Probes for imaging huntingtin

Abstract

The present application provides imaging agents comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and methods of using the same.

Description

[0001] This application is a divisional application of the application patent application with the filing date of August 28, 2015, application number 201580058282.3 (international application number PCT / US2015 / 047407), entitled "PROBES FOR IMAGING HUNTINGTON PROTEIN".

[0002] This application claims priority to U.S. provisional application 62 / 043,603 filed August 29, 2014, which is incorporated by reference herein for all purposes.

[0003] The advent of molecular imaging methods such as positron emission tomography (PET) and single photon emission computed tomography (SPECT) has enabled the measurement of molecular and cellular mechanisms throughout the body in preclinical and clinical settings. The measurements have a wide range of diagnostic uses and their use for evaluating treatment response and aiding drug development has grown rapidly. Many experts identify the recently introduced high resolution molecular imaging technologies as a major breakthrough that will potentially cause a revolutionary paradigm shift in health care and revolutionize clinical practice.

[0004] PET involves the administration of a positron-emitting radionuclide tracer to a subject, followed by the detection of positron emission (annihilation) events in the body. The radionuclide tracer typically includes a target molecule having one or more types of positron-emitting radionuclides incorporated therein.

[0005] A number of new molecular probes labeled with positron-emitting radionuclides and related PET imaging assays are under development to target, detect, visualize, and quantify various extracellular and intracellular molecules and processes associated with diseases such as cancer, heart disease, and neurological disorders. For example, several types of drugs have been synthesized and evaluated for imaging amyloid beta (Ab) plaques in patients with Alzheimer's disease (AD), including aryl benzothiazoles, stilbenes, imidazopyridines, pyridyl benzothiazoles, pyridyl benzoxazoles, and pyridyl benzofurans (Swahn et al., Bioorganic & Medicinal Chemistry Letters, 20 (2010) 1976-1980). In addition, a styrylbenzimidazole (SBIM) derivative has been developed as a drug for imaging neurofibrillary tangles (NFTs) including hyperphosphorylated tau protein in patients with AD. In binding experiments using recombinant tau and amyloid beta 1-42 (Ab 1-42 ) aggregates, 4-[(E)-2-(6-iodo-lH-benzimidazol-2-yl)vinyl]-N,N-dimethylaniline (SBIM-3) showed a higher affinity for Ab1-42 higher affinity for tau aggregates (K d values ratio of 2.73). In in vitro autoradiography and fluorescent staining, 125 I] SBIM-3 (or SBIM-3) binds NFTs in sections of AD brain tissue. In biodistribution experiments using normal mice, all 125 I] SBIM derivatives show high initial uptake in the brain (3.20-4.11 %ID / g at 2 min post injection) and rapid clearance from the brain (0.12-0.33 %ID / g at 60 min post injection) (Matsumura et al., Bioorganic & Medicinal Chemistry, 21 (2013) 3356-3362).

[0006] Huntington's disease (HD) is a genetic, progressive neurodegenerative disease characterized by motor, cognitive and psychiatric deficits, and neurodegeneration and brain atrophy beginning in the striatum and cortex and extending to other subcortical brain areas. It belongs to a family of neurodegenerative diseases caused by mutations in which an expanded CAG repeat tract leads to long stretches of polyglutamine (polyQ) in the encoded protein. The family also includes dentatorubral pallidoluysian atrophy (DRPLA), spinal and bulbar muscular atrophy (SBMA) and spinocerebellar ataxias (SCAs). The proteins involved are unrelated beyond their polyQ repeat units, and although they are all widely expressed in the central nervous system and peripheral tissues, they produce characteristic patterns of neurodegeneration. In HD, selective neurodegeneration of the striatal gamma-aminobutyric acid-releasing spiny projection neurons is predominantly present, although neuronal loss in many other brain areas has also been reported. In the unaffected population, IT 15The number of CAG repeat units in the gene varies from 6 to 35; 36 or more repeat units define an HD allele. The length of the CAG stretch inversely correlates with the age at onset of disease, with juvenile onset cases characterized by stretches of more than 60 repeats. The prevalence of HD is 5-10 cases per 100,000 people worldwide, making it the most common inherited neurodegenerative disease. The HTT protein is a 348-kDa multidomain protein that contains a polyphormic glutamine / proline-rich region at its amino terminus. The longer polyQ domain appears to induce a conformational change within the protein that causes it to form intracellular aggregates, which in most cases appear as nuclear inclusions. However, aggregates can also form outside the nucleus. The HTT protein is found in the nucleus, cell body, dendrites, and nerve terminals of neurons and also associates with numerous organelles including the Golgi apparatus, endoplasmic reticulum, and mitochondria.

[0007] Several clinical trials are underway to reduce or diminish symptoms and slow progression in clinically diagnosed HD. As is consistent with other medical conditions, treatment ideally begins at or before the earliest signs of disease are detected. There are at least two major challenges in designing clinical trials for pre-HD: selecting participants most likely to show measurable changes during the course of the clinical trial, and developing outcome measures that are sensitive to intervention and can show differences in the natural history of pre-HD. To meet these and other challenges for preventive clinical trials, there is a need for an indicator for very early stage disease.

[0008] In view of the central role of aggregated forms of the HTT protein in the pathogenesis of HD, there is a need for molecular probes for molecular imaging using PET in living subjects that bind with high sensitivity and specificity to the abnormalities. The compounds described herein meet this and other needs.

[0009] The present application provides an imaging agent comprising a compound of Formula I:

[0010]

[0011] wherein

[0012] X is selected from NR4, O, and S;

[0013] Y is selected from CR4and N;

[0014] Z1, Z2, Z3, and Z4are independently selected from CH and N, provided that at least two of Z1, Z2, Z3, and Z4are CH;

[0015] R1is selected from the group consisting of heteroaryl, heterocyclenyl and heterocycloalkyl, each optionally substituted with one or two groups independently selected from cyano, halo, lower alkyl optionally substituted with amino, alkylamino or di(alkyl)amino, lower alkoxy optionally substituted with lower alkoxy, optionally substituted amino, haloalkyl, di(alkyl)aminocarbonyl, alkylaminocarbonyl and aminocarbonyl, or

[0016] R1is phenyl optionally substituted with one or two groups independently selected from cyano, heteroaryl, halo, phenoxy, benzyloxy, heteroaryl, lower alkyl optionally substituted with amino, (alkyl)amino or di(alkyl)amino, lower alkoxy, optionally substituted amino, di(alkyl)aminocarbonyl, alkylaminocarbonyl and aminocarbonyl;

[0017] L1is -O- and L2is -(CR7R8) m - or -(CR7R8) m -O-; or

[0018] L1is -NR3- and L2is -C(O)- or -(CR7R8) m -; or

[0019] L1is -NR3- and L2is -C(O)(O)(CR7R8) m -; or

[0020] L1is -NR3- and L2is -C(O)(CR7R8) m (O)-; or

[0021] L1is -NR3- and L2is -C(O)(CR7R8) m -; or

[0022] L1is -NR3- and L2is -C(O)CR7=CR8-; or

[0023] L1is -C(O)- and L2is -NR3; or

[0024] L1is -(CR7R8) m - and L2is -NR3-, -C(O)- or -O-; or

[0025] L1is absent and L2is absent; or

[0026] L1and L2together are -CH=CH-, -C≡C- or heterocyclenyl;

[0027] L3is -CH=CH- or L3is absent;

[0028] R2is selected from the group consisting of heterocycloalkyl, aryl and heteroaryl, each optionally substituted with one or two groups selected from:

[0029] -OC(O)-R6,

[0030] -C(O)O-R6,

[0031] amino,

[0032] halogen,

[0033] haloalkyl,

[0034] phenyl,

[0035] heteroaryl,

[0036] cyano,

[0037] (lower alkyl)thio,

[0038] phenoxy,

[0039] phenoxy methyl,

[0040] heteroaryloxy,

[0041] heteroaryloxy substituted by lower alkyl,

[0042] hydroxy,

[0043] lower alkenyloxy,

[0044] lower alkoxy,

[0045] lower alkoxy substituted by lower alkoxy, amino, (alkyl)amino, (dialkyl)amino, heterocycloalkyl, heteroaryl or halogen,

[0046] lower alkyl, and

[0047] lower alkyl substituted by amino, (alkyl)amino, (dialkyl)amino, hydroxy or lower alkoxy;

[0048] R3is selected from hydrogen and lower alkyl;

[0049] R4is selected from hydrogen, halogen, cyano and lower alkyl;

[0050] R5is selected from lower alkyl, lower alkoxy and halogen;

[0051] R6is lower alkyl;

[0052] R7is selected from hydrogen, hydroxy, trifluoromethyl and lower alkyl;

[0053] R8is selected from hydrogen and lower alkyl;

[0054] n is 0 or 1 ; and

[0055] m is 0, 1 or 2;

[0056] wherein the compound of Formula I or a pharmaceutically acceptable salt thereof is labeled with one or more positron-emitting radionuclides.

[0057] The present application also provides a method of producing a diagnostic image in an individual, comprising administering to the individual an effective amount of an imaging agent described herein, and producing an image of at least a portion of the individual. BRIEF DESCRIPTION OF DRAWINGS

[0058] Figure 1 shows the binding of compound 3 of method 14 in four regions of the brain of mice that are wild type or heterozygous or homozygous for a knock-in allele of zQ175. 11 AUC values of the binding of C-labeled compound 3 in mice that are wild type or heterozygous or homozygous for a knock-in allele of zQ175.

[0059] The following words, phrases and symbols used in the specification are intended to have the meanings ascribed to them unless otherwise indicated.

[0060] A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -CONH2is attached through the carbon atom.

[0061] The term "group," "radical," or "moiety" as used herein means a functional group or moiety of a molecule that can be attached to a bond or other moiety of a molecule.

[0062] When a range of values (for example, C 1-6 alkyl) is given, each intervening value, as well as all the intervening ranges between the stated values are included. For example, "C 1-6 alkyl" includes C1, C2, C3, C4, C5, C6, C 1-6 , C 2-6 , C 3-6 , C 4-6 , C 5-6 , C 1-5 , C 2-5 , C 3-5 , C 4-5 , C 1-4 , C 2-4 , C 3-4 , C 1-3 , C 2-3 and C 1-2 alkyl.

[0063] When a moiety is defined as optionally substituted, it can be substituted itself or as part of another group. For example, if R x is defined as "C 1-6 alkyl or OC 1-6 alkyl, where C 1-6 alkyl is optionally substituted with halo", then a C1-6 Alkyl groups and the components of OC 1-6 A portion of the C of an alkyl group 1-6 Alkyl groups can all replace halogenated compounds.

[0064] The term "alkyl" encompasses straight-chain and branched alkyl groups having the indicated number of carbon atoms, typically from 1 to 20 carbon atoms, such as from 1 to 8 carbon atoms, or from 1 to 6 carbon atoms. For example, C1-C6 alkyl encompasses straight-chain and branched alkyl groups having 1 to 6 carbon atoms. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, 3-methylpentyl, etc. When referring to an alkyl residue with a specific number of carbon atoms, it is intended to encompass all geometric isomers having that number of carbon atoms; thus, for example, "butyl" is intended to include n-butyl, sec-butyl, isobutyl, and tert-butyl; "propyl" includes n-propyl and isopropyl. "Lower alkyl" refers to an alkyl group having 1 to 6 carbon atoms.

[0065] "Alkoxy" refers to an alkyl group with the indicated number of carbon atoms connected by an oxygen bridge, such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentylooxy, 2-pentyloxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, 3-methylpentoxy, etc. Alkoxy groups typically have 1 to 6 carbon atoms connected by an oxygen bridge. "Lower alkoxy" refers to an alkoxy group with 1 to 6 carbon atoms. "Cycloalkoxy" refers to a cycloalkyl group that is also connected by an oxygen bridge.

[0066] "Alkenyl" refers to an unsaturated branched or straight-chain alkyl group having the indicated number of carbon atoms (e.g., 2 to 8 or 2 to 6 carbon atoms) and at least one carbon-carbon double bond, which is obtained by removing one molecule of hydrogen from the adjacent carbon atom of the respective alkyl group. Alkenyl groups include, but are not limited to, vinyl, propenyl, and butenyl groups. "Lower alkenyl groups" refers to alkenyl groups having 2 to 6 carbon atoms.

[0067] "Alynyl" refers to an unsaturated branched or straight-chain alkyl group having the indicated number of carbon atoms (e.g., 2 to 8 or 2 to 6 carbon atoms) and at least one carbon-carbon triple bond, which is obtained by removing two molecules of hydrogen from adjacent carbon atoms of the respective alkyl group. Alynyl groups include, but are not limited to, ethynyl, propynyl (e.g., prop-1-yn-1-yl, prop-2-yn-1-yl), and butynyl (e.g., but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl). "Lower alkynyl" refers to an alkynyl group having 2 to 6 carbon atoms.

[0068] "Aryl" refers to an aromatic carbocyclic ring having the indicated number of carbon atoms, e.g., 6 to 12 or 6 to 10 carbon atoms. The aryl group can be a single ring or a multiple ring (e.g., bicyclic, tricyclic). In some instances, both rings in a multiple ring aryl group are aromatic (e.g., naphthyl). In other instances, a multiple ring aryl group can include a non-aromatic ring (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl) fused to an aromatic ring, provided that the multiple ring aryl group is attached to the parent structure through an atom in an aromatic ring. Thus, 1,2,3,4-tetrahydronaphthalen-5-yl (where the moiety is attached to the parent structure through an aromatic carbon atom) is considered to be an aryl group, while 1,2,3,4-tetrahydronaphthalen-1-yl (where the moiety is attached to the parent structure through a non-aromatic carbon atom) is not considered to be an aryl group. Similarly, 1,2,3,4-tetrahydroquinolin-8-yl (where the moiety is attached to the parent structure through an aromatic carbon atom) is considered to be an aryl group, while 1,2,3,4-tetrahydroquinolin-1-yl (where the moiety is attached to the parent structure through a non-aromatic nitrogen atom) is not considered to be an aryl group. However, the term "aryl" does not include or overlap with "heteroaryl" no matter where the point of attachment is (e.g., quinolin-5-yl and quinolin-2-yl are both heteroaryl). In some instances, aryl is phenyl or naphthyl. In some instances, aryl is phenyl.

[0069] Divalent groups derived from substituted phenyl derivatives and having a free valence at a ring atom are named substituted phenylene. Divalent groups derived from univalent polycyclic hydrocarbon groups whose names end in "-yl" by removal of one hydrogen atom from a carbon atom having a free valence are named by adding "-enyl" to the name of the corresponding univalent group, e.g., naphthyl with two points of attachment is named naphthylene.

[0070] "Cycloalkyl" denotes a non-aromatic, fully saturated carbocyclic ring having the indicated number of carbon atoms, e.g., 3 to 10 or 3 to 8 or 3 to 6 ring carbon atoms. Cycloalkyl groups can be monocyclic or polycyclic (e.g., bicyclic, tricyclic). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, as well as bridged ring and clathrate ring groups (e.g., norbornane, bicyclo[2.2.2]octane). Additionally, one ring in a polycyclic cycloalkyl group can be aromatic, provided that the polycyclic cycloalkyl group is attached to the parent structure through a non-aromatic carbon. For example, 1,2,3,4-tetrahydronaphthalen-1-yl (where the moiety is attached to the parent structure through a non-aromatic carbon atom) is a cycloalkyl group, while 1,2,3,4-tetrahydronaphthalen-5-yl (where the moiety is attached to the parent structure through an aromatic carbon atom) is not considered to be a cycloalkyl group.

[0071] "Cycloalkenyl" denotes nonaromatic carbocyclic rings having the indicated number of carbon atoms (e.g., 3 to 10, or 3 to 8, or 3 to 6 ring carbon atoms) and at least one carbon-carbon double bond obtained by removal of one molecule of hydrogen from adjacent carbon atoms of the corresponding cycloalkyl. Cycloalkenyl groups can be monocyclic or polycyclic (e.g., bicyclic, tricyclic). Examples of cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, and cyclohexenyl, as well as bridged ring and clathrate ring groups (e.g., bicyclo[2.2.2]octenyl). Additionally, one ring of a polycyclic cycloalkenyl group can be aromatic, provided that the polycyclic cycloalkenyl group is attached to the parent structure through a nonaromatic carbon atom. For example, inden-1-yl (where the moiety is attached to the parent structure through a nonaromatic carbon atom) is considered a cycloalkenyl group, while inden-4-yl (where the moiety is attached to the parent structure through an aromatic carbon atom) is not considered a cycloalkenyl group.

[0072] The term "halo" includes fluoro, chloro, bromo, and iodo and the term "halogen" includes fluoro, chloro, bromo, and iodo.

[0073] "Haloalkyl" includes straight chain and branched carbon chains having the indicated number of carbon atoms (e.g., 1 to 6 carbon atoms) substituted with at least one halogen atom. In cases where the haloalkyl group contains more than one halogen atom, the halogens can be the same (e.g., dichloromethyl) or different (e.g., chlorofluoromethyl). Examples of haloalkyl groups include, but are not limited to, chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 2-chloroethyl, 2,2-dichloroethyl, 2,2,2-trichloroethyl, 1,2-dichloroethyl, pentachloroethyl, and pentafluoroethyl.

[0074] "Heteroaryl" refers to an aromatic ring containing the indicated number of atoms (e.g., 5 to 12 membered or 5 to 10 membered heteroaryl) containing one or more heteroatoms selected from N, O, and S (e.g., 1, 2, 3, or 4 heteroatoms) and the remaining ring atoms are carbon. Heteroaryl does not contain adjacent S and O atoms. In some embodiments, the total number of S and O atoms in a heteroaryl group is no more than 2. In some embodiments, the total number of S and O atoms in a heteroaryl group is no more than 1. Unless otherwise specified, a heteroaryl group can be attached to the parent structure through a carbon or nitrogen atom, as valence allows. For example, "pyridyl" includes 2-pyridyl, 3-pyridyl, and 4-pyridyl and "pyrrolyl" includes 1-pyrrolyl, 2-pyrrolyl, and 3-pyrrolyl. When a nitrogen is present in a heteroaryl ring, the nitrogen can be in an oxidized state (i.e., N + -O - ) when the nature of the adjacent atoms and groups permit. Additionally, when a sulfur is present in a heteroaryl ring, the sulfur can be in an oxidized state (i.e., S+ -O - or SO2) is present. The heteroaryl group can be monocyclic or polycyclic (e.g., bicyclic, tricyclic).

[0075] In some cases, the heteroaryl group is monocyclic. Examples include pyrrole, pyrazole, imidazole, triazole (e.g., 1,2,3-triazole, 1,2,4-triazole, 1,3,4-triazole), tetrazole, furan, isoxazole, oxazole, oxadiazole (e.g., 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole), thiophene, isothiazole, thiazole, thiadiazole (e.g., 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole), pyridine, pyridazine, pyrimidine, pyrazine, triazine (e.g., 1,2,4-triazine, 1,3,5-triazine), and tetrazine.

[0076] In some cases, both rings in the polycyclic heteroaryl are aromatic.Examples include indole, isoindole, indazole, benzimidazole, benzotriazole, benzofuran, benzoxazole, benzisoxazole, benzoxadiazole, benzothiophene, benzothiazole, benzisothiazole, benzothiadiazole, 1H-pyrrolo[2,3-b]pyridine, 1H-pyrazolo[3,4-b]pyridine, 3H-imidazo[4,5-b]pyridine, 3H-[1,2,3]triazolo[4,5-b]pyridine, 1H-pyrrolo[3,2-b]pyridine, 1H-pyrazolo[4,3-b]pyridine, 1H-imidazo[4,5-b]pyridine, 1H-[1,2,3]triazolo[4,5-b]pyridine, 1H-pyrrolo[2,3-c]pyridine, 1H-pyrazolo[3,4-c]pyridine, 3H-imidazo[4,5-c]pyridine, 3H-[1,2,3]triazolo[4,5-c]pyridine, 1H-pyrrolo[3,2-c]pyridine, 1H-pyrazolo[4,3-c]pyridine, 1H-imidazo[4,5-c]pyridine, 1H-[1,2,3]triazolo[4,5-c]pyridine, furano[2,3-b]pyridine, oxazolo[5,4-b]pyridine, isoxazolo[5,4-b]pyridine, [1,2,3]oxadiazolo[5,4-b]pyridine, furano[3,2-b]pyridine, oxazolo[4,5-b]pyridine, isoxazolo[4,5-b]pyridine, [1,2,3]oxadiazolo[4,5-b]pyridine, furano[2,3-c]pyridine, oxazolo[5,4-c]pyridine, isoxazolo[5,4-c]pyridine, [1,2,3]oxadiazolo[5,4-c]pyridine, furano[3,2-c]pyridine, oxazolo[4,5-c]pyridine, isoxazolo[4,5-c]pyridine, [1,2,3]oxadiazolo[4,5-c]pyridine, thieno[2,3-b]pyridine, thiazolo[5,4-b]pyridine, isothiazolo[5,4-b]pyridine, [1,2,3]thiadiazolo[5,4-b]pyridine, thieno[3,2-b]pyridine, thiazolo[4,5-b]pyridine, isothiazolo[4,5-b]pyridine, [1,2,3]thiadiazolo[4,5-b]pyridine, thieno[2,3-c]pyridine, thiazolo[5,4-c]pyridine, isothiazolo[5,4-c]pyridine, [1,2,3]thiadiazolo[5,4-c]pyridine, thieno[3,2-c]pyridine, thiazolo[4,5-c]pyridine, isothiazolo[4,5-c]pyridine, [1,2,3]thiadiazolo[4,5-c]pyridine, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, phthalazine, naphthyridine (e.g., 1,8-naphthyridine, 1,7-naphthyridine, 1,6-naphthyridine, 1,5-naphthyridine, 2,7-naphthyridine, 2,6-naphthyridine), imidazo[1,2-a]pyridine, 1H-pyrazolo[3,4-d]thiazole, 1H-pyrazolo[4,3-d]thiazole, and imidazo[2,1-b]thiazole.

[0077] In other instances, polycyclic heteroaryl groups can include non-aromatic rings (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl) fused to the heteroaryl ring, provided that the polycyclic heteroaryl group is attached to the parent structure through an atom in an aromatic ring. For example, 4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl (where the moiety is attached to the parent structure through an aromatic carbon atom) is considered a heteroaryl group, while 4,5,6,7-tetrahydrobenzo[d]thiazol-5-yl (where the moiety is attached to the parent structure through a non-aromatic carbon atom) is not considered a heteroaryl group.

[0078] "Heterocycloalkyl" refers to non-aromatic, fully saturated rings having the number of atoms indicated (e.g., 3- to 10-membered or 3- to 7-membered heterocycloalkyl), which include one or more heteroatoms (e.g., 1, 2, 3, or 4 heteroatoms) selected from N, O, and S, and the remaining ring atoms are carbon. Heterocycloalkyl groups can be monocyclic or polycyclic (e.g., bicyclic, tricyclic).

[0079] Examples of monocyclic heterocycloalkyl groups include oxiranyl, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, and thiomorpholinyl.

[0080] When a nitrogen is present in a heterocycloalkyl ring, the nitrogen can be present in an oxidized state (i.e., N + -O - ) when adjacent atoms and groups permit. Examples include piperidinyl N-oxides and morpholinyl N-oxides. Additionally, when a sulfur is present in a heterocycloalkyl ring, the sulfur can be present in an oxidized state (i.e., S + -O - or -SO2-) when adjacent atoms and groups permit. Examples include thiomorpholinyl S-oxides and thiomorpholinyl S,S-dioxides.

[0081] Additionally, one ring of a polycyclic heterocycloalkyl group can be aromatic (e.g., aryl or heteroaryl), provided that the polycyclic heterocycloalkyl group is attached to the parent structure through a non-aromatic carbon or nitrogen atom. For example, 1,2,3,4-tetrahydroquinolin-1-yl (where the moiety is attached to the parent structure through a non-aromatic nitrogen atom) is considered a heterocycloalkyl group, while 1,2,3,4-tetrahydroquinolin-8-yl (where the moiety is attached to the parent structure through an aromatic carbon atom) is not considered a heterocycloalkyl group.

[0082] "Heterocyclic alkenyl" refers to a non-aromatic ring (e.g., 3- to 10-membered or 3- to 7-membered heterocyclic alkenyl) having the indicated number of atoms, containing one or more heteroatoms selected from N, O, and S (e.g., 1, 2, 3, or 4 heteroatoms), with the remaining ring atoms being carbon and having at least one double bond, said double bond being obtained by removing a molecule of hydrogen from an adjacent carbon atom, an adjacent nitrogen atom, or adjacent carbon and nitrogen atoms in the respective heterocyclic alkyl group. Heterocyclic alkenyl groups can be monocyclic or polycyclic (e.g., bicyclic or tricyclic). When nitrogen is present in the heterocyclic alkenyl ring, said nitrogen can be in an oxidized state (i.e., N2) where permitted by adjacent atoms and groups. + -O - Sulfur exists. Additionally, when sulfur is present in a heterocyclic alkenyl ring, it can be oxidized to an oxidized state (i.e., S) where adjacent atoms and groups permit. + -O - (or -SO2-) may be present. Examples of heterocyclic alkenyl groups include dihydrofuranyl (e.g., 2,3-dihydrofuranyl, 2,5-dihydrofuranyl), dihydrothiophenyl (e.g., 2,3-dihydrothiophenyl, 2,5-dihydrothiophenyl), dihydropyrrolyl (e.g., 2,3-dihydro-1H-pyrrolyl, 2,5-dihydro-1H-pyrrolyl), dihydroimidazoyl (e.g., 2,3-dihydro-1H-imidazoyl, 4,5-dihydro-1H-imidazoyl), pyranyl, dihydropyranyl (e.g., 3,4-dihydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl), tetrahydropyridyl (e.g., 1,2,3,4-tetrahydropyridyl, 1,2,3,6-tetrahydropyridyl), and dihydropyridine (e.g., 1,2-dihydropyridine, 1,4-dihydropyridine). Furthermore, one ring in a polycyclic heterocyclic alkenyl group may be aromatic (e.g., aryl or heteroaryl), provided that the polycyclic heterocyclic alkenyl group is connected to the parent structure via a non-aromatic carbon or nitrogen atom. For example, 1,2-dihydroquinoline-1-yl (wherein the portion is connected to the parent structure via a non-aromatic nitrogen atom) is considered a heterocyclic alkenyl group, while 1,2-dihydroquinoline-8-yl (wherein the portion is connected to the parent structure via an aromatic carbon atom) is not considered a heterocyclic alkenyl group.

[0083] As used in this application, the term "heterocyclic group" refers to a non-aromatic monocyclic divalent group having 3 to 5 ring atoms. Examples of heterocyclic groups include 1,2-oxetane, 2,2-oxetane, 1,2-azacyclopropane, 2,2-azacyclopropane, 2,2-oxetane, 2,3-oxetane, 2,4-oxetane, 3,3-oxetane, 2,2-azacyclobutane, 2,3-azacyclobutane, 2,3-azacyclobutane, 3,3-azacyclobutane, 2,3-tetrahydrofuran, and 3,4-tetrahydrofuran.

[0084] "Optional" or "optionally" means that the subsequently described event or circumstance can or can not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "optionally substituted alkyl" includes "alkyl" as defined herein and "substituted alkyl". For any group containing one or more substituents, it is understood that the group is optionally substituted with up to the maximum number of substituents possible.

[0085] The term "substituted" as used herein means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is oxo (i.e., =0), two hydrogens on the atom are replaced. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. Stable compounds or stable structures are compounds that are sufficiently robust to survive isolation from a reaction mixture and subsequent formulation into an agent having at least one practical use. Unless otherwise indicated, substituents are named into the core structure. For example, it is understood that when (cycloalkyl)alkyl is listed as a possible substituent, the point of attachment to the core structure is in the alkyl portion.

[0086] Unless specifically defined otherwise, the term "substituted" alkyl (including but not limited to C1-C4alkyl), "substituted" cycloalkyl, "substituted" cycloalkenyl, "substituted" aryl, "substituted" heterocycloalkyl, "substituted" heterocycloalkenyl, and "substituted" heteroaryl means, respectively, an alkyl, cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl, and heteroaryl group in which one or more (e.g., up to five and, e.g., up to three) hydrogen atoms are replaced by a substituent selected independently from the group consisting of:

[0087] -R a , -OR b , -O(C1-C2alkyl)O- (e.g., methylenedioxy-), -SR b , guanidinyl (-NHC(=NH)NH2), guanidinyl in which one or more hydrogens are replaced by C1-C4alkyl, -NR b R c , halogen, cyano, oxo (as a substituent of a heterocycloalkyl), nitro, -COR b , -CO2R b , -CONR b R c , -OCOR b , -OCO2R a , -OCONR b R c , -NRc COR b , -NR c CO2R a , -NR c CONR b R c , -SOR a , -SO2R a , -SO2NR b R c and -NR c SO2R a ,

[0088] wherein R a is selected from C1-C6alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl;

[0089] R b is selected from H, C1-C6alkyl, aryl and heteroaryl; and

[0090] R c is selected from hydrogen and C1-C4alkyl; or

[0091] R b and R cwith the nitrogen to which they are attached form a heterocycloalkyl group; and wherein each C1-C6alkyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl is optionally substituted with one or more, for example one, two or three, substituents independently selected from the group consisting of C1-C4alkyl, C3-C6cycloalkyl, aryl, heteroaryl, aryl-C1-C4alkyl-, heteroaryl-C1-C4alkyl-, C1-C4haloalkyl-, -OC1-C4alkyl, -OC1-C4alkylphenyl, -C1-C4alkyl-OH, -C1-C4alkyl-O-C1-C4alkyl, -OC1-C4haloalkyl, halogen, -OH, -NH2, -C1-C4alkyl-NH2, -N(C1-C4alkyl)(C1-C4alkyl), -N(C1-C4alkyl)(C1-C4alkylheteroaryl), -NH(C1-C4alkyl), -N(C1-C4alkyl)(C1-C4alkylphenyl), -NH(C1-C4alkylphenyl), cyano, nitro, oxo (as a substituent of heteroaryl), -CO2H, -C(O)OC1-C4alkyl, -CON(C1-C4alkyl)(C1-C4alkyl), -CONH(C1-C4alkyl), -CONH2, -NHC(O)(C1-C4alkyl), -NHC(O)(phenyl), -N(C1-C4alkyl)C(O)(C1-C4alkyl), -N(C1-C4alkyl)C(O)(phenyl), -C(O)C1-C4alkyl, -C(O)C1-C4phenyl, -C(O)C1-C4haloalkyl, -OC(O)C1-C4alkyl, -SO2(C1-C4alkyl), -SO2(phenyl), -SO2(C1-C4haloalkyl), -SO2NH2, -SO2NH(C1-C4alkyl), -SO2NH(phenyl), -NHSO2(C1-C4alkyl), -NHSO2(phenyl), and -NHSO2(C1-C4haloalkyl).

[0092] The term "substituted amino" refers to the group -NHR d or -NR d R d wherein each R d is independently selected from the group consisting of optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted acyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, alkoxycarbonyl, sulfinyl, and sulfonyl, wherein substituted alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl each refers to alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl, respectively, wherein one or more (for example up to 5 and for example up to 3) hydrogen atoms have been replaced with a substituent independently selected from the group consisting of:

[0093] -R a , -OR b, -O(C1-C2alkyl)O- (e.g., methylenedioxy-), -SR b , guanidinyl, guanidinyl wherein one or more hydrogens are replaced by lower alkyl, -NR b R c , halogen, cyano, nitro, -COR b , -CO2R b , -CONR b R c , -OCOR b , -OCO2R a , -OCONR b R c , -NR c COR b , -NR c CO2R a , -NR c CONR b R c , -CO2R b , -CONR b R c , -NR c COR b , -SOR a , -SO2R a , -SO2NR b R c and -NR c SO2R a ,

[0094] wherein R a is selected from the group consisting of optionally substituted C1-C6alkyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0095] R b is selected from the group consisting of H, optionally substituted C1-C6alkyl, optionally substituted aryl, and optionally substituted heteroaryl; and

[0096] R c is selected from the group consisting of hydrogen and optionally substituted C1-C4alkyl;

[0097] wherein each optionally substituted group is optionally substituted with one or more, for example one, two or three, substituents independently selected from the group consisting of C1-C4alkyl, aryl, heteroaryl, aryl-C1-C4alkyl-, heteroaryl-C1-C4alkyl-, C1-C4haloalkyl-, -OC1-C4alkyl, -OC1-C4alkylphenyl, -C1-C4alkyl-OH, -OC1-C4haloalkyl, halogen, -OH, -NH2, -C1-C4alkyl-NH2, -N(C1-C4alkyl)(C1-C4alkyl), -NH(C1-C4alkyl), -N(C1-C4alkyl)(C1-C4alkylphenyl), -N(C1-C4alkyl)(C1-C4alkylheteroaryl), -NH(C1-C4alkylphenyl), cyano, nitro, oxo (as a substituent of heteroaryl), -CO2H, -C(O)OC1-C4alkyl, -CON(C1-C4alkyl)(C1-C4alkyl), -CONH(C1-C4alkyl), -CONH2, -NHC(O)(C1-C4alkyl), -NHC(O)(phenyl), -N(C1-C4alkyl)C(O)(C1-C4alkyl), -N(C1-C4alkyl)C(O)(phenyl), -C(O)C1-C4alkyl, -C(O)C1-C4phenyl, -C(O)C1-C4haloalkyl, -OC(O)C1-C4alkyl, -SO2(C1-C4alkyl), -SO2(phenyl), -SO2(C1-C4haloalkyl), -SO2NH2, -SO2NH(C1-C4alkyl), -SO2NH(phenyl), -NHSO2(C1-C4alkyl), -NHSO2(phenyl), and -NHSO2(C1-C4haloalkyl).

[0098] The term "substituted amino" also refers to -NR e R f wherein R e and R f together with the nitrogen to which they are attached form an optionally substituted 5- to 7-membered nitrogen-containing, non-aromatic heterocyclic ring, optionally containing 1 or 2 additional heteroatoms selected from nitrogen, oxygen and sulfur.

[0099] "Aminocarbonyl" encompasses a group of the formula -(C=O)(optionally substituted amino), wherein substituted amino is as described herein.

[0100] The compounds described herein include, but are not limited to, their optical isomers, racemates, and other mixtures thereof. In these instances, a single enantiomer or diastereomer, i.e., an optically active form, can be obtained by asymmetric synthesis or by resolution of a racemate. A racemate can be resolved into its component enantiomers by, for example, conventional methods such as, for example, crystallization in the presence of a resolving agent or chromatographic techniques using, for example, a chiral high pressure liquid chromatography (HPLC) column. The term "isomers" refers to different compounds that have the same molecular formula. The term "stereoisomers" refers to isomers having the same structure except they are non-superimposable mirror images of one another. The term "enantiomers" refers to a pair of stereoisomers that are non-superimposable mirror images of each other. A 1 : 1 mixture of a pair of enantiomers is a "racemic" mixture. Where appropriate, the symbol "(±)" can be used to denote a racemic mixture. The term "diastereomers" refers to stereoisomers that have at least two asymmetric centers of which non are mirror images of one another. The absolute stereochemistry is specified where appropriate by the Cahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer the stereochemistry at each chiral carbon can be specified by R or S notation. Resolved compounds whose absolute configuration is unknown can be designated (+) or (-), depending upon the direction (right or left) in which they rotate the plane of polarized light. The absolute stereochemistry of substituted double bonds can be specified where appropriate by the Cahn-Ingold-Prelog system for R or S designations.

[0101] When the compounds described herein exist in various tautomeric forms, the term "compound" includes all tautomeric forms of the compound. Such compounds also include crystal forms, including polymorphs and clathrates. Similarly, the term "salt" includes all tautomeric forms and crystal forms of the compound. The term "tautomer" refers to structural isomers that interconvert by a

[0102] Pharmaceutically acceptable forms of the compounds described in this application include their pharmaceutical salts and mixtures thereof. In some embodiments, the compounds described in this application are in the form of pharmaceutical salts.

[0103] "Medicinal salts" include, but are not limited to, salts with inorganic acids, such as hydrochlorides, phosphates, pyrophosphates, hydrobroms, sulfates, sulfites, and nitrates; and salts with organic acids, such as malates, maleates, fumarates, tartrates, succinates, citrates, lactates, methanesulfonates, p-toluenesulfonates, 2-hydroxyethylsulfonates, benzoates, salicylates, stearates, haloalkanoates such as trifluoroacetates, and alkanoates such as acetates and HOOC-(CH2). n -COOH (where n is 0-4) salts, etc. Similarly, pharmaceutical cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium, and ammonium. Furthermore, if the compound described in this application is obtained as an acid addition salt, the free base can be obtained by alkalizing the solution of the acid addition salt. Conversely, if the product is a free base, the addition salt, and particularly pharmaceutical addition salts, can be obtained by dissolving the free base in a suitable organic solvent and treating the solution with acid according to conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize the various synthetic methodologies that can be used to prepare non-toxic pharmaceutical addition salts.

[0104] The term "administer" as used in this application in conjunction with diagnostic agents, such as positron emission tomography-labeled compounds described herein, refers to the direct administration of the diagnostic agent to or onto a target tissue or to the patient systemically, whereby the diagnostic agent is used for pathological imaging of said tissue or tissue associated with its target. The "administer" composition may be performed by injection, infusion, or in combination with other known techniques.

[0105] The term "Curie" (Ci) is a unit of measurement for radioactivity. One Ci is an amount of radioactivity measured in units of 3.7 × 10⁻⁶. 10 The amount of any radioactive material that decays at a rate of decays per second. The term "millicurie" (mCi) refers to 10-1... -3 Curie. It should be understood that the International Classification of Radioactivity (SI) unit, the becquerel, is equal to one decay per second. Therefore, 1 becquerel = 2.7 × 10⁻⁶ -11 Curie.

[0106] As used in this application, the term "diagnostic imaging" refers to the use of electromagnetic radiation to produce images of the internal structures of a human or animal body for diagnostic purposes.

[0107] The term "effective amount" for compounds used in this application refers to a predetermined amount calculated to achieve the desired effect, such as an amount sufficient to acquire a desired image of an individual's target organ. In some cases, the target organ is the brain.

[0108] The term "huntingtin" or "HTT protein" as used herein refers to the protein encoded by the human huntingtin gene (HTT gene) located on the short (p) arm of chromosome 4 at position 16.3. More precisely, the ITT protein is encoded by the ITT gene located on chromosome 4 from base pair 3,076,407 to base pair 3,245,686. 15

[0109] The term "HTT protein aggregate" as used herein refers to an insoluble fibrillar amyloid comprising misfolded ITT protein molecules.

[0110] The term "β-amyloid aggregate" as used herein refers to an insoluble fibrillar amyloid comprising misfolded β-amyloid molecules.

[0111] The term "imaging agent" as used herein refers to a compound described herein labeled with one or more positron-emitting isotopes or radionuclides. A positron-emitting agent-labeled compound need only be enriched with detectable isotopes to the extent that allows detection using techniques appropriate for the particular application.

[0112] The term "pathological process" as used herein refers to an altered endogenous biological process that can be associated with abnormal production and / or functionalization of proteins, peptides, RNA and other substances associated with the biological process.

[0113] The term "PET imaging" as used herein refers to the use of a positron-emitting agent-labeled compound to produce an image of the internal structure of a human or animal body.

[0114] The term "pharmaceutical composition" refers to a composition comprising at least one imaging agent described herein, whereby the composition is suitable for investigation for a particular effective outcome in a mammal, such as but not limited to a human. The skilled artisan will understand and recognize techniques suitable for determining whether a composition has the intended effective outcome according to their needs.

[0115] The term "positron-emitting radionuclide" as used herein refers to a radioisotope that exhibits a particular type of radioactive decay, known as β+ decay, in which a proton within the nucleus of the radionuclide is converted into a neutron and simultaneously releases a positron and an electron neutrino (v e ). Some examples of positron-emitting radionuclides include 15 O, 13 N, 11 C, 18 F, 76 Br, and 124 ​I. These radionuclides have half-lives of about 2, 10, 20, 110 minutes, 16 hours and 4.2 days, respectively.

[0116] The term "tomographic imaging" as used herein refers to the process of imaging by sectioning. The images can be viewed individually, as a series of two-dimensional slices or together as a computer-generated three-dimensional image view.

[0117] The present application provides an imaging agent comprising a compound of Formula I:

[0118]

[0119] wherein

[0120] X is selected from NR4, O and S;

[0121] Y is selected from CR4and N;

[0122] Z1, Z2, Z3and Z4are independently selected from CH and N, provided that at least two of Z1, Z2, Z3and Z4are CH;

[0123] R1is selected from heteroaryl, heterocyclenyl and heterocycloalkyl, each optionally substituted with one or two groups independently selected from cyano, halo, lower alkyl optionally substituted with amino, alkylamino or di(alkyl)amino, lower alkoxy optionally substituted with lower alkoxy, optionally substituted amino, haloalkyl, di(alkyl)aminocarbonyl, alkylaminocarbonyl and aminocarbonyl, or

[0124] R1is phenyl optionally substituted with one or two groups independently selected from cyano, heteroaryl, halo, phenoxy, benzyloxy, heteroaryl, lower alkyl optionally substituted with amino, (alkyl)amino or di(alkyl)amino, lower alkoxy, optionally substituted amino, di(alkyl)aminocarbonyl, alkylaminocarbonyl and aminocarbonyl;

[0125] L1is -O- and L2is -(CR7R8) m - or -(CR7R8) m -O-; or

[0126] L1is -NR3- and L2is -C(O)- or -(CR7R8) m -; or

[0127] L1is -NR3- and L2is -C(O)(O)(R7R8) m -; or

[0128] L1is -NR3- and L2is -C(O)(R7R8) m (O)-; or

[0129] L1is -NR3- and L2is -C(O)(R7R8) m -; or

[0130] L1is -NR3- and L2is -C(O)CR7=CR8-; or

[0131] L1is -C(O)- and L2is -NR3; or

[0132] L1is -(R7R8) m - and L2is -NR3-, -C(O)- or -O-; or

[0133] L1is absent and L2is absent; or

[0134] L1and L2together are -CH=CH-, -C≡C- or heterocyclylenyl;

[0135] L3is -CH=CH- or L3is absent;

[0136] R2is selected from the group consisting of heterocycloalkyl, aryl and heteroaryl, each optionally substituted with one or two groups selected from:

[0137] -OC(O)-R6,

[0138] -C(O)O-R6,

[0139] amino,

[0140] halo,

[0141] haloalkyl,

[0142] phenyl,

[0143] heteroaryl,

[0144] cyano,

[0145] (lower alkyl)sulfanyl,

[0146] phenoxy,

[0147] phenoxy methyl,

[0148] heteroaryloxy,

[0149] heteroaryloxy substituted with lower alkyl,

[0150] hydroxy,

[0151] lower alkenyloxy,

[0152] lower alkoxy,

[0153] lower alkyl, and

[0154] lower alkyl, and

[0155] lower alkyl, and

[0156] R3is selected from hydrogen and lower alkyl;

[0157] R4is selected from hydrogen, halogen, cyano and lower alkyl;

[0158] R5is selected from lower alkyl, lower alkoxy and halogen;

[0159] R6is lower alkyl;

[0160] R7is selected from hydrogen, hydroxy, trifluoromethyl and lower alkyl;

[0161] R8is selected from hydrogen and lower alkyl;

[0162] n is 0 or 1 ; and

[0163] m is 0, 1 or 2;

[0164] wherein the compound of formula I or a pharmaceutically acceptable salt thereof is labeled with one or more positron emitting radionuclides.

[0165] The present application provides an imaging agent comprising a compound of formula I or a pharmaceutically acceptable salt thereof:

[0166]

[0167] wherein

[0168] X is selected from NR4, O and S;

[0169] Y is selected from CR4and N;

[0170] Z1, Z2, Z3and Z4are independently selected from CH and N, provided that at least two of Z1, Z2, Z3and Z4are CH;

[0171] R1is selected from heteroaryl and heterocycloalkyl, each optionally substituted with one or two groups independently selected from cyano, halogen, lower alkyl, lower alkoxy optionally substituted with lower alkoxy, optionally substituted amino and aminocarbonyl, or

[0172] R1is phenyl optionally substituted with one or two groups independently selected from cyano, halogen, lower alkyl optionally substituted with amino, (alkyl)amino or di(alkyl)amino, lower alkoxy, optionally substituted amino and aminocarbonyl;

[0173] L1is -O- and L2is -(CR7R8) m - or -(CR7R8) m -0-; or

[0174] L1is -NR3- and L2is -C(O)- or -(CR7R8) m -; or

[0175] L1is -(CR7R8) m - and L2is -NR3-, -C(O)- or -O-; or

[0176] L1is absent and L2is absent; or

[0177] L1and L2together are -CH=CH-, -C≡C- or heterocyclylenyl;

[0178] R2is selected from the group consisting of heterocycloalkyl, aryl and heteroaryl, each optionally substituted with one or two groups selected from:

[0179] -OC(O)-R6,

[0180] hydroxy,

[0181] lower alkenyloxy,

[0182] lower alkoxy,

[0183] lower alkoxy substituted with lower alkoxy, amino, (alkyl)amino, (dialkyl)amino, heterocycloalkyl or halogen,

[0184] lower alkyl, and

[0185] lower alkyl substituted with amino, (alkyl)amino, (dialkyl)amino, hydroxy or lower alkoxy;

[0186] R3is selected from the group consisting of hydrogen and lower alkyl;

[0187] R4is selected from the group consisting of hydrogen, halogen, cyano and lower alkyl;

[0188] R5is selected from the group consisting of lower alkyl, lower alkoxy and halogen;

[0189] R6is lower alkyl;

[0190] R7is selected from the group consisting of hydrogen, hydroxy, trifluoromethyl and lower alkyl;

[0191] R8is selected from the group consisting of hydrogen and lower alkyl;

[0192] n is 0 or 1 ; and

[0193] m is 0, 1 or 2;

[0194] wherein said compound of Formula I or a pharmaceutically acceptable salt thereof is labeled with one or more positron emitting radionuclides.

[0195] In some embodiments, X is O.

[0196] In some embodiments, X is S.

[0197] In some embodiments, X is NR4.

[0198] In some embodiments, Y is CR4.

[0199] In some embodiments, R4 is hydrogen. In some embodiments, R4 is halogen. In some embodiments, R4 is bromo. In some embodiments, R4 is cyano. In some embodiments, R4 is lower alkyl. In some embodiments, R4 is methyl.

[0200] In some embodiments, Y is N.

[0201] In some embodiments, Z1, Z2, Z3 and Z4 are CH.

[0202] In some embodiments, Z1 is N and Z2, Z3 and Z4 are CH.

[0203] In some embodiments, Z2 is N and Z1, Z3 and Z4 are CH.

[0204] In some embodiments, Z2 and Z4 are N and Z1 and Z3 are CH.

[0205] In some embodiments, R1 is selected from the group consisting of phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-3-yl-1-oxide, pyridin-4-yl, 1H-pyrazol-4-yl, pyrazin-2-yl, pyridazin-3-yl, pyridazin-4-yl, pyrimidin-4-yl, pyrimidin-5-yl, 2,3-dihydropyridazin-3-one-6-yl, 1,2-dihydropyridin-2-one-5-yl, 1,2-dihydropyrazin-2-one-5-yl, 1,3-thiazol-5-yl, 5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl, 1H-imidazol-1-yl, 1-benzofuran-2-yl, 1-benzofuran-5-yl, 2,3-dihydro-1-benzofuran-2-yl, quinolinone-2-yl, and 5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl, each optionally substituted with one or two groups independently selected from the group consisting of halogen, lower alkyl, lower alkoxy, and optionally substituted amino.

[0206] In some embodiments, R1 is

[0207]

[0208] wherein

[0209] W is selected from CH, N and N(O);

[0210] p is selected from 0, 1 and 2;

[0211] R9, at each occurrence, is independently selected from cyano, halo, lower alkyl, halo- lower alkyl, lower alkyl substituted with -NR 10 R 11 , lower alkoxy, -C(O)NR 10 R 11 and -NR 10 R 11 ;

[0212] R 10 is selected from hydrogen and lower alkyl;

[0213] R 11 is selected from hydrogen, lower alkyl and -C(O)R 12 ; and

[0214] R 12 is selected from hydrogen and lower alkyl.

[0215] In some embodiments,

[0216] W is selected from CH and N;

[0217] p is selected from 0, 1 and 2;

[0218] R9, at each occurrence, is independently selected from cyano, halo, lower alkyl, lower alkoxy, -C(O)NR 10 R 11 and -NR 10 R 11 ;

[0219] R 10 is selected from hydrogen and lower alkyl;

[0220] R 11 is selected from hydrogen, lower alkyl and -C(O)R 12 ; and

[0221] R 12 is selected from hydrogen and lower alkyl.

[0222] In some embodiments, W is CH. In some embodiments, W is N. In some embodiments, W is N(O).

[0223] In some embodiments, p is 0.

[0224] In some embodiments, p is 1.

[0225] In some embodiments, R9is selected from cyano, halo, methyl and methoxy.

[0226] In some embodiments, R1is

[0227]

[0228] wherein

[0229] W1and W2are selected from CH and N, provided that at least one of W1and W2is CH;

[0230] p is selected from 0, 1 and 2; and

[0231] R9is, at each occurrence, independently selected from lower alkyl. In some embodiments, R1is 1H-pyrazol-4-yl optionally substituted with lower alkyl.

[0232] In some embodiments, L1is -O- and L2is -(CR7R8) m - or -(CR7R8) m - O-. In some embodiments, L1is -O- and L2is -(CR7R8) m -.

[0233] In some embodiments, L1is -O-, L2is -(CR7R8) m - or -(CR7R8) m - O- and R2is phenyl, pyridin-2-yl, pyridin-3-yl, pyrazin-2-yl, pyrimidin-5-yl, 1H- imidazol-4-yl, 1H-imidazol-2-yl or 1H-pyrazol-4-yl, each of which is optionally substituted with one or two groups independently selected from lower alkyl, hydroxy, lower alkoxy, lower alkoxy substituted with amino, (alkyl)amino, (dialkyl)amino or lower alkoxy, lower alkyl and lower alkyl substituted with hydroxy, lower alkoxy, amino, (alkyl)amino or (dialkyl)amino.

[0234] In some embodiments, L1is -O-, L2is -(CR7R8) m - and R2is phenyl, pyridin-2-yl, pyridin-3-yl, pyrazin-2-yl, pyrimidin-5-yl, 1H- imidazol-4-yl, 1H-imidazol-2-yl or 1H-pyrazol-4-yl, each of which is optionally substituted with one or two groups independently selected from lower alkyl, hydroxy, lower alkoxy, lower alkoxy substituted with amino, (alkyl)amino, (dialkyl)amino or lower alkoxy, lower alkyl and lower alkyl substituted with hydroxy, lower alkoxy, amino, (alkyl)amino or (dialkyl)amino.

[0235] In some embodiments, L1is -NR3- and L2is -C(O)- or -(CR7R8) m- In some embodiments, L1is -NR3- and L2is -C(O)-. In some embodiments, R3is hydrogen.

[0236] In some embodiments, L1is -NR3-, L2is -C(O)- or -(CR7R8) m - and R2is phenyl, pyridin-3-yl or pyrazin-2-yl, each optionally substituted with lower alkyl, hydroxy or lower alkoxy.

[0237] In some embodiments, L1is -NR3-, L2is -C(O)- or -(CR7R8) m - and R2is phenyl, pyridin-3-yl or pyrazin-2-yl, each optionally substituted with lower alkoxy.

[0238] In some embodiments, L1is -NR3-, L2is -C(O)- and R2is phenyl, pyridin-3-yl or pyrazin-2-yl, each optionally substituted with lower alkoxy.

[0239] In some embodiments, L1is -NR3- and L2is -(CR7R8) m wherein m is 1. In some embodiments, R3is hydrogen.

[0240] In some embodiments, L1is -NR3-, L2is -(CR7R8) m wherein m is 1, and R2is phenyl or phenyl substituted with lower alkoxy.

[0241] In some embodiments, L1is -NR3- and L2is -(CR7R8) m wherein m is 0. In some embodiments, R3is hydrogen.

[0242] In some embodiments, L1is -NR3-, L2is -(CR7R8) m wherein m is 0, and R2is phenyl, [l,2,4]triazolo[4,3-a]pyridin-3-yl, pyrimidin-4-yl or pyrimidin-2-yl, each optionally substituted with lower alkoxy.

[0243] In some embodiments, L1is absent and L2is absent.

[0244] In some embodiments, L1is absent, L2is absent and R2is phenyl, pyrimidin-2-yl, pyridazin-3-yl, pyrazin-2-yl, piperazin-1-yl, 1H-pyrazol-4-yl, 1,2,3,4-tetrahydroisoquinolin-1-one-2-yl, 2,3-dihydro-1H-isoindol-1-one-2-yl, 1,2-dihydroisoquinolin-1-one-2-yl, or 5H,6H,7H-pyrrolo[3,4-b]pyridin-7-one-2-yl, each of which is optionally substituted with one or two groups independently selected from 5-methoxypyrimidin-2-yl, hydroxy, and lower alkoxy.

[0245] In some embodiments, L1and L2together are -CH=CH- or -C≡C-.

[0246] In some embodiments, L1and L2together are -CH=CH- or -C≡C- and R2is phenyl or pyridin-3-yl, each of which is optionally substituted with one or two groups independently selected from hydroxy and lower alkoxy.

[0247] In some embodiments, L1and L2together are heterocyclyl ene. In some embodiments, L1and L2together are piperazin-1,4-diyl. In some embodiments, L1and L2together are heterocyclyl ene and R2is pyrimidin-2-yl optionally substituted with one or two groups independently selected from hydroxy and lower alkoxy. In some embodiments, L1and L2together are piperazin-1,4-diyl and R2is pyrimidin-2-yl optionally substituted with one or two groups independently selected from hydroxy and lower alkoxy.

[0248] In some embodiments, L1is -(CR7R8) m and L2is -NR3-, -C(O)-, or -O-.

[0249] In some embodiments, L1is -(CR7R8) m , L2is -NR3-, -C(O)-, or -O- and R2is pyridin-2-yl or pyridin-2-yl substituted with lower alkoxy.

[0250] In some embodiments, m is 1 and R7and R8are hydrogen at each occurrence.

[0251] In some embodiments, m is 2 and R7and R8are hydrogen at each occurrence.

[0252] In some embodiments, m is 1, R7is hydroxy, trifluoromethyl, or lower alkyl and R8is hydrogen.

[0253] In some embodiments, m is 2, R7in one occurrence is hydroxy, trifluoromethyl or lower alkyl, and R7in the other occurrence and R8at each occurrence is hydrogen.

[0254] The application also provides a compound of Formula I selected from:

[0255] 4-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]piperazine-1 -carboxylic acid tert-butyl ester;

[0256] 4-methoxy-N-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]benzamide;

[0257] 4-methoxy-N-[2-(pyridin-4-yl)-1,3-benzoxazol-5-yl]benzamide;

[0258] N-[(4-methoxyphenyl)methyl]-2-(pyridin-3-yl)-1,3-benzoxazol-5-amine;

[0259] 2-(3-bromopyridin-4-yl)-6-[2-(morpholin-4-yl)ethoxy]-1,3-benzothiazole;

[0260] 5-methoxy-N-[2-(3-methylphenyl)-1,3-benzoxazol-5-yl]pyridine-2-carboxamide;

[0261] 6-methoxy-N-[2-(3-methylphenyl)-1,3-benzoxazol-5-yl]pyridine-3-carboxamide;

[0262] 2-methoxy-N-[2-(3-methylphenyl)-1,3-benzoxazol-5-yl]pyrimidine-5-carboxamide;

[0263] 5-methoxy-N-[2-(3-methylphenyl)-1,3-benzoxazol-5-yl]pyrazine-2-carboxamide;

[0264] 4-methoxy-N-[2-(3-methylphenyl)-[1,3]oxazolo[5,4-b]pyridin-6-yl]benzamide;

[0265] 5-(4-methoxyphenyl)-2-(pyridin-3-yl)-1,3-benzoxazole;

[0266] N-(4-methoxyphenyl)-2-(pyridin-3-yl)-1,3-benzoxazol-5-amine;

[0267] 2-(pyridin-3-yl)-N-{[1,2,4]triazolo[4,3-a]pyridin-3-yl}-1,3-benzoxazol-5-amine;

[0268] 2-(pyridin-3-yl)-N-(pyrimidin-4-yl)-1,3-benzoxazol-5-amine;

[0269] 2-(pyridin-3-yl)-N-(pyrimidin-2-yl)-1,3-benzoxazol-5-amine;

[0270] 5-(5-methoxypyridin-2-yl)-2-(pyridin-3-yl)-1,3-benzoxazole;

[0271] 5-(2-methoxypyrimidin-5-yl)-2-(pyridin-3-yl)-1,3-benzoxazole;

[0272] 5-(5-methoxypyrimidin-2-yl)-2-(pyridin-3-yl)-1,3-benzoxazole;

[0273] 5-(6-methoxypyridazin-3-yl)-2-(pyridin-3-yl)-1,3-benzoxazole;

[0274] 5-(5-methoxypyrazin-2-yl)-2-(pyridin-3-yl)-1,3-benzoxazole;

[0275] 1 -methyl-4-[5-(pyrimidin-5-ylmethoxy)-1 -benzofuran-2-yl]-1 H-pyrazole-3- carbonitrile;

[0276] 4-[5-(pyrimidin-5-ylmethoxy)-1 -benzofuran-2-yl]pyridine-3-carbonitrile;

[0277] 4-{5-[(5-methoxypyridin-2-yl)methoxy]-1 -benzofuran-2-yl}pyridine-3- carbonitrile;

[0278] 4-{5-[(5-methoxypyridin-2-yl)methoxy]-1 -benzofuran-2-yl}pyridine;

[0279] 4-{5-[(1 -methyl-1 H-imidazol-4-yl)methoxy]-1 -benzofuran-2-yl}pyridine-3- carbonitrile;

[0280] 4-{5-[(1 -methyl-1 H-imidazol-2-yl)methoxy]-1 -benzofuran-2-yl}pyridine-3- carbonitrile;

[0281] 5-methoxy-2-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]-2,3-dihydro-1 H- isoindol-1 -one;

[0282] 3-{6-[(E)-2-(4-methoxyphenyl)vinyl]-[1,3]oxazolo[5,4-b]pyridin-2-yl}pyridine;

[0283] 4-[5-(pyridin-3-yloxy)-1-benzofuran-2-yl]pyridine-3-carbonitrile;

[0284] 6-methoxy-2-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]-1,2,3,4-tetrahydroisoquinolin-1-one;

[0285] dimethyl({3-[4-({[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]oxy}methyl)phenoxy]propyl})amine;

[0286] 5-[(1-methyl-1H-pyrazol-4-yl)methoxy]-2-(pyridin-3-yl)-1,3-benzoxazole;

[0287] 5-[(4-methoxyphenyl)methoxy]-2-(pyridin-3-yl)-1,3-benzoxazole;

[0288] 5-[(3-methoxyphenyl)methoxy]-2-(pyridin-3-yl)-1,3-benzoxazole;

[0289] 5-[(5-methoxypyridin-2-yl)methoxy]-2-(pyridin-3-yl)-1,3-benzoxazole;

[0290] 2-(pyridin-3-yl)-5-(pyridin-3-ylmethoxy)-1,3-benzoxazole;

[0291] 5-{5H,6H-imidazo[2,1-b][1,3]thiazol-3-ylmethoxy}-2-(pyridin-3-yl)-1,3-benzoxazole;

[0292] 1-(pyridin-2-yl)-2-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]ethan-1-ol;

[0293] 1-(pyridin-2-yl)-2-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]ethan-1-one;

[0294] 6-methoxy-2-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]-1,2-dihydroisoquinolin-1-one;

[0295] 2-(pyridin-3-yl)-N-[2,2,2-trifluoro-1-(4-methoxyphenyl)ethyl]-[1,3]oxazolo[5,4-b]pyridin-6- amine;

[0296] 3-{6-[2-(4-methoxyphenyl)ethynyl]-[1,3]oxazolo[5,4-b]pyridin-2-yl}pyridine;

[0297] 3-{6-[2-(4-methoxyphenyl)ethynyl]-[1,3]oxazolo[5,4-b]pyridin-2-yl}pyridine;3-{6-[(Z)-2-(4-methoxyphenyl)ethenyl]-[1,3]oxazolo[5,4-b]pyridin-2-yl}pyridine;

[0298] 5-methoxy-2-[2-(pyridin-3-yl)-[1,3]oxazolo[5,4-b]pyridin-6-yl]-2,3-dihydro-1H- isoindol-1-one;

[0299] 5-[(5-methoxypyrazin-2-yl)methoxy]-2-(pyridin-3-yl)-1,3-benzoxazole;

[0300] 3-methoxy-6-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]-5H,6H,7H-pyrrolo[3,4-b]pyridin- 7-one;

[0301] 2-(pyridin-3-yl)-6-(pyridin-3-ylmethoxy)-1,3-benzoxazole;

[0302] 3-{6-[2-(pyridin-3-yl)ethynyl]-[1,3]oxazolo[5,4-b]pyridin-2-yl}pyridine;

[0303] 5-{[(5-methoxypyridin-2-yl)oxy]methyl}-2-(pyridin-3-yl)-1,3-benzoxazole;

[0304] 4-[5-(pyridin-3-ylmethoxy)-1-benzofuran-2-yl]pyridine-3-carbonitrile;

[0305] 4-{5-[(1-methyl-1H-pyrazol-4-yl)methoxy]-1-benzofuran-2-yl}pyridine-3-carbonitrile;

[0306] 3-[5-(pyridin-3-ylmethoxy)-1-benzofuran-2-yl]pyridine-4-carbonitrile;

[0307] 3-{5-[(1-methyl-1H-pyrazol-4-yl)methoxy]-1-benzofuran-2-yl}pyridine-4-carbonitrile;

[0308] 3-{6-[1-(5-methoxypyridin-2-yl)ethoxy]-[1,3]oxazolo[5,4-b]pyridin-2-yl}pyridine;

[0309] 4-{5-[(5-methoxypyrazin-2-yl)methoxy]-1-benzofuran-2-yl}pyridine-3-carbonitrile;

[0310] 6-({[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]oxy}methyl)pyridin-3-ol;

[0311] 5-{[5-(prop-2-en-1-yloxy)pyrazin-2-yl]methoxy}-2-(pyridin-3-yl)-1,3-benzoxazole;

[0312] 5-({[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]oxy}methyl)-1,2-dihydropyrazin-2-one;

[0313] 1-methyl-5-({[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]oxy}methyl)-1,2-dihydropyrazin-2-one;

[0314] 5-[4-(5-methoxypyrimidin-2-yl)piperazin-1-yl]-2-(pyridin-3-yl)-1,3-benzoxazole;

[0315] 3-{6-[(5-methoxypyridin-2-yl)methoxy]-[1,3]oxazolo[5,4-b]pyridin-2-yl}pyridine;

[0316] 5-(1-methyl-1H-pyrazol-4-yl)-2-(pyridin-3-yl)-1,3-benzoxazole;

[0317] 3-{6-[(6-methoxypyridin-3-yl)methoxy]-[1,3]oxazolo[5,4-b]pyridin-2-yl}pyridine;

[0318] 5-[(5-methoxypyridin-2-yl)methoxy]-2-(pyridin-4-yl)-1,3-benzoxazole;

[0319] [(3-{5-[(5-methoxypyridin-2-yl)methoxy]-1,3-benzoxazol-2-yl}phenyl)methyl]dimethylamine;

[0320] 5-[(5-methoxypyridin-2-yl)methoxy]-2-(1-methyl-1H-pyrazol-4-yl)-1,3-benzoxazole;

[0321] 5-[(5-methoxypyridin-2-yl)methoxy]-2-(pyrazin-2-yl)-1,3-benzoxazole;

[0322] 5-[(5-methoxypyridin-2-yl)methoxy]-2-(1-methylpiperidin-4-yl)-1,3-benzoxazole;

[0323] 5-[(5-methoxypyridin-2-yl)methoxy]-2-(1,3-thiazol-5-yl)-1,3-benzoxazole;

[0324] 5-[2-(pyridin-2-yloxy)ethoxy]-2-(pyridin-3-yl)-1,3-benzoxazole;

[0325] 4-[5-(1H-pyrazol-4-ylmethoxy)-1-benzofuran-2-yl]pyridine-3-carbonitrile;

[0326] 3-{[(2-{5H,6H-imidazo[2,1-b][1,3]thiazol-3-yl}-1-benzofuran-5-yl)oxy]methyl}pyridine;

[0327] 2-(3-fluoroazetidin-1-yl)-5-[(5-methoxypyridin-2-yl)methoxy]-1,3-benzoxazole;

[0328] 2-{3H,4H,5H,6H,7H-imidazo[4,5-c]pyridin-5-yl}-5-[(5-methoxypyridin-2-yl)methoxy]-1,3-benzoxazole;

[0329] 5-[(5-methoxypyridin-2-yl)methoxy]-2-{2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridin-5-yl}-1,3-benzoxazole;

[0330] 2-{5H,6H,7H,8H-imidazo[1,5-a]pyrazin-7-yl}-5-[(5-methoxypyridin-2-yl)methoxy]-1,3-benzoxazole;

[0331] 5-[(5-methoxypyridin-2-yl)methoxy]-2-{5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl}-1,3-benzoxazole;

[0332] 7-{5-[(5-methoxypyridin-2-yl)methoxy]-1,3-benzoxazol-2-yl}-5,6,7,8-tetrahydro-1,7-naphthyridine;

[0333] 2-(1H-imidazol-1-yl)-5-[(5-methoxypyridin-2-yl)methoxy]-1,3-benzoxazole;

[0334] 2-{5H,6H,7H,8H-imidazo[1,2-a]pyrazin-7-yl}-5-[(5-methoxypyridin-2-yl)methoxy]-1,3-benzoxazole;

[0335] 4-(5-{[1-(2-methoxyethyl)-1H-pyrazol-4-yl]methoxy}-1-benzofuran-2-yl)pyridine-3-carbonitrile;

[0336] 2-[5-(2-methoxyethoxy)pyridin-3-yl]-5-[(5-methoxypyridin-2-yl)methoxy]-1,3-benzoxazole;

[0337] N-(5-{5-[(5-methoxypyridin-2-yl)methoxy]-1,3-benzoxazol-2-yl}pyridin-2- yl)acetamide;

[0338] 5-{5-[(5-methoxypyridin-2-yl)methoxy]-1,3-benzoxazol-2-yl}pyridin-2-amine;

[0339] Methyl({[4-({[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]oxy}methyl)phenoxy]methyl})amine;

[0340] 4-(5-{[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]methoxy}-1-benzofuran-2-yl)pyridine-3- carbonitrile;

[0341] Dimethyl({2-[4-({[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]oxy}methyl)phenoxy]ethyl})amine;

[0342] 5-{[5-(2-methoxyethoxy)pyridin-2-yl]methoxy}-2-(pyridin-3-yl)-1,3-benzoxazole;

[0343] 4-[5-({1-[2-(dimethylamino)ethyl]-1H-pyrazol-4-yl}methoxy)-1-benzofuran-2-yl]pyridine- 3-carbonitrile;

[0344] 5-{5-[(5-methoxypyridin-2-yl)methoxy]-1,3-benzoxazol-2-yl}-N-methylpyridin-2-amine;

[0345] 3-{[(2-{2-bromo-5H,6H-imidazo[2,1-b][1,3]thiazol-3-yl}-1-benzofuran-5-yl)oxy]methyl}pyridine;

[0346] 5-[(5-methoxypyrazin-2-yl)methoxy]-1-methyl-2-(pyridin-3-yl)-1H-1,3-benzodiazole;

[0347] 6-[(5-methoxypyrazin-2-yl)methoxy]-1-methyl-2-(pyridin-3-yl)-1H-1,3-benzodiazole;

[0348] 5-[(5-methoxypyrazin-2-yl)methoxy]-2-(pyridin-3-yl)-1H-1,3-benzodiazole;

[0349] 5-[(5-methoxypyridin-2-yl)methoxy]-2-(piperazin-1-yl)-1,3-benzoxazole;

[0350] N-methyl-6-({[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]oxy}methyl)pyridin-3- amine;

[0351] 3-[5-(pyridin-3-ylmethoxy)-1-benzofuran-2-yl]-5H,6H-imidazo[2,1- b][1,3]thiazole-2-carbonitrile;

[0352] 5-{5-[(5-methoxypyridin-2-yl)methoxy]-1,3-benzoxazol-2-yl}-N-methylpyridine- 2-carboxamide;

[0353] 5-[(5-methoxypyridin-2-yl)methoxy]-2-(1-methyl-1H-imidazol-4-yl)-1,3- benzoxazole;

[0354] 5-methoxy-N-{[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]methyl}pyridin-2-amine;

[0355] 4-(5-{5H,6H-imidazo[2,1-b][1,3]thiazol-3-ylmethoxy}-1-benzofuran-2-yl)pyridine- 3-carbonitrile;

[0356] 5-({5-[2-(morpholin-4-yl)ethoxy]pyridin-2-yl}methoxy)-2-(pyridin-3-yl)-1,3- benzoxazole;

[0357] 2-bromo-6-{5-[(5-methoxypyridin-2-yl)methoxy]-1-benzofuran-2-yl}benzonitrile;

[0358] acetic acid 4-{[2-(4-chlorophenyl)-1,3-benzoxazol-5-yl]carbamoyl}phenyl ester;

[0359] N-(2-phenyl-1,3-benzoxazol-5-yl)benzamide;

[0360] 4-methoxy-N-[2-(3-methylphenyl)-1,3-benzoxazol-5-yl]benzamide;

[0361] 2-methoxy-N-[2-(4-methoxyphenyl)-1,3-benzoxazol-5-yl]benzamide;

[0362] 4-methoxy-N-[2-(4-methoxyphenyl)-1,3-benzoxazol-5-yl]benzamide;

[0363] 3-methoxy-N-[2-(4-methoxyphenyl)-1,3-benzoxazol-5-yl]benzamide;

[0364] 3-{5-[(5-methoxy-pyridin-2-yl)methoxy]-1,3-benzoxazol-2-yl}pyridin-1-ium-1-olate;

[0365] 2-phenoxy-N-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]acetamide;

[0366] N-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]-1-benzofuran-2-carboxamide;

[0367] N-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]-6-(trifluoromethyl)pyridine-3-carboxamide;

[0368] N-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]quinoxaline-2-carboxamide;

[0369] 6-phenoxy-N-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]pyridine-3-carboxamide;

[0370] N-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]-2H-1,3-benzodioxole-5-carboxamide;

[0371] 3-(benzyloxy)-N-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]benzamide;

[0372] 3-phenoxy-N-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]benzamide;

[0373] N-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]quinoline-2-carboxamide;

[0374] N-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]-2,3-dihydro-1-benzofuran-2-carboxamide;

[0375] 5-methyl-N-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]pyridine-3-carboxamide;

[0376] N-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]quinoxaline-6-carboxamide;

[0377] (2E)-3-(4-methoxyphenyl)-N-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]prop-2-enamide;

[0378] 5-methoxy-N-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]pyridine-2-carboxamide;

[0379] 3-cyano-N-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]benzamide;

[0380] 4-(methylthio)-N-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]benzamide;

[0381] N-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]benzylcarbamate;

[0382] 5-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]pyrazin-2-ol;

[0383] 5-[(5-methoxypyridin-2-yl)methoxy]-2-(pyrimidin-5-yl)-1,3-benzoxazole;

[0384] 2-(2,3-dihydro-1-benzofuran-2-yl)-5-[(5-methoxypyridin-2-yl)methoxy]-1,3-benzoxazole;

[0385] 2-[(2R)-2,3-dihydro-1-benzofuran-2-yl]-5-[(5-methoxypyridin-2-yl)methoxy]-1,3-benzoxazole;

[0386] 2-[(2S)-2,3-dihydro-1-benzofuran-2-yl]-5-[(5-methoxypyridin-2-yl)methoxy]-1,3-benzoxazole;

[0387] 5-[5-(2-methoxyethoxy)pyrimidin-2-yl]-2-(pyridin-3-yl)-1,3-benzoxazole;

[0388] 5-[(5-methoxypyridin-2-yl)methoxy]-2-(5-methylpyridin-3-yl)-1,3-benzoxazole;

[0389] 5-[(5-methoxypyridin-2-yl)methoxy]-2-(2-methylpyridin-4-yl)-1,3-benzoxazole;

[0390] 5-[(5-methoxypyridin-2-yl)methoxy]-2-(3-phenoxyphenyl)-1,3-benzoxazole;

[0391] 6-{5-[(5-methoxypyridin-2-yl)methoxy]-1,3-benzoxazol-2-yl}-2-methyl-2,3-dihydropyridazin-3-one;

[0392] 5-[(5-methoxypyridin-2-yl)methoxy]-2-(pyridazin-3-yl)-1,3-benzoxazole;

[0393] 5-[(5-methoxypyridin-2-yl)methoxy]-2-(pyridin-3-yl)-1,3-benzoxazole;

[0394] 5-{5-[(5-methoxypyridin-2-yl)methoxy]-1,3-benzoxazol-2-yl}-1,2-dihydropyridin-2- one;

[0395] 5-{5-[(5-methoxypyridin-2-yl)methoxy]-1,3-benzoxazol-2-yl}-1 -methyl-1,2-dihydropyridin- 2-one;

[0396] 5-phenyl-N-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]-1,3,4-oxadiazole-2-carboxamide;

[0397] 5-[(5-methoxypyridin-2-yl)methoxy]-2-(pyrimidin-4-yl)-1,3-benzoxazole;

[0398] 5-[(5-bromopyridin-2-yl)methoxy]-2-(pyridin-3-yl)-1,3-benzoxazole;

[0399] 5-(pyridin-2-ylmethoxy)-2-(pyridin-3-yl)-1,3-benzoxazole;

[0400] N-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]-1 -benzofuran-5-carboxamide;

[0401] 2-phenyl-N-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]pyrimidine-5-carboxamide;

[0402] N-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]-4-(pyrimidin-2-yl)benzamide;

[0403] 1 -methyl-N-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]-1 H-pyrazole-4-carboxamide;

[0404] 4-[(6-methylpyrazin-2-yl)oxy]-N-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]benzamide;

[0405] 4-(phenoxymethyl)-N-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]benzamide;

[0406] 2-phenoxy-N-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]pyridine-3-carboxamide;

[0407] 4-cyano-N-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]benzamide;

[0408] 6-methoxy-N-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]pyridine-2-carboxamide;

[0409] 2-methyl-N-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]pyridine-4-carboxamide;

[0410] 3-methoxy-N-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]pyridine-2-carboxamide;

[0411] 4-methoxy-N-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]pyridine-2-carboxamide;

[0412] 4-hydroxy-N-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]pyridine-2-carboxamide;

[0413] 3-methoxy-N-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]-1,2-oxazole-5-carboxamide;

[0414] 5-methoxy-N-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]pyridine-3-carboxamide;

[0415] 6-({[2-(1-methyl-1H-pyrazol-4-yl)-1,3-benzoxazol-5-yl]oxy}methyl)pyridin-3-ol;

[0416] 5-[(5-methoxypyrazin-2-yl)methoxy]-2-(1-methyl-1H-pyrazol-4-yl)-1,3-benzoxazole;

[0417] 2-methoxy-5-({[2-(1-methyl-1H-pyrazol-4-yl)-[1,3]oxazolo[5,4-b]pyridin-6-yl]oxy}methyl)pyrazine;

[0418] 3-{6-[(5-bromopyridin-2-yl)methoxy]-[1,3]oxazolo[5,4-b]pyridin-2-yl}pyridine;

[0419] 3-methoxy-6-({[2-(pyridin-3-yl)-[1,3]oxazolo[5,4-b]pyridin-6-yl]oxy}methyl)pyridazine;

[0420] 3-{5-[(5-methoxypyridin-2-yl)methoxy]-1,3-benzoxazol-2-yl}benzonitrile;

[0421] 4-{5-[(5-methoxypyridin-2-yl)methoxy]-1,3-benzoxazol-2-yl}benzonitrile;

[0422] 5-(1 -methyl- 1 H-pyrazol-4-yl)-2-({[2-(pyridin-3-yl)- [1,3]oxazolo[5,4-b]pyridin-6-yl]oxy}methyl)pyridine;

[0423] 3-methoxy-5-({[2-(pyridin-3-yl)-[1,3]oxazolo[5,4-b]pyridin-6-yl]oxy}methyl)pyridine;

[0424] 4-methoxy-2-({[2-(pyridin-3-yl)-[1,3]oxazolo[5,4-b]pyridin-6-yl]oxy}methyl)pyridine;

[0425] 2-({[2-(1 -methyl- 1 H-pyrazol-4-yl)-[1,3]oxazolo[5,4-b]pyridin-6-yl]oxy}methyl)pyrazine;

[0426] [(3-{5-[(5-methoxypyridin-2-yl)methoxy]-1,3-benzoxazol-2-yl}phenyl)methyl](methyl)amine;

[0427] N-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]carbamic acid (5-methoxypyridin-2-yl)methyl ester;

[0428] 2-(5-methoxypyridin-2-yl)-5-[(5-methoxypyridin-2-yl)methoxy]-1,3-benzoxazole;

[0429] 2-(1 -benzofuran-2-yl)-5-[(5-methoxypyridin-2-yl)methoxy]-1,3-benzoxazole;

[0430] 5-[(5-methoxypyridin-2-yl)methoxy]-2-[6-(trifluoromethyl)pyridin-3-yl]-1,3-benzoxazole;

[0431] 2-(1 -benzofuran-5-yl)-5-[(5-methoxypyridin-2-yl)methoxy]-1,3-benzoxazole;

[0432] 2-{5-[(5-methoxypyridin-2-yl)methoxy]-1,3-benzoxazol-2-yl}quinoline;

[0433] 2-[3-(benzyloxy)phenyl]-5-[(5-methoxypyridin-2-yl)methoxy]-1,3-benzoxazole;

[0434] 5-[(5-methoxy-pyridin-2-yl)methoxy]-2-[4-(pyrimidin-2-yl)phenyl]-1,3-benzoxazole;

[0435] 2-[(E)-2-(4-methoxyphenyl)ethenyl]-5-[(5-methoxy-pyridin-2-yl)methoxy]-1,3-benzoxazole;

[0436] 5-methoxy-2-({[2-(pyridin-3-yl)-[1,3]oxazolo[5,4-b]pyridin-6-yl]oxy}methyl)pyrimidine;

[0437] 6-({[2-(1-methyl-1H-pyrazol-4-yl)-[1,3]oxazolo[5,4-b]pyridin-6-yl]oxy}methyl)pyridin-3-amine;

[0438] 5-{5-[(5-hydroxy-pyridin-2-yl)methoxy]-1,3-benzoxazol-2-yl}-N-methyl-pyridine-2-carboxamide;

[0439] 6-{6-[(5-methoxy-pyridin-2-yl)methoxy]-[1,3]oxazolo[5,4-b]pyridin-2-yl}-2-methyl-2,3-dihydro-pyridazin-3-one;

[0440] 2-methyl-6-({[2-(pyridin-3-yl)-[1,3]oxazolo[5,4-b]pyridin-6-yl]oxy}methyl)-2,3-dihydro-pyridazin-3-one;

[0441] 2-{6-[(5-methoxy-pyridin-2-yl)methoxy]-[1,3]oxazolo[5,4-b]pyridin-2-yl}pyrazine;

[0442] 5-{6-[(5-methoxy-pyridin-2-yl)methoxy]-[1,3]oxazolo[5,4-b]pyridin-2-yl}-N-methyl-pyridine-2-carboxamide;

[0443] 5-{5-[(5-methoxy-pyridin-2-yl)methoxy]-1,3-benzoxazol-2-yl}-1-methyl-1,2-dihydropyrazin-2-one;

[0444] 6-(6-{[5-(2-fluoroethoxy)-pyridin-2-yl]methoxy}-[1,3]oxazolo[5,4-b]pyridin-2-yl)-2-methyl-2,3-dihydro-pyridazin-3-one;

[0445] 5-methoxy-2-({[2-(pyridin-3-yl)-[1,3]oxazolo[5,4-b]pyridin-6-yl]oxy}methyl)pyridin-1-ium-1-olate;

[0446] 3-{6-[(5-methoxypyridin-1 -yl)methoxy]-[1,3]oxazolo[5,4-b]pyridin-2-yl}pyridin-1 -ium-1 -olate;

[0447] 5-{5-[(5-methoxypyridin-2-yl)methoxy]-1,3-benzoxazol-2-yl}-2-(methylcarbamoyl)pyridin-1 -ium-1 -olate;

[0448] N-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]carbamic acid (5-hydroxypyridin-2-yl)methyl ester;

[0449] 5-methoxy-N-[2-(1 -methyl-6-oxo-1,6-dihydropyridazin-3-yl)-1,3-benzoxazol-5-yl]pyridine-2-carboxamide;

[0450] 5-methoxy-N-[2-(1 -methyl-6-oxo-1,6-dihydropyridazin-3-yl)-1,3-benzoxazol-5-yl]pyridine-3-carboxamide;

[0451] 4-methoxy-N-[2-(1 -methyl-6-oxo-1,6-dihydropyridazin-3-yl)-1,3-benzoxazol-5-yl]pyridine-2-carboxamide;

[0452] 1 -methyl-N-[2-(1 -methyl-6-oxo-1,6-dihydropyridazin-3-yl)-1,3-benzoxazol-5-yl]-6-oxo-1,6-dihydropyridazin-3-carboxamide;

[0453] [(5-{5-[(5-methoxypyridin-2-yl)methoxy]-1,3-benzoxazol-2-yl}pyridin-3-yl)methyl](methyl)amine;

[0454] 6-{5-[(5-hydroxypyridin-2-yl)methoxy]-1,3-benzoxazol-2-yl}-2-methyl-2,3-dihydropyridazin-3-one; and

[0455] N-(5-methoxypyridin-3-yl)-2-(pyridin-3-yl)-1,3-benzoxazole-5-carboxamide;

[0456] or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I or a pharmaceutically acceptable salt thereof is labeled with one or more positron emitting radionuclides.

[0457] The present application also provides a compound of Formula I selected from:

[0458] 4-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]piperazine-1 -carboxylic acid tert-butyl ester;

[0459] 4-methoxy-N-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]benzamide;

[0460] 4-methoxy-N-[2-(pyridin-4-yl)-1,3-benzoxazol-5-yl]benzamide;

[0461] N-[(4-methoxyphenyl)methyl]-2-(pyridin-3-yl)-1,3-benzoxazol-5-amine;

[0462] 2-(3-bromopyridin-4-yl)-6-[2-(morpholin-4-yl)ethoxy]-1,3-benzothiazole;

[0463] 5-methoxy-N-[2-(3-methylphenyl)-1,3-benzoxazol-5-yl]pyridine-2-carboxamide;

[0464] 6-methoxy-N-[2-(3-methylphenyl)-1,3-benzoxazol-5-yl]pyridine-3-carboxamide;

[0465] 2-methoxy-N-[2-(3-methylphenyl)-1,3-benzoxazol-5-yl]pyrimidine-5-carboxamide;

[0466] 5-methoxy-N-[2-(3-methylphenyl)-1,3-benzoxazol-5-yl]pyrazine-2-carboxamide;

[0467] 4-methoxy-N-[2-(3-methylphenyl)-[1,3]oxazolo[5,4-b]pyridin-6-yl]benzamide;

[0468] 5-(4-methoxyphenyl)-2-(pyridin-3-yl)-1,3-benzoxazole;

[0469] N-(4-methoxyphenyl)-2-(pyridin-3-yl)-1,3-benzoxazol-5-amine;

[0470] 2-(pyridin-3-yl)-N-{[1,2,4]triazolo[4,3-a]pyridin-3-yl}-1,3-benzoxazol-5-amine;

[0471] 2-(pyridin-3-yl)-N-(pyrimidin-4-yl)-1,3-benzoxazol-5-amine;

[0472] 2-(pyridin-3-yl)-N-(pyrimidin-2-yl)-1,3-benzoxazol-5-amine;

[0473] 5-(5-methoxypyridin-2-yl)-2-(pyridin-3-yl)-1,3-benzoxazole;

[0474] 5-(2-methoxy-pyrimidin-5-yl)-2-(pyridin-3-yl)-1,3-benzoxazole;

[0475] 5-(5-methoxy-pyrimidin-2-yl)-2-(pyridin-3-yl)-1,3-benzoxazole;

[0476] 5-(6-methoxy-pyridazin-3-yl)-2-(pyridin-3-yl)-1,3-benzoxazole;

[0477] 5-(5-methoxy-pyrazin-2-yl)-2-(pyridin-3-yl)-1,3-benzoxazole;

[0478] 1 -methyl-4-[5-(pyrimidin-5-ylmethoxy)-1 -benzofuran-2-yl]-1 H-pyrazole-3-carbonitrile;

[0479] 4-[5-(pyrimidin-5-ylmethoxy)-1 -benzofuran-2-yl]pyridine-3-carbonitrile;

[0480] 4-{5-[(5-methoxypyridin-2-yl)methoxy]-1 -benzofuran-2-yl}pyridine-3-carbonitrile;

[0481] 4-{5-[(5-methoxypyridin-2-yl)methoxy]-1 -benzofuran-2-yl}pyridine;

[0482] 4-{5-[(1 -methyl-1 H-imidazol-4-yl)methoxy]-1 -benzofuran-2-yl}pyridine-3-carbonitrile;

[0483] 4-{5-[(1 -methyl-1 H-imidazol-2-yl)methoxy]-1 -benzofuran-2-yl}pyridine-3-carbonitrile;

[0484] 5-methoxy-2-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]-2,3-dihydro-1 H-isoindol-1 -one;

[0485] 3-{6-[(E)-2-(4-methoxyphenyl)vinyl]-[1,3]oxazolo[5,4-b]pyridin-2-yl}pyridine;

[0486] 4-[5-(pyridin-3-yloxy)-1 -benzofuran-2-yl]pyridine-3-carbonitrile;

[0487] 6-methoxy-2-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]-1,2,3,4-tetrahydroisoquinolin-1 -one;

[0488] Dimethyl({3-[4-({[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]oxy}methyl)phenoxy]propyl})amine;

[0489] 5-[(1-Methyl-1H-pyrazol-4-yl)methoxy]-2-(pyridin-3-yl)-1,3-benzoxazole;

[0490] 5-[(4-Methoxyphenyl)methoxy]-2-(pyridin-3-yl)-1,3-benzoxazole;

[0491] 5-[(3-Methoxyphenyl)methoxy]-2-(pyridin-3-yl)-1,3-benzoxazole;

[0492] 5-[(5-Methoxypyridin-2-yl)methoxy]-2-(pyridin-3-yl)-1,3-benzoxazole;

[0493] 2-(Pyridin-3-yl)-5-(pyridin-3-ylmethoxy)-1,3-benzoxazole;

[0494] 5-{5H,6H-Imidazo[2,1-b][1,3]thiazol-3-ylmethoxy}-2-(pyridin-3-yl)-1,3-benzoxazole;

[0495] 1-(Pyridin-2-yl)-2-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]ethan-1-ol;

[0496] 1-(Pyridin-2-yl)-2-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]ethan-1-one;

[0497] 6-Methoxy-2-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]-1,2-dihydroisoquinolin-1-one;

[0498] 2-(Pyridin-3-yl)-N-[2,2,2-trifluoro-1-(4-methoxyphenyl)ethyl]-[1,3]oxazolo[5,4-b]pyridin-6- amine;

[0499] 3-{6-[2-(4-Methoxyphenyl)ethynyl]-[1,3]oxazolo[5,4-b]pyridin-2-yl}pyridine;

[0500] 3-{6-[(Z)-2-(4-Methoxyphenyl)vinyl]-[1,3]oxazolo[5,4-b]pyridin-2-yl}pyridine;

[0501] 5-Methoxy-2-[2-(pyridin-3-yl)-[1,3]oxazolo[5,4-b]pyridin-6-yl]-2,3-dihydro-1H-isoindol-1-one;

[0502] 5-[(5-methoxypyrazin-2-yl)methoxy]-2-(pyridin-3-yl)-1,3-benzoxazole;

[0503] 3-methoxy-6-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]-5H,6H,7H-pyrrolo[3,4-b]pyridin-7-one;

[0504] 2-(pyridin-3-yl)-6-(pyridin-3-ylmethoxy)-1,3-benzoxazole;

[0505] 3-{6-[2-(pyridin-3-yl)ethynyl]-[1,3]oxazolo[5,4-b]pyridin-2-yl}pyridine;

[0506] 5-{[(5-methoxypyridin-2-yl)oxy]methyl}-2-(pyridin-3-yl)-1,3-benzoxazole;

[0507] 4-[5-(pyridin-3-ylmethoxy)-1-benzofuran-2-yl]pyridine-3-carbonitrile;

[0508] 4-{5-[(1-methyl-1H-pyrazol-4-yl)methoxy]-1-benzofuran-2-yl}pyridine-3-carbonitrile;

[0509] 3-[5-(pyridin-3-ylmethoxy)-1-benzofuran-2-yl]pyridine-4-carbonitrile;

[0510] 3-{5-[(1-methyl-1H-pyrazol-4-yl)methoxy]-1-benzofuran-2-yl}pyridine-4-carbonitrile;

[0511] 3-{6-[1-(5-methoxypyridin-2-yl)ethoxy]-[1,3]oxazolo[5,4-b]pyridin-2-yl}pyridine;

[0512] 4-{5-[(5-methoxypyrazin-2-yl)methoxy]-1-benzofuran-2-yl}pyridine-3-carbonitrile;

[0513] 6-({[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]oxy}methyl)pyridin-3-ol;

[0514] 5-{[5-(prop-2-en-1-yloxy)pyrazin-2-yl]methoxy}-2-(pyridin-3-yl)-1,3-benzoxazole;

[0515] 5-({[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]oxy}methyl)-1,2-dihydropyrazin-2-one;

[0516] 1 -Methyl-5-({[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]oxy}methyl)-1,2-dihydropyrazin- 2-one;

[0517] 5-[4-(5-Methoxy-pyrimidin-2-yl)piperazin-1-yl]-2-(pyridin-3-yl)-1,3-benzoxazole;

[0518] 3-{6-[(5-Methoxy-pyridin-2-yl)methoxy]-[1,3]oxazolo[5,4-b]pyridin-2-yl}pyridine;

[0519] 5-(1 -Methyl-1 H-pyrazol-4-yl)-2-(pyridin-3-yl)-1,3-benzoxazole;

[0520] 3-{6-[(6-Methoxy-pyridin-3-yl)methoxy]-[1,3]oxazolo[5,4-b]pyridin-2-yl}pyridine;

[0521] 5-[(5-Methoxy-pyridin-2-yl)methoxy]-2-(pyridin-4-yl)-1,3-benzoxazole;

[0522] [(3-{5-[(5-Methoxy-pyridin-2-yl)methoxy]-1,3-benzoxazol-2-yl}phenyl)methyl]dimethylamine;

[0523] 5-[(5-Methoxy-pyridin-2-yl)methoxy]-2-(1 -methyl-1 H-pyrazol-4-yl)-1,3-benzoxazole;

[0524] 5-[(5-Methoxy-pyridin-2-yl)methoxy]-2-(pyrazin-2-yl)-1,3-benzoxazole;

[0525] 5-[(5-Methoxy-pyridin-2-yl)methoxy]-2-(1 -methylpiperidin-4-yl)-1,3-benzoxazole;

[0526] 5-[(5-Methoxy-pyridin-2-yl)methoxy]-2-(1,3-thiazol-5-yl)-1,3-benzoxazole;

[0527] 5-[2-(Pyridin-2-yloxy)ethoxy]-2-(pyridin-3-yl)-1,3-benzoxazole;

[0528] 4-[5-(1 H-Pyrazol-4-ylmethoxy)-1 -benzofuran-2-yl]pyridine-3-carbonitrile;

[0529] 3-{[(2-{5H,6H-Imidazo[2,1-b][1,3]thiazol-3-yl}-1 -benzofuran-5-yl)oxy]methyl}pyridine;

[0530] 2-(3-fluoroazetidin-l-yl)-5-[(5-methoxypyridin-2-yl)methoxy]-l,3-benzoxazole;

[0531] 2-{3H,4H,5H,6H,7H-imidazo[4,5-c]pyridin-5-yl}-5-[(5-methoxypyridin-2-yl)methoxy]-l,3-benzoxazole;

[0532] 5-[(5-methoxypyridin-2-yl)methoxy]-2-{2H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridin-5-yl}-l,3-benzoxazole;

[0533] 2-{5H,6H,7H,8H-imidazo[l,5-a]pyrazin-7-yl}-5-[(5-methoxypyridin-2-yl)methoxy]-l,3-benzoxazole;

[0534] 5-[(5-methoxypyridin-2-yl)methoxy]-2-{5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl}-l,3-benzoxazole;

[0535] 7-{5-[(5-methoxypyridin-2-yl)methoxy]-l,3-benzoxazol-2-yl}-5,6,7,8-tetrahydro-l,7-naphthyridine;

[0536] 2-(lH-imidazol-l-yl)-5-[(5-methoxypyridin-2-yl)methoxy]-l,3-benzoxazole;

[0537] 2-{5H,6H,7H,8H-imidazo[l,2-a]pyrazin-7-yl}-5-[(5-methoxypyridin-2-yl)methoxy]-l,3-benzoxazole;

[0538] 4-(5-{[l-(2-methoxyethyl)-lH-pyrazol-4-yl]methoxy}-l-benzofuran-2-yl)pyridine-3-carbonitrile;

[0539] 2-[5-(2-methoxyethoxy)pyridin-3-yl]-5-[(5-methoxypyridin-2-yl)methoxy]-l,3-benzoxazole;

[0540] N-(5-{5-[(5-methoxypyridin-2-yl)methoxy]-l,3-benzoxazol-2-yl}pyridin-2-yl)acetamide;

[0541] 5-{5-[(5-methoxypyridin-2-yl)methoxy]-l,3-benzoxazol-2-yl}pyridin-2-amine;

[0542] Methyl({[4-({[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]oxy}methyl)phenyl]methyl})amine;

[0543] 4-(5-{[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]methoxy}-1-benzofuran-2-yl)pyridine-3- carbonitrile;

[0544] Dimethyl({2-[4-({[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]oxy}methyl)phenoxy]ethyl})amine;

[0545] 5-{[5-(2-methoxyethoxy)pyridin-2-yl]methoxy}-2-(pyridin-3-yl)-1,3-benzoxazole;

[0546] 4-[5-({1-[2-(dimethylamino)ethyl]-1H-pyrazol-4-yl}methoxy)-1-benzofuran-2-yl]pyridine- 3-carbonitrile;

[0547] 5-{5-[(5-methoxypyridin-2-yl)methoxy]-1,3-benzoxazol-2-yl}-N-methylpyridin-2-amine;

[0548] 3-{[(2-{2-bromo-5H,6H-imidazo[2,1-b][1,3]thiazol-3-yl}-1-benzofuran-5-yl)oxy]methyl}pyridine;

[0549] 5-[(5-methoxypyrazin-2-yl)methoxy]-1-methyl-2-(pyridin-3-yl)-1H-1,3-benzodiazole;

[0550] 6-[(5-methoxypyrazin-2-yl)methoxy]-1-methyl-2-(pyridin-3-yl)-1H-1,3-benzodiazole;

[0551] 5-[(5-methoxypyrazin-2-yl)methoxy]-2-(pyridin-3-yl)-1H-1,3-benzodiazole;

[0552] 5-[(5-methoxypyridin-2-yl)methoxy]-2-(piperazin-1-yl)-1,3-benzoxazole;

[0553] N-methyl-6-({[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]oxy}methyl)pyridin-3-amine;

[0554] 3-[5-(pyridin-3-ylmethoxy)-1-benzofuran-2-yl]-5H,6H-imidazo[2,1-b][1,3]thiazole-2- carbonitrile;

[0555] 5-{5-[(5-methoxypyridin-2-yl)methoxy]-l,3-benzoxazol-2-yl}-N-methylpyridine-2- carboxamide;

[0556] 5-[(5-methoxypyridin-2-yl)methoxy]-2-(l-methyl-lH-imidazol-4-yl)-l,3-benzoxazole;

[0557] 5-methoxy-N-{[2-(pyridin-3-yl)-l,3-benzoxazol-5-yl]methyl}pyridin-2-amine;

[0558] 4-(5-{5H,6H-imidazo[2,l-b][l,3]thiazol-3-ylmethoxy}-l-benzofuran-2-yl)pyridine-3- carbonitrile;

[0559] 5-({5-[2-(morpholin-4-yl)ethoxy]pyridin-2-yl}methoxy)-2-(pyridin-3-yl)-l,3-benzoxazole;

[0560] 2-bromo-6-{5-[(5-methoxypyridin-2-yl)methoxy]-l-benzofuran-2-yl}benzonitrile;

[0561] acetic acid 4-{[2-(4-chlorophenyl)-l,3-benzoxazol-5-yl]carbamoyl}phenyl ester;

[0562] N-(2-phenyl-l,3-benzoxazol-5-yl)benzamide;

[0563] 4-methoxy-N-[2-(3-methylphenyl)-l,3-benzoxazol-5-yl]benzamide;

[0564] 2-methoxy-N-[2-(4-methoxyphenyl)-l,3-benzoxazol-5-yl]benzamide;

[0565] 4-methoxy-N-[2-(4-methoxyphenyl)-l,3-benzoxazol-5-yl]benzamide; and

[0566] 3-methoxy-N-[2-(4-methoxyphenyl)-l,3-benzoxazol-5-yl]benzamide,

[0567] or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I or a pharmaceutically acceptable salt thereof is labeled with one or more positron emitting radionuclides.

[0568] The compound of Formula I or a pharmaceutically acceptable salt thereof is labeled with one or more positron emitting radionuclides. Suitable positron emitting radionuclides that can be incorporated into the compounds described herein include, but are not limited to 11 C, 13 N,15 O, 18 F, 52 Fe, 62 Cu, 64 Cu, 68 Ga, 74 As, 82 Rb, 89 Zr, 122 I and 124 I. In some embodiments, the one or more positron-emitting radionuclides are selected from 11 C, 13 N, 15 O, 18 F, 76 Br and 124 I. In some embodiments, the one or more positron-emitting radionuclides are selected from 11 C, 13 N, 15 O and 18 F.

[0569] Non-metallic radionuclides can be covalently attached to the compounds described herein through reactions well known in the art. When the radionuclide is a metallic positron emitter, it will be appreciated that labeling can require the use of a chelator. Such chelators are well known in the art.

[0570] PET imaging agents can be labeled with positron emitters 11 C or 18 F. Methods for introducing 11 C include, but are not limited to, alkylation using 11 C]methyl iodide or 11 C]methyl triflate. Carbon-11 has a half-life of about 20 minutes, so 11 C needs to be produced on-site in a cyclotron, and is typically produced as 11 C]carbon dioxide. The 11 C]carbon dioxide is converted to a chemical species suitable for radiosynthesis (typically 11 C]methyl iodide, etc.), and after the appropriate radiochemical purity and specific radioactivity have been determined, the synthesis of the radiopharmaceutical is performed on-site and used in the PET imaging study. Typical methods for introducing 18 F can include, but are not limited to, displacement of a halogen, tosylate, or other leaving group with 18 F]tetrabutylammonium fluoride or 18 F]potassium fluoride kryptofix-222. Fluorine-18 has a half-life of about 110 minutes, so 18F]The synthesis of radiopharmaceuticals need not necessarily take place at a cyclotron site or close to a PET imaging research center. General methods for introducing these positron emitters are described in the literature (Miller et al., Angewandte Chemie International Edition, 47 (2008), 8998-9033).

[0571] The present application provides a method of producing a diagnostic image in an individual, comprising administering to the individual an effective amount of an imaging agent described herein, and producing an image of at least a portion of the individual.

[0572] The present application also provides a method of producing a diagnostic image in a biological sample, comprising contacting the biological sample with an effective amount of an imaging agent described herein, and producing an image of the compound labeled with a positron emitter in relation to the biological sample. In this method, the contacting and producing can both be performed in vitro, or the contacting is performed in vivo and the producing is performed in vitro.

[0573] The present application also provides a method for detecting the presence or absence of a neurodegenerative pathological process associated with a huntingtin protein (HTT protein) in an individual, comprising: administering an effective amount of a compound labeled with a positron emitter described herein; producing an image to detect the presence or absence of HTT protein aggregates in the brain of the individual; and detecting the presence or absence of the pathological process. In some embodiments, the HTT protein aggregates are present in the basal ganglia of the brain of the individual. In some embodiments, the pathological process is Huntington's disease (HD). In some embodiments, the effective amount of the imaging agent comprises about 0.1 to about 20 mCi. In some embodiments, the effective amount of the imaging agent comprises about 10 mCi. In some embodiments, producing an image comprises positron emission tomography (PET) imaging, PET together with computed tomography imaging (PET / CT), PET together with magnetic resonance imaging (PET / MRI), or a combination thereof. In some embodiments, producing an image comprises PET imaging.

[0574] The present application also provides a diagnostic method for monitoring the progression of a disease in a patient using an imaging agent by quantifying changes in the level of target aggregates in the patient.

[0575] The application also provides methods for detecting the presence or absence of a neurodegenerative pathological process associated with huntingtin protein (HTT protein) in an individual, comprising: administering an effective amount of a compound labeled with a positron emitting agent as described herein; generating an image to detect the presence or absence of HTT protein aggregates in the individual; and detecting the presence or absence of the pathological process. In some embodiments, the HTT protein monomers or aggregates are present in the brain, liver, heart, or muscle of the individual. In some embodiments, the HTT protein aggregates are present in the basal ganglia, cortex, hippocampus, or brainstem of the brain of the individual. In some embodiments, the pathological process is Huntington's disease (HD). In some embodiments, the effective amount of the imaging agent comprises about 0.1 to about 20 mCi. In some embodiments, the effective amount of the imaging agent comprises about 10 mCi. In some embodiments, generating an image comprises positron emission tomography (PET) imaging, PET in conjunction with computed tomography imaging (PET / CT), PET in conjunction with magnetic resonance imaging (PET / MRI), or a combination thereof. In some embodiments, generating an image comprises PET imaging.

[0576] The application also provides methods for detecting the presence or absence of a neurodegenerative pathological process associated with beta-amyloid protein in an individual, comprising: administering an effective amount of a compound labeled with a positron emitting agent as described herein; generating an image to detect the presence or absence of beta-amyloid protein aggregates in the individual; and detecting the presence or absence of the pathological process. In some embodiments, the beta-amyloid protein monomers or aggregates are present in the brain, liver, heart, or muscle of the individual. In some embodiments, the beta-amyloid protein aggregates are present in the basal ganglia, cortex, hippocampus, or brainstem of the brain of the individual. In some embodiments, the pathological process is Alzheimer's disease (AD). In some embodiments, the effective amount of the imaging agent comprises about 0.1 to about 20 mCi. In some embodiments, the effective amount of the imaging agent comprises about 10 mCi. In some embodiments, generating an image comprises positron emission tomography (PET) imaging, PET in conjunction with computed tomography imaging (PET / CT), PET in conjunction with magnetic resonance imaging (PET / MRI), or a combination thereof. In some embodiments, generating an image comprises PET imaging.

[0577] The present application provides compounds with suitable HTT protein aggregate or beta-amyloid aggregate binding kinetics that act as effective imaging agents for HTT protein aggregates or beta-amyloid aggregates. The requirements for the present compounds to act as effective imaging agents for HTT protein aggregates are: 1) high affinity for HTT protein aggregates; 2) low affinity for nearby structures; 3) slow dissociation kinetics with HTT protein aggregates, which can be conveniently expressed as the dissociation rate constant k diss where A and B refer to the HTT protein aggregate and the imaging agent, and k assn is the association rate constant.

[0578] d[AB] / dt = k assn [A][B] - k diss [AB]

[0579] The part of the brain most affected by HD and therefore most likely to contain abnormal HTT protein is a group of nerve cells located in the base of the brain, collectively known as the basal ganglia. The basal ganglia organize body movements driven by muscles or "motor movements". The main components of the basal ganglia are the caudate and putamen (together called the striatum) and the globus pallidus (external and internal regions). The substantia nigra and subthalamic nucleus are also usually included as part of the basal ganglia.

[0580] The term basal ganglia refers to a group of subcortical nuclei primarily responsible for motor control as well as playing other roles such as motor learning, executive function and behavior, and emotion. Damage to the basal ganglia network underlies several movement disorders. Normal function of the basal ganglia requires fine-tuning of neuronal excitability within each nucleus to determine the precise degree of facilitation or inhibition of movement at any given instant. This is mediated by the complex organization of the striatum, in which the excitability of medium spiny neurons is controlled by several presynaptic and postsynaptic mechanisms as well as interneuronal activity, and fixed by several recurrent or internal basal ganglia loops. The motor circuit of the basal ganglia has two entry points, the striatum and the thalamic nuclei, and one exit, the globus pallidus pars interna, which connects with the cortex via the motor thalamus.

[0581] The present application provides a method for imaging a part of the brain of an individual, comprising administering to the individual a compound labeled with a positron emitting agent as described herein, for example to the vascular system of the individual, which thereby passes the blood-brain barrier, and then generating an image of at least part of the brain of the individual in which the compound is distributed.

[0582] The present application also provides a pharmaceutical composition comprising an effective amount of a compound labeled with a positron emitting agent described herein, or a salt thereof, and one or more pharmaceutically acceptable excipients, diluents, or carriers.

[0583] The imaging agent or pharmaceutical composition thereof can be administered to a patient in need of treatment by any suitable route. Routes of administration can include, for example, parenteral administration (including subcutaneous, intramuscular, intravenous, administration by, for example, a drip patch). Other suitable routes of administration include, but are not limited to, oral, rectal, nasal, topical (including buccal and sublingual), infusion, vaginal, intradermal, intraperitoneal, intracranial, intrathecal and epidural administration, or oral or nasal inhalation administration, by means of, for example, a nebulizer or inhaler, or by implantation.

[0584] The imaging agent or pharmaceutical composition thereof can also be administered via microspheres, liposomes, other microparticulate delivery systems or sustained release formulations placed in certain tissues, including the blood. Suitable examples of sustained release carriers include semi-permeable polymeric matrices which are in the form of shared articles, such as suppositories or microcapsules. Examples of techniques and procedures as mentioned above and other techniques and procedures which can be used according to the present application are found in Remington's Pharmaceutical Sciences, 18th edition, Gennaro, A.R., Lippincott Williams & Wilkins; 20th edition (Dec. 15, 2000) ISBN 0-912734-04-3 and Pharmaceutical Dosage Forms and Drug Delivery Systems; Ansel, N.C. et al. 7th Edition ISBN 0-683305-72-7, the entire disclosures of which are incorporated herein by reference.

[0585] The present application also provides the use of a compound labeled with a positron emitting agent described herein in the preparation of an imaging agent for use in a method of diagnosing an individual.

[0586] The present application provides methods of producing diagnostic images, including positron emission tomography (PET). PET involves administering to an individual a positron- emitting radionuclide tracer. Once the tracer has had sufficient time to associate with a target of interest, the individual is placed within a scanning device comprising a ring of scintillation detectors. The emitted positrons travel a short (isotope-dependent) distance through the individual's tissue until they interact with an electron. This interaction annihilates both the electron and positron, thereby producing a pair of photons moving in approximately opposite directions. The above phenomenon is detected when they reach the scintillation detectors in the scanning device. Unpaired photons are ignored.

[0587] The present application also provides methods of producing diagnostic images, including PET in conjunction with computed tomography imaging (PET / CT) or PET in conjunction with magnetic resonance imaging (PET / MRI). Computed tomography uses X-rays to show brain structures, while magnetic resonance imaging uses magnetic fields and radio waves.

[0588] Other uses of the disclosed imaging agents and methods will become apparent to those skilled in the art based on (among other things) a review of the disclosure.

[0589] As will be recognized, the steps of the methods described herein need not be performed in any particular number or in any particular order. Other objects, advantages and novel features of the present disclosure will become apparent to those skilled in the art from a review of this specification, particularly when considered in conjunction with the following examples, which are intended to be exemplary only. Examples

[0590] Commercially available reagents and solvents (HPLC grade) were used without further purification. 1 H NMR spectra were recorded on a Bruker DRX 500 MHz spectrometer or a Bruker DPX 250 MHz spectrometer (in deuterated solvents). Chemical shifts (δ) are in parts per million. SCX chromatography was performed using Biotage Isolute Flash SCX-2 (samples were loaded in methanol and eluted with methanol, then 5% ammonia in methanol).

[0591] Analytical HPLC-MS (METCR1278) was performed on a Shimadzu LCMS-2010EV system using a reverse phase Atlantis dC18 column (3 μm, 2.1 X 50 mm) with a gradient of 5-100% B (A = water / 0.1% formic acid, B = acetonitrile / 0.1% formic acid) over 3 minutes, an injection volume of 3 μL, and a flow rate = 1.0 mL / minute. UV spectra were recorded at 215 nm using an SPD-M20A photodiode array detector. Mass spectra were acquired over the range m / z 150 to 850 at a sampling rate of 2 scans / second using an LCMS2010EV. Data were integrated and reported using Shimadzu LCMS-Solutions and PsiPort software.

[0592] Analytical HPLC-MS (METCR1673) was performed on a Shimadzu LCMS-2010EV system using a reverse phase Supelco Ascentis Express (2.7 μm, 2.1 X 30 mm) with a gradient of 5-100% B (A = water / 0.1% formic acid, B = acetonitrile / 0.1% formic acid) over 1.6 minutes, an injection volume of 3 μL, and a flow rate = 1.0 mL / minute. UV spectra were recorded at 215 nm using an SPD-M20A photodiode array detector. Mass spectra were acquired over the range m / z 100 to 100 at a sampling rate of 2 scans / second using an LCMS2010EV. Data were integrated and reported using Shimadzu LCMS-Solutions and PsiPort software.

[0593] Alternatively, (METCR1416) analytical HPLC-MS was performed on a Shimadzu LCMS-2010EV system using a reverse phase Water Atlantis dC18 column (3 μm, 2.1 X 100 mm) with a gradient of 5-100% B (A = water / 0.1% formic acid, B = acetonitrile / 0.1% formic acid) over 7 minutes, an injection volume of 3 μL, and a flow rate = 0.6 mL / minute. UV spectra were recorded at 215 nm using an SPD-M20A photodiode array detector. Mass spectra were acquired over the range m / z 150 to 850 at a sampling rate of 2 scans / second using an LCMS2010EV. Data were integrated and reported using Shimadzu LCMS-Solutions and PsiPort software.

[0594] Alternatively, (MET-uHPLC-AB-101) analytical HPLC-MS was performed on a Waters Acquity UPLC system with Waters PDA and ELS detectors using a Phenomenex Kinetex-XB C-18 column (1.7 μΜ, 2.1 mm X 100 mm, column temperature 40 °C, gradient 5-100% B (A = water / 0.1% formic acid; B = acetonitrile / 0.1% formic acid) over 5.3 minutes, then 100% B over 0.5 minutes, flow rate = 0.6 mL / minute. UV spectra were recorded at 215 nm using a Waters Acquity photodiode array detector. Mass spectra were acquired over the range m / z 150 to 850 at a sampling rate of 5 scans / second using a Waters SQD. Data were integrated and reported using Waters MassLynx and OpenLynx software.

[0595] All example compounds exhibited LC purity > 95%, unless otherwise stated.

[0596] Commercially available compounds

[0597]

[0598]

[0599] Table 1

[0600] Method 1

[0601] Scheme for Method 1

[0602]

[0603] Step 1, Method 1: 4-Methoxy-N-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]benzamide

[0604] To a stirred solution of 2-(pyridin-3-yl)-1,3-benzoxazol-5-amine (53 mg, 0.25 mmol) in pyridine (1 mL) was added 4-methoxybenzoyl chloride (41 μί, 0.293 mmol) and the mixture was stirred at room temperature for 16 hours. Water (10 mL) was added and the mixture was stirred for 3 hours. The precipitate was filtered off and triturated with ether under sonication to give the title compound 63 mg (62% yield) as a beige powder.

[0605] Example 1, Method 1: 4-Methoxy-N-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]benzamide

[0606] δ HNMR (500 MHz, DMSO) 10.29 (s, 1H), 9.36 (d, J = 1.7 Hz, 1H), 8.81 (dd, J = 4.8, 1.6 Hz, 1H), 8.54 (dt, J = 8.0, 1.9 Hz, 1H), 8.32 (s, 1H), 8.00 (d, J = 8.8 Hz, 2H), 7.82-7.77 (m, 2H), 7.66 (dd, J = 7.9, 4.8 Hz, 1H), 7.09 (d, J = 8.8 Hz, 2H), 3.85 (s, 3H). Tr (MET-uHPLC-AB-101) = 2.73 min, (ES + )(M+H) + 346.

[0607] The following examples were prepared using Method 1 as described above:

[0608]

[0609]

[0610]

[0611] Table 2

[0612] Method 2

[0613] Scheme for Method 2

[0614]

[0615] Step 1, Method 2: N-[(4-methoxyphenyl)methyl]-2-(pyridin-3-yl)-1,3-benzoxazol-5- amine

[0616] To a stirred suspension of 2-(pyridin-3-yl)-1,3-benzoxazol-5-amine (50 mg, 0.24 mmol) in 1,2-dichloroethane (1 mL) was added 4-methoxybenzaldehyde (32 mg, 0.24 mmol) followed by sodium triacetoxyborohydride (60 mg, 0.28 mmol) and the mixture was stirred at room temperature overnight. The mixture was treated with sodium triacetoxyborohydride (60 mg, 0.28 mmol) and acetic acid (0.026 mL, 0.47 mmol) and stirred at 40 °C for 48 h. The mixture was then diluted with ethyl acetate (20 mL), washed with water (15 mL) and saturated sodium bicarbonate solution (15 mL). The organic extract was dried over sodium sulfate, filtered and concentrated. Purification by preparative HPLC (acetonitrile / water) gave the title compound (13.8 mg, 18% yield) as a white solid.

[0617] Example 1, Method 2: N-[(4-methoxyphenyl)methyl]-2-(pyridin-3-yl)-1,3-benzoxazol-5- amine

[0618] δ H NMR (500 MHz, DMSO) 9.26 (dd, J = 2.2, 0.6 Hz, 1H), 8.75 (dd, J = 4.8, 1.6 Hz, 1H), 8.44 (dt, J = 8.0, 1.9 Hz, 1H), 7.61 (ddd, J = 8.0, 4.8, 0.7 Hz, 1H), 7.54 - 7.45 (m, 1H), 7.33 (d, J = 8.6 Hz, 2H), 6.93 - 6.85 (m, 2H), 6.84 - 6.76 (m, 2H), 6.34 (t, J = 5.9 Hz, 1H), 4.24 (d, J = 5.9 Hz, 2H), 3.72 (s, 2H). Tr (MET-uHPLC-AB-101) = 2.98 min, (ES + (M+H) + 332.

[0619] The following examples were prepared using Method 2 as described above:

[0620]

[0621] Table 3

[0622] Method 3

[0623] Scheme for Method 3

[0624]

[0625] Step 1, Method 3: 6-methoxy-N-[2-(3-methylphenyl)-1,3-benzoxazol-5-yl]pyridine-3- carboxamide

[0626] To a stirred suspension of 6-methoxypyridine-3-carboxylic acid (75 mg, 0.49 mmol) in dichloromethane (1 mL) was added 1-chloro-N,N-2-trimethylprop-1-en-1-amine (71 μL, 0.54 mmol). The mixture was stirred at room temperature for 2 hours. Then 2-(3-methylphenyl)-1,3-benzoxazol-5-amine (100 mg, 0.45 mmol) was added followed by triethylamine (68 μL, 0.49 mmol). The mixture was stirred at room temperature for 60 hours. Water (5 mL) was added to the mixture and the organic layer was separated. The aqueous layer was extracted twice with dichloromethane (5 mL). The organic layers were combined and washed with saturated aqueous potassium carbonate solution (5 mL). Purification by FCC (silica gel, 0-20% ethyl acetate / dichloromethane) and trituration with a minimum amount of diethyl ether gave the title compound 24 mg (15% yield) as a white solid.

[0627] Example 1 Method 3: 6-methoxy-N-[2-(3-methylphenyl)-1,3-benzoxazol-5-yl]pyridine-3- carboxamide

[0628] δ H NMR (500 MHz, DMSO) 10.42 (s, 1 H), 8.82 (d, J = 2.4 Hz, 1 H), 8.27 (d, J = 8.4 Hz, 2H), 8.04 (s, 1 H), 8.01 (d, J = 7.6 Hz, 1 H), 7.77 (d, J = 8.8 Hz, 1 H), 7.73 (dd, J = 8.8, 1.9 Hz, 1 H), 7.51 (t, J = 7.6 Hz, 1 H), 7.46 (d, J = 7.6 Hz, 1 H), 6.98 (d, J = 8.7 Hz, 1 H), 3.95 (s, 3H), 2.44 (s, 3H). Tr (MET-uHPLC-AB-101 ) = 3.68 min, (ES + )(M+H) + 360.

[0629] The following examples were prepared using Method 3 as described above:

[0630]

[0631]

[0632] Table 4

[0633] Method 4

[0634] Scheme for Method 4

[0635]

[0636] Step 1, Method 4: N-(5-bromo-2-chloropyridin-3-yl)-3-methylbenzamide

[0637] To a stirred solution of 5-bromo-2-chloropyridin-3-amine (500 mg, 2.41 mmol) in pyridine (5 mL) at 0 °C was added 3-methylbenzoyl chloride (410 mg, 2.65 mmol). The mixture was stirred at room temperature for 1 h. Water (50 mL) was added to the mixture. The precipitate was filtered off and washed with water to give the title compound 653 mg (83% yield) as an off-white solid. H NMR (500 MHz, DMSO) 8.59 (d, J = 2.1 Hz, 1H), 8.51 (d, J = 2.1 Hz, 1H), 8.07 - 7.99 (m, 2H), 7.53 (q, J = 7.7 Hz, 2H), 2.45 (s, 3H). Tr (METCR1278) = 2.58 min, (ES + (M+H) + 325 / 327.

[0638] Step 2, Method 4: 6-bromo-2-(3-methylphenyl)-[1,3]oxazolo[5,4-b]pyridine

[0639] To a mixture of N-(5-bromo-2-chloropyridin-3-yl)-3-methylbenzamide (200 mg, 0.61 mmol), copper(I) iodide (6 mg, 0.03 mmol), N,N'-dimethylethan-1,2-diamine (7 μL, 0.06 mmol) and potassium carbonate (170 mg, 1.23 mmol) was added 1,4-dioxane (1 mL). The reaction mixture was stirred at reflux for 24 h. The mixture was added to a dilute aqueous ammonia solution (100 mL). The aqueous layer was extracted with ethyl acetate (3 x 100 mL). The ethyl acetate layers were combined, dried over sodium sulfate and concentrated to give the title compound 120 mg (67% yield) as a beige solid. H NMR (500 MHz, DMSO) 8.59 (d, J = 2.1 Hz, 1H), 8.51 (d, J = 2.1 Hz, 1H), 8.07 - 7.99 (m, 2H), 7.53 (q, J = 7.7 Hz, 2H), 2.45 (s, 3H). Tr (METCR1278) = 2.58 min, (ES + (M+H) + 289 / 291.

[0640] Step 3, Method 4: 2-(3-methylphenyl)-[1,3]oxazolo[5,4-b]pyridin-6-amine

[0641] A mixture of 6-bromo-2-(3-methylphenyl)-[l,3]oxazolo[5,4-b]pyridine (230 mg, 0.8 mmol), benzophenone imine (217 mg, 1.19 mmol), tris(dibenzylideneacetone)dipalladium(0) (44 mg, 0.05 mmol), 9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (41 mg, 0.07 mmol) and cesium carbonate (415 mg, 1.27 mmol) in N,N-dimethylacetamide (2 mL) was stirred at 120 °C under nitrogen for 16 hours. The mixture was cooled to room temperature and water (50 mL) was added. The mixture was then extracted with ethyl acetate (3 x 25 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was dissolved in tetrahydrofuran (5 mL) and the mixture was treated with 2N hydrochloric acid (2 mL). The mixture was stirred at room temperature for 1 hour. The crude material was purified using an SCX cartridge and triturated with diethyl ether. 20 mg of 123 mg was purified by FCC (silica gel, 0-5% ethyl acetate / dichloromethane) to give the title compound 14 mg (8% yield) as a yellow solid. H NMR (500 MHz, DMSO) δ 8.04-7.89 (m, 2H), 7.72 (d, J = 2.5 Hz, 1H), 7.56-7.42 (m, 2H), 7.31 (d, J = 2.5 Hz, 1H), 5.36 (s, 2H), 2.43 (s, 3H). Tr (MET-uHPLC-AB-101) = 2.54 min, (ES + (M+H) + 226.

[0642] Step 4, Method 4: 4-Methoxy-N-[2-(3-methylphenyl)-[l,3]oxazolo[5,4-b]pyridin-6- yl]benzamide

[0643] To a stirred solution of 2-(3-methylphenyl)-[l,3]oxazolo[5,4-b]pyridin-6-amine (0.249 mmol) in pyridine (1 mL) was added 4-methoxybenzoyl chloride (41 μί, 0.293 mmol) and the mixture was stirred at room temperature for 16 hours. Water (10 mL) was added and the mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated. Purification by FCC (silica gel, 0-20% ethyl acetate / dichloromethane) gave the title compound 55 mg (52% yield) as a white powder.

[0644] Example 1, Method 4: 4-Methoxy-N-[2-(3-methylphenyl)-[l,3]oxazolo[5,4-b]pyridin-6- yl]benzamide

[0645] δH NMR (500 MHz, DMSO) 10.47 (s, 1H), 8.67 (d, J = 2.3 Hz, 1H), 8.62 (d, J = 2.3 Hz, 1H), 8.10 - 7.94 (m, 4H), 7.58 - 7.44 (m, 2H), 7.15 - 7.05 (m, 2H), 3.86 (s, 3H), 2.45 (s, 3H). Tr (MET-uHPLC-AB-101) = 3.64 min, (ES + )(M+H) + 360.

[0646] The following examples were prepared using Method 4 as described above:

[0647]

[0648] Table 5

[0649] Method 5

[0650] Scheme for Method 5

[0651]

[0652] Step 1, Method 5: 5-(4-methoxyphenyl)-2-(pyridin-3-yl)-1,3-benzoxazole

[0653] In a sealed tube under nitrogen 4-methoxyphenylboronic acid (61 mg, 0.4 mmol) and 5-bromo-2-(3-pyridyl)-1,3-benzoxazole (100 mg, 0.36 mmol) were dissolved in 1,4-dioxane (2 mL). 2M sodium carbonate (0.36 mL, 0.73 mmol) was added followed by tetrakis(triphenylphosphine)palladium(0) (21 mg, 0.018 mmol) and the mixture was stirred at 110 °C overnight. The mixture was cooled to room temperature, diluted with water (15 mL) and extracted with ethyl acetate (2 x 15 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated. Purification by FCC (silica gel, 0-70% ethyl acetate / heptane) gave the title compound 74 mg (67% yield) as a white solid.

[0654] Example 1, Method 5: 5-(4-methoxyphenyl)-2-(pyridin-3-yl)-1,3-benzoxazole

[0655] δ HNMR (500 MHz, chloroform) 9.50 (s, 1H), 8.78 (d, J = 4.0 Hz, 1H), 8.54 (dt, J = 8.0, 1.9 Hz, 1H), 7.94 (d, J = 1.3 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.62 - 7.54 (m, 3H), 7.50 (dd, J = 7.9, 4.9 Hz, 1H), 7.05 - 6.98 (m, 2H), 3.87 (s, 3H). Tr (MET-uHPLC-AB-101) = 3.58 min, (ES + )(M+H) + 303.

[0656] The following examples were prepared using Method 5 as described above:

[0657]

[0658] Table 6

[0659] Method 6

[0660] Scheme for Method 6

[0661]

[0662] Step 1, Method 6: N-(4-methoxyphenyl)-2-(pyridin-3-yl)-1,3-benzoxazol-5-amine

[0663] To a pressure tube was added 9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (32 mg, 0.055 mmol), tris(dibenzylideneacetone)dipalladium(0) (17 mg, 0.018 mmol) and 1,4-dioxane (2 mL). The mixture was degassed using a stream of nitrogen for 10 minutes. To the mixture was then added p-methoxyaniline (25 mg, 0.2 mmol), 2-(pyridin-3-yl)-1,3-benzoxazol-5-amine (50 mg, 0.18 mmol) and cesium carbonate (178 mg, 0.55 mmol) and the mixture was stirred at 110 °C overnight. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated. Purification by preparative HPLC (acetonitrile / water) gave the title compound 18 mg (31% yield) as a yellow powder.

[0664] Example 1, Method 6: N-(4-methoxyphenyl)-2-(pyridin-3-yl)-1,3-benzoxazol-5-amine

[0665] δ HNMR (500 MHz, DMSO) 9.31 (d, J = 1.6 Hz, 1H), 8.78 (dd, J = 4.8, 1.6 Hz, 1H), 8.48 (dt, J = 8.0, 1.9 Hz, 1H), 7.98 (s, 1H), 7.67 - 7.59 (m, 2H), 7.27 (d, J = 2.2 Hz, 1H), 7.12 - 7.05 (m, 2H), 7.03 (dd, J = 8.8, 2.3 Hz, 1H), 6.93 - 6.86 (m, 2H), 3.73 (s, 3H). Tr (MET-uHPLC-AB-101) = 3.17 min, (ES + )(M+H) + 318.

[0666] The following examples were prepared using Method 6 as described above:

[0667]

[0668]

[0669] Table 7

[0670] Method 7

[0671] Scheme for Method 7

[0672]

[0673] Step 1, Method 7: 2-(pyridin-3-yl)-N-(pyrimidin-4-yl)-1,3-benzoxazol-5-amine

[0674] 4-chloropyrimidine hydrochloride (71 mg, 0.47 mmol), 2-(pyridin-3-yl)-1,3-benzoxazol-5-amine (50 mg, 0.24 mmol), diisopropylethylamine (0.12 mL, 0.71 mmol) and 2-propanol (1 mL) were heated in a microwave at 120 °C for 3 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. Purification by preparative HPLC (acetonitrile / water) gave the title compound 7.2 mg (11% yield) as an off-white solid.

[0675] Example 1, Method 7: 2-(pyridin-3-yl)-N-(pyrimidin-4-yl)-1,3-benzoxazol-5-amine

[0676] δ HNMR (500 MHz, DMSO) 9.79 (s, 1H), 9.35 (d, J = 2.1 Hz, 1H), 8.81 (dd, J = 4.8, 1.6 Hz, 1H), 8.66 (s, 1H), 8.53 (dt, J = 8.0, 1.9 Hz, 1H), 8.33 (d, J = 2.0 Hz, 1H), 8.29 (d, J = 5.9 Hz, 1H), 7.79 (d, J = 8.8 Hz, 1H), 7.66 (dd, J = 8.0, 4.8 Hz, 1H), 7.60 (dd, J = 8.8, 2.1 Hz, 1H), 6.82 (dd, J = 5.9, 1.1 Hz, 1H). Tr (MET-uHPLC-AB-101) = 1.23 min, (ES + )(M+H) + 290.

[0677] The following examples were prepared using Method 7 as described above:

[0678]

[0679]

[0680] Table 8

[0681] Method 8

[0682] Scheme for Method 8

[0683]

[0684] Step 1, Method 8: 2-(pyridin-3-yl)-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3- benzoxazole

[0685] A suspension of 5-bromo-2-(3-pyridinyl)-1,3-benzoxazole (200 mg, 0.73 mmol), bis(pinacolato)diboron (221 mg, 0.87 mmol) and potassium acetate (214 mg, 2.18 mmol) in DMSO (4 mL) was degassed with nitrogen for 5 minutes. [1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride (27 mg, 0.036 mmol) was added and the reaction mixture was stirred at 80 °C under nitrogen for 16 hours. The reaction mixture was then cooled to room temperature, diluted with water (20 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated. Purification by FCC (silica gel, 0-40% ethyl acetate / heptane) afforded the title compound 143 mg (61% yield) as a white solid. Tr (MET CR1278) = 2.25 mins, (ES + )(M+H) +323.

[0686] Step 2, Method 8: 5-(5-methoxy pyrimidin-2-yl)-2-(pyridin-3-yl)-1,3-benzoxazole

[0687] In a sealed tube under nitrogen, 2-chloro-5-methoxy pyrimidine (69 mg, 0.48 mmol) and 2-(pyridin-3-yl)-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzoxazole (140 mg, 0.43 mmol) were dissolved in 1,4-dioxane (3 mL). 2M sodium carbonate (0.43 mL, 0.87 mmol) was added followed by tetrakis(triphenylphosphine)palladium(0) (25 mg, 0.022 mmol). The reaction mixture was stirred at 110 °C overnight. The reaction mixture was cooled to room temperature, diluted with water (20 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. Purification by FCC (silica gel, 0-2% methanol / dichloromethane) afforded the title compound 24 mg (18% yield) as a white solid.

[0688] Example 1, Method 8: (125-1) 5-(5-methoxy pyrimidin-2-yl)-2-(pyridin-3-yl)-1,3-benzoxazole

[0689] δ H NMR (500 MHz, DMSO) 9.38 (d, J = 2.0 Hz, 1H), 8.83 (dd, J = 4.8, 1.6 Hz, 1H), 8.69 (s, 2H), 8.66 (d, J = 1.5 Hz, 1H), 8.57 (dt, J = 8.0, 1.9 Hz, 1H), 8.46 (dd, J = 8.6, 1.7 Hz, 1H), 7.93 (d, J = 8.6 Hz, 1H), 7.67 (dd, J = 7.9, 4.8 Hz, 1H), 3.98 (s, 3H). Tr (MET-uHPLC-AB-101) = 2.87 min, (ES

[0690] (M+H) + (M+H) + 305.

[0691] The following examples were prepared using Method 8 as described above:

[0692]

[0693] Table 9

[0694] Method 9

[0695] Scheme for Method 9

[0696] (M+H)

[0697] Step 1, Method 9: 5-(Methoxymethoxy)-1-benzofuran

[0698] Sodium hydride (60% in mineral oil, 579 mg, 14.48 mmol) was suspended in anhydrous N,N-dimethylformamide (25 mL) and cooled to 0 °C. A solution of 5-hydroxybenzofuran (1.85 g, 13.79 mmol) in N,N-dimethylformamide (10 mL) was added slowly. The mixture was stirred under nitrogen and allowed to warm to room temperature over 1.5 h. The mixture was cooled to 0 °C and chloro(methoxy)methane (1.1 mL, 14.48 mmol) was added dropwise over 30 min. The reaction mixture was allowed to warm to room temperature and stirred for 3 h. Water (5 mL) was added and the mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed with water (5 x 50 mL), brine (10 mL), dried over magnesium sulfate, filtered and concentrated to give the title compound 2.3 g (89% yield) as a pale yellow oil. Tr(METCR1278) = 1.95 min, not ionised.

[0699] Step 2, Method 9: [5-(Methoxymethoxy)-1-benzofuran-2-yl]boronic acid

[0700] 5-(Methoxymethoxy)-1-benzofuran (1.00 g, 5.35 mmol) was dissolved in anhydrous tetrahydrofuran (15 mL) and cooled to -78 °C under nitrogen. 1.6 M n-butyllithium / hexanes (3.51 mL, 5.62 mmol) was added dropwise and stirred at -78 °C for 1 h. Triisopropyl borate (2.47 mL, 10.7 mmol) was added dropwise and the reaction mixture was stirred for 2 h. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. 2 M hydrochloric acid (16 mL) was added and the reaction mixture was stirred for 1 h. The reaction mixture was diluted with water (10 mL) and extracted with tert-butyl methyl ether (3 x 40 mL). The combined organic extracts were washed with brine (10 mL), dried over magnesium sulfate, filtered and concentrated. Purification by FCC (silica gel, 20-80% ethyl acetate / heptane) gave the crude title compound 374 mg (31% yield) as a beige solid which was used in the next step without further purification.

[0701] Step 3, Method 9: 4-[5-(Methoxymethoxy)-1-benzofuran-2-yl]pyridine-3- carbonitrile

[0702] (1R,4S)-Bicyclo[2.2.1]hept-2-yl[(1S,4R)-bicyclo[2.2.1]hept-2-yl]phosphane- chloro[2'-(dimethylamino)biphenyl-2-yl]palladium (1 :1) (47 mg, 0.08 mmol) was added and the reaction mixture was heated to 75 °C for 1.5 hours. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was partitioned between ethyl acetate (50 mL) and water (20 mL), the phases were separated and the aqueous phase was extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated. Purification by FCC (silica gel, 0-50% ethyl acetate / heptane) gave the title compound 254 mg (52% yield) as a pale yellow solid. Tr(MET-uHPLC-AB-101) = 3.20 min, (ES + )(M+H) + 281.

[0703] Step 4, Method 9: 4-(5-Hydroxy-1-benzofuran-2-yl)pyridine-3-carbonitrile

[0704] To a solution of 4-[5-(methoxymethoxy)-1-benzofuran-2-yl]pyridine-3-carbonitrile (240 mg, 0.86 mmol) in tetrahydrofuran (10 mL) was added 3M hydrochloric acid (2.8 mL) and the mixture was stirred at 60 °C for 2 hours. The reaction mixture was cooled to room temperature and saturated aqueous sodium bicarbonate solution (50 mL) and ethyl acetate (100 mL) were added. The mixture was filtered (glass fibre filter paper) and dried in vacuo for 2 hours to give the title compound 207 mg (quantitative yield) as a yellow solid. Tr(MET-uHPLC-AB-101) = 2.41 min, (ES + )(M+H) + 237.

[0705] Step 5, Method 9: 4-{5-[(5-Methoxypyridin-2-yl)methoxy]-1-benzofuran-2-yl}pyridine- 3-carbonitrile

[0706] To a solution of 4-(5-hydroxy-l-benzofuran-2-yl)pyridine-3-carbonitrile (98%, 50 mg, 0.21 mmol), 2-(chloromethyl)-5-methoxypyridine hydrochloride (44 mg, 0.23 mmol) and potassium iodide (34 mg, 0.21 mmol) in dry N,N-dimethylformamide (2 mL) was stirred at room temperature for 5 minutes. Sodium hydride (60% in mineral oil, 25 mg, 0.62 mmol) was added and the reaction mixture was stirred under nitrogen for 15 hours. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate (50 mL) and water (20 mL), the aqueous layer was extracted with ethyl acetate (2 x 30 mL), the combined organic phases were washed with water (10 mL), brine (10 mL), dried over sodium sulfate, filtered and concentrated. Purification by FCC (silica gel, 0-100% ethyl acetate in heptane) gave the title compound 34.8 mg (47% yield) as a white powder.

[0707] Example 1, Method 9: 4-{5-[(5-methoxypyridin-2-yl)methoxy]-l-benzofuran-2- yl}pyridine-3-carbonitrile

[0708] δ H NMR (500 MHz, DMSO) 9.12 (s, 1H), 8.92 (d, J = 5.4 Hz, 1H), 8.30 (d, J = 2.9 Hz, 1H), 8.07 (d, J = 5.4 Hz, 1H), 7.99 - 7.88 (m, 1H), 7.65 (d, J = 9.0 Hz, 1H), 7.52 (d, J = 8.6 Hz, 1H), 7.48 - 7.39 (m, 2H), 7.18 (dd, J = 9.0, 2.6 Hz, 1H), 5.16 (s, 2H), 3.84 (s, 3H). Tr (MET-uHPLC-AB-101) = 3.15 min, (ES+) (M+H) + 358.

[0709] The following examples were prepared using Method 9 as described above:

[0710]

[0711]

[0712] Table 10

[0713] Method 10

[0714] Scheme for Method 10

[0715]

[0716] Step 1, Method 10: 5-Methoxy-2-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]-2,3- dihydro-1H-isoindol-1-one

[0717] Ethyl 2-(bromomethyl)-4-methoxybenzoate (100 mg, 0.37 mmol, described in WO2009042907), 2-(pyridin-3-yl)-1,3-benzoxazol-5-amine (93 mg, 0.44 mmol) and diisopropylethylamine (77 μL, 0.44 mmol) were dissolved in ethanol (4 mL) and heated to 110 °C in a pressure tube for 18 h. The reaction mixture was cooled to room temperature and treated with a solution of lithium hydroxide monohydrate in water (0.5 mL) (46 mg, 1.10 mmol). The reaction mixture was stirred at room temperature for 1.5 h and then concentrated. Trituration in boiling ethyl acetate-ethanol (1 :1 v / v) followed by recrystallisation from DMSO gave the title compound 5 mg (5% yield) as a yellow powder.

[0718] Example 1, Method 10: 5-Methoxy-2-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]-2,3- dihydro-1H-isoindol-1-one

[0719] δ H NMR (500 MHz, DMSO + 5% DCl / D2O) 9.56 (d, J = 1.76 Hz, 1H), 9.18

[0720] (d, J = 1.53, 8.20 Hz, 1H), 9.10 - 9.04 (m, 1H), 8.35 (d, J = 2.08 Hz, 1H), 8.24 (dd, J = 5.70, 8.09 Hz, 1H), 8.03 (dd, J = 2.17, 9.00 Hz, 1H), 7.92 (d, J = 9.00 Hz, 1H), 7.70 (d, J = 8.43 Hz, 1H), 7.22 (d, J = 1.76 Hz, 1H), 7.08 (dd, J = 2.16, 8.44 Hz, 1H), 5.05 (s, 2H), 3.85 (s, 3H). Tr (MET-uHPLC-AB-101) = 2.88 min, (ES + )(M+H) + 358.

[0721] The following examples were prepared using Method 10 as described above:

[0722]

[0723] Table 11

[0724] Method 11

[0725] Scheme for Method 11

[0726]

[0727] Step 1, Method 11: N-(5-bromo-2-chloropyridin-3-yl)pyridine-3-carboxamide

[0728] To a stirred solution of 5-bromo-2-chloropyridin-3-amine (1.00 g, 4.82 mmol) in pyridine (10 mL) was added nicotinoyl chloride hydrochloride (0.94 g, 5.30 mmol) under ice cooling. The mixture was stirred at room temperature for 1 hour. The mixture was concentrated, diluted with water (60 mL) and extracted with ethyl acetate (3 x 60 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated to give the title compound 1.1 g as a grey solid. The aqueous extract was filtered to give additional 0.18 g of the title compound for a total of 1.28 g (85% yield) as a grey powder. Tr (METCR1278) = 1.57 min, (ES + ) (M+H) + 312, 314.

[0729] Step 2, Method 11: 3-{6-bromo-[l,3]oxazolo[5,4-b]pyridin-2-yl}pyridine

[0730] To a pressure tube was added N-(5-bromo-2-chloropyridin-3-yl)pyridine-3-carboxamide (318 mg, 0.68 mmol), copper(I) iodide (6.5 mg, 0.034 mmol), N,N'-dimethylethan-l,2-diamine (6.0 mg, 0.068 mmol) and potassium carbonate (0.19 g, 1.36 mmol) in 1,4-dioxane (4 mL). The mixture was degassed using a stream of nitrogen for 10 minutes and heated at 110 °C for 16 hours. The mixture was then diluted with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated. The residue was triturated with methanol (4 mL) to give the title compound 95 mg (50% yield) as a light brown powder. Tr (METCR1278) = 1.85 min, (ES + ) (M+H) + 276 / 278.

[0731] Step 3, Method 11: 3-{6-[(E)-2-(4-methoxyphenyl)vinyl]-[l,3]oxazolo[5,4-b]pyridin-2-yl}pyridine

[0732] To a pressure tube was added 3-{6-bromo-[l,3]oxazolo[5,4-b]pyridin-2-yl}pyridine (95 mg, 0.18 mmol), 4-methoxystyrene (78 mg, 0.58 mmol), triphenylphosphine (15 mg, 0.058 mmol) and potassium carbonate (120 mg, 0.87 mmol) in N,N-dimethylformamide (1 mL). The mixture was degassed using a stream of nitrogen for 5 minutes and then heated at 90 °C for 2 hours. The mixture was allowed to cool to room temperature, diluted with water (10 mL) and filtered to give a brown solid which was dried under vacuum (80 mg). To the solid in the pressure tube was then added 4-methoxystyrene (78 mg, 0.58 mmol), triphenylphosphine (15 mg, 0.058 mmol) and potassium carbonate (120 mg, 0.87 mmol) in N,N-dimethylformamide (1 mL). The mixture was degassed using a stream of nitrogen for 5 minutes and then heated at 90 °C for 2 hours. The mixture was then allowed to cool to room temperature, diluted with water (10 mL) and filtered to give a black solid which was washed with ethyl acetate (2 mL). The solid was then dissolved in DMSO (2 mL), filtered and the filtrate concentrated under reduced pressure. Purification by FCC (silica gel, 0-2% methanol / dichloromethane) and recrystallisation in DMSO:acetonitrile (1 :1) gave the title compound 2 mg (2% yield) as a white powder.

[0733] Example 3, Method 11 : 3-{6-[(E)-2-(4-methoxyphenyl)vinyl]-[l,3]oxazolo[5,4- b]pyridin-2-yl}pyridine

[0734] δ H NMR (500 MHz, DMSO) 9.38 (d, J = 1.7 Hz, 1H), 8.85 (dd, J = 4.8, 1.6 Hz, 1H), 8.65 - 8.52 (m, 3H), 7.69 (dd, J = 8.0, 4.8 Hz, 1H), 7.58 (d, J = 8.7 Hz, 2H), 7.44 (d, J = 16.5 Hz, 1H), 7.29 (d, J = 16.5 Hz, 1H), 6.99 (d, J = 8.7 Hz, 2H), 3.79 (s, 3H). Tr (MET-uHPLC-AB-101) = 3.54 min, (ES + )(M+H) + 330.

[0735] The following examples were prepared using Method 11 as described above:

[0736]

[0737] Table 12

[0738] Method 12

[0739] Scheme for Method 12:

[0740]

[0741] Step 1, Method 12: (4-[5-(pyridin-3-yloxy)-l-benzofuran-2-yl]pyridine-3- carbonitrile

[0742] Cesium carbonate (138 mg, 0.42 mmol), 2,2,6,6-tetramethylheptane-3,5-dione (47 μL, 0.21 mmol) and copper(I) iodide (4 mg, 0.02 mmol) were dissolved in N,N- dimethylformamide (1 mL) and stirred in a screw cap vial at room temperature for 5 minutes. 4-(5-Hydroxy-l-benzofuran-2-yl)pyridine-3-carbonitrile (50 mg, 0.21 mmol, prepared by Method 9) and 3-iodopyridine (46 mg, 0.22 mmol) were added and the reaction mixture was sealed and heated to 60 °C for 16 hours then to 90 °C for 24 hours. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was sonicated in ethyl acetate (20 mL) and passed through a pad of diatomaceous earth. The pad was washed with ethyl acetate (2 x 20 mL). The combined organic phases were washed with water (10 mL), brine (10 mL), dried over sodium sulfate, filtered and concentrated. Purification by preparative HPLC (acetonitrile / water + 0.2% ammonium hydroxide) gave the title compound 12.5 mg (18% yield) as a brown powder.

[0743] Example 1, Method 12: 4-[5-(pyridin-3-yloxy)-l-benzofuran-2-yl]pyridine-3- carbonitrile

[0744] δ H NMR (500 MHz, DMSO) 9.14 (s, 1 H), 8.95 (d, J = 5.4 Hz, 1 H), 8.41 (s,

[0745] 1 H), 8.37 (dd, J = 3.9, 2.1 Hz, 1 H), 8.10 (d, J = 5.4 Hz, 1 H), 7.99 (s, 1 H), 7.80 (d, J = 8.9 Hz, 1 H), 7.59 (d, J = 2.5 Hz, 1 H), 7.47 - 7.39 (m, 2 H), 7.28 (dd, J = 8.9, 2.6 Hz, 1 H). Tr (MET-uHPLC-AB-101) = 2.65 min, (ES + )(M+H) + 314.

[0746] The following examples were prepared using Method 12 as described above:

[0747]

[0748] Table 13

[0749] Method 13

[0750] Method 13

[0751]

[0752] Step 1, Method 13: 6-Methoxy-2-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]-1,2,3,4-tetrahydroisoquinoline-1-one

[0753] 2-(2-chloroethyl)-4-methoxybenzoyl chloride (226 mg, 0.97 mmol, described in WO2007093366) and 2-(pyridin-3-yl)-1,3-benzoxazol-5-amine (205 mg, 0.97 mmol) were dissolved in anhydrous tetrahydrofuran (10 mL) under nitrogen. Sodium hydride (60% in mineral oil, 78 mg, 1.9 mmol) was added, and the mixture was heated to 60 °C and maintained for 2 hours. The reaction mixture was cooled to room temperature, quenched with water (10 mL), and extracted with ethyl acetate (4 x 15 mL). The combined organic extracts were washed with water (15 mL) and brine (15 mL), dried over magnesium sulfate, filtered, and concentrated. Preparative HPLC purification (acetonitrile / water + 0.1% formic acid) gave 23 mg (5% yield) of the title compound as a white powder.

[0754] Example 1, Method 13: 6-Methoxy-2-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]-1,2,3,4-tetrahydroisoquinoline-1-one

[0755] δ H NMR(500MHz,DMSO)9.37(d,J=1.63Hz,1H),8.82(dd,J=1.59,

[0756] 4.81Hz,1H),8.56(dt,J=1.87,7.99Hz,1H),7.93-7.82(m,3H),7.67(dd,J=4.82,7.96Hz,1H),7.50(dd ,J=2.08,8.70Hz,1H),6.97-6.91(m,2H),4.01(t,J=6.46Hz,2H),3.85(s,3H),3.15(t,J=6.41Hz,2H). Tr(MET-uHPLC-AB-101)=2.83min,(ES + (M+H) + 372.

[0757] The following examples were prepared using Method 13 as described above:

[0758]

[0759] Table 14

[0760] Method 14

[0761] Scheme for Method 14

[0762]

[0763] Step 1, Method 14: 2-(pyridin-3-yl)-l,3-benzoxazol-5-ol

[0764] To a stirred solution of 2-(pyridin-3-yl)-l,3-benzoxazol-5-amine (350 mg, 1.66 mmol) in sulfuric acid (1.76 mL, 33.14 mmol) in water (5.25 mL) was added portionwise at room temperature. The solution was cooled to 0-5 °C and a solution of sodium nitrite (126 mg, 1.82 mmol) in water (3.5 mL) was added dropwise. The mixture was stirred at 0-5 °C for 30 minutes. A solution of copper (II) nitrate (20.5 g, 109.4 mmol) in water (35 mL) was added to the reaction mixture followed by copper (I) oxide (237 mg, 1.66 mmol). The mixture was shaken vigorously for 10 minutes. The mixture was then basified with saturated sodium bicarbonate solution until the pH reached 8-9. 10% Aqueous ammonia (30 mL) was added and the resulting aqueous solution was extracted with ethyl acetate (2 x 150 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated. Purification by FCC (silica gel, 0-5% methanol / dichloromethane) gave the title compound 127 mg (36% yield) as a yellow powder. Tr (MET-uHPLC-AB-101) = 1.77 min, (ES + )(M+H) + 213.

[0765] Step 2, Method 14: 5-[(4-methoxyphenyl)methoxy]-2-(pyridin-3-yl)-l,3-benzoxazole

[0766] Under nitrogen atmosphere, a solution of 2-(pyridin-3-yl)-1,3-benzoxazol-5-ol (30 mg, 0.14 mmol) in N,N-dimethylformamide (1 mL) was added to sodium hydride (60% in mineral oil, 5.7 mg, 0.14 mmol) and the mixture was stirred at room temperature for 30 minutes. A solution of 4-methoxybenzyl bromide (28 mg, 0.14 mmol) in N,N-dimethylformamide (0.5 mL) was added and the mixture was stirred at room temperature for 1 hour. The mixture was quenched with water (0.5 mL), diluted with water (15 mL), and extracted with ethyl acetate (2 x 15 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The extract was purified by FCC (silica gel, 20-100% ethyl acetate / heptane), ground in acetonitrile (2 mL), and dried under vacuum to give 12 mg (26% yield) of the title compound as a white powder.

[0767] Example 1, Method 14: 5-[(4-methoxyphenyl)methoxy]-2-(pyridin-3-yl)-1,3-benzoxazole

[0768] δ H NMR(500MHz,DMSO)9.32(d,J=1.8Hz,1H),8.80(dd,J=4.8,1.6

[0769] Hz,1H),8.50(dt,J=8.0,1.9Hz,1H),7.72(d,J=8.9Hz,1H),7.65(dd,J=7.9,4.8Hz,1H),7.47(d,J=2.5Hz ,1H),7.42(d,J=8.6Hz,2H),7.10(dd,J=8.9,2.5Hz,1H),6.96(d,J=8.6Hz,2H),5.11(s,2H),3.76(s,3H). Tr(MET-uHPLC-AB-101)=3.56min,(ES + (M+H) + 333.

[0770] The following examples were prepared using method 14 as described above:

[0771]

[0772]

[0773] Table 15

[0774] Method 15

[0775] Solution 15

[0776]

[0777] Step 1, Method 15: N-Methoxy-N-methyl-2-[2-(pyridin-3-yl)-1,3-benzoxazol-6- yl]acetamide

[0778] To a stirred solution of 2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]acetic acid (200 mg, 0.79 mmol) in N,N-dimethylformamide (2 mL) was added N-methoxy-methylamine hydrochloride (92 mg, 0.94 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (329 mg, 0.86 mmol) and diisopropylethylamine (0.41 mL, 2.36 mmol). The mixture was stirred at room temperature for 2 hours then partitioned between ethyl acetate (20 mL) and water (20 mL). The organic extract was dried over sodium sulfate, filtered and concentrated. Purification by FCC (silica gel, 50-100% ethyl acetate in heptane) gave a white solid which was dissolved in ethyl acetate (20 mL) and washed with water (2 x 15 mL). The organic extract was dried over sodium sulfate, filtered and concentrated to give the title compound 162 mg (69% yield) as a white solid. Tr(METCR1278) = 1.54 min, (ES + ) (M+H) + 298.

[0779] Step 2, Method 15: 1-(Pyridin-2-yl)-2-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]ethan-1- one

[0780] To a solution of 2-bromopyridine (94 mg, 0.59 mmol) in tetrahydrofuran (4 mL) was added dropwise n-butyllithium (1.6 M in hexanes, 0.40 mL, 0.64 mmol) at -78 °C. After stirring at -78 °C for 30 minutes, a solution of N-methoxy-N-methyl-2-[2-(pyridin-3-yl)-1,3-benzoxazol-6-yl]acetamide (160 mg, 0.54 mmol) in tetrahydrofuran (2 mL) was added dropwise. The reaction mixture was then stirred at -78 °C for 1 hour, then allowed to warm to room temperature and stirred for 1 hour. The mixture was cooled to -78 °C and quenched using saturated ammonium chloride (1 mL). The mixture was then diluted with water (30 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated. Purification by FCC (silica gel, 0-100% ethyl acetate in heptane) gave the title compound 44 mg (26% yield) as a white solid. δ HNMR (500 MHz, Chloroform) 9.46 (d, J = 1.6 Hz, 1H), 8.79 - 8.73 (m, 2H), 8.51 (dt, J = 8.0, 1.9 Hz, 1H), 8.07 (d, J = 7.8 Hz, 1H), 7.84 (td, J = 7.7, 1.7 Hz, 1H), 7.78 (d, J = 1.3 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.53 - 7.45 (m, 2H), 7.38 (dd, J = 8.4, 1.6 Hz, 1H), 4.70 (s, 2H). Tr (MET-uHPLC-AB-101) = 2.82 min, (ES + )(M+H) + 316.

[0781] Step 3, Method 15: 1-(Pyridin-2-yl)-2-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]ethan-1-ol

[0782] Sodium borohydride (5 mg, 0.13 mmol) was added to a stirred solution of 1-(pyridin-2-yl)-2-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]ethan-1-one (34 mg, 0.11 mmol) in anhydrous tetrahydrofuran (1 mL) and methanol (0.044 mL, 1.08 mmol) at room temperature under nitrogen. The reaction mixture was stirred at this temperature for 2 hours. The mixture was quenched with water (0.5 mL), diluted with water (15 mL) and extracted with ethyl acetate (2 x 15 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated. Purification by FCC (silica gel, 20-100% ethyl acetate / heptane) afforded the title compound 7 mg (20% yield) as a white solid.

[0783] Example 1, Method 15: 1-(Pyridin-2-yl)-2-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]ethan-1-ol

[0784] δ H NMR (500 MHz, DMSO) 9.33 (s, 1H), 8.80 (d, J = 4.2 Hz, 1H), 8.60-

[0785] 8.47 (m, 2H), 7.78 (t, J = 7.6 Hz, 1H), 7.70-7.62 (m, 2H), 7.59 (s, 1H), 7.46 (d, J = 7.8 Hz, 1H), 7.31-7.23 (m, 2H), 5.55 (br. s, 1H), 4.89 (dd, J = 7.6, 4.5 Hz, 1H), 3.27 (dd, J = 13.8, 4.4 Hz, 1H), 3.04 (dd, J = 13.6, 8.0 Hz, 1H). Tr (MET-uHPLC-AB-101) = 1.43 min, (ES + )(M+H) + 318.

[0786] The following examples were prepared using Method 15 as described above:

[0787]

[0788] Table 16

[0789] Method 16

[0790] Scheme for Method 16

[0791]

[0792] Step 1, Method 16: 6-Methoxy-2-[2-(pyridin-3-yl)-l,3-benzoxazol-5-yl]-l,2- dihydroisoquinolin-l-one

[0793] A round bottom flask was charged with 6-methoxyisoquinoline-l(2H)-one (64 mg, 0.36 mmol), 5-bromo-2-(pyridin-3-yl)-l,3-benzoxazole (150 mg, 0.55 mmol), copper(I) iodide (14 mg, 0.07 mmol), L-proline (17 mg, 0.15 mmol), and anhydrous potassium carbonate (100 mg, 0.73 mmol) under nitrogen. DMSO (5 mL) was added and the mixture was heated to 120 °C overnight. Water (6 mL) and ethyl acetate (10 mL) were added and the mixture was filtered through. The solid was washed with ethyl acetate (2 x 5 mL) and water (2 x 2 mL) and recrystallized from a mixture of methanol (40 mL) and DMSO (3 mL) while hot to give the title compound 23 mg (17% yield) as an off-white powder.

[0794] Example 1, Method 16: 6-Methoxy-2-[2-(pyridin-3-yl)-l,3-benzoxazol-5-yl]-l,2- dihydroisoquinolin-l-one

[0795] δ HNMR (500 MHz, DMSO) 9.41 (br. s, 1H), 8.85 (br. s, 1H), 8.59 (d, J = 8.0 Hz, 1H), 8.18 (d, J = 8.8 Hz, 1H), 8.00 - 7.94 (m, 2H), 7.69 (dd, J = 7.9, 4.8 Hz, 1H), 7.55 (dd, J = 8.6, 2.1 Hz, 1H), 7.51 (d, J = 7.4 Hz, 1H), 7.23 (d, J = 2.5 Hz, 1H), 7.14 (dd, J = 8.9, 2.5 Hz, 1H), 6.69 (d, J = 7.4 Hz, 1H), 3.91 (s, 3H). Tr (MET-uHPLC-AB-101) = 2.86 min, (ES + )(M+H) + 370.

[0796] The following examples were prepared using Method 16 as described above:

[0797]

[0798] Table 17

[0799] Method 17

[0800] Scheme for Method 17

[0801]

[0802] Step 1, Method 17: 2-(pyridin-3-yl)-N-[2,2,2-trifluoro-1-(4-methoxyphenyl)ethyl]- [1,3]oxazolo[5,4-b]pyridin-6-amine

[0803] To a stirred solution of 2,2,2-trifluoro-l-(4-methoxyphenyl)ethanone (51 mg, 0.25 mmol) in tetrahydrofuran (2.5 mL) at -78 °C was added 1 M titanium (IV) chloride in dichloromethane (0.25 mL, 0.25 mmol). The mixture was then left stirring at -78 °C for 10 minutes before 2-(pyridin-3-yl)-[l,3]oxazolo[5,4- b]pyridin-6-amine (53 mg, 0.25 mmol, prepared via Method 19) was added and the mixture was allowed to warm to room temperature. Triethylamine (0.1 mL, 0.75 mmol) was added and the mixture was stirred at room temperature for 3 hours. Methanol (0.2 mL) followed by sodium borohydride (28 mg, 0.75 mmol) was added to the mixture and the mixture was stirred at room temperature overnight. The mixture was treated with sodium borohydride (28 mg, 0.75 mmol) and stirred at room temperature overnight. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (2 x 15 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated. Purification via preparative HPLC (acetonitrile / water) gave the title compound 1.7 mg (yield 2%) as a brown solid.

[0804] Example 1, Method 17: 2-(pyridin-3-yl)-N-[2,2,2-trifluoro-l-(4- methoxyphenyl)ethyl]-[l,3]oxazolo[5,4-b]pyridin-6-amine

[0805] δ H NMR (500 MHz, DMSO) 9.29 (d, J = 1.7 Hz, 1H), 8.80 (dd, J = 4.8, 1.6 Hz, 1H), 8.48 (dt, J = 8.0, 1.9 Hz, 1H), 8.06 (d, J = 2.6 Hz, 1H), 7.66 (d, J = 2.6 Hz, 1H), 7.64 (dd, J = 8.0, 4.9 Hz, 1H), 7.56 (d, J = 8.7 Hz, 2H), 7.08 (d, J = 10.3 Hz, 1H), 6.97 (d, J = 8.8 Hz, 2H), 5.64 (p, J = 8.4, 7.9 Hz, 1H), 3.74 (s, 3H). Tr (MET-uHPLC-AB-101) = 3.23 min, (ES + )(M+H) + 401.

[0806] The following examples were prepared using Method 17 as described above:

[0807]

[0808] Table 18

[0809] Method 18

[0810] Scheme of method 18

[0811]

[0812] Step 1, Method 18: 3-{6-[2-(4-methoxyphenyl)ethynyl]-[l,3]oxazolo[5,4- b]pyridin-2-yl}pyridine

[0813] A mixture of 3-{6-bromo-[l,3]oxazolo[5,4-b]pyridin-2-yl}pyridine (50 mg, 0.18 mmol, prepared via Method 11), 1-ethynyl-4-methoxybenzene (72 mg, 0.54 mmol) and copper(I) iodide (3 mg, 0.013 mmol) in 1,4-dioxane (1.5 mL) and triethylamine (0.13 mL, 0.90 mmol) was degassed under a stream of nitrogen for 10 minutes. Palladium(II) dichloride-triphenylphosphine (1 :2:2) (9 mg, 0.013 mmol) was added and the mixture was stirred at 80 °C for 2 hours. The reaction was then scaled up proportionally: 3-{6-bromo-[l,3]oxazolo[5,4-b]pyridin-2-yl}pyridine (200 mg, 0.72 mmol), 1-ethynyl-4-methoxybenzene (287 mg, 2.17 mmol), copper(I) iodide (10 mg, 0.053 mmol), triethylamine (0.50 mL, 3.61 mmol) and palladium(II) dichloride-triphenylphosphine (1 :2:2) (37 mg, 0.052 mmol) in 1,4-dioxane (6 mL) and stirred at 80 °C for 2.5 hours. The two reaction mixtures were then combined, diluted with water (35 mL) and extracted with ethyl acetate (2 x 35 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated. Purification by FCC (silica gel, 0-100% ethyl acetate / heptane followed by 0-10% methanol / dichloromethane) afforded the title compound 188 mg (63% yield) as a brown solid. Tr(METCR1278) = 2.24 min, (ES + )(M+H) + 328.

[0814] Step 2, Method 18: 3-{6-[(Z)-2-(4-methoxyphenyl)vinyl]-[l,3]oxazolo[5,4- b]pyridin-2-yl}pyridine

[0815] To a stirred solution of 3-{6-[2-(4-methoxyphenyl)ethynyl]-[l,3]oxazolo[5,4- b]pyridin-2-yl}pyridine (88 mg, 0.27 mmol) and quinoline (0.032 mL, 0.27 mmol) in tetrahydrofuran (4 mL) and ethanol (4 mL) under nitrogen in a pressure vessel was added Lindlar catalyst (9 mg, 0.032 mmol). The mixture was placed under a hydrogen atmosphere (1 bar), heated to 80 °C and stirred at this temperature overnight. The mixture was filtered through Celite® and rinsed with tetrahydrofuran (10 mL), then the filtrate was concentrated. The mixture was then treated with Lindlar catalyst (8.6 mg, 0.032 mmol), placed under a hydrogen atmosphere (3.5 bar), heated to 80 °C and stirred at this temperature overnight. The mixture was filtered through Celite® and rinsed with tetrahydrofuran (10 mL). The filtrate was concentrated and purified by FCC (silica gel, 0-3% methanol / dichloromethane) and by preparative HPLC (acetonitrile / water) to give the title compound 6.2 mg (7% yield) as a white powder.

[0816] Example 1, Method 18: 3-{6-[(Z)-2-(4-methoxyphenyl)vinyl]-[l,3]oxazolo[5,4- b]pyridin-2-yl}pyridine

[0817] δ H NMR (500 MHz, DMSO) 9.35 (d, J = 1.9 Hz, 1H), 8.84 (dd, J = 4.8, 1.6 Hz, 1H), 8.54 (dt, J = 8.0, 1.9 Hz, 1H), 8.25 (d, J = 1.8 Hz, 1H), 8.05 (d, J = 1.8 Hz, 1H), 7.67 (dd, J = 8.0, 4.8 Hz, 1H), 7.17 (d, J = 8.7 Hz, 2H), 6.85 (d, J = 8.7 Hz, 2H), 6.79 (d, J = 12.1 Hz, 1H), 6.69 (d, J = 12.1 Hz, 1H), 3.74 (s, 3H). Tr (MET-uHPLC-AB-101) = 3.53 min, (ES + )(M+H) + 330.

[0818] The following examples were prepared using Method 18 as described above:

[0819]

[0820]

[0821] Table 19

[0822] Method 19

[0823] Scheme of Method 19

[0824]

[0825] Step 1, Method 19: 2-(pyridin-3-yl)-[1,3]oxazolo[5,4-b]pyridin-6-amine

[0826] To a pressure tube was added 9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine (189 mg, 0.33 mmol), tris(dibenzylideneacetone)dipalladium(0) (100 mg, 0.11 mmol), 3-{6-bromo-[1,3]oxazolo[5,4-b]pyridin-2-yl}pyridine (300 mg, 1.09 mmol, prepared via Method 11), benzophenone imine (236 mg, 1.30 mmol) and cesium carbonate (1.06 g, 3.26 mmol) in N,N-dimethylacetamide (6 mL). The mixture was degassed using a stream of nitrogen for 10 minutes. The mixture was then heated to 110 °C and stirred at this temperature overnight. The mixture was then diluted with water (70 mL) and extracted with ethyl acetate (2 x 70 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated. The residue was diluted with tetrahydrofuran (15 mL), 2M hydrochloric acid (6 mL) was added and the mixture was left to stand at room temperature for 1 hour. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL). The aqueous extract was then basified to pH 8-9 using saturated sodium bicarbonate solution and extracted with ethyl acetate (2 x 50 mL). The organic extracts were dried over sodium sulfate, filtered and concentrated. The solid was triturated with dichloromethane to give the title compound 94 mg as a light brown solid. The filtrate was then concentrated and purified by FCC (silica gel, 0-100% heptane / ethyl acetate followed by 10% methanol / dichloromethane) to give the title compound 18 mg (total 112 mg, 40% yield) as a light brown solid. Tr(METCR1278) = 1.17 min, (ES + )(M+H) + 213.

[0827] Step 2, Method 19: 5-methoxy-2-[2-(pyridin-3-yl)-[1,3]oxazolo[5,4-b]pyridin-6-yl]-2,3-dihydro-1H- isoindol-1-one

[0828] Under nitrogen atmosphere, a solution of 2-(pyridin-3-yl)-[1,3]oxazolo[5,4-b]pyridin-6-amine (50 mg, 0.18 mmol) in tetrahydrofuran (2 mL) was added to sodium hydride (60% in mineral oil, 15 mg, 0.37 mmol). The suspension was stirred at room temperature for 10 minutes. A solution of ethyl 2-(bromomethyl)-4-methoxybenzoate (50 mg, 0.18 mmol, described in WO2009042907) in tetrahydrofuran (1 mL) was added, and the mixture was stirred at room temperature for 1 hour. The mixture was heated to 60 °C and stirred for 2 hours, then allowed to stand overnight at room temperature. The mixture was diluted with water (6 mL) and filtered to give a brown solid (22 mg). Recrystallization from DMSO (1 mL) and acetonitrile (1 mL) and then from DMSO (2 mL) gave 1.5 mg (2% yield) of the title compound as a grayish-white powder.

[0829] Example 1, Method 19: 5-Methoxy-2-[2-(pyridin-3-yl)-[1,3]oxazolo[5,4-b]pyridin-6-yl]-2,3-dihydro-1H-isoindol-1-one

[0830] δ H NMR(250MHz,DMSO)9.40(s,1H),8.90(d,J=2.4Hz,1H),8.85(d,J

[0831] =5.5Hz,1H),8.74(d,J=2.4Hz,1H),8.57(dt,J=8.0,1.9Hz,1H),7.76(d,J=8.5Hz,1H),7.67(d d,J=8.3,4.6Hz,1H),7.28-7.20(m,1H),7.13(dd,J=8.4,2.2Hz,1H),5.10(s,2H),3.93(s,3H). Tr(MET-uHPLC-AB-101)=2.67min,(ES + (M+H) + 359.

[0832] The following examples were prepared using method 19 as described above:

[0833]

[0834] Table 20

[0835] Method 20

[0836] Method 20

[0837]

[0838] Step 1, Method 20: 5-methoxypyrazine-2-carboxylic acid methyl ester

[0839] To 5-chloropyrazine-2-carboxylic acid methyl ester (2.00 g, 11.6 mmol) was added 0.5 M sodium methoxide in methanol (27.8 mL, 13.9 mmol) under nitrogen. The mixture was refluxed at 90 °C for 15 minutes. Water (80 mL) was added and the mixture was extracted with ethyl acetate (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated to give the title compound 1.68 g (79% yield) as a white powder. H NMR (500 MHz, Chloroform) δ 8.88 (d, J = 1.2 Hz, 1H), 8.28 (d, J = 1.2 Hz, 1H), 4.05 (s, 3H), 4.00 (s, 3H). Tr (METCR1278) = 1.23 min, (ES + )(M+H) + 169.

[0840] Step 2, Method 20: (5-methoxypyrazin-2-yl)methanol

[0841] To a stirred solution of 5-methoxypyrazine-2-carboxylic acid methyl ester (200 mg, 1.19 mmol) in anhydrous tetrahydrofuran (8 mL) was added sodium borohydride (270 mg, 7.14 mmol) under nitrogen. The mixture was refluxed at 65 °C for 15 minutes before methanol (1.59 mL, 39.2 mmol) was added slowly. The reaction mixture was refluxed at 65 °C for 1.5 hours. The mixture was quenched with water (0.5 mL) and then diluted with water (15 mL) and extracted with ethyl acetate (2 x 25 mL) and then 20% 2-propanol / dichloromethane (25 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated to give the title compound 115 mg (69% yield) as a white crystalline solid. H NMR (500 MHz, DMSO) δ 8.28 - 8.16 (m, 2H), 5.41 (t, J = 5.8 Hz, 1H), 4.54 (d, J = 5.6 Hz, 2H), 3.90 (s, 3H). Tr (METCR1278) = 0.74 min, (ES + )(M+H) + 141.

[0842] Step 3, Method 20: Methanesulfonic acid (5-methoxypyrazin-2-yl)methyl ester

[0843] To a stirred solution of (5-methoxypyrazin-2-yl)methanol (73 mg, 0.52 mmol) in dichloromethane (1 mL) under nitrogen was added triethylamine (0.08 mL, 0.73 mmol) followed by methanesulfonyl chloride (0.042 mL, 0.55 mmol). The mixture was stirred at room temperature for 1 hour. The mixture was then partitioned between dichloromethane (10 mL) and water (10 mL). The organic extract was dried over sodium sulfate, filtered and concentrated to give the title compound 59 mg (52% yield) as a yellow oil. Tr(METCR1278) = 1.25 min, (ES + )(M+H) + 219.

[0844] Step 4, Method 20: 5-[(5-Methoxypyrazin-2-yl)methoxy]-2-(pyridin-3-yl)-1,3- benzoxazole

[0845] To a stirred solution of (5-methoxypyrazin-2-yl)methanol (73 mg, 0.52 mmol) in dichloromethane (1 mL) under nitrogen was added triethylamine (0.08 mL, 0.73 mmol) followed by methanesulfonyl chloride (0.042 mL, 0.55 mmol). The mixture was stirred at room temperature for 1 hour. The mixture was then partitioned between dichloromethane (10 mL) and water (10 mL). The organic extract was dried over sodium sulfate, filtered and concentrated to give the title compound 59 mg (52% yield) as a yellow oil. Tr(METCR1278) = 1.25 min, (ES

[0846] Example 1, Method 20: 5-[(5-Methoxypyrazin-2-yl)methoxy]-2-(pyridin-3-yl)-1,3- benzoxazole

[0847] δ H NMR (500 MHz, DMSO) 9.32 (s, 1H), 8.86-8.75 (m, 1H), 8.56-8.47 (m, 1H), 8.42 (s, 1H), 8.35 (s, 1H), 7.74 (d, J = 8.9 Hz, 1H), 7.68-7.61 (m, 1H), 7.54 (s, 1H), 7.14 (d, J = 8.9 Hz, 1H), 5.23 (s, 2H), 3.92 (s, 3H). Tr(MET-uHPLC-AB-101) = 2.94 min, (ES + )(M+H) + 335.

[0848] The following examples are prepared using method 20 as described above:

[0849]

[0850] Table 21

[0851] Method 21

[0852] Scheme of Method 21

[0853]

[0854] Step 1, Method 21: 3-Methoxy-6-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]-5H,6H,7H-pyrrolo[3,4-b]pyridin-7-one

[0855] Tetrahydrofuran (2 mL) was added to sodium hydride (60% in mineral oil, 15 mg, 0.38 mmol) and 2-(pyridin-3-yl)-1,3-benzoxazol-5-amine (41 mg, 0.19 mmol) under nitrogen atmosphere. The suspension was stirred at room temperature for 10 minutes. Then a solution of methyl 3-(bromomethyl)-5-methoxypyridine-2-carboxylic acid (50 mg, 0.19 mmol, described in Heterocycles (2013), 87(10), 2071-2079) in tetrahydrofuran (1 mL) was added and the mixture was stirred at 60 °C for 2 hours, then at 70 °C for 2 hours, then at 80 °C for 2 hours, followed by stirring at room temperature for 2 days. The mixture was diluted with water (2 mL) and filtered to give a solid, which was ground in ethyl acetate (2 mL) to give 18 mg (26% yield) of the title compound as a brown powder.

[0856] Example 1, Method 21: 3-Methoxy-6-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]-5H,6H,7H-pyrrolo[3,4-b]pyridin-7-one

[0857] δ H NMR(250MHz,DMSO)9.38(d,J=1.5Hz,1H),8.81(dd,J=4.8,1.7

[0858] Hz, 1H), 8.54 (dt, J = 8.0, 2.1 Hz, 1H), 8.48 (d, J = 2.7 Hz, 1H), 8.31 (d, J = 1.9 Hz, 1H), 8.02 (dd, J = 8.9, 2.2 Hz, 1H), 7.86 (d, J = 9.0 Hz, 1H), 7.73 - 7.58 (m, 2H), 5.06 (s, 2H), 3.99 (s, 3H). Tr (MET-uHPLC-AB-101) = 2.26 min, (ES + )(M+H) + 359.

[0859] The following examples were prepared using Method 21 as described above:

[0860]

[0861] Table 22

[0862] Method 22

[0863] Scheme for Method 22

[0864]

[0865] Step 1, Method 22: N-(2,4-dihydroxyphenyl)pyridine-3-carboxamide

[0866] To a stirred solution of 4-aminobenzene-1,3-diol hydrochloride (0.50 g, 3.09 mmol) in pyridine (6 mL) was added nicotinoyl chloride hydrochloride (0.55 g, 3.09 mmol) in portions under ice cooling. The mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo and the residue was diluted with water (50 mL) and extracted with ethyl acetate (2 x 60 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated. Purification by FCC (silica gel, 30-100% ethyl acetate / heptane) gave the title compound 148 mg (21% yield) as a light brown solid. H NMR (250 MHz, DMSO) 9.47 (d, J = 88.0 Hz, 3H), 9.10 (d, J = 1.7 Hz, 1H), 8.73 (dd, J = 4.8, 1.5 Hz, 1H), 8.28 (dt, J = 7.9, 1.9 Hz, 1H), 7.53 (dd, J = 7.7, 5.1 Hz, 1H), 7.20 (d, J = 8.6 Hz, 1H), 6.36 (d, J = 2.6 Hz, 1H), 6.24 (dd, J = 8.6, 2.6 Hz, 1H). Tr (MET CR1278) = 0.79 min, (ES + )(M+H) + 231.

[0867] Step 2, Method 22: 2-(pyridin-3-yl)-l,3-benzoxazol-6-ol

[0868] N-(2,4-dihydroxyphenyl)pyridine-3-carboxamide (150 mg, 0.65 mmol) and acetic acid (3 mL) were heated in a microwave at 200 °C for 30 minutes. The mixture was then concentrated in vacuo and the residue triturated in ethyl acetate (10 mL) to give the title compound 55 mg (40% yield) as a light brown powder. H NMR (500 MHz, DMSO) 9.96 (s, 1H), 9.28 (d, J = 1.7 Hz, 1H), 8.76 (dd, J = 4.8, 1.5 Hz, 1H), 8.45 (dt, J = 8.0, 1.9 Hz, 1H), 7.67 - 7.59 (m, 2H), 7.12 (d, J = 2.2 Hz, 1H), 6.89 (dd, J = 8.6, 2.3 Hz, 1H). Tr (METCR1278) = 1.38 min, (ES + (M+H) + 213.

[0869] Step 3, Method 22: 2-(pyridin-3-yl)-6-(pyridin-3-ylmethoxy)-l,3-benzoxazole

[0870] To sodium hydride (60% in mineral oil, 10 mg, 0.25 mmol) was added a solution of 2-(pyridin-3-yl)-l,3-benzoxazol-6-ol (50 mg, 0.24 mmol) in N,N- dimethylformamide (1 mL) and the mixture stirred at room temperature for 30 minutes. Sodium hydride (60% in mineral oil, 10 mg, 0.25 mmol) and 3-(bromomethyl)pyridine hydrobromide (66 mg, 0.26 mmol) were dissolved in N,N-dimethylformamide (1 mL) and stirred at room temperature for 10 minutes. This suspension was then added to the reaction mixture and the mixture stirred at room temperature for 1 hour. The mixture was quenched with water (0.5 mL) and then diluted with water (15 mL) and extracted with ethyl acetate (2 x 15 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated. Purification by FCC (silica gel, 0 to 3% methanol / dichloromethane) gave the title compound 39 mg (55% yield) as an off-white powder.

[0871] Example 1, Method 22: 2-(pyridin-3-yl)-6-(pyridin-3-ylmethoxy)-l,3-benzoxazole

[0872] δ HNMR(500MHz,DMSO)9.30(d,J=1.8Hz,1H),8.78(dd,J=4.8,1.6

[0873] Hz,1H),8.72(d,J=1.9Hz,1H),8.57(dd,J=4.8,1.6Hz,1H),8.48(dt,J=8.0,1.9Hz,1H),7.92(dt,J=7.8,1.9Hz,1H),7.76(d,J=8. 7Hz, 1H), 7.64 (dd, J=8.0, 4.8Hz, 1H), 7.58 (d, J=2.4Hz, 1H), 7.45 (dd, J=7.8, 4.8Hz, 1H), 7.14 (dd, J=8.7, 2.4Hz, 1H), 5.27 (s, 2H). Tr(MET-uHPLC-AB-101)=1.68min,(ES + (M+H) + 304.

[0874] The following examples were prepared using method 22 as described above:

[0875]

[0876] Table 23

[0877] Method 23

[0878] Scheme of Method 23

[0879]

[0880] Step 1, Method 23: Methyl 2-(pyridin-3-yl)-1,3-benzoxazole-5-carboxylate

[0881] Methyl 3-amino-4-hydroxybenzoate (200 mg, 1.2 mmol) was suspended in 1,4-dioxane (3 mL), and pyridine-3-carbonyl chloride hydrochloride (234 mg, 1.32 mmol) was added. The mixture was then heated in a microwave oven to 200 °C and held for 15 min. This operation was repeated 5 times. All reaction mixtures were combined and then partitioned between ethyl acetate (100 mL) and saturated sodium bicarbonate aqueous solution (80 mL). The organic extract was dried over sodium sulfate, filtered, and concentrated. FCC purification (silica gel, 20–100% ethyl acetate / heptane) yielded 560 mg (37% yield) of the title compound as a light brown solid. HNMR (500 MHz, DMSO) 9.37 (d, J = 1.7 Hz, 1H), 8.84 (dd, J = 4.8, 1.6 Hz, 1H), 8.56 (dt, J = 8.0, 1.9 Hz, 1H), 8.37 (d, J = 1.4 Hz, 1H), 8.09 (dd, J = 8.6, 1.7 Hz, 1H), 7.97 (d, J = 8.6 Hz, 1H), 7.68 (ddd, J = 8.0, 4.8, 0.7 Hz, 1H), 3.91 (s, 3H). Tr (METCR1278) = 1.74 min, (ES + )(M+H) + 255.

[0882] Step 2, Method 23: [2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]methanol

[0883] To a stirred solution of methyl 2-(pyridin-3-yl)-1,3-benzoxazole-5-carboxylate (340 mg, 1.34 mmol) in anhydrous tetrahydrofuran (12 mL) was added 4M lithium aluminum hydride / tetrahydrofuran (0.25 mL, 1.00 mmol) under nitrogen. The mixture was stirred at 0 °C for 30 minutes. The mixture was quenched by careful addition of water (1 mL) followed by saturated ammonium chloride solution (0.5 mL). The mixture was stirred at 0 °C for 20 minutes. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (2 x 15 mL). The organic extracts were dried over sodium sulfate, filtered and concentrated. Purification by FCC (silica gel, 0-15% methanol / dichloromethane) gave the title compound 197 mg (65% yield) as an off-white solid. Tr (MET-uHPLC-AB-101) = 1.7 min, (ES + )(M+H) + 227.

[0884] Step 3, Method 23: 5-(chloromethyl)-2-(pyridin-3-yl)-1,3-benzoxazole

[0885] To a stirred solution of [2-(pyridin-3-yl)-l,3-benzoxazol-5-yl]methanol (50 mg, 0.22 mmol) in dichloromethane (1 mL) under nitrogen, was added triethylamine (0.068 mL, 0.48 mmol) followed by methanesulfonyl chloride (0.036 mL, 0.46 mmol) under ice cooling. The mixture was then allowed to warm to room temperature and stirred for 48 h. The mixture was again treated with triethylamine (0.068 mL, 0.48 mmol) and methanesulfonyl chloride (0.036 mL, 0.46 mmol) and stirred at room temperature for 2 h. The mixture was partitioned between dichloromethane (10 mL) and water (10 mL). The organic extract was dried over sodium sulfate, filtered and concentrated to give the title compound 75 mg (91% yield) as an orange solid. Tr(METCR1278) = 1.86 min, (ES + )(M+H) + 245.

[0886] Step 4, Method 23: 5-{[(5-methoxypyridin-2-yl)oxy]methyl}-2-(pyridin-3-yl)-l,3- benzoxazole

[0887] A suspension of 5-(chloromethyl)-2-(pyridin-3-yl)-l,3-benzoxazole (50 mg, 0.20 mmol), 5-methoxy-l,2-dihydropyridin-2-one (28 mg, 0.22 mmol) and silver carbonate (38 mg, 0.14 mmol) in toluene (2 mL) was stirred at 80 °C for 24 h. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated. Purification by preparative HPLC (acetonitrile / water) gave the title compound 2.4 mg (4% yield) as an off-white powder.

[0888] Example 1, Method 23: 5-{[(5-methoxypyridin-2-yl)oxy]methyl}-2-(pyridin-3-yl)-l,3- benzoxazole

[0889] δ H NMR (500 MHz, DMSO) 9.35 (d, J = 2.0 Hz, 1H), 8.81 (dd, J = 4.8, 1.5

[0890] Hz, 1H), 8.54 (dt, J = 8.0, 1.9 Hz, 1H), 7.91 (s, 1H), 7.87 (d, J = 3.1 Hz, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.66 (dd, J = 8.0, 4.8 Hz, 1H), 7.55 (dd, J = 8.4, 1.5 Hz, 1H), 7.42 (dd, J = 8.9, 3.1 Hz, 1H), 6.87 (d, J = 8.9 Hz, 1H), 5.42 (s, 2H), 3.77 (s, 3H). Tr (MET-uHPLC-AB-101) = 3.22 min, (ES + )(M+H) + 334.

[0891] The following examples were prepared using Method 23 as described above:

[0892]

[0893] Table 24

[0894] Method 24

[0895] Scheme for Method 24

[0896]

[0897] Step 1, Method 24: 5-(Chloromethyl)pyrimidine hydrochloride

[0898] To a solution of pyrimidin-5-ylmethanol (48 mg, 0.43 mmol) in dichloromethane (3 mL) at 0 °C was added thionyl chloride (0.26 mL, 3.6 mmol) slowly dropwise. The mixture was heated to reflux (50 °C) for 2 h, then the mixture was concentrated. Dichloromethane (5 mL) was added and the mixture was concentrated (x3) to give the title compound as a yellow oil which was used directly in the next step. Tr (MET CR1278) = 0.90 min, (ES + )(M+H) + 129 / 131.

[0899] Step 2, Method 24: 4-[5-(pyrimidin-5-ylmethoxy)-1-benzofuran-2-yl]pyridine-3- carbonitrile

[0900] Dissolve 4-(5-hydroxy-l-benzofuran-2-yl)pyridine-3-carbonitrile (90%, 80 mg, 0.3 mmol, prepared via Method 9), 5-(chloromethyl)pyrimidine hydrochloride (0.43 mmol) and potassium iodide (56 mg, 0.34 mmol) in anhydrous N,N-dimethylformamide (6 mL) and stir at room temperature for 5 minutes. Add sodium hydride (60% in mineral oil, 37 mg, 0.91 mmol) and stir the reaction mixture at room temperature for 3 hours. Add water (0.1 mL) and remove the solvent in vacuo. Partition the residue between ethyl acetate (50 mL) and water (50 mL) and extract the aqueous phase with ethyl acetate (2 x 50 mL). Dry the combined organic extracts over sodium sulfate, filter through and concentrate. Purify via FCC (silica gel, 0-80% ethyl acetate in heptane) to give the title compound 30.3 mg (30% yield) as an off-white solid.

[0901] Example 1, Method 24: 4-[5-(Pyrimidin-5-ylmethoxy)-l-benzofuran-2-yl]pyridine-3- carbonitrile

[0902] δ H NMR (500 MHz, DMSO) 9.19 (s, 1H), 9.12 (s, 1H), 8.96 (s, 2H), 8.92 (d, J = 5.4 Hz, 1H), 8.08 (d, J = 5.5 Hz, 1H), 7.96 (s, 1H), 7.67 (d, J = 9.0 Hz, 1H), 7.53 (d, J = 2.6 Hz, 1H), 7.21 (dd, J = 9.0, 2.6 Hz, 1H), 5.26 (s, 2H). Tr (MET-uHPLC-AB-101) = 2.8 min, (ES + )(M+H) + 329.

[0903] The following examples were prepared using Method 24 as described above:

[0904]

[0905] Table 25

[0906] Method 25

[0907] Scheme for Method 25

[0908]

[0909] Step 1, Method 25: l-(5-Methoxypyridin-2-yl)ethan-l-ol

[0910] To a stirred solution of 5-methoxypyridine-2-carbaldehyde (220 mg, 1.60 mmol) in tetrahydrofuran (3 mL) at ice-cooling was added 1.4 M methylmagnesium bromide in tetrahydrofuran (1.15 mL, 1.60 mmol). The mixture was stirred at ice-cooling for 30 minutes. The mixture was quenched with saturated aqueous ammonium chloride solution (0.5 mL), diluted with water (15 mL) and extracted with ethyl acetate (2 x 15 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated to give the title compound 218 mg (89% yield) as a yellow oil. H NMR (500 MHz, DMSO) 8.17 (d, J = 2.9 Hz, 1H), 7.42 (d, J = 8.6 Hz, 1H), 7.36 (dd, J = 8.7, 2.9 Hz, 1H), 5.23 (d, J = 4.6 Hz, 1H), 4.72 - 4.64 (m, 1H), 3.80 (s, 3H), 1.32 (d, J = 6.5 Hz, 3H).

[0911] Step 2, Method 25: 3-{6-[1-(5-methoxypyridin-2-yl)ethoxy]-[1,3]oxazolo[5,4- b]pyridin-2-yl}pyridine

[0912] To a stirred solution of 1-(5-methoxypyridin-2-yl)ethan-1-ol (20 mg, 0.13 mmol), 2-(pyridin-3-yl)-[1,3]oxazolo[5,4-b]pyridin-6-ol (22 mg, 0.10 mmol, prepared by Method 30) and triphenylphosphine (41 mg, 0.16 mmol) in dry tetrahydrofuran (1 mL) at 0 °C was added diisopropyl azodicarboxylate (0.031 mL, 0.16 mmol). The mixture was allowed to warm to room temperature and stirred overnight. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (2 x 15 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated. Purification by FCC (silica gel, 50-100% ethyl acetate in heptane) and purification by preparative HPLC (acetonitrile / water) gave the title compound 7.4 mg (21% yield) as a colourless crystalline solid.

[0913] Example 2, Method 25: 3-{6-[1-(5-methoxypyridin-2-yl)ethoxy]-[1,3]oxazolo[5,4- b]pyridin-2-yl}pyridine

[0914] δ H NMR (500 MHz, DMSO) 9.31 (d, J = 1.9 Hz, 1H), 8.81 (dd, J = 4.8, 1.6

[0915] Hz, 1H), 8.50 (dt, J = 8.0, 1.9 Hz, 1H), 8.28 (d, J = 2.9 Hz, 1H), 8.12 (d, J = 2.7 Hz, 1H), 7.87 (d, J = 2.7 Hz, 1H), 7.65 (dd, J = 7.9, 4.8 Hz, 1H), 7.49 (d, J = 8.7 Hz, 1H), 7.38 (dd, J = 8.7, 3.0 Hz, 1H), 5.63 (q, J = 6.4 Hz, 1H), 3.80 (s, 3H), 1.64 (d, J = 6.4 Hz, 3H). Tr (MET-uHPLC-AB-101) = 2.6 min, (ES + )(M+H) + 349.

[0916] The following examples were prepared using Method 25 as described above:

[0917]

[0918] Table 26

[0919] Method 26

[0920] Scheme for Method 26

[0921]

[0922] Step 1, Method 26: 4-{5-[(5-methoxypyrazin-2-yl)methoxy]-l-benzofuran-2-yl}pyridine-3- carbonitrile

[0923] To a solution of sodium hydride (60% in mineral oil, 11.8 mg, 0.29 mmol) was added a solution of 4-(5-hydroxy-l-benzofuran-2-yl)pyridine-3-carbonitrile (57 mg, 0.27 mmol, prepared via Method 9) in N,N-dimethylformamide (1 mL) under nitrogen and the mixture was stirred at room temperature for 30 minutes. A solution of (5-methoxypyrazin-2-yl)methyl methanesulfonate (64 mg, 0.3 mmol, prepared via Method 20) in N,N-dimethylformamide (0.5 mL) was added and the mixture was stirred at room temperature overnight. The mixture was then quenched with water (3 mL) and cooled to room temperature. The resulting suspension was filtered, washed with water (3 mL), methanol (2 mL) and heptane (5 mL) to afford the title compound 63 mg (65% yield) as a brown powder.

[0924] Example 1, Method 26: 4-{5-[(5-methoxypyrazin-2-yl)methoxy]-l-benzofuran-2-yl}pyridine-3- carbonitrile

[0925] δ HNMR(500MHz,DMSO)9.12(s,1H),8.92(d,J=5.4Hz,1H),8.42(d,J

[0926] =1.0Hz,1H),8.35(d,J=1.3Hz,1H),8.08(d,J=5.4Hz,1H),7.95(s,1H),7.66(d,J=9.0 Hz, 1H), 7.52 (d, J = 2.6 Hz, 1H), 7.19 (dd, J = 9.0, 2.6 Hz, 1H), 5.22 (s, 2H), 3.93 (s, 3H). Tr(MET-uHPLC-AB-101)=3.5min,(ES + (M+H) + 359.

[0927] The following examples were prepared using method 26 as described above:

[0928]

[0929] Table 27

[0930] Method 27

[0931] Scheme of Method 27

[0932]

[0933] Step 1, Method 27: Methyl 5-(methoxymethoxy)pyridine-2-carboxylic acid

[0934] Sodium hydride (60% in mineral oil, 144 mg, 3.59 mmol) was suspended in anhydrous N,N-dimethylformamide (5 mL) and cooled to 0 °C. Methyl 5-hydroxypyridine-2-carboxylic acid (500 mg, 3.27 mmol) dissolved in N,N-dimethylformamide (5 mL) was slowly added to the suspension. The reaction mixture was stirred under nitrogen and warmed to room temperature over 30 minutes. The reaction mixture was cooled to 0 °C and chloro(methoxy)methane (0.26 mL, 3.43 mmol) was added dropwise over 15 minutes. The reaction mixture was warmed to room temperature and stirred for 16 hours. Water (20 mL) was added and the solvent was removed under vacuum. The mixture was partitioned between ethyl acetate and water (1:1; 100 mL) and extracted with ethyl acetate (3 x 60 mL). The combined organic phases were washed with water (3 x 80 mL) and brine (50 mL), dried over magnesium sulfate, filtered, and concentrated under vacuum to give 0.6 g (89% yield) of the title compound, an orange oil that solidified upon standing. Tr(METCR1278) = 1.33 min, (ES + (M+H) + 198.

[0935] Step 2, Method 27: [5-(Methoxymethoxy)pyridin-2-yl]methanol

[0936] Methyl 5-(methoxymethoxy)pyridine-2-carboxylate (0.39 g, 1.9 mmol) was dissolved in anhydrous tetrahydrofuran (15 mL) and cooled to 0 °C under a nitrogen atmosphere. 2.4 M Lithium aluminium hydride / tetrahydrofuran (0.87 mL, 2.09 mmol) was added dropwise over 5 minutes and the reaction mixture was stirred at 0 °C for 1.5 hours. A solution of Rochelle salt (1 mL) was added dropwise over 10 minutes with vigorous stirring and the reaction mixture was allowed to warm to room temperature over 1 hour. An emulsion formed which was filtered through filter paper. The filter paper was washed with saturated sodium bicarbonate solution (10 mL) followed by ethyl acetate (3 x 10 mL). The phases were separated and the aqueous phase was extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with brine (10 mL) and dried over sodium sulfate, filtered and concentrated to give the title compound 276 mg (86% yield) as an orange oil. Tr(METCR1278) = 1.09 min, (ES + )(M+H) + 170.

[0937] Step 3, Method 27: Methyl [5-(methoxymethoxy)pyridin-2-yl]methanesulfonate

[0938] [5-(Methoxymethoxy)pyridin-2-yl]methanol (276 mg, 1.63 mmol) was dissolved in dichloromethane (5 mL), cooled to 0 °C and stirred under a nitrogen atmosphere. Triethylamine (250 μL, 1.79 mmol) was added followed by dropwise addition of methanesulfonyl chloride (133 μL, 1.71 mmol). The reaction mixture was stirred for 45 minutes and allowed to warm to room temperature. Water (5 mL) was added and the phases were separated. The aqueous layer was extracted with dichloromethane (3 x 15 mL). The combined organic extracts were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound 275 mg (59% yield) as a dark red oil which was used in the next step without further purification. Tr(METCR1278) = 1.35 min, (ES + )(M+H) + 248.

[0939] Step 4, Method 27: 5-{[5-(Methoxymethoxy)pyridin-2-yl]methoxy}-2-(pyridin-3-yl)- 1,3-benzoxazole

[0940] Methanesulfonic acid [5-(methyloxymethoxy)pyridin-2-yl]methyl ester (276 mg, 1.11 mmol) and 2-(pyridin-3-yl)-1,3-benzoxolan-5-ol (215 mg, 1.01 mmol, prepared via Method 14) were dissolved in anhydrous N,N-dimethylformamide (8 mL) and stirred under a nitrogen atmosphere at 0 °C for 10 minutes. Sodium hydride (60% in mineral oil, 122 mg, 3.04 mmol) was added and the reaction mixture was stirred for 16 hours. Water (1 mL) was added and the reaction mixture was stirred for 10 minutes. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate (50 mL) and water (20 mL). The aqueous phase was extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated. Purification by FCC (silica gel, 10-100% ethyl acetate / heptane) afforded the title compound, 135 mg (36% yield) as a white solid. Tr(METCR1278) = 1.78 min, (ES + )(M+H) + 364.

[0941] Step 5, Method 27: 6-({[2-(pyridin-3-yl)-1,3-benzoxol-5-yl]oxy}methyl)pyridin-3-ol

[0942] To a solution of 5-{[5-(methyloxymethoxy)pyridin-2-yl]methoxy}-2-(pyridin-3-yl)-1,3- benzoxazole (135 mg, 0.37 mmol) in tetrahydrofuran (20 mL) was added 3M aqueous hydrochloric acid (1.3 mL) and the mixture was stirred at 60 °C for 1 hour. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was diluted with water (10 mL) and solid sodium bicarbonate was added until pH 8. The mixture was diluted with water. The mixture was filtered through filter paper and suction collected to afford the title compound 101 mg (85% yield) as a beige solid.

[0943] Example 1, Method 27: 6-({[2-(pyridin-3-yl)-1,3-benzoxol-5-yl]oxy}methyl)pyridin-3-ol

[0944] δ H NMR (500 MHz, DMSO) 9.33 (d, J = 2.0 Hz, 1 H), 8.80 (dd, J = 4.8, 1.5

[0945] Hz, 1H), 8.51 (dt, J = 8.0, 1.9 Hz, 1H), 8.13 (d, J = 2.8 Hz, 1H), 7.73 (d, J = 8.9 Hz, 1H), 7.65 (dd, J = 8.0, 4.8 Hz, 1H), 7.47 (d, J = 2.5 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.19 (dd, J = 8.4, 2.8 Hz, 1H), 7.12 (dd, J = 8.9, 2.5 Hz, 1H), 5.12 (s, 2H). Tr (MET-uHPLC-AB-101) = 1.91 min, (ES + )(M+H) + 320.

[0946] The following examples were prepared using Method 27 as described above:

[0947]

[0948] Table 28

[0949] Method 28

[0950] Scheme for Method 28

[0951]

[0952] Step 1, Method 28: 5-(prop-2-en-1-yloxy)pyrazine-2-carboxylic acid prop-2-en-1-yl ester

[0953] To a solution of sodium hydride (60% in mineral oil, 1.16 g, 29.0 mmol) in N,N- dimethylformamide (25 mL) was added allyl alcohol (9.90 mL, 144.9 mmol) dropwise under nitrogen and the mixture was stirred at room temperature for 20 minutes. A solution of 5-chloropyrazine-2-carboxylic acid methyl ester (5 g, 29.0 mmol) in N,N-dimethylformamide (25 mL) was added and the mixture was stirred at 90 °C for 20 minutes. The mixture was quenched with water (5 mL), diluted with water (200 mL) and extracted with ethyl acetate (2 x 200 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated. Purification by FCC (silica gel, 0-30% ethyl acetate in heptane) gave the title compound 2.31 g (27% yield) as a pale yellow oil. δ HNMR (500 MHz, DMSO) 8.85 (s, 1H), 8.45 (s, 1H), 6.07 (dddd, J = 25.3, 22.6, 10.7, 5.5 Hz, 2H), 5.43 (ddd, J = 17.2, 9.2, 1.5 Hz, 2H), 5.34 - 5.25 (m, 2H), 4.94 (d, J = 5.5 Hz, 2H), 4.83 (d, J = 5.5 Hz, 2H). Tr (METCR1278) = 1.83 min, (ES + )(M+H) + 221.

[0954] Step 2, Method 28: [5-(prop-2-en-1-yloxy)pyrazin-2-yl]methanol

[0955] Sodium borohydride (2.17 g, 57.4 mmol) was added to a stirred solution of 5-(prop-2-en-1-yloxy)pyrazine-2-carboxylic acid prop-2-en-1-yl ester (2.3 g, 10.4 mmol) in anhydrous tetrahydrofuran (150 mL) under nitrogen. The mixture was refluxed at 55 °C for 15 min, then methanol (14 mL, 344.6 mmol) was added slowly. The reaction mixture was refluxed at 65 °C for 30 min, then quenched with water (10 mL). The mixture was diluted with water (200 mL) and extracted with ethyl acetate (2 x 200 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated. Purification by FCC (silica gel, 20-60% ethyl acetate / heptane) gave the title compound 1.09 g (63% yield) as a colorless oil. δ H NMR (500 MHz, DMSO) 8.25 (s, 1H), 8.19 (s, 1H), 6.07 (ddt, J = 16.1, 10.6, 5.4 Hz, 1H), 5.44 - 5.36 (m, 2H), 5.28 - 5.23 (m, 1H), 4.84 (d, J = 5.4 Hz, 2H), 4.54 (d, J = 5.6 Hz, 2H). Tr (METCR1278) = 1.23 min, (ES + )(M+H) + 167.

[0956] Step 3, Method 28: Methanesulfonic acid [5-(prop-2-en-1-yloxy)pyrazin-2-yl]methyl ester

[0957] To a stirred suspension of [5-(prop-2-en-l-yloxy)pyrazin-2-yl]methanol (200 mg, 1.20 mmol) in dichloromethane (10 mL) was added triethylamine (0.18 mL, 1.32 mmol) under nitrogen. The mixture was cooled to 0 °C and methanesulfonyl chloride (0.098 mL, 1.26 mmol) was added. The mixture was allowed to warm to room temperature and stirred for 20 minutes. The mixture was partitioned between dichloromethane (30 mL) and water (30 mL). The organic extract was dried over sodium sulfate, filtered and concentrated to give the title compound 309 mg (quantitative yield) as a yellow oil which was used directly in the next step. Tr(METCR1278) = 1.61 min, (ES + )(M+H) + 245.

[0958] Step 4, Method 28: 5-{[5-(prop-2-en-l-yloxy)pyrazin-2-yl]methoxy}-2-(pyridin-3-yl)-l,3- benzoxazole

[0959] To a solution of [5-(prop-2-en-l-yloxy)pyrazin-2-yl]methanesulfonate (291 mg, 1.19 mmol) and 2-(pyridin-3-yl)-l,3-benzoxazol-5-ol (230 mg, 1.08 mmol, prepared via Method 14) in N,N-dimethylformamide (6 mL) was added sodium hydride (60% in mineral oil, 48 mg, 1.19 mmol) under nitrogen. The mixture was stirred at room temperature overnight. The mixture was quenched with water (1 mL), diluted with water (30 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated. Purification by FCC (silica gel, 0-2% methanol / dichloromethane) gave the title compound 262 mg (67% yield) as an off-white solid. Tr(MET-uHPLC-AB-101) = 3.46 min, (ES + )(M+H) + 361.

[0960] Step 5, Method 28: 5-({[2-(pyridin-3-yl)-l,3-benzoxazol-5-yl]oxy}methyl)-l,2-dihydropyrazin-2- one

[0961] A solution of 5-{[5-(prop-2-en-l-yloxy)pyrazin-2-yl]methoxy}-2-(pyridin-3- yl)-l,3-benzoxazole (250 mg, 0.69 mmol) and N,N-dimethylbarbituric acid (108 mg, 0.69 mmol) in N,N-dimethylformamide (10 mL) was degassed with a stream of nitrogen for 10 minutes. Tetra(triphenylphosphine)palladium(0) (16 mg, 0.014 mmol) was then added and the mixture stirred under a nitrogen atmosphere for 1 hour. The mixture was diluted with water (20 mL) and the precipitate filtered off and dried under vacuum to give the crude product, 186 mg. 50 mg of the crude product was stirred in dichloromethane (2 mL) at room temperature for 2 hours. The solid was filtered off and dried under vacuum to give the title compound 44 mg (20% yield) as an off-white powder. Tr(MET-uHPLC-AB-101) = 1.86 min, (ES + )(M+H) + 321.

[0962] Step 6, Method 28: l-Methyl-5-({[2-(pyridin-3-yl)-l,3-benzoxazol-5-yl]oxy}methyl)- 1,2-dihydropyrazin-2-one

[0963] To a stirred suspension of 5-({[2-(pyridin-3-yl)-l,3-benzoxazol-5-yl]oxy}methyl)-l,2- dihydropyrazin-2-one (30 mg, 0.094 mmol) and silver carbonate (65 mg, 0.23 mmol) in dry toluene (2 mL) in a pressure tube was added iodomethane (0.014 mL, 0.22 mmol). The mixture was heated at 100 °C for 2 hours and then at 140 °C for 1 hour. The mixture was diluted with ethyl acetate (10 mL), filtered through glass fibre GFF paper and washed with ethyl acetate (2 x 5 mL). The filtrate was concentrated under vacuum and purified by preparative HPLC (acetonitrile / water) to give the title compound 3.2 mg (10% yield) as an off-white solid.

[0964] Example 1, Method 28: l-Methyl-5-({[2-(pyridin-3-yl)-l,3-benzoxazol-5-yl]oxy}methyl)- 1,2-dihydropyrazin-2-one

[0965] δ H NMR (500 MHz, DMSO) 9.33 (d, J = 2.0 Hz, 1H), 8.80 (dd, J = 4.8, 1.6

[0966] Hz, 1H), 8.51 (dt, J = 8.0, 1.9 Hz, 1H), 8.06-8.02 (m, 1H), 7.96 (s, 1H), 7.74 (d, J = 8.9 Hz, 1H), 7.66 (dd, J = 8.0, 4.8 Hz, 1H), 7.55 (d, J = 2.5 Hz, 1H), 7.12 (dd, J = 8.9, 2.5 Hz, 1H), 4.97 (s, 2H), 3.46 (s, 3H). Tr (MET-uHPLC-AB-101) = 2.03 min, (ES + )(M+H) + 335.

[0967] The following examples were prepared using Method 28 as described above:

[0968]

[0969] Table 29

[0970] Method 29

[0971] Scheme for Method 29

[0972]

[0973] Step 1, Method 29: 5-Methoxy-2-(piperazin-l-yl)pyrimidine

[0974] To two microwave tubes were added 2-chloro-5-methoxypyrimidine (2 x 250 mg, 3.46 mmol) and piperazine (2 x 1.49 g, 34.6 mmol). Isopropanol (2 x 2.5 mL) was added to each tube and the reaction mixture was stirred in the microwave at 140 °C for 1 hour. The reaction mixtures were combined, diluted with diethyl ether (50 mL), filtered, the filtrate was concentrated and partitioned between water (50 mL) and diethyl ether (50 mL). The aqueous layer was extracted with diethyl ether (2 x 50 mL). The combined organic extracts were washed with brine (50 mL), dried over magnesium sulfate, filtered and concentrated to give the title compound 277 mg (32% yield) as a white solid. H NMR (500 MHz, Chloroform) δ 8.10 (s, 2H), 3.80 (s, 3H), 3.78 - 3.73 (m, 4H), 3.03 - 2.93 (m, 4H).

[0975] Step 2, Method 29: 5-[4-(5-Methoxypyrimidin-2-yl)piperazin-l-yl]-2-(pyridin-3-yl)-l,3-benzoxazole

[0976] 5-Bromo-2-(pyridin-3-yl)-1,3-benzoxazole (200 mg, 0.73 mmol), 5-methoxy-2-(piperazin-1-yl)pyrimidine (180 mg, 0.87 mmol), sodium tert-butoxide (84 mg, 0.87 mmol), and tetrahydrofuran (5 mL) were degassed under nitrogen for 20 min. Palladium(II) acetate (8 mg, 0.04 mmol) and [2',6'-di(propyl-2-yloxy)biphenyl-2-yl](dicyclohexyl)phosphine (17 mg, 0.04 mmol) were added, and the reaction mixture was stirred at 70 °C for 20 h. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate (20 mL) and water (20 mL). The aqueous layer was extracted with ethyl acetate (2 x 20 mL). The combined organic extracts were washed with brine (20 mL), dried over magnesium sulfate, filtered, and concentrated. The compound was purified by FCC (silica gel, 25-100% ethyl acetate / heptane) and ground with diethyl ether (5 mL) to give 43 mg (15% yield) of the title compound as a pale yellow solid.

[0977] Example 1, Method 29: 5-[4-(5-methoxypyrimidin-2-yl)piperazin-1-yl]-2-(pyridin-3-yl)-1,3-benzoxazole

[0978] δ H NMR(500MHz,DMSO)9.32(d,J=2.1Hz,1H),8.79(dd,J=4.8,1.5

[0979] Hz,1H),8.50(dt,J=8.0,1.9Hz,1H),8.25(s,2H),7.69(d,J=9.0Hz,1H),7.65(dd,J=8.0,4.8Hz,1H), 7.38(d,J=2.3Hz,1H),7.22(dd,J=9.0,2.4Hz,1H),3.86-3.80(m,4H),3.79(s,3H),3.27-3.21(m,4H). Tr(MET-uHPLC-AB-101)=3.13min,(ES + (M+H) + 389.

[0980] The following examples were prepared using method 29 as described above:

[0981]

[0982] Table 30

[0983] Method 30

[0984] Solution 30

[0985]

[0986] Step 1, Method 30: 2-(pyridin-3-yl)-[l,3]oxazolo[5,4-b]pyridin-6-ol

[0987] To a stirred solution of sulfuric acid (4.82 mL, 90.5 mmol) in water (15 mL) was added 2-(pyridin-3-yl)-[l,3]oxazolo[5,4-b]pyridin-6-amine (960 mg, 4.52 mmol, prepared via Method 19) in portions at room temperature. The solution was cooled to 0-5 °C and a solution of sodium nitrite (343 mg, 4.98 mmol) in water (10 mL) was added dropwise. The mixture was stirred at 0-5 °C for 10 minutes. Copper (II) nitrate trihydrate (55.1 g, 226.2 mmol) in water (100 mL) was added followed by copper (I) oxide (647 mg, 4.52 mmol). The mixture was shaken vigorously for 10 minutes. The mixture was basified with saturated sodium bicarbonate until pH 8-9. 33% Ammonium hydroxide (20 mL) was added and the aqueous solution was extracted with ethyl acetate (2 x 500 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated. Trituration in dichloromethane (10 mL) gave the title compound 390 mg (40% yield) as a yellow solid. H NMR (500 MHz, DMSO) 9.34 (s, 1H), 8.82 (d, J = 4.6 Hz, 1H), 8.53 (dt, J = 7.9, 1.9 Hz, 1H), 7.96 (d, J = 2.5 Hz, 1H), 7.66 (dd, J = 7.7, 4.7 Hz, 1H), 7.62 (d, J = 2.5 Hz, 1H). Tr (METCR1278) = 1.25 min, (ES + (M+H) + 214.

[0988] Step 2, Method 30: 3-{6-[(5-methoxypyridin-2-yl)methoxy]-[l,3]oxazolo[5,4- b]pyridin-2-yl}pyridine

[0989] To a solution of 2-(pyridin-3-yl)-[l,3]oxazolo[5,4-b]pyridin-6-ol (50 mg, 0.24 mmol) and 2-(chloromethyl)-5-methoxypyridine hydrochloride (46 mg, 0.24 mmol) in N,N- dimethylformamide (2 mL) under nitrogen was added sodium hydride (60% in mineral oil, 21 mg, 0.52 mmol) and the mixture was stirred at room temperature overnight. The mixture was quenched with water (1 mL), diluted with water (15 mL) and extracted with ethyl acetate (2 x 15 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated. Purification by FCC (silica gel, 0-3% methanol / dichloromethane) followed by preparative HPLC (acetonitrile / water) afforded the title compound 29.3 mg (37% yield) as an off-white powder.

[0990] Example 1, Method 30: 3-{6-[(5-methoxypyridin-2-yl)methoxy]-[l,3]oxazolo[5,4- b]pyridin-2-yl}pyridine

[0991] δ H NMR (500 MHz, DMSO) 9.35 (d, J = 2.1 Hz, 1H), 8.83 (dd, J = 4.8, 1.5

[0992] Hz, 1H), 8.22 (d, J = 2.7 Hz, 1H), 8.08 (d, J = 2.7 Hz, 1H), 7.67 (dd, J = 8.0, 4.8 Hz, 1H), 7.57 (d, J = 8.6 Hz, 1H), 7.45 (dd, J = 8.6, 3.0 Hz, 1H), 5.27 (s, 2H), 3.84 (s, 3H). Tr (MET-uHPLC-AB-101) = 2.36 min, (ES + )(M+H) + 335.

[0993] The following examples were prepared using Method 30 as described above:

[0994]

[0995] Table 31

[0996] Method 31

[0997] Scheme for Method 31

[0998]

[0999] Step 1, Method 31 : 5-(1 -Methyl- 1 H-pyrazol-4-yl)-2-(pyridin-3-yl)- 1,3-benzoxazole

[1000] Step 1, Method 31 : 5-(1 -Methyl- 1 H-pyrazol-4-yl)-2-(pyridin-3-yl)- 1,3-benzoxazole

[1001] Step 1, Method 31 : 5-(1 -Methyl- 1 H-pyrazol-4-yl)-2-(pyridin-3-yl)- 1,3-benzoxazole

[1002] δ H NMR (500 MHz, DMSO) 9.36 (d, J = 2.1 Hz, 1H), 8.81 (dd, J = 4.8, 1.5

[1003] Hz, 1H), 8.54 (dt, J = 8.0, 1.9 Hz, 1H), 8.22 (s, 1H), 8.04 (d, J = 1.5 Hz, 1H), 7.96 (s, 1H), 7.80 (d, J = 8.5 Hz, 1H), 7.74 - 7.56 (m, 2H), 3.88 (s, 3H). Tr (MET-uHPLC-AB-101) = 2.39 min, (ES + )(M+H) + 277.

[1004] The following examples were prepared using Method 31 as described above:

[1005]

[1006] Table 32

[1007] Method 32

[1008] Scheme for Method 32

[1009]

[1010] Step 1, Method 32: 5-(Chloromethyl)-2-methoxypyridine

[1011] To a stirred solution of (6-methoxypyridin-3-yl)methanol (75 mg, 0.54 mmol) in dichloromethane (2 mL) under nitrogen was added triethylamine (0.083 mL, 0.59 mmol) followed by methanesulfonyl chloride (0.044 mL, 0.57 mmol). The mixture was stirred at room temperature for 1 h. The mixture was partitioned between dichloromethane (10 mL) and water (10 mL). The organic extract was dried over sodium sulfate, filtered and concentrated to give the title compound 88 mg (quantitative yield) as a yellow oil. Tr(METCR1278) = 1.63 min, (ES + )(M+H) + 158 / 160.

[1012] Step 2, Method 32: 3-{6-[(6-methoxypyridin-3-yl)methoxy]-[l,3]oxazolo[5,4- b]pyridin-2-yl}pyridine

[1013] To a solution of 2-(pyridin-3-yl)-[l,3]oxazolo[5,4-b]pyridin-6-ol (90 mg, 0.42 mmol, prepared by Method 30) and 5-(chloromethyl)-2-methoxypyridine (73 mg, 0.46 mmol) in N,N-dimethylformamide (4 mL) under nitrogen was added sodium hydride (60% in mineral oil, 19 mg, 0.46 mmol) and the mixture was stirred at room temperature overnight. The mixture was quenched with water (1 mL), diluted with water (30 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated. Purification by FCC (silica gel, 0-3% methanol / dichloromethane) and recrystallization from DMSO:acetonitrile (1:1, 10 mL) gave the title compound 25.2 mg (18% yield) as an off-white powder.

[1014] Example 1, Method 32: 3-{6-[(6-methoxypyridin-3-yl)methoxy]-[l,3]oxazolo[5,4- b]pyridin-2-yl}pyridine

[1015] δ H NMR (500 MHz, DMSO) 9.35 (d, J = 2.0 Hz, 1H), 8.83 (dd, J = 4.8, 1.6

[1016] Hz, 1H), 8.55 (dt, J = 8.0, 1.9 Hz, 1H), 8.32 (d, J = 2.2 Hz, 1H), 8.19 (d, J = 2.7 Hz, 1H), 8.10 (d, J = 2.7 Hz, 1H), 7.86 (dd, J = 8.5, 2.4 Hz, 1H), 7.67 (dd, J = 8.0, 4.8 Hz, 1H), 6.87 (d, J = 8.5 Hz, 1H), 5.22 (s, 2H), 3.86 (s, 3H). Tr (MET-uHPLC-AB-101) = 2.78 min, (ES + )(M+H) + 335.

[1017] The following examples were prepared using Method 32 as described above:

[1018]

[1019] Table 33

[1020] Method 33

[1021] Scheme for Method 33

[1022]

[1023] Step 1, Method 33: 5-Methoxy-2-[4-(methoxymethoxy)phenoxy methyl]pyridine

[1024] To a stirred solution of 4-(methoxymethoxy)phenol (1.1 g, 7.13 mmol, described in Journal of Organic Chemistry, 71(22), 2006, 8614) and 2-(chloromethyl)-5- methoxypyridine hydrochloride (1.39 g, 7.13 mmol) in N,N-dimethylformamide (40 mL) was added sodium hydride (60% in mineral oil, 599 mg, 15.0 mmol) under nitrogen and the mixture was stirred at room temperature for 16 hours. The mixture was then quenched with water (4 mL), diluted with water (150 mL) and extracted with ethyl acetate (2 x 150 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated to give the title compound 2.2 g (quantitative yield) as a light brown oil. H NMR (500 MHz, DMSO) 8.27 (d, J = 2.8 Hz, 1H), 7.53 - 7.34 (m, 2H), 6.94 (s, 4H), 5.09 (s, 2H), 5.04 (s, 2H), 3.83 (s, 3H), 3.35 (s, 3H). Tr (MET CR1278) = 1.71 min, (ES + )(M+H) +276.

[1025] Step 2, Method 33: 4-[(5-methoxypyridin-2-yl)methoxy]phenol

[1026] To a solution of 5-methoxy-2-[4-(methoxymethoxy)phenoxy methyl]pyridine (1.96 g, 7.12 mmol) in tetrahydrofuran (100 mL) was added 3M aqueous hydrochloric acid (23.4 mL) and the mixture was stirred at room temperature overnight. The mixture was then stirred at 40 °C for 5 hours. The mixture was diluted with saturated aqueous sodium bicarbonate (200 mL) and extracted with ethyl acetate (2 x 250 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated to give the title compound 1.46 g (87% yield) as a light pink powder. H NMR (500 MHz, DMSO) 8.92 (s, 1H), 8.26 (d, J = 2.7 Hz, 1H), 7.47-7.37 (m, 2H), 6.86-6.78 (m, 2H), 6.69-6.62 (m, 2H), 4.98 (s, 2H), 3.83 (s, 3H). Tr (METCR1278) = 1.32 min, (ES + (M+H) + 232.

[1027] Step 3, Method 33: 4-[(5-methoxypyridin-2-yl)methoxy]-2-nitrophenol

[1028] To a stirred suspension of 4-[(5-methoxypyridin-2-yl)methoxy]phenol (1.46 g, 6.31 mmol) in 1,2-dimethoxyethane (30 mL) and sulfolane (15 mL) at -50 °C under nitrogen was added a suspension of nitronium tetrafluoroborate (845 mg, 6.31 mmol). The mixture was stirred at -50 °C for 30 minutes then slowly warmed to room temperature. The mixture was concentrated in vacuo and the residue was purified by FCC (silica gel, 20-50% ethyl acetate / heptane then 10% methanol / dichloromethane) to give the title compound 659 mg (33% yield) as a yellow powder. HNMR (500 MHz, DMSO) 10.49 (s, 1H), 8.28 (d, J = 2.8 Hz, 1H), 7.51 (d, J = 3.1 Hz, 1H), 7.48 (d, J = 8.6 Hz, 1H), 7.42 (dd, J = 8.6, 2.9 Hz, 1H), 7.28 (dd, J = 9.1, 3.1 Hz, 1H), 7.07 (d, J = 9.1 Hz, 1H), 5.09 (s, 2H), 3.83 (s, 3H). Tr (METCR1278) = 1.75 min, (ES + )(M+H) + 277.

[1029] Step 4, Method 33: 2-Amino-4-[(5-methoxypyridin-2-yl)methoxy]phenol

[1030] To 4-[(5-methoxypyridin-2-yl)methoxy]-2-nitrophenol (460 mg, 1.66 mmol) and sodium hydrosulfite (1.16 g, 6.66 mmol) was added ethanol (25 mL) and water (25 mL) and the mixture was stirred at 75 °C for 2.5 hours. The mixture was then treated with sodium hydrosulfite (0.58 g, 3.33 mmol) and the mixture was stirred at 75 °C for 30 minutes. The mixture was diluted with water (150 mL) and extracted with ethyl acetate (2 x 150 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated to give the title compound 292 mg (71% yield) as a light brown solid. H NMR (500 MHz, DMSO) 8.49 (s, 1H), 8.25 (t, J = 1.8 Hz, 1H), 7.40 (d, J = 1.8 Hz, 2H), 6.50 (d, J = 8.5 Hz, 1H), 6.27 (d, J = 2.9 Hz, 1H), 6.02 (dd, J = 8.5, 2.9 Hz, 1H), 4.91 (s, 2H), 4.55 (s, 2H), 3.82 (s, 3H). Tr (METCR1278) = 1.23 min, (ES + )(M+H) + 247.

[1031] Step 5, Method 33: N-{2-Hydroxy-5-[(5-methoxypyridin-2-yl)methoxy]phenyl}-1- methyl-1H-pyrazole-4-carboxamide

[1032] To a stirred solution of 2-amino-4-[(5-methoxypyridin-2-yl)methoxy]phenol (95 mg, 0.39 mmol) and diisopropylethylamine (0.077 mL, 0.46 mmol) in tetrahydrofuran (2 mL) under nitrogen was added a portion of 1-methyl-1H-pyrazole-4-carbonyl chloride (60 mg, 0.46 mmol). The mixture was stirred at room temperature for 30 minutes. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (2 x 15 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated to give the title compound 131 mg (96% yield) as a light brown solid. Tr(METCR1278) = 1.36 min, (ES + )(M+H) + 355.

[1033] Step 6, Method 33: 5-[(5-Methoxypyridin-2-yl)methoxy]-2-(1-methyl-1H-pyrazol-4-yl)-1,3- benzoxazole

[1034] N-{2-Hydroxy-5-[(5-methoxypyridin-2-yl)methoxy]phenyl}-1-methyl-1H-pyrazole-4- carboxamide (65 mg, 0.18 mmol) and acetic acid (1 mL) were heated in a microwave at 200 °C for 30 minutes. The mixture was concentrated in vacuo and the residue was diluted with saturated aqueous sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated. Purification by FCC (silica gel, 20-80% ethyl acetate / heptane) and preparative HPLC (acetonitrile / water) gave the title compound 36 mg (58% yield) as a white solid.

[1035] Example 1, Method 33: 5-[(5-Methoxypyridin-2-yl)methoxy]-2-(1-methyl-1H-pyrazol-4-yl)-1,3- benzoxazole

[1036] δ H NMR (500 MHz, DMSO) δ 8.52 (s, 1H), 8.30 (d, J = 2.9 Hz, 1H), 8.08 (s,

[1037] 1H), 7.59 (d, J = 8.8 Hz, 1H), 7.51 (d, J = 8.6 Hz, 1H), 7.43 (dd, J = 8.6, 3.0 Hz, 1H), 7.33 (d, J = 2.5 Hz, 1H), 7.01 (dd, J = 8.8, 2.5 Hz, 1H), 5.15 (s, 2H), 3.95 (s, 3H), 3.84 (s, 3H). Tr(MET-uHPLC-AB-101) = 2.46 min, (ES+ )(M+H) + 337.

[1038] The following examples were prepared using Method 33 as described above:

[1039]

[1040] Table 34

[1041] Method 34

[1042] Scheme for Method 34

[1043]

[1044] Step 1, Method 34: N-{2-hydroxy-5-[(5-methoxypyridin-2-yl)methoxy]phenyl}-1,3- thiazole-5-carboxamide

[1045] A stirred solution of 2-amino-4-[(5-methoxypyridin-2-yl)methoxy]phenol (150 mg, 50% purity, 0.30 mmol, prepared via Method 33), 1,3-thiazole-5-carboxylic acid (43 mg, 0.33 mmol) and ethyl carbodiimide hydrochloride (76 mg, 0.40 mmol) in pyridine (1 mL) was stirred at room temperature for 16 hours under nitrogen. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated to give the crude title compound 220 mg as a brown solid which was used without further purification. Tr (METCR1278) = 1.44 min, (ES + )(M+H) + 358.

[1046] Step 2, Method 34: 5-[(5-methoxypyridin-2-yl)methoxy]-2-(1,3-thiazol-5-yl)-1,3- benzoxazole

[1047] N-{2-hydroxy-5-[(5-methoxypyridin-2-yl)methoxy]phenyl}-1,3-thiazole-5-carboxamide (109 mg, 0.30 mmol) and acetic acid (2 mL) were heated at 200 °C in a microwave for 40 minutes. The mixture was concentrated and the residue diluted with saturated aqueous sodium bicarbonate solution (10 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated. Purification by FCC (silica gel, 25-80% ethyl acetate / heptane) and preparative HPLC (acetonitrile / water) gave the title compound 32 mg (31% yield) as a white powder.

[1048] Example 1, Method 34: 5-[(5-methoxypyridin-2-yl)methoxy]-2-(1,3-thiazol-5-yl)- 1,3-benzoxazole

[1049] δ H NMR (500 MHz, DMSO) 9.39 (s, 1H), 8.70 (s, 1H), 8.30 (d, J = 2.9 Hz,

[1050] 1H), 7.70 (d, J = 8.9 Hz, 1H), 7.52 (d, J = 8.6 Hz, 1H), 7.46 - 7.40 (m, 2H), 7.12 (dd, J = 8.9, 2.6 Hz, 1H), 5.17 (s, 2H), 3.84 (s, 3H). Tr (MET-uHPLC-AB-101) = 2.71 min, (ES + )(M+H) + 340.

[1051] The following examples were prepared using Method 34 as described above:

[1052]

[1053]

[1054] Table 35

[1055] Method 35

[1056] Scheme for Method 35

[1057]

[1058] Step 1, Method 35: 2-(pyridin-2-yloxy)ethan-1-ol

[1059] A mixture of sodium hydride (60% in mineral oil, 139 mg, 3.48 mmol) and 2- bromopyridine (500 mg, 3.16 mmol) was dissolved in N,N-dimethylformamide (5 mL). Ethane-1,2-diol (2.12 mL, 37.98 mmol) was added dropwise and the mixture was heated at 130 °C overnight. The mixture was cooled to room temperature, water (20 mL) was added and the mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with water (2 x 10 mL), dried over sodium sulfate, filtered and concentrated. Purification by FCC (silica gel, 2-40% ethyl acetate in heptane) gave the title compound 135 mg (31 % yield) as a colourless oil. δ HNMR (500 MHz, chloroform) 8.23 - 8.06 (m, 1H), 7.61 (ddd, J = 9.0, 7.1, 2.0 Hz, 1H), 6.91 (ddd, J = 7.0, 5.1, 0.8 Hz, 1H), 6.81 (d, J = 8.4 Hz, 1H), 4.53 - 4.41 (m, 2H), 4.02 - 3.90 (m, 2H), 3.81 (br. s, 1H). Tr (METCR1278) = 0.59 min, (ES + )(M+H) + 140.

[1060] Step 2, Method 35: 2-(2-chloroethoxy)pyridine

[1061] To a stirred solution of 2-(pyridin-2-yloxy)ethan-1-ol (56 mg, 0.4 mmol) in dichloromethane (2 mL) was added triethylamine (0.06 mL, 0.44 mmol) followed by methanesulfonyl chloride (0.03 mL, 0.42 mmol) under nitrogen at 0 °C. The mixture was stirred at room temperature for 2 hours. The mixture was cooled to 0 °C, triethylamine (0.06 mL, 0.44 mmol) and methanesulfonyl chloride (0.03 mL, 0.42 mmol) were added and the mixture was stirred at room temperature for 4 hours. The mixture was partitioned between dichloromethane (10 mL) and water (10 mL). The organic extract was dried over sodium sulfate, filtered and concentrated to give the crude title compound 58 mg (91% yield) as a yellow oil which was used directly in the next step.

[1062] Step 3, Method 35: 5-[2-(pyridin-2-yloxy)ethoxy]-2-(pyridin-3-yl)-1,3-benzoxazole

[1063] Under nitrogen atmosphere, a solution of 2-(pyridin-3-yl)-1,3-benzoxazol-5-ol (57 mg, 0.27 mmol, prepared by method 14) in N,N-dimethylformamide (1 mL) was added to sodium hydride (60% in mineral oil, 12 mg, 0.3 mmol) and the mixture was stirred at room temperature for 30 minutes. A solution of 2-(2-chloroethoxy)pyridine (57 mg, 0.36 mmol) in N,N-dimethylformamide (0.5 mL) was added and the mixture was stirred at room temperature overnight. The mixture was heated to 60 °C and held for 3 hours, cooled to room temperature, and sodium hydride (60% in mineral oil, 12 mg, 0.3 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was quenched with water (3 mL), extracted with ethyl acetate (3 x 5 mL), washed with water (2 x 5 mL), dried over sodium sulfate, filtered, and concentrated. The title compound was purified by FCC (silica gel, 1-10% methanol / dichloromethane) and recrystallized from tert-butyl methyl ether: ethyl acetate (9:1, 10 mL) to give 15 mg (17% yield) of white crystals.

[1064] Example 1, Method 35: 5-[2-(pyridin-2-yloxy)ethoxy]-2-(pyridin-3-yl)-1,3-benzoxazole

[1065] δ H NMR(500MHz,DMSO)9.32(d,J=1.6Hz,1H),8.80(dd,J=4.8,1.6

[1066] Hz,1H),8.51(dt,J=8.0,1.9Hz,1H),7.74(dd,J=6.8,1.9Hz,1H),7.71(d,J=8.9Hz,1H),7.65(dd,J=8.0,4.8Hz,1H), 7.47-7.40(m,2H),7.03(dd,J=8.9,2.5Hz,1H),6.41(d,J=8.7Hz,1H),6.24(td,J=6.7,1.3Hz,1H),4.35-4.26(m,4H). Tr(MET-uHPLC-AB-101)=2.25min,(ES + (M+H) + 334.

[1067] The following examples were prepared using method 35 as described above:

[1068]

[1069] Table 36

[1070] Method 36

[1071] Scheme of method 36

[1072]

[1073] Step 1, Method 36: tert-Butyl 4-methyl-1H-pyrazole-1-carboxylate

[1074] To a solution of 4-methyl-1H-pyrazole (3.1 g, 37.8 mmol) and N,N- diethylethanamine (10.5 mL, 75.3 mmol) in dichloromethane (100 mL) was added di-tert-butyl dicarbonate (9.1 g, 41.7 mmol) and the mixture was stirred at room temperature for 6 hours. The mixture was diluted with ethyl acetate (300 mL), washed with water (100 mL) and brine (100 mL), dried over magnesium sulfate, filtered and concentrated. Purification by FCC (silica gel, 0-30% ethyl acetate in heptane) gave the title compound 5.56 g (81% yield) as a yellow oil. H NMR (500 MHz, Chloroform) 7.82 (s, 1H), 7.52 (s, 1H), 2.08 (s, 3H), 1.63 (s, 9H).

[1075] Step 2, Method 36: tert-Butyl 4-(bromomethyl)-1H-pyrazole-1-carboxylate

[1076] A mixture of tert-butyl 4-methyl-1H-pyrazole-1-carboxylate (4 g, 21.95 mmol) and N-bromosuccinimide (4.3 g, 24.16 mmol) in carbon tetrachloride (50 mL) was heated to 70 °C. After the addition of 2,2'-diazene-1,2-diylbis(2-methylpropanenitrile) (0.5 g, 3.04 mmol), the mixture was refluxed for 18 hours. After cooling to room temperature, the solid was removed by filtration and the filtrate was concentrated. Purification by FCC (silica gel, 0-20% ethyl acetate in heptane) gave the title compound 2.94 g (43% yield) as a colourless solid. H NMR (500 MHz, Chloroform) 8.10 (s, 1H), 7.73 (s, 1H), 4.39 (s, 2H), 1.65 (s, 9H). Tr (METCR1278) = 1.70 min, (ES + )(2M+Na) + 545, 92%.

[1077] Step 3, Method 36: tert-Butyl 4-({[2-(3-cyanopyridin-4-yl)-4,5-dihydro-1- benzofuran-5-yl]oxy}methyl)-1H-pyrazole-1-carboxylate

[1078] To a vigorously stirred solution of 4-(5-hydroxy-l-benzofuran-2-yl)pyridine-3- carbonitrile (275 mg, 1.16 mmol, prepared via Method 9) and tert-butyl 4- (bromomethyl)-lH-pyrazole-l-carboxylate (83%, 550 mg, 1.75 mmol) in N,N- dimethylformamide (15 mL) was added potassium iodide (20 mg, 0.12 mmol) and sodium hydride (60% in mineral oil, 60 mg, 1.5 mmol). After 2 hours, the mixture was added to water (100 mL) and brine (100 mL) and then extracted with ethyl acetate (3 x 100 mL). The combined organic extracts were washed with brine (50 mL), dried over magnesium sulfate, filtered and concentrated. Purification by FCC (silica gel, 0-80% ethyl acetate in heptane) afforded the title compound 259 mg (53% yield). δ H NMR (500 MHz, chloroform) 8.93 (s, 1H), 8.83 (d, J = 5.3 Hz, 1H), 8.17 (s, 1H), 7.96 (d, J = 5.4 Hz, 1H), 7.91 (s, 1H), 7.80 (s, 1H), 7.48 (d, J = 9.0 Hz, 1H), 7.17 (d, J = 2.5 Hz, 1H), 7.08 (dd, J = 9.0, 2.6 Hz, 1H), 5.03 (s, 2H), 1.66 (s, 9H). Tr (METCR1278) = 2.12 min, (ES + (M+Na) + 439.

[1079] Step 4, Method 36: 4-[5-(lH-pyrazol-4-ylmethoxy)-l-benzofuran-2-yl]pyridine-3- carbonitrile

[1080] To a solution of tert-butyl 4-({[2-(3-cyanopyridin-4-yl)-4,5-dihydro-l- benzofuran-5-yl]oxy}methyl)-lH-pyrazole-l-carboxylate (255 mg, 0.61 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (2 mL) and the mixture stirred at room temperature for 3 hours. The volatiles were removed in vacuo and the residue partitioned between ethyl acetate (200 mL) and saturated aqueous sodium bicarbonate solution (100 mL). After separation, the organic layer was washed with brine (50 mL), dried over magnesium sulfate, filtered and concentrated. The residue was triturated with ethyl acetate and heptane to afford the title compound 132 mg (69% yield) as an off-white crystalline solid.

[1081] Example 1, Method 36: 4-[5-(lH-pyrazol-4-ylmethoxy)-l-benzofuran-2-yl]pyridine-3- carbonitrile

[1082] δH NMR (500 MHz, DMSO) δ 12.84 (s, 1H), 9.12 (s, 1H), 8.92 (d, J = 5.4 Hz,

[1083] 1H), 8.07 (d, J = 5.4 Hz, 1H), 7.99 - 7.91 (m, 1H), 7.88 (s, 1H), 7.69 - 7.56 (m, 2H), 7.47 (d, J = 2.6 Hz, 1H), 7.10 (dd, J = 9.0, 2.6 Hz, 1H), 5.04 (s, 2H). Tr (MET-uHPLC-AB-101) = 2.68 min, (ES + )(M+H) + 317.

[1084] The following examples were prepared using Method 36 as described above:

[1085]

[1086] Table 37

[1087] Method 37

[1088] Scheme for Method 37

[1089]

[1090] Step 1, Method 37: 1-[5-(pyridin-3-ylmethoxy)-1-benzofuran-2-yl]ethan-1-one

[1091] To a suspension of 3-(bromomethyl)pyridine hydrobromide (861 mg, 3.40 mmol), 1-(5- hydroxy-1-benzofuran-2-yl)ethan-1-one (500 mg, 2.84 mmol) and potassium iodide (50 g, 0.3 mmol) in N,N-dimethylformamide (25 mL) was added sodium hydride (60% in mineral oil, 270 mg, 6.75 mmol) at 0 °C. The ice bath was removed and the mixture was stirred at room temperature for 16 hours, after which it was added to brine (100 mL) and water (100 mL). The mixture was extracted with ethyl acetate (3 x 100 mL), the combined organic layers were washed with brine (50 mL), dried over magnesium sulfate, filtered and concentrated. Purification by FCC (silica gel, 20-100% ethyl acetate in heptane) afforded the title compound 626 mg (83% yield) as a colorless crystalline solid. Tr (MET-uHPLC-AB-101) = 1.7 min, (ES + )(M+H) + 268.

[1092] Step 2, Method 37: 2,2-dibromo-1-[5-(pyridin-3-ylmethoxy)-1-benzofuran-2-yl]ethan-1- one

[1093] To a suspension of 1-[5-(pyridin-3-ylmethoxy)-1-benzofuran-2-yl]ethan-1-one (1.5 g, 5.61 mmol) and pyridinium tribromide (2.2 g, 6.9 mmol) in acetic acid (30 mL) was added hydrobromic acid (30% in acetic acid, 1.1 mL) and the mixture was stirred at room temperature for 18 hours. After removal of the volatiles in vacuo, the residue was partitioned between ethyl acetate (300 mL) and saturated aqueous sodium bicarbonate solution (150 mL). The organic layer was separated, washed with brine (100 mL), dried over magnesium sulfate, filtered and concentrated. Purification by FCC (silica gel, 0-100% ethyl acetate / heptane) afforded the title compound 472 mg (20% yield) as a colorless solid. δ H NMR (500 MHz, Chloroform) 8.72 (s, 1H), 8.61 (d, J = 3.9 Hz, 1H), 7.81 (d, J = 7.8 Hz, 1H), 7.76 (d, J = 0.7 Hz, 1H), 7.53 (d, J = 9.1 Hz, 1H), 7.36 (dd, J = 7.8, 4.8 Hz, 1H), 7.24 (dd, J = 9.1, 2.6 Hz, 1H), 7.19 (d, J = 2.5 Hz, 1H), 6.70 (s, 1H), 5.14 (s, 2H).

[1094] Step 3, Method 37: 3-{[(2-{5H,6H-imidazo[2,1-b][1,3]thiazol-3-yl}-1-benzofuran-5-yl)oxy]methyl}pyridine

[1095] A mixture of 2,2-dibromo-1-[5-(pyridin-3-ylmethoxy)-1-benzofuran-2-yl]ethan-1-one (470 mg, 1.11 mmol) and imidazolidine-2-thione (114 mg, 1.12 mmol) in ethanol (20 mL) and acetic acid (10 mL) was stirred at reflux for 16 hours. The solvents were removed in vacuo and the residue was partitioned between ethyl acetate (200 mL) and saturated aqueous sodium bicarbonate solution (100 mL). The organic layer was washed with brine (50 mL), dried over magnesium sulfate, filtered and concentrated. Purification by SCX cartridge and preparative HPLC (acetonitrile / water + 0.2% ammonium hydroxide) afforded the title compound 49 mg (15% yield) as a colorless crystalline solid.

[1096] Example 1, Method 37: 3-{[(2-{5H,6H-imidazo[2,1-b][1,3]thiazol-3-yl}-1-benzofuran-5-yl)oxy]methyl}pyridine

[1097] δ H NMR (500 MHz, DMSO) 8.69 (d, J = 1.7 Hz, 1H), 8.55 (dd, J = 4.8, 1.6

[1098] Hz, 1H), 7.89 (dd, J = 7.8, 1.8 Hz, 1H), 7.52 (d, J = 9.0 Hz, 1H), 7.43 (dd, J = 7.8, 4.8 Hz, 1H), 7.27 (d, J = 2.6 Hz, 1H), 7.17 (s, 1H), 7.05 (dd, J = 8.9, 2.6 Hz, 1H), 6.52 (s, 1H), 5.19 (s, 2H), 4.27 - 3.97 (m, 4H). Tr (MET-uHPLC-AB-101) = 1.15 min, (ES + )(M+H) + 350.

[1099] The following examples were prepared using Method 37 as described above:

[1100]

[1101] Table 38

[1102] Method 38

[1103] Scheme for Method 38

[1104]

[1105] Step 1, Method 38: 5-[(5-methoxypyridin-2-yl)methoxy]-2,3-dihydro-l,3-benzoxazole-2- thione

[1106] A solution of 2-amino-4-[(5-methoxypyridin-2-yl)methoxy]phenol (50% purity, 450 mg, 0.91 mmol, prepared via Method 33) and potassium ethylxanthate (161 mg, 1.00 mmol) in ethanol (3 mL) was stirred in a sealed tube at 85 °C overnight. The mixture was concentrated in vacuo to give the title compound 263 mg (quantitative yield) as a brown solid. Tr (MET CR1278) = 1.59 min, (ES + )(M+H) + 289.

[1107] Step 2, Method 38: 2-chloro-5-[(5-methoxypyridin-2-yl)methoxy]-l,3-benzoxazole

[1108] To a stirred solution of 5-[(5-methoxypyridin-2-yl)methoxy]-2,3-dihydro-l,3- benzoxazole-2-thione (263 mg, 0.91 mmol) in thionyl chloride (1 mL) was added N,N- dimethylformamide (0.03 mL). The mixture was stirred at 65 °C for 1 h. The mixture was concentrated in vacuo and purified by FCC (silica gel, 10-40% ethyl acetate / heptane) to give the title compound 117 mg (44% yield) as a white solid. H NMR (500 MHz, DMSO) δ 8.29 (d, J = 2.9 Hz, 1H), 7.67 (d, J = 9.0 Hz, 1H), 7.50 (d, J = 8.6 Hz, 1H), 7.46 - 7.38 (m, 2H), 7.11 (dd, J = 9.0, 2.6 Hz, 1H), 5.16 (s, 2H), 3.83 (s, 3H). Tr (MET-uHPLC-AB-101) = 2.92 min, (ES + (M+H) + 291 / 293.

[1109] Step 3, Method 38: 7-{5-[(5-methoxypyridin-2-yl)methoxy]-l,3-benzoxazol-2-yl}- 5,6,7,8-tetrahydro-l,7-naphthyridine

[1110] 2-chloro-5-[(5-methoxypyridin-2-yl)methoxy]-l,3-benzoxazole (9 mg, 0.031 mmol), 5,6,7,8-tetrahydro-l,7-naphthyridine dihydrochloride (14 mg, 0.068 mmol) and 2-propanol (0.4 mL) were heated in a microwave at 150 °C for 20 min. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated. Purification by FCC (silica gel, 20-100% ethyl acetate / heptane) gave the title compound 5.5 mg (46% yield) as an off-white powder.

[1111] Example 1, Method 38: 7-{5-[(5-methoxypyridin-2-yl)methoxy]-l,3-benzoxazol-2-yl}- 5,6,7,8-tetrahydro-l,7-naphthyridine

[1112] δ H NMR (500 MHz, DMSO) δ 8.42 (d, J = 4.5 Hz, 1H), 8.28 (d, J = 2.8 Hz,

[1113] 1H), 7.64 (d, J = 7.6 Hz, 1H), 7.47 (d, J = 8.6 Hz, 1H), 7.41 (dd, J = 8.6, 2.9 Hz, 1H), 7.32 (d, J = 8.7 Hz, 1H), 7.26 (dd, J = 7.6, 4.8 Hz, 1H), 6.99 (d, J = 2.4 Hz, 1H), 6.67 (dd, J = 8.7, 2.5 Hz, 1H), 5.08 (s, 2H), 4.78 (s, 2H), 3.91 (t, J = 5.9 Hz, 2H), 3.83 (s, 3H), 2.98 (t, J = 5.8 Hz, 2H). Tr (MET-uHPLC-AB-101) = 2.28 min, (ES + )(M+H) + 389.

[1114] The following examples were prepared using Method 38 as described above:

[1115]

[1116]

[1117] Table 39

[1118] Method 39

[1119] Scheme for Method 39

[1120]

[1121] Step 1, Method 39: Methyl 6-{[(tert-butoxy)carbonyl]amino}pyridine-3-carboxylate

[1122] A solution of methyl 6-aminopyridine-3-carboxylate (1 g, 6.57 mmol), di-tert- butyl dicarbonate (1.72 g, 7.89 mmol), and N,N-dimethylaminopyridine (56 mg, 0.46 mmol) in tetrahydrofuran (60 mL) was stirred at room temperature overnight. The mixture was concentrated in vacuo to give the title compound 1.79 g (quantitative yield) as a light brown solid. Tr (MET CR1278) = 1.99 min, (ES + )(M+H) + 253.

[1123] Step 2, Method 39: 6-{[(tert-butoxy)carbonyl]amino}pyridine-3-carboxylic acid

[1124] To a stirred solution of methyl 6-{[(tert-butoxy)carbonyl]amino}pyridine-3- carboxylate (1.66 g, 6.58 mmol) in ethanol (75 mL) and tetrahydrofuran (75 mL) was added 2N sodium hydroxide (23.0 mL, 46.1 mmol). The mixture was stirred at 55 °C overnight. The mixture was then concentrated to remove the ethanol and tetrahydrofuran and the resulting aqueous solution was neutralized using 1 N hydrochloric acid (46.1 mL). The resulting precipitate was filtered and dried under vacuum to give the title compound 729 mg (46% yield) as an off-white powder. H NMR (500 MHz, DMSO) 13.04 (s, 1H), 10.25 (s, 1H), 8.75 (s, 1H), 8.40-8.06 (m, 1H), 7.91 (d, J = 7.0 Hz, 1H), 1.48 (s, 9H). Tr (METCR1278) = 1.57 min, (ES + (M+H) + 239.

[1125] Step 3, Method 39: tert-Butyl N-[5-({2-hydroxy-5-[(5-methoxypyridin-2-yl)methoxy]phenyl} carbamoyl)pyridin-2-yl]carbamate

[1126] A stirred solution of 2-amino-4-[(5-methoxypyridin-2-yl)methoxy]phenol (50% purity, 150 mg, 0.30 mmol, prepared via Method 33), 6-{[(tert-butoxy)carbonyl]amino}pyridine-3- carboxylic acid (80 mg, 0.33 mmol) and ethyl carbodiimide hydrochloride (76 mg, 0.40 mmol) in pyridine (1 mL) was stirred at room temperature under nitrogen for 16 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated to give the title compound 190 mg (quantitative yield) as a light brown solid. Tr (METCR1278) = 1.78 min, (ES + (M+H) + 467.

[1127] Step 4, Method 39: N-(5-{5-[(5-methoxypyridin-2-yl)methoxy]-1,3-benzoxazol-2-yl}pyridin-2- yl)acetamide and 5-{5-[(5-methoxypyridin-2-yl)methoxy]-1,3-benzoxazol-2-yl}pyridin-2-amine

[1128] N-[5-({2-hydroxy-5-[(5-methoxypyridin-2-yl)methoxy]phenyl}carbamoyl)pyridin-2-yl]carbamate tert-butyl ester (142 mg, 0.30 mmol) and acetic acid (2 mL) were heated in a microwave oven at 200 °C for 40 min. The mixture was concentrated and the residue was diluted with a saturated aqueous solution of sodium bicarbonate (20 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The extract was purified by FCC (silica gel, 25-80% ethyl acetate / heptane) to give 54 mg (45% yield) of N-(5-{5-[(5-methoxypyridin-2-yl)methoxy]-1,3-benzoxazol-2-yl}pyridin-2-yl)acetamide as a light pink powder. The fraction containing 5-{5-[(5-methoxypyridin-2-yl)methoxy]-1,3-benzoxazol-2-yl}pyridine-2-amine was concentrated and purified preparatively by HPLC (acetonitrile / water) to give 2.7 mg (3% yield) of 5-{5-[(5-methoxypyridin-2-yl)methoxy]-1,3-benzoxazol-2-yl}pyridine-2-amine, which is a grayish-white powder.

[1129] Example 1, Method 39: N-(5-{5-[(5-methoxypyridin-2-yl)methoxy]-1,3-benzoxazol-2-yl}pyridin-2-yl)acetamide

[1130] δ H NMR (500MHz, DMSO) 10.92 (s, 1H), 9.06 (d, J = 2.3Hz, 1H), 8.48 (dd,

[1131] J=8.8,2.4Hz,1H),8.33-8.27(m,2H),7.69(d,J=8.9Hz,1H),7.53(d,J=8.6Hz,1H),7 .47-7.41(m,2H),7.10(dd,J=8.9,2.5Hz,1H),5.19(s,2H),3.84(s,3H),2.16(s,3H). Tr(MET-uHPLC-AB-101)=2.66min,(ES + (M+H) + 391.

[1132] Example 2, Method 39: 5-{5-[(5-methoxypyridin-2-yl)methoxy]-1,3-benzoxazol-2-yl}pyridin-2-amine

[1133] δ H NMR(500MHz,DMSO)8.70(d,J=2.3Hz,1H),8.30(d,J=2.9Hz,

[1134] 1H), 8.04 (dd, J = 8.8, 2.4 Hz, 1H), 7.59 (d, J = 8.8 Hz, 1H), 7.51 (d, J = 8.6 Hz, 1H), 7.43 (dd, J = 8.6, 3.0 Hz, 1H), 7.33 (d, J = 2.5 Hz, 1H), 6.99 (dd, J = 8.8, 2.5 Hz, 1H), 6.81 (s, 2H), 6.58 (d, J = 8.8 Hz, 1H), 5.15 (s, 2H), 3.83 (s, 3H). Tr (MET-uHPLC-AB-101) = 1.76 min, (ES + )(M+H) + 349.

[1135] The following examples were prepared using Method 39 as described above:

[1136]

[1137] Table 40

[1138] Method 40

[1139] Scheme for Method 40

[1140]

[1141] Step 1, Method 40: methyl 4-({[(tert-butoxy)carbonyl](methyl)amino}methyl)benzoate

[1142] To methyl 4-{[(tert-butoxy carbonyl)amino]methyl}benzoate (200 mg, 0.75 mmol) and sodium hydride (60% in mineral oil, 32 mg, 0.79 mmol) was added N,N- dimethylformamide (2 mL) under nitrogen. The mixture was stirred at room temperature for 10 minutes. Methyl iodide (49 μL, 0.79 mmol) was added and the mixture was stirred at room temperature for 1 hour. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (2 x 20 mL). The organic extracts were dried over sodium sulfate, filtered, and concentrated. Purification by FCC (silica gel, 0-40% ethyl acetate / heptane) gave the title compound 151 mg (72% yield) as a light yellow oil. δ H NMR (500 MHz, DMSO) 7.95 (d, J = 8.1 Hz, 2H), 7.34 (d, J = 8.1 Hz, 2H), 4.44 (s, 2H), 3.84 (s, 3H), 2.79 (s, 3H), 1.39 (d, J = 43.9 Hz, 9H). Tr (MET CR1278) = 2.03 min, (ES + )(M-t-Bu+H) +224, (M-t-Bu + acetonitrile) + 265.

[1143] Step 2, Method 40: tert-Butyl N-{[4-(hydroxymethyl)phenyl]methyl}-N- methylcarbamate

[1144] To a stirred solution of methyl 4-({[(tert-butoxy)carbonyl](methyl)amino}methyl)benzoate (148 mg, 0.53 mmol) in anhydrous tetrahydrofuran (7 mL) was added 2.4 M lithium aluminum hydride in tetrahydrofuran (0.23 mL, 0.56 mmol) under nitrogen. The mixture was stirred at 0 °C for 30 minutes. The mixture was quenched by careful addition of water (1 mL) followed by saturated ammonium chloride solution (0.5 mL). The mixture was stirred at 0 °C for 5 minutes. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated to give the title compound 124 mg (93% yield) as a light yellow oil. H NMR (500 MHz, DMSO) 7.29 (d, J = 7.7 Hz, 2H), 7.16 (d, J = 7.8 Hz, 2H), 5.14 (t, J = 5.7 Hz, 1H), 4.47 (d, J = 5.6 Hz, 2H), 4.34 (s, 2H), 2.73 (s, 3H), 1.41 (d, J = 12.9 Hz, 9H). Tr (METCR1278) = 1.71 min, (ES + (M + Na) + 273 (M - t-Bu + H) + 196.

[1145] Step 3, Method 40: tert-Butyl N-({4-[(methanesulfonyloxy)methyl]phenyl}methyl)-N- methylcarbamate

[1146] To a stirred solution of tert-butyl N-{[4-(hydroxymethyl)phenyl]methyl}-N- methylcarbamate (120 mg, 0.48 mmol) in dichloromethane (4 mL) was added triethylamine (0.073 mL, 0.52 mmol) followed by methanesulfonyl chloride (0.039 mL, 0.50 mmol) under nitrogen with ice cooling. The mixture was allowed to warm to room temperature and stirred for 2 hours. The mixture was treated with methanesulfonyl chloride (0.013 mL, 0.17 mmol) and stirred at room temperature for 1 hour. The mixture was partitioned between dichloromethane (20 mL) and water (20 mL). The organic extract was dried over sodium sulfate, filtered and concentrated to give the crude title compound 157 mg (57% yield) as a yellow oil which was used directly in the next step. Tr (METCR1278) = 1.93 min, (ES +)(M+Na) + 352,57%.

[1147] Step 4, Method 40: tert-Butyl N-methyl-N-{[4-({[2-(pyridin-3-yl)-1,3-benzoxazol-5- yl]oxy}methyl)phenyl]methyl}carbamate

[1148] To a solution of tert-butyl N-({4-[(methanesulfonyloxy)methyl]phenyl}methyl)-N- methylcarbamate (92 mg, 0.43 mmol) and 2-(pyridin-3-yl)-1,3-benzoxazol-5-ol (157 mg, 0.48 mmol, prepared via Method 14) in N,N-dimethylformamide (3 mL) was added sodium hydride (60% in mineral oil, 19 mg, 0.48 mmol) under nitrogen. The mixture was stirred at room temperature overnight. The mixture was then quenched with water (1 mL), diluted with water (30 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated. Purification via FCC (silica gel, 20-100% ethyl acetate / heptane) afforded 42 mg of the title compound (22% yield) as an off-white solid. H NMR (500 MHz, DMSO) 9.33 (d, J = 2.1 Hz, 1H), 8.80 (dd, J = 4.8, 1.5 Hz, 1H), 8.51 (d, J = 8.0 Hz, 1H), 7.73 (d, J = 8.9 Hz, 1H), 7.65 (dd, J = 8.0, 4.8 Hz, 1H), 7.51 - 7.44 (m, 3H), 7.25 (d, J = 7.8 Hz, 2H), 7.13 (dd, J = 8.9, 2.5 Hz, 1H), 5.18 (s, 2H), 4.38 (s, 2H), 2.76 (s, 3H), 1.40 (d, J = 23.8 Hz, 9H). Tr (METCR1278) = 2.47 min, (ES + (M+H) + 446 (M+Na) + 468 (M-tBu+H) + 390,88%.

[1149] Step 5, Method 40: Methyl({[4-({[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]oxy}methyl)phenyl]methyl})amine

[1150] To a solution of N-methyl-N-{[4-({[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]oxy}methyl)phenyl]methyl}carbamate tert-butyl ester (40 mg, 0.09 mmol) in dichloromethane (2 mL), 4 M hydrogen chloride / 1,4-dioxane (3 mL) was added, and the mixture was allowed to stand at room temperature for 1 hour. The mixture was concentrated under vacuum and purified by preparative HPLC (acetonitrile / water + 0.2% ammonium hydroxide) to give 19.5 mg (63% yield) of the title compound as a grayish-white solid.

[1151] Example 1, Method 40: Methyl({[4-({[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]oxy}methyl)phenyl]methyl})amine)

[1152] δ H NMR(500MHz,DMSO)9.31(s,1H),8.79(d,J=3.6Hz,1H),8.50(t,J

[1153] =7.5Hz,1H),7.72(t,J=7.8Hz,1H),7.64(dd,J=7.8,5.0Hz,1H),7.49-7.45(m,1H),7.42(d,J=7.9Hz,2H), 7.33(d,J=7.8Hz,2H),7.15-7.08(m,1H),5.16(d,J=4.2Hz,2H),3.63(s,2H),3.23(br.s,1H),2.25(s,3H). Tr(MET-uHPLC-AB-101)=1.76min,(ES + (M+H) + 346.

[1154] The following examples were prepared using method 40 as described above:

[1155]

[1156] Table 41

[1157] Method 41

[1158] Solution 41

[1159]

[1160] Step 1, Method 41: 4-{5-[(1-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-1H-pyrazole-4-yl)methoxy]-1-benzofuran-2-yl}pyridine-3-carboxynitrile

[1161] To a suspension of 4-[5-(1 H-pyrazol-4-ylmethoxy)-1 -benzofuran-2-yl]pyridine-3- carbonitrile (72 mg, 0.28 mmol, prepared via Method 36), (2-bromoethoxy)(tert- butyldimethylsilyl)dimethylsilane (100 mg, 0.42 mmol) and potassium iodide (10 mg, 0.06 mmol) in N,N-dimethylformamide (5 mL) was added sodium hydride (60% in mineral oil, 15 mg, 0.38 mmol) and the mixture stirred at room temperature for 2 hours. The mixture was added to water (50 mL) and brine (50 mL) and then extracted with ethyl acetate (3 x 50 mL). The combined extracts were washed with brine (50 mL), dried over magnesium sulfate, filtered and concentrated. Purification by FCC (silica gel, 0-50% ethyl acetate in heptane) afforded the title compound 79 mg (73% yield) as a colourless oil. H NMR (500 MHz, chloroform) 8.93 (s, 1 H), 8.83 (d, J = 5.1 Hz, 1 H), 7.97 (d, J = 5.4 Hz, 1 H), 7.92 (s, 1 H), 7.60 (s, 1 H), 7.57 (s, 1 H), 7.47 (d, J = 9.0 Hz, 1 H), 7.19 (d, J = 2.5 Hz, 1 H), 7.08 (dd, J = 9.0, 2.6 Hz, 1 H), 5.01 (s, 2 H), 4.23 (t, J = 5.2 Hz, 2 H), 3.94 (t, J = 5.2 Hz, 2 H), 0.84 (s, 9 H), -0.06 (s, 6 H). Tr (METCR1278) = 2.52 min, (ES + )(M+H) + 475.

[1162] Step 2, Method 41 : 4-(5-{[1 -(2-hydroxyethyl)-1 H-pyrazol-4-yl]methoxy}-1 - benzofuran-2-yl)pyridine-3-carbonitrile

[1163] To a solution of 4-{5-[(1-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-1 H-pyrazol-4- yl)methoxy]-1 -benzofuran-2-yl}pyridine-3-carbonitrile (79 mg, 0.17 mmol) in anhydrous tetrahydrofuran (10 mL) at 0 °C was added 1 M tert-butyl ammonium fluoride in tetrahydrofuran (200 μί, 0.2 mmol). The ice bath was removed and the mixture stirred at room temperature for 3 hours before partitioning between ethyl acetate (200 mL) and water (50 mL). The organic layer was washed with brine (50 mL), dried over magnesium sulfate, filtered and concentrated. Purification by FCC (silica gel, 0-10% methanol in dichloromethane) afforded the title compound 59 mg (98% yield) as a colourless crystalline solid.

[1164] Example 1, Method 41: 4-(5-{[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]methoxy}-1-benzofuran-2-yl)pyridine-3-carboxynitrile

[1165] δ H NMR(500MHz,DMSO)9.12(s,1H),8.92(d,J=5.4Hz,1H),8.07(d,J

[1166] =5.4Hz,1H),7.95(s,1H),7.84(s,1H),7.62(d,J=9.0Hz,1H),7.55(s,1H),7.47(d,J=2.6Hz,1H),7.1 1(dd,J=9.0,2.6Hz,1H),5.00(s,2H),4.89(t,J=5.2Hz,1H),4.13(t,J=5.7Hz,2H),3.80-3.63(m,2H). Tr(MET-uHPLC-AB-101)=2.58min,(ES + (M+H) + 361.

[1167] The following examples were prepared using method 41 as described above:

[1168]

[1169] Table 42

[1170] Method 42

[1171] Scheme of Method 42

[1172]

[1173] Step 1, Method 42: Dimethyl({2-[4-({[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]oxy}methyl)phenoxy]ethyl})amine

[1174] {2-[4-(chloromethyl)phenoxy]ethyl}dimethylamine hydrochloride (95 mg, 0.38 mmol, described in Bioorg. Med. Chem. Lett. 15 (2005) 2891-2893) and 2-(pyridin-3-yl)-1,3-benzoxol-5-ol (98 mg, 0.38 mmol, prepared via Method 14) were dissolved in dry N,N-dimethylformamide (5 mL) under nitrogen. Sodium hydride (60% in mineral oil, 46 mg, 1.14 mmol) was added and the mixture was stirred at room temperature for 20 hours. Additional sodium hydride (ca. 30 mg) was added and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was then quenched with water (5 mL) and 2M sodium hydroxide (5 mL) and then extracted with ethyl acetate (3 x 10 mL). The combined organic extracts were washed with brine (10 mL), dried, filtered and concentrated. Purification via preparative HPLC (acetonitrile / water + 0.2% ammonium hydroxide) gave the title compound 9.2 mg (6% yield) as a white powder.

[1175] Example 1 Method 42: Dimethyl({2-[4-({[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]oxy}methyl)phenoxy]ethyl})amine

[1176] δ H NMR (500 MHz, DMSO) 9.33 (d, J = 2.0 Hz, 1 H), 8.80 (dd, J = 4.8, 1.6

[1177] Hz, 1 H), 8.51 (dt, J = 8.0, 1.9 Hz, 1 H), 7.72 (d, J = 8.9 Hz, 1 H), 7.65 (dd, J = 8.0, 4.8 Hz, 1 H), 7.47 (d, J = 2.5 Hz, 1 H), 7.41 (d, J = 8.6 Hz, 2 H), 7.10 (dd, J = 8.9, 2.5 Hz, 1 H), 6.96 (d, J = 8.6 Hz, 2 H), 5.10 (s, 2 H), 4.04 (t, J = 5.8 Hz, 2 H), 2.61 (t, J = 5.8 Hz, 2 H), 2.20 (s, 6 H). Tr (MET-uHPLC-AB-101 ) = 1.91 min, (ES + )(M+H) + 390.

[1178] The following examples were prepared using Method 42 as described above:

[1179]

[1180] Table 43

[1181] Method 43

[1182] Regimen of Method 43

[1183]

[1184] Step 1, Method 43: Methyl 5-(2-methoxyethoxy)pyridine-2-carboxylate

[1185] To sodium hydride (60% in mineral oil, 131 mg, 3.26 mmol) and methyl 5- hydroxypyridine-2-carboxylate (500 mg, 3.27 mmol) was added anhydrous N,N- dimethylformamide (5 mL) under nitrogen and the mixture was stirred at room temperature for 15 minutes. A solution of 1-bromo-2-methoxyethane (477 mg, 3.43 mmol) in N,N- dimethylformamide (5 mL) was added slowly. The mixture was stirred at room temperature overnight, then heated at 65 °C for 3.5 hours. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated to give the title compound 688 mg (quantitative yield) as a light brown oil. H NMR (500 MHz, DMSO) 8.39 (d, J = 2.9 Hz, 1H), 8.03 (d, J = 8.7 Hz, 1H), 7.53 (dd, J = 8.7, 2.9 Hz, 1H), 4.31 - 4.23 (m, 2H), 3.84 (s, 3H), 3.72 - 3.66 (m, 2H), 3.31 (s, 3H). Tr (METCR1278) = 1.25 min, (ES + (M+H) + 212.

[1186] Step 2, Method 43: [5-(2-methoxyethoxy)pyridin-2-yl]methanol

[1187] Lithium aluminium hydride (2.4 M in tetrahydrofuran, 0.93 mL, 2.22 mmol) was added to a stirred solution of methyl 5-(2-methoxyethoxy)pyridine-2-carboxylate (148 mg, 0.53 mmol) in anhydrous tetrahydrofuran (35 mL) under nitrogen. The mixture was stirred at 0 °C for 30 minutes. The mixture was then quenched by careful addition of water (2 mL), followed by saturated ammonium chloride solution (1 mL). The mixture was stirred at 0 °C for 5 minutes, then diluted with water (100 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated to give the title compound 243 mg (63% yield) as a clear oil. HNMR (500 MHz, DMSO) δ 8.18 (d, J = 2.7 Hz, 1H), 7.41 - 7.34 (m, 2H), 5.28 (t, J = 5.7 Hz, 1H), 4.48 (d, J = 5.1 Hz, 2H), 4.15 (dd, J = 5.3, 3.7 Hz, 2H), 3.69 - 3.61 (m, 2H), 3.30 (s, 3H). Tr (METCR1278) = solvent front, (ES + )(M+H) + 184.

[1188] Step 3, Method 43: Methanesulfonic acid [5-(2-methoxyethoxy)pyridin-2- yl]methyl ester

[1189] To a stirred solution of [5-(2-methoxyethoxy)pyridin-2-yl]methanol (88 mg, 0.48 mmol) in dichloromethane (3 mL) was added triethylamine (0.07 mL, 0.53 mmol) followed by methanesulfonyl chloride (0.04 mL, 0.5 mmol) under nitrogen at 0 °C and the mixture was stirred at room temperature for 2 hours. The mixture was then partitioned between dichloromethane (10 mL) and water (10 mL). The organic extract was dried over sodium sulfate, filtered and concentrated to give the title compound 119 mg (95% yield) as a brown oil which was used in the next step.

[1190] Step 4, Method 43: 5-{[5-(2-methoxyethoxy)pyridin-2-yl]methoxy}-2-(pyridin-3-yl)- 1,3-benzoxazole

[1191] To a solution of sodium hydride (60% in mineral oil, 21 mg, 0.53 mmol) in N,N- dimethylformamide (2 mL) was added 2-(pyridin-3-yl)-1,3-benzoxol-5-ol (102 mg, 0.48 mmol prepared by Method 14) under nitrogen and the mixture was stirred at room temperature for 30 minutes. After this time, a solution of methanesulfonic acid [5-(2- methoxyethoxy)pyridin-2-yl]methyl ester (125 mg, 0.48 mmol) in N,N-dimethylformamide (1 mL) was added and the mixture was left stirring at room temperature overnight. Sodium hydride (60% in mineral oil, 21 mg, 0.53 mmol) and potassium iodide (8 mg, 0.05 mmol) were added and the mixture was stirred at room temperature for 2 hours. The mixture was then quenched with water (8 mL) and extracted with ethyl acetate (2 x 5 mL) and the combined organic extracts were washed with water (4 x 5 mL), dried over sodium sulfate, filtered and evaporated. Purification by FCC (silica gel, 0-10% methanol / dichloromethane) and recrystallisation from tert-butyl methyl ether (9 mL) gave the title compound 31 mg (17% yield) as a white powder.

[1192] Example 1, Method 43: 5-{[5-(2-methoxyethoxy)pyridin-2-yl]methoxy}-2-(pyridin-3- yl)-1,3-benzoxazole

[1193] δ H NMR (500 MHz, DMSO) 9.33 (d, J = 2.1 Hz, 1H), 8.80 (dd, J = 4.8, 1.6

[1194] Hz, 1H), 8.51 (dt, J = 8.0, 1.9 Hz, 1H), 8.31 (d, J = 2.9 Hz, 1H), 7.74 (d, J = 8.9 Hz, 1H), 7.65 (dd, J = 8.0, 4.8 Hz, 1H), 7.55 - 7.42 (m, 3H), 7.14 (dd, J = 8.9, 2.5 Hz, 1H), 5.19 (s, 2H), 4.23 - 4.15 (m, 2H), 3.70 - 3.63 (m, 2H), 3.31 (s, 3H). Tr (MET-uHPLC-AB-101) = 2.61 min, (ES + )(M+H) + 378.

[1195] The following examples were prepared using Method 43 as described above:

[1196]

[1197] Table 44

[1198] Method 44

[1199] Scheme for Method 44

[1200]

[1201] Step 1, Method 44: 4-(5-{[1-(2-oxoethyl)-1H-pyrazol-4-yl]methoxy}-1-benzofuran-2- yl)pyridine-3-carbonitrile

[1202] To a solution of 4-(5-{[l-(2-hydroxyethyl)-lH-pyrazol-4-yl]methoxy}-l- benzofuran-2-yl)pyridine-3-carbonitrile (48 mg, 0.13 mmol, prepared via Method 41) in dichloromethane (10 mL) was added l,l,l-triacetoxy-l,l-dihydro-l,2- benziodoxol-3(lH)-one (57 mg, 0.13 mmol) and the mixture was stirred at room temperature for 4 hours. l,l,l-triacetoxy-l,l-dihydro-l,2-benziodoxol-3(lH)-one (57 mg, 0.13 mmol) was added and stirring was continued for 12 hours. l,l,l-triacetoxy-l,l-dihydro-l,2-benziodoxol-3(lH)-one (57 mg, 0.13 mmol) was added and the mixture was stirred for 2 hours. The mixture was diluted with ethyl acetate (200 mL) and washed with saturated aqueous sodium bicarbonate solution, 10% aqueous sodium thiosulfate solution (50 mL, 1 : 1) and brine (50 mL). The organic phase was dried over magnesium sulfate, filtered and concentrated. Purification by FCC (silica gel, 0-10% methanol / dichloromethane) afforded the title compound 43 mg (90% yield) as a colourless resin. Tr (METCR1278) = 1.62 min, (ES + )(M+H) + 377.

[1203] Step 2, Method 44: 4-[5-({l-[2-(dimethylamino)ethyl]-lH-pyrazol-4- yl}methoxy)-l-benzofuran-2-yl]pyridine-3-carbonitrile

[1204] To a solution of 4-(5-{[l-(2-hydroxyethyl)-lH-pyrazol-4-yl]methoxy}-l- benzofuran-2-yl)pyridine-3-carbonitrile (48 mg, 0.13 mmol, prepared via Method 41) in dichloromethane (10 mL) was added l,l,l-triacetoxy-l,l-dihydro-l,2- benziodoxol-3(lH)-one (57 mg, 0.13 mmol) and the mixture was stirred at room temperature for 4 hours. l,l,l-triacetoxy-l,l-dihydro-l,2-benziodoxol-3(lH)-one (57 mg, 0.13 mmol) was added and stirring was continued for 12 hours. l,l,l-triacetoxy-l,l-dihydro-l,2-benziodoxol-3(lH)-one (57 mg, 0.13 mmol) was added and the mixture was stirred for 2 hours. The mixture was diluted with ethyl acetate (200 mL) and washed with saturated aqueous sodium bicarbonate solution, 10% aqueous sodium thiosulfate solution (50 mL, 1 : 1) and brine (50 mL). The organic phase was dried over magnesium sulfate, filtered and concentrated. Purification by FCC (silica gel, 0-10% methanol / dichloromethane) afforded the title compound 43 mg (90% yield) as a colourless resin. Tr (METCR1278) = 1.62 min, (ES

[1205] Example 1, Method 44: 4-[5-({l-[2-(dimethylamino)ethyl]-lH-pyrazol-4- yl}methoxy)-l-benzofuran-2-yl]pyridine-3-carbonitrile

[1206] δ H NMR (500 MHz, DMSO) 9.12 (s, 1H), 8.92 (d, J = 5.4 Hz, 1H), 8.07 (d, J

[1207] = 5.4 Hz, 1H), 7.95 (s, 1H), 7.87 (s, 1H), 7.62 (d, J = 9.0 Hz, 1H), 7.53 (s, 1H), 7.46 (d, J = 2.6 Hz, 1H), 7.11 (dd, J = 9.0, 2.6 Hz, 1H), 5.00 (s, 2H), 4.17 (t, J = 6.5 Hz, 2H), 2.62 (t, J = 6.5 Hz, 2H), 2.15 (s, 6H). Tr (MET-uHPLC-AB-101) = 1.85 min, (ES + )(M+H) + 388.

[1208] The following examples were prepared using Method 44 as described above:

[1209]

[1210] Table 45

[1211] Method 45

[1212] Scheme for Method 45

[1213]

[1214] Step 1, Method 45: 6-(methylamino)pyridine-3-carboxylic acid

[1215] To a solution of 6-(methylamino)pyridine-3-carbonitrile (1.0 g, 7.51 mmol) in ethanol (20 mL) and tetrahydrofuran (20 mL) was added sodium hydroxide (2.4 g, 60.0 mmol) and the mixture was stirred at reflux for 16 hours. After cooling, the solids were collected, washed with ethyl acetate (50 mL) and dried under vacuum. The solids were taken up in water (30 mL) and then acidified to pH 3 with 1 N hydrochloric acid. After dilution with tetrahydrofuran (300 mL) and washing with brine (50 mL), the solution was dried over magnesium sulfate, filtered and concentrated to give the title compound 1.2 g (84% yield, 80% NMR purity) as an off-white solid. δ H NMR (500 MHz, DMSO) 12.80 (s, 1H), 8.44 (s, 2H), 7.93 (d, J = 8.7 Hz, 1H), 6.77 (d, J = 8.6 Hz, 1H), 2.92 (s, 3H).

[1216] Steps 2 and 3, Method 45: 5-{5-[(5-methoxypyridin-2-yl)methoxy]-l,3- benzoxazol-2-yl}-N-methylpyridin-2-amine

[1217] To a solution of 2-amino-4-[(5-methoxypyridin-2-yl)methoxy]phenol (50% pure, 125 mg, 0.25 mmol, prepared by Method 33) and 6-(methylamino)pyridine-3- carboxylic acid (80% pure, 63 mg, 0.33 mmol) in pyridine (2 mL) was added l-(3- (dimethylamino)-propyl)-3-ethylcarbodiimide hydrochloride (70 mg, 0.37 mmol) and the mixture was stirred at room temperature for 18 hours. The solvent was removed in vacuo and the residue taken up in ethyl acetate (200 mL). The solution was washed with water (50 mL) and brine (50 mL). The organic extract was dried over magnesium sulfate, filtered and concentrated. This was taken up in acetic acid (3 mL) and heated in a microwave at 200 °C for 40 minutes. After cooling, the volatiles were removed in vacuo and the residue partitioned between ethyl acetate (200 mL) and saturated aqueous sodium bicarbonate solution (100 mL). The organic layer was washed with brine (50 mL), dried over magnesium sulfate, filtered and then pre-adsorbed onto a small amount of silica gel. Purification by FCC (silica gel, 0-10% methanol / dichloromethane) and preparative HPLC (acetonitrile / water) gave the title compound 9.9 mg (17% yield) as an off-white solid.

[1218] Example 1, Method 45: 5-{5-[(5-methoxypyridin-2-yl)methoxy]-l,3-benzoxazol-2- yl}-N-methylpyridin-2-amine

[1219] δ H NMR (500 MHz, DMSO) δ 8.77 (d, J = 2.2 Hz, 1H), 8.30 (d, J = 2.9 Hz,

[1220] 1H), 8.03 (d, J = 7.6 Hz, 1H), 7.59 (d, J = 8.8 Hz, 1H), 7.51 (d, J = 8.6 Hz, 1H), 7.42 (dd, J = 8.6, 2.9 Hz, 1H), 7.39 - 7.34 (m, 1H), 7.33 (d, J = 2.5 Hz, 1H), 6.99 (dd, J = 8.8, 2.5 Hz, 1H), 6.60 (d, J = 8.9 Hz, 1H), 5.15 (s, 2H), 3.83 (s, 3H), 2.86 (d, J = 4.8 Hz, 3H). Tr (MET-uHPLC-AB-101) = 1.98 min, (ES + )(M+H) + 363.

[1221] The following examples were prepared using method 45 as described above:

[1222]

[1223]

[1224] Table 46

[1225] Method 46

[1226] Solution 46

[1227]

[1228] Step 1, Method 46: 3-{[(2-{5H,6H-imidazo[2,1-b][1,3]thiazo-3-yl}-1-benzofuran-5-yl)oxy]methyl}pyridine

[1229] At 0 °C, 0.43 M bromine / dichloromethane (0.2 mL, 0.086 mmol) was added to a solution of 3-{[(2-{5H,6H-imidazo[2,1-b][1,3]thiazo-3-yl}-1-benzofuran-5-yl)oxy]methyl}pyridine (30 mg, 0.086 mmol, prepared by method 37) in dichloromethane. After removing the ice bath, the mixture was stirred at room temperature for 1 hour, followed by dilution with ethyl acetate. The solid was collected by filtration and then dried under vacuum. Preparative HPLC purification (acetonitrile / water + 0.2% ammonium hydroxide) gave 9.9 mg (27% yield) of the title compound as a grayish-white solid.

[1230] Example 1, Method 46: 3-{[(2-{2-bromo-5H,6H-imidazo[2,1-b][1,3]thiazo-3-yl}-1-benzofuran-5-yl)oxy]methyl}pyridine

[1231] δ H NMR(500MHz,DMSO)8.70(d,J=1.8Hz,1H),8.55(dd,J=4.8,1.6

[1232] Hz,1H),7.94-7.85(m,1H),7.57(d,J=9.0Hz,1H),7.49-7.40(m,2H),7.36(d ,J=2.6Hz,1H),7.11(dd,J=9.0,2.6Hz,1H),5.20(s,2H),4.15-4.00(m,4H). Tr(MET-uHPLC-AB-101)=1.36min,(ES + (M+H) + 428 / 430.

[1233] The following examples were prepared using Method 46 as described above:

[1234]

[1235] Table 47

[1236] Method 47

[1237] Scheme for Method 47

[1238]

[1239] Step 1, Method 47: 5-[(5-methoxypyrazin-2-yl)methoxy]-2-nitroaniline

[1240] To a stirred solution of 3-amino-4-nitrophenol (220 mg, 1.43 mmol) in N,N- dimethylformamide (5 mL) was added potassium tert-butoxide (160 mg, 1.42 mmol) under nitrogen and the mixture was stirred at room temperature for 5 minutes. A solution of (5- methoxypyrazin-2-yl)methyl methanesulfonate (311 mg, 1.43 mmol, prepared by Method 20) in N,N-dimethylformamide (3 mL) was added and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic extracts were washed with 0.2 M sodium hydroxide (3 x 50 mL), dried over sodium sulfate, filtered and concentrated to give the title compound 213 mg (54% yield) as a bright yellow solid. H NMR (500 MHz, DMSO) δ 8.39 - 8.30 (m, 2H), 7.53 (d, J = 3.0 Hz, 1H), 7.28 (s, 2H), 7.24 (dd, J = 9.2, 3.0 Hz, 1H), 7.01 (d, J = 9.2 Hz, 1H), 5.10 (s, 2H), 3.92 (s, 3H). Tr (METCR1278) = 1.72 min, (ES + (M+H) + 277.

[1241] Step 2, Method 47: N-{5-[(5-methoxypyrazin-2-yl)methoxy]-2-nitrophenyl}pyridine-3- carboxamide

[1242] To a stirred solution of 5-[(5-methoxypyrazin-2-yl)methoxy]-2-nitroaniline (213 mg, 0.77 mmol) in tetrahydrofuran (8 mL) was added diisopropylethylamine (0.16 mL, 0.92 mmol) followed by pyridine-3-carbonyl chloride hydrochloride (144 mg, 0.81 mmol). The mixture was stirred at room temperature overnight. The mixture was diluted with water (30 mL) and saturated aqueous sodium bicarbonate solution (10 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated to give the title compound 239 mg (81% yield) as a bright yellow solid. H NMR (500 MHz, DMSO) 10.74 (s, 1H), 9.10 (d, J = 2.1 Hz, 1H), 8.73 (d, J = 4.6 Hz, 1H), 8.42 (d, J = 1.2 Hz, 1H), 8.35 (d, J = 1.4 Hz, 1H), 8.27 (dt, J = 7.9, 1.9 Hz, 1H), 7.65 (d, J = 8.9 Hz, 1H), 7.61 (s, 1H), 7.54 (dd, J = 8.6, 4.0 Hz, 1H), 7.39 (d, J = 8.7 Hz, 1H), 5.25 (s, 2H), 3.93 (s, 3H). Tr (METCR1278) = 1.72 min, (ES + (M+H) + 382.

[1243] Step 3, Method 47: 5-[(5-methoxypyrazin-2-yl)methoxy]-2-(pyridin-3-yl)-1H-1,3- benzoxazole

[1244] To a stirred solution of 5-[(5-methoxypyrazin-2-yl)methoxy]-2-nitroaniline (213 mg, 0.77 mmol) in tetrahydrofuran (8 mL) was added diisopropylethylamine (0.16 mL, 0.92 mmol) followed by pyridine-3-carbonyl chloride hydrochloride (144 mg, 0.81 mmol). The mixture was stirred at room temperature overnight. The mixture was diluted with water (30 mL) and saturated aqueous sodium bicarbonate solution (10 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated to give the title compound 239 mg (81% yield) as a bright yellow solid.δ HNMR (500 MHz, DMSO) 12.97 (s, 1H), 9.30 (d, J = 1.9 Hz, 1H), 8.65 (d, J = 4.8 Hz, 1H), 8.44 (d, J = 8.0 Hz, 1H), 8.41 (s, 1H), 8.35 (s, 1H), 7.60-7.51 (m, 2H), 7.24 (s, 1H), 6.96 (dd, J = 8.7, 2.3 Hz, 1H), 5.21 (s, 2H), 3.92 (s, 3H). Tr (MET-uHPLC-AB-101) = 1.74 min, (ES + )(M+H) + 334.

[1245] Step 4, Method 47: 6-[(5-methoxypyrazin-2-yl)methoxy]-1-methyl-2-(pyridin-3-yl)-1H-1,3-benzodiazole and 5-[(5-methoxypyrazin-2-yl)methoxy]-1-methyl-2-(pyridin-3-yl)-1H-1,3-benzodiazole

[1246] Step 4, Method 47: 6-[(5-methoxypyrazin-2-yl)methoxy]-1-methyl-2-(pyridin-3-yl)-1H-1,3-benzodiazole and 5-[(5-methoxypyrazin-2-yl)methoxy]-1-methyl-2-(pyridin-3-yl)-1H-1,3-benzodiazole

[1247] Example 1, Method 47: 5-[(5-methoxypyrazin-2-yl)methoxy]-1-methyl-2-(pyridin-3-yl)-1H-1,3-benzodiazole

[1248] δ H NMR (500 MHz, DMSO) 9.04 (s, 1H), 8.73 (d, J = 3.8 Hz, 1H), 8.40 (d, J

[1249] = 1.0 Hz, 1H), 8.34 (d, J = 1.3 Hz, 1H), 8.26 (dt, J = 7.9, 1.7 Hz, 1H), 7.60 (dd, J = 7.9, 4.6 Hz, 1H), 7.56 (d, J = 8.8 Hz, 1H), 7.37 (d, J = 2.3 Hz, 1H), 7.05 (dd, J = 8.8, 2.3 Hz, 1H), 5.21 (s, 2H), 3.92 (s, 3H), 3.88 (s, 3H). Tr (MET-uHPLC-AB-101) = 1.70 min, (ES + )(M+H) + 348.

[1250] Example 2, Method 47: 6-[(5-methoxypyrazin-2-yl)methoxy]-1-methyl-2-(pyridin-3- yl)-1H-1,3-benzoxazole

[1251] δ H NMR (500 MHz, DMSO) 9.04 (s, 1H), 8.73 (s, 1H), 8.45-8.41 (m, 1H), 8.35 (d, J = 1.3 Hz, 1H), 8.25 (d, J = 7.9 Hz, 1H), 7.64-7.58 (m, 2H), 7.38 (d, J = 2.3 Hz, 1H), 6.98 (dd, J = 8.7, 2.4 Hz, 1H), 5.25 (s, 2H), 3.93 (s, 3H), 3.88 (s, 3H). Tr (MET-uHPLC-AB-101) = 1.74 min, (ES + )(M+H) + 348.

[1252] The following examples were prepared using Method 47 as described above:

[1253]

[1254]

[1255] Table 48

[1256] Method 48

[1257] Scheme for Method 48

[1258]

[1259] Step 1, Method 48: 5-[(5-methoxypyridin-2-yl)methoxy]-2-(piperazin-1-yl)-1,3- benzoxazole

[1260] tert-Butyl 4-{5-[(5-methoxypyridin-2-yl)methoxy]-l,3-benzoxazol-2-yl}piperazine- 1 -carboxylate (50 mg, 0.11 mmol, prepared via Method 38) was stirred in 4 M hydrogen chloride in 1,4-dioxane (1 mL) for 2 hours. The reaction mixture was diluted with water (10 mL) and solid sodium bicarbonate was added portionwise until pH 8. The solution was extracted with dichloromethane (3 x 10 mL) and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated. Purification via preparative HPLC (acetonitrile / water + 0.2% ammonium hydroxide) afforded 11.3 mg (29% yield) of the title compound as a white solid.

[1261] Example 1, Method 48: 5-[(5-methoxypyridin-2-yl)methoxy]-2-(piperazin-1-yl)-1,3- benzoxazole

[1262] δ H NMR (500 MHz, DMSO) δ 8.28 (d, J = 2.9 Hz, 1H), 7.47 (d, J = 8.6 Hz,

[1263] 1H), 7.42 (dd, J = 8.6, 2.9 Hz, 1H), 7.26 (d, J = 8.7 Hz, 1H), 6.93 (d, J = 2.5 Hz, 1H), 6.64 (dd, J = 8.7, 2.6 Hz, 1H), 5.08 (s, 2H), 3.84 (s, 3H), 3.53 - 3.46 (m, 4H), 2.82 - 2.73 (m, 4H). Tr (MET-uHPLC-AB-101) = 1.33 min, (ES + )(M+H) + 341.

[1264] The following examples were prepared using Method 48 as described above:

[1265]

[1266] Table 49

[1267] Method 49

[1268] Scheme for Method 49

[1269]

[1270] Step 1, Method 49: Methyl 5-aminopyridine-2-carboxylate

[1271] Methyl 5-amino pyridine-2-carboxylate (850 mg, 5.59 mmol), di-tert-butyldicarbonate (1.34 g, 6.15 mmol) and 4-dimethylaminopyridine (68 mg, 0.56 mmol) were suspended in dichloromethane (10 mL) and stirred at room temperature for 20 h. The reaction mixture was concentrated to give a white powder. The powder was suspended in ethyl acetate (20 mL), sonicated, heated to boiling and then filtered. The filtrate was diluted with additional ethyl acetate (20 mL) and loaded onto silica gel. Purification by FCC (silica gel, 18-100% ethyl acetate / heptane) gave the crude title compound 862 mg (51% yield) as a white powder which was used in the next step without further purification. H NMR (500 MHz, DMSO) 7.97 (d, J = 2.7 Hz, 1H), 7.74 (d, J = 8.6 Hz, 1H), 6.91 (dd, J = 8.6, 2.7 Hz, 1H), 6.18 (s, 2H), 3.76 (s, 3H).

[1272] Step 2, Method 49: Methyl 5-{[(tert-butoxy)carbonyl]amino}pyridine-2- carboxylate

[1273] Methyl 5-amino pyridine-2-carboxylate (850 mg, 5.59 mmol), di-tert-butyldicarbonate (1.34 g, 6.15 mmol) and 4-dimethylaminopyridine (68 mg, 0.56 mmol) were suspended in dichloromethane (10 mL) and stirred at room temperature for 20 h. The reaction mixture was concentrated to give a white powder. The powder was suspended in ethyl acetate (20 mL), sonicated, heated to boiling and then filtered. The filtrate was diluted with additional ethyl acetate (20 mL) and loaded onto silica gel. Purification by FCC (silica gel, 18-100% ethyl acetate / heptane) gave the crude title compound 862 mg (51% yield) as a white powder which was used in the next step without further purification. H NMR (500 MHz, DMSO) 10.01 (s, 1H), 8.71 (d, J = 2.3 Hz, 1H), 8.06 (dd, J = 8.7, 2.4 Hz, 1H), 8.00 (d, J = 8.6 Hz, 1H), 3.83 (s, 3H), 1.49 (s, 9H). Tr (METCR1278) = 1.64 min, (ES + (M+H) + 253, 83%.

[1274] Step 3, Method 49: Methyl 5-{[(tert-butoxy)carbonyl](methyl)amino}pyridine-2- carboxylate

[1275] Methyl 5-{[(tert-butoxy)carbonyl]amino}pyridine-2-carboxylate (406 mg, 1.34 mmol) was dissolved in anhydrous N,N-dimethylformamide (5 mL) and cooled to 0 °C. Sodium hydride (60% in mineral oil, 136 mg, 3.34 mmol) was added and the mixture was stirred for 15 minutes. Iodomethane (100 μL, 1.60 mmol) was added and the mixture was stirred at room temperature for 18 hours. The reaction mixture was quenched by the addition of water (5 mL) and extracted with ethyl acetate (2 x 15 mL). The combined organic extracts were washed with brine (3 x 10 mL), dried over magnesium sulfate, filtered, and concentrated. Purification by FCC (silica gel, eluant: 50-75% ethyl acetate in heptane) afforded the title compound 180 mg (51% yield) as a yellow oil. H NMR (500 MHz, DMSO) 8.70 (d, J = 2.5 Hz, 1H), 8.03 (d, J = 8.5 Hz, 1H), 7.91 (dd, J = 8.5, 2.6 Hz, 1H), 3.87 (s, 3H), 3.27 (s, 3H), 1.43 (s, 9H). Tr (METCR1278) = 1.68 min, (ES + (M+H) + 267.

[1276] Step 4, Method 49: tert-Butyl N-[6-(hydroxymethyl)pyridin-3-yl]-N-methylcarbamate

[1277] Methyl 5-{[(tert-butoxy)carbonyl](methyl)amino}pyridine-2-carboxylate (170 mg, 0.64 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL) and cooled to 0 °C under nitrogen. 1.2 M diisobutylaluminum hydride in toluene (1.06 mL, 1.28 mmol) was added and the mixture was stirred for 1.5 hours. 1.2 M diisobutylaluminum hydride in toluene (0.13 mL) was added and the mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with saturated aqueous Rochelle's salt solution (20 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic extracts were washed with brine (10 mL), dried over magnesium sulfate, filtered, and concentrated to afford the title compound 120 mg (63% yield) as a colorless gum. H NMR (500 MHz, DMSO) 8.41 (d, J = 2.5 Hz, 1H), 7.71 (dd, J = 8.4, 2.6 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 5.40 (t, J = 5.7 Hz, 1H), 4.53 (d, J = 5.2 Hz, 2H), 3.19 (s, 3H), 1.39 (s, 9H). Tr (METCR1278) = 1.68 min, (ES +(M+H) + 239.81%.

[1278] Step 5, Method 49: N-{6-[(methanesulfonyloxy)methyl]pyridin-3-yl}-N-methylcarbamate tert-butyl ester

[1279] N-[6-(hydroxymethyl)pyridin-3-yl]-N-methylcarbamate tert-butyl ester (120 mg, 0.4 mmol) was dissolved in dichloromethane (3 mL) under nitrogen atmosphere and cooled to 0 °C. Triethylamine (84 μL, 0.60 mmol) and methanesulfonyl chloride (34 μL, 0.44 mmol) were added, and the mixture was stirred and heated to room temperature for 18 hours. The reaction mixture was diluted with dichloromethane (5 mL) and washed with water (5 mL) and brine (5 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated to give 124 mg (42% yield) of the crude title compound as an orange oil. The product also contained 47% alkyl chloride. Tr(METCR1278) = 1.69 min, (ES + (M+H) + 317,43% (methanesulfonate). Tr(METCR1278)=1.82min,(ES + (M+H) + 257 / 259, 37% (chloride).

[1280] Step 6, Method 49: N-methyl-N-[5-({[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]oxy}methyl)pyridin-2-yl]tert-butyl carbamate

[1281] Under nitrogen atmosphere, a mixture of N-{6-[(methanesulfonyloxy)methyl]pyridin-3-yl}-N-methylcarbamate tert-butyl ester and N-[6-(chloromethyl)pyridin-3-yl]-N-methylcarbamate tert-butyl ester (43% + 37% , 120 mg, 0.34 mmol total alkylating agent) and 2-(pyridin-3-yl)-1,3-benzoxazol-5-ol (90 mg, 0.34 mmol, prepared by method 14) was dissolved in anhydrous N,N-dimethylformamide (5 mL) and cooled to 0 °C. Sodium hydride (60% in mineral oil, 41 mg, 1.04 mmol) was added, and the mixture was stirred and heated to room temperature for 18 hours. The reaction mixture was quenched with water (5 mL) and extracted with ethyl acetate (3 x 15 mL). The combined ethyl acetate extracts were washed with brine (3 x 10 mL), dried over magnesium sulfate, filtered, and concentrated. The title compound was purified by FCC (silica gel, 12-100% ethyl acetate / heptane) to give 52 mg (31% yield) as a brown powder. δ HNMR (500 MHz, DMSO) 9.33 (d, J = 1.6 Hz, 1H), 8.80 (dd, J = 4.8, 1.6 Hz, 1H), 8.56 (d, J = 2.5 Hz, 1H), 8.51 (dt, J = 8.0, 1.9 Hz, 1H), 7.78 (dd, J = 8.4, 2.6 Hz, 1H), 7.75 (d, J = 8.9 Hz, 1H), 7.68 - 7.62 (m, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.50 (d, J = 2.5 Hz, 1H), 7.16 (dd, J = 8.9, 2.6 Hz, 1H), 5.25 (s, 2H), 3.22 (s, 3H), 1.40 (s, 9H). Tr (METCR1278) = 2.05 min, (ES + )(M+H) + 433, 80%.

[1282] Step 7, Method 49: N-methyl-6-({[2-(pyridin-3-yl)-l,3-benzoxazol-5-yl]oxy}methyl)pyridin-3-amine

[1283] N-methyl-N-[5-({[2-(pyridin-3-yl)-l,3-benzoxazol-5-yl]oxy}methyl)pyridin-2- yl]carbamic acid tert-butyl ester (52 mg, 0.12 mmol) was dissolved in 4 M hydrogen chloride in 1,4-dioxane (1 mL) and water (0.1 mL). The mixture was stirred at room temperature for 1.5 hours and concentrated. Purification by SCX and preparative HPLC (acetonitrile / water + 0.1% formic acid) gave 12 mg (30% yield) of the title compound as an off-white powder.

[1284] Example 1, Method 49: N-methyl-6-({[2-(pyridin-3-yl)-l,3-benzoxazol-5-yl]oxy}methyl)pyridin-3-amine

[1285] δ H NMR (500 MHz, DMSO) 9.32 (d, J = 1.5 Hz, 1H), 8.80 (dd, J = 4.8, 1.6

[1286] Hz, 1H), 8.51 (dt, J = 8.0, 1.9 Hz, 1H), 7.94 (d, J = 2.7 Hz, 1H), 7.72 (d, J = 8.9 Hz, 1H), 7.65 (ddd, J = 8.0, 4.8, 0.7 Hz, 1H), 7.47 (d, J = 2.5 Hz, 1H), 7.29 (d, J = 8.4 Hz, 1H), 7.10 (dd, J = 8.9, 2.5 Hz, 1H), 6.90 (dd, J = 8.4, 2.9 Hz, 1H), 5.98 (d, J = 5.0 Hz, 1H), 5.06 (s, 2H), 2.70 (d, J = 5.0 Hz, 3H). Tr (MET-uHPLC-AB-101) = 1.67 min, (ES + )(M+H) + 333.

[1287] The following examples were prepared using Method 49 as described above:

[1288]

[1289] Table 50

[1290] Method 50

[1291] Scheme for Method 50

[1292]

[1293] Step 1, Method 50: l-(5-hydroxy-l-benzofuran-2-yl)ethan-l-one

[1294] A mixture of 2,5-dihydroxybenzaldehyde (5.0 g, 36.2 mmol), l-chloropropan-2-one (3.6 mL, 43.7 mmol), and potassium carbonate (6.0 g, 43.4 mmol) in acetone (100 mL) was heated to reflux for 18 h. After cooling, the suspension was diluted with acetone (100 mL) and filtered through a pad of celite. The filtrate was concentrated and the residue taken up in ethyl acetate (300 mL), washed with water (50 mL) and brine (50 mL), dried over magnesium sulfate, filtered, and adsorbed onto a small amount of silica gel. Purification by FCC (silica gel, 0-60% ethyl acetate / heptane) gave the title compound 2.99 g (47% yield) as a colorless crystalline solid. H NMR (500 MHz, DMSO) 9.48 (s, 1H), 7.80-7.65 (m, 1H), 7.50 (d, J = 8.9 Hz, 1H), 7.07 (d, J = 2.4 Hz, 1H), 6.98 (dd, J = 8.9, 2.5 Hz, 1H), 2.52 (s, 3H). Tr (MET CR1278) = 1.34 min, (ES+ )(M+H) + 177.

[1295] Step 2, Method 50: l-[5-(Methoxymethoxy)-l-benzofuran-2-yl]ethan-l-one

[1296] To a solution of l-(5-hydroxy-l-benzofuran-2-yl)ethan-l-one (2.84 g, 16.1 mmol) and chloro(methoxy)methane (3.0 mL, 39.5 mmol) in N,N-dimethylformamide (40 mL) at 0 °C was added sodium hydride (60% in mineral oil, 1.6 g, 40 mmol) in two portions. After 10 min, the ice bath was removed and the mixture was stirred at room temperature for 18 h. After the addition of methanol (5 mL), stirring was continued for 30 min, after which the mixture was added to water (200 mL) and brine (200 mL). The mixture was extracted with ethyl acetate (4 x 150 mL), the combined organic layers were washed with brine (100 mL), dried over magnesium sulfate, filtered, and concentrated. The residue was dissolved in tetrahydrofuran (100 mL) and adsorbed onto a small amount of silica gel. Purification by FCC (silica gel, 0-50% ethyl acetate / heptane) afforded the title compound 2.48 g (70% yield) as an off-white solid. H NMR (500 MHz, DMSO) 7.84-7.79 (m, 1H), 7.64 (d, J = 9.0 Hz, 1H), 7.42 (d, J = 2.5 Hz, 1H), 7.22 (dd, J = 9.0, 2.6 Hz, 1H), 5.23 (s, 2H), 3.40 (s, 3H), 2.55 (s, 3H). Tr (METCR1278) = 1.70 min, (ES + )(M+H) + 221.

[1297] Step 3, Method 50: Ethyl 3-[5-(methoxymethoxy)-l-benzofuran-2-yl]-3- oxopropionate

[1298] To a solution of l-[5-(methoxymethoxy)-l-benzofuran-2-yl]ethan-l-one (2.45 g, 11.1 mmol) in diethyl carbonate (50 mL, 413 mmol) was added sodium hydride (60% in mineral oil. 890 mg, 22.3 mmol). After stirring at room temperature for 10 minutes, the mixture was heated to 100 °C for 18 hours. The volatiles were removed in vacuo and the residue partitioned between ethyl acetate (300 mL), water (100 mL), and acetic acid (2 mL). The organic layer was separated, washed with brine (50 mL), dried over magnesium sulfate, filtered, and concentrated. Purification by FCC (silica gel, 0-20% ethyl acetate / heptane) afforded the title compound 2.58 g (79% yield) as an off-white solid. H NMR (500 MHz, DMSO) 7.91 (s, 1H), 7.66 (d, J = 9.0 Hz, 1H), 7.44 (d, J = 2.5 Hz, 1H), 7.25 (dd, J = 9.0, 2.5 Hz, 1H), 5.24 (s, 2H), 4.24-3.96 (m, 4H), 3.40 (d, J = 2.2 Hz, 3H), 1.18 (t, J = 7.1 Hz, 3H). Tr (METCR1278) = 1.86 min, (ES + (M+H) + 293.

[1299] Step 4, Method 50: 2-Bromo-3-[5-(methoxymethoxy)-l-benzofuran-2-yl]-3- oxopropanoic acid ethyl ester and 2-bromo-3-(4-bromo-5-hydroxy-l-benzofuran-2-yl)- 3-oxopropanoic acid ethyl ester

[1300] To a solution of 3-[5-(methoxymethoxy)-l-benzofuran-2-yl]-3-oxopropanoic acid ethyl ester (2.5 g, 8.55 mmol) in tetrahydrofuran (100 mL) was added phenyltrimethylammonium tribromide (3.4 g, 9.04 mmol) and the mixture was stirred at room temperature for 18 hours. After dilution with ethyl acetate (100 mL), the mixture was filtered through celite and the filtrate was concentrated. The residue was taken up in ethyl acetate (300 mL), washed with 10% aqueous sodium thiosulfate (50 mL) and brine (50 mL), dried over magnesium sulfate, filtered, and concentrated to afford the title compound 3.20 g (quantitative yield) (3.3 / 1 mixture by NMR) as a yellow oil. (X = H, major): δ HNMR (500 MHz, DMSO) 9.62 (s, 1H), 8.03-7.92 (m, 1H), 7.54 (d, J = 9.0 Hz, 1H), 7.12 (d, J = 2.4 Hz, 1H), 7.06 (dd, J = 9.0, 2.5 Hz, 1H), 6.39 (s, 1H), 4.22 (q, J = 7.1 Hz, 2H), 1.16 (t, J = 7.1 Hz, 3H). (X = H, major) Tr (METCR1278) = 1.76 min, (ES + )(M+H) + 327 / 329. (X = Br, minor) Tr (METCR1278) = 1.91 min, (ES + )(M+H) + 407.

[1301] Step 5, Method 50: 3-(5-Hydroxy-l-benzofuran-2-yl)-5H,6H-imidazo[2,l- b][l,3]thiazole-2-carboxylic acid ethyl ester and 3-(4-bromo-5-hydroxy-l- benzofuran-2-yl)-5H,6H-imidazo[2,l-b][l,3]thiazole-2-carboxylic acid ethyl ester

[1302] A mixture of crude 2-bromo-3-[5-(methoxymethoxy)-l-benzofuran-2-yl]-3- oxopropionic acid ethyl ester and 2-bromo-3-(4-bromo-5-hydroxy-l- benzofuran-2-yl)-3-oxopropionic acid ethyl ester (ratio: 3.3 / 1, max. 8.55 mmol total) and imidazolidine-2-thione (880 mg, 8.61 mmol) in ethanol (20 mL) and acetic acid (20 mL) was stirred at reflux for 18 h. The solvent was removed in vacuo and the residue was triturated with a mixture of ethyl acetate and acetonitrile (20 mL, 1 / 1), filtered and dried in vacuo to give the title compound 2.58 g (70% yield) (hydrobromide, 3 / 1 mixture by LCMS) as a yellow solid. (X = H, major) Tr (MET-uHPLC-AB-101) = 1.52 min, (ES + )(M+H) + 331 and (X = Br, minor) Tr (MET-uHPLC-AB-101) = 1.81 min, (ES + )(M+H) + 409 / 411.

[1303] Step 5, Method 50: 3-[5-(pyridin-3-ylmethoxy)-l-benzofuran-2-yl]-5H,6H- imidazo[2,l-b][l,3]thiazole-2-carboxylic acid ethyl ester and 3-[4-bromo-5-(pyridin-3- ylmethoxy)-l-benzofuran-2-yl]-5H,6H-imidazo[2,l-b][l,3]thiazole-2-carboxylic acid ethyl ester

[1304] To a suspension of 3-(5-hydroxy-l-benzofuran-2-yl)-5H,6H-imidazo[2,l- b][l,3]thiazole-2-carboxylic acid ethyl ester hydrobromide and 3-(4-bromo-5- hydroxy-l-benzofuran-2-yl)-5H,6H-imidazo[2,l-b][l,3]thiazole-2-carboxylic acid ethyl ester hydrobromide (3 / 1 mixture, 500 mg, 1.15 mmol), 3-(bromomethyl)pyridine hydrobromide (480 mg, 1.90 mmol), and potassium iodide (20 mg, 0.12 mmol) in N,N-dimethylformamide (20 mL) at 0 °C was added sodium hydride (60% in mineral oil, 170 mg, 4.26 mmol). The ice bath was removed and the mixture was stirred at 60 °C for 90 minutes before partitioning between water (100 mL), brine (100 mL), and ethyl acetate (200 mL). The aqueous layer was extracted with ethyl acetate (2 x 100 mL). The combined organic extracts were washed with brine (100 mL), dried over magnesium sulfate, filtered, and adsorbed onto a small amount of silica gel. Purification by FCC (silica gel, 0-10% methanol / dichloromethane), followed by trituration with methanol (3 mL) gave a mixture of the title compounds 257 mg (51% yield) (4.3 / 1 mixture, by LCMS) as a yellow solid. (X = H, major) Tr(MET-uHPLC-AB-101) = 1.53 min, (ES + )(M+H) + 422and (X = Br, minor) Tr(MET-uHPLC-AB-101) = 1.77 min, (ES + )(M+H) + 500 / 502.

[1305] Step 6, Method 50: 3-[5-(pyridin-3-ylmethoxy)-l-benzofuran-2-yl]-5H,6H- imidazo[2,l-b][l,3]thiazole-2-carboxylic acid ethyl ester and 3-[4-bromo-5-(pyridin-3- ylmethoxy)-l-benzofuran-2-yl]-5H,6H-imidazo[2,l-b][l,3]thiazole-2-carboxylic acid ethyl ester

[1306] A solution of 3-[5-(pyridin-3-ylmethoxy)-l-benzofuran-2-yl]-5H,6H- imidazo[2,l-b][l,3]thiazole-2-carboxylic acid ethyl ester (81%, 124 mg, 0.24 mmol) in 7 M ammonia in methanol (40 mL) was heated to 80 °C in a pressure tube for 24 h, then stirred at room temperature for 3 days. The mixture was added to saturated aqueous ammonium chloride solution (300 mL), then extracted with ethyl acetate (4 x 100 mL). The combined organic extracts were washed with brine (100 mL), dried over magnesium sulfate, filtered, then adsorbed onto a small amount of silica gel. Purification by FCC (silica gel, 0-15% methanol / dichloromethane) gave the title compound 47 mg (37% yield) as a yellow solid. H NMR (500 MHz, DMSO) δ 8.69 (d, J = 1.8 Hz, 1H), 8.55 (dd, J = 4.7, 1.7 Hz, 1H), 7.89 (d, J = 7.9 Hz, 1H), 7.58 (d, J = 9.0 Hz, 1H), 7.52 (s, 1H), 7.44 (dd, J = 7.5, 4.7 Hz, 1H), 7.36 (d, J = 2.6 Hz, 1H), 7.33 (bs, 2H), 7.12 (dd, J = 9.0, 2.6 Hz, 1H), 5.22 (s, 2H), 4.16-3.94 (m, 4H). Tr (METCR1278) = 1.03 min, (ES + (M+H) + 393,74%.

[1307] Step 7, Method 50: 3-[5-(Pyridin-3-ylmethoxy)-l-benzofuran-2-yl]-5H,6H- imidazo[2,l-b][l,3]thiazole-2-carbonitrile

[1308] To a solution of 3-[5-(pyridin-3-ylmethoxy)-l-benzofuran-2-yl]-5H,6H- imidazo[2,l-b][l,3]thiazole-2-carboxamide (74%, 44 mg, 0.083 mmol) and pyridine (0.02 mL, 0.248 mmol) in tetrahydrofuran (10 mL) at 0 °C was added trifluoroacetic anhydride (50 μί, 0.35 mmol). After stirring for 10 min, the mixture was added to saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed with brine (50 mL), dried over magnesium sulfate, filtered and concentrated. Purification by preparative HPLC (acetonitrile / water + 0.2% ammonium hydroxide) gave the title compound 12 mg (39% yield) as a yellow solid.

[1309] Example 1, Method 50: 3-[5-(pyridin-3-ylmethoxy)-l-benzofuran-2-yl]-5H,6H- imidazo[2,l-b][l,3]thiazole-2-carbonitrile

[1310] δ H NMR (500 MHz, DMSO) 8.71 (d, J = 1.9 Hz, 1 H), 8.56 (dd, J = 4.8, 1.5

[1311] Hz, 1 H), 7.96 - 7.85 (m, 1 H), 7.70 - 7.57 (m, 2 H), 7.51 - 7.37 (m, 2 H), 7.20 (dd, J = 9.2, 2.6 Hz, 1 H), 5.22 (s, 2 H), 4.34 - 4.18 (m, J = 5.1 Hz, 4 H). Tr (MET-uHPLC-AB-101) = 1.22 min, (ES + )(M+H) + 375.

[1312] The following examples were prepared using Method 50 as described above:

[1313]

[1314] Table 51

[1315] Method 51

[1316] Scheme for Method 51

[1317]

[1318] Step 1, Method 51: 5-N-{2-hydroxy-5-[(5-methoxypyridin-2-yl)methoxy]phenyl}-2-N- methylpyridine-2,5-dicarboxamide

[1319] To a solution of 2-amino-4-[(5-methoxypyridin-2-yl)methoxy]phenol (100 mg, 0.41 mmol, prepared by Method 33) in pyridine (2 mL) and 6-(methylcarbamoyl)pyridine-3- carboxylic acid (80 mg, 0.45 mmol, prepared as described in PCT Int. Appl 2006003378) in pyridine (2 mL) was added N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (101.2 mg, 0.53 mmol) and the mixture was stirred at room temperature for 18 hours. The solvent was removed in vacuo and the residue taken up in ethyl acetate (50 mL), washed with water (2 x 10 mL) and dried over sodium sulfate. Filtered and concentrated to give 164 mg of the title compound (89% yield, 72% purity) as a yellow powder. The crude product was used directly in the next step.

[1320] Step 2, Method 51: 5-{5-[(5-methoxypyridin-2-yl)methoxy]-1,3-benzoxazol-2-yl}-N-methylpyridin-2-carboxamide

[1321] Crude 5-N-{2-hydroxy-5-[(5-methoxypyridin-2-yl)methoxy]phenyl}-2-N-methylpyridin-2,5-dicarboxamide (164 mg, 2.91 mmol, 72% purity) was suspended in acetic acid (3 mL) and heated in a microwave oven at 200 °C for 40 min. After cooling, the volatiles were removed under vacuum, and the residue was partitioned between ethyl acetate (2 mL) and a saturated sodium bicarbonate aqueous solution (10 mL). The mixture was filtered, the solid was washed with warm methanol (30 mL), and the solution was concentrated. FCC purification (silica gel, 12-100% ethyl acetate / heptane) yielded 9 mg (8% yield) of the title compound as a white powder.

[1322] Example 1, Method 51: 5-{5-[(5-methoxypyridin-2-yl)methoxy]-1,3-benzoxazol-2-yl}-N-methylpyridin-2-carboxamide

[1323] δ H NMR(500MHz,DMSO)9.34(d,J=2.0Hz,1H),8.97(q,J=4.8Hz,

[1324] 1H),8.68(dd,J=8.2,2.1Hz,1H),8.31(d,J=2.9Hz,1H),8.23(d,J=8.2Hz,1H),7.77(d,J=8.9Hz,1H),7.53(d,J=8.6Hz,1H),7. 51(d,J=2.5Hz,1H),7.44(dd,J=8.6,3.0Hz,1H),7.17(dd,J=8.9,2.5Hz,1H),5.20(s,2H),3.84(s,3H),2.85(d,J=4.8Hz,3H). Tr(MET-uHPLC-AB-101)=2.71min,(ES + (M+H) + 391.

[1325] The following examples were prepared using method 51 as described above:

[1326]

[1327] Table 52

[1328] Method 52

[1329] Scheme of Method 52

[1330]

[1331] Step 1, Method 52: N-{2-Hydroxy-5-[(5-methoxypyridin-2-yl)methoxy]phenyl}-1- methyl-1H-imidazole-4-carboxamide

[1332] To a solution of 2-amino-4-[(5-methoxypyridin-2-yl)methoxy]phenol (50%, 300 mg, 0.61 mmol, prepared via Method 33) and 1-methyl-1H-imidazole-4-carboxylic acid (85 mg, 0.67 mmol) in pyridine (3 mL) was added 1-(3-(dimethylamino)-propyl)-3- ethylcarbodiimide hydrochloride (150 mg, 0.78 mmol) and the mixture was stirred at room temperature for 18 hours. The solvent was removed in vacuo and the residue taken up in ethyl acetate (200 mL), washed with water (50 mL) and brine (50 mL), dried over magnesium sulfate, filtered and concentrated. The residue was dissolved in methanol (50 mL) and stirred at reflux for 2 days. Upon cooling, the crude product was pre-adsorbed onto a small amount of silica gel and then purified by FCC (silica gel, 0-10% methanol / ethyl acetate) to give the title compound 25 mg (12% yield) as an off-white solid. Tr(METCR1278) = 1.35 min, (ES + )(M+H) + 355.

[1333] Step 2, Method 52: 5-[(5-Methoxypyridin-2-yl)methoxy]-2-(1-methyl-1H-imidazol-4- yl)-1,3-benzoxazole formate

[1334] N-{2-Hydroxy-5-[(5-methoxypyridin-2-yl)methoxy]phenyl}-1-methyl-1H-imidazole-4- carboxamide (25 mg, 0.07 mmol) was suspended in acetic acid (1 mL) and heated in a microwave at 200 °C for 40 minutes. Upon cooling, the volatiles were removed in vacuo and the residue partitioned between ethyl acetate (100 mL) and saturated aqueous sodium bicarbonate solution (50 mL). The organic layer was washed with brine (50 mL), dried over magnesium sulfate, filtered and concentrated. Purification by preparative HPLC (acetonitrile / water + 0.1% formic acid) gave the title compound 8.6 mg (32% yield) as an off-white solid.

[1335] Step 2, Method 52: 5-[(5-Methoxypyridin-2-yl)methoxy]-2-(1-methyl-1H-imidazol-4- yl)-1,3-benzoxazole formate

[1336] δ HNMR (500 MHz, DMSO) 8.33 (s, 1H), 8.30 (d, J = 2.9 Hz, 1H), 8.04 (d, J

[1337] = 1.0 Hz, 1H), 7.83 (s, 1H), 7.60 (d, J = 8.8 Hz, 1H), 7.51 (d, J = 8.6 Hz, 1H), 7.43 (dd, J = 8.6, 3.0 Hz, 1H), 7.33 (d, J = 2.5 Hz, 1H), 7.00 (dd, J = 8.8, 2.5 Hz, 1H), 5.15 (s, 2H), 3.83 (s, 3H), 3.76 (s, 3H). Tr (MET-uHPLC-AB-101) = 1.96 min, (ES + )(M+H) + 337.

[1338] The following examples were prepared using Method 52 as described above:

[1339]

[1340] Table 53

[1341] Method 53

[1342] Scheme for Method 53

[1343]

[1344] Step 1, Method 53: 2-(pyridin-3-yl)-1,3-benzoxazole-5-carbaldehyde

[1345] To a stirred solution of [2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]methanol (149 mg, 0.66 mmol, prepared via Method 23) in tetrahydrofuran (10 mL) was added 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (307 mg, 0.72 mmol) under nitrogen. The mixture was stirred at room temperature for 1.5 hours. The mixture was filtered through and concentrated. The residue was triturated in dichloromethane-methanol (9:1, 5 mL) and filtered through. The filtrate was concentrated and purified via FCC (silica gel, 12-100% ethyl acetate / heptane) to give the title compound 152 mg (100% yield) as a white powder. δ HNMR (500MHz, DMSO) 10.13 (s, 1H), 9.39 (s, 1H), 8.85 (d, J = 4.8Hz, 1H), 8.59 (d, J = 8.0Hz, 1H), 8.41 (s, 1H), 8.06 (s, 2H), 7.69 (dd, J = 8.0, 4.9Hz, 1H). Tr(METCR1278)=1.57min,(ES + (M+H) + 225.

[1346] Step 1, Method 53: 5-Methoxy-N-{[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]methyl}pyridin-2-amine

[1347] A solution of 2-(pyridin-3-yl)-1,3-benzoxazole-5-carboxaldehyde (50 mg, 0.22 mmol) and 5-methoxypyridin-2-amine (30 mg, 0.25 mmol) in toluene (5 mL) was prepared with diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid (68 mg, 0.27 mmol), thiourea (3 mg, 0.04 mmol), and molecular sieves ( The mixture was treated with 223 mg of 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester (40 mg, 0.16 mmol) and stirred at 70 °C overnight. After filtration through diatomaceous earth, the filtrate was concentrated and the residue was purified by FCC (silica gel, 20-100% ethyl acetate / heptane) to give 72 mg (97% yield) of the title compound as a grayish-white powder.

[1348] Example 1, Method 53: 5-Methoxy-N-{[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]methyl}pyridin-2-amine

[1349] δ H NMR(500MHz, DMSO)9.34(d,J=1.9Hz,1H),8.80(dd,J=4.8,1.5Hz,1H),8.52(dt,J=8.0,1.9Hz,1H),7.77-7.70(m,3H),7.65(dd,J=8.0,4.8Hz, 1H), 7.44 (dd, J=8.4, 1.3Hz, 1H), 7.14 (dd, J=9.0, 3.0Hz, 1H), 6.79 (t, J=6.1Hz, 1H), 6.52 (d, J=9.0Hz, 1H), 4.55 (d, J=6.1Hz, 2H), 3.67 (s, 3H). Tr(MET-uHPLC-AB-101)=1.49min,(ES+ )(M+H) + 333.

[1350] The following examples were prepared using Method 53 as described above:

[1351]

[1352] Table 54

[1353] Method 54

[1354] Scheme for Method 54

[1355]

[1356] Step 1, Method 54: 5-({5-[2-(morpholin-4-yl)ethoxy]pyridin-2-yl}methoxy)-2- (pyridin-3-yl)-1,3-benzoxazole

[1357] 6-({[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]oxy}methyl)pyridin-3-ol (50%, 59 mg, 0.09 mmol, prepared via Method 27), 4-(2-chloroethyl)morpholine hydrochloride (20 mg, 0.11 mmol) and potassium iodide (15 mg, 0.09 mmol) were dissolved in dry N,N-dimethylformamide (1 mL), sodium hydride (7 mg, 0.28 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was heated to 60 °C for 4 hours. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and water (1:1, 10 mL). The aqueous phase was extracted with ethyl acetate (2 x 10 mL). The combined organic phases were washed with water (2 x 1 mL), brine (2 mL), dried over sodium sulfate, filtered and concentrated. Purification by preparative HPLC (acetonitrile / water + 0.2% ammonium hydroxide) gave the title compound 2 mg (5% yield) as a white solid.

[1358] Example 1, Method 54: 5-({5-[2-(morpholin-4-yl)ethoxy]pyridin-2-yl}methoxy)-2- (pyridin-3-yl)-1,3-benzoxazole

[1359] δ H NMR (500 MHz, DMSO) 9.32 (s, 1H), 8.80 (d, J = 3.8 Hz, 1H), 8.50 (dt,

[1360] J = 8.0, 1.9 Hz, 1 H), 8.30 (d, J = 2.8 Hz, 1 H), 7.73 (d, J = 8.9 Hz, 1 H), 7.65 (dd, J = 8.0, 4.8 Hz, 1 H), 7.59 - 7.33 (m, 3 H), 7.13 (dd, J = 8.9, 2.5 Hz, 1 H), 5.18 (s, 2 H), 4.17 (t, J = 5.7 Hz, 2 H), 3.64 - 3.45 (m, 4 H), 2.70 (t, J = 5.7 Hz, 2 H), 2.49 - 2.41 (m, 4 H). Tr (MET-uHPLC-AB-101) = 1.59 min, (ES + )(M+H) + 433.

[1361] The following examples were prepared using Method 54 as described above:

[1362]

[1363] Table 55

[1364] Method 55

[1365] Scheme for Method 55

[1366]

[1367] Step 1, Method 55: (5-methoxy-1-benzofuran-2-yl)boronic acid

[1368] To a solution of 5-methoxy-1-benzofuran (1.0 g, 6.75 mmol) in anhydrous tetrahydrofuran (15 mL) was added 2.5 M n-butyllithium / hexanes (2.8 mL, 7.00 mmol) slowly at -78 °C under a nitrogen atmosphere. After stirring at -78 °C for 1 h, triisopropyl borate (3.12 mL, 13.5 mmol) was added dropwise and the mixture was stirred at -78 °C for 30 min. The dry ice bath was removed, 2 M aqueous hydrochloric acid (20 mL) was added and the mixture was allowed to warm to room temperature with stirring overnight. The reaction mixture was poured into water (25 mL) and extracted with diethyl ether (3 x 20 mL). The combined organic phases were washed with brine (20 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure. Di chloromethane (20 mL) was added and the mixture was sonicated for 10 min. A small amount of methanol (ca. 1 mL) was added to completely dissolve the solid and the solution was sonicated for 10 min. Heptane (20 mL) was added and the precipitated solid was collected by vacuum filtration and dried under vacuum for 2 h to give the title compound 476 mg (37% yield) as a white solid. HNMR (500 MHz, DMSO) 8.53 (s, 2H), 7.46 (d, J = 8.94 Hz, 1H), 7.39 (s, 1H), 7.19 (d, J = 2.51 Hz, 1H), 6.93 (dd, J = 2.60, 8.92 Hz, 1H), 3.78 (s, 3H).

[1369] Step 2, Method 55: 2-Bromo-6-(5-methoxy-l-benzofuran-2-yl)benzonitrile

[1370] A mixture of (5-methoxy-l-benzofuran-2-yl)boronic acid (156 mg, 0.813 mmol), 2-bromo-6-iodobenzonitrile (250 mg, 0.81 mmol) and 2M sodium carbonate (0.82 mL, 1.64 mmol) in N,N-dimethylformamide (10 mL) was sonicated under a stream of nitrogen for 20 minutes. [l,l'-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride complex with dichloromethane (50 mg, 0.14 mmol) was added and the mixture was stirred at 70 °C for 2 hours. After cooling, the mixture was added to water (100 mL) and brine (100 mL). The mixture was extracted with ethyl acetate (3 x 100 mL), the combined extracts were washed with brine (50 mL), dried over magnesium sulfate, filtered and concentrated. Purification by FCC (silica gel, 0-50% ethyl acetate / heptane) gave the title compound 168 mg (37% yield, 82% purity by LCMS) as an off-white solid which was used directly in the next step. The sample was purified by preparative HPLC (acetonitrile / water + 0.1% formic acid) δ H NMR (500 MHz, DMSO) 8.09 (d, J = 8.0 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.76 (t, J = 8.1 Hz, 1H), 7.70 (s, 1H), 7.58 (d, J = 9.0 Hz, 1H), 7.32 (d, J = 2.6 Hz, 1H), 7.02 (dd, J = 9.0, 2.6 Hz, 1H), 3.81 (s, 3H). Tr (MET-uHPLC-AB-101) = 5.45 min, (ES + (M+H) + 328 / 330.

[1371] Step 3, Method 55: 2-Bromo-6-(5-hydroxy-l-benzofuran-2-yl)benzonitrile

[1372] To a stirred solution of 2-bromo-6-(5-hydroxy-l-benzofuran-2-yl)benzonitrile (0.12 g, 0.38 mmol) and 2-(chloromethyl)-5-methoxypyridine hydrochloride (0.07 g, 0.38 mmol) in N,N-dimethylformamide (8 mL) was added sodium hydride (60% in mineral oil, 0.03 g, 0.84 mmol) in portions at 0 °C under nitrogen. The mixture was allowed to warm to room temperature and stirred for 48 h. The mixture was quenched with water (4 mL) and the solvent removed in vacuo. The residue was partitioned between ethyl acetate (150 mL) and water (150 mL) and the aqueous layer extracted with ethyl acetate (3 x 100 mL). The combined organic extracts were washed with brine (2 x 20 mL), dried over magnesium sulfate, filtered and concentrated. Purification by preparative HPLC (acetonitrile / water + 0.2% ammonium hydroxide) gave the title compound 29 mg (17% yield) as a white crystalline solid. H NMR (500 MHz, Chloroform) δ 8.05 (d, J = 8.12 Hz, 1H), 7.70 (s, 1H), 7.66 (d, J = 7.23 Hz, 1H), 7.53 (t, J = 8.08 Hz, 1H), 7.40 (d, J = 8.80 Hz, 1H), 7.06 (d, J = 2.54 Hz, 1H), 6.91 (dd, J = 2.57, 8.81 Hz, 1H).

[1373] Step 4, Method 55: 2-Bromo-6-{5-[(5-methoxypyridin-2-yl)methoxy]-l- benzofuran-2-yl}benzonitrile

[1374] To a stirred solution of 2-bromo-6-(5-hydroxy-l-benzofuran-2-yl)benzonitrile (0.12 g, 0.38 mmol) and 2-(chloromethyl)-5-methoxypyridine hydrochloride (0.07 g, 0.38 mmol) in N,N-dimethylformamide (8 mL) was added sodium hydride (60% in mineral oil, 0.03 g, 0.84 mmol) in portions at 0 °C under nitrogen. The mixture was allowed to warm to room temperature and stirred for 48 h. The mixture was quenched with water (4 mL) and the solvent removed in vacuo. The residue was partitioned between ethyl acetate (150 mL) and water (150 mL) and the aqueous layer extracted with ethyl acetate (3 x 100 mL). The combined organic extracts were washed with brine (2 x 20 mL), dried over magnesium sulfate, filtered and concentrated. Purification by preparative HPLC (acetonitrile / water + 0.2% ammonium hydroxide) gave the title compound 29 mg (17% yield) as a white crystalline solid.

[1375] Example 1, Method 55: 2-Bromo-6-{5-[(5-methoxypyridin-2-yl)methoxy]-l- benzofuran-2-yl}benzonitrile

[1376] δ H NMR (500 MHz, DMSO) δ 8.31 (d, J = 2.9 Hz, 1H), 8.10 (d, J = 8.0 Hz,

[1377] 1H), 7.94 (d, J = 8.1 Hz, 1H), 7.77 (t, J = 8.1 Hz, 1H), 7.70 (s, 1H), 7.61 (d, J = 9.0 Hz, 1H), 7.52 (d, J = 8.6 Hz, 1H), 7.48 - 7.36 (m, 2H), 7.12 (dd, J = 9.0, 2.6 Hz, 1H), 5.16 (s, 2H), 3.84 (s, 3H). Tr (MET-uHPLC-AB-101) = 4.12 min, (ES + )(M+H) + 437 / 439.

[1378] The following examples were prepared using Method 55 as described above:

[1379]

[1380] Table 56

[1381] Method 56

[1382] Scheme for Method 56

[1383]

[1384] Step 1, Method 56: 4-(5-{5H,6H-imidazo[2,1-b][1,3]thiazol-3-ylmethoxy}-1- benzofuran-2-yl)pyridine-3-carbonitrile hydrochloride

[1385] To a mixture of 4-(5-hydroxy-l-benzofuran-2-yl)pyridine-3-carbonitrile (150 mg, 0.63 mmol, prepared via Method 9), 3-(chloromethyl)-5H,6H-imidazo[2,l- b][l,3]thiazole (170 mg, 0.97 mmol), and potassium iodide (10 mg, 0.06 mmol) in N,N- dimethylformamide (10 mL) was added sodium hydride (60% in mineral oil, 90 mg, 2.25 mmol). The mixture was stirred at room temperature for 3 hours, then was added to a mixture of water (150 mL) and brine (150 mL) and extracted with ethyl acetate (4 x 100 mL). The combined organic extracts were washed with brine (100 mL), dried over magnesium sulfate, filtered, and concentrated. The residue was taken up in methanol (30 mL) and 1 M hydrochloric acid (3 mL) was added, after which the volatiles were removed in vacuo. The residue was triturated with DMSO:water (3 mL, 4: 1 mixture) to give the title compound 19 mg (7% yield) as an off-white crystalline solid.

[1386] Example 1, Method 56: 4-(5-{5H,6H-imidazo[2,1-b][1,3]thiazol-3-ylmethoxy}-1- benzofuran-2-yl)pyridine-3-carbonitrile hydrochloride

[1387] δ H NMR (500 MHz, DMSO) 9.68 (s, 1H), 9.13 (s, 1H), 8.94 (d, J = 5.4 Hz,

[1388] 1H), 8.08 (d, J = 5.4 Hz, 1H), 7.96 (s, 1H), 7.70 (d, J = 9.0 Hz, 1H), 7.55 (d, J = 2.6 Hz, 1H), 7.21 (dd, J = 9.0, 2.6 Hz, 1H), 7.06 (s, 1H), 5.17 (s, 2H), 4.48 (dd, J = 11.2, 8.2 Hz, 2H), 4.31 (dd, J = 11.2, 8.2 Hz, 2H). Tr (METCR1416) = 2.96 min, (ES + (M+H) + 375.

[1389] The following examples were prepared using Method 56 as described above:

[1390]

[1391] Table 57

[1392] Method 57

[1393] Scheme for Method 57

[1394]

[1395] Step 1, Method 57: 2-(3-bromopyridin-4-yl)-6-methoxy-1,3-benzothiazole

[1396] Dissolve 2-amino-5-methoxybenzene-1-thiol (80%, 1 g, 5.15 mmol, described in J. Med. Chem., (2003) 46, 2740), 3-bromopyridine-4-carbaldehyde (0.98 g, 5.26 mmol) and sodium metabisulfite (1 g, 5.26 mmol) in anhydrous dimethyl sulfoxide (5 mL). Stir the reaction mixture at 120 °C for 2 hours. Cool the mixture to room temperature and add water (100 mL). Filter the resulting black precipitate and wash with water. Dissolve the precipitate in dichloromethane. Pass the suspension through a pad of silica gel. Wash the pad with dichloromethane to give the title compound 1.123 g (68% yield) as a purple solid. δ HNMR (500 MHz, DMSO) 8.99 (s, 1H), 8.71 (d, J = 5.0 Hz, 1H), 8.13 (d, J = 5.0 Hz, 1H), 8.07 (d, J = 9.0 Hz, 1H), 7.83 (d, J = 2.0 Hz, 1H), 7.23 (dd, J = 8.9, 2.2 Hz, 1H), 3.88 (s, 3H). Tr (MET-uHPLC-AB-101) = 3.57 min, (ES + )(M+H) + 321 / 323.

[1397] Step 2, Method 57: 2-(3-bromopyridin-4-yl)-l,3-benzothiazol-6-ol

[1398] To a suspension of 2-(3-bromopyridin-4-yl)-6-methoxy-l,3-benzothiazole (200 mg, 0.62 mmol) in dichloromethane (6 mL) was added boron tribromide (1 M in dichloromethane, 2.80 mL, 2.80 mmol) and the mixture was stirred at room temperature for 24 hours. The reaction mixture was quenched with water (10 mL), neutralized with solid sodium bicarbonate (6 mmol) and extracted with dichloromethane:ethanol 4: 1 solution (3 x 20 mL). The organic layers were combined, washed with water (20 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by FCC (silica gel, 0-100% ethyl acetate / toluene, then 5-20% methanol / ethyl acetate, then 0-30% methanol / dichloromethane, then acetonitrile). The silica gel column was washed with dichloromethane:isopropanol 4: 1 solution (3 x 100 mL). The suspension was filtered. The filtrate was combined with fractions containing the title compound and concentrated. The residue was dissolved in hot methanol and filtered. The filtrate was allowed to stand at room temperature for 18 hours. The precipitate was filtered. 50 mg was sonicated in 2 M aqueous sodium hydroxide solution (5 mL). The mixture was washed with ethyl acetate (5 mL). The aqueous phase was treated with 2 M hydrochloric acid solution until pH 7 and extracted with ethyl acetate (3 x 10 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was triturated in hot ethyl acetate and filtered to give the title compound 5.4 mg (3% yield) as an off-white solid. H NMR (500 MHz, DMSO) 8.97 (s, 1H), 8.69 (d, J = 5.0 Hz, 1H), 8.11 (d, J = 5.0 Hz, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.50 (d, J = 2.2 Hz, 1H), 7.08 (dd, J = 8.9, 2.3 Hz, 1H). Tr (MET-uHPLC-AB-101) = 2.67 min, (ES + )(M+H) +307 / 309.

[1399] Step 3, Method 57: 2-(3-bromopyridin-4-yl)-6-[2-(morpholin-4-yl)ethoxy]-1,3- benzothiazole

[1400] Step 3, Method 57: 2-(3-bromopyridin-4-yl)-6-[2-(morpholin-4-yl)ethoxy]-1,3- benzothiazole

[1401] Step 3, Method 57: 2-(3-bromopyridin-4-yl)-6-[2-(morpholin-4-yl)ethoxy]-1,3- benzothiazole

[1402] δ H NMR (500 MHz, Chloroform) 8.91 (s, 1H), 8.63 (d, J = 5.1 Hz, 1H), 8.12 (d, J = 9.0 Hz, 1H), 7.42 (d, J = 2.3 Hz, 1H), 7.18 (dd, J = 9.0, 2.5 Hz, 1H), 4.26 (s, 2H), 3.79 (s, 4H), 2.92 (s, 2H), 2.67 (s, 4H). Tr (MET-uHPLC-AB-101) = 1.59 min, (ES

[1403] = 5.1 Hz, 1H), 8.04 (d, J = 9.0 Hz, 1H), 7.42 (d, J = 2.3 Hz, 1H), 7.18 (dd, J = 9.0, 2.5 Hz, 1H), 4.26 (s, 2H), 3.79 (s, 4H), 2.92 (s, 2H), 2.67 (s, 4H). Tr (MET-uHPLC-AB-101) = 1.59 min, (ES + )(M+H) + 420 / 422.

[1404] The following examples were prepared using Method 57 as described above:

[1405]

[1406] Table 58

[1407] Method 58

[1408] Scheme for Method 58

[1409]

[1410] Step 1, Method 56: 4-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]piperazine-1- carboxylic acid tert-butyl ester

[1411] To a sealed tube was added 5-bromo-2-(pyridin-3-yl)-1,3-benzoxazole (200 mg, 0.73 mmol), piperazine-1-carboxylic acid tert-butyl ester (162 mg, 0.87 mmol), cesium carbonate (568 mg, 1.74 mmol), [2',6'-bis(prop-2-yloxy)biphenyl-2-yl](dicyclohexyl)phosphane (17 mg, 0.04 mmol), and tetrahydrofuran (5 mL). The reaction mixture was degassed by sparging with nitrogen for 20 minutes. Palladium(II) acetate (8 mg, 0.04 mmol) was added and the reaction mixture was stirred at 70 °C overnight. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate (15 mL) and water (15 mL). The aqueous layer was separated and extracted with ethyl acetate (2 x 15 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. Purification by FCC (silica gel, 10-100% ethyl acetate / heptane) afforded the title compound 235 mg (85% yield) as a yellow powder.

[1412] Example 1, Method 58: 4-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]piperazine-1- carboxylic acid tert-butyl ester

[1413] δ H NMR (500 MHz, DMSO) 9.32 (d, J = 2.1 Hz, 1H), 8.79 (dd, J = 4.8, 1.6

[1414] Hz, 1H), 8.50 (dt, J = 8.0, 1.9 Hz, 1H), 7.68 (d, J = 9.0 Hz, 1H), 7.64 (dd, J = 8.0, 4.8 Hz, 1H), 7.35 (d, J = 2.4 Hz, 1H), 7.17 (dd, J = 9.0, 2.4 Hz, 1H), 3.49 (d, J = 4.9 Hz, 4H), 3.16 - 3.09 (m, 4H), 1.43 (s, 9H). Tr (MET-uHPLC-AB-101) = 3.5 min, (ES + )(M+H) + 381.

[1415] The following examples were prepared using Method 58 as described above:

[1416]

[1417] Table 59

[1418] Method 59

[1419] Scheme of method 59

[1420]

[1421] Step 1, Method 59: 5-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]pyrazin-2-ol

[1422] 5-(5-methoxypyrazin-2-yl)-2-(pyridin-3-yl)-1,3-benzoxazole (344 mg, 0.96 mmol, prepared using Method 8) and sodium iodide (216 mg, 1.44 mmol) were suspended in acetonitrile (30 mL), chloro(trimethyl)silane (182 μΐ, 1.44 mmol) was added and the reaction mixture was sealed and stirred at room temperature for 60 hours. The reaction mixture was heated to 70 °C for 8 hours. The reaction mixture was stirred at room temperature for 15 hours. The reaction mixture was filtered through filter paper and the precipitate was washed with water (10 mL) and diethyl ether (2 x 10 mL). The solid was dried under vacuum to give the title compound, 220 mg (78% yield) as a brown solid.

[1423] Example 1, Method 59: 5-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]pyrazin-2-ol

[1424] δ H NMR (500 MHz, DMSO) 12.67 (br. s., 1 H), 9.38 (d, J = 2.1 Hz, 1 H), 8.83

[1425] (dd, J = 4.8, 1.6 Hz, 1 H), 8.56 (dt, J = 8.0, 1.9 Hz, 1 H), 8.38 - 8.24 (m, 1 H), 8.20 (br. s., 1 H), 8.16 (d, J = 1.1 Hz, 1 H), 8.02 (dd, J = 8.6, 1.5 Hz, 1 H), 7.88 (d, J = 8.6 Hz, 1 H), 7.68 (dd, J = 8.0, 4.8 Hz, 1 H). Tr (MET-uHPLC-AB-101) = 1.88 min, (ES + )(M+H) + 291.

[1426] The following examples were prepared using Method 59 as described above:

[1427]

[1428] Table 60

[1429] Method 60

[1430] Scheme of method 60

[1431]

[1432] Step 1, Method 60: 2-chloro-5-(2-methoxyethoxy)pyrimidine

[1433] Step 1, Method 60: 2-chloro-5-(2-methoxyethoxy)pyrimidine H NMR (500 MHz, DMSO) δ 8.55 (s, 2H), 4.37-4.21 (m, 2H), 3.78-3.59 (m, 2H), 3.30 (s, 3H). Tr (METCR1278) = 1.36 min, (ES + (M+Na) + 189.

[1434] Step 2, Method 60: 5-[5-(2-methoxyethoxy)pyrimidin-2-yl]-2-(pyridin-3-yl)-1,3- benzoxazole

[1435] Step 2, Method 60: 5-[5-(2-methoxyethoxy)pyrimidin-2-yl]-2-(pyridin-3-yl)-1,3- benzoxazole

[1436] Example 1, Method 60: 5-[5-(2-methoxyethoxy)pyrimidin-2-yl]-2-(pyridin-3-yl)- 1,3-benzoxazole

[1437] δ H NMR (500 MHz, DMSO) 9.39 (d, J = 2.1 Hz, 1H), 8.83 (dd, J = 4.8, 1.6

[1438] Hz, 1H), 8.71 (s, 2H), 8.68 (d, J = 1.6 Hz, 1H), 8.64 - 8.52 (m, 1H), 8.47 (dd, J = 8.6, 1.7 Hz, 1H), 7.94 (d, J = 8.6 Hz, 1H), 7.68 (dd, J = 7.9, 4.9 Hz, 1H), 4.69 - 4.11 (m, 2H), 3.85 - 3.58 (m, 2H), 3.33 (s, 3H). Tr (MET-uHPLC-AB-101) = 2.85 min, (ES + )(M+H) + 349.

[1439] The following examples were prepared using Method 60 as described above:

[1440]

[1441] Table 61

[1442] Method 61

[1443] Scheme for Method 61

[1444]

[1445] Step 1, Method 61: 6-fluoro-N-{2-hydroxy-5-[(5-methoxypyridin-2-yl)methoxy]phenyl}pyridine-3-carboxamide

[1446] 2-Amino-4-[(5-methoxypyridin-2-yl)methoxy]phenol (300 mg, 1.16 mmol, prepared using method 33), 6-fluoropyridine-3-carboxylic acid (180 mg, 1.27 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (244 mg, 1.27 mmol) were suspended in pyridine (10 mL). The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 60 hours. The solvent was removed under vacuum, and the residue was partitioned between ethyl acetate (100 mL) and water (100 mL). The aqueous phase was extracted with ethyl acetate (2 x 50 mL), and the combined organic phases were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The solution was purified by FCC (silica gel, 30-100% ethyl acetate / heptane) to give the title compound, 278 mg (61% yield), as a white powder. Tr(METCR1673)=1.02min,(ES + (M+H) + 369.

[1447] Step 2, Method 61: 5-{5-[(5-methoxypyridin-2-yl)methoxy]-1,3-benzoxazol-2-yl}-1,2-dihydropyridin-2-one

[1448] 6-Fluoro-N-{2-hydroxy-5-[(5-methoxypyridin-2-yl)methoxy]phenyl}pyridine-3-carboxamide (278 mg, 0.72 mmol) was suspended in acetic acid (5 mL). The reaction mixture was microwaved (200 W, 250 psi max) at 180 °C for 30 min. The reaction mixture was microwaved again at 200 °C for 3 h. The reaction mixture was concentrated under vacuum, and the residue was partitioned between saturated sodium bicarbonate solution (50 mL) and ethyl acetate (100 mL). The aqueous phase was extracted with ethyl acetate (2 x 100 mL), and the combined organic phases were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The solution was purified by FCC (silica gel, 0-15% methanol / dichloromethane) and recrystallized from DMSO (3 mL) to give the title compound, 77.6 mg (30% yield), as a white solid. HNMR (500 MHz, DMSO) 12.23 (br. s., 1H), 8.30 (d, J = 2.9 Hz, 1H), 8.21 (d, J = 2.4 Hz, 1H), 8.05 (dd, J = 9.6, 2.6 Hz, 1H), 7.60 (d, J = 8.9 Hz, 1H), 7.51 (d, J = 8.6 Hz, 1H), 7.43 (dd, J = 8.6, 3.0 Hz, 1H), 7.35 (d, J = 2.5 Hz, 1H), 7.02 (dd, J = 8.9, 2.5 Hz, 1H), 6.52 (d, J = 9.6 Hz, 1H), 5.16 (s, 2H), 3.84 (s, 3H). Tr (MET-uHPLC-AB-101) = 2.14 min, (ES + )(M+H) + 350.

[1449] Step 3, Method 61 : 5-{5-[(5-methoxypyridin-2-yl)methoxy]-1,3-benzoxazol-2-yl}- 1 -methyl- 1,2-dihydropyridin-2-one

[1450] Step 3, Method 61 : 5-{5-[(5-methoxypyridin-2-yl)methoxy]-1,3-benzoxazol-2-yl}- 1 -methyl- 1,2-dihydropyridin-2-one

[1451] Example 1, Method 61 : 5-{5-[(5-methoxypyridin-2-yl)methoxy]-1,3-benzoxazol-2-yl}- 1 -methyl- 1,2-dihydropyridin-2-one

[1452] δ H NMR NMR (500 MHz, DMSO) 8.70 (d, J = 2.5 Hz, 1H), 8.30 (d, J = 2.9

[1453] Hz,1H),8.04(dd,J=9.5,2.6Hz,1H),7.59(d,J=8.9Hz,1H),7.51(d,J=8.6Hz,1H),7.42(dd,J=8.6,2.9Hz,1H),7 .34(d,J=2.5Hz,1H),7.03(dd,J=8.9,2.5Hz,1H),6.56(d,J=9.5Hz,1H),5.16(s,2H),3.83(s,3H),3.57(s,3H). Tr(MET-uHPLC-AB-101)=2.41min,(ES + (M+H) + 364.

[1454] The following examples were prepared using method 61 as described above:

[1455]

[1456] Table 62

[1457] Method 62

[1458] Scheme of Method 62

[1459]

[1460] Step 1, Method 62: 2-(pyridin-3-yl)-1,3-benzoxazol-5-ol

[1461] 2-(pyridin-3-yl)-5-(tetramethyl-1,3,2-dioxoboronacyclopentan-2-yl)-1,3-benzoxazole (0.73 g, 1.58 mmol, prepared using method 8) was dissolved in tetrahydrofuran (10 mL) and water (10 mL), sodium perborate tetrahydrate (0.61 g, 3.95 mmol) was added, and the reaction mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. A saturated ammonium chloride solution (30 mL) was added to the reaction mixture, and the product was extracted with ethyl acetate (3 x 100 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated. FCC purification (silica gel, 20-60% ethyl acetate / heptane, followed by 10% methanol / dichloromethane) gave the title compound, 160 mg (48% yield), as a yellow powder. HNMR (500 MHz, DMSO) 9.61 (s, 1H), 9.31 (d, J = 2.1 Hz, 1H), 8.78 (dd, J = 4.8, 1.6 Hz, 1H), 8.49 (dt, J = 8.0, 1.9 Hz, 1H), 7.73 - 7.51 (m, 2H), 7.13 (d, J = 2.4 Hz, 1H), 6.89 (dd, J = 8.8, 2.4 Hz, 1H). Tr (METCR1410) = 0.91 min, (ES + )(M+H) + 213.

[1462] Step 2, Method 62: 5-[(5-Bromopyridin-2-yl)methoxy]-2-(pyridin-3-yl)-1,3- benzoxazole

[1463] Step 2, Method 62: 5-[(5-Bromopyridin-2-yl)methoxy]-2-(pyridin-3-yl)-1,3- benzoxazole

[1464] Step 2, Method 62: 5-[(5-Bromopyridin-2-yl)methoxy]-2-(pyridin-3-yl)-1,3- benzoxazole

[1465] δH NMR (500 MHz, DMSO) 9.47 - 9.17 (m, 1H), 8.80 (dd, J = 4.8, 1.6 Hz, 1H), 8.74 (d, J = 2.2 Hz, 1H), 8.51 (dt, J = 8.0, 1.9 Hz, 1H), 8.11 (dd, J = 8.4, 2.4 Hz, 1H), 7.75 (d, J = 8.9 Hz, 1H), 7.65 (ddd, J = 8.0, 4.8, 0.7 Hz, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 2.5 Hz, 1H), 7.16 (dd, J = 8.9, 2.6 Hz, 1H), 5.26 (s, 2H). Tr (MET-uHPLC-AB-101) = 3.44 min, (ES + )(M+H) + 382 / 384.

[1466] The following examples were prepared using Method 62 as described above:

[1467]

[1468] Table 63

[1469] Method 63

[1470] Scheme of Method 63

[1471]

[1472] Step 1, Method 63: 2-phenyl-N-[2-(pyridin-3-yl)-l,3-benzoxazol-5-yl]pyrimidine-5- carboxamide

[1473] To a stirred solution of 2-(pyridin-3-yl)-l,3-benzoxazol-5-amine (100 mg, 0.47 mmol) in pyridine was added ethyl carbodiimide hydrochloride (91 mg, 0.47 mmol) and 2-phenylpyrimidine-5-carboxylic acid (95 mg, 0.47 mmol). The reaction mixture was stirred at room temperature for 16 hours. Water (10 mL) was added to the reaction mixture and a precipitate was formed. The precipitate was collected by filtration and dried in an oven for 16 hours to give the title compound 157 mg (84% yield) as a brown solid.

[1474] Example 1, Method 63: 2-phenyl-N-[2-(pyridin-3-yl)-l,3-benzoxazol-5-yl]pyrimidine-5- carboxamide

[1475] δ H NMR (500 MHz, DMSO) 10.82 (s, 1H), 9.40 (s, 2H), 9.37 (s, 1H), 8.82 (d, J = 4.6 Hz, 1H), 8.55 (d, J = 7.8 Hz, 1H), 8.49 (d, J = 6.5 Hz, 2H), 8.36 (s, 1H), 7.87 (d, J = 8.8 Hz, 1H), 7.79 (d, J = 8.8 Hz, 1H), 7.67 (dd, J = 7.7, 5.0 Hz, 1H), 7.59 (d, J = 6.9 Hz, 3H). Tr (MET-uHPLC-AB-101) = 3.26 min, (ES + )(M+H) + 394.

[1476] The following examples were prepared using Method 63 as described above:

[1477]

[1478]

[1479]

[1480]

[1481] Table 64

[1482] Method 64

[1483] Scheme of Method 64

[1484]

[1485] Step 1, Method 64: N-(5-bromo-2-hydroxyphenyl)-1-methyl-1H-pyrazole-4- carboxamide

[1486] Step 1, Method 64: N-(5-bromo-2-hydroxyphenyl)-1-methyl-1H-pyrazole-4- carboxamide H NMR (500 MHz, DMSO) 10.15 (s, 1H), 9.14 (s, 1H), 8.35 (s, 1H), 7.99 (s, 1H), 7.89 (d, J = 2.5 Hz, 1H), 7.15 (dd, J = 8.6, 2.5 Hz, 1H), 6.86 (d, J = 8.6 Hz, 1H), 3.89 (s, 3H). Tr (METCR1673) = 1.03 min, (ES + (M+H) + 296 / 298, 58%.

[1487] Step 2 Method 64: 5-bromo-2-(1-methyl-1H-pyrazol-4-yl)-1,3-benzoxazole

[1488] N-[5-bromo-2-(sodioxy)phenyl]-l-methyl-lH-pyrazole-4-carboxamide (82%, 770 mg, 2.13 mmol) was suspended in acetic acid (10 mL) in a pressure tube. N-(5-bromo-2- hydroxyphenyl)-l-methyl-lH-pyrazole-4-carboxamide (58%, 718 mg, 2.43 mmol) was suspended in acetic acid (10 mL) in a pressure tube. Both tubes were sealed and the mixtures were heated to 180 °C for 18 hours. Each solution was cooled to room temperature and then concentrated to dryness. The residues were dissolved in ethyl acetate and combined, then washed with saturated aqueous sodium bicarbonate solution (20 mL) and brine (20 mL). The organic phase was dried over magnesium sulfate, filtered and concentrated on silica gel. Purification by FCC (silica gel, 12-100% ethyl acetate / heptane) gave the title compound 572 mg (58% yield) as a light orange powder. δ H NMR (500 MHz, DMSO) 8.58 (s, 1H), 8.18-8.07 (m, 1H), 7.92 (d, J = 1.9 Hz, 1H), 7.69 (d, J = 8.6 Hz, 1H), 7.51 (dd, J = 8.6, 2.0 Hz, 1H), 3.96 (s, 3H). Tr (MET-uHPLC-AB-101) = 2.99 min, (ES + (M+H) + 278 / 280.

[1489] Step 3 Method 64: 2-(l-methyl-lH-pyrazol-4-yl)-5-(tetramethyl-l,3,2-dioxaborolan-2-yl)- 1,3-benzoxazole

[1490] A suspension of 5-bromo-2-(l-methyl-lH-pyrazol-4-yl)-l,3-benzoxazole (560 mg, 2.01 mmol), bis(pinacolato)diboron (562 mg, 2.21 mmol) and potassium acetate (0.54 g, 5.5 mmol) in anhydrous 1,4-dioxane (25 mL) was degassed with nitrogen for 5 minutes. [l,l'-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride (147 mg, 0.20 mmol) was added and the reaction mixture was stirred at 100 °C under nitrogen for 1 hour. The reaction mixture was diluted with methyl tert-butyl ether (10 mL) and filtered through celite. The filtrate was evaporated to give a brown residue 1.57 g which was used in the next step without purification. Tr (MET CR1673) = 1.32 min, (ES + (M+H) + 326, 82%.

[1491] Step 4 Method 64: 2-(l-Methyl-lH-pyrazol-4-yl)-l,3-benzoxazol-5-ol

[1492] Step 4 Method 64: 2-(l-Methyl-lH-pyrazol-4-yl)-l,3-benzoxazol-5-ol H NMR (500 MHz, DMSO) 9.43 (s, 1H), 8.50 (s, 1H), 8.06 (s, 1H), 7.47 (d, J = 8.7 Hz, 1H), 7.00 (d, J = 2.4 Hz, 1H), 6.77 (dd, J = 8.7, 2.4 Hz, 1H), 3.95 (s, 3H). Tr (METCR1673) = 0.97 min, (ES + (M+H) + 216.

[1493] Step 4 Method 64: 2-(l-Methyl-lH-pyrazol-4-yl)-l,3-benzoxazol-5-ol

[1494] Step 4 Method 64: 2-(l-Methyl-lH-pyrazol-4-yl)-l,3-benzoxazol-5-ol HNMR (500 MHz, DMSO) 8.73 (d, J = 2.2 Hz, 1H), 8.52 (s, 1H), 8.10 (dd, J = 8.4, 2.4 Hz, 1H), 8.08 (s, 1H), 7.61 (d, J = 8.8 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.33 (d, J = 2.5 Hz, 1H), 7.03 (dd, J = 8.8, 2.5 Hz, 1H), 5.22 (s, 2H), 3.95 (s, 3H). Tr (METCR1673) = 1.25 min, (ES + )(M+H) + 385 / 387.

[1495] Step 6 Method 64: 2-(l-Methyl-lH-pyrazol-4-yl)-5-{[5-(tetramethyl-l,3,2-dioxaborolan-2- yl)pyridin-2-yl]methoxy}-l,3-benzoxazole

[1496] A suspension of 5-[(5-bromopyridin-2-yl)methoxy]-2-(l-methyl-lH-pyrazol-4-yl)-l,3- benzoxazole (410 mg, 1.06 mmol), bis(pinacolato)diboron (297 mg, 1.17 mmol) and potassium acetate (261 mg, 2.66 mmol) in anhydrous 1,4-dioxane (15 mL) was degassed with nitrogen for 5 minutes. Bis(diphenylphosphino)ferrocene]palladium(II) dichloride (78 mg, 0.11 mmol) was added and the reaction mixture was stirred at 100 °C under nitrogen for 17 hours. The reaction mixture was diluted with tert-butyl methyl ether (20 mL), filtered and concentrated. The residue was triturated in 1:1 heptane:tert-butyl methyl ether and filtered to give the title compound 479 mg (100% yield) as a grey powder. H NMR (500 MHz, DMSO) 8.77 (s, 1H), 8.52 (s, 1H), 8.08 (s, 1H), 8.05 (dd, J = 7.8, 1.7 Hz, 1H), 7.60 (d, J = 8.8 Hz, 1H), 7.57 (d, J = 7.7 Hz, 1H), 7.31 (d, J = 2.5 Hz, 1H), 7.03 (dd, J = 8.9, 2.6 Hz, 1H), 5.27 (s, 2H), 3.95 (s, 3H), 1.31 (s, 12H). Tr (METCR1673) = 0.91 min, (ES + )(M+H) + 351 [corresponding boronic acid].

[1497] Step 7 Method 64: 6-({[2-(l-methyl-lH-pyrazol-4-yl)-l,3-benzoxazol-5-yl]oxy}methyl)pyridin-3-ol

[1498] Step 1 Method 64: 6-({[2-(l-methyl-lH-pyrazol-4-yl)-l,3-benzoxazol-5-yl]oxy}methyl)pyridin-3-ol

[1499] Step 1 Method 64: 6-({[2-(l-methyl-lH-pyrazol-4-yl)-l,3-benzoxazol-5-yl]oxy}methyl)pyridin-3-ol

[1500] δΗ NMR (500 MHz, DMSO) 9.97 (s, 1H), 8.51 (s, 1H), 8.13 (d, J = 2.7 Hz, 1H), 8.08 (s, 1H), 7.58 (d, J = 8.8 Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.31 (d, J = 2.5 Hz, 1H), 7.19 (dd, J = 8.4, 2.8 Hz, 1H), 6.99 (dd, J = 8.8, 2.5 Hz, 1H), 5.09 (s, 2H), 3.95 (s, 3H). Tr (MET-uHPLC-AB-101) = 1.87 min, (ES + )(M+H) + 323.

[1501] The following examples were prepared using Method 64 as described above:

[1502]

[1503] Table 65

[1504] Method 65

[1505] Scheme for Method 65

[1506]

[1507] Step 1, Method 65: 3-{6-[(5-bromopyridin-2-yl)methoxy]-[l,3]oxazolo[5,4- b]pyridin-2-yl}pyridine

[1508] To a suspension of 2-(pyridin-3-yl)-[l,3]oxazolo[5,4-b]pyridin-6-ol (120 mg, 0.56 mmol, prepared using Method 30) and (5-bromopyridin-2-yl)methanol (95%, 123 mg, 0.62 mmol) in toluene (3 mL) was added cyanomethylidene tributylphosphonium (0.25 mL, 0.95 mmol) and the mixture was heated at 100 °C in a sealed tube for 3 hours. Upon cooling, the mixture was partitioned between ethyl acetate (300 mL) and saturated sodium bicarbonate solution (100 mL). The organic layer was washed with brine (50 mL), dried over magnesium sulfate, filtered and evaporated. The solid residue was triturated with ethyl acetate (~ 5 mL) and then recrystallised from a hot mixture of tetrahydrofuran and acetonitrile (5 mL, 1 : 1) to give the title compound 74 mg (34% yield) as an off-white solid. δ H NMR (500 MHz, DMSO) 9.40-9.26 (m, 1H), 8.83 (dd, J = 4.8, 1.6 Hz, 1H), 8.74 (d, J = 2.3 Hz, 1H), 8.54 (dt, J = 8.0, 1.9 Hz, 1H), 8.25 (d, J = 2.7 Hz, 1H), 8.13 (dd, J = 8.4, 2.4 Hz, 1H), 8.08 (d, J = 2.7 Hz, 1H), 7.73-7.64 (m, 1H), 7.60 (d, J = 8.4 Hz, 1H), 5.33 (s, 2H). Tr (MET-uHPLC-AB-101) = 3.08 min, (ES + (M+H) + 383, 385

[1509] Step 2, Method 65: 5-(l-methyl-lH-pyrazol-4-yl)-2-({[2-(pyridin-3-yl)-[l,3]oxazolo[5,4- b]pyridin-6-yl]oxy}methyl)pyridine

[1510] A mixture of 3-{6-[(5-bromopyridin-2-yl)methoxy]-[l,3]oxazolo[5,4- b]pyridin-2-yl}pyridine (69 mg, 0.16 mmol), (l-methyl-lH-pyrazol-4-yl)boronic acid (22 mg, 0.18 mmol) and 2M sodium carbonate (0.16 mL) was suspended in anhydrous 1,2-dimethoxyethane (1 mL) and anhydrous ethanol (1 mL) and degassed under a stream of nitrogen for 5 minutes. Tetrakis triphenylphosphine palladium(0) (9 mg, 0.01 mmol) was added and the reaction mixture heated to 90 °C in a sealed tube for 2 hours. (l-Methyl-lH-pyrazol-4-yl)boronic acid (22 mg, 0.18 mmol) and tetrakis triphenylphosphine palladium(0) (9 mg, 0.01 mmol) were added and the reaction mixture heated to 90 °C for 2 hours. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate (100 mL) and water (50 mL), the precipitate was filtered from the mixture and triturated with hot ethanol, filtered and washed with diethyl ether to give the title compound 39 mg (56% yield) as a grey solid.

[1511] Example 1, Method 65: 5-(l-methyl-lH-pyrazol-4-yl)-2-({[2-(pyridin-3-yl)- [l,3]oxazolo[5,4-b]pyridin-6-yl]oxy}methyl)pyridine

[1512] δ H NMR (500 MHz, DMSO) 9.35 (d, J = 1.7 Hz, 1H), 8.85 (d, J = 2.0 Hz,

[1513] 1H), 8.83 (dd, J = 4.8, 1.6 Hz, 1H), 8.55 (dt, J = 8.0, 1.9 Hz, 1H), 8.27 (s, 1H), 8.25 (d, J = 2.7 Hz, 1H), 8.10 (d, J = 2.7 Hz, 1H), 8.02 (dd, J = 8.1, 2.3 Hz, 1H), 7.98 (s, 1H), 7.67 (dd, J = 8.0, 4.8 Hz, 1H), 7.59 (d, J = 8.1 Hz, 1H), 5.33 (s, 2H), 3.88 (s, 3H). Tr (MET-uHPLC-AB-101) = 2.25 min, (ES + )(M+H) + 385.

[1514] The following examples were prepared using Method 65 as described above:

[1515]

[1516] Table 66

[1517] Method 66

[1518] Solution 66

[1519]

[1520] Step 1, Method 66: 3-{5-[(5-methoxypyridin-2-yl)methoxy]-1,3-benzoxazol-2-yl}benzylnitrile

[1521] 2-Amino-4-[(5-methoxypyridin-2-yl)methoxy]phenol (190 mg, 0.77 mmol, prepared using method 33) was added to a solution in methanol (10 mL) and 3-formylbenzylnitrile (70 mg, 0.53 mmol), and the reaction mixture was stirred at room temperature for 90 minutes. Methanol was then removed under vacuum, and the residue was dissolved in dichloromethane (25 mL). The mixture was cooled to 0 °C, and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (205 mg, 0.9 mmol) was added. The ice bath was removed, and the mixture was stirred at room temperature for 2 hours. It was then diluted with dichloromethane (100 mL) and filtered. The solid was washed with dichloromethane (2 x 50 mL), and the washes and filtrates were combined, dried over magnesium sulfate, filtered, and concentrated. The solution was purified by FCC (silica gel, 0-80% ethyl acetate / heptane) and ground with ethanol to give the title compound (65.2 mg, 34% yield) as a grayish-white solid.

[1522] Example 1, Method 66: 3-{5-[(5-methoxypyridin-2-yl)methoxy]-1,3-benzoxazol-2-yl}benzylnitrile

[1523] δ H NMR(500MHz,DMSO)8.53(s,1H),8.47(d,J=8.0Hz,1H),8.31(d,J

[1524] =2.9Hz,1H),8.09(d,J=7.8Hz,1H),7.83(t,J=7.9Hz,1H),7.73(d,J=8.9Hz,1H),7.53(d,J=8.6Hz,1H),7 .48(d,J=2.5Hz,1H),7.43(dd,J=8.6,3.0Hz,1H),7.15(dd,J=8.9,2.5Hz,1H),5.19(s,2H),3.84(s,3H). Tr(MET-uHPLC-AB-101)=3.49min,(ES + (M+H) + 358.

[1525] The following examples were prepared using method 66 as described above:

[1526]

[1527] Table 67

[1528] Method 67

[1529] Solution 67

[1530]

[1531] Step 1, Method 67: 3-Methoxy-5-({[2-(pyridin-3-yl)-[1,3]oxazolo[5,4-b]pyridin-6-yl]oxy}methyl)pyridine

[1532] 2-(pyridin-3-yl)-[1,3]oxazolo[5,4-b]pyridin-6-ol (86%, 100 mg, 0.4 mmol, prepared using method 30) and (5-methoxypyridin-3-yl)methanol (65 mg, 0.44 mmol) were suspended in anhydrous toluene (3 mL). Cyanomethylenetributylphosphine (0.16 mL, 0.61 mmol) was added, and the reaction mixture was heated to 100 °C in a sealed tube and maintained for 18 hours. The reaction mixture was cooled to room temperature, and the solvent was removed under vacuum. The residue was ground with diethyl ether and heptane. FCC purification (silica gel, 0-10% methanol / dichloromethane) yielded 45 mg (33% yield) of the title compound as a grayish-white solid.

[1533] Example 1, Method 67: 3-Methoxy-5-({[2-(pyridin-3-yl)-[1,3]oxazolo[5,4-b]pyridin-6-yl]oxy}methyl)pyridine

[1534] δ H NMR(500MHz,DMSO)9.35(d,J=2.0Hz,1H),8.83(dd,J=4.8,1.5

[1535] Hz,1H),8.55(dt,J=8.0,1.9Hz,1H),8.32(d,J=1.2Hz,1H),8.29(d,J=2.8Hz,1H),8.24(d,J=2.7H z, 1H), 8.11 (d, J = 2.7Hz, 1H), 7.67 (ddd, J = 8.0, 4.8Hz, 1H), 7.54 (s, 1H), 5.31 (s, 2H), 3.86 (s, 3H). Tr(MET-uHPLC-AB-101)=1.94min,(ES + (M+H) + 335.

[1536] The following examples were prepared using method 67 as described above:

[1537]

[1538] Table 68

[1539] Method 68

[1540] Scheme for Method 68

[1541]

[1542] Step 1, Method 68: 3-Formyl-N-{2-hydroxy-5-[(5-methoxypyridin-2-yl)methoxy]phenyl}benzamide

[1543] To a solution of 3-formylbenzoic acid (61 mg, 0.41 mmol), 2-amino-4-[(5- methoxypyridin-2-yl)methoxy]phenol (112 mg, 0.45 mmol) in pyridine (5 mL) was added ethyl carbodiimide hydrochloride (104 mg, 0.55 mmol) and the resulting mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was partitioned between dichloromethane and water, the dichloromethane layer was separated, dried over sodium sulfate, filtered and concentrated to give the crude product which was used in the next step without further purification.

[1544] Step 2, Method 68: 3-{5-[(5-Methoxypyridin-2-yl)methoxy]-l,3-benzoxazol-2-yl}benzaldehyde

[1545] A solution of 3-formyl-N-{2-hydroxy-5-[(5-methoxypyridin-2-yl)methoxy]phenyl}benzamide (178 mg, 0.38 mmol, -80% purity) in acetic acid (4 mL) was heated to 180 °C in the microwave for 50 min. The mixture was diluted with water and aqueous sodium bicarbonate solution was added to give pH 8, the aqueous layer was extracted with dichloromethane (100 mL) and the combined organic layers were dried over sodium sulfate, filtered and concentrated. Purification by preparative HPLC (acetonitrile / water + 0.1% formic acid) gave 34 mg (25% yield over two steps) of the title compound as an off-white solid. δ HNMR (500 MHz, chloroform) 10.15 (s, 1H), 8.73 (s, 1H), 8.50 (d, J = 7.8 Hz, 1H), 8.34 (d, J = 2.8 Hz, 1H), 8.06 (d, J = 7.7 Hz, 1H), 7.72 (t, J = 7.7 Hz, 1H), 7.52 (d, J = 8.9 Hz, 1H), 7.49 (d, J = 8.6 Hz, 1H), 7.37 (d, J = 2.5 Hz, 1H), 7.26 (dd, J = 8.6, 2.9 Hz, 1H), 7.11 (dd, J = 8.9, 2.5 Hz, 1H), 5.24 (s, 2H), 3.90 (s, 3H). Tr (METCR1678) = 1.29 min (ES + )(M+H) + 361.

[1546] Step 3, Method 68: [(3-{5-[(5-methoxypyridin-2-yl)methoxy]-1,3-benzoxazol-2- yl}phenyl)methyl](methyl)amine

[1547] To a solution of 3-{5-[(5-methoxypyridin-2-yl)methoxy]-1,3-benzoxazol-2-yl}benzaldehyde (34 mg, 0.09 mmol) in toluene (5 mL) was added a solution of methylamine in ethanol (33 wt%, 0.5 mL) and the volatiles evaporated. The residue was dissolved in toluene and a further solution of methylamine in ethanol (33 wt%, 0.5 mL) and magnesium sulfate added. The mixture was stirred for 15 min, filtered through and concentrated to give the crude imine which was dissolved in 1,2-dichloroethane (5 mL). Sodium triacetoxyborohydride (30 mg, 0.14 mmol) and a drop of acetic acid were added and the reaction mixture stirred overnight. The mixture was diluted with water, aqueous sodium bicarbonate added and the organic layer separated, dried over sodium sulfate, filtered through and concentrated. Purification by FCC (silica gel, dichloromethane:methanol:7M methanolic ammonia (98:1.5:0.5)) gave the title compound 19 mg (54% yield) as an off-white solid.

[1548] Example 1, Method 68: [(3-{5-[(5-methoxypyridin-2-yl)methoxy]-1,3-benzoxazol-2- yl}phenyl)methyl](methyl)amine

[1549] δ H NMR (500 MHz, DMSO) 8.30 (d, J = 2.7 Hz, 1H), 8.16 (s, 1H), 8.04 (d, J = 7.9 Hz, 1H), 7.73 (t, J = 7.9 Hz, 1H), 7.52 (d, J = 8.9 Hz, 1H), 7.49 (d, J = 8.6 Hz, 1H), 7.37 (d, J = 2.5 Hz, 1H), 7.26 (dd, J = 8.6, 2.9 Hz, 1H), 7.11 (dd, J = 8.9, 2.5 Hz, 1H), 5.24 (s, 2H), 3.90 (s, 3H). Tr (METCR1678) = 1.29 min (ES

[1550] = 6.6 Hz, 1 H), 7.69 (d, J = 8.9 Hz, 1 H), 7.60-7.48 (m, 3 H), 7.43 (m, 2 H), 7.10 (dd, J = 8.9, 2.4 Hz, 1 H), 5.18 (s, 2 H), 3.84 (s, 3 H), 3.78 (s, 2 H), 2.31 (s, 3 H). Tr (METCR 1600) = 4.47 min (ES + (M+H) + 376.

[1551] The following examples were prepared using Method 68 as described above:

[1552]

[1553] Table 69

[1554] Method 69

[1555] Scheme for Method 69

[1556]

[1557] Step 1, Method 69: N-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]carbamic acid (5- methoxypyridin-2-yl)methyl ester

[1558] (5-methoxypyridin-2-yl)methanol (66 mg, 0.47 mmol) and carbonyldiimidazole (92 mg, 0.57 mmol) were dissolved in dichloromethane (2 mL) and stirred at room temperature for 4 hours. 2-(pyridin-3-yl)-1,3-benzoxazol-5-amine (100 mg, 0.47 mmol) was added and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with ethyl acetate (25 mL), washed with water (3 x 20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated. Purification by preparative HPLC (acetonitrile / water + 0.1% formic acid) gave the title compound 12.3 mg (7% yield) as a light pink solid.

[1559] Example 1, Method 69: N-[2-(pyridin-3-yl)-1,3-benzoxazol-5-yl]carbamic acid (5- methoxypyridin-2-yl)methyl ester

[1560] δ H NMR (500 MHz, DMSO) 10.02 (s, 1 H), 9.33 (d, J = 1.6 Hz, 1 H), 8.80 (dd,

[1561] J = 8.0, 1.9 Hz, 1 H), 8.29 (dd, J = 2.7, 0.8 Hz, 1 H), 8.00 (s, 1 H), 7.75 (d, J = 8.8 Hz, 1 H), 7.65 (ddd, J = 8.0, 4.9, 0.8 Hz, 1 H), 7.52 - 7.38 (m, 3 H), 5.18 (s, 2 H), 3.84 (s, 3 H). Tr (MET-uHPLC-AB-101) = 2.38 min, (ES + )(M+H) + 377.

[1562] The following examples were prepared using Method 69 as described above:

[1563]

[1564] Table 70

[1565] Method 70

[1566] Scheme for Method 70

[1567]

[1568] Step 1, Method 70: N-{2-Hydroxy-5-[(5-methoxypyridin-2-yl)methoxy]phenyl}-5- methoxypyridine-2-carboxamide

[1569] To a solution of 2-amino-4-[(5-methoxypyridin-2-yl)methoxy]phenol (80%, 100 mg, 0.32 mmol, prepared using Method 33) in pyridine was added 5-methoxypyridine-2- carboxylic acid chloride (55 mg, 0.32 mmol). The reaction mixture was stirred at room temperature for two days. The pyridine was removed in vacuo and the residue taken up in dichloromethane (30 mL). This was washed with water (2 x 25 mL), brine (15 mL), dried over magnesium sulfate, filtered and concentrated to give the title compound 130 mg (67% yield) as a red solid. This was used directly in the next step.

[1570] Step 2, Method 70: 2-(5-Methoxypyridin-2-yl)-5-[(5-methoxypyridin-2-yl)methoxy]- 1,3-benzoxazole

[1571] N-{2-Hydroxy-5-[(5-methoxypyridin-2-yl)methoxy]phenyl}-5- methoxypyridine-2-carboxamide (130 mg, 0.27 mmol) was taken up in acetic acid (3 mL) and heated in a microwave at 200 °C for 1 h. The acetic acid was removed in vacuo and the residue was dissolved in dichloromethane (30 mL). The organic layer was washed with saturated sodium bicarbonate solution (2 x 30 mL), brine (15 mL) and dried over magnesium sulfate. The magnesium sulfate was filtered off and the dichloromethane was removed in vacuo. Purification by FCC (silica gel, 0-10% methanol / dichloromethane) followed by recrystallization from ethanol gave the title compound 6.6 mg (7% yield) as an off-white solid.

[1572] Example 1, Method 70: 2-(5-Methoxypyridin-2-yl)-5-[(5-methoxypyridin-2- yl)methoxy]-l,3-benzoxazole

[1573] δ H NMR (500 MHz, DMSO) δ 8.48 (d, J = 2.8 Hz, 1H), 8.31 (d, J = 2.8 Hz,

[1574] 1H), 8.27 (d, J = 8.8 Hz, 1H), 7.71 (d, J = 8.9 Hz, 1H), 7.62 (dd, J = 8.8, 2.9 Hz, 1H), 7.53 (d, J = 8.6 Hz, 1H), 7.49 - 7.41 (m, 2H), 7.11 (dd, J = 8.9, 2.5 Hz, 1H), 5.19 (s, 2H), 3.95 (s, 3H), 3.84 (s, 3H). Tr (MET-uHPLC-AB-101) = 2.82 min, (ES + )(M+H) + 364.

[1575] The following examples were prepared using Method 70 as described above:

[1576]

[1577]

[1578] Table 71

[1579] Method 71

[1580] Scheme for Method 71

[1581]

[1582] Step 1, Method 71: 5-Methoxymethylpyrimidine-2-carboxylic acid methyl ester

[1583] To a round bottom flask was added 5-bromopyrimidine-2-carboxylic acid methyl ester (0.83 g, 3.82 mmol), di-tert-butyl ({3,6-dimethoxy-2-[2,4,6-tris(prop-2-yl)phenyl]phenyl})phosphine (0.02 g, 0.04 mmol) and cesium carbonate (1.74 g, 5.35 mmol) sequentially. The solids were combined and then evacuated under vacuum and purged with nitrogen three times. Methanol (0.61 g, 19.12 mmol) was then added to the flask via syringe. In a separate flask, methylsulfonate (2-(di-tert-butylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'- biphenyl) palladium(II) (0.03 g, 0.04 mmol) was weighed out, evacuated and purged with nitrogen twice. Dioxane (3.8 mL) was added to the flask and the flask was shaken until a green solution was obtained; this solution was then transferred to the first flask via syringe. The resulting reaction mixture was heated to 50 °C for 4 hours. The reaction mixture was cooled, diluted with ethyl acetate and filtered through Celite®. The volatiles were evaporated and the residue was purified by FCC (silica gel, 50-100% ethyl acetate / heptane) to give the title compound 0.25 g (32% yield) as an off-white solid. H NMR (500 MHz, ...

Claims

1. A compound of formula (I) or a pharmaceutical salt thereof, in X is O; Y is either CH or N; Z1, Z2, Z3 and Z4 are independently selected from CH and N, provided that at least two of Z1, Z2, Z3 and Z4 are CH; R1 is 2,3-dihydropyridazin-3-one-6-yl, which may optionally be substituted with one or two groups independently selected from the following: halogen, C 1-6 Alkyl and C 1-6 Alkoxy; L1 is -O- and L2 is -(CR7R8) m -; L3 does not exist; R2 is phenyl, pyridin-2-yl, pyridin-3-yl, pyrazin-2-yl, pyrimidin-5-yl, 1H-imidazol-4-yl, 1H-imidazol-2-yl, or 1H-pyrazol-4-yl, each optionally substituted with one of the following groups: halogen; hydroxyl; C 1-6 Alkyl group; substituted with C 1-6 Alkoxy, amino, (C 1-6 alkyl)amino or (diC) 1-6 C of alkyl)amino 1-6 Alkoxy; C 1-6 Alkyl groups; and those substituted with C 1-6 Alkoxy, amino, (C 1-6 alkyl)amino or (diC) 1-6 C of alkyl)amino 1-6 alkyl; R5 is selected from C 1-6 Alkyl, C 1-6 Alkoxy groups and halogens; R7 is hydrogen; R8 is selected from hydrogen and C. 1-6 alkyl; n is 0 or 1; and m is 1 or 2.

2. The compound or salt of claim 1, wherein R2 is pyridin-2-yl, pyridin-3-yl, pyrazin-2-yl, pyrimidin-5-yl, 1H-imidazol-4-yl, 1H-imidazol-2-yl, or 1H-pyrazol-4-yl, each optionally substituted with a group independently selected from: hydroxyl; C 1-6 Alkyl groups; substituted with amino groups, (C 1-6 alkyl)amino, (diC) 1-6 alkyl)amino or C 1-6 C of alkoxy 1-6 Alkoxy; C 1-6 Alkyl groups; and those substituted with C 1-6 Alkoxy, amino, (C 1-6 alkyl)amino or (diC) 1-6 C of alkyl)amino 1-6 alkyl.

3. The compound or salt of claim 1, wherein Y is CH.

4. The compound or salt of claim 1, wherein Y is N.

5. The compound or salt of claim 1, wherein R1 is a substitution with one or two C atoms. 1-6 2,3-Dihydropyridazin-3-one-6-yl of alkyl group.

6. The compound or salt of claim 1, wherein R2 is pyridin-2-yl, optionally substituted with a group independently selected from: halogen; hydroxyl; C 1-6 Alkyl group; substituted with C 1-6 Alkoxy, amino, (C 1-6 alkyl)amino or (diC) 1-6 C of alkyl)amino 1-6 Alkoxy; C 1-6 Alkyl groups; and those substituted with C 1-6 Alkoxy, amino, (C 1-6 alkyl)amino or (diC) 1-6 C of alkyl)amino 1-6 alkyl.

7. The compound or salt of claim 1, wherein R2 is a substituted C 1-6 Pyridin-2-yl of alkoxy group.

8. The compound or salt of claim 1, wherein Z1, Z2, Z3 and Z4 are independently CH.

Images