazol-3-yl)ethynyl)pyridin-2-yl)-6-methoxy-l-methyl-lH- benzoldlimidazoleStep A: 5-bromo-6-fluoro-N-(4-methoxy-2-(methylamino)phenyl)picolinamide26090

[0141] To a solution of 5-methoxy-Nl -methylbenzene- 1,2-diamine (1.2 g, 7.9 mmol) in pyridine (30 ml) was added 5-bromo-6-fluoropicolinoyl chloride (1.1 g, 4.7 mmol) at 0 °C. The reaction was stirred at rt for 2 h, concentrated, and chromatographed (silica gel, 2 to 17 % EtOAc: petroleum ether) to afford 5-bromo-6-fluoro-N-(4-methoxy-2- (methylamino)phenyl)picolinamide as a solid. ESI-MS m / z [M + H]: 355.9.Step B: 2-(5-bromo-6-fluoropyridin-2-yl)-6-methoxy-l-methyl-lH-benzold1imidazole

[0142] A solution of 5-bromo-6-fluoro-N-(4-methoxy-2-(methylamino)phenyl)picolinamide (800 mg, 2.26 mmol) in AcOH (35 ml) was stirred at 110 °C for 2h, concentrated, and chromatographed (silica gel, 5 to 50% EtOAc: petroleum ether) to afford 2-(5-bromo-6- fluoropyridin-2-yl)-6-methoxy-l-methyl-lH-benzo[d]imidazole as a solid. ESI-MS m / z [M + H]: 336.0.Step C: 2-(6-fluoro-5-((trimethylsilyl)ethynyl)pyridin-2-yl)-6-methoxy-l -methyl- 1H- benzo[d1imidazole

[0143] To a solution of 2-(5-bromo-6-fluoropyridin-2-yl)-6-methoxy-l -methyl- 1H- benzo[d]imidazole (500 mg, 1.49 mmol) in DMF (25 ml) was added ethynyltrimethylsilane (292 mg, 2.97 mmol), EtsN (301 mg, 2.97 mmol), Pd(PPh3)2Ch (104 mg, 0.149 mmol) and Cu(I)I (28.3 mg, 0.149 mmol). The reaction was stirred at 80°C for 16 h, cooled to rt, diluted with water (100 ml), extracted with EtOAc (3 x 50 ml), washed with brine (100 ml), dried, filtered, concentrated, and chromatographed (silica gel, 3 to 10% EtOAc: petroleum ether) to afford 2-(6- fluoro-5-((trimethylsilyl)ethynyl)pyridin-2-yl)-6-methoxy-l-methyl-lH-benzo[d]imidazole as a solid. ESI-MS m / z [M + H]: 354.3.Step D: 2-(5-ethynyl-6-fluoropyridin-2-yl)-6-methoxy-l-methyl-lH-benzord1imidazole

[0144] To a solution of 2-(6-fluoro-5-((trimethylsilyl)ethynyl)pyridin-2-yl)-6-methoxy-l- methyl-lH-benzo[d]imidazole (360 mg, 1.018 mmol) in MeOH (15 ml) was added K2CO3 (28226090 mg, 2.04 mmol). The reaction was stirred at rt for 40 min, and filtered. The filtrate was concentrated and chromatographed (silica gel, 5 to 13% EtOAc: petroleum ether) to afford 2-(5- ethynyl-6-fluoropyridin-2-yl)-6-methoxy-l-methyl-lH-benzo[d]imidazole as a solid. ESI-MS m / z [M + H]: 282.2.Step E: 2-(6-fluoro-5-((l -methyl- lH-pyrazol-3-yl)ethynyl)pyridin-2-yl)-6-methoxy-l -methyl- IH-benzoldlimidazole

[0145] To a solution of 2-(5-ethynyl-6-fluoropyridin-2-yl)-6-methoxy-l-methyl-lH- benzo[d]imidazole (100 mg, 0.356 mmol) in DMF (15 ml) was added 3-iodo-l-methyl-lH- pyrazole (111 mg, 0.533 mmol), Pd(PPh3)2C12 (25.0 mg, 0.036 mmol), DIEA (310 Dl, 1.79 mmol) and Cu(I)I (6.77 mg, 0.036 mmol). The reaction was stirred at 30°C for 4 h, cooled to rt, diluted with water (30 ml), extracted with EtOAc (3 x 30 ml), washed with brine (50 ml), dried, filtered, concentrated, and chromatographed (silica gel, 0.5 to 4% MeOH: DCM) to afford 2-(6- fluoro-5-((l-methyl-lH-pyrazol-3-yl)ethynyl)pyri din-2 -yl)-6-m ethoxy- 1 -methyl-lH- benzo[d]imidazole as a solid. 'H NMR (300 MHz, DM SO-6 / 6) 8: 8.26 (m, 2 H), 7.83 (d, 1 H, J = 2.4 Hz), 7.61 (d, 1 H, J= 8.7 Hz), 7.20 (d, 1 H, J= 2.1 Hz), 6.91 (dd, 1 H, J= 8.7 Hz, 2.4 Hz), 6.21 (d, 1 H, J= 2.4 Hz), 4.20 (s, 3 H), 3.90 (s, 3 H), 3.86 (s, 3 H); ESI-MS m / z [M + H]: 362.1.EXAMPLE 105-methoxy-2-(5-((5-methoxypyridin-2-yl)ethynyl)pyridin-2-yl)-3-methyl-3H-imidazo[4,5- blpyridine10Step A: 6-fluoro-N-methyl-3-nitropyridin-2-amine

[0146] To a solution of 2,6-difluoro-3-nitropyridine (20 g, 130 mmol) in EtOH (250 ml) was added methylamine (11.76 g, 125 mmol) dropwise at 0°C. The reaction was warmed to rt and stirred for 30 min, the product was collected by filtration, and washed with ethanol (20 ml) to26090 afford 6-fluoro-N-methyl-3-nitropyridin-2-amine as a solid.1H NMR (300 MHz, DMSO-t / 6) 6: 8.81 (brs, 1 H), 8.59 (m, 1 H), 6.43 (dd, 1 H, J= 3.3 Hz, 9.0 Hz), 2.98 (d, 3 H, J= 4.8 Hz).Step B: 6-methoxy-N-methyl-3-nitropyridin-2-amine

[0147] To a solution of 6-fluoro-N-methyl-3-nitropyridin-2-amine (2 g, 12 mmol) in MeOH (50 ml) was added the solution of NaOMe (1 M, 58.4 ml, 58.4 mmol). After stirring for 16h, the product was collected via filtration to give 6-methoxy-N-methyl-3-nitropyridin-2-amine as a solid. ESI-MS m / z [M + H]: 184.0.Step C: 6-methoxy-A2-methylpyridine-2,3-di amineH MeO N N¥ Y ^^NH2

[0148] To a solution of 6-methoxy-N-methyl-3-nitropyridin-2-amine (1.8 g, 9.8 mmol) in AcOH (20 m) was added zinc (2.6 g, 39.3 mmol) at 0 °C. The reaction was warmed to rt and stirred for 2 h, then concentrated and dissolved in water (100 ml). The pH was adjusted to 8 by aq Na2CC>3, then extracted with EtOAc (3 x 100 ml), washed with brine (l x 200 ml), dried, filtered, concentrated, and chromatographed (silica gel, 10 to 30% EtOAc: petroleum ether) to afford 6-methoxy-A2-methylpyridine-2,3-diamine as a solid. ESI-MS m / z [M + H]: 154.0.Step D: 5-bromo-N-(6-methoxy-2-(methylamino)pyridin-3-yl)picolinamide

[0149] To a solution of 6-methoxy-A2-methylpyridine-2,3-diamine (700 mg, 4.57 mmol) in pyridine (20 ml) was added 5-bromopicolinoyl chloride (1007 mg, 4.57 mmol). The reaction was stirred at rt for 2 h, concentrated, and chromatographed (silica gel, 20 to 50% EtOAc: petroleum ether) to afford 5-bromo-N-(6-methoxy-2-(methylamino)pyridin-3-yl)picolinamide as a solid.ESI-MS m / z [M + H]: 339.0.Step E: 2-(5-bromopyridin-2-yl)-5-methoxy-3-methyl-3H-imidazo[4,5-b1pyridine26090

[0150] A solution of 5-bromo-N-(6-methoxy-2-(methylamino)pyridin-3-yl)picolinamide (1.0 g, 3.0 mmol) in AcOH (30 ml) was stirred at 130°C for 16h. The reaction was allowed to cool to rt, and diluted with water (100 ml). The product was collected via filtration, and washed with Et2O (20 ml) to afford 2-(5-bromopyridin-2-yl)-5-methoxy-3-methyl-3H-imidazo[4,5-b]pyridine as a solid. ESI-MS m / z [M + H]: 321.0.Step F: 5-methoxy-2-(5-((5-methoxypyri din-2 -yl)ethynyl)pyri din-2 -yl)-3-methyl-3H- imidazo[4,5-b1pyridine

[0151] To a solution of 2-(5-bromopyridin-2-yl)-5-methoxy-3-methyl-3H-imidazo[4,5- b]pyridine (100 mg, 0.313 mmol) in DMF (10 ml) was added 2-ethynyl-5-methoxypyridine (83 mg, 0.63 mmol), Pd(PPh3)2C12 (22.0 mg, 0.031 mmol), Cu(I)I (5.97 mg, 0.031 mmol) and EtsN (63.4 mg, 0.627 mmol). The reaction was stirred at 80°C for 4 h, quenched with water (20 ml), extracted with EtOAc (3 x 20ml), washed with brine (5 x 20ml), dried, filtered, concentrated, and chromatographed (silica gel, 1 to 5% MeOH: DCM) to afford 5-methoxy-2-(5-((5- methoxypyridin-2-yl)ethynyl)pyridin-2-yl)-3-methyl-3H-imidazo[4,5-b]pyridine as a solid.XH NMR (300 MHz, DM SO-6 / 6) 8: 8.92 (s, 1 H), 8.34 (m, 2 H), 8.15 (d, 1 H, J= 8.4 Hz), 8.07 (d, 1 H, J= 8.4 Hz), 7.70 (d, 1 H, J= 8.7 Hz), 7.48 (m, 1 H), 6.79 (d, 1 H, J= 8.7 Hz), 4.21 (s, 3 H), 3.99 (s, 3 H), 3.90 (s, 3 H); ESI-MS m / z [M + H]: 372.1.EXAMPLE 115-((6-(7-methoxy-rL2.41triazolorL5-a1pyridin-2-yl)pyridin-3-yl)ethynyl)-N-methylpyri din-2- amine11Step A: E2-diamino-4-methoxypyridin-l-ium 2,4,6-trimethylbenzenesulfonate

[0152] To solution of 4-methoxypyridin-2-amine (0.952 g, 7.66 mmol) in DCM (50 ml) at 0°C was added O-(mesitylsulfonyl)hydroxylamine (1.5 g, 7.0 mmol). The reaction was stirred at 0°C for 1 h, then poured into Et2O: hexane (50:200 ml). The product was collected via filtration and26090 washed with hexane (3 x 100 ml) to afford l,2-diamino-4-methoxypyridin-l-ium 2,4,6- trimethylbenzenesulfonate as a solid, which was directly used in the next step without characterization.Step B: 2-(5-bromopyridin-2-yl)-7-methoxy- triazolori,5-a]pyridine

[0153] A mixture of l,2-diamino-4-methoxypyridin-l-ium 2,4,6-trimethylbenzenesulfonate (500 mg, 1.47 mmol), and 5-bromopicolinoyl chloride (650 mg, 2.95 mmol) in pyridine (20 ml) was heated to 100 °C for 2 h in the vial. The reaction was cooled to rt, diluted with water (100 ml), extracted with EtOAc (3 x 30 ml), washed with brine (100 ml), dried, filtered, concentrated, and chromatographed (silica gel, 1 to 2% MeOH: DCM) to afford 2-(5-bromopyridin-2-yl)-7- methoxy-[l,2,4]triazolo[l,5-a]pyridine as a solid. 'H NMR (300 MHz, DMSO-t / 6) 6: 8.80 (s, 2 H), 8.10 (m, 1 H), 7.93 (d, 1 H, J= 8.4 Hz), 7.23 (d, 1 H, J= 2.6 Hz), 6.89 (m, 1H), 3.89 (s, 3H). Step C: tert-butyl (5-((6-(7-methoxy-ri,2,41triazolo|T,5-a]pyridin-2-yl)pyridin-3- yl)ethynyl)pyridin-2-yl)(methyl)carbamate

[0154] A mixture of 2-(5-bromopyridin-2-yl)-7-methoxy-[l,2,4]triazolo[l,5-a]pyridine (100 mg, 0.328 mmol), tert-butyl (5-ethynylpyridin-2-yl)(methyl)carbamate (114 mg, 0.492 mmol), Pd(PPh3)2Cl2(23.0 mg, 0.033 mmol), Et3N (332 mg, 3.28 mmol) and Cu(I)I (3.12 mg, 0.016 mmol) in DMF (20 ml) was stirred at 80°C for 1 h. The reaction was cooled to rt, diluted with water (100 ml), extracted with EtOAc (3 x 30 ml), washed with brine (30 ml), dried, filtered, concentrated, and chromatographed (silica gel, 1 to 2% MeOH: DCM) to afford tert-butyl (5-((6- (7-methoxy-[l,2,4]triazolo[l,5-a]pyridin-2-yl)pyridin-3-yl)ethynyl)pyridin-2- yl)(methyl)carbamate as a solid. ESI-MS m / z [M + H]: 457.1.Step D: 5-((6-(7-methoxy-rE2,41triazolo[E5-a1pyridin-2-yl)pyridin-3-yl)ethynyl)-N- methylpyridin-2-amine

[0155] To a solution of tert-butyl (5-((6-(7-methoxy-[l,2,4]triazolo[l,5-a]pyridin-2-yl)pyridin- 3-yl)ethynyl)pyridin-2-yl)(methyl)carbamate (60 mg, 0.13 mmol) in DCM (50 ml), was added TFA (150 mg, 1.31 mmol). The reaction was stirred for 12 h, concentrated, and neutralized with26090NaHCOs. The mixture was concentrated, and chromatographed (silica gel, 1 to 2% MeOH: DCM) to afford 5-((6-(7-methoxy-[l,2,4]triazolo[l,5-a]pyridin-2-yl)pyridin-3-yl)ethynyl)-N- methylpyridin-2-amine as a solid. 'H NMR (300 MHz, DMSO-t / 6) 6: 8.85 (bs, 1 H), 8.27 (s, 2 H), 8.04 (d, 1 H, J= 7.5 Hz), 7.56 (d, 1 H, J= 8.4 Hz), 7.28 (s, 1 H), 7.07 (d, 1 H, J= 4.5 Hz), 6.90 (d, 1 H, J= 7.2 Hz), 6.49 (d, 1 H, J= 8.7 Hz), 3.94 (s, 3 H), 2.81 (d, 3 H, J= 4.5 Hz); ESIMS m / z [M + H]: 357.2.

[0156] The compounds in Table 1 were made employing procedures of the preceding schemes and examples, using appropriate materials.Table 12609026090260902609026090260902609026090260902609026090260902609026090Radiochemical Synthesis of [11C]-LigandsExample 1-1 (2-(5-((6-((methyl-11C)amino)pyridin-3-yl)ethynyl)pyridin-2-yl)imidazolL2-a1pyridin-6- yDmethanol (radiolabeled version of Example 1)

[0157] To a solution of (2-(5-bromopyridin-2-yl)imidazo[l,2-a]pyridin-6-yl)methanol (1 g, 3.29 mmol) in DMF (10 mL) was added sodium hydride (0.395 g, 9.86 mmol) (60 % in mineral oil) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred for 30 min, and then bromo(methoxy)methane (0.822 g, 6.58 mmol) was added and stirred an additional 5h at 0 °C. The resulting mixture was quenched by water (30 mL) and extracted with ethyl acetate (4 x 30 mL). The combined organic layer was washed by brine (5 x 100 mL) and dried over anhydrous Na2SC>4 and filtered. The filtrate was concentrated and purified by silica gel column chromatography (5% MeOH in DCM) to afford 2-(5-bromopyridin-2-yl)-6- ((m ethoxymethoxy )methyl)imidazo[ 1 ,2-a]pyridine.26090Step B: tert-butyl 5- 6- 6- methoxymethoxy)methyl)imidazo[L2-a1pyridin-2-yl)pyridin-3- yl)ethynyl)pyridin-2-yl)carbamate

[0158] To a solution of 2-(5-bromopyri din-2-yl)-6-((m ethoxymethoxy )methyl)imidazo[ 1,2- a]pyridine (100 mg, 0.287 mmol) in DMF (8 mL) was added tert-butyl (5-ethynylpyridin-2- yl)carbamate (125 mg, 0.574 mmol), triethylamine (87 mg, 0.862 mmol), copper(I) iodide (2.73 mg, 0.014 mmol) and Pd(PPh3)2Ch (20.16 mg, 0.029 mmol) at ambient temperature under nitrogen atmosphere. The reaction mixture was stirred at 80°C for 2h. After cooling down to the ambient temperature, NF OH (2 mL) was put in the mixture. Then the resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with 3% MeOH in DCM to afford tert-butyl (5-((6-(6-((methoxymethoxy)methyl)imidazo[l,2- a]pyridin-2-yl)pyridin-3-yl)ethynyl)pyridin-2-yl)carbamate. 'H NMR (300MHz, DMSO-t / 6) 6: 10.11 (s, 1 H), 8.77 (s, 1 H), 8.60 (s, 1 H), 8.54 (s, 1 H), 8.49 (s, 1 H), 8.13 (d, 1 H, J= 8.1 Hz), 8.03 (d, 1 H, J= 7.8 Hz), 7.90 (m, 2 H), 7.61 (d, 1 H, J= 9.6 Hz), 7.27 (d, 1 H, J= 9.6 Hz), 4.70, (s, 2 H), 4.58 (s, 2 H), 3.31, (s, 3 H), 1,48 (s, 9 H); ESI-MS m / z [M + H]: 486.1.Step C: (2-(5 -^- methyl-11C)amino)pyri din-3 -yl)ethynyl)pyri din-2 -yl)imidazolL2-a1pyridin- 6-yl)methanol

[0159] [nC]Methyliodide was trapped in a 0.9 mL vial containing tert-butyl (5-((6-(6- ((m ethoxymethoxy )methyl)imidazo[l,2-a]pyridin-2-yl)pyri din-3 -yl)ethynyl)pyridin-2- yl)carbamate (0.97 mg, 2.00 pmol) and CS2CO3 (14.0 mg, 43.0 pmol) in DMF (300 pL) at rt. The resulting reaction mixture was heated for 3 minutes at 75 °C and HC1 (30%) (300 pL, 2.96 mmol) was added. After 3 minutes at 75 °C the solution was transferred in a 0.9 mL vial containing water (700 pL) at rt, mixed and injected into the semi-preparative HPLC column. The product was purified using Gemini, 5 pm, 10 x 250 mm (Phenomenex), at a flow rate of 5 mL / min. The mobile phase was acetonitrile / aq. NaH2?4 (10 mM) from 20 to 70 % in 15 min. The radioactivity fraction eluting between 6.7 and 7.6 minutes was collected, evaporated under negative pressure diluted with 0.9% saline solution (3 mL) and transferred into a sterile container.

[0160] The final product was tested for chemical and radiochemical purity by means of an analytical HPLC system (Waters) using a Xbridge Cl 8, 5 pm, 4.6 x 150 mm column (Waters) at a flow rate of 1.5 mL / min. The mobile phase was a mixture consisting of 15 % of acetonitrile and 85 % of 0.1 trifluoroacetic acid in water. [nC]l concentration was determined by means of an26090 ultraviolet detector (254 nm). Confirmation of the identity of the product was determined by coinjection of a sample of [11C] 1, and radiochemical purity was determined using a sodium iodide detector (Bioscan). The retention time for [11C]1 was 3.15 min, the chemical and radiochemical purities were 100%.EXAMPLE 1-2(2-(5-((6-((methyl-11C)amino)pyridin-3-yl)ethynyl)pyridin-2-yl)imidazo[L2-a1pyridin-8- yDmethanol (radiolabeled version of Example 3)[11C]3Step A: (2-(5-((6-((m ethyl-1din-3 -yl)ethynyl)pyri din-2 -yl)imidazo[L2-a1pyridin-8-yl)methanol

[0161] [nC]Methyliodide was trapped in a 0.9 mL vial containing (5-((6-(8- (hydroxymethyl)imidazo[l,2-a]pyridin-2-yl)pyridin-3-yl)ethynyl)pyridin-2-yl)carbamate((0.32 mg, 0.73 pmol) and CS2CO3 (7.10 mg, 22.0 pmol) in DMF (300 pl). The resulting reaction mixture was heated for 3 minutes at 100°C and HC1 (2N) (700 pl) was added. After 3 minutes at 140°C, the solution was transferred in a 0.9 ml vial containing water (700 pL) at rt, mixed and injected into the semi-preparative HPLC column. The product was purified using Zorbax Eclipse XDB C18 (Agilent), at a flow rate of 5 ml / min. The mobile phase was acetonitrile / 0.1% TFA. The portion of acetonitrile was 10% for 5 min increased to 60% over 5 min and increased to 90% over 5 min. The radioactivity fraction eluting between 6.2 and 6.5 minutes was collected, evaporated under negative pressure diluted with 0.9% saline solution (3 ml) and transferred into a sterile container.

[0162] The final product was tested for chemical and radiochemical purity by means of an analytical HPLC system (Waters) using a Xbridge Cl 8, 5 pm, 4.6 x 150 mm column (Waters) at a flow rate of 1.5 mL / min. The mobile phase was a mixture consisting of 15 % of acetonitrile and 85 % of 0.1 % trifluoroacetic acid in water. [11C]3 concentration was determined by means of an ultraviolet detector (254 nm). Confirmation of the identity of the product was determined by coinjection of a sample of [nC]3, and radiochemical purity was determined using a sodium26090 iodide detector (Bioscan). The retention time for [11C]3 was 4.8 min, the chemical and radiochemical purities were 100%.EXAMPLE 1-3(2-(6-((6-((methyl-11C)amino)pyridin-3-yl)ethynyl)pyridin-3-yl)imidazo[L2-a1pyridin-8- yDmethanol (radiolabeled version of Example 5)Step A: (2-(6-((6-aminopyri din-3 -yl)ethynyl)pyri din-3 -yl)imidazo[L2-a1pyridin-8-yl)methanol

[0163] A solution of tert-butyl (5-((5-(8-(((tert-butyldimethylsilyl)oxy)methyl)imidazo[l,2- a]pyridin-2-yl)pyridin-2-yl)ethynyl)pyridin-2-yl)carbamate (200 mg, 0.360 mmol) in DCM (10 ml) and TFA (4 ml) was stirred for 3 h. The reaction was concentrated to give a residue, (2-(6- ((6-aminopyri din-3 -yl)ethynyl)pyri din-3 -yl)imidazo[l,2-a]pyridin-8-yl)m ethanol, which was used in the next step directly without purification. ESI-MS m / z [M + H]: 342.1.Step B: 5-((5-(8-(((tert-butyldimethylsilyl)oxy)methyl)imidazori.2-a1pyridin-2-yl)pyridin-2- yl)ethynyl)pyridin-2-amine

[0164] To a solution of (2-(6-((6-aminopyri din-3 -yl)ethynyl)pyri din-3 -yl)imidazo[ 1,2- a]pyridin-8-yl)methanol (110 mg, 0.322 mmol) in DMF (15 ml) was added IH-imidazole (21.9 mg, 0.322 mmol) and TBSC1 (48.6 mg, 0.322 mmol). The reaction was stirred for 30 min, diluted with water (80 ml), extracted with EtOAc (2 x 60 ml), washed with brine (5 x 50 ml), dried, filtered, concentrated, and chromatographed (silica gel, 0.5 to 2% MeOH: DCM) to afford 5-((5- (8-(((tert-butyldimethylsilyl)oxy)methyl)imidazo[l,2-a]pyridin-2-yl)pyridin-2- yl)ethynyl)pyri din-2- as a solid. ESI-MS m / z [M + H]: 456.4.Step C: (2-(6-((6-((m ethyl-1din-3 -yl)ethynyl)pyri din-3 -yl)imidazo[L2-a1pyridin-8-yl)methanol

[0165] [nC]Methyliodide was trapped in a 0.9 mL vial 5-((5-(8-(((tert- butyldimethylsilyl)oxy)methyl)imidazo[l,2-a]pyridin-2-yl)pyridin-2-yl)ethynyl)pyridin-2-amine (0.78 mg, 1.76 pmol) and sodium tert-butoxide 3N (1.4 pl, 2.80 pmol) in DMF (300 pl). The resulting reaction mixture was heated for 3 minutes at 80 °C and TBAF in water (300 pL) was added. After 2 minutes at 80°C, the solution was transferred in a 0.9 mL vial containing water (700 pF) at rt, mixed and injected into the semi-preparative HPLC column. The product was purified using Gemini, 5 pm, 10 x 250 mm (Phenomenex), at a flow rate of 5 ml / min. The mobile phase was acetonitrile / aq. NaH2P4 (10 mM) f from 20 to 90 % in 15 min. The radioactivity fraction eluting between 7.7 and 7.9 minutes was collected, evaporated under negative pressure diluted with 0.9% saline solution (3 ml) and transferred into a sterile container.

[0166] The final product was tested for chemical and radiochemical purity by means of an analytical HPLC system (Waters) using a XBridge Phenyl 3.5 pm 4.6x150 mm column (Waters) at a flow rate of 2.0 ml / min. The mobile phase was a mixture consisting of 10 % of acetonitrile and 90 % of 0.1 % TFA in water. [nC]5 concentration was determined by means of an ultraviolet detector (254 nm). Confirmation of the identity of the product was determined by coinjection of a sample of [nC]5, and radiochemical purity was determined using a sodium iodide detector (Bioscan). The retention time for [nC]5 was 6.7 min, the chemical and radiochemical purities were 100%.Radiochemical Synthesis of [3H]-Ligands EXAMPLE 2-1 (2-(5-((6-((methyl- / 3)amino)pyridin-3-yl)ethynyl)pyridin-2-yl)imidazo[L2-a1pyridin-6- yDmethanol (radiolabeled version of Example 1)[3H]-1Step A: tert-butyl (5-((6-(6-((methoxymethoxy )methyl)imidazo[L2-a1pyri din-2 -yBpyri din-3 - yl)ethynyl)pyridin-2-yl)(methyl- / 3)carbamate

[0167] To a solution of tert-butyl (5-((6-(6-((methoxymethoxy)methyl)imidazo[l,2-a]pyridin-2- yl)pyridin-3-yl)ethynyl)pyridin-2-yl)carbamate (5.1 mg, 10.5 p mol) in DMA (25 p 1) under Ar wad added KHMDS (0.5 M, 18 pl, 9.0 p mol). The suspension was stirred at rt for 1 h, and then3H-methyl nosylate (50 mCi) in 3 x 20 p 1 of DMA was added. The reaction was stirred for 12 h at 40°C, diluted with ethanol, concentrated to yield tert-butyl (5-((6-(6-((m ethoxymethoxy )methyl)imidazo[l,2-a]pyridin-2-yl)pyri din-3 -yl)ethynyl)pyridin-2- yl)(methyl- / 3)carbamate which was taken on without further purification.Step B: (2-(5-((6-((methyl- / 3)amino)pyridin-3-yl)ethynyl)pyridin-2-yl)imidazoll,2-a1pyridin-6- yDmethanol

[0168] To a solution of tert-butyl (5-((6-(6-((methoxymethoxy)methyl)imidazo[l,2-a]pyridin-2- yl)pyridin-3-yl)ethynyl)pyridin-2-yl)(methyl-t3)carbamate in DCM (100 pj) was added TFA (200 p 1). The reaction was stirred at rt for 12 h, concentrated, rediluted with DCM (100 p 1) and EtiN (200 p 1), and then concentrated. The crude product was dissolved in DMSO and purified (10x25 Gemini NX C18, 0.05M pH 10 TEAA (70:30) MeCN) to yield (2-(5-((6-((methyl- G)amino)pyri din-3 -yl)ethynyl)pyridin-2-yl)imidazo[l,2-a]pyridin-6-yl)m ethanol (22.2 mCi, 83.88 Ci / mmol molar activity). ESI-MS m / z [M + H]: 362.1.EXAMPLE 2-2(2-(6-((6-((methyl- / 3)amino)pyridin-3-yl)ethynyl)pyridin-3-yl)imidazo[L2-a1pyridin-8-Step A: 2-(6-bromopyridin-3-yl)-8-(((tert-butyldimethylsilyl)oxy)methyl)imidazo[L2-a1pyridine

[0169] To a solution of (2-(6-bromopyri din-3 -yl)imidazo[l,2-a]pyridin-8-yl)methanol (2 g, 6.58 mmol) in DMF (50 ml) was added IH-imidazole (0.895 g, 13.15 mmol) and tertbutylchlorodimethylsilane (1.487 g, 9.86 mmol). After stirring at rt for 1 h, the reaction was26090 diluted with ethyl acetate (400 mL), washed with brine(5 * 300 mL) dried over anhydrous sodium sulfate, concentrated and chromatographed (silica gel (0.3% to 33% EtOAc: pet. ether) to afford 2-(6-bromopyridin-3-yl)-8-(((tert-butyldimethylsilyl)oxy)methyl)imidazo[l,2-a]pyridine as a solid. ESI-MS m / z [M + H]: 418.0.Step B: tert-butyl (5-((5-(8-(((tert-butyldimethylsilyl)oxy)methyl)imidazo[L2-a1pyridin-2- yl)pyridin-2-yl)ethynyl)pyridin-2-yl)carbamate

[0170] To a solution of 2-(6-bromopyridin-3-yl)-8-(((tert- butyldimethylsilyl)oxy)methyl)imidazo[l,2-a]pyridine (400 mg, 0.956 mmol) in THF (10 ml) was added tert-butyl (5-ethynylpyridin-2-yl)carbamate (417 mg, 1.912 mmol), triethylamine (290 mg, 2.87 mmol), Pd(PPh3)4 (HO mg, 0.096 mmol) and copper(I) iodide (18.21 mg, 0.096 mmol) at ambient temperature. The final reaction mixture was irradiated with microwave radiation at 75°C under a an atmosphere of nitrogen for 3.5 h, concentrated under a reduced pressure to give a residue which was chromatographed (silica gel, 0.5 to 1% MeOH: DCM) to afford tert-butyl (5-((5-(8-(((tert-butyldimethylsilyl)oxy)methyl)imidazo[l,2-a]pyridin-2-yl)pyridin-2- yl)ethynyl)pyridin-2-yl)carbamate as a solid. ESI-MS m / z [M + H]: 556.2.Step C: tert-butyl (5-((5-(8-(((tert-butyldimethylsilyl)oxy)methyl)imidazol 1,2-alpyri din-2 - yl)pyridin-2-yl)ethynyl)pyridin-2-yl)(methyl- / 3)carbamate

[0171] In a glove box, tert-butyl (5-((5-(8-(((tert-butyldimethylsilyl)oxy)methyl)imidazo[l,2- a]pyridin-2-yl)pyridin-2-yl)ethynyl)pyridin-2-yl)carbamate (3.6 mg, 6.48 p mol) was suspended in DMA (100 pl) and KHMDS (0.5M in toluene, 10 p 1, 5.0 p mol) was added under Ar in a 1 cc reactivial. The suspension immediately turned yellow and was stirred for 30 mins at rt.3H-m ethyl nosylate (100 mCi) was evaporated in a 1 cc reactivial and dissolved in DMA (25 pl) and this solution was transferred to the reaction followed by 2 x 25 pl rinses of DMA. The reaction was then heated at 70°C for two hours and then overnight at rt. The reaction was then quenched with the addition of saturated ammonium chloride solution (100 p 1) and partitioned between ca 2 cc of 0.3 M sodium bicarbonate and ca 3 cc methylene chloride. The methylene chloride layer was removed, and the aqueous fraction extracted with a further 3 x ca 3 cc of methylene chloride. The26090 methylene chloride extracts were passed through a sodium sulphate filter, combined and evaporated to dryness and used directly in the next step.Step D: (2-(6-((6-((methyl- / 3)amino)pyridin-3-yl)ethynyl)pyridin-3-yl)imidazo[E2-a1pyridin-8- yDmethanoltert-butyl (5-((5-(8-(((tert-butyldimethylsilyl)oxy)methyl)imidazo[l,2-a]pyridin-2-yl)pyridin-2- yl)ethynyl)pyridin-2-yl)(methyl-t3)carbamate (0.575 mg, 0.999 p mol) was suspended in DCM (500 p 1) and TFA (200 pl) was added. The suspension immediately went into solution and the reaction was stirred for 5 hours, evaporated to dryness, dissolved in DCM, evaporated to dryness, then EtiN was added and removed by evaporation. The batch was dissolved in DMSO (0.6 cc) and chromatographed (10 x250 mm Gemini C18 column with a mobile phase of 0.05M pH 10 TEAA (75:25) MeCN @ 5cc / min, 357 nm). Fractions containing the purified product were diluted with water, concentrated on a pair of C18 cartridges and eluted with 30 cc EtOH. (36.7 mCi, 84.66 Ci / mmol molar activity). ESI-MS m / z [M + H]: 362.0.Procedures for tissue homogenate binding assays

[0172] Frozen human brain samples of Alzheimer’s disease (AD) were purchased from Analytic Biological Services Inc. The samples were postmortem tissue from donors with clinical diagnosis of AD. As much of the white matter was dissected out of the frontal cortex in order to enrich the tissue preparations for gray matter. Brain homogenates of gray matter enriched frontal cortex were prepared by homogenizing the tissue in ice cold Phosphate Buffered Saline (PBS), pH 7.4 at 80 mg wet weight tissue per 1 ml for 45 seconds at 4°C on setting 16 of Polytron. The homogenate was further diluted with ice cold PBS to 30 mg wet weight tissue per 1 ml and homogenized for an additional minute as described above. Homogenates were aliquotted in 5 ml / tube and stored at -70 °C until use.

[0173] For hot saturation binding assay, various concentrations of radioligand were prepared in Assay Buffer (PBS plus 0.1% BSA) plus 20% DMSO ranging from 0.26 to 37 nM for [3H] compound of Example ([3H]-5). 25 p 1 of radioligand was added to 225 p 1 of crude brain homogenates diluted to 2.0 mg / ml in Assay Buffer) for final concentration of radioligand ranging from 0.26 to 37 nM and final crude brain homogenates of 500 p g wet weight / assay tube (incubation, filtration, and determination of amount of radioligand used in assay are described below). Self-block with unlabeled compound was used to determine non-specific binding.26090Saturation data was analyzed using Graphpad / Prism software. Figure 1 shows an example of hot saturation binding of [3H]-5. The radioligand shows high affinity for tau in AD brain homogenates with measured dissociation constant of 9.2 nM.

[0174] For displacement tau binding assay, unlabeled test compounds were dissolved in DMSO at 1 mM. Dilutions of tests compounds to various concentrations were made in 100% DMSO at lOOOx final assay concentration and 0.225 p 1 aliquots were dispensed into assay plates. Brain homogenates were diluted to 2.0 mg / ml from original 30 mg / ml volume in Assay Buffer, and 200 p 1 were added to the assay plate for a final concentration of 500 p g wet weight / assay tube. [3H]- 1 (Example 2-1) was prepared at lOx final concentration in Assay Buffer plus 20% DMSO and 25 p 1 was added to the assay plate for final assay concentration of 3.0 nM. The assay plate was preincubated at rt for 30 min without radioligand in the preincubation buffer. Following preincubation, 25 pL radioligand was added into the incubation buffer at 3nM concentration. The vials were incubated at 37 °C for 90 minutes. Unbound and bound ligand were separated by filtration of bound onto GF / C filter plates (pre-treated for 30 min with 0.1% BSA) using a Combicell 12-well harvester and washing away unbound with ice cold PBS at pH 7.4 on cycle 3- 3-3. Filters were placed in Pico Pro scintillation vials (Fisher 6000252) and counted in 2ml Ultima Gold on PerkinElmer Tri-Carb 2900TR for 1 min for dpm, after sitting in scintillation fluid for more than 4 hours at rt. Data was analyzed using GraphPad Prism 6.0 software (one-site competition, bottom restrained to zero, Kd value 3.0 nM, ligand concentration 3.5 nM). As shown in Figure 2, 1 (unlabeled) self-displaced [3H]-1 (Example 2-1) with Ki value of 14 nM.

[0175] Homogenates from AD and non-AD human brain samples were assessed for their immunoreactivity to anti-A antibody 6E10 and an anti-phospho-tau antibody PHF6 or AT8. The brain sections with the highest levels of PHF6 or AT8 immunoreactivity were chosen for the displacement tau binding assay and the brain sections with the highest levels of 6E10 combined with low levels of PHF6 or AT8 immunoreactivity were chosen for the amyloid tissue homogenate binding assay.

[0176] Procedure for the amyloid binding assay (counterscreen) was identical to the Tau binding assay using [3H]-105[3H]-105 as the reference radioligand.26090

[0177] Tau Ki and / or Amyloid Ki data for representative compounds of the instant disclosure are found in Table 2.Table 22609026090

[0178] While the disclosure has been described and illustrated with reference to certain particular embodiments thereof, those skilled in the art will appreciate that various adaptations, changes, modifications, substitutions, deletions, or additions of procedures and protocols may be made without departing from the spirit and scope of the disclosure. It is intended, therefore, that the disclosure be defined by the scope of the claims that follow and that such claims be interpreted as broadly as is reasonable.

Claims

WHAT IS CLAIMED IS:

1. A compound of formula I:V, W2, W4, and X independently represent C(R) or N;W1and W3independently represent C or N;Z is S, C(R), N(R) or N;ZHs S, C(R), or N;Z2and Z3independently are absent or selected from C(H) or N;Z4is absent or represents C(R5) or N;R represents hydrogen, halogen, -C^alkyl, or -OC|_6alkyl said alkyl optionally substituted with 1 to 3 groups of halogen;R1is absent or is selected from -C^alkyl, -(CH2)nOR, -OCH2CH(OH)CH2F, -C5.10heterocyclyl, -O(CH2)nhalogen and -(CH2)nhalogen; said alkyl and heterocyclyl optionally substituted with 1 to 3 groups selected from halogen, OH, -C^alkyl, -00, _6alkyl, C1.3haloalkyl, and -OC1.3haloalkyl;R is absent or represents halogen, -C^alkyl, -0C|_6alkyl, -(CH2)n0R, C1.3haloalkyl, or OC^3haloalkyl;R3and R5are independently selected from -Cj.6alkyl, -(CH2)nhalogen, -O(CH2)nhalogen, -C i- shaloalkyl, -OC i-shaloalkyl, -(CH2)nN(R)2, -OC^g alkyl, and -(CH2)nOR, said alkyl optionally substituted with 1 to 3 groups of halogen;R4, when present, is hydrogen, or -C^alkyl; n represents an integer from 0-4, and m represents 0 or 1, provided that only one of Z2, Z3and Z4 is absent.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof wherein W1, W2, W3and W4, respectively are selected from the group consisting of:1) C, N, C, C(H);2) C, C(H), N, C(H);3) N, C(H), C, C(H); and4) N, N, C, C(H).

3. The compound according to any one of claims 1 and 2 or a pharmaceutically acceptable salt thereof wherein W1, W2, W3and W4, respectively are C, N, C, and C(H); X is N and V is C(H).

4. The compound according to any one of claims 1 and 2 or a pharmaceutically acceptable salt thereof wherein W1, W2, W3and W4, respectively are C, N, C, and C(H); X is C(H) and V is N.

5. The compound according to any one of claims 1 and 2 or a pharmaceutically acceptable salt thereof wherein W1, W2, W3and W4, respectively are C, C(H), N, and C(H); X is N and V is C(H).

6. The compound according to any one of claims 1 and 2 or a pharmaceutically acceptable salt thereof wherein W1, W2, W3and W4, respectively are N, C(H), C, and C(H); X is C(H) and V is N.

7. The compound according to any one of claims 1 and 2 or a pharmaceutically acceptable salt thereof wherein W1, W2, W3and W4, respectively are N, N, C, and C(H); X is N and V is C(H).

8. The compound according to any one of claims 1 through 7 or a pharmaceutically acceptable salt thereof wherein Z, Z1, Z2, Z3, and Z4together form a group selected from optionally substituted pyridine, pyrimidine, pyrazole, thiazole, isothiazole, and pyrazine.

9. The compound according to any one of claims 1 through 8 or a pharmaceutically acceptable salt thereof wherein Z, Z1, Z2, Z3, and Z4together form a group selected from optionally substituted pyridine or pyrimidine.

10. The compound according to any one of claims 1 through 9 or a pharmaceutically acceptable salt thereof wherein R1is selected from the group consisting of CH2OH, OH, -OCH3, -OCH2F, -O(CH2)2F, -OCF3, and OCH2CH(OH)CH2F.

11. The compound according to any one of claims 1 through 10 or a pharmaceutically2 acceptable salt thereof wherein R is selected from the group consisting of halogen, -C6alkyl, -OCj.6 alkyl, -(CH2)nOR, C1.3haloalkyl, and OC1.3haloalkyl.

12. The compound according to any one of claims 1 through 10 or a pharmaceutically acceptable salt thereof wherein R3is selected from the group consisting of -Cj.6alkyl, - (CH2)nhalogen, -O(CH2)nhalogen, -(CH2)nN(R)2, -OC^ alkyl, and -(CH2)nOR, said alkyl optionally substituted with 1 to 3 groups of halogen.

13. The compound according to any one of claims 1 through 12 or a pharmaceutically acceptable salt thereof wherein R3is selected from the group consisting of fluorine, CH3, (CH2)nOH, CF3, NH2, NHCH3, NH(CH2)I-3F, OCH3, O(CH2)nF, and OCH2CH3.

14. The compound according to any one of claims 1 through 13 or a pharmaceutically acceptable salt thereof which are isotopically labeled 2H, 3H, 11C, 13C, 14C, 13N, 1$N, 1$O, 170, 180, 18F, 35S, 36CL, 82Br, 76Br, 77Br, 123i, 124iand 13 ll.2609015. The compound according to any one of claims 1-4, and 8-14 represented by structural formula la:la or a pharmaceutically acceptable salt thereof.

16. The compound according to any one of claims 1-4, and 8-14 represented by structural formula lb:or a pharmaceutically acceptable salt thereof.

17. The compound according to any one of claims 1-8 and 10-14 represented by structural formula Ic:or a pharmaceutically acceptable salt thereof.

18. A compound which is selected from the group consisting of:(2-(6-((6-((methyl- / 3)amino)pyridin-3-yl)ethynyl)pyridin-3-yl)imidazo[l,2-a]pyridin-8- yl)methanol,26090(2-(5-((6-((methyl- / 3)amino)pyridin-3-yl)ethynyl)pyridin-2-yl)imidazo[l,2-a]pyridin-6- yl)methanol,(2-(6-((6-((methyl-11C)amino)pyridin-3-yl)ethynyl)pyridin-3-yl)imidazo[l,2-a]pyridin-8- yl)methanol,(2-(5-((6-((methyl-11C)amino)pyridin-3-yl)ethynyl)pyridin-2-yl)imidazo[l,2-a]pyridin-8- yl)methanol,(2-(5-((6-((methyl-11C)amino)pyridin-3-yl)ethynyl)pyridin-2-yl)imidazo[l,2-a]pyridin-6- yl)methanol, 5-((6-(7-methoxy-[l,2,4]triazolo[l,5-a]pyridin-2-yl)pyridin-3-yl)ethynyl)-N-methylpyridin-2- amine,5-methoxy-2-(5-((5-methoxypyridin-2-yl)ethynyl)pyridin-2-yl)-3-methyl-3H-imidazo[4,5- b]pyridine,2-(6-fluoro-5-((l -methyl- lH-pyrazol-3-yl)ethynyl)pyridin-2-yl)-6-methoxy-l -methyl-lH- benzo[d]imidazole,(2-(6-((6-(methylamino)pyridin-3-yl)ethynyl)pyridin-3-yl)-2H-indazol-7-yl)methanol,6-methoxy-2-(5-((l -methyl- lH-pyrazol-3-yl)ethynyl)pyridin-2-yl)-lH-benzo[d]imidazole,6-methoxy-l -methyl-2-(5-((l -methyl- lH-pyrazol-3-yl)ethynyl)pyri din-2 -yl)-lH- benzo[d]imidazole,(2-(6-((6-(m ethylamino)pyri din-3 -yl)ethynyl)pyri din-3 -yl)imidazo[l,2-a]pyridin-8-yl)methanol, (2-(5-((2-(methylamino)pyrimidin-5-yl)ethynyl)pyridin-2-yl)imidazo[l,2-a]pyridin-6- yl)methanol,(2-(5-((6-(methylamino)pyridin-3-yl)ethynyl)pyridin-2-yl)imidazo[l,2-a]pyridin-8-yl)methanol,(2-(5-((2-((2-fluoroethyl)amino)pyrimidin-5-yl)ethynyl)pyridin-2-yl)imidazo[l,2-a]pyridin-6- yl)methanol, (2-(5-((6-(methylamino)pyridin-3-yl)ethynyl)pyridin-2-yl)imidazo[l,2-a]pyridin-6-yl)methanol, [2-[5-[2-[6-(methylamino)-3-pyridyl]ethynyl]-2-pyridyl]imidazo[l,2-a]pyridin-7-yl]methanol,5-[2-[6-(6-methoxyimidazo[l,2-a]pyridin-2-yl)-3-pyridyl]ethynyl]-N-methyl-pyridin-2-amine,5-[2-[6-(7-methoxyimidazo[l,2-a]pyridin-2-yl)-3-pyridyl]ethynyl]-N-methyl-pyridin-2-amine, [2-[5-[2-[2-(2-fluoroethoxy)pyrimidin-5-yl]ethynyl]-2-pyridyl]imidazo[l,2-a]pyridin-8- yl]methanol,[2-[5-[2-(2-ethoxypyrimidin-5-yl)ethynyl]-2-pyridyl]imidazo[l,2-a]pyridin-8-yl]methanol, 5-[2-[6-(6-methoxyimidazo[l,2-a]pyridin-2-yl)-3-pyridyl]ethynyl]-N-methyl-pyrimidin-2-amine,[2-[5-[2-[2-(2-fluoroethoxy)pyrimidin-5-yl]ethynyl]-2-pyridyl]imidazo[l,2-a]pyridin-6- yl]methanol,N-(2-fluoroethyl)-5-[2-[6-(6-methoxyimidazo[l,2-a]pyridin-2-yl)-3-pyridyl]ethynyl]pyrimidin-2- amine, 5-[2-[6-(6-methoxyimidazo[l,2-a]pyridin-2-yl)-3-pyridyl]ethynyl]pyrimidin-2-amine, [2-[5-[2-[2-(2-fluoroethylamino)pyrimidin-5-yl]ethynyl]-2-pyridyl]imidazo[l,2-a]pyridin-8- yl]methanol,[2-[5-[2-(6-amino-3-pyridyl)ethynyl]-6-fluoro-2-pyridyl]imidazo[l,2-a]pyridin-7-yl]methanol, [2-[5-[2-(2-aminopyrimidin-5-yl)ethynyl]-6-fluoro-2-pyridyl]imidazo[l,2-a]pyridin-7- yl]methanol,[2-[6-fluoro-5-[2-[2-(methylamino)pyrimidin-5-yl]ethynyl]-2-pyridyl]imidazo[l,2-a]pyridin-8- yl]methanol,[2-[5-[2-(6-amino-3-pyridyl)ethynyl]-6-fluoro-2-pyridyl]imidazo[l,2-a]pyridin-6-yl]methanol,[2-[6-fluoro-5-[2-[2-(methylamino)pyrimidin-5-yl]ethynyl]-2-pyridyl]imidazo[l,2-a]pyridin-7- yl]methanol,[2-[6-fluoro-5-[2-[2-(methylamino)pyrimidin-5-yl]ethynyl]-2-pyridyl]imidazo[l,2-a]pyridin-6- yl]methanol,[2-[5-[2-(2-aminopyrimidin-5-yl)ethynyl]-6-fluoro-2-pyridyl]imidazo[l,2-a]pyridin-6- yl]methanol,[2-[6-fluoro-5-[2-[6-(methylamino)-3-pyridyl]ethynyl]-2-pyridyl]imidazo[l,2-a]pyridin-6- yl]methanol,5-[2-[2-fluoro-6-(6-methoxyimidazo[l,2-a]pyridin-2-yl)-3-pyridyl]ethynyl]pyridin-2-amine, [2-[5-[2-(2-aminopyrimidin-5-yl)ethynyl]-6-fluoro-2-pyridyl]imidazo[l,2-a]pyridin-8- yl]methanol,[2-[6-fluoro-5-[2-[6-(methylamino)-3-pyridyl]ethynyl]-2-pyridyl]imidazo[l,2-a]pyridin-7- yl]methanol,5-[2-[2-fluoro-6-[7-(4-fluoro-l-piperidyl)imidazo[l,2-a]pyridin-2-yl]-3- py ri dy 1 ] ethy ny 1 ] py rimi din-2-amine,[2-[6-fluoro-5-[2-[6-(methylamino)-3-pyridyl]ethynyl]-2-pyridyl]imidazo[l,2-a]pyridin-8- yl]methanol,5-[2-[6-(7-methoxyimidazo[l,2-a]pyridin-2-yl)-3-pyridyl]ethynyl]-N-methyl-pyridin-2-amine,5-[2-[2-fluoro-6-(6-methoxyimidazo[l,2-a]pyridin-2-yl)-3-pyridyl]ethynyl]pyrimidin-2-amine,6-methoxy-l-methyl-2-[5-[2-(2-pyridyl)ethynyl]-2-pyridyl]benzimidazole,6-methoxy-l-methyl-2-[5-(2-pyrazin-2-ylethynyl)-2-pyridyl]benzimidazole,6-methoxy-l-methyl-2-[5-(2-pyrimidin-5-ylethynyl)-2-pyridyl]benzimidazole,6-methoxy-l-methyl-2-[5-[2-(l-methylpyrazol-4-yl)ethynyl]-2-pyridyl]benzimidazole,5-[2-[6-(6-methoxy-l-methyl-benzimidazol-2-yl)-3-pyridyl]ethynyl]thiazole,4-[2-[6-(6-methoxy-l-methyl-benzimidazol-2-yl)-3-pyridyl]ethynyl]isothiazole,[2-[5-[2-[6-(methylamino)-3-pyridyl]ethynyl]-2-pyridyl]indazol-7-yl]methanol,3-methyl-2-[5-[2-[6-(methylamino)-3-pyridyl]ethynyl]-2-pyridyl]benzimidazol-5-ol,6-methoxy-l-methyl-2-[5-[2-(2-methylpyrimidin-5-yl)ethynyl]-2-pyridyl]benzimidazole,5-[2-[6-(6-methoxy-lH-benzimidazol-2-yl)-3-pyridyl]ethynyl]-N-methyl-pyridin-2-amine, [2-[5-[2-(5-methoxy-2-pyridyl)ethynyl]-2-pyridyl]indazol-7-yl]methanol,6-[2-[6-(6-methoxy-l-methyl-benzimidazol-2-yl)-3-pyridyl]ethynyl]pyridin-3-ol,2-[5-[2-(5-methoxy-2-pyridyl)ethynyl]-2-pyridyl]-3-methyl-benzimidazol-5-ol,6-methoxy-2-[5-[2-(5-methoxy-2-pyridyl)ethynyl]-2-pyridyl]-lH-benzimidazole,5-[2-[6-(6-methoxy-l-methyl-benzimidazol-2-yl)-3-pyridyl]ethynyl]pyrimidin-2-amine,3-methyl-2-[5-[2-[2-(methylamino)pyrimidin-5-yl]ethynyl]-2-pyridyl]benzimidazol-5-ol,2-[5-[2-(2-methoxypyrimidin-5-yl)ethynyl]-2-pyridyl]-3-methyl-benzimidazol-5-ol,2-[5-[2-(6-fluoro-2-pyridyl)ethynyl]-2-pyridyl]-6-methoxy-l-methyl-benzimidazole,2-[5-[2-(6-fluoro-3-pyridyl)ethynyl]-2-pyridyl]-6-methoxy-l-methyl-benzimidazole, [3-methyl-2-[5-[2-[6-(methylamino)-3-pyridyl]ethynyl]-2-pyridyl]benzimidazol-4-yl]methanol, 5-[2-[5-(6-methoxy-l-methyl-benzimidazol-2-yl)-2-pyridyl]ethynyl]-N-methyl-pyridin-2-amine,5-[2-[6-(6-methoxy-l-methyl-benzimidazol-2-yl)-3-pyridyl]ethynyl]-N-methyl-pyridin-2-amine,5-[2-[6-(6-methoxy-l-methyl-benzimidazol-2-yl)-3-pyridyl]ethynyl]-N-methyl-pyrimidin-2- amine,5-methoxy-2-[5-[2-(5-methoxy-2-pyridyl)ethynyl]-2-pyridyl]-l-methyl-benzimidazole,6-methoxy-2-[5-[2-(5-methoxypyrazin-2-yl)ethynyl]-2-pyridyl]-l-methyl-benzimidazole, 2-[5-[2-(2-ethoxypyrimidin-5-yl)ethynyl]-2-pyridyl]-3-methyl-benzimidazol-5-ol,5-[2-[6-[6-(fluoromethoxy)-l-methyl-benzimidazol-2-yl]-3-pyridyl]ethynyl]pyrimidin-2-amine,[2-[6-fluoro-5-[2-(5-methoxy-2-pyridyl)ethynyl]-2-pyridyl]indazol-7-yl]methanol,[2-[6-fluoro-5-[2-(3-methoxy-4-pyridyl)ethynyl]-2-pyridyl]indazol-7-yl]methanol,[2-[2-fluoro-6-[2-(5-methoxy-2-pyridyl)ethynyl]-3-pyridyl]imidazo[l,2-a]pyridin-8-yl]methanol,5-[2-[2-fluoro-6-(6-methoxy-l-methyl-benzimidazol-2-yl)-3-pyridyl]ethynyl]pyrimidin-2-amine, 2-[5-[2-[l-(2-fluoroethyl)pyrazol-3-yl]ethynyl]-2-pyridyl]-6-methoxy-l-methyl-benzimidazole,6-methoxy-2-[5-[2-(5-methoxy-2-pyridyl)ethynyl]-3-methyl-2-pyridyl]-l-methyl-benzimidazole,260905-[2-[6-[6-(fluoromethoxy)-l-methyl-benzimidazol-2-yl]-3-pyridyl]ethynyl]-N-methyl- pyrimidin-2-amine, 2-[5-[2-[5-(fluoromethoxy)-2-pyridyl]ethynyl]-2-pyridyl]-6-methoxy-l-methyl-benzimidazole, 2-[6-fluoro-5-[2-(5-methoxy-2-pyridyl)ethynyl]-2-pyridyl]-6-methoxy-l-methyl-benzimidazole, 2-[5-[2-[2-(2-fluoroethylamino)pyrimidin-5-yl]ethynyl]-2-pyridyl]-3-methyl-benzimidazol-5-ol,5-[2-[2-fluoro-6-(6-methoxy-l-methyl-benzimidazol-2-yl)-3-pyridyl]ethynyl]-N-methyl- pyrimidin-2-amine,6-(fluoromethoxy)-2-[5-[2-(5-methoxy-2-pyridyl)ethynyl]-2-pyridyl]-l-methyl-benzimidazole, 2-[5-[2-[2-(2-fluoroethoxy)pyrimidin-5-yl]ethynyl]-2-pyridyl]-3-methyl-benzimidazol-5-ol, 2-[5-[2-[5-(2-fluoroethoxy)-2-pyridyl]ethynyl]-2-pyridyl]-6-methoxy-l-methyl-benzimidazole, N-(2-fluoroethyl)-5-[2-[6-(6-methoxy-l-methyl-benzimidazol-2-yl)-3-pyridyl]ethynyl]pyrimidin- 2-amine,N-(2-fluoroethyl)-5-[2-[5-(6-methoxy-l-methyl-benzimidazol-2-yl)-2-pyridyl]ethynyl]pyrimidin- 2-amine, 6-(2-fluoroethoxy)-2-[5-[2-(5-methoxy-2-pyridyl)ethynyl]-2-pyridyl]-l-methyl-benzimidazole, 2-[6-[2-[2-(2-fluoroethoxy)pyrimidin-5-yl]ethynyl]-3-pyridyl]-6-methoxy-l -methylbenzimidazole,2-[5-[2-[2-(2-fluoroethoxy)pyrimidin-5-yl]ethynyl]-2-pyridyl]-6-methoxy-l -methylbenzimidazole,6-methoxy-l-methyl-2-[5-[2-[2-(trifluoromethyl)pyrimidin-5-yl]ethynyl]-2- py ri dy 1 ]b enzimi dazol e,N-(2-fluoroethyl)-5-[2-[6-(6-methoxy-l-methyl-benzimidazol-2-yl)-3-pyridyl]ethynyl]-N- methyl-pyrimidin-2-amine,1-fluoro-3-[2-[5-[2-(5-methoxy-2-pyridyl)ethynyl]-2-pyridyl]-3-methyl-benzimidazol-5-yl]oxy- propan-2-ol,6-methoxy-2-[5-[2-(2-methoxypyrimidin-5-yl)ethynyl]-2-pyridyl]-l-methyl-benzimidazole,2-[5-[2-(2-ethoxypyrimidin-5-yl)ethynyl]-2-pyridyl]-6-methoxy-l-methyl-benzimidazole, [2-[2-[6-(6-methoxy-l-methyl-benzimidazol-2-yl)-3-pyridyl]ethynyl]thiazol-4-yl]methanol, 6-methoxy-l-methyl-2-[5-[2-(3-pyridyl)ethynyl]-2-pyridyl]benzimidazole,[5-[2-[6-(6-methoxy-l-methyl-benzimidazol-2-yl)-3-pyridyl]ethynyl]-2-pyridyl]methanol, 6-(2-fluoroethyl)-2-[5-[2-(5-methoxy-2-pyridyl)ethynyl]-2-pyridyl]-l-methyl-benzimidazole, or a pharmaceutically acceptable salt thereof.

19. The compound according to any of claims 1-18 which is isotopically labeled with2H,3H,HC, °C,14c,13N,15N,15o,17o,18o,18F,35s,36ci,82Br,76Br,77Br,123I,124I,125I or131I.

20. A pharmaceutical composition comprising a compound according to any one of claims 1-19 and a pharmaceutically acceptable carrier.

21. A composition for imaging of tau aggregates, comprising a radio-labeled compound of claim 19 and a pharmaceutically acceptable carrier.

22. A method of inhibiting tau aggregation in a mammal, comprising administering the composition of claim 21 in an amount effective to inhibit tau aggregation.

23. A method for measuring tau deposits in a patient comprising the steps of administering a detectable quantity of a compound of claim 19 or a pharmaceutically acceptable salt or deuterated version thereof, and detecting the binding of the compound to tau deposits in the patient.

24. The method according to claim 23 wherein detection is carried out by performing PET imaging, single photon emission computed tomography, magnetic resonance imaging, or autoradiography.

25. The method according to claim 23 for diagnosing and monitoring the treatment of Alzheimer’s Disease, familial Alzheimer’s Disease, Down’s Syndrome, Cognitive Deficit in Schizophrenia, frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration, chronic traumatic encephalopathy, and Pick’s disease.

26. Use of a compound according to claim 1, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating and / or preventing Alzheimer’s Disease, familial Alzheimer’s Disease, Down’s Syndrome, Cognitive Deficit in Schizophrenia, frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration, chronic traumatic encephalopathy, and Pick’s disease.

27. A compound of claim 1, or pharmaceutically acceptable salt thereof, for use in therapy.

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